coursebook-1 - pass program

Course Instructors: Dr. Francis, Dr. Wolf and Dr. Bautista

PASS PROGRAM USMLE REVIEW STEPS 1, 2 AND 3 Course Instructors: Dr. Francis, Dr. Wolfe & Dr. Bautista Lecture

Page

Note Pages

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Welcome to the Program

45

Low Energy State

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Vitamins, Minerals, Trace Elements

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Cellular Physiology

64

Membrane Physiology

71

Inflamation

76

Electrolyte Physiology

80

Pulmonary Physiology

87

Neuromuscular Physiology

105

Vascular Physiology

116

Cardiac Physiology

125

Gastrointestinal Physiology (GI)

135

Endocrinology

159

Rheumatology

171

Reproductive Endocrinology

184

Renal Physiology

192

Nephritic-Nephrotic

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Neurophysiology

220

Hematology

238

Hemostasis

244

Lymphoma & Leukemia

248

Biochemistry

251

Amino Acids

254

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Protein Structure and Function

262

Enzymes

277

Anabolic Pathways

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Catabolic Pathways

292

Cancers

303

Immunology

329

Immunodeficiencies

335

Leukocytes

344

Lymphocytes

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Granulocytes

358

The Four Hypersensitivities

366

Antibiotics

369

Microbiology

371

Viruses

408

Note Pages

413

Obstectrics and Gynecology

453

Surgery & Trauma (Dr. Cordova)

477

Antibiotics (Dr. Cordova) Biochemistry, Glycolysis, Gluconeogenesis & TCA

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PASS PROGRAM USMLE REVIEW STEPS 1, 2 and 3 Week 1

Monday Introduction 7:15-9:00 7:15 9:00 am Low Energy State 1 hr break Vitamins 10:00-12:00 Minerals Trace elements

Tuesday Wednesday Thursday Behavioral science Test taking/Time mgt. Membrane Phys EKG Phys Psychiatry Arrhythmias Endocrine Phys Endo Path

Friday Cardio Pathology Cardiac Phys Murmurs

Psych

Endo

Neuromuscular Vascular Phys

Cardio

Tuesday Surgery Principals

Wednesday Pulmonary phys

Thursday Renal Phys

Friday Neuro Phys

Trauma

Pulm Path

Renal Path

Neuro Path

Ansthesia

Pulm

Renal

Neurology

LUNCH 1:30-4:00pm Cellular Phys

Week 2 7:15-9:00 1 hr break 10:00-12:00

Monday Gastrointestinal Physiology GI Path

LUNCH 1:30-4:00pm GI Week 3 7:15-9:00 7:15 9:00 1 hr break 10:00-12:00

Monday Amino Acids Protein structure Protein function

Tuesday

Wednesday Thursday Friday Glycolysis Ketogenesis Nucleotides Gluconeogenesis Glycogen Fructose/Galactose Pentose Pathway Pyruvate metab.

OB GYN OB/GYN Pharm

LUNCH 1:30-4:00 pm Quaternary protein Reproductive Repro Pharm Week 4

Monday Oncology

7:15-9:00 1 hr break 10:00-12:00

Tuesday Pediatricts Development

TCA cycle Lipolysis

Amino acids Fatty acid synth.

Wednesday Leukocytosis Leukemia's Myelodysplasia

Thursday Rheumatology

Pediatricts Pharm

Normal Flora Gram+/-

DNA

Friday Myobacteria, Spiro.

Rickettsia Virus

LUNCH O l Oncology 1:30-4:00pm

Dr. Francis •Cellular physiology •Behavioral •Cardiology •Pulmonary •Biochemistry •Reproductive •Immunology •Pediatricts •Oncology

I Immunology l Imm. Deficiency

Granulocytes G l t Hypersensitivities Transplantation

Dr. Wolf •Time management •Endocrine •Rheumatology •Gastrointestinal •Renal •Neurology • Microbiology/Antibiotics •OB/GYN

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FFungus Parasites Protozoa

Closing remarks!!!

Teaching Associates •AntibioticsAntibiotics Dr Cordova (date TBA) •Surgery/Ansthesia- Dr Cordova •Hematology- Dr Qi •Statistics- Dr Qi

(date TBA) (date TBA)

•DNA/RNA- Dr Bautista •Biochem pathways- Dr Lee

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4/30/2008

Making the most out of your time here at the PASS program !!!

Study smart not hard

NBME- National Board of Medical Examiners

Power is in g ! knowledge

For profit company NBME- National Board of Medical Examiners

What do you want to do when you finish medical school?

• Shortage of family doctors throughout US

• You’re the next cutting edge physician • 20,000 new residents • Your p pay? y • Radiology, Dermatology, Ortho.

• Shortage of OB/GYN physicians p y in Fl, Texas, California, and Michigan

• Those making decisions, control how many come across the bridge

• Cutoff for USMLE Step’s were raised from 182 to 185?

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How do they comprise a test that is written for you to fail?

Why do so many fail the test?

• A physician sits and writes a question based

off of the discipline they want to test you on

ZOO THEORY

• A psychologists h l i t rewords d th the question ti th the way your mind thinks… – This is why the wrong answers always look good

55 PASS PASS rules rules in in answering answering question question

A 38 y/o woman has congestive heart failure, premature ventricular contractions and repeated episodes of ventricular tachycardia. Her blood pressure is normal and there are no murmurs. Her heart is markedly enlarged. Coronary angiography shows no abnormalities.

•• 1. 1. Cover Coverthe theanswers answers • 2. Read the last sentence and decide if it is • 2. Read the last sentence and decide if a clue or concept question it is a clue or concept • 3. Read the vignette, and isolate the facts question of the vignette 3. Comprise Read the vignette, and isolate the •• 4. a thought process facts the click vignette • 5. Lookof down, and move !!!!!!!

Which of the following is the most likely diagnosis ?

• 4. Comprise a thought process • 5. Look down, click and move !!!!!!!

A.Acute rheumatic fever B.Congenital fibroelastosis C.Constrictive pericarditis D.Myocardial infarction E.Primary cardiomyopathy

A.Acute rheumatic fever B.Congenital fibroelastosis C.Constrictive pericarditis D.Myocardial infarction E.Primary cardiomyopathy

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A 23 y/o man who is HIV positive has a 2 week history of midsternal chest pain that is aggravated by eating spicy foods; the pain is unrelated to exertion or position and he reports no dysphagia. Treatment with H2 receptor blocking agents has provided no relief. He takes clotrimazole for thrush and zidovudine ((AZT). ) He has a CD4+ T lymphocyte count of 220/mm3 (N>500).

USMLE Step 2 and Step 3 approach What is the next best step in management?

Is the patient stable? (based on hemodynamics) - Unstable: ABC’s - Stable: read the vignette Do you have enough information to make a definitive diagnosis? - Yes- treat - No- order a test (BLIS) blood/labs/image/surgery

Which of the following is the most appropriate next step in management?

A.Therapeutic trial of acyclovir B.24 Hour pH probe C.Acid perfusion test D.Esophageal manometry E.Esophagoscopy

A.Therapeutic trial of acyclovir B.24 Hour pH probe C.Acid perfusion test D.Esophageal manometry E.Esophagoscopy

Procrastination in doing questions

Procrastination in doing questions • How many read all the choices in the explanation?

• How many read before doing questions? Wh t are you ttesting What ti ? 2 weeks later, what happens?

– Prior exposure to future f questions – I have a lot of details in my head

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4/30/2008

It’s ok to be wrong !!!!

Procrastination in doing questions

• Block of 50 question and get 45/50 correct, are you any more prepared for the boards from the moment you started that test?

• How many do the questions in tutor mode?

• If you get 30 /50 wrong, you will not be very happy

–Driving a car and lost

• Found a hole, that can be fixed • Remember every time you fall

Why do we not listen to our first thought?

My friends told me to do as many questions as I can before I take the test…

• We are scared of being wrong

• 6000 questions • Multiple banks • You are doing questions to learn from them • Do we order test to learn about a pathology (i.e. Hypothyroidism – TSH panel)

• We do not want our over all average to be lower than the mean

3 steps to studying: 1. Obtain the information 2. Questions 3. Results of the bank

• Questions: Organ – 50 question

What bank to use? Q-Bank

USMLE Rx.

USMLEworld

system based

– Do they ask you 50 new things?

Do you see a pattern?

– Pathological presentation does not change, just the story line (clues are so important)

At the end of your first week, you will be evaluated by several tutors to determine which is the best test bank for you to use.

– Will you see the pattern in mixed blocks?

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What do most students do…

What should I do, with the results of my question bank?

• Vignette….. Downs syndrome – Answer: Endocardial cushion defect

• 50 questions completed (what is right or wrong)

• • • • •

Example: Polyhydramnios: Down syndrome What is the most common cardiac abnormality? • Write the subject matter • Look for patterns in the question • This is what you will read about

Read about it from the author Transcribe to note cards on ECD Read the notes about ECD Read the CMDT about ECD “Harrisons” and read about ECD

Are you any more prepared for Downs syndrome on the boards?

NBME practice exam…

Not enough time in the day !!!!!!! - Exercise - 210 score - Proper sleep hygiene -Take time out to reward yourself

• On line at http://www.NBME.org – Step 1 – 5 forms (do not take form 3) – Step 2 – 3 forms – Step 3 – 1 form

• When should I take may NBME ?

Tutoring:

PASS program clues vs. class notes

• This is your time to ask questions that you may have with the material

• You should drill the PP-clues with a partner for at least 1 hour a night. ( ½ hour new, ½ hour random review)

• Do questions with your tutor (remember its ok to be wrong)

• Caution in drilling class notes: – Teacher vs. Student

• Your tutor is there to help you find and fix your weakness

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Tutoring cont. • Try several tutors to find the chemistry that works for you • If you can not make it to your secession, please inform your tutor, so they can fill the spot with another student • Once you are comfortable with a couple of tutors, there is a request book in the back. (The key word, just a “request book”)

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Physiology: Weeks One & Two

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WHO USES ENERGY? • • • • •

INTRODUCTION: THE MOST POWERFUL CONCEPT IN MEDICINE

THE LOW ENERGY STATE

BRAIN MUSCLES PRIMARY ACTIVE TRANSPORT HEART MEMBRANE MOVEMENT

•

RAPIDLY DIVIDING CELLS – – – – – – – – – – – – –

SKIN HAIR GI RESPIRATORY RENAL(PCT) BLADDER ENDOMETRIUM ENDOTHELIUM BREASTS SPERM GERM CELLS CUTICLES BONE MARROW • RED BLOOD CELLS • WHITE BLOOD CELLS • PLATELETS

SIGNS OF DISEASE: WHAT YOU

PRESENTATION OF A DISEASE

CAN SEE

• When it bothers the patient enough, he or she will see the doctor as soon as possible

• TACHYPNEA and DYSPNEA

– Weakness so that the patient can not go to work – Shortness of breath scares people; they think they might die

SYMPTOMS: THE PATIENT’S

MOST COMMON INFECTIONS

COMPLAINTS • WEAKNESS • SHORTNESS OF BREATH

• PULMONARY INFECTIONS • URINARY TRACT INFECTIONS

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OTHER COMPLICATIONS • • • •

COMPLICATIONS, cont • Endothelium – atrophic • Endometrium – atrophic • Breasts – atrophic • Sperm count – low • GI – nausea, vomiting and diarrhea • Renal- PCT shuts down

Dry skin Hair dry and brittle Nails brittle Bone marrow suppressed – Anemia – Leukopenia – Thrombocytopenia

• Bladder – atrophic; leads to UTIs • Respiratory – weak cough > infections • Germ cells – unable to replicate > leads to skin and GI cancers • CNS: MR (children) and dementia (adults) • CV – heart failure

ANYTIME YOU CAN CONNECT TO THE LOW ENERGY STATE … • APPLY THE ENTIRE CONCEPT • THIS ACCOUNTS FOR APPROXIMATELY 98% OF ILLNESSES • WHENEVER IN DOUBT > ASSUME IT IS A LOW ENERGY STATE

MOST COMMON CAUSE OF DEATH?

HEART FAILURE!!!

STOP GUESSING!!!

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Vitamin A • A cofactor for PTH • Necessary for CSF production • Used for epithelial maturation, especially hair, skin, and eyes • Most unique function is night vision • A mild antioxidant

VITAMINS, MINERALS and TRACE ELEMENTS THE BEGINNING

Vitamin A deficiency • • • •

Vitamin A excess

Poor night vision Decreased CSF production: asymptomatic Hypoparathyroidism Epithelial cells fail to mature

• Pseudotumor cerebri: excess CSF production • Hyperparathyroidism: moans, groans,bones and stones

Vitamin B1: Thiamine

Pseudotumor Cerebri • Sign: papilledema • Symptom: headache • Evaluation: CT scan ( shows enlarged ventricles) • Treatment: d/c vitamin A; serial LPs (30cc at a time) • Main complication: blindness • This is the only cause of increased ICP where you don’t have to worry about herniation

• Necessary for four important enzymes: – Pyruvate dehydrogenase – Alpha-ketogluterate dehydrogenase – Branched chain amino acid dehydrogenase – Transketolase

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Vitamin B2: Riboflavin

Thiamine Deficiency • Beriberi

• Used in cofactors ( FAD) • Best source is milk • Sunlight breaks riboflavin down

– Dry beriberi – Wet beriberi

• Wernicke’s Encephalopathy – Receptive aphasia

• Wernicke-Korsakoff syndrome – Mamillary bodies now also involved – Confabulation – Inability to move short-term memory to long-term memory

Vitamin B3: Niacin

Riboflavin deficiency • Angular Cheilosis

• Necessary for cofactors ( NAD, NADH, NADP, NADPH) • Needed by pyruvate dehydrogenase, alpha-ketogluterate dehydrogenase, and branched chain amino acid dehydrogenase

Vitamin B4: Lipoic acid

Niacin deficiency • Pallegra : 4 D’s diarrhea, dermatitis, dimentia and death • Hatnup’s disease: presents just like pallegra

• Needed by pyruvate dehydrogenase, alpha-ketogluterate dehydrogenase, and branched chain amino acid dehydrogenase

– Defective renal transport of tryptophan

• No deficiency state

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Vitamin B5: Panthotenic Acid

Vitamin B6: Pyridoxine

• Needed by pyruvate dehydrogenase, dehydrogenase, alpha-ketogluterate dehydrogenase, and branched chain amino acid dehydrogenase

• Needed by all transaminases • INH pulls pyridoxine out of the body • Forms the cofactor pyridoxalphosphate

• No deficiency state

Vitamin B9: Folate

Pyridoxine deficiency • neuropathy

• The first vitamin to run out whenever you have rapidly dividing cells • Used to make tetrahydrofolate (THF) from which you make nucleotides

Vitamin B12: Cyanocobalamin

Folate deficiency • • • •

Megaloblastic anemia Hypersegmented neutrophils Neural tube defects in fetuses Mcc: overcooked vegetables

• Needed by two enzymes: – Homocysteine methyltransferase – Methylmalonyl-CoA mutase

• Used to make tetrahydrofolate • Used to recycle odd-numbered carbon fatty acids

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Vitamin B12 deficiency

Vitamin C

• Megaloblastic anemia • Hypersegmented neutrophils • Neuropathy, especially involving the dorsal column pathways and corticospinal tracts • Mcc: pernicious anemia (type A gastritis)

• Used for hydroxylation • Hydroxylates proline and lysine in collagen and elastin • Main antioxidant in the GI system

Vitamin C deficiency

Vitamin D

• Scurvy • Bleeding from hair follicles and gums

• Necessary for bone and teeth formation • Stimulates osteoblastic activity • Stimulates calcium AND phosphorous absorption and reabsorption • Mineralizes bones and teeth

Vitamin E

Vitamin D deficiency • Rickets: in children • Lateral bowing of the legs • Osteomalacia: in adults

• The main antioxidant in your blood • Absorbs free radicals

• Vitamin D resistant rickets – Defective renal reabsorption of phosphorous – As phosphorous leaks out, it pulls calcium with it

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Diseases involving oxidation • • • •

Antioxidants

Cancer Alzheimer’s disease Coronary artery disease Hemolytic anemia ( esp. G6PD)

• • • •

Biotin

Vitamin E: in blood Vitamin C: in GI tract Vitamin A Beta-Carotene

Biotin deficiency

• Necessary for carboxylation

• Many carboxylases would lose their function

Vitamin K

Warfarin

• Needed for gamma-carboxylation • Adds a third (gamma) carboxyl group to the vitamin k dependent clotting factors

• • • • • • •

– Clotting factors II, VII, IX, X, Protein C & Protein S – Protein C has shortest half life, followed by factor VII

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Competitive inhibitor of vitamin K Given orally Always give heparin first Crosses the placenta Teratogenic Follow PT ( prothrombin time ) INR 2 to 3x normal

Heparin

What are germs good for?

• Acts as a cofactor for antithrombin III • Blocks thrombin, as well as clotting factors IX, X, XI, and XII – Follow by measuring PTT ( INR 2 – 3X NL) – To reverse the action: protamine sulphate – If patient acutely bleeding: give FFP to reverse immediately

MINERALS

Vitamins related to gut flora • They make: 90% of vitamin K – Biotin – Folate – Panthotenic acid

• They help absorb – Vitamin B12

Calcium

Minerals • • • • •

• Intracellular calcium needed for all muscle contraction • Smooth muscle uses extracellular calcium for second messenger systems • Atrium is ONLY membrane that uses calcium to depolarize • Cardiac ventricle depends on extracellular calcium to trigger off its intracellular calcium release

Calcium Magnesium Zinc Copper Iron

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Magnesium

Calcium, cont • Used for axonal transport • Presynaptic influx of calcium necessary for release of ALL neurotransmitters • Needed for normal bone and teeth development

• A cofactor for ALL kinases • A cofactor for PTH • Interacts with potassium as well, but location currently unknown

Zinc

Copper

• Needed by hair, skin, sperm and taste buds

• Needed by lysine hydroxylase in the formation of collagen • Also needed by complex IV of electron transport system

• Zinc deficiency: dysguisia

Movement disorder in a middleaged person

Copper excess • Wilson’s disease

• HUNTINGTON’S DISEASE (90%)

– Autosomal recessive – Ceruloplasmin deficiency – Copper deposition in lenticular nucleus (basal ganglia), iris (Kayser-Fleischer rings) and in the liver (causing cirrhosis) – Tx: penicillamine

– Autosomal dominant – Trinucleotide repeats – Involves caudate nucleus – Has anticipation – Treat with antipsychotics – Mcc of death: suicide

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• WILSON’S DISEASE – Autosomal recessive – Ceruloplasmin def – Copper deposition in lenticular nucleus, liver and iris – Treat: penicillamine

Trinucleotide repeats • • • • •

Iron

Huntington’s disease Fragile X Fredrieck’s ataxia Prader Willi syndrome Myotonic dystrophy

• Needed for formation of heme and hemoglobin • Ferrous iron binds oxygen • Needed by complex III and IV of electron transport system

And finally… the trace elements

Trace Elements • • • • • •

Chromium

Chromium Selenium Molebdenum Manganese Tin Flouride

Selenium

• Enhances insulin action • Def: causes diabetes

• Needed primarily by the heart • Excess: breath smells like garlic ( arsenic as well) • Def: dilated cardiomyopathy

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Molebdenum and Manganese

Tin

• Needed by many enzymes in glycolysis • Xanthine oxidase: needs both elements

• Needed for hair growth

Flouride • Needed for teeth and bone growth • Excess: blocks enolase of glycolysis

THE END BUT, it is really the beginning…

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CELLULAR PHYSIOLOGY • CELL ORGANELLS

NECROSIS

IRREVERSIBLE CELLULAR INJURY • APOPTOSIS

• • • • • • • •

• NECROSIS

– CELL MEMBRANE DISSOLVES FIRST – PROGRAMMED CELL DEATH – NONINFLAMMATORY

– NUCLEUS DISSOLVES FIRST – UNEXPECTED – INVOLVES INFLAMMATION

– PYKNOSIS – KARYORHEXXIS – KARYOLYSIS

– PYKNOSIS – KARYORHEXXIS – KARYOLYSIS

NECROSIS • • • • • • • •

ISCHEMIC(COAGULATIVE) PURULENT GRANULOMATOUS FIBRINOUS CASEOUS FAT HEMORRHAGIC LIQUEFACTIVE

NECROSIS


• • • • • • • •

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NECROSIS • • • • • • • •

NECROSIS


• • • • • • • •

NECROSIS • • • • • • • •

NECROSIS


• • • • • • • •


MESS WITH THE CHROMOSOMES

NECROSIS • • • • • • • •



• MONOSOMIES: DIE! DIE! DIE! – MCC: NONDISJUNCTION • 90% IN DAD, USUALLY IN MEIOSIS 1; BUT SPERM DIE ON A DAILY BASIS • FEWER OCCUR IN MOM; BUT MOM KEEPS HER EGGS FOR LIFE AND IS THEREFORE MORE LIKELY TO TRANSMIT HERS • IF ONE WERE TO SURVIVE TO BE BORN, IN THE LEAST, THINGS WILL NOT GROW

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TURNER SYNDROME • • • • •

WEBBED NECK CYSTIC HYGROMA GONADAL STREAKS SHIELD-SHAPED CHEST COARCTATION OF AORTA

TRISOMIES

TRISOMIES • TRISOMIE 18: EDWARDS SYNDROME

• DIE! DIE! • FEW LIVE • TRISOMIE 13: PATAU SYNDROME

– ROCKERBOTTOM FEET (IN 95%)

– POLYDACTYLY – PALATE IS HIGH-ARCHED – PEE-ING SYSTEM ABNORMALITY

TRISOMIES

DOWN’S SYNDROME

• TRISOMIE 21: DOWNS SYNDROME

• MENTAL RETARDATION – 100% – IQ: AVERAGE IS 85 TO 100 WITH A STANDARD DEVIATION OF 15 – SUPERIOR INTELLIGENCE: IQ > 130 – MILD MR: IQ < 70 – MODERATE MR: IQ < 55 – SEVERE MR: IQ < 40 – PROFOUND MR: IQ < 25 – NEEDS 24HR CARE – MILD TO MODERATE MR CAN BE TAUGHT BASIC ADLS

– MCC: NONDISJUNCTION – ROBERTSONIAN TRANSLOCATION: HIGHEST INCIDENCE (33% OF OFFSPRING) – HAS MANY THINGS TO CONSIDER

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DOWN’S SYNDROME • EARLY-ONSET ALZHEIMER DISEASE • HIGHER FREQUENCY OF AML;BUT ALL IS THE MOST COMMON LEUKEMIA • 20 TO 40% HAVE congenital heart DISEASE • -ENDOCARDIAL CUSHION DEFECTS – VSD and ASD – VSD – ASD

DOWN’S SYNDROME

DOWN’S SYNDROME

• CYANOTIC CONGENITAL HEART DISEASE

• • • • • •

– TRANSPOSITION OF GREAT ARTERIES – TETROLOGY OF FALOT

50% HAVE HYPOTHYROIDISM WIDELY-PACED CRANIAL SUTURES MACROGLOSSIA DUODENAL ATRESIA HIRSCHSPRUNG’S DISEASE CLUES: – MONGLIAN SLANT TO EYES – WIDELY SPACED FIRST AND SECOND TOES – SIMIAN CREASE

Chemotherapy

TRISOMIES • XXX: Normal female; has two barr bodies • XXY: Klinefelter’s syndrome. Tall male with gynecomastia, small penis and testicles • X- Fragile X syndrome – Mcc of chromosomal induced MR – Short stature; macrochordism – Collagen disorder (increased risk of MVP) – Isolated using the drug METHOTREXATE

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ANTIMETABOLITES

CHEMOTHERAPY • • • • •

• • • •

ARA-A ARA-C 5-FU: blocks thymidylate synthetase 6-MERCAPTOPURINE: promotes gout; recognized by xanthine oxidase • THIOGUANINE • METHOTREXATE: inhibits dihydrofolate reductase(as does TRIMETHOPRIM and PYREMETHAMINE)

Stops rapidly dividing cells Attacks the nucleus in some way Causes irreversible cellular death WILL kill some patients No such thing as safe chemo

– Most commonly used antimetabolite – Used to treat molar pregnancies – Used to treat STEROID RESISTANT disease( followed by AZOTHIOPRINE and CYCLOSPORINE)

ANTIMETABOLITES

ANTIMETABOLITES

• METHOTREXATE

• AZOTHIOPRINE

– Causes folate deficiency and megaloblastic anemia – Give LEUCOVORIN > FOLINIC ACID to prevent the anemia

– Used for steroid resistant diseases( behind METHOTREXATE and before CYCLOSPORINE)

ALKYLATING AGENTS

ALKYLATING AGENTS • • • • • • • • •

• Bind to double stranded DNA • Used primarily for slow growing cancers • Cause the most nausea and vomiting – ONDANSETRON: serotonin blocker used to treat nausea and vomiting in chemotherapy

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Bleomycin Busulphan Adriamycin Cisplatnin Cyclophosphamide Isophosphamide Mitomycin Antimycin Acridine dyes

• • • • • •

Hydroxyurea Melphalan Mechlorethamine Procarbazine Dacarbazine Chlorambucil

• FOR RESCUES • Desroxzasane • Mesna

MICROTUBULE INHIBITORS

NUTRIENT DEPLETION

• Vinblastine • Vincristine • Paclitaxel

• L-ASPARAGINASE

IMMUNEMODULATORS • LEVAMISOLE

IRREVERSIBLE CELLULAR DEATH • NUCLEAR DAMAGE • LYSOSOMAL DAMAGE • MITOCHONDRIAL DAMAGE • OCCURS IN 6 HOURS in all tissues

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IRREVERSIBLE CELLULAR DEATH

IRREVERSIBLE CELLULAR DEATH

• NUCLEAR DAMAGE • LYSOSOMAL DAMAGE • MITOCHONDRIAL DAMAGE

• OCCURS IN 20 MINUTES IN THE

• OCCURS IN 6 HOURS in all tissues except the brain

The End? To Be Continued…

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BRAIN

WHAT A MEMBRANE DOES • PROVIDE SHAPE • AMPHIPATHIC

MEMBRANE PHYSIOLOGY

– HYDROPHILIC and HYDROPHOBIC – WATER SOLUBLE and FAT SOLUBLE – HYDROPHOBIC wants to be INSIDE away from water – HYDROPHILIC wants to be OUTSIDE in contact with water

A MEMBRANE’S JOB IS NEVER DONE

FAT SOLUBLE COMPOUNDS

STEROID HORMONES

• DO NOT interact with the outer cell membrane. They go right through and head for the nucleus • HAVE NUCLEAR MEMBRANE RECEPTORS • Concentration gradient is only limiting factor

• • • •

MADE FROM CHOLESTEROL FAT SOLUBLE( hydrophobic) Do NOT interact with cell membrane ALL have a nuclear membrane receptor except CORTISOL • CORTISOL has a cytoplasmic receptor; but it still translocates to the nuclear membrane

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WATER SOLUBLE COMPOUNDS Factors affecting diffusion

WATER SOLUBLE HORMONES

• • • • • • • •

• HYDROPHILIC • CAN NOT simply go through a fat soluble membrane • Must bind to the outside membrane to a receptor • Requires a SECOND MESSENGER • But first, what about ANY water soluble compound?

CONCENTRATION GRADIENT SIZE of molecule Net charge on molecule pH (affects the net charge of a molecule) THICKNESS of membrane SURFACE AREA of membrane FLUX (dx/dt) REFLECTION COEFFICIENT – NUMBER OF PARTICLES RETURNED / NUMBER OF PARTICLES SENT TO MEMBRANE

FICK’S EQUATION

OTHER FUNCTIONS OF A MEMBRANE

• Factors that FAVOR diffusion go in the NUMERATOR • Factors that NEGATIVELY affect diffusion go in the DENOMINATOR

• CREATE and MAINTAIN concentration gradients • SELECTIVE permeability • Has SATURATED fats( no double bonds) • Has UNSATURATED fats( double bonds) – Easier to break down – Better temperature regulation – More fluidity of movement, especially lateral

ESSENTIAL FATS

OTHER MEMBRANE FUNCTIONS

• Can get them ONLY through the diet • LINOLENIC • LINOLEIC

• PHAGOCYTOSIS: requires energy – ENDOCYTOSIS: primarily for nutrition – EXOCYTOSIS: primarily for getting rid of waste products ( i.e. lipofuscin ) – PINOCYTOSIS: for movement of fluids and electrolytes

– Used to make ARACHADONIC ACID – Arachadonic acid becomes essential if linoleic acid is missing from the diet

• SKIN is only organ that does this process

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OTHER MEMBRANE FUNCTIONS

OTHER MEMBRANE FUNCTIONS • TEMPERATURE REGULATION

• ALL membranes can depolarize • Resting membrane potentials

– RADIATION > concentration gradient – CONDUCTION > requires contact – CONVECTION > movement of environment drags heat out of the body

ELECTROLYTE MOVEMENT • • • • • •

CONCENTRATION GRADIENT ELECTRICAL GRADIENT DRIVING FORCE NERNST NUMBER (E-ion) CONDUCTANCE (G-ion) PERMEABILITY – CHANNELS: small ions – PORES: medium-sized molecules (sweat) – TRANSPORT PROTEINS

TRANSPORT PROTEINS

SECOND MESSENGERS

• PRIMARY ACTIVE TRANSPORT >requires an ATPase. Going against a gradient • SECONDARY ACTIVE TRANSPORT

• C-amp > most common second messenger

– Requires sodium’s gradient – SYNPORT or COTRANSPORT >moving in the same direction as sodium – ANTIPORT > movement in opposite direction as sodium

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PHOSPHODIESTERASE INHIBITORS

SECOND MESSENGERS, cont

• CAFFIENE • THEOPHYLLINE

• IP3 -DAG

• SILDENAFIL • VARDENAFIL • TADALAFIL

IP3-DAG SYSTEM

CALCIUM –CALMODULIN SYSTEM

• All HYPOTHALAMIC HORMONES, except CRH • All SMOOOTH MUSCLE CONTRACTION by hormone or neurotransmitter

• 4 calcium molecules: 1 calmodulin • All SMOOTH MUSCLE CONTRACTION by DISTENTION

CALCIUM

TYROSINE KINASE

• Used as a second messenger by GASTRIN only

• INSULIN and all GROWTH FACTORS

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NITRIC OXIDE

NITRATES

• NITRIC OXIDE > GUANYLATE CYCLASE > elevates c-GMP

• VASODILATORS • TACHYPHYLAXIS; rapid tolerance

• NITRATES • ENDOTOXIN • ANP

• Nitroglycerin • Dinilatrate • Sodium Nitroprusside

The End Insane in the membrane

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INFLAMMATION

SHUTTING DOWN THE Na-K ATPase • Potassium still leaks out • Cell becomes more negative > less likely to depolarize

EKG CHANGES

SHUTTING DOWN THE Na-K ATPase, cont • With Na trapped within the cell, calcium also gets trapped within the cell

• Na-K ATPase shuts down when a vessel is 70% stenosed • Potassium leaks out, making cells more negative • This is why you get ST-wave DEPRESSION

– This increases contractility • DIGITALIS • DIGITOXIN • OUBAIN

ST-WAVE DEPRESSION • • • • •

FOLLOW-UP FOR ANGINA

Early ischemia 70% stenosis SYMPTOMS BEGIN Subendocardial ischemia STABLE ANGINA

• PAIN GOES AWAY – Hospitalize for 24hours – Do serial EKGs and CIEs (Q6h x 24h) – If negative workup, then discharge home – Do a regular STRESS TEST in 6 weeks – Do STRESS THALLIUM test in 6 weeks

– Comes on with exertion; goes away with rest – 30% flow is enough at rest, but not on exertion – TX: VASODILATORS > increase radius increases flow

• Thallium flows through the coronary arteries – Look for COLD AREAS: NO FLOW( ISCHEMIC)

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FOLLOW-UP FOR ANGINA, cont

FOLLOW-UP FOR ANGINA, cont

• If you think they might have had an MI, then do a Ca-PYROPHOSPHATE scan

• IF PATIENT UNABLE TO PERFORM THE STRESS TEST:

– Cells that die calcify – Dead cells will take up the CaPYROPHOSPHATE

– DOBUTAMINE STRESS TEST – DIPYRIDAMOLE STRESS TEST

• Look for a HOT SPOT

EKG CHANGES

UNSTABLE ANGINA

• Na gets trapped within a cell when there is at least 90% stenosis • Cells become more POSITIVE

• 90% stenosis • EVENTS OCCUR • PLAQUE RUPTURED, and platelets are closing off the rest of the lumen • TX: Aspirin > Nitrates> Oxygen > Heparin > tPa > Morphine > B-blockers > Take to CATH LAB for angiogram

ANGIOGRAM FINDINGS

ANGIOGRAM FINDINGS, cont

• LEFT MAIN CORONARY ARTERY OCCLUSION ( 70% stenosis or more) • THREE OR MORE VESSELL DISEASE

• ANY SINGLE OR DOUBLE VESSELL DISEASE • TX: PTCA with STENT placement coated with CLOPIDOGREL

• TX: GO STRAIGHT TO SURGERY

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• • • •

CELLS ARE MORE LIKELY TO DEPOLARIZE WHEN ISCHEMIC

WITH Na and Ca trapped within the cell

After a stroke: SEIZURES After an MI: ARRYTHMIAS After ischemic bowel: BLOODY DIARREA After a DVT: CRAMPS

• Since atria use Ca to depolarize, the trapped Ca may cause atrial arrythmias • Contractility of muscles increases

WITH CELL DYING,

SWELLING

• Sodium continues to accumulate inside cell • Chloride will follow • WATER will follow next • SWELLING is therefore the FIRST visible change of cellular injury

• • • • •

Cerebral edema Papilledema Hydropic changes Dilated lymphatics Third spacing

INFLAMMATION TIME LINE

WHEN TOO MUCH SODIUM INSIDE CELL….

• < 24 hours: SWELLING • AT 24 hours: NEUTROPHILS show up and peak at 3 days • T-cells and MACROPHAGES: show up at day 4 and peak at day 7 • FIBROBLASTS: show up at day 7, peak at day 30, and take 3 to 6 months to complete their work ( chronic inflammation)

• Sodium begins to leak OUT of the cell now that concentration gradient is reversed • The only way for sodium to get out is to use the Na-Ca exchange protein which is concentration driven

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IF BLOOD SUPPLY NEVER RETURNS TO THE CELL

WHEN ALL CALCIUM NOW TRAPPED WITHIN THE CELL

• The sodium can pull ALL the calcium into the cell • WHILE calcium is moving into cell, more atrial arrythmias may develop

• Cells that depend on EXTRACELLULAR calcium will lose function – SMOOTH MUSCLE – ATRIUM – VENTRICLE

SIGN OF CHRONIC DISEASE • ON BIOPSY: you see evidence of fibrosis • ON X-RAY: you see calcifications

ALL inflammatory processes… DONE!!!

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Electrolyte Movement

Electrolyte Physiology

• • • • • •

Something in the way she moves me…

– CHANNELS: small ions – PORES: medium-sized molecules (sweat) – TRANSPORT PROTEINS

Electrolyte Movement • • • • • •


CONCENTRATION GRADIENT ELECTRICAL GRADIENT DRIVING FORCE NERNST NUMBER (E-ion) CONDUCTANCE (G-ion) PERMEABILITY

• • • • • •







• • • • • •



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Electrolyte Movement • Depolarize: to become positive from baseline • Overshoot: more positive than the threshold potential • Repolarization: to become negative from a positive potential • Hyperpolarization ( or undershoot): to become more negative than baseline potential


Sodium Channels

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HEART BLOCKS • NORMAL PR-interval : <0.2sec • FIRST DEGREE HEART BLOCK: fixed and prolonged PR-interval – Problem is AT the SA node or BETWEEN the SA node and the AV node – NO treatment necessary – Speeding up the heart rate( exercise) will make the block disappear

HEART BLOCKS, cont

HEART BLOCKS, cont

• SECOND DEGREE HEART BLOCK • MOBITZ 1: progressive lengthening of PRinterval until QRS is dropped

• MOBITZ II: PR-interval is normal; QRS complexes are dropped erratically – Late ischemia at the AV node – Some cells are negative; some cells are positive – ALL must have a pacemaker

– Early ischemia at the AV node – Also called WENCKEBACK’S – Put in pacemaker if symptomatic; do nothing if asymptomatic

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HEART BLOCKS, cont

QRS COMPLEXES • Premature ventricular complex (PVC)

• THIRD DEGREE HEART BLOCK

– No P- wave; wide QRS complex; a pause following the QRS complex – BIGEMINY: A PVC every other beat – TRIGEMINY: A PVC every third beat – VENTRICULAR TACHYCARDIA: three or more consecutive PVCs with a minimum heart rate of 150 – VENTRICULAR FIBRILLATION: NO recognizable QRS complexes

– COMPLETE AV DISSOCIATION – AV-node has INFARCTED – P-waves and QRS complexes have NO relationship – ALL must have a pacemaker

VENTRICULAR TACHYCARDIA

VENTRICULAR FIBRILLATION

• IF PATIENT STABLE: treat with medication • IF PATIENT UNSTABLE:

• EPINEPHRINE • TREAT LIKE VENTRICULAR TACHYCARDIA

– SHOCK with 200joules – SHOCK with 300joules – SHOCK with 360(max)joules – LIDOCAINE – SHOCK – BRETYLIUM or AMIODORONE

ELECTROLYTES AFFECT DEPOLARIZATIONS

ATRIAL ARRHYTHMIAS • • • • •

Premature atrial contraction (PAC) Multifocal atrial tachycardia Paroxysmal supraventricular tachcardia Atrial flutter Atrial fibrillation – – – –

• FOUR SPECIALIZED MEMBRANES – NEURONS – SKELETAL MUSCLES – SMOOTH MUSCLES – CARDIAC MUSCLE

If ACUTE and STABLE: treat with medication If ACUTE and UNSTABLE: DEFIBRILLATE If CHRONIC: treat medically; put on coumadin May defibrillate after minimum 2 weeks on coumadin

• ATRIUM: uses calcium to depolarize • VENTRICLE: uses sodium to depolarize; uses intracellular calcium to contract; depends on extracellular calcium to trigger off intracellular calcium release

• TX: use synchronized button

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HYPERMAGNESEMIA • • • •

HYPOMAGNESEMIA

LESS LIKELY TO DEPOLARIZE AFFECTS CALCIUM AND POTASSIUM GETS IN THE WAY OF SODIUM TX: IV normal saline; loop diuretic

• • • •

MORE LIKELY TO DEPOLARIZE AFFECTS CALCIUM and POTASSIUM AFFECTS all KINASES TX: magnesium sulphate

HYPERCALCEMIA

HYPOCALCEMIA

• LESS LIKELY TO DEPOLARIZE everywhere except the atrium( more likely) • SMOOTH MUSCLE: initially less likely (blocks nerve) to depolarize, then more likely to CONTRACT (due to second messenger systems) • TX: IV normal saline; loop diuretics

• MORE LIKELY TO DEPOLARIZE everywhere except the atrium( less likely) • WILL AFFECT SECOND MESSENGER SYSTEMS • SMOOTH MUSCLE: initially more likely to depolarize( nerve fires more) followed by less likely to CONTRACT (affects second messenger systems)

HYPERKALEMIA

HYPOKALEMIA

• Initially MORE LIKELY TO DEPOLARIZE • Potassium will flow into the cell, taking the membrane potential closer to threshold • Potassium gets trapped INSIDE the cell during repolarization; repolarization therefore takes longer > LESS LIKELY TO DEPOLARIZE

• LESS LIKELY TO DEPOLARIZE • Potassium will rush out of the cells, making them more negative – Cells repolarize even faster – Cells repolarize too much • • • •

– Peaked T waves – Widened T waves – Prolonged QT interval • Predisposes to arrythmias

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Narrow T waves Flat T waves Flipped and inverted T wave The U wave( exaggerated flipped T wave)

HYPERNATREMIA

HYPONATREMIA • MORE LIKELY TO DEPOLARIZE • SODIUM will now leak out of a cell by Na-K exchange • When calcium leaks INTO cell in exchange for sodium leaking OUT, cells become more positive • TX: IV normal saline; correct slowly

• MORE LIKELY TO DEPOLARIZE • SODIUM rushes into the cells, making them more positive • After sometime, the NA-K ATP-ase kicks Into high gear, making the cells more negative( less likely to depolarize) • TX: IV normal saline; correct slowly

– Use 3% saline if sodium under 120 with symptoms – Use fluid restriction if hyponatremia due to SIADH

Hyponatremia

The End: Turn off the lytes

Antiarrhythmics

Class 1: Na channel blockers • 1a – Quinidine – Procainamide – Disepyramide

• 1b – – – –

Lidocaine Tocainide Mixelitine Phenytoin

• 1c – Encainide – Flecainide – propofenone

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Class II: Beta Blockers

Class II: Beta Blockers

• All end in –lol • Specific beta 1: begins with A thru M, but NOT L or C • Nonspecific: begins with N thru Z, including L and C

• • • • • • •

Class III: K Channel blockers

Class IV: Ca Channel blocker

• • • •

• • • • • • •

Napa ( from procainamide) Sotalol Bretylium Amiodorone

IF YOU PLAY WITH LYTES…

Propanolol Esmalol Sotalol Timalol Butexalol Labetalol Carvedilol

Verapamil Diltiazem Nifedipine Nicardipine Nimodipine Femlodipine Amlodipine

Acebutalol Atenalol Pindalol

Quinidine Procainamide Phenytoin

You may go down IN FLAMES

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PULMONARY PHYSIOLOGY PULMONARY PHYSIOLOGY TAKING A DEEP BREATH

Foregut Endoderm

Neural Crest

• Respiratory Tract • GI Tract > from the mouth to the second part of the duodenum

• Tracheal cartilage • Laryngeal cartilage

Embryogenesis

Surfactant

• Develops in the first trimester like every other organ • Surfactant production is NOT complete until approximately 32 to 34 weeks • Brain develops first in embryo: notochord visible by 3 weeks; brain formed by 8 weeks

• Decreases atmospheric pressure’s effect on the alveoli > PREVENTS ATELECTASIS • Increases compliance of alveoli • Compliance = change in volume / change in pressure

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You know surfactant production is complete when… • Lecithin / sphyngomyelin ratio is 2:1 or greater or… • You detect phosphatidylglycerol, a breakdown product of surfactant

When there was NO surfactant

If mom comes in with preterm labor… • • • • • • •

• Check L / S ratio • Check for phosphatidylglycerol • If both of the above are negative – Beclamethasone – Betamethasone – If baby still born early, then there is synthetic surfactant that can be applied

Alveoli would collapse: Atelectasis > leads to very poor compliance > increases work of breathing > weakness and shortness of breath > oxygen is given > oxygen has difficult time diffusing across > oxygen builds up, causing free radical formation > alveoli develop hyaline membrane in order to protect themselves

Restrictive Lung Disease • Have poor compliance • Have trouble breathing in • Have poor diffusion • Have increased A-a gradient • pO2 =low pCO2 =low pH =high

• Develop a secondary perfusion problem • LOW ENERGY state • LOW VOLUME state • ALL die from heart failure known as COR PULMONALE = right sided heart failure due to pulmonary HTN (severe RVH)

Hyaline Membrane Disease THE FIRST RESTRICTIVE LUNG DISEASE

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Complications, cont

COMPLICATIONS of HMD ( or RLD) • As compliance drops, the need for pressure support increases • As diffusion decreases, the need for oxygen increases • More oxygen means more free radicals, which means more hyaline membrane • Bring in the JET VENTILATOR

• More pressure support can lead to a PNEUMOTHORAX – Kussmaul sign: increased JVD on inspiration – Pulsus paradoxicus: exaggerated drop in BP ( more than 10mm) or in pulse rate ( more than 10 bpm) – Loss of pulse and BP – Cyanosis – Hamman’s sign: subcutaneous emphysema

As free radicals traumatize the AIRWAY…

Pneumothorax • Spontaneous • Traumatic

• • • • • •

• Asymptomatic • symptomatic

Airway produces mucus to protect itself Airway thickens Goblet cell hyperplasia Airway lumen narrows Increased REID index BRONCHOPULMONARY DYSPLASIA – The first obstructive lung disease

EVERY lung disease presents with

Obstructive Lung Disease • • • • • • • •

the SAME signs and symptoms!!!

Difficulty breathing OUT Problem with VENTILATION ABG: pO2 = nl or low pCO2 = high pH=low Too much airway mucus Airway thickening Goblet cell hyperplasia Increased Reid Index Mcc of death is BRONCHIECTASIS

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Can it really be this easy???

Amniotic Fluid Production

Role of Amniotic Fluid

• 80% is a filtrate of mom’s plasma • To SUBTRACT:

• Main function is shock absorption • Secondary action is to prevent atmospheric pressure from affecting the fetus, especially the lungs

– Swallow ( a reflex) – Digest ( need patent UGI)

• 20% comes directly from the fetus • To ADD: – Process the swallowed fluid, then add 20% more than was swallowed, then URINATE

Potter’s Syndrome

Problem with amniotic fluid • POLYHYRAMNIOS – Autonomic dysfunction ( Riley-Day syndrome) – Neuromuscular disease ( WerdnigHoffman syndrome) – UGI atresia

OLIGOHYDRAMNIOS RENAL agenesis or obstruction

• When OLIGOHYDRAMNIOS leads to pressure effects on the fetus ( everything is flattened) • Will lead to pulmonary aplasia or hypoplasia due to the positive pressure

• Esophageal atresia • Duodenal atresia

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It is important to have negative pressure in the thoracic cavity!

Prune Belly Syndrome • Absence of abdominal wall musculature • Fetus is unable to urinate in utero • Fetus is unable to bear down and raise abdominal pressure for urination • OLIGOHYDRAMNIOS • Unable to urinate due to neuromuscular weakness? – Teach to (self) catheterize

Diaphragmatic Hernias • The diaphragm forms from Ventral to Dorsal • Bochtalek defect: rear defect • Morgagni defect: anterior, midline defect – Visible by sonography in utero – Bowel sounds in chest exam • Must repair surgically immediately after birth

Extrathoracic Airway

Intrathoracic Airway

• From the lips to the glottis • Narrows on inspiration; expands on expiration • NOT protected by the thoracic cage

• From the glottis to the alveoli • Expands on inspiration; narrows on expiration • Protected by the thoracic cage • Has a vacuum surrounding it

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Trachea

Aspiration

• Has 16 to 20 C-shaped cartilage rings, with the opening to the C facing posteriorly

• If patient is unable to speak, then the object is lodged in the trachea • LARGE OBJECTS tend to lodge at the glottis 90% of time • Perform the Heimlick Maneuver • Perform Back Thrusts if less than 2 y/o • If still unable to dislodge the object…

– This allows partial collapse of the airway during swallowing to prevent aspiration

• Has three anatomic narrowings – The glottis – Midway: due to anterior compression by aorta – Carina: located at T4 (level of nipple)

– Perform emergency cricothyroidotomy

Aspiration, cont

Evaluation for aspiration

• Small objects tend to lodge in the right lower lobe

• Inspiratory film: all lobes are inflated • Expiratory film: the lobe with the aspirated object does NOT collapse • Tx: bronchoscopy

– Recurrent RLL pneumonia: R/O FB aspiration • Do inspiratory-expiratory films

– Right mainstem bronchus is larger and straighter than the left • If person is sitting or standing UP, the object will lodge in the superior segment • If patient is lying DOWN, the object will lodge in the posterior segment

Airway Anatomical Divisions • Dead space • Respiratory unit • Dead space ventilation • Alveolar ventilation • Total ventilation

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Histology • Pneumocytes – Type 1: macrophages – Type 2: produce surfactant

• Goblet cells: produce mucus to trap debris – Mucus moves 1 inch per cough

• Smooth muscle • Clara “dust” cells • cartilage

Epithelium

Cilia

• Upper 1/3 of trachea has squamous cells • Mid 1/3 of trachea is a combination • Main respiratory epithelium is tall columnar ciliated epithelium • The more you smoke, the longer the zone of squamous cells

• Line the entire airway • Beat in one direction > orad • Has the 9 + 2 configuration (9 microtubules surrounding 2 actin proteins) • Need a Dynein arm to have flexibility

Kartagener’s Syndrome

Lung Sounds

• Dynein arm is defective • An obstructive lung disease

• • • •

• Bronchiectasis • Infertility • Situs Inversus

Stridor: narrowing in extrathoracic airway Wheeze: narrowing in intrathoracic airway Rhonchi: air moving over mucus Crackles: collapsed airways “popping” open – Surfactant is missing – Alveoli have been scarred down

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Lung Sounds, cont

Lung Sounds, cont

• Decreased breath sounds: space between alveolus and chest wall is occupied • Dullness to percussion: as above • Increased fremitus: consolidation on same side or atelectasis on opposite side • Bronchophony, egophony, or e to a changes: as above

• Tracheal deviation: towards atelectasis and away from a pneumothorax • Hyperresonance: pneumothorax on same side or atelectasis on opposite side

Lung Infections

Airway Infections • Epiglotitis: H. Influenza B • Tracheitis: C. Diptheria • Pneumonia

• Croup • Bronchiolitis • Bronchitis – Acute – chronic

– Rusty colored sputum: Strep Pneumonia – Curant jelly sputum: Klebsiella Pneumonia – Sulphur granules: Actinomyces Israelii – Frequent after the flu: Staph Aureus – Malodorous smell or gas formation: Anaerobes

• Pneumonia – Airway – interstitial

• tracheitis

Interstitial Pneumonias

Interstitial pneumonias • Fungus, cont

• Atypicals

– Paracoccidiomycosis: South America – Aspergillus: moldy hay or moldy basement – Sporothrix: rose thorn

– Chlamydia: from 0 to 2 mo – Mycoplasma: from 10 to 30 y/o – Legionella: over 40 y/o

• Pneumoconioses

• Fungus

– Asbestosis – Silicosis – Bissinosis – berrylliosis

– Histoplasmosis: midwest – Blastomycosis: northeast – Coccidiomycosis: southwest

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Lung Masses

Interstitial pneumonias, cont • Nocardia: the only G+ that is partially acid fast • Sarcoidosis: noncaseating granulomas; large hilar adenopathy; high ACE levels

• Most common MASS in children: hamartoma • Most common MASS in adults: granulomas • Most common TUMOR: adenoma

Central Cancers

Peripheral Cancers

• Squamous Cell Carcinoma: produces PTH • Small Cell Carcinoma

• Bronchogenic adenocarcinoma • Bronchioalveolar adenocarcinoma

– Anaplastic – Located at the carina – Produces 4 hormones: • • • •

• Carcinoid syndrome – flushing, wheezing and diarrhea – Too much serotonin – Measure 5-HIAA in the urine

ACTH: 90% ADH: 5% PTH: 3% TSH: 2%

• Large cell adenocarcinoma

Risk factors for lung cancer

Time for the PHYSIOLOGY of the lung!!

• Primary smoking – Risk increases with amount AND duration – If you STOP smoking: 5 yrs > reversal of damage visible; 15 yrs > risk back to baseline

• Radon • Second hand smoke – (1) sidestream smoke (2) mainstream smoke

• Pneumoconioses

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Three PHYSIOLOGIC parts to the lung • Intrathoracic space – Chest wall – Pleural space

• Pulmonary vasculature • Pulmonary airway

Lung Volumes

Lung Volumes, cont

• RV: the amount of air left in the lungs AFTER

• TV: the amount of air you take IN during a

forced expiration

NORMAL inhalation effort

• IRV: the amount of air you can FORCE

– Can not be physiologically forced out – Maintains some compliance in the airway

INSPIRE after a normal inhalation effort

• ERV: the amount of air that can still be FORCED

• TLC: ALL the air in your lungs at the END of a

out AFTER a normal exhalation

deep breath ( RV + ERV +TV + IRV)

– Fills up the dead space; decreases the tidal volume that you would have to take in

• VC: all the air you can breathe in AFTER forced

• FRC: a combination of RV and ERV

exhalation ( ERV + TV + IRV)

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Compliance and Air Flow

Inspiration • Beginning: expansile forces of the CHEST WALL is greater ( 0 to 49%) • Middle: expansile forces of the LUNG is greater ( 50 to 99%) • End: recoil force of the chest wall EQUALS the expansile force of the lung

Expiration

Breathing in… • FRC: baseline > intrathoraxic pressure is negative ( - 3 to – 5) • TV: intrathoraxic pressure gets more negative ( -10 to -12) • TLC: intrathoraxic pressure most negative (-20 to -25) • Intrathoraxic Pressure should always be NEGATIVE

• Beginning: recoil forces of the CHEST WALL are greater ( 0 to 49%) • Middle: recoil forces of the LUNG are greater ( 50 to 99%) • End: the recoil force of the lung EQUALS the expansile force of the chest wall

Intrathoracic Pressure

Intrathoraxic Pressure • Should ALWAYS remain negative • Should decrease with inspiration • If it gets positive, then it will resist any blood or air from entering the thorax • If you do not breathe in, there will be NO pressure gradient for blood to enter the thorax

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Pericardial Tamponade

Positive Intrathoracic Pressure • Kussmaul sign: increased JVD with inspiration • Pulsus paradoxicus: exaggerated drop in BP( more than 10mmHg) or pulse ( more than 10bpm) on inspiration

• • • • •

Mcc: trauma or cancer CXR: enlarged cardiac shadow ECHO: compressed small heart Tx: pericardiocentesis If recurrent: put in a pericardial window

• Mcc: pericardial tamponade or pneumothorax

Pneumothorax • Traumatic • Spontaneous – Associated with estrogen use or collagen disease – Less than 25% occupation & asymptomatic – More than 25% occupation or symptomatic

• Tx: chest tube placement

Pulmonary Vasculature

Flow ( Q ) • As you breathe in, the lung Inflates, pulling on traction fibers attached to vessels • As vessels DILATE, flow increases • As flow increases, oxygen dilates the vessels, significantly increasing Q • The increased Q keeps the pulmonary valve open longer, INCREASING S-2 splitting

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Flow ( Q ) is greater to the bottom of the lungs because…

S-2 Splitting

• (1) gravity • (2) less resistance • (3) more oxygen goes to the bottom of the lungs with each breath • Normal RR = 12 to 16 breaths/min • Q increases on inspiration and decreases on expiration.

• Increases on inspiration due to Increased pulmonary blood flow • Decreases on expiration due to decreased pulmonary blood flow • This is why RIGHT sided heart sounds increase on INSPIRATION • This is why LEFT sided heart sounds increase on EXPIRATION

Oxygenation

Ventilation (V)

• Directly related to DIFFUSION and PERFUSION • More oxygenation is accomplished at the bottom of the lungs only on inspiration • Most of oxygenation is accomplished at the top of the lungs > ALWAYS OPEN!

• Inversely related to pCO-2 • Definition: patent airway • Measurement: pCO-2 ( on ABG’s) • More V to the bottom of the lungs only on inspiration • Most V at the top of the lungs because it is ALWAYS PATENT

The Law of V / Q

Pulmonary Airway

• V /Q is greatest at the top of the lungs, equally matched in the middle, least at the bottom • If you change one, you MUST change the other in the SAME direction • ANY V / Q mismatch will lead to hypoxia

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Pulmonary Airway Pressure The Only Pressure That Gets Positive With Each Breath

How The Brain Monitors Pulmonary Physiology

Signals from the lungs and chest wall • J-receptors: found in the interstitium of lungs – Senses interstitial particles – Increases respiratory rate

• Slow adapting receptors: found in the ribs, especially the sternocostal junctions – Senses stretch and inflation – Causes exhalation

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SINUSES • • • •

BODIES

Maxillary Ethmoid Sphenoidal Frontal

• AORTIC BODY: found in the arch of the aorta – Measures pCO-2, pH, and H+ ions

• CAROTID BODY: located at the bifurcation of the internal and external carotids – Measures PO2, PCO2, pH, and H+ ions

BRAIN • More sensitive to elevated pCO-2 • Hypoxia and Hypercarbia are synergistic • Forms of pCO-2: – 90% in the form of HCO-3 – 7% as carbaminohemoglobin and carboxyhemoglobin – 3% is dissolved ( .03pCO2 )

Medulla • Responsible for BASIC functions; has a RR of 8 to 10 • BRAIN DEAD: no function above the medulla • COMATOSE: cerebral cortex is still alive, but patient unable to respond

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Pons • RESPONDS to the environment • Locked-In syndrome: damage to pons; patient only able to blink as response • Most sensitive to osmotic shifts > Central Pontine Demylinolysis • Apneustic center: senses hypoxia; causes inspiration • Pneumotactic center: senses hypercarbia; causes exhalation

Kussmaul Breathing • RAPID, DEEP breathing • Means METABOLIC ACIDOSIS

Apneustic Breathing • Pneumotactic center is desensitized, as in COPD • A lesion below the pneumotactic center but above the apneustic center

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Apnea • Central Apnea: NO inspiratory effort, with or without bradycardia, in 20 seconds or more – Apnea monitor – Tx: Caffiene; theophylline

• Obstructive Apnea: occlusion of airway during sleep, usually caused by obesity – – – –

Weight loss Progesterone CPAP Surgery: Uvulopalatoplasty

Lesions to MEDULLA

THE END

Lesions to MEDULLA • Hypoglycemia • Ischemia – Thoracic outlet syndrome – Subclavian steal syndrome

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Obstructive Lung Diseases

And now for a few good CLUES

• Bronchitis – Acute – chronic

• Bronchiolitis • Asthma – Intrinsic – extrinsic

• Cystic fibrosis • Bronchiectasis

Really! The End!!

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• Emphysema – – – –

Panacinar Centroacinar Distoacinar Bullous • Staph aureus • Pseudomonas

NEUROLOGICAL CONTROL NEUROMUSCULAR PHYSIOLOGY “I WANT A CONTRACT”

Central Nervous System

Inhibitory Neurotransmitters

• Involves the BRAIN and SPINAL CORD

• GABA: brain; causes an influx of chloride

• PARASYMPATHETIC system

• GLYCINE: spinal cord; causes an influx of chloride

– Controls the craniosacral divisions

• SYMPATHETIC system – Controls the thoracolumbar divisions

PARASYMPATHETIC SYSTEM

SYMPATHETIC SYSTEM

• Uses acetylcholine for preganglionic fibers and postganglionic fibers • DEPOLARIZES the head and neck as well as below the belt • HYPERPOLARIZES the thoracolumbar areas • Has long preganglionic fibers, short postganglionic fibers

• Uses acetylcholine for preganglionic fibers; uses primarily NE for postganglionic fibers • Some pathways use DA or SEROTONIN • DEPOLARIZES the brain and the thoracolumbar areas • HYPERPOLARIZES the sacral area • Has short preganglionic fibers, long postganglionic fibers

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Second Messengers • PARASYMPATHETIC: c-GMP • SYMPATHETIC: c-AMP • Smooth muscle contraction by neurotransmitter or hormone: IP3/DAG • Smooth muscle contraction by distention: calcium-calmodulin

Sympathetic Receptors

Parasympathetic Receptors • Most are MUSCARINIC except at ganglia or neuromuscular junctions which are NICOTINIC

• Many are NICOTINIC, except for sweat glands which are muscarinic or…

Alpha 1 Receptors

Alpha 2 Receptors

• Arteries: vasoconstriction • Sphincters: tighten • Radial muscles of the eyes: mydriasis w/o cycloplegia

• All presynaptic sympathetic fibers: inhibit NE release • Islet cells of pancreas: inhibit insulin secretion

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Beta 1 Receptors

Beta 2 Receptors

• CNS: increased activity • SA NODE: increase heart rate and contractility • JG Apparatus: increased renin release • Alpha cells of pancreas: increased glucagon release

• CNS: increased activity • Ventricles: increased contractility but NOT rate • Lungs: bronchodilation • Arterioles: vasodilation • Islet cells of pancreas: increased insulin • Uterus and Bladder: relaxation

If you want to stimulate… • • • •

If you want to inhibit…

You want to depolarize Make the cell more positive Make Na move INTO the cell Make Ca move into SA node

• CNS: make CL move into cell • PNS: make K move out of cells • In either case, cells become more NEGATIVE and are less likely to depolarize

NOW FOR THE MUSCLES!

TYPES of MUSCLES • CARDIAC muscle • SKELETAL muscle • SMOOTH muscle

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STRIATED MUSCLES

Smooth Muscle

• Cardiac muscle • Skeletal muscle

• Appear smooth due to lack of striations

• Striations due to sarcomeres

Skeletal Muscle

Cardiac Muscle

• Use intracellular calcium for contraction • 100% electrochemically coupled • Function as motor units( one nerve fiber and all the muscle fibers it innervates • Demonstrate RECRUITMENT • NO AUTONOMICS • NO SYNCYTIAL activity

• Uses intracellular calcium for contraction • Needs extracellular calcium to trigger off intracellular calcium release • Complete SYNCYTIAL activity • The most gap junctions • Complete AUTONOMICS • Can function without innervation, neurotransmitters or hormones

Smooth Muscle

NEUROMUSCULAR TRANSMISSION

• Uses intracellular calcium for contraction • Needs extracellular calcium for its second messenger system ( when it flows inside the cell) • Has AUTONOMICS • Has partial SYNCYTIAL activity • Can function without innervation, neurotransmitters or hormones

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MUSCLE CONTRACTION • Calcium binds trop-C • Trop-C releases trop-I • Trop-I releases tropomyosin • Tropomyosin releases actin binding sites • Myosin heads bind actin • CONTRACTION occurs

MUSCLE CONTRACTION, cont • • • • •

• Myosin heads release ADP from previous rd • Myosin heads bind new ATP • Myosin heads hydrolyze ATP • RELEASE occurs • Myosin heads return to start position

Clinical Application

Tropomyosin binds actin Trop-I binds tropomyosin Trop-C binds trop-I Ca-ATPase pumps Ca back into SR Phospholambin inhibits Ca-ATPase when it is done pumping

Diagnosis of a Myocardial Infarction

Management of an MI

• EKG: Na-K pump stops > peaked T-wave > STwave depression > ST-wave elevation > T-wave depression, then inversion > Q-wave • Troponin I: rises at 2 hours > peaks in 2days > positive up to 7 days • CK-mb: rises in 6 hours > peaks in 12 hours > gone in 24 to 36 hours • LDH 1: rises in 24 hours > peaks in 48hours > gone in 72 hours

• • • • • •

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24 hour hospitalization Check EKG Q6 Check CIE’s Q6 Monitor for arrythmias Discharge after 24 hours IF asymptomatic Re-evaluate in 6 weeks

In 6 Weeks… • Exercise stress test – Positive IF: chest pain is reproduced; ST-wave changes; drop in BP

The Functional Unit of Muscles

• Stress Thallium test

– A perfusion test; looking for a COLD spot

• Dobutamine or Dipyridamole stress test – Use when patient unable to exercise

THE SARCOMERE

• Calcium Pyrophosphate scan

– Taken up by DEAD tissue; looking for HOT spot

• 2-D echo

– Evaluates anatomy of heart; measures SV and CO

MUSCLE DIFFERENCES

CARDIAC MUSCLE

Smooth Muscle

• In addition to wave of depolarization, calcium MUST flow into the T-tubules during phase 2 for contraction to occur • Ventricle depends on EXTRACELLULAR calcium to trigger its contraction

• Has NO sarcomeres • Contains NO troponin > actin and myosin are always bound ( LATCHING) • Contains BASAL BODIES • Has NO myosin ATPase activity – Has MLCK and MLCP working together

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As Muscle Contracts… • • • • •

Length/Tension Curve

LENGTH decreases FORCE and TENSION increase A band stays the same Amount of OVERLAP increases The H band and I band therefore shrink

Golgi Tendon Organs

Muscle Strain

• Located at muscle insertions • Monitor the force of muscle contractions • Allows muscle to hold MAXIMUM muscle contraction force for only one second • Once it fires, muscle fibers MUST relax • Prevents destruction of sarcomeres

• Overstretching or tearing a muscle • When a muscle is torn, it goes into spasm to keep the fibers together for proper healing – Tx: rest it > apply heat > NSAIDS > muscle relaxants

JOINT SPRAIN

Frank-Starling Curve

• TORN tendon or ligament • Tx: Rest it > Ice Compression > Elevate the extremity

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Congestive Heart Failure after a myocardial infarction

Congestive Heart Failure • • • • • •

Over 50% mortality in 5 years Most common medicare diagnosis Muscle fibers are overstretched Dilated ventricle Increased EDV and ESV Decreased contractility > decreased CO and EF

• AT LEAST 40% of myocardium lost • EJECTION FRACTION is less than 45% • Due to left coronary artery infarcts 90% of time

Treating CHF: Applying Frank-Starling Curve

NEUROMUSCULAR PROFILE

• Decrease volume – Restrict sodium intake – Restrict volume intake

• Increase contractility – Digitalis – Dobutamine – Dopamine

• Decrease TPR – Ace inhibitors

ALL YOU NEED NOW IS THE CLUE…

Inflammatory Myopathies • • • • • •

Myositis Polymyositis Dermatomyositis Fibrositis Fibromyalgia Polymyalgia rheumatica • Temporal Arteritis

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• ALL HAVE: – – – –

High ESR High WBC count Myoglobinemia High AST, ALT and Aldolase

Muscular Dystrophies

Neuropathies

• Duchenne’s

• • • •

– Gower’s sign – Waddling gait – Pseudohypertrophy of the calf – Dystrophin protein – X-linked recessive; onset BEFORE age 5

Guillian Barre Diabetes mellitus Syphilis Myesthenia Gravis / Myesthenic or “Eaton Lambert” syndrome

• Becker’s – Onset AFTER age 5

• Myotonic

Acetylcholinesterase inhibitors: reversible • • • •

Acetylcholinesterase inhibitors: irreversible

Edrephonium Neostigmine Pyridostigmine Physostigmine

• AKA Organophosphates – End in ….phate ( diflorophate; echothiophate) – End in ….thion ( malathion; nalathion; parathion)

If they come back complaining about more weakness…

Anticholinergic Drugs

• Myesthenia Gravis has gotten worse or… • Cholinergic crisis

• Side effects are sympathetic except for… • HOT, DRY SKIN! • • • • • •

• REPEAT EDREPHONIUM TEST!! – IF patient gets better > disease is worse • Increase neostigmine

– IF patient gets worse > cholinergic crisis • Hold neostigmine > give atropine > decrease neostigmine

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Atropine Glycopyrollate Pilocarpine Benztropine Trihexyphenidyl ipratropium

Neoplastic Associations

Neuropathies, cont

• Myesthenia Gravis: THYMOMA

• Multiple sclerosis • Metachromatic leukodystrophy

• Myesthenic syndrome: SMALL CELL CARCINOMA; a paraneoplastic syndrome – Sarcoplasmic reticulum is slow to sequester calcium; cancer blocks some calcium channels

Treatment of MS

Lower Motor Neuron Disease

• STEROIDS • IV GAMMGLOBULINS • PLASMAPHARESIS

• Amyotrophic lateral sclerosis • Werdnig-Hoffman Disease • Polio

Cerebellar Disease in 5 to 10 Y/O children

Cerebral Palsy • Any permanent neurological damage suffered PRIOR to age 21 years

• Ataxia Telangiectasia • Fredrick’s Ataxia • Adrenoleukodystrophy

• Spastic Diplegia – Midline cortical problem

• Spastic Hemiplegia – Cortical problem on ONE SIDE of the brain

• Choreoathetosis – BASAL GANGLIA is involved: kernicterus

• Atonic – FRONTAL CORTEX: involves the CST

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THE END

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VASCULAR PHYSIOLOGY

I’m Talking About SMOOTH…

YOU GOTTA HAVE SOME FLOW

SMOOTH MUSCLE, that is

Smooth Muscle

Arterioles

• THICKEST layer of smooth muscle is found in the aorta • MOST smooth muscle by surface area found in the arterioles • LEAST smooth muscle found In the veins and veinules

• Considered the STOPCOCKS of the vascular tree • MOST smooth muscle by surface area allows most vasodilatation and vasoconstriction • Maintain AUTOREGULATION • Do the MOST to regulate BP, up or down

AUTOREGULATION

Veins and Veinules

• Between BP 60 to 160 systolic : cerebral, coronary, and renal perfusion remains constant

• • • •

Have the most CAPACITANCE Have the least smooth muscle 60% of blood ( the most) is pooled here Depend on skeletal muscle contractions to squeeze blood upward • Have one-way valves which move blood from superficial to deep veins

• ISCHEMIC infarct: BP went below 60 systolic • HEMORRHAGIC infarct: BP went above 160 systolic

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CONTROL of vessels • • • •

If Hypovolemia Develops…

VEINS: under parasympathetic control This is why veins are usually dilated Blood flow rate is quite slow example: subdural hematomas

• VENOCONSTRICTION is first response to loss of volume > gets volume back into circulation • Venoconstriction is most significant in skin and GI – Poor skin turgor – Loss of bowel sounds and ileus

A-V Anastamoses

CONTROL of vessels, cont

• Shunt blood away from nonessential organs • More concentrated in fingertips, tips of toes, tip of nose, lips and earlobes

• ARTERIES: under sympathetic control • This is why arteries are usually constricted • Reactive hyperemia: cutting an artery or the nerve to that artery causes immediate vasodilatation • i.e. epidural hematoma

– Severe vasoconstriction – hypothermia

Receptors

Capillaries

• ARTERIES: alpha one ( IP3/DAG)

• Have the thinnest membranes • Made for diffusion • Have the greatest surface area

– vasoconstriction

• ARTERIOLES: beta 2 ( c-AMP) – vasodilatation

• VEINS: alpha 1 ( IP3/DAG) – venoconstriction

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As Blood Flows Through the Capillaries…

In the Veins and Venules…

• Fluid diffuses out; large proteins (albumin) stay in • Osmotic pressure rises in the capillaries • Concentration gradient pushes particles out of capillaries

• Osmotic pressure is now high enough to PULL waste products into vessels • Blood PULLS waste products back into circulation

Total Pressure in a vessel

As a Vessel Narrows… • • • •

Velocity increases Flow decreases Resistance increases Blood Pressure rises

Resistance in Series

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Resistance in Parallel

During Diastole… • • • •

Ventricles are relaxing Very LOW RESISTANCE in coronaries Aortic valve is closed Aorta has MORE TRANSMURAL PRESSURE

• MORE CORONARY BLOOD FLOW

In Summary…

During Systole… • Ventricles are CONTRACTING • There is HIGH RESISTANCE in coronary vessels • Velocity in aorta is too high • Aortic valve is open • LOW TRANSMURAL PRESSURE

• LESS blood flow through coronary arteries during SYSTOLE • MORE blood flow through coronary arteries during DIASTOLE • Most work is done in systole! • A-V O2 difference created during systole • Therefore: MOST O2 EXTRACTION occurs in systole

• LESS CORONARY BLOOD FLOW

Let’s Look at FLOW

A-V O2 Difference • • • •

At REST: the heart extracts 97% of O2 With EXERCISE: skeletal muscle After EATING: GI system During INTENSE CONCENTRATION: the brain

• LOWEST A-V O2 difference: the kidneys, at all times

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POISSOILE’ LAW

NEUROLOGICAL control of blood pressure

Regulation of Radius • • • • • • •

CNS: pCO2 pO2 LUNGS: pO2 MUSCLES: pCO2 pH CV: adenosine SKIN: temp pCO2 GI: food, especially fats RENAL: PGE2; dopamine; ANP

Carotid Sinus

REMEMBER!

• Located at the bifurcation of the common carotid • Responds to FLOW or STROKE VOLUME • Increased STRETCH means increased FLOW • Sensory nerve : CN IX • Efferent nerve : CN X

• Stroke volume, carotid sinus stretch, CN IX firing and CN X firing ALWAYS go in the same direction • CN IX and CN X are ALWAYS firing – Amount of firing varies always in SAME DIRECTION as the stroke volume

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Autonomic Dysfunction • • • •

Low Volume State • Low stroke volume > low carotid stretch > low CN IX firing > decreased CN X firing >increased heart rate > increased NE from NTS in medulla > increased TPR > decreased RBF > decreased GFR >

Mcc: DIABETES MELLITUS In Newborns: Riley-Day syndrome In Parkinsonism: Shy-Dragger syndrome In elderly: Sick Sinus syndrome

Low Volume State

• > increased renin, angiotensinogen, aldosterone secretion > increased Na reabsorption > increased total body Na > decreased urinary Na > decreased FENa > increased urinary K > >>>

• • • •

Decreased serum Na( dilutional) Decreased serum Cl ( dilutional) Decreased serum K (real and dilutional) Decreased urine pH ( aldosterone excretes H) • Increased serum Ph (metabolic alkalosis) • Increased TPR

Most common cause of hyponatremia?

Most common cause of hypokalemia?

• LOW VOLUME STATE


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Most common cause of hypochloremia?

Most common cause of high TPR ?



Most common cause of metabolic alkalosis?

Ace Inhibitors • • • • • • •

• LOW VOLUME STATE • ALKALOSIS favors calcium precipitation with phosphate – KIDNEY STONES !!!!

Angiotensin Receptor Blockers

Ace Inhibitors • • • •

Stop conversion of AT-1 to AT-II Increased bradykinin VASODILATION and VENODILATION Decreased preload and afterload BALANCED dilation Contain sulphur Decrease mortality in CHF; decreases proteinuria in diabetic nephropathy

Captopril Lisenopril Enalopril rinilopril

• Losartan • Vosartan • Do not contain sulphur • NO elevation in bradykinin

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What is a VASCULITIS?

Vasculitis • • • • • •

Schistocytes ( Burr cells; helmet cells) Petechiae, purpura and ecchymoses LOW ENERGY STATE LOW VOLUME STATE Restrictive lung disease profile CELL MEDIATED inflammation

Ig-A nephropathies

All You Need Now is the Clue!!!

• Berger’s • Henoch-Schonlein Purpura • Alport’s

More vasculitides • • • • • • • •

More vasculitides

Buerger’s DIC HUS TTP DM Syphilis Takayasu kawasaki

• • • • • • •

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Temporal arteritis Ankylosing Spondylitis PAN Wegener’s Goodpasture’s Leukocytoclastic Churg-Strauss

Collagen Vascular Diseases with LOW COMPLEMENT

Collagen Vascular Diseases • • • • •

CREST syndrome Scleroderma Progresive Systemic Sclerosis MCTD RA / JRA (Still’s disease)

• • • • • •

– Felty’s: RA & leukopenia and splenomegaly – Becet’s : RA & GI ulcerations – Sjogren’s : RA & xeropthalmia, xerostomia

THIS IS THE END

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PSGN Serum Sickness SBE SLE MPGN : type l, ll Cryoglobulinemia

CARDIAC PHYSIOLOGY THE HEART OF THE MATTER

PRESSURE is the GRADIENT of the organs!

OPENING SNAP • A valve is popping open during diastole – TRICUSPID STENOSIS – MITRAL STENOSIS

EJECTION CLICK

MIDSYSTOLIC CLICK

• A valve is popping open during systole

• Blood is coming at high velocity, slapping the mitral valve on the way out • Occurs closer to S-1 with standing and closer to S-2 with lying down

– AORTIC STENOSIS – PULMONARY STENOSIS

– MITRAL VALVE PROLAPSE • Occurs in 7% of normal women (estrogen connection)

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SOFT S-1

LOUD S-1

• One of the two valves that contribute to this sound is NOT closing

• Either you have a stiff valve that bangs shut: TRICUSPID or MITRAL STENOSIS • Or the ventricle is contracting harder

– TRICUSPID REGURGITATION – MITRAL REGURGITATION – VALVE IS NOT THERE! • Tricuspid atresia • Mitral atresia – BOTH ARE CYANOTIC

SOFT S-2

LOUD S-2 • Either one of the valves is stiff and BANGS shut when it tries to open

• One of the two valves that contribute to this sound is NOT closing – AORTIC REGUGITATION – PULMONARY REGURGITATION – OR the valve is not present

• AORTIC STENOSIS • PULMONARY STENOSIS • Or there is HIGH pressure in front of the valves (systemic or pulmonary hypertension)

• AORTIC ATRESIA • PULMONARY ATRESIA – BOTH ARE CYANOTIC

S-3

S-3

• Sound made by a noncompliant ventricle • ????????????????

• VOLUME overload • DILATED ventricle • DECOMPENSATION • S-3 said to be normal ONLY in an adolescent female

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ESTROGEN CONNECTION

S-4

• Estrogen is a muscle relaxant • Causes liver to produce many proteins

• Sound made by an atrial kick

– High ESR or CRP – Lipoproteins – TBG – Angiotensinogen – Clotting factors

• PRESSURE overload • HYPERTROPHY • COMPENSATION • Most common gallop (atherosclerosis)

• Especially fibrinogen, but not factor 11

MURMURS CAUSED BY…

MURMURS! MURMURS! MURMURS!

• TERBULENCE • Reynold’s number > 2500 – Murmur: if it is in the heart – Bruit: if it is in a vessel • Occurs when you have 70% stenosis

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MURMUR GRADES

A SYSTOLIC MURMUR

• • • • •

Grade 1: barely audible Grade 2: easily audible Grade 3: pretty loud Grade 4: palpable thrill Grade 5: able to hear with stethoscope off the chest • Grade 6: able to hear across the room without stethoscope

• Valves that are supposed to be open are stenotic ( PULMONARY or AORTIC STENOSIS) • OR valves that should be closed are not closing ( MITRAL REGURGITATION or TRICUSPID REGURGITATION)

HOLOSYSTOLIC ( PANSYSTOLIC) MURMURS

SYSTOLIC MURMURS • • • • •

Aortic stenosis Pulmonary stenosis Mitral regurgitation Tricuspid regurgitation Ventricular septal defect

• Tricuspid regurgitation • Mitral regurgitation • VSD

PANSYSTOLIC – increases on INSPIRATION

PANSYSTOLIC – increases on EXPIRATION

• Tricuspid regurgitation

• Mitral regurgitation • VSD • Radiates into the axilla: MITRAL

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AORTIC STENOSIS

SYSTOLIC EJECTION MURMURS

• Radiates to the carotids( neck) • LOUDER with leaning forward, making a fist, blowing up a blood pressure cuff, or squatting

• Aortic stenosis • Pulmonary stenosis

• Crescendo – decrescendo or diamond shaped murmur • PULSUS TARDUS • DELAYED CAROTID UPSTROKE

IHSS

IHSS, cont

• Autosomal dominant • Muscle fibers are hypertrophied but disorganized • Any young athlete who dies suddenly, especially during peak exercise • Septum is asymmetrically thick, especially the top > causes SUBAORTIC stenosis

• Excessive hypertrophy compresses the coronary arteries • Excessive hypertrophy obliterates the ventricular space • Murmur is LOUDER with standing or with Valsalva; decreased with increased TPR • PULSUS BISFERIENS

IHSS, cont

DIASTOLIC MURMURS

• Tx: need to decrease contractility; allow time for adequate ventricular filling

• Either the valves that should be open are stenotic (MITRAL STENOSIS or TRICUSPID STENOSIS) • Or the valves that should be closed are regurgitant ( AORTIC REGURGITATION or PULMONARY REGURGITATION)

– Beta – blockers – Adequate fluid intake – Bar from organized sports – Do an ECHO on entire family

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DIASTOLIC BLOWINNG or DECRESCENDO MURMUR

Aortic Regurgitation Radiates to carotids; LOUDER with leaning forward, making a fist, blowing up a blood pressure cuff, or squatting Austin-Flint murmur: mitral regurgitation Widens the pulse pressure bounding pulses waterhammer pulse head-bobbing Quincke’s pulses

• AORTIC REGURGITATION • PULMONARY REGURGITATION • Increases on inspiration: Pulmonary regurgitation • Increases on expiration: Aortic regurgitation

Pulmonary Regurgitation

Diastolic Rumbles

• Radiates to the back • Louder on inspiration • Graham-Steele murmur: tricuspid regurgitation

• TRICUSPID STENOSIS • MITRAL STENOSIS • Increases on inspiration: tricuspid regurgitation • Increases on expiration: mitral regurgitation

CARDIAC PATHOLOGY

CARDIOMYOPATHIES • DILATED • HYPERTROPHIC • RESTRICTIVE – CVD – Amyloidosis – Hemochromatosis

• CONSTRICTIVE – Tamponade ( Kussmaul sign; Pulsus Parodoxicus) • Trauma • cancer

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EFFUSIONS • Transudate: mostly water • Exudate: mostly protein • Transudate: sp. G < 1.012 – Protein < 2grams

• Exudate: sp. G > 1.012 – Protein > 2grams

• • • •

Congenital Heart Diseases

Cyanotic Congenital Heart Disease

VSD ASD PDA Coarctation

• • • • • • • • •

VALVULAR DISEASES: most common

Transposition of Great Arteries Tetrology of Falot Tricuspid Atresia Total Anomalous Pulmonary Venous Return Truncus arteriosus Pulmonary Atresia Aortic Atresia Hypoplastic Left Heart Ebstien’s Anomaly

Pulmonary Disease

causes

• • • •

Aortic stenosis: aging Aortic regurgitation: aging Mitral stenosis: Rheumatic fever Mitral regurgitation: MVP, SBE, collagen diseases • Tricuspid stenosis: Rheumatic fever, carcinoid syndrome • Tricuspid regurgitation: acute endocarditis

• Most common cause is ALWAYS congenital • Pulmonary valve is protected on BOTH sides

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Flow – Volume Loops

Antiarrhythmics

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Na – Channel Blockers • Class Ia – Quinidine – Procainamide – Disepyramide

Wolf-Parkinson-White Syndrome

• Class Ic – Encainide – Flecainide – Propofenone

• Class Ib – – – –

Lidocaine Tocainide Mixeletine Phenytoin

Class II – Beta Blockers

Class IV – Ca Channel Blockers • • • • • • •

Verapamil Diltiazem Nefedipine Nicardipine Nimodipine Amlodipine Femlodipine

• End in – lol • Specific B-1: begin with A thru M (not L,C) • Specific B-2: begin with N thru Z (incl L,C)

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Class II – Beta Blockers • • • • • • •

Propanolol Esmalol Timolol Butexalol Sotalol Labetalol Carvidalol

Class III: K – channel Blockers

Acebutalol Atenalol Pindalol

• • • •

THE END

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Napa Sotalol Bretylium Amiodorone

4/29/2008

Foregut (rotation 90°) Celiac artery

Parasympathetic: Vagus

Sympathetic:splanchnic nerves T5-T9

Midgut (rotation 270°)

PHYSIOLOGY

Superior mesenteric

Parasympathetic: Vagus

Sympathetic: splanchnic nerves T9-T12

Hindgut ( Septation) Inferior mesenteric

` `

`

Gives rise to the GI, from mouth to second part of duodenum, including the respiratory tract

` `

Lungs and upper GI have many congenital connections

`

Parasympathetic: pelvic splanchnic nerves

Sympathetic: lumbar splanchnic nerves: L1-L2

Extends from the second part of duodenum to the spleenic flexure Develops in the YOLK SAC Must go through a 270 degree rotation as it migrates from yolk sac into abdominal cavity MIDGUT ROTATION requires ciliary action ◦ KARTAGENER’S: SITUS INVERSUS

`

FROM splenic flexure to the anus

`

WATERSHED AREA: the spleenic flexure

` CNS

` ORAL

` PHARYNGEAL

l t bl d supply l ◦ H Has th the least blood ◦ Most susceptible to ischemic infarcts

` ESOPHAGEAL ` UGI ` LGI

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`

SENSORY INFORMATION ◦ ◦ ◦ ◦ ◦

`

THINKING about food HEARING about food SMELLING food TOUCHING food TASTING food

◦ ALL sensory information must reach the cortex; ◦ Response is via the CORTOCOBULBAR pathway via the vagus

`

◦ Highly selective parietal cell vagotomy now

Responsible for setting time: Circadian rhythms

Melatonin – from tryptophan- milk and turkey

Neurotransmitter: melatonin Light outside- melatonin low- DAYTIME Dark outsideoutside melatonin highhigh NIGHT

- Bright lights in companies, casinos - 1st, 2nd, 3rd shift workers/ workers comp

Morning- catabolic processes are in their highest function- working out in the morning is the best

Feeding Center (HUNGER) `

Satiety Center `

◦ Lateral hypothalamus

`

Stimulus:

◦ Feeding (hunger) ↓ Glucose If sugar remains normal the center will not fire

Destruction: Anorexia

`

Bulimia

ANOREXIA NERVOSA `

Location:

`

◦ Vento-medial nucleus of the hypothalamus

Location:

LIMBIC SYSTEM- responsible for basic urges ◦ Hippocampus – long term memory ◦ Amygdala- reward and fear, mating

◦ No longer do a vagotomy for peptic ulcer disease (can’t enjoy food)

`

Cortex can over ride any basic urge: (outer layer of the cerebrum-forgut)

`

Stimulus:

◦ Stop feeding: ↑Glucose

`

Stomach stretch will stimulate satiety center Can override- Cortex

`

Destruction:

`

Starvation Desentasize your hunger center Body ody dys dysmorphic o p c disorder Small body frame and thinks they are over weight Young female trying to please her mother BMI < 17

` ` ` ` ` ` ` `

Enjoys eating Chunky female Trying to please her b f i d boyfriend Purging Abrasion on knuckles Tooth enamel erosion Laxative abuse BMI > 25

Hypothalamic obesity syndrome

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`

` ` ` `

` `

`

Lesion of the satiety center (Ventormedial) Uniparental disomy- one parent carrying lesion Paternal in origin T i Trinucletide l id repeats Chromosome 15

Norepinephrine or Serotonin (more important), so many people use Amphetamines for weight loss…

80% of time > stimulates satiety center

`

20% of time > stimulates hunger center

Men: 5 feet = 106 lbs Women: 5 feet= 100 lbs

`

Add 5 lbs for each inch past that…

`

Small frame: add 15 lbs Large frame: add 30 lbs

`

(i.e. male 5’10”: 106 + 50 +30 = 186 lbs)

`

Very aggressive appetite Die due to over eating

`

`

`

`

They are taken up presynaptically, causing release of all catecholamines ◦ Increase DA, NE and Serotonin ◦ Nausea/ vomiting -(DA) (DA) stimulates ◦ Neuromuscular- basal ganglia- tics (DA)

`

◦ Methylphenidate- ritilan (1st line) [drug dependence] x Narcolepsey – (hipnogogic)hallucinations as you fall asleep

`

◦ Pemolinex hepatic necrosis (hepatitis)- off the market 2005 `

◦ DexadrineD d i d dexatrim t i - weight i ht loss l OTC

Amphetamine tox. clue – vertical nystagmus

Controls MENSES- progesterone stimulates hunger system Pregnancy- due to corpus luetum

FOOD craving…….

◦ LSD- hallucinations from Seratonin (slow, lazy) ◦ PCP- hallucinations from Seratonin (violent, aggressive) ◦ ECSTACY- hallucinations from Seratonin (stimulate thirst)

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STRESS RESPONSE:

Controls TEMPERATURE: ◦ ANTERIOR Hypothalamus: cools (inhibits NE)

`

x Parasympathetic first (HR dec.) increased gastric motility, increase acid production

x Lesion anterior- die from: hyperthermia

◦ POSTERIOR Hypothalamus: warms

x Sympathetic second (B/P inc) constipation,

◦ Acetametaphen: for use with fever (stimulate anterior hypothalamus- cools), then it blocks posterior so you do not go back up again

Stress from burn- Curlings ulcer ICP- Cushing's ulcer

pulls blood from GI, so you can not buffer acid

x Lesion posterior- die from hypothermia

Seizure- foam at the mouth, defecate, urinate (all parasympathetic)

◦ Toxicity- microsteatosis, Reye syndrome in children ◦ Tx: N-acetylcystine-reducing agent ◦ - 4 hour level will determine if you use it

`

Put food into mouth- salivary glands respond

`

SALIVARY GLANDS ◦ ◦ ◦ ◦

Hollywood and sphincter control

Parotid [ in front of ear ](serous)-water - CN 9 Lingual [ on tongue ] (most serous) CN 7 Sublingual [under tongue] (most mucus) CN 7 Submandibular [jaw] (mucus) CN 7

◦ Saliva in your mouth has to be HYPOTONIC (cracker) ◦ Food on your cheek- food will get stuck (gummy bear)

`

Acetylcholine- CNS: excitatory, PNS: activates muscles

` `

`

Methacholine- dx asthma (old), beta 2 agonist to bring you out

` ` `

`

` `

Pilocarpine- sweat test ( > 60), open angle glaucoma (chronic)

`

Carbachol- post op urinary retention (stimulate bladder emptying) Bethanecol- post op urinary retention

`

Norepinephrine- α and β1 Epinephrine- has methyl group (hormone) Ephedrine- OTC med Pseudoephedrine – stress incont. Phenylephrine- neurogenic shock Tx (constrict) RESULT: remove the blood supply to the GI causing a decreased saliva that has increased osmolarity (less saliva- more salt) Exercise- mouth dry, white film in corner

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MCC: of malabsorption in children `

CFTR gene on chromosome 7

`

Defective CHLORIDE transport

`

`

`

` `

`

Chloride traps sodium, increasing the salt content and thickness of secretions

`

Affects GI tract, lungs, pancreatic duct, sweat glands and epididymus

Worst bacterial enemies:

`

◦ Staph Aureus and Pseudomonas Auregenosa

` `

◦ MUST cover Staph Aureus with one antibiotic and Pseudomonas Auregenosa with two antibiotics

` `

`

A normal phenomenon: GERD

`

ESOPHAGITIS- tissue inflammation (T-cell/Mac)

`

BARRETT’S ESOPHAGUS- short to long columnar

`

`

`

Malabsorption develops as pancreatic ducts become clogged Infertility in men develops as epididymus is clogged (unable to ejaculate) Obstructive lung disease develops over the years (unable to cough up thick mucus)

IgA Lipase- little fat break down Amylase: breaks alpha 1,4 bonds Lysozyme: a detergent HCO3: sources off acid HCO3 three h id ◦ From food- drinks ◦ Produced by bacteria ( strep mutans) ◦ Reflux

◦ Dx: Pilocarpine: Cl sweat test < 40 Normal 40 – 60 Heterozygous > 60 CF

`

Meconium ileus: first presentation in neonate

`

`

MALORY WEIS SYNDROME- tears in submucosa (ETOH, vomiting)

INCISORS: cut 10 – 15 months BICUSPIDS: chop 15- 18 months MOLARS: grind 18 – 24 months P i h fall f ll out by b age 8 and d are Primary teeth replaced by permanent teeth

BOORHAAVE’S SYNDROME- Rupture of esophagus

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` ` ` `

`

`

Tip of tongue rises > Sides of tongue rise and fold medially > Tip of tongue rises to hard palate > Gravity begins bolus rolling > When bolus approaches trachea trachea, epiglottis Closes off glottis > Bolus rolls over epiglottis/touches the pharynx> CN 9, 10 sense the bolus > UES opens relaxes > Bolus drops into esophagus

Masseter- closes Temporalis- (closes) moves jaw forward and back Medial Pterygoids (closes) Lateral Pterygoids- (opens) lowers jaw Innervated by cranial nerve 5 (Trigeminal)mandibular V3 Develop from first branchial arch

`

`

UPPER ESOPHAGEAL SPHINCTER

◦ Voluntary ◦ Skeletal muscle in upper 1/3 of esophagus ◦ Constrictors of the pharynx

`

y p y g ◦ Stylopharyngeus

◦ Develops from 4th pharyngeal arch

`

◦ Innervated by

x CN 9(stylopharyngeus) x CN10(all others)

Nucleus Ambiguous

`

Nucleus Ambiguus: innervates the UESefferent vagus (motor CN 10) Dorsal motor nucleus: innervates the rest of GI – efferent vagus (motor CN 10) Primary peristalsis: requires vagus nerve and Auerbach’s plexus; begins just distal to the UES only Secondary peristalsis: intrinsic to smooth muscle; can begin anywhere in GI

1° Peristalsis UES

- Vagus CN 10 - Auerbauch (VIP)

2º Peristalsis - Stretch from food

No receptive relaxation: Achalasia

Dorsal motor nucleus of CN 10 (Vagus) LES

Receptive relaxation

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Esophageal Pathology

Choanal atresia: lack apoptosis /bluefeeding ` Esophageal atresia w/ distal TE fistula `

◦ Vomit on first feeding

`

UES

Schatzki rings: -Intermittent dysphagia - Around LES

LES

`

Plummer Vinson Syndrome

Zencker’s: congenital Traction diverticula: occurs due to large bolus

UES

Iron deficiency

Zencker’s Diverticulium C Congenital it l

Traction Diverticulium

LES

Strips of mucosal tissue- lack apoptosis Risk of esophageal cancer Young woman Microcytic anemia

Patients with a history of GERD > 5 years (Screening for Barrette’s esoph.-sq. to columnar) Tx: PPI’s, upper endoscopy every 2-3 years

`

Abnormal esophageal acid exposure

`

> 4 week trial of PPI’s still having symptoms

`

Patient’s with long standing cirrhosis: screening for varices Tx: Propranolol- decreases risk of bleeding

`

E l d GERD iin patients i i h unexplained l i d Exclude with chest pain GERD symptoms with a negative upper endoscopy

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`

`

Best initial test for dysphagia

`

Not the best test if the problem is due to an obvious obstruction, then the best test is upper endoscopy

`

`

Achalasia- bird beak

`

Diffuse esophageal spasm- cork screw

`

Diagnosis: GERD

`

NGT placed at the esophageal junction

`

`

Diagnosis: Dysphagia Unexplained chest pain w/o mechanical obst. Transducer T d placed l d iin esophagous h to record d pressure Most accurate test for Achalasia, Esophageal spasm

Dilute hydrochloric Dil h d hl i acid id iis iinjected j d through h h the NGT to reproduce the symptoms of GERD

`

OLD TEST..PPI’s and 24 hour pH monitor

`

ALWAYS THE WRONG ANSWER !!!!!!!!!

Orad Region

Fundus LES

Caudad Region

Cardia

`

FOOD

◦ Thin muscle wall

`

Body

Pyloris

Orad region- fundus and proximal portion of the body Caudad region - distal portion of the body and the antrum ◦ Thicker muscle wall ◦ Region responsible for mixing the food

Antrum – G cells Duod

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`

`

`

Receptive relaxation: relaxation of the lower esophagous sphinctor and the orad region to accept food into the stomach.

`

Vagovagal reflex reflex- both afferent and efferent limbs of the reflex are carried in the vagus nerve

`

VIP

Mechanoreceptors detect distension of the stomach and relay this information to the CNS via sensory neurons CNS then sends efferent information to the smooth muscle wall of the orad stomach, causing it to relax Neurotransmitter released from f the postganglionic vagal nerve fibers is VIP

Afferent

Vagus

`

Vagotomy eliminates receptive relaxation

Efferent

`

During fasting- periodic gastric contrations occur MMC “ migrating myoelectric complexes”

`

Mediated d d my Motilin l

`

Occur ever 90 minutes

`

`

Takes approximately 3 hours to empty

`

Rate must be regulated to provide adequate time to ◦ neutralize the gastric H+ in the duodenum ◦ adequate time for absorption of nutrients

Function to clear the stomach of any residue remaining from a previous meal

Four major components: `

Two factors slow or inhibit gastric emptying:

`

◦ Fat and H+ in the duodenum

◦ Fat- mediated by CCK (secreted by duodenum)

`

◦ H+- mediated by reflexes of the enteric nerves (myenteric plexus) ensures content is delivered to the duodenum slowly

`

`

Hydrochloric acid (HCL)- function is to reduce pH for the conversion of pepsinogen to pepsin Pepsinogen (inactive) Low pH converts it to the active form- pepsin for protein digestion Intrinsic factor-for the absorption of Vit. B12 in the ileum (essential) Mucus- protects the gastric mucosa from HCL

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Glands of the Antrum of the Stomach

Glands of the Body of the Stomach ` ` `

Empty their secretory products via ducts Opening of the glands are called pits Lined with epithelial cells

`

Contain 2 cell type:

◦ Mucus cells- mucus and HCO3 are protective ◦ G-cells (secrete gastrin into circulation)

Gastric Lumen

Gastric Lumen

Epithelial cells

Mucous cells

Parietal cells

Epithelial cells

Mucous cells HCL & Intrinsic factor G - cell

Chief cells

` `

` ` `

Mucus from goblet cells Prostaglandins (PGE2) HCO3: alkaline tide Aspirinirreversible block Cox 1 & 2 A i i i ibl bl kC NSAIDs - reversible inhibit COX Steroids

` COX

replace PGE

`

(Vasocon/Vasodilation- alprostadil)

` Cox

Gastrin

Pepsinogen

`

` Misoprostyl-

Mucus, Pepsinogen, and HCO3-

2 inhibitors

◦ Celecoxib- only one left ◦ Rofecoxib- off the market ◦ Valdecoxib – off the market ◦ (problem if on > 18 mo)- block

1 – GI

COX 2- Joints

Gastric ulcers due to lack of blood supply; sympathetic output causes vasoconstriction

`

CUSHING’S ULCER

`

CURLING’S ULCER

`

STRESS ULCER

prostacyclins- inhibit platelet agg.

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Regulation of H+ Secretion

`

`

Superficial erosions

`

Type A Gastritis (located in body) ◦ ◦ ◦ ◦

`

` Type

Is the most common cause of upper GI bleeding in older children and adults

Autoimmune etiology Antiparietal cell antibody Atrophic gastritis Adenocarcinoma risk

B gastritis (located in antrum)

◦ Due to a breakdown in barrier protection

◦ “NOT TOO MUCH ACID!” ◦ Associated with Helicobacter Pylori Body

Gastric Ulcer

`

Duodenal Ulcers ◦ Pain is worse 30 to 40 minutes after a meal and also at night

◦ Pain is worse during the meal ◦ Located in the antrum

◦ Located in the second part of the duodenum

◦ Associated with H. Pylori 70% of time

◦ Associated with H. Pylori 95% of time

◦ Associated with CANCER 20% of time

◦ Cancer risk < 1%

◦ Endoscopy on ALL patients

◦ Treat empirically with medication

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` Surgical

indications:

`

◦Intractable pain- meds fail Hemorrhage massive UGB ◦Hemorrhage◦Obstruction- Scarring ◦Perforation- Retroperitoneal R/O- CT

`

Definition: a mass made of undigestible materials ◦ Most common type: yp Hair ◦ Causes a gastric outlet obstruction ◦ TX: endoscopy and removal

SLIDING TYPE: 90%

`

◦ Involve sliding of the fundus into the esophageal hiatus

ROLLING TYPE: ◦ Due to a defect in the diaphragm q g y surgery ◦ Requires

◦ MCC: obesity; restrictive lung disease

◦ Risk of strangulation and infarction

◦ TX: conservative measures; medications; x surgery( Nissan fundoplication)- no belch

◦ High incidence of GERD

`

Rare

`

Hypertrophy of the pyloric muscle

`

Large RUGAL FOLDS on biopsy

`

Presents at 3 to 4 weeks of life

`

H l i off goblet bl cells ll Hyperplasia

`

PROJECTILE vomiting J g

`

Cells ooze out proteins

`

Olive sign; string sign on Barrium;

◦ Like nephrotic syndrome ◦ Low albumin

` `

DX: ultrasound TX: correct fluids and electrolytes pyloromyotomy

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`

`

`

PROTEIN: no protein digestion in the mouth; significant digestion in the stomach; completed in the small bowel SUGARS: significant g digestion g in the mouth;; it stalls in the stomach; completed in the small bowel

Now we call it CHYME

FATS: negligible digestion in the mouth; it stalls in the stomach; completes in the small bowel

` Zymogens:

` Secretin ` CCK

` First

trypsin activated by enterokinase

` Motilin ` GIP ` VIP

` Trypsin

then activates all other enzymes

` Somatostatin ` Enterokinase

`

`

Breaks alpha 1,4 glycosidic bonds ◦ ◦ ◦ ◦

inactive enzymes

`

Lactose Sucrose Maltose Alpha-dextrins p

` ` `

◦ Fructose is only sugar with its own transport system `

Lactase Sucrase Maltase Alpha-dextrinase Sucrase def is most common primary disacharidase deficiency Lactase def is most common secondary disacharidase deficiency ◦ First enzyme to disappear in gastroenteritis; last one to return( in about 48 hours)

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` `

`

`

The most common severe abdominal pain Pain is mid-epigastric, boring through to the back Children: MCC is

(1)abdominal trauma (2) infections

`

`

Causes a severe ileus

`

Severe dehydration

`

Ransons criteria: x Age > 55 years

x Cocksackie B, Mumps virus `

Phlegmon: inflamed pancreas with the intestines wrapped around it

x Blood sugar rises above 200

x WBC > 16,000 x LDH > 350 x AST > 250

Adults: MCC is (1) alcohol (2) gallstones

` MANAGEMENT:

Poor prognosis in first 24 hours if…

(for ANY abdominal pain) ◦ NPO ◦ NG tube ◦ IV normal saline ◦ Meperidine ◦ Abdominal x-ray

◦ Patient needs more than 6 liters of fluid ◦ pO2 < 55 (ARDS) ◦ Hemoglobin drops by 2 or more grams ◦ Calcium drops to below 8

` Hemorrhagic

pancreatitis:

`

◦ Bleeding into the retroperitoneal ◦ Grey-Turner sign ◦ Cullen sign

Pseudocyst: has no epithelial lining ◦ Can become infected ( abscess) ◦ Tx: connect it to skin or small bowel

◦ TX: subtotal pancreatectomy

◦ Characterized by persistent high amylase

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`

` Virchow’s triangle

`

Lecithin

Bile Salts

RUQ colic (stone): pain comes in waves Murphy’s sign: cessation of inspiratory effort with RUQ palpation ` 80% are made of cholesterol (not seen on x-ray) ` 20% are made of calcium bilirubinate (hemolytic anemia) excess biliruben ` 90% get lodged in cystic duct (Alk phos normal)

Cholesterol

`

` 10% get lodged in the common bile duct ` (Inc. Alk phos)

3 clues for common bile duct stone:

`

◦ Pancreatitis phosphatase common bile duct ◦ High alkaline phosphatase-

`

Ultrasound; HIDA scan (most specific)- injectable radioactive

- if an obstruction- non visualization of gall bladder

Management: like ALL abdominal pains ◦ ◦ ◦ ◦ ◦

◦ High WBC count and fever- pus backs up

`

Dx:

`

NPO NGT IV Opiates- meperadine (always start with) ABD xray

Stone in common bile duct… ◦ Surgery: ERCP (endoscopic retrograde choleangopancreotophagraphy-pull it out by mouth; ◦ Laporoscopic cholecystectomy- 90% of cases ◦ Asymptomatic gallstones-ursodeoxycolic acid

◦ (DM, OCP, pregnancy) and schedule for surgery (60 % will progress)

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` Helps

EMULSIFY fats

` Comes

` Bile

Cholesterol go to the liver and forms Cholic and Chenodeoxycholic acids which are conjugated to Glycine and Taurine to form bile salts

from Phosphatidylcholine

` Modified

to make surfactant

`

` `

Cholestyramine Colestipol

` ` `

`

acids:

Side effects: need cholesterol to make Estrogen Steroids Malabsorption (diarrhea) Fat for energy Fat soluble vitamins Cause gall stone

` ` ` ` ` `

Help EMULSIFY fats

Micelle Short chain fatty acids Medium chain fatty acids Long chain fatty acids Chilomicrons Chil i VLDL IDL LDL HDL

Atherosclerosis LDL and B100 Clathrin Pits

`

Symptoms: 70% Stenosis FOAM CELL

Events: 90% Stenosis Atheroma

`

Metabolism of the lipoprotein is defective Triglycerides, cholesterol or both can be elevated

Cholesterol

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` Predisposes

pancreatitis

to xanthelesma and

`

` Defective

metabolism of VLDL, IDL or Chilomicrons

`

TYPE 1: elevated chilomicrons

`

TYPE 2A: elevated LDL

`

TYPE 2B: elevated LDL & VLDL

`

TYPE 3: elevated IDL

`

TYPE 4: elevated VLDL

`

TYPE 5: elevated VLDL & CHILOMICRONS

`

` `

Predisposes to early coronary artery disease and xanthomas Defective metabolism of LDL

STATINS: block HMG-CoA reductase Main side effects: myositis; hepatitis

◦ Lovastatin ◦ Provostatin ◦ Simvastatin ◦ Atorvastatin ◦ Cirivastatin ◦ Valdestatin ◦ Reduvastatin

` Cholestyramine- binds bile and blocks

Works best after 8pm

` Gemfibrozil : increases LPL

reabsorption

` Clofibrate

` Colestipol

` Niacin ` Probucol

` Niacin :

(-) VLDL ` Probucol

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`

Intravascular hemolysis ◦ ◦ ◦ ◦

`

Direct hyperbilirubinemia: conjugated

`

Indirect hyperbilirubinemia: unconjugated

Extravascular hemolysis ◦ Splenomegaly ◦ Something is wrong with RBC membrane x Mcc: autoimmune hemolytic anemia

◦ Criggler-Najjar syndrome, type 2 ◦ Rotors syndrome ◦ Dubin Johnson syndrome Dubin-Johnson

◦ Low albumin ◦ Gilbert syndrome ◦ Criggler-Najjar syndrome x Type 1

`

`

` DIRECT

` INDIRECT

`

Vasculitis Schistocytes Low haptoglobin Fibrin deposition in vessels tear RBCs and platelets

Newborns: choledochal cyst; biliary atresia

` `

Children and adults: pancreatitis; gallstones; sclerosing cholangitis; primary biliary cirrhosis

The Ileum: in children The Sigmoid: in adults

Diverticulosis Diverticulitis ` Volvulus ` Intussusception ` `

`

After age 40: pancreatic cancer

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` The ` An

last part of the small bowel

`

organ with NO known function

`

Begins with pain around umbilicus (visceral pain) Pain settles into RLQ ( McBurney’s point) –somatic somatic pain

`

Caused by a fecolith

`

Management: like ALL abdominal pains ◦ 30% perforate in 24 hours ◦ Incidental appendectomies can be done

`

The first part of the colon

`

The largest part of the colon

`

Cecal cancer has poor prognosis

`

`

movement

` Watershed

Many Na-K pumps controlled by aldosterone

` Haustration

` Haustration ` Mass

LAST chance to REABSORB fluids and electrolytes

` Mass

movement

area: spleenic flexure

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` `

` Sits

at a 90 degree angle with the descending colon AND rectum

`

`

` Pubococcygeus

muscle forms the sling that holds the rectum at 90 degree angle

`

`

`

Duodenum

Jejunum

Amino Acids

90

FATS

80

Sugars

90

Ileum ` ` ` ` ` `

Iron

`

90

A,D,E,K, B12 All else

`

` `

` ` ` ` `

Simethicone Loperamide Diphenoxylate Psillium Sorbitol Mg-citrate Phenophthalien Docussate sodium

Relax pubococcygeus muscle Rectum falls in line with sigmoid colon Gravity and distention start moving stool down Once stool touches internal anal sphincter, f f first urge to d defecate occurs Once stool touches external anal sphincter, last urge to defecate occurs Relaxation of pelvic floor muscles relaxes both sphincters NO sympathetic input to defecation

Ca-carbonate Aluminum hydroxide Mg-hydroxide Gaviscon Sucralfate Bismuth h H-2 Blockers ◦ ◦ ◦ ◦

100

`

PPI ◦ ◦ ◦ ◦ ◦

Omeprazole Esomeprazole Pantaprazole Robeprazole lomeprazole

Cimetidine Ranitidine Famotidine Nizatidine

90

`

` `

` `

` Abetalipoproteinemia

Mineral oil

` Ataxia

telangiectasia ` Selective Ig-A def H h i disease di ` Heavy chain ` Celiac Sprue ` Tropical Sprue ` Necrotizing enterocolitis

Cisapride Metachlopramide Sulfasalazine Sulfapyrazone

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` Irritable

bowel syndrome ` Spastic colon ` Whipple’s disease ` Toxic megacolon ` Ischemic bowel

`

Crohn’s disease ◦ ◦ ◦ ◦ ◦ ◦ ◦ ◦ ◦ ◦

Women Transmural Melena Granulomatous Creeping fat Cobblestoning Skip lesions From mouth to anus Starts in ileum Fistulas

`

Ulcerative Colitis ◦ ◦ ◦ ◦ ◦ ◦ ◦ ◦ ◦ ◦ ◦

Men Hematochezia Mucosal Starts in rectum > prox Pseudopolyps Continuous HLA B-27 Sclerosing choolangitis Toxic megacolon Lead pipe colon Colon cancer risk: 10% at 10 years x Begin annual colonoscopy at 7 years

`

Newborns: swallowed maternal blood

`

Children: epistaxis

`

Adults: Ad l gastritis ii

`

Massive UGI bleeding

◦ Children: meckels diverticulum ◦ Adults: Peptic ulcer disease

`

Newborns: swallowed maternal blood

`

Infants: anal fissure

`

Child l Children: polyps

`

Adults: IBD

`

Elderly: Angiodysplasia

` Newborns:

◦ Choanal atresia ◦ C-type esophageal atresia ◦ Duodenal atresia

x Diverticulosis x Cancer

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`3

to 4 weeks old

◦Pyloric stenosis y

`6

`4

to 6 months old

`2

years to 40 years

◦achalasia

months to 2 years of age

◦intussusception

◦Adhesions ◦Internal hernias

` FIRST

year of life

`1

◦Hirschsprung’s Hirschsprung s disease

year to 40 years

◦Adhesions Adhesions

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` After

age 40

GI Management

◦Adhesions ◦Obstipation Obstipation ◦Diverticulitis ◦Cancer

`

Measurement of radiolabeled carbon dioxide after the oral ingestion of labeled urea

`

H. pylori splits urea with urease

`

Confirm eradication of H H. pylori

`

`

`

`

`

`

If ulcer is found on endoscopy, the test of choice will be biopsy, not urea breath test

Detect steatorrhea as a sign of fat malabsorption Pick Sudan black stain when you see a patient with chronic pale pale, greasy greasy, malodorous diarrhea and no evidence of infection

Suspect chronic pancreatitis in pt’s w/steatorrhea Trypsinogen levels are low from a burned out pancreas Pick trypsinogen level only after Sudan black stain has confirmed a fat malabsorption

`

Wheat or gluten (gliadin) antigens

`

DX of celiac disease

`

Small bowel biopsy is the most accurate test for celiac disease

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`

`

`

Differentiate between intestinal malabsorption and chronic pancreatitis

`

Best initial test for Wilson’s disease Unexplained hepatic and psychiatric abnormalities with movement disorder

D-xylose is a sugar that should be absorbed if the small bowel is intact

`

Low urine levels of D-xylose- defective intestinal mucosa ( Celiac, tropical sprue and Whipple’s disease)

`

Low ceruloplasmin levels = Wilson’s disease

`

Most accurate test is a liver biopsy

`

Best initial test in the diagnosis of acute pancreatitis

`

Lipase is more specific to the pancreas

`

`

`

`

y g to the salivary y Amylase can be elevated from damage glands, esophagus or small bowel

`

Best initial test for autoimmune hepatitis

`

Young female with liver disease

`

Liver biopsy – most accurate test

Most accurate test for acute pancreatitis is abdominal CT- indicator of the need for a pancreatic biopsy

Best initital test for primary biliary cirrhosis (PBC) Middle aged female with itching (pruritus) and an elevated alkaline phosphatase with normal

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Endocrinology, cont

ENDOCRINOLOGY

Exocrine: secreted into a cavity (pancreas) Paracrine: secreted, then works only in the vicinity (somatostatin) Autocrine: secreted by the cell it works on (granulosa cells) Apocrine ( merocrine) tip of cell is secreted with the substance (sweat glands) Holocrine: entire cell is secreted with the substance (sweat glands of the arm pit and groin)

HORMONE

HORMONES

Name and where it comes from Main stimulus Main inhibitor Where does it go? g What is the main action? What is second messenger? Miscellaneous syndromes

STEROID HORMONES PROTEIN HORMONES Fat soluble Nuclear membrane receptor Affect DNA replication, transcription and translation Work via proteins NO second messengers

Water soluble Cell membrane receptors Work via second messengers

ERYTHROPOETIN Made by:

renal parenchymal cells

Signal:

hypoxia ( NOT anemia)

Inhibitor:

increased oxygen

Where it goes: bone marrow What it does: erythropoiesis Second messenger: tyrosine kinase

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POLYCYTHEMIA

POLYCYTHEMIA

First….check erythropoietin

Increased erythropoietin: due to hypoxia

Normal erythropoietin:

Acute hypoxia: tachypnea and dyspnea Chronic hypoxia: clubbing (angiogenen new vessels) (angiogenen-new Restrictive LD; COPD; RENAL CELL CARCINOMA- adults Wilms tumor- children

Gaisbock syndrome; Stress polycythemia; Spurious (not real) ; Due to loss of plasma volume

POLYCYTHEMIA Decreased erythropoietin: You have a cancer !!!!!!!! Angiotensin II

g on its own Bone marrow is acting

ACTH

POLYCYTHEMIA RUBRA VERA Essential thrombocythemia (platelets>600000)

ACTH

ADRENAL CORTEX

ALDOSTERONE, cont Miscellaneous syndromes: (tumor)

Zona Glomerulosa: ALDOSTERONE Stimulus: hypovolemia; hyponatremia; hyperkalemia

Too much: CONN’S SYNDROME Hypernatremia Hypokalemia (K freely filters out) Alkalosis (K/H exchange) Hypertension (3 H2O for every Na+)

Inhibition: hypervolemia Where it goes: late DCT What it does: stimulate synthesis of Na-K pumps Second messenger: none

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ALDOSTERONE, cont

21 β Hydroxylase deficiency: Decreased Aldosterone [mineral corticoid]

Too little: ADRENAL INSUFFICIENCY

(Na+ wasting)- hypotension

21 hydroxylase def 11 hydroxylase def

Lo cortisol Low co tisol [Gl [Glucocorticoid] coco ticoid] no feedback by ACTH

In adults: Abrupt withdrawal of steroids Autoimmune adrenalitis

Increased Androgensvirilization

11 β Hydroxylase deficiency:

Zona Fasciculata

Excess 11-Deoxycorticosterone-

CORTISOL

retain salt – HTN

Stimulus: stress; hypoglycemia

Aldosterone decreased – desmolase rate limiting step t iin th the pathwayth allosteric ll t i activatorti t AT II AT-II

Inhibitor: hyperglycemia

(down regulated due to the HTN)

Where it goes: everywhere >PERMISSIVE

Low cortisol- no ACTH feedback What it does: up regulates ALL receptors during stress

Increased Androgen production- virilization

Second messenger: none

Cortisol, cont

CORTISOL Physiologic affects Proteolysis Gluconeogenesis (break down protein to make glucose)

Too little: Adrenal insufficiency ( Addisons ) Too much: CUSHING’S SYNDROME

Anti-inflammatory

Pituitary adenoma: Cushing’s disease (to much ACTH) Small cell carcinoma: Cushing’s disease Adrenal adenoma: Cushing’s syndrome

Kills T-cells and eosinophil Inhibit macrophage migration Stabilizes endothelium Stabilizes mast cells Inhibits phospholipase-A

Disease affects one organ Syndrome affects many organs

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Dexamethasone suppression test

Dexamethasone suppression test

Lo-dose: 0.5mg IV Q6 x 4 If suppression occurs

Hi dose: 1 mg IV Q6 x 4 If suppression occurs Pituitary adenoma

Obesity Depression Normal variant

If suppression does NOT occur Check ACTH levels: High ACTH: SMALL CELL CARCINOMA Low ACTH: ADRENAL ADENOMA

ZONA RETICULARIS

TESTOSTERONE

Testosterone

DHT: made in testes by 5 alpha reductase

Stimulus: Controls male external genitalia in utero Increase in appetite Aggression and violence Increases libido and RBC count Stimulated by ACTH

Leads to secondary male characteristics at puberty. Responsible for hair growth Too much leads to hair loss, especially in the middle and front of scalp

Male patterned baldness FENESTERIDE blocks 5 alpha reductase FLUTAMIDE blocks DHT receptors

Second messenger: none

ADRENAL MEDULLA

Pheochromocytoma or Neuroblastoma

Epinephrine:

An excess of NE and Epi Intermittent palpitations, HTN, diaphoresis and headache

Stimulus: stress/hypoglycemia Inhibition: hyperglycemia Where it goes: liver and adrenal cortex What it does: gluconeogenesis; glycogenolysis Second messenger: c-AMP Misc. syndromes…

Neuroblastoma: hypsarrythmia (dancing eyes) opsoclonus (dancing feet)

Dx: measure urinary VMA and metanephrines ( dopamine > HVA) Phentolamine- short acting alpha blocker for diagnosis Tx: phenoxybenzamine (longer acting, not specific)

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Pheochromocytoma or Neuroblastoma

Pheochromocytoma

Difficult to differentiate benign from malignant on biopsy; they look alike

24 hr urine collection Metanephrine Vanillyl mandelic Acid (VMA) Catecholamines

Neuroblastoma is MOST common abdominal mass in children Pheochromocytoma

If elevated… CT or MRI

10% are malignant 10% are bilateral 10% are in children 10% are familial 10% are metastatic at diagnosis

If CT or MRI find nothing:

meta-iodo-benzyl-guanidine (MIBG) scinigraphy (NE analogue that concentrates in the adrenals)

Stress Hormones Epinephrine: immediately Glucagon: within 20 minutes Cortisol: within 2 to 4 hours GH: after 24 hours

Pancreatic Hormones

Insulin: within 30 min ADH: within 30 min

Glucagon: from ALPHA cells Insulin: from BETA cells

Insulin pushes the i t cells ll and d sugar into ADH normalizes the osmolarity

Somatostatin: from DELTA cells

THESE PRODUCE THE SUGAR

Pancreatic Polypeptide: from ‘F’ cells

Glucagon

Glucagonoma Pancreatic tumor

From: pancreatic alpha cells (β1 receptors) Stimulus: hypoglycemia and stress Inhibition: hyperglycemia Where it goes: adrenal cortex, liver, and adipose di tissue ti What it does: gluconeogenesis (raises sugar), glycogenolysis (glycogen), lipolysis (fat), and ketogenesis Second messenger: c-AMP Misc. syndromes…

High glucose; high lipids; and high ketones Related to MEN I ( Wermer’s) Hormone responsible for KETOACIDOSIS in type 1 diabetes

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lnsulin

β cells of the pancreas

From: pancreatic islet cells β cells (β2 and α2 receptors)

Stimulus: hyperglycemia Inhibition: hypoglycemia Wh Where it goes: everywhere h exceptt BRICKLE What it does: increase all anabolic processes Second messenger: tyrosine kinase Misc syndromes…

Somatostatin

Insulinoma vs Nessidioblastosis INSULINOMA

NESSIDIOBLASTOSIS Seen primarily in seen primarily in adults infants Causes hypoglycemia causes hypoglycemia M Measure hi high h iinsulin li and high C-peptide measure high insulin and high C-peptide Dx: cat scan Tx: subtotal Tx: remove surgically pancreatectomy

From: pancreatic DELTA cells Stimulus: insulin and glucagon Inhibition: low insulin and glucagon Where it goes: paracrine Wh What it does: inhibits insulin and glucagon Second messenger: c-AMP Misc. syndromes…

Somatostatinoma

Pancreatic Polypeptide

Usually a pancreatic tumor Severe constipation Dx: cat scan Tx: surgery

NO KNOWN FUNCTION! Whatt iis the Wh th only l know k organ with ith no known function?

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GI Hormones Stomach

GI HORMONES

Gastrin

Duodenum Secretin CCK Motilin GIP VIP Somatostatin

Secretin

CCK

From: duodenum Stimulus: low pH Inhibition: high pH Where it goes: paracrine (pancreas & gallbladder) What it does: stimulates production and secretion of bicarbonate ions from pancreas & GB Second messenger: c-AMP Misc. syndromes: none

From: duodenum Stimulus: food, especially fats Inhibition: high pH Where it goes: pancreas (digestive enzymes) and gallbladder (bile) What it does: primarily fat and protein digestion Second messenger: IP3/DAG Misc. syndromes: none

GIP

GIP Syndromes

From: duodenum Stimulus: glucose Inhibition: high pH Wh Where it goes: pancreatic ti iislet l t cells ll What it does: enhances insulin secretion Second messenger: c-GMP Misc. syndromes…

Dumping Syndrome: seen after Bilroth ll procedure Increased osmotic load dumped Into duodenum Causes osmotic diarrhea Can also cause postprandial (reactive) hypoglycemia

Causes insulin resistance over time (type 2 diabetes)

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Somatostatin

VIP

From: duodenum Stimulus: duodenal hormones Inhibition: high pH Where it goes: paracrine What it does: purely inhibitory Second messenger: c-AMP Misc. syndromes: somatostatinoma

From: duodenum (from Auerbachs plexus) Stimulus: duodenal hormones Inhibition: high pH Where it goes: paracrine What it does: purely Inhibitory to all duodenal hormones Second messenger: c-AMP Misc. syndromes…

Vipoma

Gastrin From: antrum of stomach Stimulus: high pH Inhibition: low pH Where it goes: parietal cells of the stomach (mostly in the body of stomach) What it does: production of HCL and intrinsic factor (for absorbing VIT B12) Second messenger: calcium Misc. syndromes…

Usually a pancreatic tumor WATERY or secretory diarrhea Dx: cat scan Tx: surgery

Gastrinoma

ANP ( B-type natriuretic peptide ) From: right atrium Stimulus: high volume (stretch of right Atrium) Inhibition: low volume Where it goes: kidney What it does: dilates the afferent renal artery; inhibits aldosterone Second messenger: nitric oxide Misc. syndrome…leads to polyuria, nocturia and hyponatremia in right atrial distention

Usually a pancreatic tumor Zollinger-Ellison syndrome Gastrin levels are high all the time Can be part of MEN-1 syndrome

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PTH

PTH VITAMIN D CALCITONIN

Superior parathyroids: 4th pharyngeal pouch Inferior parathyroids: 3rd pharyngeal arch Stimulus: low calcium; high phosphorus Inhibition: high calcium; low phosphorus Where it goes: (1) osteoclasts of bone (2)late DCT What it does: (1) stimulate osteoclastic activity (2) increases secretion of phosphorus (3) activates 1-alpha hydroxylase

CALCIUM METABOLISM

PTH, cont

PTH Syndromes

Second messenger: c-AMP Misc. syndromes…

HYPO-PARATHYROIDISM Primary: due to thyroidectomy Pseudo: P d receptor t nott working; ki short h t 3rd th and 5 digit Pseudopseudo HYPOPARATHYROIDISM : only difference is that calcium is normal

PTH Syndromes

Vitamin D

HYPER-PARATHYROIDISM

From: skin > liver > renal Stimulus: low calcium; low phosphorus Inhibition: high calcium; high phosphorus Where it goes: (1) kidney and (2) GI What it does: (1) production of Ca-ATPase and (2) production of CBP ;(3) stimulates osteoblastic activity Second messenger: none Misc. syndromes…

Primary: due to parathyroid adenoma; MCC of isolated hypercalcemia in adults Secondary: due to renal failure

Renal Osteodystrophy Osteitis Fibrosa Cystica- fibrous tissue Osteopenia- low density Osteomalacia- nutrition Osteosclerosis- trauma

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Calcitonin

Vitamin D syndromes

From: parafollicular cells

Deficiency: Osteomalacia in adults; Rickets in children

Stimulus: high calcium

Excess: high g calcium; high g p phosphorus p

Inhibition: low calcium Where it goes: bone What it does: inhibit osteoclastic activity Second messenger: c-AMP Misc. syndromes

Bisphosphonates

MEN Syndromes

Inhibit osteoclastic activity like calcitonin

MEN 1: pituitary adenomas, parathyroid adenomas, and pancreatic adenomas (Wermer syndrome)

Second line drugs for osteoporosis

MEN 2: medullary carcinoma of thyroid (high calcitonin), pheochromocytoma, plus or minus parathyroid adenoma( Sipple syndrome)

Very corrosive in the GI

MEN 3: men 2 with neuroma/ganglioneuroma but minus parathyroid adenoma

Stored in bone for up to 20 years i.e. etidranate; elandronate; ibondranate, residronate

Causes osteonecrosis (if received via IV)

Prolactin:

Hypothalamic Hormones

Stimulate PRL release- nipple stimulation Inhibit PRL release- DA

Pituitary Hormones

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Dopamine Agonists

Dopamine Blockers (D-2)

L-Dopa/Carbidopa Bromocriptine- old (stop lactation) Selegyline- MAO type B, increases extracellular dopamine Amantadine- antiviral (influenza A)

Phenothiazines

(-) prolactin- can’t lactate N/V CTZ Movement disorders- gross motor

Thioxanthenes

Dopamine Blockers (D-2)

Pituitary Tumors

Chlorpromazine Prochlorperazine (Compazine): anti-N/V Promethazine Fluphenazine Thioridazine- pigment retinopathy

Thiothixene- long acting (>30 days)

Butyrephenones

Nonfunctional (chromophobic) adenomas: most common pituitary tumor

Haloperidol- antipsychotic- schizophrenia, psychosis Droperidol - antimetic

Prolactinoma: most common functional pituitary tumor

At i l block Atypicals: bl k D D-4 4 receptors t Used for negative symptoms Used when pt has had extrapyramidal side effects Clozapine- agranulocytosis Onlazapine- wt. gain Resperidone- neuroleptic anesth. (fever, muscle stiffness)

ALL pituitary tumors associated with high prolactin levels High PRL > galactorrhea and amenorrhea

Hypothyroidism

Hypothyroidism:

Cretinism- Mom and fetus- hypo

3º

T4

TSH

TRH

2º

T4

TSH

TRH

1º

T4

TSH

TRH

Iodine deficiency Hashimoto’s disease DeQuarvain’s disease- Virus (painful)-self limiting Lymphocytic thyroiditis (postpartum ) Riedel’s Struma- capsule cancer (woody) Tx: Thyroxine(T-4) or L-Thyronine (T-3)

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Hyperthyroidism

THE END

Grave’s Disease ( autoimmune) < 50 y/o TSH antibody Plummer’s Syndrome: toxic multinodular goiter > 50 y/o – one area hot (iodine takeup)

Tx: propanolol Propylthiouracil- blocks peroxidation Methimazole- block peroxidation I-131- destroy the tissue Thyroxine- replacement

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First Step: Distribution • Polyarticular symmetric-

Rheumatology gy

• Monoarticular arthritis – • Oligoarticular asymmetric-

Steps to evaluate a patient

• Migratory arthropathy-

Polyarticular symmetric

First Step: Distribution • Polyarticular symmetric:

• Rheumatoid arthritis (RA) • SLE (spares joint destruction) • Viral (Hep (Hep. B, B EBV, EBV CMV CMV, B19)

• Monoarticular arthritis • Oligoarticular asymmetric • Migratory arthropathy

Monoarticular arthritis

First Step: Distribution

• OA • Gout • Septic arthritis

• Polyarticular symmetric: • Monoarticular arthritis: • Oligoarticular asymmetric: • Migratory arthropathy:

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Oligoarticular asymmetric joint

First Step: Distribution

• Spondyloarthropathies

• Polyarticular symmetric: • Monoarticular arthritis: • Oligoarticular asymmetric: • Migratory arthropathy:

Migratory arthropathy

Second step:

• Rheumatic fever • Gonococcal arthritis (disseminated) • Lyme disease

• Osteoarthritis

Pain move around the body

• Septic arthritis

Acute or Chronic…

• Crystal induced

Third step:

Fourth step:

• Is there any evidence of systemic symptoms?

• Any evidence of inflammation? • OA:

Lungs: Kidney: CNS: Skin: Hemotologic:

• RA:

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Inflammation association

CASE 1

• Morning stiffness > 1hr

•72 y/o woman presents with left knee pain.

• Red,, warm,, tender • Erythematous joint • Increased ESR and CRP

CASE 2

• Monoarticular

•30 y/o female presents with wrist wrist, MCP and PIP swelling and pain.

–OA (chronic) –Septic (acute) –Crystal induced (acute)

CASE 3

• 32 y/o male presents with knee swelling after you had seen him for left wrist pain the day before which has now resolved.

•Polyarticular –SLE –Viral –RA

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Case 4

•Migratory arthropathy

•25 y/o female presents complaining of right knee pain and swelling and left hip pain.

–GC GC –Rheumatic fever –Lyme disease

• Oligo-arthropathy

Test in Rheumatologic diseases

–Spondyloarthropathy (Reiters)

Test:

Test: • Joint Aspiration: whenever there is fluid in a joint, you need to aspirate it

• Joint Aspiration: whenever there is fluid in a joint, you need to aspirate it

• Exception: “ Contraindication” –Bleeding disorders –Anticoagulants with bleeding diathasis –Cellulitis overlying

• Exception: “ Contraindication”

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Test:

WBC ranges • OA / Traumatic arthritis

Always order the 3 C’s and a gram stain 1. 2. 3.

• Inflammatory (RA, Gout)

• Septic arthritis

Crystals: • • • • • •

Anti-Nuclear Antibodies (ANA) • Antibodies against part of the nucleus

OA / Traumatic arthritis RA SLE Gout Pseudo gout Septic

• 10% of normal people have + ANA • High AB titer

Anti-Nuclear Antibodies (ANA)

• If you think the patient may have SLE, what is your first step in management?

• 97% of SLE patients have a + ANA • So S if the h test results l come b backk negative, assume they don’t have SLE

• If positive, order…

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Ab association • • • • • • •

Rheumatoid Factor (RF)

SLE (60%), lupus nephritis SLE (30%) Drug induced lupus Neonatal lupus, Sjogrens Sjogrens CREST Mixed connective tissue dz.

• Antibodies against antibodies • Fc portion of IgG • Increase with age

Anti-Neutrophilic Cytoplasmic Antibodies (ANCA)

Diseases:

• Antibodies against certain proteins in the cytoplasm of neutrophils.

• Rheumatoid Arthritis • Systemic Lupus Erythematosus • Scleroderma (SSc) • Sjogren Syndrome

• (c) ANCA: • (p) ANCA:

Rheumatoid Arthritis

Rules of 6:

• Chronic inflammatory disease

• Morning stiffness > 1 hr - for at least 6 weeks

• Target- Synovium

• Swelling of wrist, MCP, PIP – 6 weeks

• Symmetric distribution

• Swelling of at least 3 joints- 6 weeks

• Potential to destroy cartilage and bone erosion

• Symmetric joint swelling – 6 weeks

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Extra-articular manifestations

Labs for RA

• Damage to tendon and ligaments

• RF • Anemia • ESR

• Boutinniere deformity- PIP flexion, DIP extension • Swan neck deformity- PIP extension, DIP flexion

• X-ray:

• Rheumatoid nodules- vasculitis

• Synovial fluid analysis

• Caplan syndrome- rheumatoid nodules in lungs

Mgt. for RA

CASE 5

• Patient with RA presents with a swollen painful calf. • Diagnosis?

Old Tx: NSAIDS > Steroids > Methotrexate (2yrs later) NEW TX: Start with MTX after 1 week add prednisone for 1 week only use for flare-ups Antimalarial- hydroxychloroquine- MTX backup

Alentoaxial Subluxation in RA

Systemic Lupus Erythematosus (SLE) • Systemic disease • Tissue and multiple organ damage by antibodies and immune complexes

• C1, C2 • Dx: X-ray X ray / CT

• Remember: you can have all the criteria for SLE, but if the ANA is negative, the patient does not have lupus

• Must rule out before surgery

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Organs involved with SLE • • • • • • •

Diagnosis of SLE • Best screening test

CNS: confusion, personality change Skin: Kidney: Lungs: Hematologic: Immune: Bone:

ANA

• Specific Ab’s associated • Complement levels (C3,C4,CH50) • Active lupus • Lupus nephritis

Case 6

Pregnancy and SLE • Fertility rates:

• 26 y/o female, admitted for confusion. Hx. SLE and was recently pp off p prednisone ((10 tappered mg/day). Pt was fine a couple of days ago. PE- no focal deficits. • DDx?

• Spontaneous abortions and still births • DOC Mgt.: • Exacerbation (flare up) DOC: • All pregnant women with SLE need to be screened:

Mgt. SLE

Drug induced lupus

• NSAID’s for arthritis

• Limited form of lupus due to a drug

• Antimalarials: Chloroquine

• No major organ involvement

• Steroids: for major organ involvement

• Dx: rash + anti-histone antibodies (complement normal)

• Cytotoxins:

• Mgt: Discontinue offending drug

Azathioprine Cyclophosphamide

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Scleroderma (SSc) • • • •

CREST syndrome

Chronic multisystem disease Thickening of the skin Raunaud phenomenon g involvement Visceral organ

• Limited form of scleroderma • Symmetrical skin thickening C R E S T

– GI: esophageal dysmotility, hypomotility of small intestine – Pulmonary – Renal

• Anti-centromere antibodies

Sjogren Syndrome

Spondyloarthropathies

• Chronic auto-immune disease

• Ankylosisng spondylitis

• Xerostomia and dry eyes

• Reactive Arthritis

• Lymphoproliferative disease- Malignant lymphoma

• Psoriatic Arthritis

• Bilateral parotid enlargement

• Enteropathic arthropathy

• Itchy eyes, sand under their eyes • Keratoconjunctivitis sicca

Ankylosing spondylitis

Extra-articular manifestations AS

• Inflammatory disorder of axial skeleton and peripheral joints

• Cardiac:

• Rare after age 40

• Spine:

• 90% of patients + HLA-B27

• Eyes:

• Young male 20’s, chronic lower back pain, morning stiffness > 1hr, get better with exercise

• Skin:

• Cervical spine involvement- late stage of the disease

• Mgt: NSAID’s, Physical therapy, Exercise

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Reactive Arthritis:

Reactive Arthritis Mgt.

• Complication of an infection somewhere in the body. • Non-Gonococcal urethritis:

• NSAID’s • Antibiotics (prompt)

1. 2.

• Infectious diarrhea: 1. 2. 3.

Psoriatic Arthritis

Enteropathic Arthropathy • Ulcerative colitis • Crohn’s disease

• DIP joint • Nail pitting • Sausage shaped digits

• Skin lesions: – Pyoderma gangrenosium – Erythema Nodosum

Osteoarthritis (OA)

Osteoarthritis (OA)

• Target- articular cartilage • Hypertrophy of bone • NOT an inflammatory disease

• Target- articular cartilage • Hypertrophy of bone • NOT an inflammatory disease

• MC joint affected? • 2nd most common joint affected? • Joint involved with the greatest disability?

• MC joint affected? Knee • 2nd most common joint affected? • Joint involved with the greatest disability?

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Two forms of OA:

Association with OA

• Idiopathic

• Joint pain with exercise

• Secondary (cause)

• Relieved by rest

– Arthropathies - gout – Endocrine dz – Desosition dz – Mechanical factors

• Morning stiffness (< 20- 30 min) • Slow, progressive, irreversible • NO systemic manifestations

Labs with OA

Mgt. with OA

• CRP and ESR : Normal • X-ray:

• Non- pharmacological – Correct poor posture – Weight reduction – Physical therapy

Osteophytes Unequal joint space Bouchard’s nodules (PIP) Heberden’s nodules (DIP)

• Drug therapy – First drug- Acetaminophen (contra: use ibuprofen) – Add Capsaicin

Orthopedic surgery and joint arthroplasty

Crystal Induced Arthropathies • Monosodium urate (MSU)

• Unsatisfactory medical Tx

• Calcium phrophosphate (CPPD)

• Quality of life decreased

• Calcium oxylate (CaOx) • Calcium hydroxyapatite (CaHA)

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Gout:

Predispose to Gout:

• Acute Monoarthritis • Tophi:

• Excess ETOH • Trauma • Infection

• Metaatarsophalangeal joint (first toe):

• Diuretics: Hydrochlorthiazide, Furosemide

• First episode:

• Anti-TB meds: Pyrazinamide Ethambutol

• Red, tender, warm

Diagnosis of Gout:

Mgt. Acute Gouty Arthritis

• It is made with fluid analysis of synovial fluid

• NSAID’s – Indomethacin – 50 mg 3 x day

– MSU crystals – Negative N i Birefringent Bi f i – Needle shape crystals – WBC 5,000-50,000

• Colchicine: 0.6 mg every hr until symptoms resolve • Steroids: intraarticular or oral (elderly)

Chronic Hypouricemic Therapy

Pseuod-gout:

• Low urine levels of uric acid • Usually life long therapy • Follow uric acid levels here !!!

• CPPD crystal formation

• Probenecid- under secretors

• May present acute like gout

• Allopurinol- over producers

• Knee most common joint affected

• Elderly and pre-existing joint damage

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Diagnosis of pseudo-gout

Septic Arthritis

• Arthrocentesis:

• MCC gonorrhea

– Rhomboid crystals – + Birefrengent

• 70% of cases > age 40

• X-ray: linear radiodense deposits in joint menisci “ Condro- calcinosis”

• Elderly- “Staph aureus” (pre-existing joint destruction)

• Mgt: same as acute gout

Mgt. Septic Arthritis • Non-GC: (older) – Staph aureus

THE END

• GC (younger) sexually active • Both WBC > 50,000 and negative crystals • Staph aureus- IV Vancomycin • GC- IV Ceftriaxone • Therapeudic arthrocentesis

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REPRODUCTIVE ENDOCRINOLOGY

Menstrual irregularities • The number one reason an adult woman goes to see a doctor • The number one reason a teenage female misses work or school (dysmenorrhea)

Dr. Naegle

Naegle’s Rule • Assumed that a woman’s menstrual cycle lasts 28 days long • Allows us to calculate the EDC – Begin with the last first day of menses, go forward 9 months or go backward 3 months, then add one week – If the woman’s menstrual cycle varies from 28 days, then you add/subtract the difference at the end

Some Rules

Naegle’s rule also allows us to…

• Term pregnancy: 37 to 42 weeks • Average birth weight: 2500gms to 3500gms (5 to 7 pounds) • Preterm: birth prior to 37 weeks • Postterm: birth after 42 weeks • SGA: small for gestational age • LGA: large for gestational age

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Oogenesis

Oogenesis: The Steps • One round of mitosis first: 2n to 4n (occurs in utero)

• Begins in-utero at about 5mo gestation • At birth, a female ovary contains about 400k eggs • Beginning at puberty, 8 to 10 follicles begin development; but, only ONE egg will ovulate

– Primary oocyte

• Enters meiosis 1 and arrests in Prophase (cells still at 4n) • Eggs remain arrested in meiosis 1 in prophase until ovulation occurs • If egg ovulates, it will complete meiosis 1, give off first Polar Body, and enter meiosis 2, arresting again in Metaphase(4n to 2n)

– The eggs that do not finish development will turn into small white nodules (corpus albicans)

– Secondary oocyte

Oogenesis: The Steps • If fertilization occurs, egg will complete meiosis 2, give off the second Polar Body, and form a zygote (2n to 1n)

Because mom’s eggs remain arrested for SO long…

– Tertiary oocyte

You can trace 80% of chromosomal mutations to MOM

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OCP’s • • • • • •

HRT

Norethindrone Mestranol Depo-provera Estrone Estradiol Estriol

• Decreases symptoms • Decreases osteoporosis ( decreases osteoclastic activity) • Decreases risk of CAD ( increase HDL; vasodilator) • Controversy!!

Other Hormonal Drugs

Now, introducing…TYRONE!

• Clomiphene • Leuprolide • RU-486 (mifeprostone)

Spermatogenesis

Sertoli Cells

• Begins at puberty • First sign of puberty in a male is testicular enlargement • Controlled by testosterone • LH > testosterone > spermatogenesis • FSH > Sertoli cells > produce inhibin

• Produce inhibin • Maintain the blood-testes barrier • Protect and nourish the sperm to maturity

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Spermatogenesis

Spermatogenesis, cont

• One round of mitosis: 2n to 4n

• Each day 20 to 40 million sperm mature • Complete spermatogenesis takes 41 to 72 days • Sperm can live for 5 days in fallopian tube while an egg can live for only 3 days

– Primary spermatogonium

• Meiosis 1: 4n to 2n – Secondary spermatocyte

• Meiosis 2: 2n to 1n – Tertiary spermatid

• One spermatogonium gives rise to 64 spermatids • As spermatogonia mature, they move from the basal layer into the epididymus to finish maturing

Virility

Infertility

• • • •

20 to 40 million sperm per cc of semen 4 to 5cc of semen per ejaculate No more than 40% abnormal forms 30 to 60% of sperm must still be motile after 5 minutes on a glass slide • The pH is basic

• 50% male factor – Always do sperm analysis first

• 30% female factor – Mcc is PID

• 20% miscellaneous

Before Sperm Can Leave… • Seminal vesicles: semen; fructose • Bulbourethral ( Cowper’s ) gland: HCO3 • Prostate: Zn ; acid phosphatase; hyaluronidase

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Sexual Response

Sexual Dysfunction

The Difference Between the Sexes

• In young men: premature ejaculation • In older men: stress induced impotence • In the elderly: vascular impotence

• Men have a longer refractory phase; short excitement phase • Women have a longer excitement phase; short refractory phase

– Atherosclerosis decreases blood flow – Takes longer to establish an erection – Harder to maintain an erection – Need for more direct stimulation – Longer refractory phase

To Address Premature Ejaculation… • Apply the SQUEEZE TECHNIQUE – Gently squeeze the head of the penis; it starts retrograde peristalsis in the ejaculatory duct and epididymus

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Once the sperm are deposited in the vagina…


• • • • •

Sperm hide under the semen HCO3 is released to neutralize lactic acid Zn is used for the Capacitation Reaction Fructose is used for energy 70% of sperm are dead before reaching the cervix • Acid phosphatase is used to eat through cervical mucus

• Sperm enter the uterus • They swim through the fallopian tubes • By the time the sperm approach the egg, only a few thousand sperm remain • Sperm surround the egg • They dart in and out, opening their heads to release enzymes ( Acrosomal Reaction)


Stages to Know

• Once one sperm head fuses with egg, a wall forms behind the sperm ( Crystallization Reaction)

• Zygote: 2 cell stage – 90% fertilizations occur in the ampulla – It must now migrate into the fallopian tubes – Ectopic pregnancy: mcc is PID (forms scars)

– This prevents Polyspermy – A ZYGOTE is formed when egg (1n) and the sperm head (1n) fuse

• Morula: 16 cell stage – This stage enters the uterus

• Blastula: 256 to 512 cell stage – This is the stage that implants

Formation of the Placenta

Placental Hormones • • • • • •

HCG PROGESTERONE ESTRIOL HUMAN PLACENTAL LACTOGEN INHIBIN RELAXIN

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HCG

HCG, cont

• Detectable in BLOOD one week after fertilization; in the URINE two weeks after • Has the same alpha subunit as FSH. LH, and TSH ( check the beta-HCG)

• Maintains corpus luteum production of progesterone • Can lead to Hyperemesis Gravidarum – DES • Cervical incompetence • Adenomyosis • Clear cell carcinoma of the vagina

• Maintains the corpus luteum • Increases GI motility and absorption • Sensitizes the TSH receptor

• Increases BMR

HCG, cont

How to Follow the First Trimester

• Doubles every 2 days until week 12 • HCG of 600: viable fetus • HCG of 2000: fetus visible on abdominal ultrasound

• Fundal height rises 1cm per week – Pubic symphasis = 12 weeks – Umbilicus = 20 weeks

• HCG doubles every 2days • Estriol level rises linearly • If fetus dies: estriol level falls first

Think of Molar Pregnancy if…

Progesterone • • • • • • • •

• Fundus growing higher than predicted • HCG rising faster than predicted • HTN in first trimester • Complete mole • Incomplete mole

Increase RR from pons Increase appetite Pica Increase RBC mass by 30% Causes acne Hyperpigmentation Cloasma or malasma Helps increase plasma volume by 50%

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Estrogen

Inhibin

• Smooth muscle relaxation • Stimulates protein synthesis in the liver

• Inhibits FSH • Prevents another menstrual cycle from beginning

– High ESR – Hyperlipidemia – Increased TBG – Increased angiotensinogen – Increased clotting factors

Human Placental Lactogen

Relaxin

• BLOCKS mom’s Insulin receptors • Creates insulin resistance • Gestational diabetes

• Relaxes tendons and ligaments • Stretches the pelvis

The END

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Renal Embryology: At different points of gestation, various organs are embryologically developed. For example: - Notochord at 2 wks - Brain at 4 wks - Renal system is formed at 12 wks

METANEPHROS - give rise to the kidney

URETERIC BUD - gives i rise i to t the th entire ti collecting system

Renal Pelvis Calyx

Collecting duct, major and minor calices, papillae,

hilum and ureters

URETERIC BUD

Metanephros

Ureteric bud must make contact with the metanephros or kidney will NOT develop

Gives rise to the GENITALIA in MALES

Paramesonephros (never functional) as a kidney

Has H kidney kid function prior to kidney formation

Develops into the testes, seminal vesicles, vas deferens and epididymus

To develop, you need a Y chromosome and MIF

Gives rise to female genitalia

Develops into the ovaries, fallopian tubes, uterus and upper vagina

A female can develop either by DESIGN or by DEFAULT

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Vitelline Duct:

Allantois:

Omphalomesenteric duct

IN MALES: becomes the PENIS

IN FEMALES: becomes the CLITORIS

Urogenital Sinus

IN MALES: prostate, prostatic urethra and bulbourethral ( Cowper’s) glands

Urogenital Tubercle

IN FEMALES: lower vagina, and labia minora

Cortex: outermost layer of the kidney.

L1 and L2 levels: right kidney is positioned slightly li htl lower l th than the th left l ft kidney Why?

It contains the nephrons, PCT, and DCT

Cortical nephrons are shorter in length compared to the medullary nephrons

Functions to maintain an isotonic urine

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Medulla: deeper layer of the kidney Pyramids collect urine from the collecting ducts that drain into each renal papilla p p From the papilla > calyces > ureters Responsible for hypertonic urine

Why do we sweat in different regions?

Renal Blood Supply

In hot places, we sweat and lose water. IIn cold areas, we do d nott sweatt and d thus th do d not need to preserve this water.

Right renal artery

Right renal vein

The nephrons elongate after 3-4 days Allows for more water conservation (hypertonic urine) and fluid replacement lost

Healthy Kidney Renal Blood Supply

Right gonadal vein y drains into the directly IVC. Right sided infection or cancer has a worse prognosis

Sodium and water removal

Fluid overload

Waste removal

Elevated waste- Urea, Creatinine, Potassium

Hormone production • Renin • Erythropoietin's • Prostaglandins

Left gonadal vein drains into the left renal vein

Unhealthy Kidney

Changes in hormone levels • Blood pressure • Making red blood cells • Uptake of calcium

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Divide the kidney into 4 regions.

When one of the 4 are affected, ultimately it will affect the others

Tubules

Blood vessels

Blood Vessels

20% off blood bl d from f the th CO is i going i to t the th kidneys kid

90% of it, supply’s the cortex

Only blood supply for the medulla - vasa recta

Medulla- first place to infarct in a low volume state leading to medullary necrosis

Glomeruli

Interstitium

Tubules

Glomeruli

Consist of visceral epithelial cells (foot processes-podocytes)

Glomular basement membrane (electron dense-type 4 collagen)

Parietal epithelium lines bowman's space

Fenestrae (in the endothelium)

Most glomerular diseases are immunologically mediated.

Proximal convoluted tubule (80% of reabsorption)

Loop of Henely (triple transport)

Distal convoluted tubule

Collecting tubule (for concentrating the urine).

Most tubular diseases are frequently caused by toxic or infectious agents

Interstitium

In the cortex, comprising mostly of fenestrating capillaries (so any change in space, i.e. edema is abnormal).

Most interstitial disorders are frequently caused by toxic or infectious agents.

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Patient presents with polyuria and polydyspia……

You rule out diabetes based on glucose…

What

Diagnosis

Cause Excessive fluid intake

Psychogenic DI

next?

Labs Uosm/Posm > 0.7

i.e. As much as 10-12 gallons Restrict H2O for 24 hours of H2O a day

Urine will concentrate

Posterior pituitary does not release the stored ADH

Central DI

Uosm/Posm < 0.7 ADH is i nott present, t but b t

i.e. Infarction of the pituitary when you give it, expect gland

the urine to concentrate

Renal kidneys are unresponsive to ADH

Nephrogenic DI

i.e. Renal failure, lithium, low volume state infracting the medulla of the kidney

Uosm/Posm < 0.7 ADH is present and wants to work, but it’s a receptor problem Urine will not concentrate

For burn patients: Parkland formula ( to calculate fluid deficit only) 4cc x Wt (Kg) x % burned areas Never calculate more than 50% of burned

body area Replace fluids: ▪ ½ within the first 8 hrs ( from time of trauma) ▪ Remainder over the next 16 hrs

Head and neck: 9% Each arm: 9% Front of torso: 18% Back of torso: 18% Each lower extremity: 18% Genitalia: 1%

For newborns: subtract 9% from each lower extremity and add it to the head and neck Head 27%, legs 9%

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A 36 y/o fire fighter (70 kg),was trapped in a burning building and suffered 2nd and 3rd degree burns to over 65% of his body. What will be the fluid replacement management?

Urine output : 1cc/kg/hr

70 kg x 50 % = 3500 x 4cc = 14,000 ml (14L)

7 L first 8 hrs :

2nd day ½ that, 3rd day nothing

Urine Output: 1cc/kg/hr (70 kg male)

A. 15, 20, 15 ml/hr B. 300, 250, 270 ml/hr C. Over 48 hrs, urine output has been between 50-100 ml/hr. Now on day 3, urine output 250, 300. Next step in mgt.?

7 L remaining 16 hrs

Never give a hypertonic solution… this will pull fluids out of the extracellular fluid to help fill the vascular space, which will be replaced by the intracellular fluid.

Cell

H2O

Intracellular H2O Extracellular

Ok great job on getting patient X’s blood pressure back to the normal range, but at what cost…. the tissue (oops!!!)

Exception to the rule: Hyponatremic patient ( Na <120) patients:

Body water is broken down into fluid compartments:

Intracellular fluid (2/3 of Body Water) Extracellular fluid (1/3 of Body Water) Interstitial fluid (ISF) 2/3 ECF

Use 3% (hypertonic) saline to get sodium above 120

Vascular fluid (VF) 1/3 ECF ISF

ICF

VF

ECF

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Loss of isotonic fluid:

Loss of hypotonic fluid:

Hemorrhage, Diarrhea, Vomiting

Dehydration, Diabetes Insipidus, Alcoholism

Osm

ICF

ECF

ICF

Gain of isotonic fluid: Isotonic saline

ICF

ECF

Gain of hypotonic fluid: Hypotonic saline, Water intoxication

ECF

ICF

ECF

Gain of Hypertonic fluid: Hypertonic saline, Mannitol

ICF

Renin – Angiotensinogen Pathway

ECF

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Bartter's syndrome: Renin (JG cells-afferent)

JG cell hyperplasia with renin excess No increase in blood pressure due to insensitivity of the presser effects of AT-II

AT-II (stimulates) • alpha 1 vasoconstriction • Adrenals Ad l (Z (Z. Gl Glomerlus)l ) Aldosterone release • Posterior pituitary- ADH release • CNS- thirst center

Defect in the kidney's ability to reabsorb p potassium

Liver (Angiotensinogen)release AT-I

Excessive amount of potassium is excreted from the body. This is also known as potassium wasting

Lungs (AT-I is converted to AT-II via ACE)

Hypomagnesemia – due to decreased gastrointestinal (GI) absorption (Diarrhea, malabsorption, diet)

DKA – metabolic acidosis, which causes a switch in H+/K+ pumps leading to K+ leaving the cells and intering the serum.

Not a true hyperkalemia, just ions shifted in the wrong place.

or increased renal loss(diuresis due to alcohol, thiazides and loop diuretics)

Kidneys will Kid ill recognize i the th high hi h K+ and d start t t to secrete it in the urine. (Hyperkalemia to Hypokalemia)

•

Always look a pH first, then HCO3-

• You should be able to differentiate based off of these two

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ACID / BASE Disorders:

For example…

Respiratory PaCO2 ↑

If the patient’s pH is acidic, you should expect that patient’s HCO3- to be low (buffering)

HCO3- ↑ (compensations) HCO3- normal

(non-compensation)

Acidosis A id i Metabolic HCO3- ↓

If not, then the problem has to be

respiratory

PaCO2 ↓ (compensation) PaCO2 normal

(non-compensation)

ACID / BASE Disorders:

Respiratory PaCO2 ↓

HCO3- ↓ (compensating) HCO3- normal

Arterial

(non-compensation)

Alk l i Alkalosis Metabolic HCO3- ↑

Serum

PaCO2 ↑ (compensating) PaCO2 normal

pH 7.3 pCO2 30 mm Hg pO2 95 mm Hg HCO3- 14 mEq/L

What is the diagnosis?

(non-compensation)

Metabolic acidosis Arterial Serum

pH pCO2 pO2 HCO3-

7.3 (ACID) 30 mm Hg 95 mm Hg 14 mEq/L (low)

Check anion gap... Na+ - (Cl- + HCO3-) (N: 8-12 mEq/L) Increased anion gap MUD PILES •M- methanol •U- uremia •D- DKA •P- paraldehyde or phenformin •I- iron tablets or INH •L- lactic acidosis •E- ethylene glycol •S- salicylates

What is the diagnosis?

Metabolic Acidosis w/respiratory compensation

Normal anion gap •Diarrhea •Renal tubular acidosis •Hyperchloremia

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PCT

Diuretics

Acetazolamide, Dorzolamide:

Mannitol:

Ethacrynic Acid (no sulfa) Furosemide (sulfa)

Hydrochlorothiazide (sulfa) Indapamine (no hyperlipidemia)

Intra- Renal

Pre- Renal

Post-Renal

Spironolactone: Amiloride: Triamterene: (no anti-androgenic effects)

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• Volume depletion

Kidneys stop functioning properly: increase in… Creatinine BUN and/ or Decreased urine output… •

Oli Oliguria i : decrease d iin urine i output ( < 400 cc/day) /d )

•

Anuria ( < 100 cc/day)

PreRenal

(inflow to the kidneys)

• • • • •

Dehydration (nausea, vomiting) Burns ( massive) Third spacing (i.e. liver chirossis) Diarrhea Decrease in Aldosterone (Addisons)

• Cardiovascular • Hypotension (CHF) • Coarctation / tamponade

• Decrease in Oncotic pressure • Low Albumin • Nephrotic syndrome • Edematous states ( Cirrhosis)

• Renal Artery Vasoconstriction • Medications ( NSAID's- block PG's, ACE-I) • Anatomical Renal Artery Stenosis

• Decreased Vascular Resistance • Shock

• Intra-renal problems

Pre-Renal

• Drugs ( Gentamicin, Amphoteracin B, Cisplatin) takes 5 to 7 days to damage

BUN/Cr > 20/1

Renal

Urine Na+ < 10

(Kidneys)

FeNa+ < 1%

• Crushing injuries-cell lysis • dipstick positive (NO RBC's)

UOsm > 500

• Thromboembolism, ATN

Renal BUN/Cr < 20/1

PostRenal

Urine Na+ > 20

( out flow obstruction)

FeNa+

• Crystals• Uric acid - tumor lysis • Oxilate stones- antifreeze or malabsorption

Both kindeys need to be affected to see any deficit

> 2%

Low specific gravity (can not concentrate urine)

• Bladder obstruction • Prostate enlargement • Pelvic tumors • Urethral strictures (foley,retroperitoneal fibrosis) • Urethral obstruction • Tumor • Stones

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Post- Renal

Obstruction (hydronephrosis)

Increased post void residual volume

positive orthostatics dry d mucous membranes b increase for thirst rapid heart rate skin tenting (turgor)

Consider (co-morbid) conditions that could lead to their pre-renal problem

For a renal problem (intra-renal)consider drug history

Myoglobin is a normal intracellular proteins: - toxic to the kidneys - intra-renal damage

Knowing the patients drugs could prevent unnecessary test for the patient and time wasted in determining the cause.

If you suspect arteroemboli, look for…

Any recent history of exposure to possible toxins that could be nephro-toxic.

If you suspect a pre-renal problemthe patients usually have

subcutaneous nodules digital ischemia or immobility

With Glomerulonephritis: red cast edema (protein loss) hypertension (renin pathway)

Check the urine (RBC's, WBC's, cast, eosinophils), Electrolytes

If you suspect a post-renal problem, check for…

FeNa+ can destinguish between prerenal and renal problems

prostate disease (Prostitis, BPH, Prostatic CA)

DRE, urinary cath as well as ultrsound can rule out an obstruction

all can lead to an enlarged bladder with pain

radiating to the flanks

Renal biopsy only when the cause of intra-renal can not be determined

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Urinalysis CLUES Attempt to balance fluids and electrolytes

Drug induced hypersensitivity Glomular nephritis

Dialysis if necessarynecessary Hyperkalemia, Hyperkalemia

Metabolic acidosis, Fluid overload, Pericarditis, Encephalopathy

Infection Discontinue medications if they are the cause of the renal disease

Myoglobinuria

Nephrotic syndrome

• RBC cast • WBC's • Bacteria

Uric Acid (Gout) • Crystals

Urinalysis CLUES Multiple myeloma

Eosinophils • (Most common causeCephlosporins)

•

Glomerular Disease: Have you ever noticed, that when you wake up in the morning and urinate, there is a soapy appearance to your urine in the toilet bowl?

• Proteinuria (bence jones)

• Blood dipstick +, but no red blood cells

Why is it, that when a nurse is going to do a morning U/A on a patient, you ask her to get a mid-steam catch?

• Proteinuria > 3.5gm/d • Fat cast

When we look at nephritic or nephrotic syndromes, we need to decide what sets them apart from each other. Aside from a few details, it just comes down to protein loss and the magical number is 3 5g/day 3.5g/day. If less than 3.5 g/day then we name that “Nephritic” and if greater than 3.5 g/day, we call that “Nephrotic.”

Hypertension

Macroscopic / Microscopic hematuria (smokey brown urine)

Oliguria

Edema

Why 3.5 g/day?

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Treat any hypertension, fluid overload and uremia with… Salt and water restrictions, diuretics and if needed, dialysis

24 hour U/A ( best initial test) - look for hematuria, proteinuria If GFR is decrease…think auto immune auto-immune check complement, ANCA and anti-GBM

Renal biopsy (most definitive) - LM, IF, or EM to help in the diagnosis

If the underlying cause is inflammation of the glouerular, the give corticosteroids

1. Post Strep GN 2. Good Pasture GN 3. RPGN 4. IgA Nephropathy 5. Membranoproliferative GN (can be both)

Proteinuria (> 3.5 g/day) Generalized edema Hypoalbuminemia

Generalized Edema

Foamy urine

Ascites

Hypercoagulable state

Hyperlipidemia.

Approximately one-third of all cases are the result of systemic diseases such as DM, SLE, or amyloidosis.

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U/A - proteinuria (>3.5 g/day), lipiduria

Diet restrictions of salt and protein

Blood chemistry- decreased albumin (<3g/dL), hyperlipidemia

Diuretics and antihyperlipidemics If the patient is a diabetic- put them on an ACE-I for it decreases the prograssion of the disease

Always look for secondary causes

Renal biopsy (definitive): LM, IF, EM

Vaccinate (PPV 23)- patients at risk of Streptococcus pneumoniae infections

Nephrotic Syndrome

1.Membranous GN 2.Minimal change disease 3.Focal Segmental GN 4. Amyloidosis 5.Nodular Glomular Sclerosis

Mcc in children: minimal change disease Mcc in adults: membraneous nephropathy Mcc in Blacks and Hispanics: FSGN Fat cast

Block aldosterone Have sulfur in them- anaphylaxis, hapton to RBC’s Angioedema- block C1 esterase inhibitor

Serum Na- dec. , K -inc., pH –dec (hangs onto H+)) S i (

Captopril Lisenopril Enalopril

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Acute Renal Failure

Pa

FLOW

X

Pb

If you increase resistance at X • Pa pressure will increase • Pb pressure will decrease GFR- look at Cr clearance: Renal Blood Flow- assocated with Cr clearance (Lab) use inulin

Renal Plasma flow BUN (lab) use PAH

Flow will decrease throughout

GC

Glomerular cap pressure

Peritubular cap pressure

GFR

Post- efferent

Renal plasma flow Efferent

1. Constrict efferent

2. Dilate efferent

3. Constrict afferent

4. Dilate afferent

A

A

E

E GC

GC

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A

A

E GC

E GC

Glomerula Filtration Rate (GFR)

Rate at which plasma is filtered into bowman’s capsule.

∏ = Oncotic

Units of filtration: (Volume filtered per unit of time) e.g. ml/min, L/day

Decreased in pregnancy, liver failure, over hydration y

GFR = Kf [ (PGC-PBC)-(∏ GC-∏BC)] P= Hydrstatic Inreased in kidney stone, obstruction

Breakdown of bowman’s capsule

PGC is the main factor that determines GFR (promotes filtration)

The negative charge of the filtering membrane inhibits the filtering of proteins [anions ((-)] )]

If the negative charge is not present, significant protein filtration takes place

∏ GC

PGC

PBC opposes filtration Does not affect the rate of filtration, except in obstruction

PBC

Should not be a factor ∏BC

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Filtration fraction (FF) – fraction of material that enters the kidney, that is filtered normally (.20 or 20%)

• • •

Carriers are easily saturated Carriers have high affinity for the substrate Low back leak

The entire filtered load is reabsorbed until the carriers are saturated, then the excess is excreted.

GFR 140 ml/min RPF 400 ml/min .35 or 35% FF Constrict Efferents

Morning glucose is 600 mg/100ml, how much will leave the kidneys?

Tubular Secretion (PAH): (para-amino-hippurate)

120 (GFR) x 6 = 720mg

Secreted from the peritubular capillaries into the PCT.

will be filtered

There are enough carrier to secrete 4 times the amount filtered.

How much will leave in the urine?

If you inject 100 mg of PAH into a patient, how much will be excreted?

(normal carrier Tm 375 mg/min) So urine dipstick will measure

345 mg/min

100 mg (20% filtered and 80% secreted)

Protein Lipid soluble

Inulin Manitol (filtered, not secreted or reabsorbed)

Glucose

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Theoretical volume of plasma from which a substance is removed over a period of time…

Calculate the clearance ? V = 2ml/min Px = 2mg/ ml Ux = 2mg / ml 2 x 2 = 2 ml/ min 2

If the kidneys are too small…

Kidney Pathology

Each kidney measures about 3 to 7 inches

If kidneys too small… Renal Artery Stenosis

If kidneys too large… Polycystic kidney disease Medullary sponge kidneys Medullary cystic kidneys

Renal Artery Stenosis atherosclerosis fibromuscular dysplasia Unilateral Abdominal bruit Low volume state Dx: ultrasound; renal vein renin elevated

( higher renin output indicates stenosis)

Treatment

Goldblat Kidney

Avoid ACE-inhibitors once HTN is severe (AT-II Dependent)

Ipsilateral atherectomy h (or stent if not a surgical candidate) and contralateral nephrectomy

RAS: most common cause of secondary hypertention

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If you have large kidneys… Polycystic

Polycystic Kidney Disease

kidney disease

Medullary sponge Medullary cystic

ADULT TYPE AD

Bilateral, HTN, RF SAH - berry aneurysms

kidneys

▪ In posterior communicating artery ▪ CN 3- blown pupil ▪ Worst headache ▪ Tx: Transplant

kidneys

INFANTILE TYPE AR Unilateral NO HTN NO RF

Medullary Sponge Kidneys

Medullary Cystic Kidneys

Multiple cysts destroy the medulla

Many holes develop in the medulla

Polyuria Polydypsia Low volume state

Polyuria Polydypsia Low volume state

Occasional kidney stone

Multiple kidney stones

Dx: Sonogram (bubbles)

Dx: Sonogram (holes)

Ureters: 3 anatomical narrowings

Kidney stones

Hilum Mid

ureter: caused by going over the iliac bones

Ureteropelvic junction ( where it enters the bladder)

Most common type: calcium

MCC: hypercalciuria

Tx: Normal saline Opiates for pain Thiazides decrease hypercalciuria by forcing the PCT and Loop to increase Ca2+ absorption

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Urease Positive Bugs

Kidney stones

Struvite stones (Staghorn calculus)

Triple phosphate stones

C M NH4 Ph Ca-Mg-NH4-Phosphate h t

MCC: urease positive UTIs

Tx: normal saline; opiates for pain

Proteus Pseudomonas Ureoplasma Nocardia N di Cryptococcus Helicobacter Pylori Staph Saprophyticus Brucellosis

Kidney stones

Kidney stones

Cystine stones

Uric acid stones

CYSTINURIA Cysteine

The only stone NOT visible on xray (radiolucent)

Ornithine Lysine Arginine

Associated with rapid cellular death (burn pt, CA, massive trauma) Tx:

normal saline opiates for pain

AD Coffin lid, enveloped Defective renal transport of amino acids

Tx: normal saline; opiates for pain

Kidney Stones: management

Kidney stones Oxalate stones

IV normal saline Opiates for pain < 5mm (½ cm)

Due to malabsorption in GI tract

When you have malabsorption, calcium gets trapped in the malabsorbed fat (saponification) and do not therefore bind oxalates from proteins breakdown. Oxalate get absorbed in the GI

Can be hexagonal

Let it pass

5mm to 1cm Lithotripsy (whorl pool)

> 1cm Open laparotomy (i.e. struvate)

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Kidney Stones: management -Street- Heroin (short -For

acting)

If pyelonephritis develops: percutaneous nephrostomy stent placement to drain the pus

Dx: KUB; spiral CT; IVP; Sonogram (if with hydronephrosis) Ureteroscopy- if stone is in the middle or lower 1/3 of ureter

withdraws- Methadone (long acting)

-Kidney stones stones-

Morphine

-Abdominal pain-

Meperadine (no contraction of sphincter of odi)

HYDRONEPHROSIS

BPH

Newborns: (1)malimplantation of the ureters (lack 2 90º) (2) posterior urethral valves

Most common cause of urinary obstruction in adult men

Children: UTIs

Obstruction is periurethral (central) : Dx DRE

Adolescents: urethral strictures ( from STDs)

Tx: terazosin or doxazosin (alpha 1 blockers) loosen sphinctor

Adult men: BPH

Adult women: uterine prolapse and cystocele

Tamsulosin (Flomax)- least side effects 2nd line - Fenesteride (block 5 alpha recductase) Sx –TURP (transurethral resection of prostate)

HYDRONEPHROSIS

UNILATERAL Kidney stones

Bladder Allantois develops into…

BILATERAL Retroperitoneal

fibrosis

Urachus develops in the abdomen and descends into the pelvis …

▪ Methysergide (seretonin – Rx for migranes) ▪ Nitrofurantoins

forming the Bladder

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Urachal Cyst

Exotrophy of the Bladder

Urachus retains attachment to the umbilicus

Bladder was caught outside the abdominal cavity

Clue: urine drains from the umbilicus

Predisposes to bladder cancer (MC complication)

Tx: surgery

Risk for bladder cancer persists even after surgery (UA and CT every year)

Tx: surgery

MCC: Atherosclerosis

< 4 cm diameter - control HTN - follow

Location: 90% occur below the renal arteries

Presentation: 1. Ripping, tearing pain down the lower back 2. Pulsating abdominal mass (can only feel if they are thin)

> 6 cm in diameter - control HTN - surgery

Dx: Sono, CT scan

4 – 6 cm (surgery is the doctors call)

Incontinence MCC: 1# Trauma , 2# Collagen disease Presentation: 1. Ripping, tearing pain between the shoulder blades Diagnosis: Spiral CT Treatment: Type A – control HTN, surgery Type B- control HTN, pray (not much connective tissue)

The involuntary loss of urine

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Urge Incontinence

Urge Incontinence, cont

Detrusser muscle activity is increased. A spastic bladder ( UMN lesion) Bladder capacity is low due to repetitive bladder emptying Sphincter pressure is normal Gotta go…gotta go…gotta go

- hourly for 2 to 3 days days, - then every 2 hours for 2 to 3 days, - then every 3 hours for 2 to 3 days, - then every four hours (normal)

Tx: Imipramine (in children) TCA Oxybutynin (in adults) Blocks Ach (M) (to decrease bladder contractions)

Stress Incontinence

Due to weak pelvic floor muscles

Estrogen connection

Any increase in abdominal pressure ( like from sitting down, laughing, coughing, sneezing, etc) causes a sudden loss of urine

Detrussor muscle function is normal

Bladder capacity is normal

Sphincter pressure is decreased

Tx: have patient urinate around the clock beginning with…

Stress Incontinence, cont

MCC: obesity; estrogen connection

Tx: weight loss; Kegle exercises to tighten up pelvic floor muscles Use pseudoephedrine to tighten up the

sphincter (alpha adrenergic) Suggest diapers or panty liners in the

meantime

Overflow Incontinence, cont

Overflow Incontinence

Due to an anatomical obstruction

Detrussor muscle activity is decreased due to stretching

In newborns: posterior urethral valves

Bl dd capacity Bladder it iis iincreased d

In children: strictures

Sphincter pressure is increased

Sx: a weak urine stream; dribbling after urination; urgency; frequency

Causes:

In adult men: BPH In adult women: uterine prolapse and

cystoceles

Tx: surgically remove the obstruction

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Urethra: Penis

Develops dorsal (top) to ventral (bottom)

Fuses from the tip to the base of penis or clitoris

Hypospadia yp p The most common congenital genitourinary abnormality!

Hypospadia ( still zipping)

Located at the base of the penis just next to the anus

Predisposes to UTIs

Tx: surgical correction immediately to prevent UTIs

Circumcision

Inflammatory Problems

Done primarily for cosmetic reasons

UTI argument

Penile cancer argument

Should be done in first 48 hours

Clean by pulling the foreskin up, then clean; pull the foreskin back, then clean

Infections

Phimosis: foreskin is scarred and adherent to the head of the penis

Paraphimosis: foreskin is scarred and adherent to the base of the penis

Ballanitis ( head of the penis ) Staph Aureus

Urethritis ( dysuria)dysuria) infection of urethra Chlamydia Trachomatis # 1 (90% asymp.) Nisseria Gonorrhea # 2 (90% symp. Men)

Tx: urology consult

(50% symp. Women) Actinomyces Israelii

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Infections, cont

Azythromycin 1gm or 2gm (Chlam + GC)

Cystitis: ( urgency and frequency)

Ceftriaxone (250 IM) Cefixeme ( 400 PO) Cefoxitin (250 IM)

Pyelonephritis: ( WBC Casts)- only nephron can form cast

Causes:

Quinolones (400 PO) Ciprofloxacin Ofloxacin Gatifloxacin

E. Coli Proteus Klebsiella Enterococcus: nitrite negative

Nephritis

Casts

Pyelonephritis: WBC Casts; sepsis Interstitial nephritis: drug allergy; collagen vascular disease Glomerulonephritis: RBC Casts; hematuria

WBC casts: nephritis

RBC casts: glomerulonephritis

Eosinophil casts: interstitial nephritis

Fat casts: nephrotic syndrome

Waxy casts: chronic renal failure

Hyaline and epithelial casts: normal findings; represent sloughed off cells, most from the PCT

Crescents: RPGN. Goodpasture’s or Wegener’s

RTAs

Type I: distal H/K exchange is defective

Type II: proximal CA does not work

Urine pH is very high; renal stones; UTIs Urine pH is very high ( distal H/K exchange still

THE END !

works) Can not reabsorb HCO3-

TYPE III: combines the above two

Type IV: hyporenin-hypoaldosterone syndrome

Urine pH is normal

Seen in diabetics; JG apparatus is infarcted

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Embryology of the Brain Primitive Streak Making Connections M ki The Th C i

Notochord Spinal cord

In the first trimester…

Amniotic Fluid

y Notochord: visible by 3 weeks

y 80% of amniotic fluid is filtrate from mom’s

plasma

y Brain: fully formed by 8 weeks

y Fetus SUBTRACTS by swallowing the

fluid y Fetus must absorb and digest the fluid

y Brain is active early with movements,

especially reflexes

y 20% is added by the fetus

y Brain is active in formation of amniotic fluid

y Fetus then urinates the additional fluid into

the sac

Polyhydramnios

Oligohydramnios

y AFI

yRenal agenesis

y Neuromuscular N l disease di

y Urinary outlet obstruction

y Autonomic dysfunction: dry eyes- Riely Day syndrome y Muscle disease: in a newborn – fasciculation- Wernig

Hoffman syndrome

y GI obstruction

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Spinal Cord

Vertebral Arches

y Develops from the notochord

y Fuse ventral to dorsal

y Goes down as far as L-1 or L-2

g at the cervical level y Begins

y End : Conus Medullaris

y Proceeds bi-directionally

y Nerves: Cauda equina

y If child born prematurely, a hole can

y Filum terminalis: anchors

be still present at either end

Lower vertebral arch defects

Upper- vertebral arch defects

y Spina Bifida Occulta

y Anencephaly – no contact to the brain y

Only has the medulla

y

Breath 8-10 ipm

ySpina Bifida Aperta

y Encephalocele

1. Meningocele

y Encephalo-meningocele

2. Meningomyelocele

AFP

y Arnold Chiari Malformation (Type I and II) y Syringomyelia

y Encephalo-meningo-myelocele

Now you need some CSF

How CSF differs from plasma y Less HCO3-

y A filtrate of plasma

y the Choroid y Made by

y More CL-

Plexus in each ventricle

y Lower pH 7.34 (acidic) y Requires Vitamin A y Up to 25 WBCs normal in first month of life normal y Requires Carbonic Anhydrase y >1 month, only up to 3 WBCs normal

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Lateral ventricles >

Vomiting Centers

foramen of Munro > 3rd ventricle >

y Chemotactic Trigger Zone: located on

aqueduct of Sylvius > 4th

the floor of the 4th ventricle

ventricle >

foramina of Lushka & Magendie

y Responds to any increase in ICP

subarachnoid layer >

CSF Flow

spinal canal > dural sinuses >

y Stimulated by dopamine

back into plasma

Vomiting Centers

Hydrocephalus

y Area Postrema: located on the blood

yNon-communicating:

side of the blood brain barrier (BBB)

y due to an obstruction

y Responds to offensive smells or

taste

yCommunicating: y overproduction of CSF

y Stimulated by dopamine

Communicating Hydrocephalus

Communicating Hydrocephalus

y Newborns: mainly premature newborns

y Adults: over ingestion of vitamin A

y Intraventricular hemorrhage

y Pseudotumor Cerebri

y Children: due to inflammation

y Elderly: due to brain atrophy

y Meningitis (posterior fossa) CN 3,

y Normal Pressure Hydrocephalus

9,10,11,12

y Ventricles enlarge

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Normal Pressure Hydrocephalus

Noncommunicating Hydrocephalus y Due to some form of obstruction

y Ventricles expands as the brain atrophies

y In newborns:

y Enlarged ventricles then compress the long midline

y MCC: Aqueductal stenosis

fibers that go to the bladder and legs y Triad:

y 2nd Dandy-Walker cyst

y In children: meningitis, especially TB

y

Dementia Incontinence Ataxia

y

Tx: VP shunt

y In elderly: cancer

y y

y In adults: cancer

The role of CSF

Neurocutaneous Syndromes

y To add cushion for the brain

Sturge Weber Syndrome: yBenign port wine stain- capillaries yOpthalmic branch of CN V yMental retardation ySeizure

y Shock absorption

y Head Injury y Coup lesions y Contracoup lesions – worst than the

coup (brain makes CSF for repair)


Neurocutaneous Syndromes Tuberous sclerosis: benign tumors y AD y Mental M l retardation d i y Seizure y Retinal angiomyolipoma y Cardiac rhabdomyoma y Pancreatic cyst / Coloboma

Osler-Weber Rendu Syndrome ySmall aneurysmal telangiectasia on the h skin k and d mucus membrane b yCauses GI bleeding yPulmonary AV fistula

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Embryology of the Brain


Prosencephalon Æ Telencephalon Æ cerebrum Diencephalon Æ thalami and BG

Von-Hippel Lindau g yCerebellar hemangioma yRetinal hemangioma yRenal cell carcinoma (increased EPO’s)

Mesencephalon Æ

Mesencephalon Æ midbrain

Rhombencephalon Æ Metencephalon Æ pons & cerebellum Myelencephalon Æ medulla

Visual Cortex

Abnormalities of the Eyes y Anisocoria: unequal pupil size

y Light must hit the retina by 3 months of age

y MCC: Congenital (AD) – check parents

or the child is blind for life

y If it occurs in childhood- inc. ICP until proven

otherwise h i – Dx: D CT, CT LP

y You must verify that a child has a RED reflex

y Amblyopia: difference in visual acuity

on eye exam at birth (retinal arteries, and if you can see them- nothing is in the way)

y Lazy eye y Tx: Patch the eye up to age 5 y Weak muscles- CN: 3,4,6

Abnormalities of the Eyes

Vision Correction: y 20/20 – 20/100 (5 times the difference)

y Strabismus: misalignment of the eyes

20 ft. – 4ft

y Isotropia y Exotropia Weak muscles of the eye….. Tx. Patch good eye

y 20/200 legally blind (no drivers license) y can not see details

y Stigmatism: corneal defect y Straight line card (pt will see a blip in the line) y Convex or a concave defect in the cornea y Laser keratotomy

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Abnormalities of the Eyes

Myopia- can not see far away

y My-opia: near sightedness (can not see far) y Focus of light is before the retina y Tx: Concave lens- disperses light

y Hyperopia: far sightedness y Focus of light is behind the retina y Tx: Convex lens- focuses light earlier

y Presbyopia: loss of accommodation seen with aging y Due to muscles weakening with age y Ability to focus on objects coming close

White Reflex

White Reflex

y Cataracts: opacification of the lens

y Retinoblastoma (rare)

y Does not allow light to hit the retina y Must be removed

y Rb gene

y Increased with high or d incidence d hh h glucose l

galactose ( sorbitol or galactitol accumulates)

y Cancer y High association with Ewing’s

y Idiopathic: 90%

sarcoma

y Diabetes or galactosemia y Rubella

Optic Nerve

Visual field deficits

Optic Tract Meyer’s Optic Chiasm Optic Radiation

Calcarine Fissure

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L

R Monocular Visual Loss Optic Nerve

Optic Radiation

L

R

Meyer’s Loop

Monocular blindness

L

Monocular blindness

R

y Newborns: cataracts or retinoblastoma y Children: optic nerve gliomas

Bitemporal Hemanopsia

L

R

y Neurofibromatosis y MEN III

y Adults: embolic phenomena y TIA (Amaurosis Fugax) y Acute retinal artery occlusion y (white retina, macula has its own blood supply) y Acute retinal vein occlusion (bluish retina)

y Elderly: macular degeneration

Optic Chiasm Lesions

y Receives the smallest arteries of the retina - atherosclerosis

L

Optic Chiasm Lesions

R

Contralateral Homonymous Hemianopia

L

R

y Pituitary tumors: 90% y Pituitary sits just beneath the chiasm

y Pineal tumors y Pineal gland sits just lateral to the

chiasm y Circadian rhythm - Responds to light

Optic Tract Lesions

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L

Optic Tract Lesions

R Contralateral Superior Quadrantanopia

L

R

yMcc: M

cancers or tumors

L

R

L

R

Contralateral Inferior Quadrantanopia

L

Contralateral Homonymous Hemianopia with Macula Sparing

R

L

Quadranopsia

R

Frontal Lobe ( Precentral Gyri)

y Can get such a lesion in

y CST (corticospinal tract) motor fibers originates from here

the Optic radiation or Meyer Meyer’ss loop

y Unique information: y Personality – is stored in the frontal lobe

y Pie in the sky

y Abstract reasoning y

(don’t cry over spilled milk)

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Frontal Lobe Lesions

Temporal Lobe

y Atonic seizures- generalized (knock out CST)

y Hearing y Balance

y Dementias

y Hallucinations ( released by serotonin) y PCP y LSD

y Alzheimer's Al h i ' y Pick’s disease

y Schizophrenia: loss of asymmetry y Posterior temporal lobe: Wernicke’s area y Frontal lobotomies

Amphetamines

Amphetamines

y Used in ADD y y y y

y Taken up presynaptically; cause release

of catecholamines

Methylphenidate (use in Narcolepsy) Pemoline Adderal Dexadrine

y OTC for weight loss

y Clue: vertical

y Dexatrim

nystagmus

y Cause hallucinations y LSD y PCP y ECSTACY

SSRI’s

Parietal Lobes y Dominant lobe: long term memory; all the

y Fluoxetine

things you learned since kindergarten y left side is dominant in 90% of right righthanded and left-handed people

y Paroxetine y Luvoxetine Depression, eating disorders y Sertraline

(MAOI- wait a month)

y Nefazadone

y Nondominant lobe: apraxia and hemineglect y Right side is nondominant in 90% of right-

y Trazadone

handed and left-handed people

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Anterior Communicating

Anterior Cerebral

Lateral Pontine Syndrome

Occlusion AICA (anterior inferior cerebellar artery) Posterior Cerebral Superior Cerebellar

CN 7- ipsilateral facial paralysis

Anterior Inferior Cerebellar Posterior Inferior Cerebellar Vertebrals

CN 8- hearing loss

Lateral Medullary Syndrome ( Wallenberg)

Medial Medullary Syndrome

Occlusion of PICA (posterior inferior cerebellar artery )

Occlusion of vertebral artery

Cerebellar peduncle- ipsilateral limb ataxia

Pyramid- contralateral spastic hemiparesis

Descending hypothalamicsipsilateral horners

CN 12- tongue deviates toward the lesion

Nucleus ambiguus- dysphagia

Median Midbrain Syndrome (Weber)

Epidural Hematoma y Middle meningeal artery

Occlusion of posterior cerebral artery

y Fracture of temporal bone

CST- contralateral spastic hemiparesis (upper limb)

y Lucid interval

Corticobulbar tract- lower face (contra)

y Lenticular shape

CN3- eye (down and out)

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Subdural Hematoma

Subarachnoid Hemorrhage

y Bridging vein

y Aneurysm rupture

y Venous bleed

y Worst headache of

their life

y Delayed onset y Shaken baby y Elderly

y Bloody spinal tap

y Crescent shape

THALAMI- SENSORY

Epithalamus

yEpithalamus y The ONLY nucleus with NO known

yThalamus

function

yHypothalamus ySubthalamic Nucleus

Hypothalamus

Thalamus

y Controls hunger y Hunger center: lateral

y ALL SENSORY information in and out of

y Satiety center: medial- 80% NE and 5HT (+)

the brain MUST stop here

y You can override via cortex – stimulus “FOOD”

y Controls menstrual cycle

y ALL information about the ARMS stay

LATERAL

y Controls temperature y Anterior: cools y Posterior: warms

y ALL information about the LEGS stay

MEDIAL

y Controls stress response (NE release)

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Acetomenophen

Stress Response

y Works at the level of the hypothalamus

y Parasympathetic discharge always first y Sympathetic discharge always second

y First, it cools the body (+ anterior hypothalamus) 2nd it resists fever (blocks posterior hypothalamus) h pothalamus)

y Stress ulcers y Curling’s ulcers

y Oxidizes the liver (toxicity) – by destroying bisulfur groups y Treat with n-acetylcystiene ( reducing agent); y the four hour level is the most important factor

y Cushing’s ulcers (triad: bradycardia, HTN, Inc. ICP) y IBS

Subthalamic Nucleus y Final relay station for coordinating

fine motor movements y Lesion: Ballismus and Hemiballismus

Substantia Nigra

Parkinson’s Disease

y Responsible for INITIATING movements

y Loss of DOPAMINE fibers from substantia nigra

to striatum (caudate and putamen)

y Uses DOPAMINE for neurotransmitter

y Unable to initiate activities

y Receives inhibitory signals from basal ganglia via ACH or GABA

y Mask like facies y Bradykinesia y Shuffling gait y Pill rolling tremor y Autonomic dysfunction: Shy Dragger syndrome

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Movement disorder in middle-aged people

Parkinson’s Disease, cont

y Huntington’s disease y y 90% y AD y Trinucleotide repeats y Caudate nucleus involved y Anticipation y Decreased GABA fibers y Treat with DA blockers (they have too much DA)

y Treatment: L-dopa/ carbidopa y 2nd

line: Bromocryptine (dopamine agonist)

y Amantadine (Tx influenza A)- increase DA

release from nerve terminal

y Selegyline (MAO-B inhibitor)- prevent DA

Wilson’s disease y < 10% y AR y Ceruloplasmin def y Copper excess y Lenticular nucleus

involved y Kayser-Fleischer rings y Liver involvement y Treat with penicillamine

breakdown

Internal Capsule

Reticular Activating System (RAS)

y ALL MOTOR fibers going in and out of the brain goes through here

y Maintain FOCUS on one item at a time y Requires NE and Serotonin

y Blood the Bl d supply l comes from f h lenticulostriate l i l i arteries i ( smallest arteries in the brain)

y cAMP second messenger (sympathetic)

y Lacunar hemorrhages: due to HTN y Causes significant MOTOR deficits

y Has a refractory period first thing in the

morning

y BAT D

Sleep cycles

Attention Deficit Disorder

y Beta waves – wide awake (eyes open) y Alpha waves - Eyes close - awake – “not asleep”

y ADD or ADHD (Not focus).

y Theta waves y light waves stage 1 and 2. (Stage 2: K complex and sleep spindles)

y RAS not working y Poor attention and focus

y Delta waves – Deep sleep big– stage 4 all motor activities (teeth

y Restlessness

griding, sleepwalking, enuresis). y y

Night terrors occur Benzos, imipramine inhibts this fase

y Unable to sit long enough to complete a task y Tx: methylphenidate (1st in children);

y Beta waves - Rem sleep. Every 90 min. (REM latency) 5-7 x night y Parasympathetic. Most of the rest. y Dreams, penile/clitoral erection y NE, EtOH, Barbs, Age inhibts this y 5-HT, Ach increase

pemoline; dexadrine; adderal

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Corticospinal Tract y Responsible for fine motor activity y Has to inhibit extension so that smooth flexion can occur

Mid-brain Mid brain

y Spasticity- can not flex y Babinski – extension of toes y Hyperreflexia y Clonus

Corticospinal Tract, cont

CST Pathology

y Fibers originate from the frontal lobes,

yAtonic seizures: depolarization

the precentral gyri

goes across the frontal cortex

y Fibers descend through the internal

yB-12 deficiency

capsule and CROSS at the medullary pyramids

yALS

Increased Intracranial Pressure y First sign: papilledema (optic nerve) y First symptom: headache y Second sign: esotropia (CN VI paralysis) abdusence

y Second symptom: diplopia or blurred vision y Third sign: Sluggish pupils

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If Herniation Continues…

Decorticate Posturing

y Second sign of herniation:

DECORTICATE posturing y Compression has occurred below CN III but above the red nucleus y Red nucleus still makes the upper extremities flex while the legs extend y UNTIL…

The Final Push

DECEREBRATE posturing

y Herniation goes beyond the red nucleus y CST and Corticorubral and rubrospinal

tracts are all lost y All extremities will extend by default y Medulla is pushed through the foramen

magnum. y DECEREBRATE posturing

Dorsal Columns, cont

Dorsal Columns y Vibratory sensation y Two-point discrimination y Position sense y (toe m0vement) y Conscious proprioception

y Gracilis: carries leg fibers; located

MEDIALLY

yCuneatus: carries arm fibers; located

y (eyes closed knowing what he is doing)

LATTERLY

y The only sensory pathway with four

synapses

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Dorsal Columns, cont

Dorsal Column Pathology

y FIRST SYNAPSE: dorsal root ganglion Fasciculus gracilis: ( lower extremities) Fasciculus cuneatus: ( upper extremities)

ySyphilis

y SECOND SYNAPSE: MEDULLA

yBrown-Sequard

yVitamin B-12 Def

y THIRD SYNAPSE: THALAMUS y FOURTH SYNAPSE: parietal lobes y ( postcentral gyri)- ALL SENSORY

Spinothalamic Tract

Spinothalamic Tract

y Pain and Temperature y (opposite all other lesions)

y FIRST SYNAPSE: dorsal root ganglion y SECOND SYNAPSE: thalamus

y The only pathway that CROSSES in the

spinal cord (only one)

y THIRD SYNAPSE: parietal lobes

y Fibers enter the spinal cord, ascend two

y ( postcentral gyri)- Sensory

levels, then cross to opposite side via the anterior white commisure

Spinothalamic Tract Pathology

Spinocerebellar Pathway

y Syringomyelia

y The only pathway in the spinal cord that crosses twice ( equivalent to ipsilateral)

y Responsible for depth perception y Signs of damage: y INTENTION TREMOR (during reach) y DYSMETRIA (heal to shin) or PRONATOR DRIFT y DYSDIODOKINESIS (rapid movement) y ROMBERG SIGN (loss of unconscious proprioception)

P

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Spinocerebellar Pathway Pathology

Spinocerebellar Pathway, cont y This pathway does NOT reach the cortex

y Alcohol attacks the vermis (midline) of the cerebellum

while other diseases attack the hemispheres

y Unconscious proprioception y (don (don’tt have to think about it)

y Fredrieck’s Ataxia-retinitis pigmentosa

y FIRST SYNAPSE: dorsal root ganglion y SECOND SYNAPSE: thalamus

y Ataxia Telangiectasia- spider vein all over your body

y THIRD SYNAPSE: cerebellum

y Adrenoleukodystrophy- defective long chain FA

PONS

Pons – Pathology

y Responsible for responding to the environment

y Locked-in Syndrome

y Contains the

y Central Pontine Demyelinolysis

y PNEUMOTACTIC (superior)inhibitory to the APNEUSTIC (bottom) responds to pO2 dec., pCO2 inc. y CNS area most sensitive to osmotic shifts

Medulla

Make sure you know the cranial nerves !

Midbrain 3,4

yControls ALL basic functions y Respiration of 8-10 ipm

Pons 5,6,7,8 Medulla 9,10,11,12

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You know it’s a spinal cord lesion when…

How Do I Figure Out Any Lesion?

y Pain and temperature loss is opposite to

all other deficits y Level of the lesion is two dermatomes above where pain and temperature loss begins and on the opposite side (Lesion L2- loss at L4)

You know it’s a CNS lesion when… y UMN signs on one side of the body y ( upper and lower extremities)

y Then the lesion is on the opposite side of the brain

Too slow grasshopper !!!!

THE END !

y Use the cranial nerves to locate the level of the

lesion

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Red Blood Cell

Hematology Hasenchecheg Qi MD MD., Ph Ph.D. D

Hemoglobin

Hemoglobin

1. A Hb is composed of:

1). four globins, proteins pair of alpha (a2): located on chromosome 16

1. Hb A

α2β2

m.c.

2. Hb A2

α2δ2

2.5%

δ chain synthesis begins late in the third trimester and in adults

3. Hb F

α2γ2

m.c. in the fetus

small amounts in an adult, may be abnormally elevated in certain forms of anemia

pair of beta (b2): located on chromosome 11. 2). four heme groups, with the iron compound which binds with the O2 2. Hb has 2 forms: T (taut) low affinity for O2 R (relaxed) high affinity for O2 3. Function

4. Hb S

1). In the lungs, each iron on Hb combines O2 reversibly. 2). Each Hb also has attached a single cysteine, which attracts nitric oxide (NO). 3). The enriched Hb circulates to the tissues, where the NO dilates the small capillaries, allowing to deliver O2 to the tissues. 4). Then the O2- and NO–free Hb picks up CO2 and free NO and transports both back to the lungs, where they are exhaled as waste.

sickle-cell hemoglobin

5. Hb H

β4

An abnormal Hb is not effectively transport O2, it is usually associated with a α-thalassemia syndrome.

6. Barts

γ4

An abnormal Hb that is not effective in O2 transport, found in α-thalassemia.

5). When RBC are destroyed the hema (iron) is stored in the liver for the manufacture of new red blood cells. Globins is converted into bile and stored in the gall bladder

Anemia

Heme Synthesis (mitochondria) Sideroblastic

Hb <11 mg/dl MCV < 80

MCV (80—100)

1. Thalassemia

4. Lead Poisoning 5. Sideroblastic anemia 1. Sickle Cell Disease 2. Hemaglubin C Disease 3. G-6-P-D deficiency 4. Thelassemia Major 5. PNH

δ-Aminolevulic acid

1. B12 deficiency

Reticulocyte

2. AOC 3. Iron deficiency anemia i

ALA Synthase

MCV > 100

> 2.0% high

1. Marrow failure

ALA dehydrase

3. Myelofibrosis 4. Ca matastasis 5. AOC 6. Renal failure

Prophobilinogen

3. Alcoholic Liver disease

Uroporphyrinogen-I

4. Drug induce

2. Aplastic Anemia 1. All the hemolytic anemia

Uroporphyrinogen-III

Extravascular

synthase Acute Intermittent Porphyria

2. All the autoimmune anemia

Protoporphyrin IX (protoheme) Fe2+

Intravascular

+ B6 Lead (Pb)

2. Folate Deficiency < 2.0 %Low

Anemia

Rate limited

Glycine + Succiny CoA

Hereditary Spherocytosis

Iron Deficiency Anemia

Ferrochelatase

Lead (Pb)

Heme

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Microcytic Anemia

Microcytic Anemia

Sideroblastic Anemia

Lead Poisoning

cause

Symptoms

Acute Intermittent Porphyria

Porphyria Cutanea Tarda

1. decrease Vit B6 (m.c.)

1. Lead Line: in gums

2. isoniazid therapy

2. CNS : Encephapathy,

Uroprophyrinogen-1 Synthase deficiency

Uroprophyrinogen decarboxylase deficiency

3. Abdominal pain (lead colic)

Clinical Feature

Clinical Feature

1. AD, variable expression

1. Photosensitivity

2. acute abdominal p pain multiple laparoscopies (scars on abdomen)

2. blistering g of skin

4. PNS: wrist and foot Drop Diagnosis:

Diagnosis:

1. BM: ring sideroblast (most specific test) An erythroblast containing granules of ferritin

1. blood lead level > 10 µg/dl

2. Lab

3. basophilic stippling (remnants of RNA) :

Treatment

Treatment

Pyridoxine

succimer (PO), EDTA

3.psychotic changes

2. increase free erythrocyte protoporhyrin

4. increase ALA and PBG (prophobilinogen) 5. no photosensitivity 6. Contraindicate: barbiturate

Anemia of Chronic Disease (AOCD)

Anemia of Chronic Disease (AOCD) Definition

Lab

1. Iron being trapped in bone marrow macrophages, causes inability to use of iron in stores.

1. serum ferritin elevated 2. serum iron low

2. long term chronic disease cause decreased liver functions,

1. decrease protein synthesis 2. Transferrin low = TIBC low

Treatment

reticuloendothelial system

3. reticulocyte count low lo

3. It can be microcytic or normocytic

Iron deficiency Anemia

Iron deficiency Anemia Cause

1. decrease intake or Increase demand

elderly, children, pregnant women

2. decrease absorption: (malabsorption)

1) decrease acid (Vc) 2) Dumping Syndrome: decrease small intestine transit time 3) after gastrectomy

3. chronic blood loss ((m.c.))

1) GI Ca (m.c. in USA) 2) GYN bleeding 3) Hookworm (m.c. rest of the world)

Sequence event due to iron deficiency:

1. decrease storage iron in intestinal mucosa, spleen, and liver

Decrease ferritin

2. decrease circulating iron

Decrease serum iron Increase TIBC

3. formation of microcytic/hypochromic anemia

Decrease RBC size

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Iron deficiency Anemia

Symptoms

1. General 2. others

Terminology

Low energy state, pallor of skin and nails, 1. Koilonychia: spooning of the fingernails

1. Hb

Hemoglobin

F12-15 g/dl, M 13-16g/dl

2. Pica Lab

Hb, MCV, Ht

Decrease

2. Ht (Hct)

Hematocrit % of RBC in the blood

40 --50%

RDW

decrease

3. MCV

mean cell (corpuscular) volume

80—100

Serum iron

decrease

4. MCH

mean cell hemoglobin

25.4—35 pg/cell

5. MCHC

mean cell hemoglobin concentration

31—36 g/dl

6. RDW

red cell distribution width (A measure of the variation in size of red blood cells)

6—12%)

7. Reticulocyte

immature RBC (1 day, normal 1.5%)

Transferrin (TIBC) increase ferritin microscope

Diagnosis Treatment

decrease

microcyte anisocytosis

abnormal size

poikilocytosis

abnormal shape

1. depend on lab 2. definitive Dx: bone marrow

< 1%, poor bone marrow response

1. diet

> 1%, good bone marrow response

2. ferrous sulfate tablets

Bluish color (polychromasia) due to free ribosome RNA

3. parenteral iron 4. blood transfusion: most effective

Terminology serum iron

100mg/dl

Ferritin

1. physiological storage iron form 2. intestinal mucosa, spleen, and liver

Hemosiderin

1. degraded ferritin + lysosomal debris 2. Prussian blue positive

Transferrin

A beta globulin in blood serum that combines with and transports iron.

Total iron-binding capacity (TIBC):

1. means transferrin level 2. Transferrin = TIBC = 300 mg/dl

% saturation of transferrin

serum iron/TIBC = 1/3

Go Back

decrease decrease normal

increase

serum ferritin

decrease

increase normal

increase

TIBC

increase

decrease normal

decrease

decrease normal

increase

B12 Deficiency Anemia

2. Decrease absorption

Thalassemia Sideroblastic minor anemia

serum Iron

% decrease saturation

B12 Deficiency Anemia

Causes 1. Dietary deficiency

Microcytic Anemia Iron AOCD deficiency

Diagnosis 1. B12 in red meat and fished

1. peripheral smear

Macroblastic anemia, hypersegmented neutrophils

3. strict vegetarians, alcoholism

2. anti-IF: initial test

sensitivity 50-80% , specificity 100%

1. decrease IF, gastrectomy or pernicious anemia

3. serum homocysteine Due to folate or B12 deficiency increase

2. B12 stores at body for more than 1 year supply.

2. Pancreatic insufficiency 3. intestinal malabsorption a. p parasites: fish tapeworm p diphyllobothrium p y latum b. bacteria: blind-loop syndrome c. Crohn’s disease

4. increase methylmalonic acid

only due to B12 deficient

5. Schilling test:

Sign and symptom

over the 24 hours, a normal result shows at least 10% of the oral intake radioactive vitamin B12 will be in the urine.

1. beefy tongue due to generalized epithelial atrophy

i. B12 injection + radiolabelled B12 orally

2. peripheral neuropathy

ii. B12 injection + radiolabelled B12 orally + IF

3. SCDSD: (Subacute combined degeneration of the spinal cord) ii. demyelination of the posterior columns and lateral corticospinal tracts and spinocerebellar tracts iii. Urinary and fecal incontinence, impotence iv. Dementia

Treatment

Treatment

B12 oral Or parenteral

After give B12, may develop hypokalemia in 48 hrs, because potassium rapidly go into cells

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Autoimmune Hemolytic Anemia (AIHA)

Folate Deficiency

Go Back

Warm AIHA

Folate Deficiency

Cold AIHA

Mechanism

antibodies initiate The IgG attach to a RBC, complement lysis of leaving their FC portion sticking out. The FC is red blood cells recognized and grabbed onto by monocytes and macrophages in the spleen.

Antibody

1. IgG to Rh type 2. IgA

1. IgM

Cause

1. Methyldopa 2. Penicillin

1. Quinidine

1. serum homocysteine increase: due to both folate and B12 deficiency

coomb’s test +

IgG, or IgG + C3

C3

Treatment

Cold agglutinin

negative

positive

Treatment

1. steroid 2. splenectomy 3. treat causes 4. Cyclophosphamide

1. Cyclophosphamide 2. Chlorambucil

1. contain in green leaves vegetable 2. 3 month supply Cause by 1. cause by “tea and toast” life-style 2. Methotrexate 3 Ph 3. Phenytoin t i 4. Pregnancy Lab

Folic acid

Hereditary Spherocytosis

Normocytic Anemia Intravascular (SH GTP)

Extravascular

Definition

Microangiopathic Hemolytic Anemia

increase methemoglobin (oxidized hemoglubin) Rx; methylene blue

no methemoglobin 1. increase shictocytes (fragmented RBC) 2. Helmet cell

markedly decrease haptoglobin

decrease heptoglobin

1. Sickle Cell Disease 2. Hemaglubin C Disease 3. G-6-P-D deficiency 4. Thelassemia Major 5. PNH

Hereditary spherocytosis

2. defect spectrin in RBC membrane Clinical feature

1. splenomegaly

Lab

1. increase spherocytes

2. increase risk for acute aplastic crisis with Parovirus B19 infection 2. normocytic hyperchronic 3. increase MCHC 4. increase osmotic fragility

1. DIC 2. TTP 3. HUS 4. Prosthetic Heart Valve 5. HELLP

Rx

Sickle Cell Disease Sickle Cell Diasese

Hemoglobin C Disease

single nucleotide change in codon casues valine (neutral) to replace normal glutamic acid (acidic) at 6 position of the β-globin chain

single nucleotide change in codon causes lysine (basic) to replace normal glutamic acid (acidic) at 6 position of the βglobin chain

Hemoglobin S

Sign:

1. become less soluble under decreasing oxygen concentrations

1. splenomegaly

Sickle Cell Disease Affecting factors

1. increase concentration (dehydration), make it worse decrease concentration make it better 2. Decrease pH decrease oxygen affinity: worse 3. increase HbF: better

Increase RBC destruction cause

2. target cell 2. The deoxygenated molecules form rigid rods called polymers into crystals that distort the red blood cells into a sickle shape. 3. These abnormally sickle-shaped cells are both rigid and sticky.

1. AD,

1 Erythroid hyperplasia 1. 2. increase bilirubin

3. rod-shaped crystals in RBCs

Genitic types 1. heterozygous (AS): trait blood urine and resistance to malaria 2. Homozygous (SS):Sickle cell disease

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Sickle Cell Disease

Vaso-occlusion

1. Hand-foot syndrome (dactylitis)

1st sign of SD, in children

2. Vaso-occusive (painful) crisis

Rx: 1. Self –limiting, last 2-7 days 2. hydration: NS 3. Morphine for pain 4. keep warm 5. Oxygen

3. Autosplenoectomy

1. Howell-Jolly bodies in peripheral blood: remnantt off nuclear l chromatin h ti 2. increase infection of encapsulated organisms, Rx: vaccinations

4. Leg ulcers

increase Salmonella osteomyelitis (leg pain)

5. Avascular necrosis of the joints

M.c. hip, 2nd shoulder

6. Priapism

Emergencies, Rx: transfusion

7. Acute chest syndrome

Emergencies, Rx: transfusion

8. Aplastic crisis

with infection of B19, Rx: folic acid

Treatment

1. Hydroxyurea; increase HbF 2. BM transplantation

G-6 PD Deficiency

Thalassemia Syndrome

G-6 PD Deficiency

Definition: quantitative, not qualitative, abnormalities of hemoglobin

G-6 PD deficiency causes decrease glutathione peroxidase (antioxidant) Clinical Feature 1. X-link R i. African American type: ii. Mediterranean type 2 H 2. Heinz i b bodies: di oxidation id ti off h hemoglobin l bi

1. α-thalassemia

2. β-thalassemia

1. decrease α-globin chains , excess β-chains

1. decrease β-globin chains, excess α-chains

2. most commen in Asian population

2. most common in Mediterranean

3. expression in prenatally and postnatally

expressed postnatally only

3. Bite cell: to eat heinz bodies by splenic macrophages Treatment

α-Thalassemia Genetic Normal

4 α-chain (αα/αα)

Silent carrier

1. deletion 1α-chain 2. (-α/αα),

α-Thal trait (minor)

deletion 2 α-chain

Genetic 1. β-Thal minor

1. deletion 3 α-chain 2. (--/-α)

Hydrops fetalis 1. deletion 4 α-chain, 2. lethal in utero (--/--)

1. normal: 2 β chains, 2. point mutations,

asymptomatic, increased HbA2 or HbF

2. β-Thal intermedia a severe anemia, but no transfusions needed 1. Genotype: cis (--/αα) type in Asian

3. β-Thal major (Cooley Syndrome)

1). normal at brith 2). develop at about 6 month as HbF decrease 3). severe hemolytic anemia a. increase bilirubin, gallstones b. Congestion heart failure is most common cause of death 4). Erythroid hyperplasia in BM: x-ray: “crewcut” skull , “chipmunk” face 5). Peripheral in the blood: Numerous target cells

Treatment

1. do not require specific treatment 2. β-major: blood transfusions 1 or 2 / month: SE: Hemochromatosis, treat with deferoxamine 3. splenectomy eliminates severe hemolytic anemia: 4. Bone marrow transplantation

2 G 2. Genotype: t trans t (-α/-α) ( / ) type in African-American Hb H disease (major)

β-Thalassemia

1. increase Hb H, 2. forms Heinz bodies increase barts Hb

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PNH

Summery

Paroxysmal Nocturnal Hemoglubinuria decreased glycosyl phosphatidyl inositol (GPI) linked proteins, especially decay accelerating factor (DAF) Function of DAF: 1. inhibit the activation of the complement cascade by breaking down C3 convertase 2. decrease O2, trigger complement pathway

RBC shapes

Diseases

Anisocytosis

Iron deficiency anemia

Poikilocytosis


Shperocytes

1. hereditary spherocytosis

Target cells

Thalassemia, Hb C disease, Liver Disease

Symptoms and Complication

Bite cell

G6PD deficiency

aplastic anemia, leukemia, venous thrombosis

Teardrop cells

Myelofibrosis

Diagnosis

Elliptocytes

Hereditary elliptocytosis

1. Ham’s test (Acidosis in vitro)

Acanthocytes

abetalipoproteinemia

2. sucrose lysis test (sugar water test)

Echinocytes (burr cells)

uremia

Schistocytes (Helmet cells)

HUS, DIC, TTP

Rouleaux

Multiple myeloma

3. flow cytometry: CD55, CD59, much more sensitive and specific Treatment 1. Glucocorticoids 2. BM transplantation

Summery RBC inclusions Basophilic stipling

Cytoplasmic remnant RNA

Lead poisoning

Howell-Jolly Ho ell Joll bodies

Remnants of nuclear n clear chromatin

Iron deficienc deficiency anemia

Other types Anemia

Diseases

1. Diamond-Blackfan Syndrome: congenital pure RBCs anemia 2. Fanconi anemia (Constitutional) pencytopenia with abnormal structures

Ring sideroblasts

Iron trapped Sideroblastic anemia abnormally in mitrochondria forming a ring around nucleus Heinz-bodies G6PD

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Hemostasis Bleeding g Disorder

3:1 = M:E (myeloid to erythroid) ratio.

Hasenchecheg Qi MD., Ph.D.

Hemostasis 1. vascular wall injury

Bleeding

1. bleed 2. transient vasoconstriction

changes blood flow cause turbulence and stasis Reynolds number = (diameter) (velocity) (density)/viscosity > 2000 = turbulent flow < 2000 = laminar flow

3. thrombogenic factors 1. release tissue factor, activate VII ((extrinsic) ti i ) 2. active factor XII (intrinsic) due to expose subendothelial collagen 3. release vWF

Hemostasis

2. transient clotting

platelet clotting

bleeding time 2—7 min

3. Secondary clotting

Extrinsic Coagulation factor

PT: Prothrombin Time 12sec

Intrinsic Coagulation factor

PTT: Partical Throboplastin Time 30sec

Platelets

1. platelets adhesion

Coagulation Factors

1. vWF adheres to subendothelial collagen 2. Platelets adhere to vWF by glycoprotein Ib

2. platelets activation

Adhesion

1. platelets changes shape and degranulation

Aggregation

2. synthesis of TXA2 3. platelets 1. ADP aggregation clopidogrel, Ticlopidine

ADP

2. TXA2

Vitamin K

3. GpIIb/IIIa Abciximab, Eptifibatide, Tirofiban

‫ ץ‬Glutamyl Carboxylase

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Bleeding Disorder Platelet

Thrombomodulin (transmembrane protein) + Thrombin (60 hrs) Protein C

150,000—450,000/mm3

bleeding time: 2—7 min

1. Decrease Platelet account 2. Abnormal Platelet function 3. Von Willebrand Disease (vWD)

C-activated protein

(Half life 14 hrs)

AD/AR, vWF

+

attributed to Factor 8 deficiency

Protein S

Wafarin:

1. bleeding time prolong 2. ristocetin 3. PTT prolong Rx: Desmopressin acetate (DDAVP)

Transient deficiency of protein C

Inactivates Factor V leiden: variant of factor V

Factors Va and VIIIa

4. Bernard-Soulier Syndrome

Gp Ib deficient

Rx: Platelet

5.Glanzmann Thrombasthenia

Gp IIb/IIIa deficient

Rx:

Thrombocytopenia

Thrombocytosis

Immune Thrombocytopenia Purpura

Thrombotic Thrombosytopenia Purpura

Hemolytic Uremic Syndrome

Disseminated Intravascular Coagulation

Thrombocytosis (reactive)

Essential Thrombocythemia (ET)

1. anti-platelet

Fever Anemia Thromcytopenia

Diarrhea Renal failure

1. D-dimers

Cause

Clinical Features

2. Platelet count decrease

1. Bleeding, hemolysis

1. Increased platelet count

2. Inflammation

2. increased BT

3. Iron deficiency, Stress

3. increased BM megakaryocytes

2. Increase BM megakaryocyte 3. acute form: child after viral infection

Renal failure

3. Bleeding time increase

4 chronic: adult 4. women 20-40 yo

Neuropathy

4 PT and PTT increase 4.

Treatment

Treatment

Treatment

Treatment

1. child self limited in 6mo, or prednisone

plasmapheresis

1. adult: plasmapheresis

1. supportive

2. child: self limited

2. FFP 3. Cryoprecipitate 4. treat causes

2. adult a. prednisone b. IVIG, anti Rh (D): fast c. splenoectomy, Vaccine d. platelet transfusion

4 postsplenectomy 4. t l t 5. Malignancy

Disorder of Coagulation

von Willebrand’s Disease

Hemophillia A

Hypercoagulation

Hemophillia B

vWF deficiency,

VIII deficiency,

IX deficiency,

1. XII deficiency

Thrombosis, no bleeding

PTT prolong,

AD/AR,

XR,

XR,

2. XIII deficiency

Normal PT and PTT

May have VIII deficiency

vWF normal

Clinical Feature

Clinical Feature

Rare, newborn bleeding from cut umbilical cord

1. Cutaneous and mucosal bleeding

1. joint and soft tissue bleeding

3. Antithrombin (AT) III deficiency

Thrombosis

PTT prolong

4. Antiphospholipid antibody Syndrome

Thrombosis Recurrent abortion

PTT prolong

Di Diagnosis i

5. Factor V leiden

Leiden variant of factor V, (Activated protein C resistance)

recurrent DVT

6. Protein C Deficiency

Active Factors Va and VIIIa

1. dermal vascular thrombosis 2. skin necrosis

2. Menorrhagia,

2. Hemarthrosis: m.c.

3. GI bleeding

3. Intracranial bleeding: 2nd m.c.

Di Diagnosis i

Di Diagnosis i

1. BT increase, may with increase PTT

1. PTT increase

1. PTT increase

Treatment

Treatment

Treatment

Do not give Aspirin/NSAIDs 1. DDAVP (desmopressin)

1. factor VIII

2. Factor VIII concentrations, give all Pt with vWD after major trauma or during surgery

2. FPP not recommended because virus infections

(reduced ristocetin-induced platelet aggregation)

1. factor IX

Dx. Clot solubility test in 5M urea, positive

Rx: life-along anticoagulation (Warfarin)

7. Protein S Deficiency

Treatment of Acute hemarthrosis 1. Analgesia, (Codeine) 2. Immobilization 3. Synovectomy (arthroscopic) or radiosynovectomy for severe and recurrent hemarthrosis

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Streptokinase

+

Urokinase Alteplase (tPA) Reteplase (rPA)

Plasma: no cells from blood

Anistreplase

Serum: no coagulation factor from plasma. include all the ion and antibodies, immunoglobulin.

Heparin

Thrombolytics

Anticoagulation Medications LMWH

Warfarin

Low-Molecular –Weight Heparin

VIt K antagonist

Inhibit IIa and Xa

Mostly inhibit Xa

Inhibit II, VII, IX, X, and protein C and S

Half-lift time

Half-lift time

Half-lift time

1 hour

3-24 hours

4 days

Administration

Administration

Administration

1. therapeutic dose: IV heparin, monitor PTT

1. subcutaneously PTT monitor not necessary

1. orally: monitor PTT, Monitor INR (2-3)

SE and Advantage

2. prophylactic dose: SC low-dose low dose heparin heparin, PTT monitor not necessary SE and Advantage

SE and Advantage

1. Bleeding

1. easer use out Pt

1. Hemorrhage

2. Heparin-induced thrombocytopenia (HIT)

2. no HIT or osteoporosis

2. skin necrosis ( decrease protein C)

3. Osteoporosis

4. no osteoporosis

3. Teratogenic during pregnacy

4. Transient alopecia

5. more expensive

5. rebound hypercoagulability d/t depression of ATIII SE Treatment

SE Treatment

1. stop medication, 2. Give PPF, 3. Warferin over dose may also give Vit K

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Lymphoma & L k i Leukemia

3:1 = M:E (myeloid to erythroid) ratio.

Hasenchecheg Qi M.D.; PH.D.

Lymphoma

Lymphoma

Non-Hodgkin Disease Precursor B-Cell

Precursor T-Cell

ALL

T-ALL

< 15 year old

Thymoma

Positive TdT

< 25 years old

Mature B cell

HD

Plasma Cell Neoplasma

Mature T cell

1. Multiple myeloma 2 MGUS (Monoclonal Gammopathy 2. undetermined significance)

Non-Hodgkin Disease

Not B-cell Not T-cell

1. L1 2. L2 3. L3

1. not infections

chronic lymphocytic leukemia, or small lymphocytic lymphoma

2. “owl-eye”

2. Hairy cell leukkemia

1. Follicular Lymphoma

1. m.c. non non-HD HD 2. t (14, 18)

2. Diffuse large Bcell lymphoma

1. EBV 2. HHV-8

3. Samll noncleaved lymphoma (Burkitt lymphoma)

1. starry-sky 2. t (8, 14)

4. Mantle Cell Lymphoma

T (11, 14)

Dx: TRAP +

3. R-S cell

Rx: 2CDA

1. ATLL

Tartrate-resistant acid phosphatase

2. MF and Sezary S. 1. NS: m.c. Lacunar cell

Acute Lymphoblastic Leukemia

Mature B cell

1. CLL: m.c.

3. Waldenstrom macroglobulinemia Terminal Deoxynucleotide transferase

HD

If > 65 years old

2chlorodeoxyadenosine

2. LP: popcorn cell 3. LD: most RS cell 4. Mixed: eosinophils, IL-5

5. MALToma (Marginal zone Lymphoma)

18: bcl bcl-2: 2: inhibits apoptosis by blocking the bax channel

8: c-myc

11: bcl-1 (cyclin D) Treat as H.pylori

Leukemia AML BM blast > 30%

MDS BM blast <30%

Myeloproliferative Syndrome

CML

P. vera

ET

MF

1. M0—M4: myelo-, WBC 2 M3: 2. M3 t (15 (15, 17) 15: PML 17: retinoic acid receptor α-gene (RAR-α)

1 t (9 1. (9, 22) 9: c-abl

1. Dry tap 2. Teardrop RBC

22: bcr 2. LAP low

3. M5: monoblasts 4. M6: erythroblasts 5. M7: megakaryocytes

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Biochemistry: Week Three

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250262

Three sources of energy • Proteins • Fats • Sugars

BIOCHEMISTRY AMINO ACIDS

AMINO ACIDS

Proteins The main intracellular buffers

An Acid

A Base

Pka is less than 7

Pka is greater than 7

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An Acid • • • • •

A Base

Dissociates early Likes to give up hydrogen ions (protons) Pka is less than 7 Strong acid: Pka 1 to 3 Weak acid: Pka 4 to 7

• • • • •

Dissociates later Likes to accept hydrogen ions (protons) Pka greater than 7 Weak base: Pka 7 to 9 Strong base: Pka greater than 9

Three Easy Words That are Hard To Understand • Dissociate: to lose a hydrogen (proton) • Soluble: charged or polar • Bioavailable: neutral

Pka 4 to 9… Can be a weak acid or a weak base

Dissociation

Dissociation To Lose A Hydrogen

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Soluble

Soluble Charged Or Polar

Soluble

Bioavailable

Water Soluble

Bioavailable

Bioavailable

Neutral

Fat Soluble

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As an acid dissociates…

AMINO ACIDS

• It gains a negative charge • It gains solubility • It loses bioavailability

As a base dissociates…

Henderson-Hasselback Equation

• It loses its positive charge • It loses solubility • It gains bioavailability

ACIDS

Henderson-Hasselback Equation

• IF you want to absorb more… – Add more Acid

• IF you don’t want to absorb it… – Add base

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Base

Acids you need to know

• IF you want to absorb more…

• • • •

– Add more base

• IF you don’t want to absorb it… – Add acid

Aspirin Barbiturates Myoglobin TCAs

Bases you need to know • Amphetamines

The main acid used in medicine NH4CL

Now we look at the ISOELECTRIC POINT

The main base used in medicine HCO3

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Isoelectric Point • NO NET charge on the molecule • Also called a zwitterion • Will NOT migrate towards anode or cathode

Cathode

Anode

Where CATIONS go: the negative electrode

Where ANIONS go: the positive electrode

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To further categorize the amino acids…

PHE, TRP, TYR

Glycine • Smallest amino acid • NO chiral carbon • Inhibitory neurotransmitter for the spinal cord

• Aromatic amino acids • Recognized by chymotrypsin

LYS, ARG

Asp, Glu

• Basic amino acids • Have a positive charge • Recognized by trypsin

• Acidic amino acids

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Asp

Cys, Met

• The only excitatory amino acid in the brain ( NMDA pathway)

• Contain sulphur • Make disulphide bonds

Asparagine, Glutamine

Serine, Threonine, Tyrosine

Involved in N- bonds

Involved in O- bonds

Leu, Iso, Val

Tyr

• Branched chain amino acids

• Used to make catecholamines • Used to make melanin

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Trp

Ketogenic Amino Acids

• Used to make serotonin

• Lysine • Arginine

Glucogenic Amino Acids

Both glucogenic and ketogenic • • • •

PHE ISO THR TRP

• ALL OTHERS

Essential Amino Acids

Essential Amino Acids

• You get them ONLY from the diet • NO cycle in YOUR body can make these • A deficiency will ALWAYS lead to a disease • Deficiencies put the body into a starvation state

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How does the body utilize energy during starvation?

Energy Utilization • • • • •

Notables

(1) plasma glucose: lasts 2 to 4 hours (2) liver glycogen: lasts 24 to 28 hours (3) proteolysis for gluconeogenesis (4) lipolysis (5) ketogenesis

Phenylketonuria

• PHE used to make TYR

• Phenylalanine hydroxylase is deficient • Unable to make tyrosine

– TYR becomes essential if PHE is deficient

– Unable to make DA and NE and EPI

• MET used to make CYS

• Unable to make melanin without tyrosine – Blonde hair; blue eyes; fair skin

– CYS becomes essential if MET is deficient

• Phenylacetate and phenylpyruvate build up – Musty odor

PKU

Newborn Screening

• Must screen all newborns at 48 hours • Must avoid aspartame (nutrisweet) • Pregnant mother must be on restricted diet especially during first 8 weeks while brain is developing • Rainbow colored wheel on food products would warn these patients against aspartame

• • • • •

PKU ( Guthrie test) Hypothyroidism (TSH) CAH Biotinidase def Galactosemia

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Albinism

Vitiligo

• Tyrosinase deficiency • Predisposed to skin cancer

• Autoimmune antibodies against melanocytes • Loss of pigmentation • Predisposed to skin cancer

Alcaptonuria (ochronosis)

Maple Syrup Urine Disease

• Homogentisic acid oxidase deficiency • Tyrosine builds up • Urine turns black when exposed to air

• Involves branched chain amino acids • Defective renal transport of these amino acids • LEUCINE • ISOLEUCINE • VALINE

Cystinuria • Defective renal transport of amino acids • Hexagonal, envelope shaped, or coffin lid shaped crystals in the urine • CYSTIENE • ORNITHINE • LYSINE • ARGININE

THE END TO BE CONTINUED…

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Protein Structure • • • •

Protein Structure and Function Putting the Amino Acids Together

Protein Structure • • • •

Primary Secondary Tertiary Quarternary

Primary Structure

Primary Secondary Tertiary Quarternary

• The amino acid sequence • Involves peptide bonds • Restriction enzymes are used to sequence proteins

Peptide Bond

Peptide Bond • Planar • Restricted mobility • R-groups are in trans-configuration

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Sequencing Before we understand the present… We need first visit the past!

Acid Hydrolysis

The history of sequencing • • • • •

Acid hydrolysis Gel electrophoresis Ninhydrin reaction Edman’s degredation Restriction peptidases

• Denatures the protein • Does NOT actually sequence the protein • Turns asparagine into aspartate (acidic form) and glutamine into glutamate (acidic form)

Gel electrophoresis

Gel Electrophoresis

• Uses agarose gel to separate proteins by size first, charge second • Smaller proteins migrate further • Larger proteins stay closer to the start site • Does NOT sequence the proteins

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Ninhydrin Reaction

Edman’s degredation • Uses phenylIsoThioCyanate (PITC) • Reacts with ANY amino acid starting on the amino terminal • Amino acids are identified by spectrophotometry (light transmission)

• Reacts with all amino acids creating a purple color • Proline reaction creates a yellow color • Good ONLY for counting prolines

• Procedure is accurate ONLY up to 100 amino acids

Restriction Peptidases

Restriction Peptidases

• Restricted by what amino acids they can recognize • Used to actually sequence proteins

• Trypsin: cuts to the right of LYS and ARG • Chymotrypsin: cuts to the right of the aromatic amino acids, PHE, TRP, TYR • Elastase: cuts to the right of GLY, ALA, SER • CNBr: cuts to the right of MET • Aminopeptidase: cuts to the right of the amino terminal amino acid

Restriction Peptidases, cont

An Example

• Carboxypeptidase: cuts to the left of any amino acid on the carboxyl terminal • Mercaptoethanol: breaks up disulfide bonds

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Secondary structure

Alpha helix

• Alpha helix • Beta pleated sheet

Beta pleated sheet

Serum proteins • Functional • Acute phase reactants

Too many proteins in your plasma • Elevated ESR or CRP

TOO many acute phase proteins…

– Indicates nonspecific inflammation

• Falsely high ESR: anemia • Falsely low ESR: sickle cell anemia; polycythemia • Acute phase reactants caused by IL-6

Leads to AMYLOIDOSIS

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AMYLOIDOSIS

Secondary Amyloidosis

• Primary: autosomal dominant

• • • • •

– Massive intracerebral hemorrhage in a young person with no prior h/o HTN

• Secondary: due to any chronic inflammatory disease

AA: chronic inflammatory disease AB: Alzhiemer’s disease AB-2: Chronic renal failure AE and AF: MEN-II AL: Multiple myeloma

• Congo red stain • Apple green birefringence

Tertiary Structure

Quarternary Structure

• 3-D structure • Most important factor is hydrophobic and hydrophilic interactions • Covalent bonds now form

• Two or more proteins are interacting • Cooperativity • Allosterism: refers to enzymes – Allosteric enzyme means the slowest enzyme; means rate-limiting enzyme; means the kinetic curve is sigmoidally shaped

Hemoglobin • Type A: 2 alpha – 2 beta chains

Hemoglobin

• Type A-2: 2 alpha – 2 delta chains

The first quarternary protein discovered

• Type F: 2 alpha – 2 gamma chains

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Hemoglobin F • • • •

Hemoglobin F

Found in the fetus Disappears by 6 months of age Has a low affinity for 2,3, DPG Has a high affinity for oxygen

Erythropoiesis

Heme Synthesis

• Begins: in yolk sac at 4 months gestation • 6 mo gestation: moves into the liver, spleen, and flat bones • 8 mo gestation: moves into the long bones • 1 year of age: liver, spleen, and flat bones close • If you lose the long bones after 1 year, the spleen can reopen causing massive splenomegaly


Lead Poisoning

• Most common cause of microcytic hypochromic anemia • In children: Mcc is inadequate intake • In young adults: Mcc is still inadequate intake • 20 to 40: IBD • > age 40: mucasal bleeding • Tx: ferrous sulphate

• Lead inhibits delta ALA dehydratase as well as ferrochetolase • Mcc: eating peeling paint from old buildings • Classic clue: basophilic stippling; elevated FEP (free erythrocyte protoporphrins)

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Heme Synthesis

Lead levels to know • Normal: < 10 • If above 10: notify PHD; treat with succimer • If above 30: notify PHD; hospitalize; do a Ca-EDTA challenge; treat with penicillamine and dimercaprol (BAL) if urinary lead is high • If above 50: do as above; skip EDTA challenge

Drug induced lupus • Antihistone antibodies • • • • • •

Lead used to be the most common cause of mental retardation…

Hydralazine INH Procainamide Penicillamine Phenytoin Ethusuximide

But NOT ANY MORE!

Mental retardation

Porphyrias

• Fetal alcohol syndrome • Fragile X syndrome • Down’s syndrome

• A group of enzyme deficiencies • Synthesize too many porphyrin rings or inadequate metabolism are the problems • Porphyrin rings in the urine make it red • Two types are most important…

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Erythrocytic Protoporphyria and Porphyria Cutanea Tarda

Acute Intermittent Porphyria • Enzyme dificiency • A build up of porhyrin rings • Porphyrin rings are deposited in visceral organs and around nerves • Recurrent severe abdominal pain and neuropathy • Tx:

• Enzyme dificiency • Porphyrin rings are deposited underneath the skin • Light reacts with the rings causing a release of heat which leads to burns • Mcc of death: skin infections • Tx: protect them from light

Opiates

Opiates • • • • • • • •

• CNS depressants • Muscle relaxants • Analgesics • Receptors: – Mu ( CNS) – Kappa: Spinal cord

Hemoglobinopathies

Heroin Methadone Morphine Meperidine Codone Oxycodone Codiene Dextromethorphan

• • • •

Loperimide Diphenoxylate Fentanyl Pentazocine

Hemoglobin S disease

• Hemoglobin S disease • Hemoglobin C disease

• Autosomal recessive • High prevalence in Africa ( natural selection) • Substitution of valine for glutamate at position 6 of beta chain • Hypoxia causes cells to sickle leading to vaso-occlusion

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Vaso-occlusive crises • • • •

Aplastic crisis

CVA PULMONARY INFARCTION SPLENIC SEQUESTRATION PRIAPISM

• Complete bone marrow suppression • Always check the reticulocyte count • Mcc: parvovirus B-19

• Tx: exchange transfusion; oxygen

Hemoglobin C disease

A Few Points to Remember… • Functional asplenia by age 6 due to infarcts

• Autosomal recessive • Substitution of LYS for GLU at position 6 of beta chain • NO sickling occurs since both amino acids are hydrophilic

– Susceptible to encapsulated organisms – Give pneumovax anytime after age 2

• Infections are mcc reason for crises • Hydroxyurea increases HgF, decreasing chance for hypoxia • Use opiates for pain • Transfuse when anemic and symptomatic

Thallesemias • • • • •

Hemoglobins

Represent gene deletions Autosomal recessive Common in Mediterainian people Minor: at least one gene remaining Major: no genes remaining

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Alpha Thalessemia

Baseline labs • RBC Mass: 3.5 to 4.5 million • Hemoglobin/Hematocrit: 15/45%

Alpha Minor

Alpha Thalessemia Major

• One gene missing

• • • • •

– Asymptomatic – ( HG 12) 75%

• Two genes missing – IF sedentary: asymptomatic – IF active: symptomatic (HG 7.5) 50%

• Three genes missing

NO genes remaining Unable to make any hemoglobin at all Hydrops Fetalis Hemoglobin Bart ( 4 gamma chains) Hemoglobin H ( 4 beta chains)

– Symptomatic in ALL (HG 4 to 5)

Beta Thalessemia: 2 genes • Beta minor (Hg 7.5) – One gene missing – If sedentary: asymptomatic – If active: symptomatic – Increased Hg A-2 and Hg F – Ineffective erythropoiesis

Blood Transfusions • Done ONLY when patient is symptomatic • One unit of PRBCs

• Beta major – Both genes missing – Able to make only Hg A-2 and Hg F – Asymptomatic until 6 months of age – Transfusion dependent

– Raises Hg by 1 to 2 grams ( 3 to 6 HCT) – Delivers 3.4 grams of iron

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Iron Overload

Hemochromatosis

• Hemosiderosis: bone marrow is overwhelmed by iron • Hemochromatosis: iron overload has involved other organs

• Primary

• Secondary

– Autosomal recessive – Too much iron absorption from duodenum – HLA A3 on chromosome 6

– Skin: bronze pigmentation – Liver: bronze cirrhosis – Pancreas: bronze diabetes – Heart: restrictive cardiomyopathy

Transfusion Related INFECTIONS

– Too many transfusions – Mcc of death in first 10 years: transfusion related infections – Mcc of death after 10 years: CHF

Transfusion related infections • • • • • • •

HIV Hepatitis B Hepaitis C Hepatitis D EBV CMV Hemorrhagic viruses

Bacterial infections Malaria Babesiosis Syphilis

COLLAGEN

Hemoglobin Saturation Curve

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4 Types of collagen • • • •

More than a quarternary structure…

Type 1: Skin Type 2: Connective tissue Type 3: Arteries Type 4: Basement membrane

It’s a TRIPLE HELIX

To synthesize collagen • • • • •

Protein synthesis for packaging…

Glycine: every third amino acid Lysine Proline OH-Proline OH-Lysine



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Who makes collagen?


• Fibroblasts: simple scarring • Myofibroblasts: if you need wound contraction

When collagen synthesis goes wrong… DESMOPLASIA COLLAGENOUS REACTION SURROUNDING A TUMOR

COLLAGEN PROFILE KELOID TOO MUCH COLLAGEN DEPOSITION

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Collagen diseases

ALL YOU NEED NOW IS A CLUE • • • • • •

• • • •

Ehlers Danlos Marfan’s homocystienuria Scurvy Osteogenesis imperfecta Minky’s kinky hair syndrome

Secondary collagen diseases

Collagen Vascular Diseases

Ankylosing spondylitis Fragile X syndrome Syphilis Takayasu’s disease

• CREST • Scleroderma • Progressive systemic sclerosis • Rheumatoid arthritis

• SLE • MCTD

– Felty’s syndrome – Becet’s syndrome – Sjogrens syndrome

ELASTIN

Elastin • • • • •

Has many GLYCINES Has PROLINES Has LYSINES Has OH-PROLINES NO hydroxylysines

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Elastin

Elastase

• Provides COMPLIANCE • Provides ELASTICITY • Has DESMOSINE

• • • • • •

Who’s afraid of staph aureus and pseudomonas?

Emphysema • Destruction of elastin • Loss of recoil • • • •

Destroys elastin Cuts to the right of GLY, ALA, and SER Alpha-one antitrypsin inhibits elastase Found in neutrophils and bacteria Smoke inhibits alpha-one antitrypsin Decreased alpha-one antitrypsin with aging

• • • •

Panacinar: alpha-one antitrypsin deficiency Centroacinar: smoking Disto-acinar: aging Bullous: staph aureus and pseudomonas

Neutropenic Burn patients Cystic fibrosis Diabetics

• If any fever, cover staph aureus with one antibiotic and cover pseudomonas with two antibiotics

Keratin • Made for tensile strength • Contains a lot of CYSTEINES

THE END… …ONLY FOR NOW

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ENZYMES

IF asked whether a reaction is possible…

THE MOST IMPORTANT PROTEINS IN YOUR BODY

THE answer is always YES!

A Reaction

ANYTHING, as we know… IS

POSSIBLE!!

An Enzyme…

An ENZYME has…

• Brings substrates together in space and time • Lowers the free Energy of activation • Stabilizes the hi energy intermediate • Is not consumed in the reaction

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Competitive inhibition

Noncompetitive inhibition

• Inhibitor is similar to the substrate • The inhibitor is competing for the active site • Affinity I decreased • Km increases • Vmax remains the same ( just add more substrate) • reversible

• • • • • • •

What makes a reaction favorable and spontaneous

NOT similar to the substrate Does NOT bind active site Binds to regulatory site Turns off the enzyme Km remains the same Vmax decreases irreversible

Effects of temperature on a reaction

E • You want it to be negative • When negative: has electrons to give • When positive: wants to accept electrons

E REDOX POTENTIAL

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Reducing agent

Oxidizing agent

• Has a negative delta E • Wants to give away electrons • Gets oxidized after the reaction

• Has a positive delta E • Wants to accept electrons • Gets reduced after the reaction

Electron Transport System

Inhibitors and Uncouplers

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Inhibitors

Uncouplers • DNP • ASPIRIN • FREE FATTY ACIDS

How to name enzymes FIRST NAME of an enzyme IS the name of the SUBSTRATE

LAST NAMES of enzymes • • • • • • • •

LAST NAME of an enzyme Is what you did to the substrate

Kinase Phosphorylase Isomerase Epimerase Mutase Transferase Lyase Carboxylase

• • • •

Synthase Synthetase Dehydrogenase Hydrolase

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Coming to a screen near you…

THE PATHWAYS

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Anabolic Pathways:

As soon as you eat…

Putting it all back together

You replenish your plasma glucose

After glucose returns to the liver…

After you turn off gluconeogenesis…

You turn off gluconeogenesis

You turn on glycogen synthesis

Glycogen Synthesis

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Pentose Pathway

NADPH is used for…

X-linked Recessive Enzymes • • • • • • •

• Fatty acid synthesis • DNA synthesis • RBC repair ( used by glutathione)

G6PD • More common in Meditteranians ( protects them from malaria) • Mcc of hemolytic crisis: ( 1) infection (2) drugs • Drugs that oxidize RBC’s: sulfa drugs; antimalarials; metronidazole; INH

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G6PD Fabry’s ( alpha galactosidase) Hunter’s ( Iduronidase) CGD ( NADPH Oxidase) Lesch-Nyhan ( HGPRT) Pyruvate Dehydrogenase Adrenoleukodystrophy ( CAT-1)

Fatty Acid Synthesis

Amino Acid Synthesis

Palmitic Acid • The main fatty acid that we make every day • Saturated FA: NO double bonds • Unsaturated FA: has double bonds • Omega FA: counting carbons from the right side – Omega 3 FA: Lowers serum cholesterol – Pocosanol

Rules for Fatty Acids

Essential Fatty Acids • • • •

• We do NOT go beyond C-16 • Double bonds have to be at least 3 carbons apart • NO double bonds after C-10

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Linolinic Linoleic ( used to make arachadonic acid) Come ONLY from the diet Your body can not make these

Irreversible Cyclo-Oxygenase Inhibitor

Arachadonic Acid

• Aspirin

Reversible Cyclo-Oxygenase inhibitors

Steroids

• NSAIDs – – – – – – –

• Antiinflammatory actions

Indomethacin Phenylbutazone Ibuprofen Naproxen Baclofen Ketorelac cyclobenzaprine

– Inhibit PLP-A – Kills T-cells and eosinophils – Inhibits macrophage migration – Stabilizes mast cells – Stabilizes endothelium

Steroids • • • • • • • •

Prednisone Methylprednisalone Triamcinalone Beclamethasone Betamethasone Hydrocortisone Dexamethasone fludrocortisone

• • • • •

• Physiologic actions – Proteolysis – gluconeogenesis

Mast Cell Stabilizers • Cromolyn • Nedacromyl

Cypropterone Megestrol Fluticasone Mometasone Danazol

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LRBs

Triglyceride Synthesis

Triglyceride Transport

Sphyngolipids

• Zifurlekast • Montelekast • Zileutin

• Chilomicrons • VLDL • IDL • Signs: – Xanthelesma – Pancreatitis

Lysosomal Storage Diseases • • • • • • • • •

Gaucher: glucocerebrosidase Fabry’s: alpha galactosidase Krabbe’s: beta galactocerebrosidase Tay Sacks: hexoseaminidase A Sandhoff’s: hexoseaminidase A & B Nieman Pick: sphyngomylinase Metachromatic leukodystrophy: arylsulphatase Hurler’s: iduronidase Hunter’s: iduronidase sulphatase

And Now… The final anabolic process

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• • • • • •

Cholesterol Synthesis

NUCLEOTIDES

NUCLEOTIDES

PURINES • Adenine • Guanine

RNA DNA ENERGY CARRIERS ( UDP & CDP) METHYL GROUP CARRIER ( S-AM) SECOND MESSENGERS

PYRIMIDINES

NUCLEOTIDES

• Thymidine • Cytidine • Uracil

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THE BLOTS • • • • •

Southern blot: DNA Northern blot: RNA Western blot: PROTEIN PCR: amplifies DNA or RNA ELIZA

EUCHROMATIN Loose DNA; has more A and T

PURINES HETEROCHROMATIN Tight DNA; has more G and C

PYRIMIDINES

RIBONUCLEOTIDE REDUCTASE

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The DNA Helix

SCID • Adenosine deaminase def • Unable to make DNA • Affects all rapidly dividing cells, especially bone marrow • Bone marrow transplant is now current therapy

HISTONES • • • • • • •

Anti-Histone Antibody • • • • • •

Help bind DNA helix H-1 H-2a H-2b H-3 H-4 Basic

CELLULAR CYCLE

Hydralazine INH Procainamide Penicillamine Phenytoin Ethusuximide

DNA REPLICATION

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TRANSCRIPTION

TRANSLATION

DIFFERENCES

MUTATIONS

• DNA Replication – – – – – –

• Translation

DNA POL alpha DNA POL beta DNA POL gamma DNA POL delta DNA POL epsilon Replication forks

• Frameshift mutations • Point mutations

– Fmet vs met

– Transition mutations – Transversion mutations • Silent mutations • Missence mutations • Nonsence mutations

• Transcription – Monocistronic – polycistronic

IT IS THE END… CAN IT BE ? YES, IT IS!!!

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OR IS IT.

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Sources of Energy • • • •

Catabolic Pathways Breaking it all down

Glucose ( 40% of diet) Proteins ( 30% of diet) Fats ( 30% of diet) Ketones ( last resort)

Breaking Down Sugars First

Breaking Down Sugars… Begins With Glycolysis

RBC Connection • RBCs use ONLY glucose for energy • Hypoglycemia will ALWAYS affect RBCs first, causing a hemolytic anemia • The only other pathway RBCs have is the pentose pathway for making NADPH to maintain the membrane

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Glycolysis

Glycolysis • The most active pathway in your body • CATABOLIC in all cells except the liver where it is ANABOLIC

How to use energy

CATABOLIC STATE • Is controlled by the sympathetic system • Second messenger is C-amp • Is controlled hormonally by epinephrine and glucagon

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DHAP • Used in the glycerol 3 phosphate shuttle • Used in triglyceride synthesis

Glyceraldehyde 3 phosphate dehydrogenase

Mercury Toxicity

• Has sulphur in the active site • Is blocked by mercury poisoning

• Mcc: (1) Tuna (2) a child biting into a thermometer • Blocks glyceraldehyde 3 phosphate dehydrogenase • LOW ENERGY STATE • RBCs affected first • Brain affected the most

Pallegra • Niacin deficiency • The 4 Ds – Dermatitis – Diarrhea – Dimentia – Death

• Hartnup’s: presents just like pallegra. – Defective renal transport of tryptophan

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Flouride Poisoning • Blocks the enzyme ENOLASE • Caused in the past by eating rocks of flouride • Rare today since flouride added to water and toothpaste • Clue: extra white teeth and bones

Gluconeogenesis

Gluconeogenesis • Controlled by epinephrine and glucagon • Second messenger is C-amp • Occurs only in the liver (90%) and the adrenal cortex (10%) • Occurs while other tissues are running glycolysis • Occurs in the mitochondria and cytoplasm

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Galactose Metabolism

To reverse glycolysis • • • •

Pyruvate carboxylase ( rate limiting) PEP Carboxykinase F16DPase G6Pase

Detecting Sugars • In the urine: CLINITEST • In the stool: positive REDUCING SUBSTANCES

Galactosuria • • • •

Galactokinase deficiency Hexokinase fills in for galactokinase Galactose in the urine ( clinitest positive) Symptoms: polyuria; polydypsia; UTIs

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Fructose Metabolism

Galactosemia • Galactose 1 phosphate uridyltransferase deficiency • Galactose 1 phosphate builds up in the cells • RBCs affected first • Brain affected the most • LOW ENERGY STATE

Fructosuria • • • • • •

Fructokinase is missing Hexokinase fills in Fructose in the urine ( clinitest positive) Polyuria Polydypsia UTIs

Fructosemia • Aldolase B is missing • Fructose 1 phosphate is trapped within the cells and can not leave • RBCs affected first • Brain affected the most • LOW ENERGY STATE

Before you enter the KREB CYCLE YOU NEED TO KNOW…

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THE FIVE FATES OF PYRUVATE

5 FATES OF PYRUVATE

Pyruvate Dehydrogenase

KREB CYCLE

Malate-Aspartate Shuttle

Glycerol 3 Phosphate Shuttle

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Fatty Acid Catabolism

Amino Acid Catabolism

• Palmitic acid: C-16 the main fatty acid we make daily • Three formulas to know: – ( C/2 – 1) : the number of rounds it takes to break down a fatty acid chain or the number of rounds it took to make a fatty acid chain – ( C/2 – 1) 2 : the number of NADPHs it cost to make a fatty acid chain – ( C - 1): the number of ATPs it cost to make it

Fatty Acid Catabolism

Adrenoleukodystrophy • Defective carnitine shuttle • Long chain free fatty acids accumulate in the cytoplasm, unable to enter mitochondria • X-linked recessive • Adrenal gland failure • Early white matter involvement

Beta - Oxidation

X-linked Recessive Enzymes • • • • • • •

G6PD Pyruvate dehydrogenase NADPH-Oxidase HGPRT (Lesch-Nyhan) Alpha-Galactosidase ( Fabry’s) Iduronidase ( Hunter’s) CAT-1 (Adrenoleukodystrophy)

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Odd numbered carbon fatty acid metabolism

Ketogenesis

IDDM ( TYPE 1 DIABETES)

Reasons NEVER to give bicarbonate in treatment of DKA…

• Autoimmune • 2 weeks after a viral (Cocksackie B) infection • Anti-islet cell antibody • Sx begin after 90% of islet cells are destroyed • Remaining 10% will undergo hyperplasia ( honeymoon period) • Signs and sx: LOW ENERGY STATE

• DKA – – – – – – – – – – –

• It merely corrects a number without correcting the actual problem • Decreased cardiac output • Causes hypokalemia • Shifts hemoglobin dissociation curve to the left • Bicarbonate ion does NOT cross the blood brain barrier ( CSF pH falls paradoxically)

Hypovolemia Lack of insulin Low body potassium Hyperkalemia Hypophosphatemia Pseudohyponatremia Correcting sodium Visceral pain False high creatinine Correcting glucose Correcting acidosis

NIDDM ( Type II Diabetes) • Genetic • Connected to obesity • Downregulation of insulin receptors • Hyperinsulinemia • Nonketotic • Hyperglycemic, nonketotic coma

Sulfonylureas • Chlorpropamide • Tolbutamide • Tolezalide

• Complications – – – – – – –

Vasculitis Clots Bleeds Nephropathy Neuropathy IDM Tx: weight loss

• Glipizide • Glyburide

• Meds • insulin

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Insulins

Other Oral Hypoglycemics • Ascarbose • Miglitol • Metformin • • • •

Piaglitazone Rotiglitazone Repaglinide Troglitazone

Dawn effect

Somoji effect

• Increase in blood sugar each morning caused by the normal increase in epinephrine, glucagon and cortisol that occurs each morning

• Actually caused by HYPOGLYCEMIA that occurred in the early morning ( 2 to 3 am) leading to reactive HYPERGLYCEMIA in the late morning ( 6 to 7 am)

• Tx: increase morning regular insulin

• Tx: decrease evening NPH insulin

Glycogen: Synthesis / Catabolism


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Glycogen Storage Diseases

Glycogen Storage Diseases • • • • • •

Von Gierke’s: glucose 6 phosphatase Anderson’s: branching enzyme Cory’s: debranching enzyme Her’s: liver phosphorylase Mcardle’s: muscle phosphorylase Pompe’s: cardiac alpha 1,4 glucosidase

The End of CATABOLISM The Beginning of ANABOLIC PATHWAYS

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Forgiveness • Through God’s love, you always have infinite forgiveness • Unfortunately, you don’t always have infinite time

The Physiology of CANCERS CELLS OUT OF CONTROL

Anaplasia

Metaplasia

• Cells revert back to their mesenchymal origin • NO MATURATION TIME NEEDED • The most aggressive type of cancer • Divides rapidly • Metastasizes early and aggressively • SENSITIVE to radiation or chemo

• Replacement of one adult cell type for another • The new cell can better handle the stress

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Desmoplasia • A collagenous reaction surrounding a tumor

Dysplasia • • • • •

Loss of cell to cell contact inhibition Cells begin to crawl on top of each other This is the FIRST STAGE OF CANCER Also known as carcinoma in situ ( CIN) Any cancer that is caught at this stage has a good prognosis if removed ( 90% 5 year survival) • ALL screening is done to find cancer at this stage

NEOPLASIA • BENIGN – – – –

Well circumscribed Freely mobile Encapsulated Does not outgrow capsule – Does not outgrow blood supply – NO METS – Obeys physio

Malignant Neoplasia

• MALIGNANT – – – – – – –

• Angiogenin • Endostatin

Not circumscribed Adherent Not encapsulated Outgrows capsule Outgrows blood supply METS Does NOT obey physio

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When you have one BILLION cells…

How long does it take for ONE BILLION cells to reassemble?

• You can SEE the cancer with the naked eyes • You can PALPATE it on exam • Chemo must kill at least one billion cells to be considered effective

If a cancer outgrows its blood supply, go to the … • • • • • •

To Name a Tumor…

BRAIN LUNGS BONE LIVER ADRENAL PERICARDIUM

• First name: the most common cell type • Last name: add - oma at the end

To Name a Cancer…

TRICKY - OMAs

• First name: most common cell type being stressed • Prefix for every glandular tissue is ADENO • Last name: carcinoma if it originates from epithelium

• Hamartoma: abnormal growth of normal tissue • Choristoma: abnormal location of normal tissue

– Sarcoma if it originates from connective tissue

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Cancers that lost their proper endings • • • • • • • •

Let us now begin…one organ at a time

Hepatoma Seminoma Lymphoma Teratoma Mesothelioma Retinoblastoma Neuroblastoma Nephroblastoma ( Wilm’s tumor)

BRAIN

Psammoma Bodies

• Most common INTRACRANIAL tumor: MENINGIOMA

• • • • •

– Displaces the brain – Psammoma bodies ( calcifications)

BRAIN, cont

Papillary carcinoma of thyroid Serous Adenocarcinoma of the ovaries Meningioma Mesothelioma


• Most common primary brain tumor: ASTROCYTOMA

• ALL have mental retardation, seizures and cerebral calcifications in common • All have tumors or cancers associated with them • All have different cutaneous findings

– GLIOMA – OLIGODENDRIGLIOMA – EPENDYMOMA

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Neurofibromatosis

Sturge – Weber syndrome

• Café au lait spots ( hyperpigmented macules) • Associated with chromosome 17/22 • Neuromas

• Port wine stain on forehead • Angiomas of retina and brain

– Peripheral neuromas: chromosome 17(type 1) – Central neuromas: chromosome 22(type 2)

• fibromas

BRAIN, cont

Pituitary

• Most common primary brain cancer: astrocytoma grade IV or GLIOBLASTOMA MULTIFORME

• Most common tumor: pituitary ADENOMA – Cell types: • • • •

• Most common cancer: METASTASES – Usually found at the grey-white matter junction

Chromophobes ( nonfunctional) 95% Acidophils (produce PRL and GH) Basophils ( produce ACTH, TSH, FSH and LH) Most common FUNCTIONAL tumor: PROLACTINOMA

• Most common cancer: ADENOCARCINOMA (rare)

Pineal

Posterior Fossa Tumors • Present with early morning vomitting • Common in children

• Most common tumor: pineal adenoma ( PINEALOMA) – CN VI palsy (esotropia) – Precocious puberty

• MEDULLOBLASTOMA – Cerebellar origin; it sits on top of the medulla

• Most common cancer: ADENOCARCINOMA (rare)

• CRANIOPHARYNGIOMA – – – –

Develops from Rathke’s pouch Has a motor oil appearance Has some calcifications May damage anterior or posterior pituitary

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Mediastinum

Posterior Mediastinum

• Anterior • Middle • Posterior

• Mostly ganglia located there • Most common tumor: NEUROMA • Most common cancer: NEUROBLASTOMA

Neural Crest Cancers • NEUROBLASTOMA – Most common abdominal mass in children – Hypsarrythmia – Opsoclonus – Highest spontaneous regression rate (2%)

Neural Crest Cancers • Paroxysmal palpitations, HTN, headache and diaphoresis • Unable to differentiate benign from malignant histologically • Must remove ALL of them • Dx: check urinary VMA, metanephrines, or HVA

• PHEOchromocytoma – Located in adrenal medulla – 10% in children – 10% bilateral – 10% metastatic – 10% familial – 10% malignant

– Phentolamine – Phenoxybenzamine

Anterior Mediastinum • • • •

Thymus

Thymus Thyroid T-cell leukemias/lymphomas Teratomas

• Most common tumor: THYMOMA – Associated with ALL autoimmune diseases except Grave’s disease – These cells are pleuripotent; – Thymus is immunopreviledged

• Most common cancer: ADENECARCINOMA (rare)

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Thyroid

Thyroid Masses • CYSTIC

• Most common mass: cyst( throglossal) • Most common tumor: follicular adenoma • Most common cancer: papillary carcinoma

• SOLID

– Thyroglossal cyst is most common – Do ultrasound to verify – Do FNA: diagnostic and therapeutic

– Local metastases only – Psammoma bodies – Risk factor: previous irradiation to the neck

– First do a thyroid scan – cold nodule and h/o previous irradiation to the neck: lobectomy – If hot nodule: treat hyperthyroidism – Cold nodule w/o h/o previous irradiation: biopsy • Do lobectomy only if malignant

Parathyroid

MEN Syndromes

• Located behind the thyroid glands • Most common tumor: parathyroid adenoma

• MEN I: pituitary, pancreatic, and parathyroid tumors ( Wermer Syndrome) • MEN II: medullary carcinoma of thyroid, pheochromocytoma, plus or minus parathyroid adenomas ( Sipple Syndrome) • MEN III: MEN II plus neuroma or ganglioneuroma but w/o PTH adenomas

– Most common cause of isolated hypercalcemia in adults

• Most common cancer:adenocarcinoma • Men Syndromes

Parafollicular Gland

Middle Mediastinum

• Also found behind the thyroid glands • Most common tumor: adenoma • Most common cancer: medullary carcinoma of thyroid (produces calcitonin)

• Contains the heart • Heart has three layers: endocardium, myocardium, and epicardium. Pericardium encases the heart

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Endocardium

Myocardium

• Most common tumor: myxoma

• Related to skeletal muscle • Most common tumor: rhabdomyoma • Most common cancer: rhabdomyosarcoma

– Usually seen in left atrium – Diastolic plop – Middle aged female who passes out, only to recover a few seconds later • Estrogen connection

• Most common cancer: angiosarcoma (rare)

Epicardium

Pericardium • Most common tumor: fibroma • Most common cancer: metastases

• Hardly ever involved in neoplasia

Lungs

Lung Cancers

• Most common mass in children: hamartoma • Most common mass in adults: granulomas • Most common tumor: adenoma • Most common cancer: metastases • Most common intrathoracic cancer: squamous cell carcinoma • Most common primary cancer: bronchogenic adenocarcinoma

• CENTRAL: squamous cell carcinoma ( produces PTH) – Small cell carcinoma ( produces ACTH, ADH, PTH and TSH)

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Lung Cancers, cont

Lung Cancers, cont

• Peripheral: bronchogenic adenocarcinoma and bronchoalveolar adenocarcinoma

• RISK FACTORS: primary smoker – risk increases with amount and duration – Radon – Second hand smoke

• Bronchoalveolar adenocarcinoma is the only primary lung cancer NOT related to smoking

• Sidestream smoke • Mainstream smoke

– Pneumoconioses: all of them increase risk of cancer except anthracosis

Pneumoconioses • • • • •

Treatment of Lung Cancer

Anthracosis Asbestosis Silicosis Bissinosis berryliosis

• Poor prognosis • Surgery done only if lesion smaller than 2cm in size and localized, and if there is a V/Q mismatch • Chemo or radiation is effective against small cell carcinomas

Pleural Cavity

Nasopharynx

• Most common tumor: mesothelioma • Most common cancer: mesothelioma

• Most common mass: polyp – Aspirin sensitive asthma: avoid aspirin or NSAIDS

– Ferrugenous bodies – Psammoma bodies – Pleural thickening

• Most common tumor: fibroma • most common cancer: nasopharyngeal carcinoma – Commonly seen in Chinese women – EBV association

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Oral Cavity

Esophagus • Most common tumor: leiomyoma • Most common cancer: squamous cell carcinoma • Most common cancer in lower 1/3rd of esophagus: adenocarcinoma

• Most common tumor: fibroma • Most common cancer: squamous cell carinoma – Floor of mouth – Lower lip – Tip of tongue

– Risk factor: Barrett’s esophagus – Almost always ulcerates – Odynophagia – Poor prognosis ( < 5% 5 year survival)

Stomach

Risk Factors for UGI Cancers

• Most common tumor: leiomyoma • Most common cancer: adenocarcinoma

• • • •

– Virchow’s nodes – Leather water bottle appearance – Linnitis plastica – Signet ring cells – Kruckenberg tumor – Severe weight loss ( due to stomach distention)

Small Intestine

Smoking Alcohol Nitrites Japanese

Appendix

• Most common tumor: leiomyoma • Most common cancer: adenocarcinoma • Most common cancer of the ileum: lymphoma

• Most common tumor: leiomyoma • Most common cancer: carcinoid – Does NOT metastasize – Carcinoid syndrome usually originates from the (1) pancreas and (2) ileum

– Early UGI obstruction – Napkin ring lesion – 70% of lymphoid tissue is located in the ileum

• Puts out large amounts of serotonin (check urinary 5-HIAA

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Colon

Colon cancer risk factors


• • • •

– Napkin ring lesion – Eaten apple core lesion – Pencil thin stool – Melena – Third most common cancer, and most common cause of cancer deaths in both sexes

Polyps

Low fiber diet High fat diet Polyps Ulcerative colitis

Liver • • • •

Hepatic Adenoma

Most common mass: cyst Most common tumor: adenoma and AVMs Most common cancer: metastases Most common primary cancer: hepatocellular adenocarcinoma

AVMs

• Associated with estrogen use or injected steroids • Tends to rupture if abdominal pressure rises significantly • Rupture can lead to acute life threatening hemorrhage

• • • •

Connect arteries to veins Increased venous oxygen Decreased AVO2 difference Risk: – Burst and bleed – Sequester platelets and cause bleeding – Sequester blood, leading to high output heart failure

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Risk Factors for Hepatocellular Carcinoma

AVM Syndromes • • • • • • • • •

• Osler – Weber – Rondu: multiple AVMs in the pulmonary circulation • Von Hipple Landau: multiple AVMs in the abdomen and brain – Has an increased incidence of renal cell carcinoma – Associated with chromosome 3p

Gallbladder

Smoking Alcohol Hepatitis B Hepatitis C Shistosomiasis Analene dyes Aflatoxin Vinyl Chloride ( Angiosarcoma) Benzene

Biliary Tract


• Most common mass: choledochal cyst • Most common tumor: cholangioma • Most common cancer: cholangiosarcoma – Risk increase with chronic scarring

• Poor prognosis because it’s hidden beneath the liver • Thickened calcified gallbladder

• PRIMARY BILIARY CIRRHOSIS – Antimitochondrial antibodies

• SCLEROSING CHOLANGITIS – Seen in ulcerative colitis

Pancreas

Pancreatic Adenomas

• Most common mass: cyst • Most common tumor: adenoma • Most common cancer: Adenocarcinoma

• Glucagonoma: elevated glucose, lipids, and ketones • Insulinoma (or nessidioblastosis): high insulin and high C-peptide • Somatostatinoma: severe constipation • Vipoma: watery diarrhea • Gastrinoma (Z-E syndrome) elevated gastrin levels all the time

– Cholestatic jaundice: blocks biliary tract – High direct ( conjugated) bilirubin – Trousseau syndrome: migratory thromphlebitis – Most common mucinous cancer

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Ovary

Other Ovarian Tumors

• Most common mass: follicular cyst • Most common tumor: serous cystadenoma • Most common cancer: serous cystadenocarcinoma

• Fibroma: associated with pleural effusion or ascites ( Meig’s syndrome) • Granulosa cell tumor: high estrogen • Yolk sack cancer: high AFP • Choriocarcinoma: high HCG • Sertoli-Leydig cell tumor: masculinization • Mucinous cystadenocarcinoma: very mucinous (pseudomyxoma peritonei) • Teratoma: struma ovarii

– Highly malignant – Most mucinous cancer in women

Uterus

Uterine Polyp

• Most common mass: polyp • Most common tumor: leiyomyoma • Most common concer: adenocarcinoma

• Presents with passing of blood clots • Tx: surgery

Fibroids

Endometrial adenocarcinoma

• Submucosal (90%): presents with menorhagia • Subserosal: presents with pelvic pain or pressure • Dependent on estrogen • Focal thickening; firm mass • Tx: OCPs; Leuprolide; surgery

• Dependent on estrogen • Presents with metrorrhagia • Metrorrhagia after age 35 requires endometrial biopsy • Tx: surgery

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Cervix

Warts

• Most common mass: warts • Most common tumor: fibromas • Most common cancer: squamous cell carcinoma

• Condyloma lata: secondary to syphilis – Fleshy appearance

• Condyloma accuminatum: secondary to HPV – Verrucous or mushroom like warts – Tx: podophyllin drops; cryosurgery

Cervical cancer

Vagina

• Squamous cell carcinoma • Risk factors: HPV; other STDs • Tx: hysterectomy

• Most common mass: warts; Bartholin cyst • Most common tumor: fibroma • Most common cancer: – Upper half: squamous cell carcinoma from the cervix – Lower half: skeletal muscle • Tumor: rhabdomyoma • Cancer: rhabdomyosarcoma (sarcoma botyroides)

Warts

Bartholin cyst

• Condyloma lata: secondary to syphilis

• Congenital • Fluctuant mass behind the labia majora • Complication: infections/ abscess formation • After first infection: treat with antibiotics • After second infection: surgery (marsupialization)

– Fleshy appearance

• Condyloma accuminatum: secondary to HPV – Verrucous or mushroom like warts – Tx: podophyllin drops; cryosurgery

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Rhabdomyoma/ Rhabdomyosarcoma

Kidney

• 90% of rhabdomyosarcomas occur under age 3 years • Increased incidence in Tuberous Sclerosis • Sarcoma botyroides: looks like a ball of grapes when removed

• Most common mass: cyst • Most common tumor: adenoma • Most common cancer: – In children: Wilm’s tumor – In adults: renal cell adenocarcinoma

Wilm’s tumor

Renal Cancer • • • • • •

90% occur on superior pole of kidney Presentation: painless hematuria; flank mass Most vascular cancer Produces erythropoietin Metastasizes via retroperitoneum Favorite metastatic site: lungs (cannon ball metastases • 20% contralateral recurrence

• Renal cancer in children • Classic clues: aniridia and hemihypertrophy

Renal Cancer, cont

Adrenal Gland

• Risk factors: smoking; Von Hippel Landau; Tuberous Sclerosis • Evaluation: UA; sonogram;IVP; CT scan; angiogram; • Tx: surgery • Annual CT scans after surgery to detect contralateral recurrence

• Most common mass: cyst • Most common tumor: adenoma • Most common cancer: adenocarcinoma

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Adrenal adenomas • • • •

Bladder

Glucagonoma Insulinoma Somatostatinoma Pheochromocytoma

• Most common mass: diverticulum • Most common tumor: leiomyoma • Most common cancer (including ureters): transitional cell adenocarcinoma

Bladder diverticulum

Bladder Cancer • Transitional cell adenocarcinoma

• Complications: UTIs and kidney stones • Tx: surgery

– Multiple primaries – Presents with painless hematuria – Tx: surgery; radiation – Risk factors: smoking; anilene dyes; benzene; aflatoxin; cyclophosphamide

• Squamous cell carcinoma – Schistosoma hematobium

Prostate

BPH

• Most common tumor: BPH • Most common cancer: adenocarcinoma

• Presentation: strains to urinate; weak stream; dribbling after urination; frequency and urgency • Tx: terazicin/doxazocin; tamsulocin; fenesteride; TURP

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Prostate Cancer

Prostate cancer screening

• Most common cancer in men • Second to lung cancer for cancer deaths in men • Tx: surgery; hormonal therapy or radiation after surgery

• Age 35: baseline rectal/prostate exam • After age 40: annual rectal/prostate exams • Annual sigmoidoscopy begins after age 40 – After 2 normal annual sigmoidoscopies, repeat in 3 to 5 years

• Colonoscopy every 3 to 5 years begin at age 50 – Full colonoscopy should follow any abnormal sigmoidoscopy

Testicles

Testicular exams

• Most common mass:

• Begin in adolescence • ANY firm testicular mass: perform an orchiectomy

– In newborns: hydrocele – In children and adults: hematoma – In older adults: varicicele

• Most common tumor: adenoma • Most common cancer: – In first year of life: yolk sak cancer – In teens to adults: seminoma

Skin

Skin Tags

• Most common mass:

• Very common • Tx: shave it off

– Skin tag (acrochordon) – hemangioma

• Most common tumor: fibroma • Most common cancer: basal cell carcinoma • Most common malignancy: squamous cell carcinoma

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Hemangiomas

fibromas

• Found anywhere on the body • An enlarged flat blood vessel • Tx: observation for 18 months; inject with steroids; laser surgery

• Very common • Easy to remove if you need to do so • Many of them seen in neurofibromatosis

All Neurocutaneous Diseases have…

Neurocutaneous Diseases • Neurofibromatosis • Sturge – Weber • Tuberous Sclerosis

• Mental retardation • Cerebral calcifications • Seizures

Neurofibromatosis

Sturge - Weber syndrome

• Café au lait spots (at least 3 with 1.5 cm diameter minimum); hyperpigmented macules • Neuromas • Fibromas • Chromosome 17/22 involved

• Port wine stain on face ( V-1) • Angiomas of retina and brain associated

– Type 1: chromosome 17; peripheral neuromas – Type 2: chromosome 22; central neuromas

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Tuberous Sclerosis

Basal cell carcinoma

• Ashen leaf spots (hypopigmented macules) • Tubors: primary brain tumors • Rhabdomyomas and rhabdomyosarcomas of the heart • Renal cell carcinoma

• Most common skin cancer; but, it does NOT behave malignantly • Usually found on the face from sun exposure • Wide resection is curative

Squamous cell carcinoma

melanoma

• Behaves malignantly • Ulcerates • Main risk factor: sun exposure (use SPF 15 ) • Predisposing skin diseases: actinic keratosis; Bowen’s disease • Diseases with increased risk: albinism; vitiligo; porphyria cutanea tarda; PKU; Wiscott-Aldridge; Job’s syndrome

• The MOST malignant skin cancer • Melanotic nevi are risk factors • Malignant risk: – – – –

Bone neoplasia

Area Borders Color Depth of invasion (worst prognostic factor)

Epiphysis • Made of cartilage • Most common tumor: chondroma • Most common cancer:chondrosarcoma

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Diaphysis • • • •

Metaphyseal osteosarcoma

Made of osteocytes Most common tumor: osteoma Most common cancer: metastases Most common primary cancer: osteosarcoma

• Seen mainly in adults • Codman’s triangle • Star burst effect on the cortex

Diaphysis • • • •

Ewing’s osteosarcoma

Made of osteocytes Most common tumor: osteoma Most common cancer: metastases Most common primary cancer:

• Primary bone cancer in children • Onion skinning seen in bone • T(11/22)

– In children: Ewing’s osteosarcoma – In adults: plasmacytoma or multiple myeloma

Multiple myeloma

Breasts

• Plasmacytoma: when single lesion • Multiple myeloma: MULTIPLE osteolytic lesions

• Most common mass: cyst • Most common tumor: – < 25y/o: fibroadenoma – >25y/o: fibrocystic disease

– IG-g: most common heavy chain – Kappa: most common light chain – Hypercalcemia – Ruleaux formation

• Most common cancer: intraductal adenocarcinoma

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Fibroadenomas

Fibrocystic disease

• Estrogen dependent • Enlarges in first two weeks of menstrual cycle

• Progesterone dependent • Enlarges in the two weeks preceeding menses • Has greenish fluid on aspiration

Intraductal adenocarcinoma

Other breast neoplasms • Intraductal papilloma: nipple bleeding • Lobular adenocarcinoma: contralateral primary; cells lined up in single file • Comedocarcinoma: focal areas of necrosis • Inflammatory adenocarcinoma: peau d’orange (infiltrates lymphatics); the most malignant cancer • Cystsarcoma phylloides: a sarcoma; explodes out of the breast, then stops growing; wide resection is adequate

• Estrogen dependent • Top locations: upper outer quadrant; nipple • Usually presents with a dimple • Metastases can be osteolytic or osteoblastic

Breast cancer screening

Cystic breast mass

• Baseline exam: age 35 • Age 40 to 50: annual breast exam by doctor; monthly SBE • Age 50 to 79: add annual mammogram • Family h/o breast cancer: begin mammography 5 years before the age of the index case

• • • •

History Physical Ultrasound Fine needle aspiration: diagnostic and therapeutic

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Firm breast mass • • • • •

Benign firm breast mass

History Physical Mammogram Lumpectomy Send to pathologist for definitive identificaton

• After lumpectomy, we are done

Malignant firm breast mass

Tamoxifin / Roloxifene

• After lumpectomy, perform a modified radical mastectomy • Nodal dissection • Check for estrogen and progesterone receptor positivity • Tamoxifin or Roloxifene for estrogen positive cases • Chemotherapy for premenopausal women and radiation for postmenopausal cases

• Anti-estrogen at the breast and pituitary • Proestrogen at the bone, liver, and the uterus (Tamoxifin only)

Cancer Profile

Cancer Antigens

• Signs and symptoms: low energy state • Cancer more common in males: under age 30 and after age 50 • Cancer more common in women: age 30 to 50 • Most common cause of death: infections, except for uterine and cervical cancers (renal failure)

• Prior to surgery: associated with… • After surgery: if it rises again, there is a 95% chance you have recurrence or metastases

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Cancer Antigens • • • • • • • •

PSA CEA S-100 AFP HCG C-MYC L-MYC N-MYC

• • • • • • •

Cancer Markers • • • • • • • • •

Desmin Vimentin Ca-125 Ca-19 BCL-2 RET RB

T(9/22) T(8/14) T(14/18) T(11/22) T(15/17) ERB HER 2 NEU BRCA P53

THE END

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Microbiology & Immunology: Week Four

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Immunology

Immunology

LISCENCED TO KILL

Study of the immune system

Antigen • HAPTEN

• IMMUNOGEN

– Less than 6000D – Too small to set off the immune system by itself

The most important factor that determines Immunogenicity is…

– Greater than 6000D – Large enough to set off the immune system by itself

Antigen • HAPTEN – Less than 6000D – Too small to set off the immune system by itself

• IMMUNOGEN – Greater than 6000D – Large enough to set off the immune system by itself

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Carrier Effect

Making use of the carrier effect

• What macrophages do for a living • • • • • • • •

Ingest Phagosome formation Digest Present MHC II complex V-beta region Invariant chain is displaced IL-1 is released

IL-1 • Fever • Nonspecific symptoms of illness • Recruits T-helper cells

Fever

Infections that cause heart block • • • • •

• Def: one degree above normal body temp • Raises heart rate 10bpm for each degree rise above normal • Allows immune cells to come around faster • Causes secretion of Ig-A

Legionella Lyme disease Chaga’s disease Diptheria Typhoid fever

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Fever • • • •

Antigen • HAPTEN

Means that IL-1 showed up By itself can NOT tell you the cause The pattern of fever can be diagnostic Causes discomfort at about 101 degrees F

• IMMUNOGEN

– Less than 6000D – Too small to set off the immune system by itself

How do you make an Immunogen less immunogenic?

– Greater than 6000D – Large enough to set off the immune system by itself

Detergent • Disrupts the ADHESION of pathogens by disrupting membrane forces

Antiseptic/Disinfectant

Sterilization

• Phenol is most common • Iodine is most common in the hospital • These chemicals DESTROY the membrane and INACTIVATE endotoxin • These chemicals actually KILL 99% of germs

• For spores – A dormant form of a bacteria – CAN NOT replicate in this form – CAN still release toxin, especially when exposed to heat – Bacillus and Clostridium

• Done at 121* C with VAPORIZED heat

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The two arms of the Immune system

Most immunogenic bacteria • SHIGELLA • Only 8 to 10 microbes required to get a full infection

• HUMORAL – BLOOD

The two arms of the Immune system • HUMORAL – BLOOD – B-CELLS – NEUTROPHILS

– TISSUE

MACROPHAGES • • • • • • • • • • •

• CELL MEDIATED – TISSUE – T-CELLS – MACROPHAGES

Microglia: brain Type-1 pneumocytes: lungs Kuffler cells: liver RES cells: spleen Dendritic cells: lymph nodes Osteoclasts: bone Mesangial cells: kidneys M cells: Peyer’s patches Langerhan’s cells: skin Monocytes: blood Connective tissue: epitheloid cells; giant cells; histiocytes

The two arms of the Immune system • HUMORAL – – – –

BLOOD B-CELLS NEUTROPHILS BACTERIA

All Else

• CELL MEDIATED – – – –

• CELL MEDIATED

• • • • • •

TISSUE T-CELLS MACROPHAGES ALL ELSE!!!

Virus Fungus Mycobacteria Protozoa Parasite Neoplasm

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Inflammation

Acute Inflammation • Look for SWELLING or NEUTROPHILS

Chronic Inflammation

Can it really be this easy?

• Cellular infiltrate: T-cells and macrophages • What you see on biopsy: fibrosis • What you see on x-ray: calcifications

THE END

Can it really be this easy?

•YES!

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Or Maybe Not….

Let The Leukocytes Loose!

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Humoral Immune Sytem • Protect the blood

Immunodeficiencies LACKING A LITTLE

Humoral Immune Sytem

Humoral Immune Sytem

• Protect the blood • B cells

• Protect the blood • B cells • Neutrophils

Humoral Immune Sytem • • • •

Cell mediated Immune System • Protect the tissues

Protect the blood B cells Neutrophils Bacterial infections

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Cell mediated Immune System

Cell mediated Immune System

• Protect the tissues • T-cells

• Protect the tissues • T-cells • Macrophages

Cell mediated Immune System • • • •

Cell mediated Immune System • Protect the tissues • T-cells • Macrophages

Protect the tissues T-cells Macrophages Nonbacterial infections

• Nonbacterial infections – – – – – –

DiGeorge syndrome

T-cell immunedeficiencies • • • • • • • •

Virus Fungus Mycobacterium Protozoa Parasite neoplasm

DiGeorge syndrome Chronic mucocutaneous candidiasis Steroids Cyclosporine Hairy cell leukemia SCID Wiscott-Aldridge syndrome HIV

• Third pharyngeal pouch is missing • Inferior parathyroids glands are missing • The only immunodeficiency with hypocalcemia

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Chronic Mucocutaneous Candidiasis

Steroids • Anti-inflammatory actions

• A T-cell defect at a submolecular level • T-cells can fight everything else under “all else” except candida • Candida infections on skin and mucous membranes • Causes chronic fatigue syndrome

– – – – –

• Physiologic actions (catabolic) – Proteolysis – Gluconeogenesis – Upregulates all receptors during stress ( permissive)

Steroids • • • • • • • •

Prednisone Hydrocortisone Methylprednisalone Triamcinalone Beclamethasone Betamethasone Fluticasone Mometasone

• • • • •

Kills T-cells and eosinophils Inhibits macrophage migration Stabilizes mast cell membranes Stabilizes endothelium Inhibits phospholipase A

Cyclosporine

Fludrocortisone Danazole Cypropterone Megesterol Dexamethasone

• Revolutionized transplantations in America • Prolongs the longevity of transplanted organs • Inhibits calcineurin which is needed to produce the interleukins • Causes gingival hyperplasia and hirsutism

Tacrilimus

Hairy Cell Leukemia

• Now used in place of cyclosporin due to much fewer side effects

• • • •

Most commonly a B-cell leukemia (75%) More frequently a T-cell leukemia (25%) Has hairy cell membrane projections Tartrate Resistant Acid Phosphatase (TRAP)

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T-cell Lymphomas

SCID

• Mycosis Fungoides ( cutaneous) • Sezary syndrome ( present in the blood) • T-cells have characteristic indented cell membrane

• • • • •

Wiscott-Aldridge syndrome • • • • • • •

• • • •

Involves adenosine deaminase deficiency DNA synthesis is disrupted Affects all rapidly dividing cells Affects T and B-cells Bone marrow transplant is now the standard of care

B-cell Immunodeficiencies • • • • • • • • • • • •

Involves T-cell interaction with B-cells X-linked recessive Fair-skinned Eczema Thrombocytopenia Normal Ig-A and Ig-E levels Increased incidence of lymphoma

Bruton’s agammaglobulinemia CVID Leukemias Lymphomas Plasmacytoma Multiple myeloma Heavy Chain disease Selective Ig-A def Selective Ig-G2 def Job’s syndrome SCID Wiscott-Aldridge syndrome

Bruton’s Agammaglobulinemia

CVID

X-linked recessive Cell signalling is defective B-cell count is normal; function is lacking Early onset

• Late onset Bruton’s ( after first year of life) • B-cell count is also normal; B-cell function is lacking • Cell signalling is defective

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Leukemias

Lymphomas

• 98 B-cells for every T-cell in periphery

• 98 B-cells for every T-cell in periphery

Plasma Cell Cancer

Heavy Chain Disease

• Plasmacytoma: only ONE lesion • Multiple Myeloma: MULTIPLE osteolytic lesions

• Ig-A Multiple Myeloma of the bowel wall • Ig-A plasma cells visible on biopsy • Causes malabsorption

– Ruleaux formation – Hypercalcemia – Ig-G is most common M-spike – Kappa light chains are most common Bence Jones protienuria

Selective Ig-A def

Selective Ig-G2 def

• Many mucosal infections • Runs with selective Ig-G2 def 95% of time • Anaphylaxis during a transfusion

• Runs with selective Ig-A def • Ig-G is main opsin ( coats encapsulated organisms) • Recurrent encapsulated organism infections

– Must use a filter for all subsequent transfusions or use blood from another Ig-A def patient

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Encapsulated Organisms • Gram positive

Job’s syndrome

• Gram negatives

– Streptococcus pneumonia

– – – – – –

• • • •

Salmonella Klebsiella H. Influenza B Pseudomonas Nisseria citrobacter

The Final Two

Cell signalling defect Increased Ig-E Fair-skinned Red-haired female

Neutrophil Defects

• SCID • WISCOTT-ALDRIDGE

• Myeloperoxidase def • NADPH-oxidase def (CGD) • Absolute neutropenia

Chronic Granulomatous Disease (CGD) NADPH-oxidase def

Myeloperoxidase def • Recurrent gram positive infections

• X-linked recessive • Negative NBT test ( detects nadph-oxidase)

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At Risk for Staph and Pseudomonas Infections

Absolute Neutropenia • ANC = ( % Neutrophils + % bands) WBC

• • • •

– < 2500 – <1500 – <1000

• At risk for staph aureus and pseudomonas infections • If any fever: cover staph aureus with one antibiotic and pseudomonas with two antibiotics

Macrophage Defects

Absolute neutropenia Cystic Fibrosis Burn patients Diabetics

Chediak-Higashi syndrome

• NADPH-Oxidase def ( CGD) • Chediak-Higashi

• Lysosomes are slow in fusing with ingested pathogen • Lysosomal inclusions • Albinism

HIV

Where CD-4 receptors are found • • • • • • •

• The two populations with the highest incidence are heterosexual Black women and the elderly • Lowest risk population: prepubertal female • HIV likes acidic medium, mucosae, and CD-4 receptors

Female cervix Blood vessels Macrophages T-helper cells CNS Testes HIV is only virus that does NOT penetrate the cells; it injects its RNA into the cells

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Cancers Common in HIV

HIV Infection

• Cervical cancer • Kaposi sarcoma ( helped by Herpes 8) • CNS and testicular lymphomas

• • • •

Attaches to CD-4 receptor using GP120 GP 41 has no known function Injects the RNA inside POLymerase protein is used to integrate the RNA into host genome • Reverse transcriptase is used for transcription • P17 and P24 used for assembly

Screening for HIV

To Prevent Attachment of HIV • CCR5 • CCR4

• • • • •

Screening for HIV, cont

ELIZA ( Ig-G antibody test) Western blot ( detects protein) Northern blot ( detects RNA) Southern blot ( detects DNA) PCR ( amplifies RNA or DNA)

PCR • MORE sensitive than Southern blot or Northern blot • Used for screening only in the first 18 months of life ( mom’s Ig-G interferes with ELIZA)

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T-helper cell Counts

HIV Treatment

• Normal: 800 to 1200 normal in newborns: 1500 • Begin treatment: CD4 counts < 500

• START with two nucleoside inhibitors and one protease inhibitor • AZT • 3TC • 4DT • DDI or DDC • Rotenovir; Indinavir; Sequinavir

– Pediatrics: < 50% ( 750)

• Begin PCP prophylaxis – CD4 count < 200 – Pediatrics: < 20%

• Begin MAI prophylaxis – CD4 count < 100 – Pediatrics: <10%

Mycobacterium Avium Intracellulare ( MAI)

PCP Prophylaxis • Trimethoprim/Sulfamethoxazole • Pentamidine aerosole

• Clarithromycin • Azithromycin

HIV: THE END • THE MOST COMMON CAUSE OF DEATH FROM AGE 19 TO 44 !!!

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Leukocytes • • • •

NORMAL: 4 to 12K Leukopenia: < 4K Leukocytosis: > 12K Your leukocyte count accounts for only 10% of total leukocytes • 90% of leukocytes are marginated

LEUKOCYTES Shoot when you see the WHITES of their eyes

When Leukocytes are needed…

Leukopenia

• Demargination: caused by epinephrine and cortisol • Pavementing:

• Most common causes: acute viral infection and drugs

– Selectrins – Integrins

• Margination • Diapedesis • Migration

Drugs that suppress the bone marrow

Viruses that commonly suppress leukocytes • Any virus can do it; but, the most common are… • Parvovirus B19 • Hepatitis E • Hepatitis C

• • • •

Vinblastine AZT Chloramphenicol benzene

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Leukocytosis

Drugs that cause agranulocytosis… • Carbamezapine • Ticlopidine • Clozapine

• • • • •

Leukocytosis

Stress demargination Infections Leukemoid reaction Leukemia Myelodysplastic syndromes

Leukemoid Reaction • Extreme demargination • Looks like leukemia because WBCs so high • Increased leukocyte alkaline phosphatase ( LAP) • Extreme stress

Leukemia • • • •

Lymphomas • Cancer of the lymph nodes • Involves the lymphocytes

Too many white cells in the periphery A cancer Acute: cancer began in the bone marrow Chronic: cancer began in the periphery

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Leukemias

Myelodysplastic syndromes • Cancer that involves the ENTIRE bone marrow • All cell lines are involved

Lymphomas

Lymphomas, cont

• Hodgkin’s lymphoma: 20 to 40 y/o

• Nonhodgkin’s lymphoma

– Characterized by the Reed-Sternberg cells which have the CD 30 marker – Commonly begins as a swollen lymph node – Most malignant lymph nodes

– Usually occurs in immunocompromised persons – Presents as an abdominal mass in America, or a jaw mass in poor countries – Most common type: follicular lymphoma

• Supraclavicular • Epitrochlear • inguinal

• BCL-2 • T( 14/18)

Burkitt’s Lymphoma • • • • •

Lymphomas

BCL-2 C-myc T( 8/14) EBV Starry sky appearance

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Lymphomas

Lymphoma: Staging • Stage 1: one group of lymph nodes involved • Stage 2: two groups of lymph nodes on same side of diaphragm involved • Stage 3: two or more groups of lymph nodes on both sides of diaphragm involved • Stage 4: metastases

Lymphoma Treatment

Lymphoma Treatment, cont

Nodular Sclerosis

Lymphocyte Predominance

• More common in women • The fewest Reed-Sternberg cells • Intermediate prognosis

• Best prognosis

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Lymphocyte Depleted

Mixed Lymphocytic/Histiocytic

• Worst prognosis • A paucity of lymphocytes

• Intermediate prognosis • Has the most Reed-Sternberg cells (lacunar cells)

Myelodysplastic Syndromes

Myelodysplastic syndromes • Hyperproliferative: – Polycythemia Rubra Vera – Essential thrombocythemia

• Hypoproliferative: – Aplastic Anemia – Myelophistic Anemia ( myelifibrosis; agnogenic myeloid dysplasia)

Polycythemia Rubra Vera

Essential Thrombocythemia

• ALL cell lines are elevated; RBCs elevated the most • HCT> 60% • Itching after a hot bath • Uric acid stones • Increased gout • Splenemegaly • Increased LAP

• ALL cell lines are increased; platelets are increased the most • Platelet count > 600K

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Aplastic Anemia

Aplastic Anemia: Viruses

• ALL cell lines are depleted • Bone marrow usually suppressed by virus or drugs • Bone marrow usually replaced by fatty infiltration • Low reticulocyte count

• Parvovirus B-19: 90% • Hepatitis E : pregnant women • Hepatitis C : occassional

Aplastic Anemia: Drugs • • • •

Myelofibrosis

Chloramphenicol AZT Benzene Vinblastine

• Bone marrow is destroyed by cancer and replaced by scarring • Tear drop cells • Low reticulocyte count

The End

Or Is It…??

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Ain’t No Groove Like A Granulocyte Groove

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Lymphocytes The ultimate control

B-Lymphocytes

B-Lymphocyte Differentiation • • • • • • • •

• Develop in the bone marrow • Mature : Bursa of Fabricus equivalent ?? • Differentiate : germinal centers of lymphoid tissue

B-Lymphocyte Differentiation • • • • • • •

Macrophage ingests antigen Macrophage forms a phagosome Lysosome digests the antigen Macrophage presents the antigen Antigen binds to MHC-II complex IL-1 IL2 IL-3

Stages of B cell development

IL-4 1L-5 IL-6 IL-10 IL-12 T cells talk to B cells via the CD-40 ligand B cells display CD-19 and CD-20

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To stimulate B cells…

Primary Response • IG-M:

• Endotoxin • Pokeweed mitogen

– Arrives in 3 days – Peaks in 2 weeks – Lasts for 2 months

• Then add labelled thymidine

• IG-G: – Arrives in 2 weeks – Peaks in 2 months – Lasts for 1 year

Vaccines Schedule

Memory

Memory Response

Memory Response

(Anamnestic) • Develops beginning at 12 months; fully developed by 15 months • Involves ONLY IG-G • IG-G has highest affinity – Arrives in 3 days – Peaks at 5 years – Lasts for 10 years

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Live Vaccines

Antibody Structure/Function • • • • • • •

MMR BCG OPV ( Sabin) Varicella Rotavirus Smallpox Yellow fever

Vaccine changes at age 6 • Pertussis no longer needed • HIB no longer needed • Only half dose diptheria needed (D becomes d)

Isotype Antibody Class: Gamma; Alpha; Mu; Delta; Epsilon

Idiotype

Allotype

The actual antigen binding site

Differences between two members of same species

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Applied to Transplants… Xenotype or Heterotype Differences between two members of different species

Isograft or Syngraft

Allografts

Twin to Twin transplants

Transplants between members of same species

Autografts

Xenograft or Heterograft

Self to Self transplants

Transplant between members of different species

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T cell maturation/differentiation

T cell differentiation • • • • • • • •

T cell differentiation

Macrophage ingests antigen Macrophage forms a phagosome Lysosome digests the antigen Macrophage presents the antigen Antigen binds to MHC-II complex IL-1 IL2 IL-3

• • • • • • •

IL-4 1L-5 IL-6 IL-10 IL-12 T cells talk to B cells via the CD-40 ligand T cells talk to macrophages via B-7 molecule (on T cell) connecting with the CD-4 receptor causing the formation of the CD-28 molecule

T Lymphocytes

At the thymus…

• Develop in the bone marrow • ALL T cells have CD3 • ALL have CD4 and CD8 labels when they leave the bone marrow • They have to go to the thymus to differentiate • Express the MHC II complex • One T cell controls many B cells

• T cells enter undifferentiated • They must go through NEGATIVE selection followed by POSITIVE selection • Thymosin and Thymopoietin control clonal deletion • Thymus is one of four immunopriviledged sites in the body – Have no lymphatics; express NO antigens

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Immunopriviledged sites • • • •

CD 8 CELLS

Brain Thymus Cornea Testicle

• First cells to make it through clonal deletion • Express MHC I complex; respond to MHC I antigens (self antigens) • T suppressors: keep infection from spreading • T cytotoxic: destroy infected cells

T Helper cells

CD 4 CELLS • • • •

T Helper 1: respond to cell mediated T Helper 2: respond to humoral Secrete every interleukin except IL-I Produce interferon gamma and TNF gamma • Control B cells and macrophages

• The second set of lymphocytes to make it through clonal deletion • Express MHC II complex; responds to foreign antigens • Speaks to B cells via CD 40 ligand; speaks to macrophages via B7 / CD28 molecule • T Helper cells

NK Cells • Develop WITH the T cells in the thymus • Do NOT go through clonal deletion • Express MHC I complex and actually COUNT MHC I antigens • Express CD 16 and CD 56 • Responsible for immunosurveillance • Can detect cancer at the one cell stage

Levamisole Enhances NK cell’s ability

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Once a T cell processes an antigen… It is considered differentiated

THE END…FOR NOW

GREED A MAN SPENDS HIS HEALTH CHASING GREAT WEALTH THEN HE SPENDS HIS WEALTH TRYING TO GET BACK HIS HEALTH

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Granulocytes

Granulocytes What do they do for a living?

Granulocytes

Granulocytes

Gram stain • Step 1: add crystal violet ( binds to exposed peptidoglycan) • Step 2: add iodine ( seals blue color into wall) • Step 3: wash with alcohol ( washes off excess crystal violet) • Step 4: add saffrin ( colors outer membranes)

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Acid fast stain

Neutrophils

• Also called Ziel Neilson stain • The pathogen stains pink;ALL other cells stain blue • Completely acid fast: mycobacterium • Partially acid fast: Nocardia ( gram positive) and Cryptosporidium ( protozoa)

• • • • • •

The most abundant granulocytes 60% of WBCs First line of defence Show up at 24 hours; peak at day 3 10% are circulating; 90% are marginated Contain myeloperoxidase and NADPHOxidase

Catalase positive bacteria • Staph Aureus • Pseudomonas • Nisseria

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Free Radicals

Abscesses • • • • •

Day 1 to 3: staph aureus Day 3 to 7: strep pyogenes After day 7: anaerobes Abscesses are anaerobic by nature Occurs most commonly in: the brain ( liquefactive necrosis) • Occurs least commonly in: the lungs (most oxygen)

• Begin coming into the area at 3 hours • Oxygen burst ( peak free radical formation) occurs at day 7 • Hi energy free radicals transfer their energy to anything in the way • Area becomes anaerobic once oxygen burst occurs – Now you have an abscess

Clues to anaerobic infections • Malodorous smells • Gas formation

Absolute Neutropenia • • • • •

Neutropenia

ANC = (% neutrophils + % bands) WBC < 2500 < 1500 < 1000 ANY FEVER: cover staph aureus w/ one antibiotic and cover pseudomonas with two antibiotics; and if fever persists after 48 hours, then cover for fungus

• Most common causes: viral infection and drugs

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Monocytes

Macrophages in the… • • • • • • • •

• A macrophage in circulation • They change names after they enter tissues • Interferon mediates their transformations after they enter different tissues • Contain ONLY nadph-oxidase for killing since free radicals can kill anything

Monocytosis

Brain Lungs Liver Kidneys Spleen Lymph nodes Skin Bone

• Peyer’s patches • Connective tissue

Granulocytes

• Mcc: viral infection ( cell mediated) • Extreme monocytosis: monocytes > 15% – – – – –

Salmonella typhi Tuberculosis EBV Lysteria Syphilis

Understanding Allergies • MAST CELLS

Primary response to allergens • First contact: asymptomatic

• EOSINOPHILS

– Allergen was ingested – Phagasome formed – Digested – Presented to T-lymphocytes – T-cells bind to B-cells by CD-40 ligand – T-cells produced IL-4 – B-cells produced Ig-E

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Understanding Allergies

Secondary response to allergens • Symptomatic • When allergen re-enters the system, Ig-E now binds the allergen • Ig-E buries the F-c portion into a mast cell • Mast cell degranulates

• MAST CELLS – Histamine (immediate) – SRS-A ( 4 to 8 hrs later) – ECF-A

• EOSINOPHILS – Histaminase – Arylsulphatase – heparin

Slow Reacting Substance of Anaphylaxis (SRS-A)

Histamine

• The most potent bronchoconstricter that we know • This is responsible for late symptoms of allergies • Produced 4 to 8 hours after initial symptoms • Responsible for killing many asthmatics before we understood it

• Responsible for all of the acute symptoms of allergies • Redness and flushing • Wheezing • Itching • Warmth • Swelling (nasal congestion; rhinitis; conjunctivitis; wheal and flare; urticaria)

Eosinophil Chemotactic Factor of Anaphylaxis ( ECF-A)

Eosinophils…

• Chemoattractant for eosinophils • Responsible for the eosinophilia seen in allergic reactions

• Are counter-regulatory • Make sure mast cells do NOT get out of hand

• In other words…

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Eosinophils…

Eosinophils…

• Histaminase: breaks down histamine

• Histaminase: breaks down histamine • Arylsulphatase: breaks down SRS-A

Eosinophils…

Heparin

• Histaminase: breaks down histamine • Arylsulphatase: breaks down SRS-A • Heparin : breaks down any clots that might have formed

• Acts as a cofactor for antithrombin III • Blocks thrombin as well as clotting factors IX,X,XI and XII ( the intrinsic clotting cascade) • Follow the PTT • INR should be 2 to 3 times normal • If INR too high, reverse it with protamine sulphate

Heparin, cont

Low Molecular Weight Heparins

• If patient acutely bleeding then give FFP to correct immediately • Side effects:

• Well standardized to minimize physician errors • BENEFITS: • NO need to do daily PTTs (saves on nursing and hospital costs) • Fewer bleeding complications • Lower incidence of heparin induced thrombocytopenia

– Bleeding – Hyperlipidemia ( activates hormone-sensitive lipase) – Heparin induced thrombocytopenia ( acts as a hapten, inducing autoimmune antibodies)

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Eosinophilia • • • • •

Eosinophilia

N A A C P

• • • • •

Neoplasia, especially lymphomas A A C P

Allergic Rashes: type 1

Eosinophilia

hypersensitivity • • • •

• Neoplasia • Allergies and Addison’s disease – Allergic rhinitis and conjunctivitis

• A • C • P

Allergic Rashes: type IV

Urticaria Erythema multiforme Stevens-Johnson syndrome Toxic Epidermal Necrolysis

Eosinophilia, cont

hypersensitivity • Atopic dermatitis • Contact dermatitis • Eczema

• • • • •

– Spongiotic – nummular

Neoplasia Allergies and Addison’s disease Asthma C P

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Asthma

Eosinophilia, cont

• Intrinsic asthma: you are born with it; colds and cold air set it off • Extrinsic asthma: caused by environmental factors

• • • • •

– Dust mites – Roach droppings – Pet dander

Eosinophilia, cont • • • • •

Neoplasia Allergies and Addison’s disease Asthma Collagen Vascular Disease P

Bands

Neoplasia Allergies and Addison’s disease Asthma Collagen Vascular disease Parasites

• Immature neutrophils with maximum germ fighting ability • Have myeloperoxidase and NADPHOxidase enzyme systems • Come straight out of the bone marrow without margination • Increased numbers = a left shift

Basophils

To Be Continued…

• Said to be precursors to mast cells • They have similar granules to mast cells

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TYPE I • Immediate hypersensitivity • Involves mast cells and eosinophils • NO COMPLEMENT involved

THE FOUR HYPERSENSITIVITIES PUTTING IT ALL TOGETHER

TYPE II

TYPE III

• Cytotoxic • A deliberate attack on self • Complement comes in after the attack

• • • •

Immune complex deposition NOT a deliberate attack on the tissue Tissue is damaged due to inflammation So much COMPLEMENT used that it measures LOW

Complement System

TYPE IV • CELL MEDIATED • T cells • Macrophages

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Angioedema

ACE Inhibitors and ARBs

• Due to C-1 esterase inhibitor deficiency • Too much C5-A produced • Causes recurrent facial swelling and abdominal pains • Mcc of death: suffocation due to airway swelling • Caused by ACE inhibitors and ARBs

• • • •

• Losartan • Vosartan

ANTIBODIES • • • • • • • • •

Antimicrosomal Antithyroglobulin Anti-TSH receptor Anti-ACH receptor Anti-myelin Anti-parietal cell Anti-mitochondrial Anti-melanocyte Anti-IgG

• • • • • • • • •

Captopril Enalopril Lisenpril Rinilopril

Antibodies

Anti-rho, La, SSA Anti-SM Anticardiolipin Anti-DS DNA Anticentromere Anti-smooth muscle Antihistone Anti-Scl 70 Anti-RNP

• • • • •

Anti-topoisomerase P-anca C-anca Anti-GBM Anti-anchoring proteins • Antiplatelet • Anti-RBC

ABO

TRANSPLANT IMMUNOLOGY

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CROSSMATCH

MIXED LYMPHOCYTE REACTION

HLA TYPING

Rejection • • • •

Hyperacute Acute Chronic Graft vs host

Now it is time for the BUGS !!!

Just when you thought it was over…

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Gram + Cocci: Semisynthetic PCN’s

• • • •

More efficacious than Vancomycin Beta-lactamase resistant PCN MRSA tx- Vancomycin (linezoid)

Antibiotics

Streptococci:

Oxacillin Cloxacillin Dicloxacillin Nafcillin

• •

pyogenes viridans pneumonia

Ampicillin + Amoxicillin: can be used for Strep infections when combined with beta-lactamase inhibitor: - Sulbactam - Amoxacillin+clavulanate A illi + l l t

• Penicillin G • Penicillin P i illi VK • Ampicillin • Amoxicillin

Effective against: Enterococci Listeria

Cephalosporins:

Cephalosporins:

1st Generation: Cefazolin 2nd Generation: Cefoxitin Cefadroxil Cefotetan Cephalexin Cefuroxime Cefprozil Loracarbef

3rd Generation:Ceftazidime 4th Generation: Cefepime Cefotaxime Ceftraxone Cefotaxime

generation: Staph p and Strep p 1st g Some gram negatives (E. coli, Moraxella)

O l C Only Ceftazidime ft idi &C Cefepime f i cover “P “Pseudomonas” d ” 3rd Generation: not good for Staph (especially Ceftazidine)

2nd generation: Moraxella, E. coli, Haemophilus, Klebsiella, Citrobacter, Proteus Vulgaris

4th Generation: Cefipime (never pick Stap/Strep)

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Allergic cross reactivity with penicillins: Allergic cross reactivity with penicillins:

•Genuine allergy to PCN has less than 5% cross reactivity with Cephalosporins

•If anaphylaxis to PCN, never pick a Cephalosporin as an answer

•Seldom anaphylactic reaction will occur

Minor infectioninfection Macrolide (Clarithromycin, Azithro) New fluoroquinolones : (Levofloxacin, goti, moxi)

•Patients usually just get a rash, so you can still use cephalosporins

Serious infections: life threatening - Vancomycin, Linezolid

Quinolones:

Aminoglycosides: -Gentamicin -Tobramycin -Amikacin

Ciprofloxacin Levofloxacin Gatifloxacin Moxifloxacin Ofloxacin Good for…. E. coli Proteus Enterobacter Haemophilius

Monobactams: -Aztreonam

Moraxella Citrobacter Serratia Kelbsiella

For the test, think of these as exclusively Gram negative agents

• Ciprofloxacin is good for pseudomonas • New fluoroquinolones- first line in pneumonia’s because it covers, Mycoplasma, Chlamydia, Legionella

Aminoglycosides have a synergistic effect with PCN

Anaerobes:

Carbapenems:

Metronidazole (Flagyl)- most active against anaerobes

- Imipenem - Meropenem

Clindamycin- less active against anaerobic gram negative bacteria in the bowel (Bacteroides fragilis, Clostridium difficle)

g infections: Best use for Gram negative - Pseudomonas - Enterobacteraceas

Carbapenems have the same efficacy as Metronidazole

Excellent staph and anarobic coverage

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• If a bacteria normally lives on a part of your body, normally exposed to OXYGEN

Microbiology: Normal Flora What is bugging you !!!

• Call it a GRAM POSITIVE

• If a bacteria lives on a part of your body NOT normally exposed to oxygen….

Skin flora • Staphylococcus aureus • Staphylococcus pyogenes • Staphylococcus epidermitis • Staphylococcus saprophyticus • Propionobacterium acne

Call it a GRAM NEGATIVE

Strep pyogenes is # 1 • Lymphangitis • Impetigo • Necrotizing fascitis • Erysipelas • Scarlet fever

Skin Infections

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Skin Infections

Skin Infections

• Cellulitis: flat, red, blanches

• Mastitis: cellulitis around the breast

Skin Infections

Skin Infections • Balanitis: infection at the head of the penis

• Panniculitis- cellulitis around abdomen

Skin Infections

Skin Infections

Periorbital cellulitis: infants, trauma Staph aureus

• Orbital cellulitis: proptosis, older patient • Strep pneumonia

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Skin Infection

Skin Infections • Carbuncle: nodular induration w/ infection

• Furuncle: hair follicle in middle of carbuncle, No pus

Skin Infections

Skin Infection

• Carbunculosis: deep skin infection • Staph aureus

• Furunculosis: many infections of hair shafts

Skin Infection

Skin Infection • Fasciitis: inflammation of fascia • Plantar or Necrotizing

• Folliculitis: infection of hair shaft

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Skin Infection

Mouth Flora

• Blepharitis: infection of eye lid

• Strep pyogenes • Strep pneumonia • H. Influenza • Nisseria catarrhalis – N. gonorrhea – N. meningitidis

Stomach Flora

Mouth Flora cont. • • • • •

Peptococcus Peptostreptococcus Fusobacterium Actinomyces Strep viridans

• Helicobacter pylori

– S. mutans – S. sanguis – S. salivarius

Curved Rods

Urease Positive Bugs • • • • • • • •

• Vibrio • Camphlobacter • Lysteria • H. pylori

Proteus Pseudomonias Ureoplasma Nocardia Cryptococcus H. Pylori Staph. Saprophyticus Brucellosis

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Small Intestinal Flora

Small Intestinal Infections • Cholecystitis • Ascending cholangitis • Appendicitis pp • Spontaneous bacterial peritonitis • Abdominal abscess

•95% E. coli

E. Coli makes…

E. Coli helps you absorb..

• 90% of your vitamin K • Biotin • Folate • Panthotenic acid

• Vitamin B12

Big MaMa anerobes

Distal ileum and colonic flora • Proteus • Klebsiella • Serratia marscencens • Acenetobacter • Citrobacter • E. coli

• Bacteroides fragilis • Strep bovis • Clostridium melanogosepticus • Clostridum difficile

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•GET READY FOR THE RIDE…..

Rectal flora • Group B Strep • E. Coli • Lysteria L t i monocytogenes t

It allll buzz Its b words d from f here on !!!!

STAPHLOCOCCUS

Gram Positives GRAM POSITIVE COCCI IN CLUSTERS

Staphylococcus aureus enzymes: • Catalase + : breaks down H2O2 • β-lactamase : breaks through β lactam containing drugs • Coagulase & Staphlokinase- eats through clots – MCC of Acute Endocarditis- eats through valves – MCC of death in burn patients in the first week

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Enzymes continued::

Staphylococcus aureus toxins:

• Lipase: breaks down fat – Panniculitis – Folliculitis – Mastitis

• Staph Scalded Skin Syndrome: – Exfoliating (Nikolski sign) – Red rash all over the body – Palms and Soles

• Elastase: breaks elastin – Bullous B ll Emphysema E h (Pneumatocelle) (P t ll )

• Toxic Shock Syndrome: – Triad: high fever, hypotension (shock), rash (P & S) – Retained tampon

• Collagenase: skin & bone (breaks peptide bonds) – – – –

MCC of osteomyolitis (2nd Salmonella) Type IV (basement membrane) Type III (endothelium- arteries affected) Type II (connective tissue)

• Erythrodermic Toxin: Scarlet fever [Strep] – Sand paper rash, palms and soles, strawberry tongue

Staphylococcus aureus toxins:

Staph epidermidis:

• Lecithinase: causes skin infections

• • • •

– subcutaneous fat

• Enterotoxin: i causes food f d poisoning – dairy products- gastroenteritis – Fast 2-6 hours

Catalase + White pigment Resides under the skin MCC of shunt infections and central line infections

• Tx: Vancomycin • Linezolid- for Vancomycin resistance – Keep patient is a negative pressure room

Staph saphrophyticus:

STREPTOCOCCUS

• Catalase + • No Pigment • Frequent cause of UTI’s: – Age 5-10- play with themselves – Age 18-24: post coital UTI, no circumcision (E. coli- MCC of UTI’s)

Gram positive cocci in chains

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Streptococcus Streptococcus

Streptokinase- responsible for β hemolysis- clear zone

• Groups: A, B, C, D

• Breaks clots – converts plasminogen to plasmin

• Types of hemolysis: – α hemolysis hemolysis- partial (green zone) – β hemolysis- complete (clear zone) – γ hemolysis- no hemolysis (red zone)

• If recent Strep infectioninfection it will not work, use tPA… - Converts plasminogen to plasminbreaks clots - Binds fibrinogen- will not clot again

Strep pneumoniae (Pneumococcus)

Thrombolytics • Urokinase- opens fistulas and grafts

• Gram + diplococci • α hemolysis (green zone) • 80 strains

• Streptokinase- β hemolytic- acute MI • Tissue plasminogen activator (tPA)acute MI, acute stroke (within 3 hrs)

Pneumococcal vaccine (pneumovax) – Covers 23 strains (98%) coverage

Antidote: aminocaproic acid (for all three)

: on it… Who should be

Group A: Strep pyogenes

– > 65 y/0

• β-hemolytic (clear zone) • 70 Strains

– > 2 y/o with Sickle cell (spleen- encapsulated organisms) – End organ failure

• Most common cause for throat infectionscan lead to “Rheumatic fever”

– PSGN (skin and throat can cause this) strain 12

• 2nd most common cause of skin infections

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Group D: Strep viridians (mutans, saguis, salivarius)

Group B: Strep agalactaciae • Most common cause of Neonatal Sepsis

• α hemolytic (green zone)

β- hemolytic (clear zone) • β

• # 1 cause of Subacute Bacterial Endocarditis • Previous damage to heart valve predispose to SBE Tx: Amoxicillin

Group D: Strep viridians (mutans, saguis, salivarius)

Enterococcus (Faecalis, Faeceum)

# 1 cause of Subacute Bacterial Endocarditis

• • • •

– Septic emboli to brain – Roth spots- emboli to retina – Osler nodes- emboli to fingers (painful) – Splinter hemorrhages- emboli to nail beds – Janeway lesions- emboli to toes

Anaerobic γ hemolytic (red zone) Likes immunocompromised patients Nitrite Negative UTI Tx: Vancomycin

Vancomycin treatment:

Vancomycin:

1. MRSA

• MOA: cell wall inhibitor – Inhibits phospholipid carrier (irreversible) – Tx for all gram +

2 Staph epidermidis 2.

Toxicity: • Red man syndrome • Intense histamine release (not allergic) • Ototoxicity • Nephrotoxicity

3. Enterococcus

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Cornybacterium Diptheria

Meningitis

• Chinese letters

• 0 to 2 mo: – Group B strep: Strep agalactaciae – E. Coli – Lysteria

• Toxin that ADP-ribosylates EF-2 – (affects translocation of protein synthesis)

• 2 mo to 10 years: – Strep pneumonia – Nisseria M.

• Intracellular pathogen

• 10 years to 21 years: • Cells die, slough off, and mix with mucus, forming a grey membrane in posterior pharynx • Do NOT scrape: will hemorrhage profusely

– Nisseria M. – Strep pneumonia

• > 21 years: – Strep pneumonia

Cornybacterium Diptheria, cont.

ADP-Ribosylators

• Toxin may also cause heart block • DPT: 2m, 4m, 6m, 18m, 5-6y

• Gs: Vibrio cholera, ETEC • Gi: Bordatella pertussus p

• Tx: antitoxin first; antibiotic (toxin is hurting the patient, not the bug)

• EF2: C. diptheria, pseudomonas

Cause heart block

:

• Lyme disease • Legionella • Typhoid yp fever • Diptheria • Chaga’s disease

SPORE FORMERS

BACILLUS & CLOSTRIDIUM

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A SPORE

Bacillus

• Made of “Ca-dipocholinate”

• Has poly D-Glutamate membrane (we have L-amino acids)

• Dormant form of the bacteria

• B. Anthrax – Has a toxin:

• C Can NOT replicate li t but b t CAN release l toxin t i especially when exposed to heat (MAD!!!)

(1) lethal factor – kills cell (2) edema factor (3) protective factor- mediates entry

– Cutaneous Anthrax: malignant pustule (skin necroses)

• Is destroyed ONLY by sterilization process

– Pulmonary Anthrax: wool sorter’s disease (hot desert) mediastinal hemorrhagic lymphadenitis

– 121 degrees centigrade vaporized heat

Clostridium

Bacillus

• C. difficile: gastroenteritis associated with antibiotic use

B. Cereus: – Fried / Reheated rice (hot wok)

– Antibiotics destroy E. coli

Two toxins: – Emetic toxin- (from the rice) fast (1-6 hrs) – diarrhea, vomiting

– Pseudomembranous colitis colitis- gray membrane with yellow plaques on colon

– Diarrheal toxin (meats, sauces): 18 hrs- increases cAMP- watery diarrhea

– Current treatment is metronidazole (promotes production of free radical)

– Most effective drug - vancomycin;

– Side effect: dysguzia, disulfiram reaction

Clostridium

Clostridium

• C. perfringens:

C. perfringens: food poisoning

Gas gangrene

– Gastroenteriti associated with holiday ham or turkey

– Known to attack extremities in diabetics • Dry gangrene- necrotic skin

• Enterotoxin

• Wet gangrene- blood to the area (risk of gas emboli)

• Immediate symptoms- diarrhea

• Tx: Immediate amputation (hyperbaric chamber) ?????

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Clostridium

Clostridium • C. tetani

• C. melanogosepticus

– Associated with dirty wound

– Associated with colon cancer ( along with strep bovis )

– Give anti-immunoglobulin g to bind toxin (into the wound)

– Produces a black pigment

– Toxin: • inhibits release of glycine (inhibitory) in the spinal cord- increasing contractionrespiratory failure • Lock jaw

:

Clostridium C. botulinum: - botulism • Toxin- inhibits presynaptic release of Ach- flaccid p paralysis y (floppy ( ppy baby) y) • Muscle won’t work- die of respiratory failure

Propionobacterium Acne

C. botulinum: - botulism :

• Progesterone stimulates propionic acid or sebum

Children- honey, molasses Do not give children honey until 6 mo of age (normal flora will appear)

• Acne more severe in women and adolescent boys

Adults- ingest spores via canned foods • Tx: antitoxin first, antibiotic second

• Refer to a dermatologist when its nodular or nodulocystic • Gram positive anaerobe; hides in the hair follicles

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Propionobacterium Acne, cont.

Retinoic acid

• White comedones: clear vesicles • Black comedones: sebum has been oxidized; turns black

• Pre vitamin A • Cause proliferation of skin cells, pushing the pathogen to the surface (hypersensitivity)

• Tx: oxy-5 or oxy-10; benzoyl peroxide or abrasive pads; antibiotics ( minocycline, clindamycin, or erythromycin ); retinoic acid

• Main side effects: – – – –

hyperlipidemia (fat soluble); hyperparathyroidism; pseudotumor cerebri; teratogenic (must do pregnancy test)

Monocytosis

Lysteria monocytogenes

• Syphilis • Tuberculosis • EBV • Lysteria monocytogenes • Salmonella typhi

• The only gram positive with endotoxin (kills quickly) • Causes monocytosis monocytosis- granulomatous inflammation • Attack placentas, causing abortions

STELS

• Requires iron to grow; high incidence in patients with hemochromatosis

Lysteria monocytogenes

Curved rods

• Causes neonatal sepsis

• Vibrio • Campylobacter • Lysteria • H. Pylori

• Causes gastroenteritis associated with migrant workers, raw cabbage, spoiled milk, ilk hot h t dogs d • Curved rod, tumbling motility • Intracellular, Cold growth • Tx: Ampicillin, Macrolide, Vancomycin

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Listeria cont.

Gram Negatives

• Listeria meningitis: –Is Is the most common cause of meningitis in… • Renal transplant patients • Adults with cancer

Hemophilus

Hemophilus

• Gram negative pleomorphic rod

• 80% are not encapsulated and therefore cause noninvasive respiratory diseases ( (non-typeable) bl )

• Has IgA protease (cuts IgA) • Part of normal flora for the posterior pharynx

• 20% are encapsulated ( poly D-glutamic acid) causes the systemic form (H. inf. B)

Hemophilus

Hemophilus

Influenza:

Influenza, type B: #1 ONLY for epiglottitis • thumb print sign • drooling g • fever • stridor

2nd MCC of sinusitis,, otitis media,, bronchitis and pneumonia Strep pneumoniae # 1

Tx: intubate immediately

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Thumb Print Sign

Hemophilus • Aegyptus: Pink eye (not viral conjunuctivitis)

A

B

Painful genital lesions

Hemophilus

• Chancroid ( H. Ducreyi)- Most common ulceration with central necrotic area. Tx: Ceftriaxone

• Ducreyi: MCC of chancroid, the most common painful genital lesion (LN unilateral)

• Herpes ( Herpes Simplex II)- small vesicular rash – Acyclovir 5x day – Pancyclovir 3x day – Valcyclovir (Valtrex) 2x day- more compliant

Remember: does not cure- dec. symptomatic days dec. viral shedding dec. recurrence Pregnancy- symptomatic within 2 weeks of planned deliver- you must do a C-section

Painful genital lesions

HiB Vaccine

• Lymphogranuloma venereum (

• Has cut HiB infections down by 90%

Chlamydia trachomatis- ulcerative LN drain (bilateral) – Tx: Doxycycline

• Given at 2m, 4m, 6m, 18m; • Last dose (at 5y) no longer needed

• Granuloma Inguinale

( Calymmatobacterium Donovini) – Donovini bodies –macrophages with the bug in it

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Nisseria

Nisseria

• Meningitidis: ferments maltose + glucose

• The only gram negative diplococci

– Presents with DIC (uses up clotting factors) • D-dimer and Fibrin split products

• Has IgA protease

– Waterhouse-Fredrickson syndrome-hemorrage into adrenal gland

• Part of normal throat flora

– MCC of meningitis from 10 to 21y/o

• Encapsulated (Has the largest capsule)

– Give Dexamethasone BEFORE antibiotic to prevent hearing loss from inflammatory neurological damage

• The ONLY gram negative that releases endotoxin during the log phase

– Give Rifampin to close contacts (>25 hrs wk)

Nisseria

Nisseria • Gonorrhea: ferments glucose

• Gonorrhea, cont

– Has pili that naturally transform each year ( phase variation)

– Fitz-Hugh-Curtis syndrome: purulent abscess right underneath the liver

– #1 for causes of purulent STDs – #2 for causes of STDs (1# Chylamidia)

– Gonococcal arthritis: it loves tendons and ligaments (i.e. tenosynovitis)

• In men: 90% of cases are symptomatic • In women: 50% are symptomatic

– When cultures positive, cover for chlamydia as well ( but not vice-versa)

– Uses the pili to walk up the uroepithelium to gain access to the blood

One dose therapy for GC and Chlamydia

Nisseria

• Azythromycin: 1gm or 2gm

• Catarrhalis : does not ferment sugar

• Ceftriaxone: 250mg I.M. • Cefixime: 400mg po • Cefoxitin: 250mg I.M.

– Most common strain in the back of the throat

• Ciprofloxacin: 500mg po • Gatifloxacin: 400mg po • Ofloxacin: 400mg po

– #3 for respiratory tract infections ( sinusitis; otitis media; bronchitis; pneumonia)

– Loves mucus

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Helicobacter Pylori • • • •

H. Pylori

Curved rod, Urease positive Silver stain – GI tissue CLO test Associated: duodenal ulcers (95%) and gastric t i ulcers l (70%)

• Treatment: Amoxicillin, Bismuth, H-2 blocker or PPI • Bismuth- suffocates • 3 drugs for 2 weeks (98% eradication) • MCC- bad water (sewer system)

• Treat ALL positive gastric cultures • Hydrogen breath test is most diagnostic if available for eradication

Urease positive bugs

E. Coli

• Protease • Pseudomonas • Ureoplasma Urolyticum • Nocardia • Cryptococcus • H. Pylori • Staph Saprophyticus • Brucellosis

• Makes:

• Makes up 95% of small intestinal normal flora

• Small intestinal infections: – – – – –

E. Coli

Acute cholecystitis- + murphy sign, colic pain Ascending cholangitis- inc. alk phos Acute appendicitis Abdominal abscess Acute spontaneous bacterial peritonitis

ETEC (Enterotoxogenic E. coli)

– 90% of vitamin K – Biotin – Folate – Panthotenic acid

• Major cause of diarrhea in developing areas • Traveler’s diarrhea (rice water)

• Helps absorb: – Vitamin B-12

• Severe watery diarrhea ( > 20 L day)

• Dorsal column • Cortical spinal tract • USA- pernicious anemia • Antiparietal cell Ab

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EPEC (Enteropathognic E. coli)

EIEC (Enteroinvasive E. coli) • Plasmid shared by Shigella

• Young children and infants

• Invades intestinal mucosa

• Causes loss of microvilli

• Produces shiga like toxin (verotoxin)

• Diarrhea from malabsorption • Bloody, purulent diarrhea

EHEC (Enterohemorrhagic E. coli)

Proteus Mirabilis

• O157:H7 (out break- epidemic)

• #2 for UTIs (1# E. coli)

• Cattle, sheep, goats

• Urease positive

• Ingestion I ti off contaminated t i t d ffood d

• Associated with high urine pH, struvite stones, staghorn calculus, high ammonia in the urine

• Bloody diarrhea, endemic HUS (renal failure)

Tx: Quinolones

• Anemia, thrombocytopenia, renal failure

Klebsiella Pneumonia

Like Immunocompromised people

• #3 for UTIs • Likes to attack alcoholics and homeless people

• Serratia Marscesens • Citrobacter • Pseudomonas auregenosa

• In lungs: curant ( blood mixed with mucus) jelly sputum; likes to attack fissures • Encapsulated

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Citrobacter

Serratia Marscesens

• Produces citric acid

• Produces a red pigment

• Encapsulated • Likes to attack 0 to 2m/o (babies) • Causes multiple cerebral abscesses

Pseudomonas Auregenosa

Pseudomonas Auregenosa

• Same enzymes as Staph aureus

• Causes: whirlpool folliculitis: – Tennis shoe folliculitis- nail through shoe

• Likes to attack diabetics, burn patients, neutropenics, and cystic fibrosis

– Malignant otitis externa- mastoid (coagulase)

• Gold G ld pigment i l k staph like h aureus – Mcc of death in second week after a burn • Also produces a green pigment – Recurrent pulmonary infections in CF

• Has a fruity grape smell when plated • Likes plastic ( endotracheal tubes; bladder catheters)

– ICHTHYMA GANGRENOSUM- blood form (black bulla on the skin)

Shigella

Salmonella

• Causes gastroenteritis associated with daycare outbreaks

• Encapsulated • Loves to attack people with sickle cell anemia ( causes osteomyelitis) • Causes gastroenteritis associated with raw chicken or raw eggs • Runs and hides in the gallbladder if you treat it with antibiotics

• Most immunogenic bacteria • Has an exotoxin ( shigatoxin) which causes seizures • S. Sonneii: common in the US

– Can precipitate cholecystitis

• S. Dysentery: common outside the US

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Salmonella Typhi

Salmonella, cont

• The cause of typhoid fever

• Causes monocytosis

• Triad: (1) Fever (2) Rose spots (3) Intestinal fire

• S. Enteritidis: d most common strain in US

• Causes heart block • Associated with contaminated water

• S. Dysentery: common outside the US

Treat with ciprofloxacin

Bordatella, cont

Bordatella Pertussis

• Causes extreme lymphocytosis (? PMN’s)

• Causes “ whooping cough” – Prodromal stage- fever, runny nose – Catarrhal stage- increase mucus – Paroxysmal stage- cough

• Mcc of death was suffocation • Vaccination

• Has an exotoxin that ADP-ribosylates Gi subunit of the G-protein

• Diagnosis: do ELIZA on nasopharyngeal washings

• Exotoxin is intracellular; kills cells

• Treatment: erythromycin; also treat close contacts with erythromycin

• High cAMP increases mucus in the lungs

Pasturella Multocida

Brucella

• Causes cellulitis associated with an infected cat or dog bite.

• Causes undulating fever (5 to 7 fever spikes per day)

• Found in the saliva of cats and dogs

• Seen primarily in vetrinarians and farmers who deliver animals

Tx: Amoxacillin

• Attaches to placenta

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Bartonella Henselae

Francisella Tularensis • Causes tularemia or oculo-glandular fever

• Silver stains • Causes cat scratch disease

• Transmitted by rabbits (90%) and deer (10%)

• Carried by kittens

• Treatment: Streptomycin

Vibrio

Miscellaneous Gram Negatives

• CHOLERA – Curved rod – Has an exotoxin that ADP ribosylates Gs and elevates cAMP – Rice water diarrhea (also ETEC)

• PARAHEMOLYTICUS – Diarrhea associated with raw fish

• VULNIFICUS – Diarrhea associated with raw oysters

Campylobacter Jejunii

Yersinia

• A curved rod

• Likes the Southwest

• Attacks the jejunum, causing a p bloody y diarrhea copious

• PESTIS

• Causes diarrhea associated with raw chickens or raw eggs

• Enterocolitica

– Bubonic plague – Pneumonic plague

– Likes to attack the ileum, causing ileitis or mesenteric adenitis (mimic append) – Causes Reiter’s syndrome

Treat with erythromycin

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HLA-B27 DISEASES

Atypicals

• Reiter’s Syndrome- any post infection arthritis • Ankylosing Spondilytis- Shoeberg test, bamboo spine • Psoriasis- silver plaque on extensor surfaces • Psoriasis w/o arthritis- HLA B13

Atypicals

Chlamydia

• Have NO cell wall

• Parasites: depend on host for ATP

• Granulomatous inflammation

• Eosinophilia

• Covered by Quinalones, Macrolides and Tetracyclines

• Has two forms: – elementary body (infectious) – reticulate body ( dormant form)

• Causes interstitial pneumonia – Symptoms out of proportion to physical findings


Chlamydia Trachomatis

Chlamydia Trachomatis

• Causes trachoma: Mcc of neonatal blindness in the world

• Do ELIZA with all pap smears

– Trachoma: destruction of cornea from scarring – Prevention: apply erythromycin to eyes

• One-dose treatment: azithromycin 1gm

• Mcc of lymphogranuloma venereum • Mcc of STDs ( 90% are asymptomatic)

• Old treatment: doxicycline for 7 days

• Mcc of infertility in WOMEN • Mcc of ectopic pregnancy ( from scarring)

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Chlamydia Pneumonia

Chlamydia Psitacii

• Mcc of atypical pneumonia (0 to 2 mo)

• Associated with parrots and parakeets

• Eosinophilia • Interstitial pneumonia

• Causes interstitial pneumonia or nonbacterial endocarditis

• Symptoms out of proportion to physical findings • Steccato coughing • Found to be connected to alzheimer’s disease and coronary artery disease

Mycoplasma Pneumonia

Mycoplasma • NO cell wall

• Mcc of atypical pneumonia from age 10 to 30

• NO epithelial lining

• Cold agglutinins gg (cryoglobulinemia) ( y g )

• Look like jellyfish

• Causes “ walking pneumonia” • Interstitial pneumonia with symptoms out of proportion to physical findings

Legionella Pneumophila

Mycoplasma Hominis

• • • • •

• An occassional cause of vaginitis

Mcc of atypical pneumonia age 40yr Interstitial pneumonia silver stains Grows on CYAE Likes standing water on heating and air conditioning systems

• Causes high rise building syndrome or hotel/motel syndrome

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Heart Blocks

Legionella Pneumophila

• First degree: fixed prolonged PR interval

• Pontiac Fever: fever and nonspecific symptoms

• Second degree:

• Legionnaire’s g disease: full blown pneumonia

– Mobitz 1: progressively prolonged PR interval until a QRS complex is dropped – Mobitz 2: normal PR interval; erratic dropping of QRS complexes


• Third degree: NO relationship between P waves and QRS complexes

• Causes heart block

Infections that cause heart blocks

Ureoplasma Urolyticum • An occasional cause of vaginitis

• Legionella • Lyme • Diptheria • Chaga’s • Typhoid fever

• Has NO cell wall or epithelial lining like mycoplasma • Urease positive

Urease Positive

Fungi

• Proteus • Pseudomonas • Ureoplasma • Nocardia • Cryptococcus • H. Pylori • Staph saprophyticus • Brucellosis

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Antifungals

FUNGI

• Bind to ergestrol

• Like warmth and moisture (skin folds, groin, axilla, vagina)

– Amphotericin B- IV for systemic fungal infections • Gets confused with cholesterol • Pokes holes in your cells- releasing K+

• Like to eat sugar- in diabetics

– – – – – –

• To prevent fungal infections, keep cool and dry • Have a unique lipid in their membrane called ergesterol

Nystatin Mycostatin Miconazole Clotrimazole Tolnaftate Terbenafine

– Flucytosine (5FC) – inhibits mitosis (acts like pyramadine)

Superficial Fungi

Antifungals • Inhibits ergesterol synthesis

• Piedre – black balls on the hair shaft

– Fluconazole- best CNS penetration – Itraconazole – Ketoconazole- inhibits P450’s, blocks 5α reductase

–Tx: cut hair

• Microsporum Beigeii- white balls on hair shaft

Inhibits microtubules - Griseofulvin

–Tx: cut hair

Cutaneous Fungi

Cutaneous Fungi

• General (4 classes):

• Tinea – Capitus - scalp – Versicolor- v on back – Corporus- body ring worm – Manis – between fingers – Nigra – palms – life lines get dark – Intertrigo- skin to skin – Cruris- jock itch - groin – Pedis – between the toes – Unguum – under nail beds (one nail affected)

– Dermatophyton – skin – Trichophyton- hair follicle – Epidermaphyton- epidermis – Microsporum- (Wood lamp +)

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Vaginitis

Deep Fungi

• Candida: curdy white discharge; pruritic – Candida part of normal flora and lactobacili keep it in check (antibiotics will destroy lactobacilli) – Tx: Fluconazle

• Onychomycosis- fungus of nails • Candidiasis – most common cause of vaginitis

• Gardnerella: G d ll fishy fi h odor; d “ clue l cells” ll ” – Tx: Metronidazole

• Trichamonas : frothy green discharge – Protozoa: flagella – Tx: Metronidazole and remember to treat partner (STD)

Systemic Fungi

Systemic Fungi

• Histoplasmosis (Midwest) pigions, bats

• Sporothrix- rose gardner, skin-potassium iodine; Amph B and Fluconazole if systemic

• Blastomycosis (North east) pigon, broad base budding

• Cryptococcus- AIDS patient with meningitis indian ink stain meningitis,

• Coccidiomycosis ( South west) Broad base budding

• Aspergillus-Moldy hay or moldy basement (mimics asthma)

• Paracoccidiomycosis (South America) shipwheel

• Rhizor/ Mucor – nose of diabetic patients

Pulmonary Infiltrate with Eosinophilia

Symptoms from the Southwest

• Allergic Bronchopulmonary Dysplasia

• Coccidiomycosis- fungus

• Loeffler’s Syndrome

• HantavirusH t i virus i (hemorrhagic) (h h i )

– – – – –

• Yersinia Pestis- bacteria

Necator Americanus Anclystoma Duodenale Strongyloides Shistosomiasis Ascaria Lumbricoides

• Churg-Strauss

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PARASITES

PARASITES

• Cause gastroenteritis • T-cells, Macrophages, Eosinophils • LOW VOLUME STATE

FARTENPOOPIN

• Chronic infections lead to iron deficiency anemia

Liver Flukes

Liver Flukes

• Toxacara : cat or dog poop

– Carti- cat larvae – Cani- dog larvae – Cutaneus larva migrans- burrowing under skin

• Schistosomiasis : walking barefoot thru a swamp

– S mansoni: liver cancer – S. hematobium: causes squamous cell carcinoma of the bladder (chronic irritation)

• Ecchnococcus : messing with sheep; raw lamb; dog food – Causes solitary ( hydatid) cyst of the liver

Liver Flukes

Hookworms • Hooks into the intestinal/bowel wall • Severe cramps and diarrhea

• Clinorchis ( or opthorchis) • Sinensis: seen in Chinese; likes the p ) biliaryy tract ((Alkaline Phosphatase)

• “NEAT NEAT AS AS” – Necator americanus – Enterobius Vermiculris- pin worm

TX for all liver flukes: Parziquantel

• Pruritis ani (eggs) • Scotch tape test- female comes out at night • Worm lives in the cecum

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Hookworms

Hookworms

“NEAT AS” • Anclystoma Duodenale

• Treatment: – Mobendazole- paralyzes microtubules (can’t hook on to tissue)

– Duodenal obstruction

• Trichuris Trichurium Trichurium- Whip worm

– Pyrantel pamaoate- specific treatment for pin worm

– Anchors into rectum – Rectal prolapse

• Ascaris lumbricoides • Strongyloides

– Thiobendazole- tx for Strongyloides

NASSA

Flat Worms

• NASSA- parasites associated with loffler syndrome (endocarditis and pneumonitis)

• Will curl around the intestine: – D. Latum- like to eat B12 – Tanea Saginatum- raw beef – Tanea Solium- raw pork, swims in aqueous q humor of the eye y – Trichinella Spiralis- raw bear meat, tunnel under skin causing myoisitis

• Necator americanus • Anclystoma duodenale • Schistosomiasis • Strongyloides • Ascaris lumbricoides

Tx: Hyclosamine Niclosamine Inhibit oxidative phosphorylation – decreasing ATP

Protozoa Brain:

Protozoa

– Naeglaria Fowleri • Swimming through swamp- cribiform plate • Fulminant meningo encephalitis – Toxoplasmosis • Cat litter (feces) • Parietal lobe ring enhanced lesion • Tx: Pyremethamine/ Sulfadiazine – Trypanosoma Rhodienses • Carried by Tsetse fly • African sleeping disease

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Protozoa

Protozoa

Cornea: • Acanthomoeba

• Erlichiosis – Dog licking face (in saliva) – Penetrates side of eye

– Contact lenses – Will eat through cornea

Protozoa

Protozoa

Heart • Trypanasoma Cruzi

Lung: • Pneumocystic Corinii

– Chagas disease – Eats g ganglia g and causes heart block – South America – Reduuvid bug

– Silver stain (also Legionella) – CD4 count < 200 – Tx: Bactrim (SMX-TMP)

Protozoa

Protozoa

GI

GI

• Giardia- gastroenteritis

• Microsporidium

– Loves fresh water/well water – Hiking in the mountains – Tx: IV Metronidazole

– MCC of diarrhea in AIDS patients

• Cryptosporidium • E. histolyticum

– Watery diarrhea – Partially acid fast – Tx: Ciprofloxacin

– Multiple liver abscesses (never do surgery) – Tx: Metronidazole (8 weeks)

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Protozoa

Protozoa Skin • Leschmaniasis (RASH)

GU • Trichimonas

– Gulf War syndrome – Sand fly

– 3rd MCC of Vaginitis – Tx: Metronidazole 2gm g x1 – Also treat partner

• Leschmania Donivini (face eaten away) – Attacks skin and nostrils

• Leschmania Rhodiensis (organ) – Systemic (attacks organs)-Kala Azar – Tx: Stibogluconate

Protozoa

Protozoa

Lymphatics • Wucheria Bacrofti

Blood

– Elephantitis – No treatment

• Babesiosis – East coast – Looks different on a smear – Tx: anti-malarial – Ixodes tick (same for Lyme disease)

Blood

Protozoa

Protozoa Blood- Plasmodium • Symptoms

• Plasmodium Malaria - MC strain world wide (fever every 3rd day) • Falciparum Falciparum- most fatal (hemolize RBC’s)

– Malaria- fever every 3rd day – Falciparum, vivax, ovale- fever every 2 days

• Treatment:

– Black water fever- urine turn black

• Vivax- go to the liver (chronic malaria)

– – – –

– Likes reticulocytes (young RBC’s)

• Ovale- go to the liver (chronic malaria) – Likes mature RBC’s

Quinine Chloraquine- mostly RBC’s Mefloquine- good liver penetration Primaquine- best liver penetration (vivax and ovale)

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Mycobacterium, Spirochetes , Rickettsia

Mycobacterium • NOT a true bacterium • Has bacterium in its name because it has a peptidoglycan wall • Atypical due to MYCOLIC ACID in its membrane • Cell mediated inflammation • If you destroy mycolic acid, you destroy mycobacterium

Mycolic Acid

Isoniazid ( INH)

• A special lipid found in the wall of mycobacterium

• • • •

• INH works by inhibiting mycolic acid synthesis

Inhibits the synthesis of mycolic acid Fat soluble Pulls vitamin B6 out of the system Must give vitamin B6 with this drug to prevent neuropathy

• Side effects: myositis; hepatitis; hepatic necrosis ( especially after age 35 years); neuropathy; oxidizes RBCs: blocks P450

Primary response to Mycobacterium

Primary Tuberculosis

• Asymptomatic • Ghon focus: naked tubercle on respiratory epithelium • Virulence Vi l factor: f CHORD FACTOR • Ghon complex: tubercle ingested by macrophages and taken to the lymph nodes • Granuloma: macrophages now surrounded by T cells

• Usually lands in the RLL in terminal bronchioles • Once GRANULOMA is formed: – Interferon – Tumor Necrosis Factor – 1 hydroxylase

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Infliximab

• As long as your T cells and macrophages stay healthy…

• An antibody against TNF • Useful in patients with RA

• You have nothing g to worryy about. .

• Decreases joint destruction

But if cell mediated immunity is ever impaired…

Secondary Tuberculosis • Fever, night sweats, weight loss, and hemoptysis • RLD profile • Cavitary lesion visible in upper lobes on the Xray

• Mycobacterium is still alive within macrophages • Mycobacterium explodes out of the macrophages h and d into i t the th airways i • Hemoptisis occurs • Mycobacterium works its way to the upper lobe and sets up a cavitary lesion • Patient now very symptomatic

Tx: first isolate patient when TB is suspected; get sputum sample for culture

Disseminated Tuberculosis • After TB replicates inside of the cavity, it then disseminates

• • • • • •

• Mycobacterium now has full access to the entire body.

In GI: causes ileum obstruction Bone: Pott’s Disease Lymph Nodes: diffuse lymphadenopathy Skin: Erythema Nodosum Along Psoas Muscle: cold abscess CNS: posterior fossa – Neuropathies – Hydrocephalus – Meningitis

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Disseminated Tuberculosis • Renal: sterile pyuria • Adrenal gland: insufficiency • In pregnant woman: treat as in anyone else • Most people don’t know they have ever come in contact with TB unless…

TB Treatment

TB Treatment

• Four drugs for 4 months for everyone

• At the end of twelve months of treatment, then culture the sputum again

• If strain of TB is sensitive to both INH and RIFAMPIN, then finish 8 more months with just these two drugs

• Sputum cultures are repeated monthly • Stop treatment when there are three consecutive negative sputum samples

• If strain of TB is NOT sensitive to both of these drugs, complete 8 more months with four drugs

• Patient may take drugs every day; or he may opt to take it every other day but witnessed by a healthcare professional

• Substitute other drugs if any bad side effects

TB Prophylaxis

Mycobacterium Family

• INH plus vitamin B6 for 9 to 12 months

• M. • M. • M. • M. • M. • M. • M.

• In pregnant women, you must still give i prophylaxis h l i • In patients with history of BCG vaccine, ignore the history, and merely follow the algorhythm

TB Leprae ( Hanson’s Disease) Avium Intracellulare Scrofulaceum f l Marinum Ulcerans Kansasii

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Dapsone

Spirochetes

• Indicated for the treatment of dermatitis herpetiformis, Pneumocystis carinii in HIV patients, and for leprosy

• So named due to their spiral shape

• For leprosy: use with clofazimine and p for 6 to 24 months rifampin

• Have axial filaments at their two ends

• Mimics PABA like sulfa drugs

• Use a lateral tumbling motion

• Side effects: megaloblastic anemia; oxidizes RBCs; coombs positive hemolytic anemia; inhibits P450 system

• Cell mediated response

Treponema Pallidum

Tertiary Syphilis

• Causes syphilis • The most common cause of painless genital ulcer

• Tabes Dorsales • Shooting, lancinating, stabbing neuropathy

• Primary syphilis- non tender chancre ( contagious )

• Syphilitic aortitis • Argyle Robertson pupil

• Secondary syphilis- 1 to 3 mo ( rash P & S )

• Syphilis loves to attack bones ( saber shins)

• Tertiary syphilis *

Toxoplasmosis

TORCH infections

• Multiple ring enhancing lesions in the parietal lobes • Caused by cat urine • Asymptomatic in healthy people (walled off in a granuloma) • Symptomatic S t ti iin pregnantt women d due tto suppressed immune system • Pregnant women should NOT change a litter box • Treat with pyremethamine/sulfadiazine combo

• They attack in the first trimester ( except herpes) • They cause severe neurological damage • All cause IUGR, microcephaly, hypotonia and developmental impairment • How do you separate them ?

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Rubella

Syphilis

• Blueberry muffin rash • Cataracts • PDA • Hearing loss l • Autism

• Loves to attack bones – Flat forehead – Saddle nose – Sniffles – Micrognathia – Rhagades – Hutchinson’s teeth – Sabre shins

Autistic

Autism

• AUTISM- below normal intelligence, difficulty forming relationships

• Four features: – Inability to bond – Impaired language development – Automatism- no control of there actions – Overreacts to small disturbances

• Asperger syndrome: milder form, normal intelligence and lack social skills • Pervasive developmental disorder of childhood

• Brain is found on autopsy to be arrested in development

• Rett’s syndrome- girls only, starts by age 4, hand wringing

• MMR controversy

Herpesvirus

Cytomegalovirus

• Attacks newborn on the way through the vagina

• Loves to attack the retina

• Loves to attack the temporal lobe, causing temporal lobe hemorrhagic encephalitis

• Mcc of Congenital blindness • Causes central calcifications

• If pregnant mother has an outbreak of lesions within two weeks of delivery, do a C-section

• Attacks the midline

• Give pregnant mother acyclovir in last month to prevent outbreaks

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Syphilis

Treponema Family

• Treatment:

• Treponema Pallidum

– Primary syphilis: 1.2 million units of long acting penicillin (Procaine or Benzathine) – Secondary syphilis: 2.4 million units, half in each h buttock b tt k – Tertiary syphilis: 2.4 million units once weekly for 3 weeks – Neonatal syphilis: 50,000 units per Kg per day in divided doses

• Treponema Pallidum variant: Bijel • Treponema Pertenue: Yawstropical form • Treponema Carateum: Pinta

Borellia Borgdorferi

Borellia Borgdorferi

Lyme Disease • Primary stage- bull’s eye rash (resolve in 1 month) • Secondaryy stageg flu like symptoms y p , organ involvement • Tertiary stage- arthritis

• Treatment: – Penicillin – Doxycycline – If a pregnant woman is bitten by a tick, treat with IV ceftriaxone – Any patient with heart block, hospitalize and treat with IV ceftriaxone

• Dx: history of Erythema Chronicum Migrans; – Do IgM and IgG titers

Leptospira Interrogans

Borellia Recurrentis

• Causes leptospirosis

• Causes Relapsing Fever

• Seen primarily in sewage workers

• Fever occurs once weekly

• Transmitted by rat urine

• Organism hides in lymph nodes and mutates slightly each week

• Weil’s Disease: attacks the liver (hepatitis) and the kidney (nephritis)

• Treat with penicillin or doxicycline

• Causes Fort Braggs Fever

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Rickettsia

Rickettsia

• Rickettsia Rickettsia: RMSF: tick borne

• Treatment: Doxicycline or Chloramphenicol

• Rickettsia Typhi: endemic typhus: flea borne • Rickettsia Prowzekii: epidemic typhus: louse borne • Rickettsia Akari: rickettsial pox: mite borne • Rickettsia Tsutsugamushi- scrub typhus; chiggers

We both wish you the best of luck on your exam !!!!

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What all viruses do… • • • • • • •

And NOW…The final topic!

VIRUSES

To prevent uncoating

Invasion Adhesion Penetration Uncoating Replication Assembly Lysogeny

To prevent replication

• Amantidine • Rimantidine

• • • • • • •

Acyclovir Pencyclovir Demcyclovir Valcyclovir Famcyclovir Gancyclovir Ribavarin

Detectives • • • • • •

The 90% • DNA Viruses

Southern blot Northern blot Western blot Southwestern blot ELIZA PCR

– Double stranded ( ex parvovirus and hepadnovirus – Replicate p in nucleus ( ex poxvirus) – Assemble on nuclear membrane – Naked ( ex herpesvirus)

• RNA Viruses – Single stranded ( ex orthomyxovirus and renovirus – Replicate p in cytoplasm y p (ex retrovirus) – Assemble on cell membrane – Enveloped (ex cocksackievirus) – +-strand vs -strand

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Encephalitis • Presents with headache and ataxia

Most Common causes of viral infections… infections

• Causes: – Arbovirus – Herpesvirus

From head to toe

Common Cold

Meningitis • AKA aseptic meningitis • Presentation: mild headache; photophobia; Kernig’s and Brudzinski’s signs • CSF CS results l • Causes: enteroviruses

• • • • •

Childhood Rashes

Common Childhood infections • • • • • • • • •

Mumps Rubeola Rubella Varicella Varicella-Zoster Fifth’s disease Roseola Pityriasis Rosea Rosacea

Rhinovirus Coronavirus vs Adenovirus Herpesvirus Influenzavirus Parainfluenzavirus

• Hand-Foot-Mouth disease • Kawasaki disease • Molluscum contagiosum i

• • • • • • •

Seborrheic dermatitis diaper dermatitis Erythema toxicum Pediculosis pubis Milia Mongolian spots Nevus Flemmeus Café au lait spots Port wine stain

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Croup

The four itchiest rashes • • • •

• Stridor and barking cough • Steeple sign on neck film • Cause:

Urticaria Scabies Dermatitis herpetiformis Lichen planus

– Parainfluenzavirus 80% mild – RSV 15% severe – Adenovirus – Influenzavirus

Bronchiolitis

Myocarditis

• All the signs and symptoms of asthma • Under 2 years of age • Caueses:

• Leads to loss of contractility • Diffuse ST wave depression on EKG • Cause:

– Parainfluenzavirus 80% mild – RSV 15% severe – Adenovirus – Influenzavirus

– Cocksackie B Virus

Pericarditis • • • •

Gastroenteritis • In adults: Adenovirus • In children: Rotavirus • Travel: Norwalk agent

Causes a friction or tri-phasic rub May lead to tamponade Diffuse ST wave elevation Cause: – Cocksackie B Virus

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Cystitis

Hepatitis

• Urgency and frequency • Cause: Adenovirus

Hepatitis

Chronic Active Hepatitis • • • • •

Active inflammation on biopsy Fibrosis present May progress to liver cancer Will lead to cirrhosis Due to Hepatitis B: Tx with interferon and lamuvidine • Due to hepatitis C: Tx with interferon and ribavarin

Chronic Carrier

Chronic Persistent Hepatitis • Elevated liver enzymes or persistent symptoms after 6 months • No active inflammation or fibrosis on liver biopsy

• • • •

Still has positive HbSag after 6 months No active inflammation or fibrosis on biopsy Still pose a threat to others Can NOT be blood donors or organ donors

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THE END

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4/29/2008

G5 P4 Ab1 G: Gravita: number of pregnancies P: Para: > 20 Weeks

Obstetrics and Gynecology

Ab: Abortive: abortions

G6 P0 Ab5

Ultrasound (Utz.)

Prenatal Diagnostic g Testing

Non-invasive imaging No adverse effects on the fetus 18-20 weeks of gestational anatomical anomalies Accuracy for gestational age: At 12 weeks +/- 5 days At 18 weeks +/- 7 days

Chorionic Villous Sampling (CVS)

Nucal Translucency 10- 14 weeks via Utz.

Aspiration of placenta tissue (9-12 wks) Sono guided Karyotyping

Thick area you should think of cystic hydroma “Down’s Syndrome”

Pregnancy loss rate 0.7%

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Percutaneous Umbilical Blood Sampling (PUBS)

Amniocentesis Transabdominal needle to withdraw amniotic fluid under sono (15-20 wks)

Fetal blood from umbilical vein (> 20 weeks)

Looking at DNA from fetal cells

Fetal karyotyping

Not enough fluid prior to 15 weeks

IgM antibody

Pregnancy loss rate (0.5%)

Blood typing

24 weeks- Rh isoimmunization (bilirubin levels)

Intrauterine Blood Transfusion

34 weeks- Lecithin-sphingomyelin

Pregnancy loss rate 1-2%

Fetoscopy

Fetal Development

Experimental (18-20 weeks)

1 week for Implantation

Fetal tissue biopsy Ichthyosis y

Genetic skin condition (fish scales)

Folic acid 1mg 4mg

Coagulation in twin-twin transfusion

Week 2-3 post conception

Weeks 4-8 Post Conception

Bilaminar germ disk:

Major organs forming Teratogenic risk

- Epiblast - Ectoderm - Hypoblast - Mesoderm Cytotrophoblast - Endoderm Synchotrophoblast Must have all 3 in order to a teratogen to cause problems

Primitive streak

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Female vs Male cells

Teratogenesis Stages

Theca Granulosa

Conception to end of first week Weeks 3-8

Leydig L di Sertoli 5 alpha reductase – DHT (external genitalia)

Post week 9

Teratogens

Teratogenic Syndromes

Ionizing radiation

Alcohol: fetal alcohol syndrome

Chemotherapy Long philtrum T b Tobacco ETOH

Midfacial hypoplasia

Cocaine Short palpebral fissure



Diethylstilbestrol (DES)

Isotretinoin (Accutane)

T-shaped uterus

Congenital deafness Congenital heart defects

Vaginal adenosisadenosis clear cell carcinoma

iPLEDGE

Incompetent cervix

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Lithium:

Streptomycin

Ebstein anomaly (R heart defect)

CN 8 damage- hearing

Tricuspid lower Very large right atrium


Teratogenic Syndromes Thalidomide: drug for N/V

Tetracycline Competes with Ca2+

Phocomelia (days 42-48)

Teeth discoloration after 4 months

Pyloric and duodenal stenosis


Teratogenic Syndromes Warfarin (Coumadin)

Valproic acid (Depakote)

Chondrodysplasia: stippled epiphysis

Neural tube defect Mgt: Migrans and Bipolar

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Human Chorionic Gonadotropin

Pregnancy Hormones

Syncytrophoblast In blood by day 10 Alpha subunit Beta subunit (specific)

Human Placental Lactogen (HPL)

High levels of hCG Twins Hydatiform moles Choriocarcinoma

Increased through pregnancy Antagonizes tago es insulin su

LOW levels: Ectopic Threatened abortion Missed abortion

Skin

Organ system changes in pregnancy

Line nigra Chloasma Chadwick sign Stria gravidarum Spider angiomata/palmer erythema

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Heart

Murmurs

Blood pressure

Systolic murmur:

Plasma volume

Diastolic murmur:

Femoral venous pressure CO Peripheral vascular resistance (PVR)

GI

Blood

Stomach:

RBC’s Plasma volume

Large bowel

WBC’s Platelets Coagulation

Renal

Pulmonary Tidal Volume

Increase in size:

Minute volume

Gl Glucosuria: i

Respiratory volume

Proteinuria:

Blood gases

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Endocrine

Fetal Circulation 3 in utero shunts:

Pituitary

Ductus venosus

Thyroid

Foramen ovale Ductus arteriosus

Fetal Hart Tone (FHT)

Fetal Testing

Doppler stethoscope: 10-12 wks

Auscultation 18-20 wks

Quickening: 16-18 weeks (primigravida 18-20)

Ultrasound Dating

Pregnancy 1st trimester

1st trimester:

< 13 weeks N/V

2nd trimester and 3rd

S tti / bl Spotting/ bleeding di

Biparietal diameter Head circumference Abd. Circumference Femur length

Wt gain 5-8 lbs Complication: spontaneous abortion

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Pregnancy 2nd trimester

Pregnancy 3rd Trimester

13 – 26 weeks

Decreased libido, back pain, urinary frequency

Round ligament pain

Lightening

Braxton-Hicks contractions

Bloody show

Quickening

Wt gain 1 lb/week

Wt gain 1 lb/wk

Complication: PROM

Complication: incompetent cervix

Mean Corpuscular Volume

Prenatal Lab Test

Hb/Hct- low due to dilution

MCV most reliable < 80 > 100

Rubella IgG antibody

Hepatitis B Virus

Antibodies present

HBV surface antibody: successful vaccination HBV surface antigen:

Absence puts patient at risk

E antigen:

Immunization:

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STD screening

Urine Screening

Cervical cultures:

Urinalysis: Proteinuria Ketones Glucose Bacteria

Syphilis: VDRL RPR MHA-TP FTA

Culture: asymptomatic bacteruria (ASB)

Mgt. Penicillin

Tuberculosis Screening

HIV screening

PPD or Tine test:

Recommended for all pregnant women

Positive skin test

Opt out: informed refusal

CXR negative

Opt in: informed consent

CXT positive

Elisa test

Alpha Fetal Protein

Detectable HIV antibodies

True causes of increased AFP:

Babies born to an HIV + mothers MCC dating MCCd ti errors

Western Blot Zidovudine

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Triple Marker Screening

Triple marker screening

MS-AFP hCG Estriol

Trisomy 21 Downs

Trisomy 18 Edward’s

MS-AFP

Accurate dating is important

hCG Estriol

Do karyotype for both

Third Trimester Lab Test

Antenatal Fetal Testing

Diabetic Test:

1hr (50 gm) oral glucose

3hr (100 gm) oral glucose

Normal: FBS: < 95, 1hr <180, 2hr < 155, 3hr < 140

Nonstress Test (NST)

Fetal Monitor Tracing

Check frequency of fetal movement External fetal HR monitor Accelerations

Base line FHR: 110-160 < 110 Bradycardia

Meds: beta adrenergic blockers, anesthetics Fetal arrhythmiaarrhythmia congenital heart block (lupus)

< 32 wks: > 10 or more BPM, lasting >10 sec

>160 Tachycardia

Meds: beat adrenergic agonist (terbutaline, ritodrine) Fever Fetal repetive movements

> 32 wks: > 15 or more BPM, lasting > 15 sec

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Early Deceleration:

Variable Decelerationcord compression

head compression

Late Decelerations- uteroplacental insufficiency ( fetal acidosis)

Biophysical profile (BPP)

5 components of fetal well being: 1. 2. 3. 4. 5.

NST: scores 0-2 for each Amniotic fluid volume Fetal g gross body y movement Fetal extremity tone Fetal breathing movements

2-5 assessed through Utz.

BPP scoring

Contraction stress test (CTS)

8-10 = reassuring (weekly BPP)

Testing fetus response to tolerate transitory decreases in blood flow

4-6 = worrisome

Presence or absence of late deceleration

> 36 wks- deliver < 36 wksk BPP every 12-24 12 24 h hours

Induce with IV oxytocin

0-2 = fetal hypoxia (deliver ASAP)

Negative test is good- no late Dcells

11 463

4/29/2008

Umbilical Artery Doppler Measures ratio of Systolic and Diastolic blood flow in umbilical artery

Infections

Increased throughout g pregnancy, p g y, since diastolic pressure falls more

Group B beta hemolytic Strep

Treat for Group B Strep if…

Normal GI tract flora

Positive urine culture GBBS

30% of women are asymptomatic carriers

Previous baby had GBBS

Vertical transmission

Screening by vaginal cultures:

Early onset

3rd trimester If + then prophylaxis IV PCN

Late onset

Preterm or Membrane rupture > 18hrs, or maternal fever…… Mgt. Prophylaxis IV PCN

Mgt: IV penicillin: if allergic- Clindamycin and Erythromycin

Toxoplasma Gondii

Varicella Chicken Pox Herpes Zoster Spread via respiratory droplets ZIG ZAG skin lesion Maternal varicella pneumonia

Parasite associated with cat feces Raw goat milk Under cooked infected meat Vertical transmission Lethal if first trimester Third trimester- asymptomatic Intracranial calcification

Mgt: administer VZIG to suspected gravid within 96 hrs of exposure

Mgt: Pyrimethamine Sulfadiazine

12 464

4/29/2008

Rubella

Cytomegalovirus (CMV)

RNA virus spread through respiratory droplets Transmission only if primary infection Fetus= VSD Neonate= congenital deafness Prevention: rubella IgG antibody screening

Spread via body secretions Life long latency, so fetus can get it on reactivation Periventricular calcification MCC of congenital deafness

Live attenuated virus- avoid pregnancy for 1 month after immunization

Mgt: Ganciclovir

Herpes Simplex Virus (HSV)

Human Immunodeficiency Virus

Multinucleated Giant Cells Maternal genital lesion is MC route for fetal infection

HIV + mothers take zidovudine starting at 14 wks until delivery

Dx: + culture from ruptured vesicle Prevention: C-section C section

C-section for delivery Breast feeding contraindicated

If membrane already ruptured and it has been >8-12 hours- too late to do a C-section

Neonate gets AZT for 6 wks, then check again

Mgt: Acyclovir

Maternal Syphilis infection

Bleeding g late during pregnancy

Primary- painless ulcer with rolled up edges (chancre)- gone in 2-3 wks Secondary- 2-3 months after contact, maculopapular skin rash and condyloma lata Tertiary- organs affected

Heart- aortitis Dorsal column- tabes dorsalis CSF +

Mgt: Vaginal delivery: Benzathine PCN and if allergic desensitization to PCN

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4/29/2008

Bleeding

Abruptio Placenta

Painful bleeding

Initial evaluation: Maternal : check vitals Fetus: FHT

Overt (external)

Concealed (internal)

Mgt: large bore IV NS Foley- monitor output If fetal jeopardy is present or +/- 36 wks- deliver

Types of Abruption

Mgt. of Abruptio

Mild- no fetal abnormality

Emergency Cesarean if mother or fetal jeopardy

Moderate- 25 – 50% surface separation

Vaginal delivery if bleeding is controlled or > 36 wks

Monitor o to for o late ate D-cells ce s

Severe- abrupt, knife like uterine pain

Conservative (in hospital)

> 50% placental separation DIC may occur Severe late D-cells

Stable and remote from term Confirm placental location on sono Replace fluids

Placenta Previa

Mgt. for Placenta Previa

Painless bleeding

Emergency Cesarean if mother or fetal jeopardy

Placenta is implanted in lower uterine segment

Vaginal delivery- lower placental edge must be > 2cm of os

Common early in pregnancy (migration)

Scheduled C-section Fetal lung maturity by amniocentesis

3 types: Total, complete or central- covers os Partial- partial cover of os Marginal, low lying- near os

Conservative (in hospital) Bed rest, preterm, confirm placental location

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Complications of Placenta Previa

Vasa Previa Fetal vessels transverse the internal OS

Villi may invade uterine tissue

Bleeding from fetoplacental circulation Endometrium

Myometrium

Serosa

Rapid fetal exsanguination

Placenta accreta 75%

Due to amniotomy (AROM)

Placenta Increta 20%

Triad:

ROM Painless vaginal bleeding Fetal bradycardia

Placenta percreta 5%

Mgt: immediate C-section

Bladder

Uterine Rupture Triad:

Obstetrical Complications p

Painful bleed Loss of FHT Head floating

MCC- classical incision MCC Myomectomy Excessive oxytocin Mgt: surgical

Abortion vs fetal demise

Fetal demise (>20 wks)

Fetal death prior to 20 weeks: Abortion

Most serious consequence…

-

Missed Threatened Inevitable Incomplete Complete

DIC (disseminated intravascular coagulation) Usually takes 3-4 wks to occur Release of thromboplastin from deteriorating fetal organs

After 20 weeks: fetal demise Must report to the state

Do not deliver until mom is ready as long as there is no DIC

15 467

4/29/2008

Twin Delivery Vaginal

Rho GAM

C-section

Pooled anti-D IgG

?

Passive antibodies (IM) B

B A

Both Cephalic

A- breech B- cephalic

IIgG G antibodies tib di attach tt h to t the th foreign RBC and lysis occurs before mom can produce an immune response

B

A

A

A- cephalic B- breech

RhoGAM given at…

Kleihauer Betke Test

Give to Rh(D) negative mothers at 28 weeks

Quantitates fetal RBC’s in mom’s blood

Within 72 hours of

Looks at a peripheral smear

Chorionic villus sampling Amniocentesis Rh+ delivery D&C

Will access if more than one vial is needed

Give 300 micrograms (1 vial)

Premature Rupture of Membrane (PROM)

Diagnosis PROM Sterile speculum

Risk of ascending infection

Pooling – clear fluid in posterior vaginal fornix

History of sudden gush of copious vaginal fluids

Nitrazine p positive ((turns p paper p blue))

Oligohydramnios on Utz.

Fern test- on microslide Chorioamnionitis:

Maternal fever Uterine tenderness Confirmed PROM

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4/29/2008

Management PROM

Preterm Labor 3 criteria: Between 20 and 37 weeks

Uterine contractions present (don’t use tocolysis)

Uterine contractions (3 in 30 min.)

Chorioamnionitis IV antibiotics, Chorioamnionitisdelivery

Cervical changes (dilation changes > 2cm)

No infection < 24 wks- dismal outcome >24- bed rest, IM betamethasone, 7 day prophylaxis of ampicillin and erythromycin

Tocolytic Agents

Types of Tocolytics

Prolong pregnancy for up to 72 hrs

MgSO4- blocks Ca2+ Monitor: DTR Antidote: IV calcium gluconate Contraindications: renal insufficiency, MG

IM betamethasone to work Transport mother/fetus to neonatal intensive care

Beta adrenergic agonist- terbutaline, ritodrine

Given parenteral

Ca2+ blockers- Nifedipine, Procardia PG inhibitors- Indomethacin

Post Date Pregnancy

HTN during p g pregnancy y

Worried about placental breakdown Fetus not getting the O2 it needs Meconium risk 42 wks maximum time in uterus Shoulder dystocia

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Preeclampsia: Mild

Eclampsia Unexplained grand mal seizures with…

Severe

HTN Proteinuria > 20 wks gestation

B/P Proteinuria

Severe diffuse cerebral vasospasms

Gestation Mgt.

Mgt. of Eclampsia

HELLP Syndrome 5-10% of preeclamptic patients H- hemolysis EL- elevated liver enzymes LP- low platelets

First protect the mothers airway IV MgSO4, with IV bolus of 5g to stop seizure

Mgt. prompt delivery at any age

Maintenance dose 2g/hr Deliver at any gestational age Lower diastolic B/P to 90-100mmHg

Fetal Presentation

Station in delivery

Cephalic- head presents first

Breech- feet or buttock first Frank (vaginal delivery)- sucking on toes Complete Footling

Compound- more than one body part present

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4/29/2008

Overview of Labor

Cardinal Movement in Labor Engagement Descent Flexion Internal rotation Extension External rotation Expulsion

Uterine changes: Contraction of upper uterine segment Exerting expelling forces

Cervical effacement: Thinning due to oxytocin and PGE2 breaking disulfide bonds in collagen fibers

Normal cervix: 2cm long/ 2cm wide

Stages of Labor Stage 1: onset of uterine contraction and ends with complete dilation

Abnormal L b Labor

Latent- cervical dilation up to 20 hrs (3-4 cm) Active – rapid cervical dilation (1.2 cm/hr)

Stage 2: complete cervical dilation to delivery (2 hrs) Stage 3: delivery to placental expulsion (30 min) Stage 4: observation of mother for preeclampsia and post partum hemorrhage

Prolonged Latent Phase

Prolonged Active Phase or Arrest Cervical dilation > 3cm… Prolonged dilation < 1.2 cm for > 2h

Cervical dilation <3cm for… > 20hrs primipara > 14 hrs multipara

Passenger problem: size or orientation

MCC iinjudicious j di i analgesia l i

Power problem: inadequate uterine contraction

Mgt. Therapeutic rest

Hypotonic muscle- IV oxytocin Contraction normal- go to C-section

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Prolonged 3rd stage

Prolapsed Umbilical Cord Obstetric emergency

Placenta has not delivered within 30 min

Cord gets compressed affecting fetal oxygenation

If it does not remove with IV oxytocin, y , then think accreta ((etc.))

Occult- head and uterine wall Partial- head and cervical os Complete- protruding into vagina

Mgt. manual removal or Hysterectomy

Mgt. Knee-chest position Elevate presenting part Immediate C-section

Shoulder Dystocia

Cesarean Section Maternal mortality and morbidity is higher than vaginal delivery

Delivery of fetal shoulder is delayed after delivery of head

Hemorrhage : > 1000 ml

Impacted of pubic symphysis

Infection

Mgt. suprapubic pressure McRoberts maneuver- thigh flexed Woods corkscrew- internal rotation Manual delivery of posterior arm

Visceral injury: bowel, bladder Thrombosis- DVT

Cervical Ceretage

Uterine Incisions

Pt’s with incompetent cervix Lower segment transverse (pull bladder down)

Shirodkar- beneath cervical mucosa- left in place with deliver of C-section

Fetus must be in longitudinal lie Cut non-contractile portion of uterus

McDonald- removed by 36 wks for vaginal delivery

Can still have VBAC (vaginal birth after c-section)

Placed at 14 wks, before cervical dilation and effacement occur

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Post Partum Fever

Gynecologic Neoplasia and Cancer

PP day 0: Atelectasis PP day 1-2: UTI PP day 2-3: Endometritis PP day 4-5: Wound infection (antibiotics and drain) PP day 5-6: Septic thrombophlebitis (IV heparin 7-10 days) PP day 7-21: Infectious mastitis (oral cloxacillin and continue breast feeding)

Human Papilloma Virus (HPV)

PAP test

Screening for premalignant lesions Transformation zone (T-zone) squamous/columnar

16, 18, 31, 33 and 35 Premalignant Cancerous

3 years after onset of sexual activity act ty o or 21 y/o

6,11 6 11 Benign condyloma acuminata

Discontinued >70 with 3 negative pap’s < 30 y/o annually (2 yrs liquid based) > 30 every 2-3 yrs after 3 (-) pap’s

Bethesda System

Diagnostic Approach

Negative- no malignancy

Accelerated repeat PAP: ASC-US

ASC- atypical squamous cells

HPV-DNA testing: ASC-US

LSIL low grade squamous intraepithelial LSILlesion (HPV or CIN I)

Colposcopy abnormal pap Colposcopy(acetic acid)

HSIL – high grade squamous intraepithelial lesion ( CIN 2,3, moderate dysplasia)

Endocervical curettage (ECC)- r/o endocervical lesion [not in pregnancy]

Cancer- invasive

Cone biopsy- PAP worse than histological

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Mgt. according to histology

Invasive Cervical CA

Observation: CIN I, repeat pap 6-12 months

Penetrated through basement membrane

Ablative: CIN 1, 2, 3: Cryotherapy

Postcoital vaginal bleeding

Excisional: CIN 1, 2, 3: LEEP (loop electrosurgical excision), cold knife

Dx. Cervical biopsy- sq. cell CA Mgt. Hysterectomy

Hysterectomy- recurrent CIN 1,2,3

Cervical Neoplasia in Pregnancy

Post Menopausal Bleeding Menopause- after 3mo or cessation of menses

Pregnancy does not change progression

Endometrial carcinoma (MCC)

p g Test female same as non-pregnant Skip ECC- cervix more vascular

Unopposed estrogen

Invasive CA: <24 wks: hysterectomy > 24 wks: wait until 32-33 wks, then C-section and hysterectomy

Dx: Endometrial sampling Mgt: Positive histology: TAH & BSO

Enlarged Uterus

Enlarged Uterus

Leiomyoma: Benign smooth muscle of the myometrium

Adenomyosis: Ectopic endometrial glands and stroma located within the myometrium of the uterine wall

More common in black females

Tender uterus in absence of pregnancy p g y

Mgt. Observation

Dx. Utz or MRI

Presurgical shrinkage 3-6 mo GnRH analog Myomectomy Embolization Hysterectomy

Mgt. Levonorgestrel intrauterine system Definitive : Hysterectomy

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Premenopausal Adnexal Mass

Ovarian Neoplasia

Simple Cyst- luteal or follicular Complex cyst- dermoid (germ layers) Dx. hCG levels to rule out pregnancy: Sonogram Mgt. Simple cyst- observation, OCP’s, (>7cm laparoscopic) Complex cyst- surgical removal

Adnexal Mass With Pain

Prepubertal Adnexal Mass

Sudden onset of severe lower abdominal pain in presence of adnexal mass….”Ovarian torsion”

Functional ovarian cyst not possible because ovarian follicles are not functioning

Mgt. untwist

p of neoplasm p Suspicious

Observation to assure revitalization Routine exam annually

Dx. Tumor markers…

LDH- dysgerminoma Beta HCG- Choriocarcinoma Alpha fetal protein- endodermal sinus tumor

Postmenopausal Adnexal Mass

Classifications

Ovaries should be atrophic

Epithelial tumor (80%)- post menopausal MC serous

Any enlargement, should draw suspicion of ovarian cancer

Germ Cell tumor (15%)- teenagers MC dysgerminoma

BRCA-1

Stromal tumor (5%)

Granulosa cell tumor- increased estrogen

Metastatic tumor- Krukenberg stomach to ovary

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Vulvar Intraepithelial Neoplasia (VIN)

Vulvar Neoplasia Vulvar lesion with pruritus Vulvar itching

Squamous dysplasia

Squamous hyperplasia ((whitish focal area))

Mgt. surgical excision

Mgt. corticosteroids

Lichen Sclerosis (bluish-white papule) Parchment like Mgt. testosterone cream

The End

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 “Trauma"

refers to a serious or critical bodily injury, wound, or shock, as from violence or accident.

477

Immediately lifethreatening injuries

Potentially lifethreatening injuries

Airway obstruction

Simple pneumo/haemothorax

Tension pneumothorax

Aortic rupture

Open pneumothorax

Blunt cardiac injury

Massive haemothorax

Pulmonary contusion

Flail chest

Tracheobronchial rupture

Cardiac tamponade

Diaphragmatic rupture

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10/13/2008

SIGNS & SYMPTOMS: (Your CLUES) 1. No, weak, noisy, labored or gurgled respiration 2. Pale, cool, clammy skin; delayed capillary refill 3. Irregular/unstable vital signs 4. Contusion, abrasion, laceration, hematoma 5. Pain, tenderness, guarding, numbness/tingling 6. Bruising, swelling, deformity, false/limited motion 7. Muscle weakness/paralysis, loss of sensation 8. Altered mental status 9. Asymmetric pupils, JVD, incontinence

OBTAIN HISTORY OF: 1. PMH/Meds/Allergies 2. Mechanism of injury/weapon description 3. Use of protective devices: helmets, seatbelts, airbags, padding 4. Substance abuse 5. Estimated blood loss at scene 6. Time of injury 7. Loss of consciousness

UNSTABLE

STABLE or UNSTABLE

 The

Famous “A B C’s” - Airway - Breathing - Circulation

 The

Famous “A B C’s” In the vignette: - GET RID OF DISTRACTORS! - Look for Pt. Stability and decide:

478

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 The

Famous “A B C’s” In the vignette:

 

- GET RID OF DISTRACTORS! - Look for Pt. Stability and decide:

 



Case: 25 y/o man falls from a tree. At the moment he is unconscious. His breathing is difficult and his mouth is full of blood. His arm has an unusual angle and there’s laceration in his forehead and chest. What is the best next step?

Case: 25 y/o man falls from a tree. At the moment he is unconscious. His breathing is difficult and his mouth is full of blood. His arm has an unusual angle and there’s laceration in his forehead and chest. What is the best next step?

AIRWAY: What to check? -No, weak, noisy, labored or gurgled respiration -Abnormal, silent or low voice or uncompleted sentences while talking - Unconsciousness 

AIRWAY: Then: Administer air ANYHOW!



- Mask w/ 100% O2 - Orotracheal intubation - Cricothyroidotomy

AIRWAY: Then: Administer air ANYHOW! - Mask w/ 100% O2

479

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

AIRWAY: Then: Administer air ANYHOW!



- Orotracheal intubation



 

AIRWAY: Then: Administer air ANYHOW! - Cricothyroidotomy

AIRWAY: Then: Administer air ANYHOW! How to choose? Rules: 1.-Use less invasive first 2.-Follow the order if the patient has been started but oxygenation didn’t succeed (Check PULSE OX. <90)



Case: 25 y/o man falls from a tree. At the moment he is unconscious. His breathing is difficult and his mouth is full of blood. His arm has an unusual angle and there’s laceration in his forehead and chest. In the ambulance the patient is intubated successfully. Physical Examination: Loud blow sound in the left when ambu is compressed. What is the best next step?

 

480

AIRWAY: Possible causes: (If diagnose is asked) - Foreign object - Body fluids (blood, vomit) - Swelling of trachea, epiglottis, tongue, uvula, etc - Disruption of airway (direct trauma) - Anesthesia, drugs - Head trauma

Case: 25 y/o man falls from a tree. At the moment he is unconscious. His breathing is difficult and his mouth is full of blood. His arm has an unusual angle and there’s laceration in his forehead and chest. In the ambulance the patient is intubated successfully. Physical Examination: Loud blow sound in the left when ambu is compressed. What is the best next step?

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10/13/2008





 

BREATHING: What to check? -Symmetry of air flow -Is air going to lungs actually? -Breath automatism -OVERVENTILATION -Crepitus in peri respiratory system



-

BREATHING: Possible causes: - Bad technique - Flail chest - Cardiac tamponade - Rupture of airway, thorax, diaphragm or arthery (hemo, pneumo thorax) - Under ventilation

 

Case: 19 y/o unmarried, at term pregnant woman has a MVA 30 minutes ago. She is able to answer the anamnesis and is lucid. At the moment she is crying, and seeks for companion, she is very worried about the baby because she doesn’t feel movements anymore and ask for the mother to be called. Temperature is 37C, Pulse 102’m, BP 60 over 40. Fetal signs negative. What is the best next step?

 

481

BREATHING: Then: CORRECT (Depends in vignette) One side airflow - Re-direct tube Crepitus peri resp. - Other way of ventilat. Pulse Ox. Low - Other way of ventilat. Air outside lungs - Re-diagnose

Case: 19 y/o unmarried, at term pregnant woman has a MVA 30 minutes ago. She is able to answer the anamnesis and is lucid. At the moment she is crying, and seeks for companion, she is very worried about the baby because she doesn’t feel movements anymore and ask for the mother to be called. Temperature is 37C, Pulse 102’m, BP 60 over 40. Fetal signs negative. What is the best next step?

CIRCULATION: What to check? -History of profuse bleeding -Hypotension -Pale, cool, clammy skin -Delayed capillary refill

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10/13/2008

CIRCULATION: What to check? -History of profuse bleeding -Hypotension -Pale, cool, clammy skin - Dry mucosas (Tounge, no tears) - Depresed fontanelles (children) -Delayed capillary refill

CIRCULATION: Then: Restore volume ASAP 1.Two IV lines (16-Gauge) 2. Plenty liquids: Ringer lactate Normal saline Blood 3. If not enough, third line in saphenous vein 4. Children <4y/o Intraosseus in tibia or frontal





CIRCULATION: Then: Control of hemorrhage - Direct pressure - Clamping artery - Curettage if obstetric







GENERAL:

SHOCK SEPTIC

DUE TO

SKIN

BACT. TOXIN

WARM

CO

SVO2

SVR PCWP

HIGH

HIGH

LOW

LOW

VOLUME BLEEDING PALE

LOW

LOW

HIGH

LOW

CARDIO HYPO

PALE MOTILITY COLD

LOW

LOW

HIGH

HIGH

VAGAL REFLEX

LOW

LOW

LOW

LOW

LIQ. DEP

NEURO

CIRCULATION: Possible causes: - Trauma in abdomen or thorax (not in cranium, not enough space to cause shock) - Bleeding (obstetric, big wounds) - Dehydration (deprivation) - Hyper urination (DI, diuretic overuse)

COLD

WARM

1) All Trauma Patients: CS, Chest, Pelvic XR 2) If unstable, proceed to laparotomy 3) If abdomen cannot be examined: CT scan of abdomen and pelvis w/ oral and IV Contrast 4) Gunshot in abdomen: Laparotomy

CO: Cardiac Output SVR: Sistemic Vascular Resistance SVO2: Systemic Venous Oxigen PCWP: Pulmonary Capilary Wedge Pressure

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BEST WAY ORGANIZATION:

From HEAD TO TOES





EPIDURAL HEMATOMA: - Bleeding between skull bone and dura mater - Rupture of Middle Meningeal Artery - PROGRESSION: - Unconciusness - Lucid interval - Coma



EPIDURAL HEMATOMA:



483

EPIDURAL HEMATOMA: - Anisocoria - Bi-concave hematoma - Tx: 1. After trauma, only image w/o symptoms at all: OBSERVATION 2. Symptoms & Immage: EMERGENCY SURGERY

SUBDURAL HEMATOMA: -Bleeding between dura mater and arachnoides - Rupture of veins crossing subdural space “Bridging veins” - Image: Concave hematoma

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

SUBDURAL HEMATOMA: - SEEN TYPICALLY IN: Elderly, demented, alcoholics



SUBDURAL HEMATOMA:

- Tx: 1.If small and no symptoms: OBSERVATION 2. Affect mental status: SURGERY





SUBARACHNOID HEMORRHAGE: - Bleeding between arachnoides and pia mater. - MCC: TRAUMA followed by Ruptured Berry Aneurism (HTN) - Blood is seen in ventricles and around brain (NOT IN BRAIN)



SUBARACHNOID HEMORRHAGE:



Tx: If due to anaeurism or AV malformation, SURGERY Otherwise: Support, observation or anti-convulsivats if needed.

SUBARACHNOID HEMORRHAGE: - “MOST SEVERE EVER” headache. - Leaves sequelae like epilepsy, blindness - IF VIGNETTE LOOKS FOR Dg: NEVER USE CONTRAST

SUBARACHNOID HEMORRHAGE:

-No mases -No ventricules -Deviation

484

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



INTRACEREBRAL HEMORRHAGE -Bleeding into brain parenchima typically in basal ganglia. -Due to Trauma, HTN, tumor. - IF VIGNETTE LOOKS FOR Dg: NEVER USE CONTRAST



INTRACEREBRAL HEMORRHAGE - Tx: Surgery is reserved for large bleedings if they are accesible.

WHEN DO WE DECIDE FOR SURGERY IN ANY CASE?

INTRACEREBRAL HEMORRHAGE

WHEN CT scan OR MRI SHOW

DEVIATION OF MIDDLE LINE

DIRECT HEAD TRAUMA:

CONSECUENCE: CONSECUENCE:

- Open or close head injury - Increased Intracranial Pressure - Reversible or Irreversible neuronal damage - DEAD

1

2 3

485

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What to do next? - After ABC’s finish PE w/ Glasgow scale - Look for signs of Intracranial Hypertension: - Decrease in the comma scale - Anisocoria - Signs of decerebration

What to do next? - Elevate head - Intubate and hyperoxigenate - Lower CO2 - Mannitol - Sedation

After stabilization:

DIFUSE AXONAL INJURY - High speed injury with stretching or shearing of brain tissue - Immage shows petechial hemorrhages in white matter tracts - Associated with immediate deep coma, cerebral edema and elevation of ICP - High mortality

- CT scan - XR of skull (look for fractures) - If Open Wound (clean and close)

486

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10/13/2008

DIVIDED IN TWO:

WHAT TO DO IN BLUNT TRAUMA:

- BLUNT TRAUMA

-

- PENETRATING TRAUMA

WHAT TO DO IN BLUNT TRAUMA: -

If UNSTABLE: -EXPLORE Respiratory compromise Hematoma Shock

WHAT TO DO IN PENETRATING TRAUMA

If STABLE: -Look for other symptoms If patient OK then REASURANCE

- Decide which ZONE is compromised

IF ZONE I & III UNSTABLE: 1)A, B, C always first! 2) Surgical exploration

Neck’s base to mandible’s angle III Mandible’s angle to Cricoid II Cricoid to Clavicle I

487

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IF ZONE I & III

IF ZONE II

STABLE: 1) Endoscopy of: Respiratory tract Esophago/Gastro Artheries 2) Reassurance if nothing found

UNSTABLE: 1)A, B, C always first! 2) Surgical exploration Always explore if musculocutaneus platysma is affected

IF ZONE II UNSTABLE:

IF ZONE I & III STABLE: 1) Endoscopy if hoarseness/hematoma: Respiratory tract Esophago/Gastro Artheries 2) Reassurance if nothing found

Musculocutaneus Platysma

488

PROBLEM

MISCELANEUS

SYMPTOM (CLUES)

TEST

TREATMENT

Rib Fracture

MCC of injury Elderly Fall

History Pain w/ resp. Hematoma/open wound Costochondral junction middle and lower ribs

CXR

Pain medication

Flail Chest

4 or more ribs fractured in 2 places

Major trauma Caves during respiration and bulges in expiration

CXR

Anesthesia and rib blockage, positive ventilation and high oxygen (avoid barotrauma) surgical stability not required

Cardiac tamponade

Liquid between heart and pericardium, CA

Trauma, URI Tachycardia Hypotension Pulsus paradoxus JVD

Echocardiogram

Pericardiocentesis, pericardial window

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10/13/2008

PROBLEM

MISCELANEUS

SYMPTOM (CLUES)

TEST

TREATMENT

Pericarditis

Inflammation of pericardium

URI Friction rub

CXR, echocardiogram, EKG, CK MB (rule out MI), ESR very high

Treat cause, NSAIDS, pericardiocentesis, pericardiostomia

Pleuritis (Pleuresy)

Inflammation of pleura

URI, CA, LES, RA, Irritants (asbestos), Drugs Stabbing pain during inspiration

CBC, thoracocentesis, CXR, Chest echo

Treat cause, NSAIDS

Tracheal/ Bronchial rupture

Violent trauma

Trauma, gunshot, infection, object Cough w/blood Gas under need skin of neck, chest

X-rays, CT scan

Object: rigid fiber optic bronchoscopy to retrieve object Others: Surgery if big plus chest tube w/ suction

PROBLEM

MISCELANEUS

SYMPTOM (CLUES)

TEST

TREATMENT

Hemothorax

Trauma, CA, thorax surgery

Respiratory failure TachycardiaAnxiet y

CXR Thoracocentesis Analysis of fluid

Treat the cause Stabilize, Stop bleeding, Thoracic tube,

Trauma (spontaneus)

Sudden sharp pain on respiration, Tachycardia, cianosis, nasal flaring, no air movement

CXR, ABG

Treat the cause, drain gas w/ needle if emergency and later w/ thoracic tube

Sounds of bowel in thorax (left) or no air in left lung

CXR, Barium swallow

Pneumothorax

Diaphragmatic rupture

Trauma, only in left side

Surgery

PROBLEM

MISCELANEUS

SYMPTOM (CLUES)

TEST

TREATMENT

Aortic rupture

Violent trauma, deacceleration

Look for wide mediastinum in CRX

If CRX not conclusive and suspicious is high, CT scan or transesophageal echo

Surgery

Pulmonary contusion

Violent trauma

With flail chest or rib fracture, but crackles

CT scan, look for atelectasia

Fluid restriction and oxygen. Prolonged symptoms possible ARDS

Cardiac contusion

Violent trauma, CPR

Abnormalities in ventricle to contract EKG right bundle branch block) Sinus tachycardia Ventricular dysrhythmia

EKG Echocardiogram

Supportive EKG monitorization

Trachea

Expansion

Breath Sounds

Percussion

Tension Pneumothorax

Away

Decreased. Chest may be fixed in hyper-expansion

Diminshed or absent

Hyper-resonant

Simple Pneumothorax

Midline

Decreased

May be diminished

May be hyperresonant. Usually normal

Haemothorax

Midline

Decreased

Diminished if large. Normal if small

Dull, especially posteriorly

Pulmonary Contusion

Midline

Normal

Normal. May have crackles

Normal

Lung collapse

Towards

Decreased

May be reduced

Normal

CARDIAC TAMPONADE

PNEUMOTHORAX

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AORTIC DISECTION

BRONCHIAL RUPTURE

INSPIRATION

DIAPHRAGMATIC RUPTURE

EXPIRATION

FLAIL CHEST

ACUTE ABDOMEN: Sudden, severe abdominal pain that is less than 24 hours in duration

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IMPORTANT POINTS: ALWAYS 1) 2) 3) 4) 5)

LOOK FOR CLUES:

PROBLEM

MISCELANEUS

SYMPTOM (CLUES)

TEST

TREATMENT

Appendiscitis

Inflamation of apendix, young people. Causes: Inflamation Fecalith Parasite Trauma Complication: peritonitis

First periumbilical and then iliac fossa (migration) Tender Mc. Burney’s point, Rovsing’s sign, Obturator sign, Psoas sign, fever, anorexia and vomit

CBC (infection) Normally clinical, and only atypical cases CT scan or ultrasound to rule out ectopic pregnancy or pregnant ladies

Laparoscopy, laparotomy

Due lith in cystic duct leading to stasis

Famous FFF’s Pain after fatty meals radiate to shoulder

ALK Phos. Elevation, CBC, Ultrasound. Best diagnosis is CT scan. HIDA if suspect and negative US

If acute: surgery If septic shock: percutaneus drainage If not acute: elective surgery

Cholecystitis

PROBLEM

MISCELANEUS

SYMPTOM (CLUES)

TEST

TREATMENT

Pancreatitis

Peptic ulcer perforation Alcohol Neoplasm Cholelithiasis, CF Renal Dz ERCP Anorexia Trauma Infection Toxins: Prils, HIV, ASA Incinerations Scorpion bite

Epigastric pain radiating to the back (belt) Cullen’s sign: Periumbilical Turner’s sign: Flanks

High Sens: Amylase High Spec: Lipase CT Scan

If cyst> 5Cm Dranaige If due to obstruction: ERCP Pancreatic CA: Surgery bad prog

Due to Shock, Atrial fib. Hypercoagulable state Watershed area SMA and IMA pancreatic flexure

Bowel distention, and bloody diarrhea, bowel sounds will be absent

Intestinal Ischemia

1) 2) 3) 4) 5) 6)

NPO to reduce risk of aspiration NG tube to decompress abdomen IV hydration/ secure via Analgesia (meperidine) Abdominal X-RAY

Neutrophilic leucocitosis (left) increase amylase. CT scan Air in bowel and inflamation of watershed area

How and why of pain, how often Time of iniciation (cronic or acute) Localization and Progresion Irradiation Scale of pain and type AGE, GENDER

DIFFERENTIAL DIAGNOSIS PROBLEM

Surgery

491

SYMPTOM (CLUE)

TEST

Biliary colic

Cystic duct blocked. Sharp and constant pain without fever. Negative Murphy's sign.

LFT WNL. Ultrasound

Cholecystitis

Cystic duct blocked with infection. Colicky brief pain at first, then constant pain in RUQ with fever caused by E coli, klebsiella, pseudomonas, B fragilis, enterococcus. Murphy's sign positive.

Increased AST, ALT, AP, WBC. Ultrasound

Choledocholithiasis

Common bile duct blocked. Colicky pain. Jaundice.

Increased bilirubin. Cholangiogram, ERCP

Cholangitis

Infection of entire biliary tract. Charcot's triad. Jaundice and fever

Increased AST, ALT, AP, bilirubin. Cholangiogram

PROBLEM

MISCELANEUS

SYMPTOM (CLUES)

TEST

TREATMENT

Diverticuliti s

Older people w/ diverticulosis becames inflamed and perforated(bulging of colon walldue to weakness) low fiber diet, family history.

Left Lowe Q pain, leucocitosis, fever

CT scan, No enemas or contrast

First episode: IV fluids and antibiotics Subsequent: Surgery

Ectopic Pregnancy

Prior PID

Acute L R or L Q pain, acute, maybe shock (rupture) localized in area. Vaginal bleeding, cullen sign

Positive pregnancy test, Ultrasound for evidence

laparoscopy and laparotomy

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PROBLEM

MISCELANEUS

SYMPTOM (CLUES)

TEST

TREATMENT

Peritonitis

Inflamation of peritoneum due to perforation

Pain, tenderness and guarding, rebound Complication of rupture of viscera

CBC leucocitosis Plain AXR, edematous vicerae, air. Lavage if doubt

Stabilization with IV liquids, correct acidosis and electrolite imbalance, Surgery, antibiotics broad spectrum

Volvulus

Malrotation of midgut,

Bowel obstruction and distension and vomitus. No passage of gases, intestinal silence.

Abdominal X-ray, upper GI series

Surgery, correct rotation, if necrosis resection of portion.

PANCREATITIS

APPENDISCITIS

CHOLECYSTITIS

PELVIC FRACTURE:

PERITONITIS

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PELVIC FRACTURE: 1) 2) 3) 4)





HAND



HAND:

Stabilize patient Military Antishock Trousers Fixate externally If blood loss, Embolize

HAND: Sacaphids: Avascular necrosis Hamate: Rupture of hook, nerve damage (Ulnar)

BOXER’S FRACTURE Tx: Mild: Immobilize Severe: Surgery w/ pins



ARM:



ARM: ◦ Tx:

- Alignement - Analgesia - Close reduction: No complication, no skin break - Open reduction: Intra-articular fracture is displaced ORIF Closed reduction was ineffective Fracture traverses a cancerous lesion When prolonged immobility - Surgery: If artery damage is suspected

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- COMPARMENT SYNDROME:

- COMPARMENT SYNDROME:

Due to inflamation of tissues underneed the skin or fascia  Nerve and circulation compression 

OPEN THE AREA!

- GANGRENE: Infection due to deep entrance of bacteria to body (diabetic foot, nail)

- GANGRENE:

AMPUTATION!

- OPEN FRACTURES: Clean the area w/ saline and pressure 2) Verify if nerves or circulations are intact 3) If < 6 hours, SUTURE AND REDUCT IN OR

- OPEN FRACTURES:

1)

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- DISLOCATION OF HIP: Shorten leg, un-anatomical position.

- DISLOCATION OF HIP:

1) Correct position 2) Emergency Reduction

FEVER: DAYS

Famous W

LUIDA

NEUROLOGICAL: -Hypoxia ARDS Post- anesthesia -Delirium Tremens -Water intoxication: HypoNA HyperNA

CAUSE

DAY 1

WIND

LUNGS

Pneumonia, Atelectasis

DAY 3

WATER

URINE

UTI

DAY 5

WOUND

INFECTION

S. Aureus

DAY 7

WALK

DVT

DAY 10

WONDER WHY

Abscess

NEPHROGENIC: -Post Surgery Urinary Retention -Hypovolemia -Clamping of ureter

ABDOMINAL: - Paralysis of intestine (Ogilvie Synd) - Adhesions - Paralytic Ileus due to Anesthesia

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INFECTION:

Do you understand that ABC’s always is first?  Can you do differential diagnosis?  Do you know what to do first?  Do you have a sequence of thinking?  Do you know basically the treatment?  Are you consistent with your thought process? 

1)Find the cause with multiple culture 2) Antibiotic Therapy

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ANTIBIOTICS What is an antibiotic? An agent that inhibits the growth or multiplication of, or kills, a living organism; usually used in reference to bacteria or other microorganisms.

Who invented them? Alexander Fleming, in 1928 is the one who purified PENICILLIN.

THE CAT? PURE LUCK?

Who is the genius?

Of course not… OR

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BASIC PRINCIPLES FOR PHARMACOTHERAPIE

TYPES OF ANTIBIOTICS Cell

Wall Inhibitors Protein P i Synthesis S h i IInhibitors hibi Metabolite Inhibitors Special Function Inhibitors

Learn

MOA Learn SIDE EFFECTS “Don’t kill a mosquito with a gun” Cost

– Benefit’s law

CELL WALL INHIBITORS

Where do you get the molds?

1.-- Penicillin 1. - Oxa Oxa,, cloxa dicloxa, dicloxa, nafi nafi-- CILLIN - Ticarcillin - Aztreonam 2.-- Cephalosporins 2. 3.-- Carbipenems 3. 4.-- Vancomycin 4.

1.--PENICILLINE 1.

1.--PENICILLINE 1.

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1.--PENICILLIN 1.

1.--PENICILLINE 1.

1. 1.-- Binds to PBP

1. 1.-- Binds to PBP

2 - Disrupt cell wall 2.2. 3. 3.-- Provoke apoptosis

1.-- PENICILLIN 1.

1.--PENICILLIN 1. 2. 2.-- Disrupt cell wall 3. 3.-- Provoke apoptosis

1.--PENICILLINE 1.

1.--PENICILLIN 1.

What does it kill? Staph. Aureus Staph. Epidirmidis Staph. Saprophiticus Strep. Pneumoniae Strep. Pyogenes Strep. Sanguis Strep. Mutans Strep. Agalactiae

Bacillus Clostridium Klebsiella Neisseria Citrobacter P. Auroginosa H. Influenza B Actinomyces israelii

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1.--PENICILLIN 1.

1.-- PENICILLIN 1.

…Or, if you don’t remember:

Side

effects:

1.- Typical: Anemia, Vomiting, 1.Diarrhea Alopecia Diarrhea, Alopecia, Photosensitivity Photosensitivity.

¾ GRAM

+ ¾ Capsulated bacteria

2.-- Special: Allergie 2.

1.-- PENICILLIN 1.

1.-- PENICILLIN 1. Resistance: - Mutate PBP, so drug cannot bind - Thicker Thi k membranes, b so ddrug cannot get in - Mutate or destroy the drug with an enzyme

Typical side effects: D to d Due destruction i off R Rapidly idl dividing cells

1.-- PENICILLIN 1.

1.-- PENICILLIN 1. Oxa, Cloxa, Oxa, Cloxa, Dicloxa Dicloxa,, Nafi –CILLIN 1.-- MOA Same as penicillin 1. 2.-- BULKIER - R - Ring 2.

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1.-- PENICILLIN 1.

1.-- PENICILLIN 1.

What does it mean? - Penicillinase can’t bind to the R group for being huge so the antibiotic won’t get deactivated and will attach PBP

What do you kill with them? - Staph. S h Aureus A

1.-- PENICILLIN 1.

1.-- PENICILLIN 1.

Can you kill OTHER gram positives and capsulated bacteria?

WHY? You could use simple penicillin for that that…

YES ! Do you kill them w/ Naficillin Naficillin?? NO !

Don’t kill a Mosquito with a gun!

1.-- PENICILLIN 1.

1.-- PENICILLIN 1.

AMPICILLIN Vs. AMOXICILLIN


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1.-- PENICILLIN 1.

1.-- PENICILLIN 1.

AMPICILLIN Vs. AMOXICILLIN Ampicillin - 80% off d drug deactivated d i d with ihP P--450 Amoxicillin - Gets ACTIVATED with PP-450

AMPICILLIN Vs. AMOXICILLIN - Ampicillin Ampicillin:: Adults

1.-- PENICILLIN 1.

1.-- PENICILLIN 1.



-

A Amoxicillin i illi + Cl Clavulanic l i ac.: To inhibit B B--Lactamase

Amoxicillin: Children Liver failure

MOA SAME MOA: SIDE EFFECTS: SAME

1.-- PENICILLIN 1.

1.-- PENICILLIN 1.

AMPICILLIN Vs. AMOXICILLIN Bugs to kill: ¾ Gram G + ¾ Capsulated bacteria ¾ E. Coli?

Ticarcillin:: Ticarcillin T kill PSEUDOMONA… To PSEUDOMONA

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1.-- PENICILLIN 1.

1.-- PENICILLIN 1.

Ticarcillin: Ticarcillin: WHY?

Ticarcillin: Ticarcillin: WHY?

1.-- PENICILLIN 1.

1.-- PENICILLIN 1.

Ticarcillin:: Ticarcillin

AZTREONAM: For GRAM – S Same principle: i i l “If you would ld kill a Gram+, then use a smaller weapon” SIDE EFFECTS: SAME

“ Pseudomona P d i li is lion attacking, ki so you need a big riffle to kill it” SIDE EFFECS: SAME

2.-- CEPHALOSPORINS 2.


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2.-- CEPHALOSPORINS 2. 1st gen

+

2de ggen

+

-

3th gen

+

-

4th gen

+


Cephalexin, cefazolin

MOA: SAME AS PNC SIDE EFFECTS EFFECTS: SAME

Cefuroxime, cefotetan

Ceftriaxone, cefotaxime

-

Cefepime



3.-- CARBAPENEMS 3.

4.-- VANCOMYCIN 4.

“THIS IS A BAZOOKA FOR TERRORISTS” IMIPENEM/CILASTATIN - To inhibit renal dihidropeptidase MOA: SAME SIDE EFFECTS: SAME $ 450 a vial QUID X 10 days…

Inhibits

cell wall of ALL GRAM+ MOA: Inhibit cell wall mucopeptide formation gen D-ala – D-ala Resistance: mut. mut. DD-ala to D D--lac

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PROTEIN SYNTHESIS INHIBITORS

4.-- VANCOMYCIN 4. RED MAN SYNDROME: - Pretreat w/ antihistaminics -LOWER INFUSSION

A good business: BUY A 30s T

C E 50s L L





OR…

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A good business: Chloramphenichol BUY Erithomycin Aminoglucosides (Macrolides Macrolides)) Tetracyclins cLindamycin

Aminoglucosides: Aminoglucosides: -Gentamicin, Gentamicin, amikacin, amikacin, streptomycin -MOA: Inhibit Initiation complex -Bactericidal -Potentiation w/ w/ampicillin ampicillin

Linezolid


PROTEIN SYNTHESIS INHIBITORS Tetracyclins: Tetracyclins: -Doxicycycline: Doxicycycline: Lyme, Tularemia, Francicella (Fecally excreted) -Minocycline: Minocycline: Propionebacterium Acne (Not even excreted) -Demeclocycline: Demeclocycline: SIADH ((Neprotox Neprotox))

Aminoglucosides: (CONT.) Aminoglucosides: - SIDE EFFECTS: SAME - PLUS: Ototox and Nephrotox



Tetracyclins:: (CONT.) Tetracyclins

Tetracyclins:: Tetracyclins

-MOA: MOA Inhibiting I hibi i the h binding bi di off aminoacyl--tRNA to the mRNA aminoacyl mRNA-ribosome complex. -Bacteriostatic

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PROTEIN YNTHESIS INHIBITORS


Tetracyclins:: Tetracyclins

Chloramphenichol: Chloramphenichol: - MOA: Inhibit peptide bond at 50s - I Inhibit hibi P P--450 - NOT IN USA - SIDE EFFECTS: SAME Plus: BM Sup. A. Anemia, GBSynd. GBSynd.

SIDE EFFECT: EFFECT IMAGINE….Plus: Ototox Nephrotox



Erithromycin: MACROLIDES Erithromycin: - Clarithrmomycin Clarithrmomycin,, azithromycin - Inhibit I hibi translocation l i by b reversibly ibl binding to 23s portion of 50s. - Bacteriostatic

Erithromycin: MACROLIDES (CONT.) Erithromycin: - Tx for: Atypical pneumonia (Mycoplasma Mycoplasma)), Mycoplasma), ) Chlamydia 2g, 2g N. N Gonorhea 1g. ((azithromycin azithromycin))



cLindamycin: cLindamycin: - MOA: Inhibit elongation factor of 50s - Uses: Anaerobes above diapragm - SIDE EFFECTS: SAME Plus: (before) No1. for Pseudo. Colitis

Linezolid: Linezolid: - MOA: Inhibit initiation of 50s AND 30s - MRSA w/ resistance to Vanco - DON’T USE IT...Like pressing the RED BUTTON

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METABOLITE INHIBITORS

cLindamycin: cLindamycin: - MOA: Inhibit elongation factor of 50s - Uses: Anaerobes above diapragm - SIDE EFFECTS: SAME Plus: (before) No1. for U. Colitis.

To destroy nucleotides:

To destroy nucleotides: What is a nucleotide?



S-ADENOSYLADENOSYL-METHIONINE (SAM) Methilate or differentiate the nucleotides… All of them…. Except: T (thimidine (thimidine), thimidine)), ) who is methilated by Folic Acid

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To destroy nucleotides: 5-FU

dUMP

TRIMETHOPRIM

Thymidylate synthase

dTMP CH2-THF

MOA: Inhibit DHF Works?....Not at all…Alone

DHF THF

DHF reductase TMX/SMX OR MTX



SULFONAMIDES

BUT:…TMX + SMX Good for: UTI, Prof and tx of Pneumocystis Carinii Carinii,, Shigella and Salmonella.

MOA: Inhibit Dihydropteroato synthetase Works?....Not at all…Alone


METABOLITE INHIBITORS SIDE EFFECTS: SAME The same as B9 defficiancy - Neural pores non non--fusion - Megaloblastic anemia - Kernikterus in neonates

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SPECIAL FUNCTION INHIBITORS


QUINOLONES: MOA:Antitopoisomerase II Inhibit WindingWinding- unwinding

Topoisomerase



NAMES: Cipro Levo Levo FLOXACIN Gati Nor

SIDE EFFECT: Besides typical: - Tendonitis T d i i or tendon d rupture - Myalgia in kids



METRONIDAZOLE:

METRONIDAZOLE: C Covers: M Monocelular l l parasites: i G. Lamblia Lamblia,, E. Hystolitica Hystolitica,, G. Vaginalis,, anaerobes below Vaginalis diapragm.. T. Terapie H. Pylori. diapragm

MOA: Free radicals and toxic metabolites formation.

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ANTI TB DRUGS

ANTI TB DRUGS

RIFAMPIN: MOA:Inhibit

RIFAMPIN:

DNA dependent RNA pol merase Crosses BBB. polymerase, BBB PROF. TB and N. Menigitidis SIDE EFFECT: Hepatotoxic (Frecuent LFT)

Enhances

PP-450 Orange body fluids.

ANTI TB DRUGS

ANTI TB DRUGS

Ethanbutol: thanbutol: MOA: Obstructs

Ethanbutol: thanbutol:

cell wall formation by disrupting arabinogalactan ssynthesis, nthesis increases permeability of cell wall.

SIDE

EFFECT: -Optic neuritis -Red Red--green color blindness -Peripheral neuropathy -Arthtalgia

ANTI TB DRUGS

ANTI TB DRUGS

Streptomycin: Aminoglucoside

Pyrazinamide yrazinamide:: MOA: Stops TB

growth by, in acid media, media, ihibiting enzime fatt fatty acid synthetase.. synthetase SIDE EFFECTS: Arthralgia Arthralgia,, hepatotoxicity.. hepatotoxicity

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ANTIFUNGAL THERAPY

ANTI TB DRUGS

Amphotericine B: MOA : Binds to ergostyerol and pokes the cell wall provoking leakage of electrolites. electrolites.

Isoniazid soniazid:: MOA: Inhibit

synthesis of mycolic acid. Enhances h PP-4450. 0 SIDE EFFECTS: Hemolys in G6PD pts, hepatotoxicity hepatotoxicity,, neurotoxicity that can be prevented w/ B6.

ANTIFUNGAL THERAPY

ANTIFUNGAL THERAPY

Amphotericine B: Used in systemic mycosis SIDE EFFECTS EFFECTS: H Hypotension, i fever and chills, flebitis if IV

ANTIFUNGAL THERAPY

ANTIFUNGAL THERAPY

Nystatin:: Same as Amphotericine B Nystatin

Nystatin: SWISH AND SWALOW Nystatin: For oral candidiasis. candidiasis.

SIDE EFFECTS EFFECTS: O Only l used d topycall for being very toxic.

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ANTIFUNGAL THERAPY

ANTIFUNGAL THERAPY

Caspofungin: Disturb integrity of Caspofungin: Cell Wall… Disruption. Indication: Aparagillosis Side effects: Increase Crea Crea,, hypokalemia,, hypersensitivity hypokalemia

Azoles:

Caspofungin:: Caspofungin

ANTIFUNGAL THERAPY

ANTIFUNGAL THERAPY

AzoLE AzoLEss: MOA: Prevent conversion of Lanosterol to Ergosterol by inhibiting fungal PP-450. FUNGISTATIC!

-Flucon -Ketocon K -Itracon

ANTIFUNGAL THERAPY

ANTIFUNGAL THERAPY

Terbinafine: Terbinafine: MOA: Inhibit Squalen epoxidase USES Onicomycosis USES: O i i Bad cases: ORAL

AZOLES AND TERBINAFINE Azoles

Terbinafine

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ANTIFUNGAL THERAPY

ANTIFUNGAL THERAPY

Flucytosine Flucytosine:: MOA: 1) Inhibit microtubules 2) Inhibit 55--FU Consequence: Inhibit DNA Synt

Flucytosine Flucytosine:: Side effecs effecs:: Typical very strong Plus: Hallucinations, psycosis, psycosis, peripheral neuropathie neuropathie..

ANTIFUNGAL THERAPY

IN ONE GRAPH:

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Objective • • • • •

Biochemistry Glycolysis, Gluconeogenesis &TCA Mong-Khanh Le, M.D.

Focus • • • • • •

Why Glycolysis? • • • • • •

Most used pathway in body Turn food into energy Start w/ Glu, Lactose, Fructose Simple Vs Complex Carbo Substrate = Glu and production = pyruvate In cytosol (what does not have Mito will depend solely on it for ATP!!!!) • Organ effected: RBC, B>>H>>K

Naming enzymes Where it happens: cytosol vs mitochondria energy usage and production Regulations Clinical significant Dzs Connections!!!! AS ALWAYS

What is in our diet USDA

Name Enzymes Review

% in Diet Converting Pathways in Calorie

Carbohydrate 55% P t i Protein 15% Lipid 30%(<10 % sat) Alc ??????

4Kcal/g 4K l/ 4Kcal/g 9Kcal/g 7Kcal/g

Glycolysis Sucrose metabolism Lactose metabolism Gluconeogenesis TriCarboxylic Acid Cycle (TCA)

• Substrate=1st name

Glycolysis TCA Urea TCA, U FAsyn, Boxidation TCA, Lactate

• What was done to substrate= 2nd part or l t name last

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Name Enz (cont)- Move around

Name Enz (cont)-Add stuff • Kinase= use ATP to add P, Mg cofactor. • Phosphorylase=Use free P adding to substrate. • Carboxylase Carboxylase= uses CO2 to add C, C uses ATP and Biotin. • Synthase= 2 substrates consumed in reaction, named after product. • Synthetase= 2 substrates consumed. Need ATP

• Isomerase= create isomer, think Fructose and Glucose • Epimerase= make epimer, differs around 1 chiral C (gluÆgalactose) • Mutase= move P fr one C to another C • Transferase= move sidechain fr 1 substrate to another (interchain)

Name Enz (cont)-remove stuff

B-compx

• Dehydrogenase= take out H+ with coFactor (ie. Tender Loving Care For Nancy). • Phosphatase= breaks phosphate bond • Hydrolase= break a bond with H2O • Lyase= cut C-C bond with cofactor • Thio= breaks S bond

• Tender Loving Care For Nancy. • PLAN F. • Dzs.

Glycolysis

Glu Transport

• Substrates=Glu and end products of Sucrose and Lactose pathways (also fr glycerol) • Final product: Pyruvate • 9 steps • 3 irrversible steps= Exclusive glycolysis • Triangle at mid way (4th reaction)

• GLU 1 & 3: basal uptake most cells. • GLU 2: Storage (liver); Glucose sensor (Bislet) • GLU-4: GLU 4 increase i by b INSULIN iin ffatt and d muscle. Increase in exercising skeletal muscle. (Fat, skeletal and heart)

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Glycolysis

Glycolysis Regulations • HK: Most Tissues, low Km= works both in fed and fast. Inhibited by its own product, G-6-P. • GK: Liver only, High Km=works during fed only. +++ by insulin • Why Glu has to be phospholation?

PFK-1

PKF-2

• Rate Limiting Step

• • • • • •

• Stimulated by: AMP, F-2,6-BP, Insulin (FIA) • Inhibited by: Citrate, ATP, PEP, Glucagon, Acidosis (the GA CAP).

PK

Fruct-6-P to F-2,6BP fed state F-2,6BP to Fruct-6-P fast state Increases glycolysis Decreases gluconeogenesis Stimulated by Insulin Inhibited by Glucagon

Glycolysis Regulations Recap Enzymes Stimulated Inhibited

Stimulated by: F1,6-P, Insulin (FI)

HK

Inhibited by: Glucagon, Glucagon Alanine, Alanine cAMP, ATP, AcetylCoA (GA AAA)

Comments

G6P

PFK-1

*AMP *F-2,6-P *Insulin

Citrate, ATP PEP, Glucagon, lowPH

Pyruvate Kinase

*F1,6-P(feed forward pos=only one in Biochem) *Insulin

Alanine, Glucagon, cAMP, ATP, AcetylCoA

RLS

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Glycolysis Dz: MODY

Glycolysis Dz=Chronic Hemolysis • Chronic Hemolysis dt RBC lacks of energy fr glycolysis. • PK Def. leads to elev 1,3BPG, which can convert to 2,3BPG. • ÆOxygen ÆO curve shift hift to t R (incr (i Km, K decr d Affinity). • ÆAlso elevate other glycolytic intermediates in RBC (inhibition to many steps) • ÆNo Heinz bodies • ÆAR

• Mature Onset Diabetes of the Young: • Liver (= GK) • Glucokinase mutations leads slow down glycolysis. l l i Pl Plasma Gl Glu iincreased. d

Other Glycolysis Dz

Other Glycolysis Dz

• Arsenate inhibits Glyceraldehyde-3-P dehydrogenase

• Phosphoglycerate kinase inhibited: increase 1,3-BPG, which converted to 2,3BPG by RBC mutaseÆ decrease Hb affinitive for O2 (shift to R, R incre Km)

• Fl Fluoride id inhibits i hibit E Enolase: l Shiny Shi white hit teeth

Other Glycolysis Dz

Other Glycolysis Dz

• Glyceraldehyde-3-P: has disulfide bonds • Æwhich can be disrupted by Alc. • ÆAlso Mercury can inhibit sulfur group of enzyme (brain, (b i llung, kid kidney))

• ANY glycolysis enz def= HEMOLYSIS

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Glycolysis Connections

Sucrose/Fructose Metabolism

• In anaerobic state, production of lactate and NADH reoxidized back to NAD+. • In RBC (no mitochrondria)Æturns to LDH solutionÆLactate pathway. pathway • What are 3 enz exclusively from glycolysis? • Net fr 1 Glu= 2 pyruvate + 2ATP +2NADH

• • • •

Fructose

Fruits 3 reactions End products: Glu, DHAP, GA3P Continues with Glycolysis after trio Rx

Fructosuria • Essential Fructosuria: FructoKinase Defpolydipsia, polyuria, and UTI. BENIGN. • Fructose Intolerance: Aldolase B def. def.fructosuria, liver and proximal renal tubular disorder. ÆWhen Fruc-1-P accumulated, it inhibits Glu production causing severe Hypoglycemia.

Point Upon Wonder

Lactose/Galactose

• Why Fructose Intolerant Pt has hypoglycemia when we give them fructose? • Why DM can eat fruit without increase their plasma Glu? • Why diet people can eat lots of fruit w/o gain wt?

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Galactose Recap

Lactose Intolerant

• End with: Glu-1-P and Glu. Both feed into Glycolysis • Uses 1ATP • 4 reactions ti • Enzymes: lactase, GK, G-1-P UT

• • • •

Type 1 Galactosuria

Latase Defieciency Osmotic diarrhea Bloated, pain Rx: AvoidÆ Soy milk or Latase added milk.

Type 2 Galactosemia • Type 2 (Classical) Galactosemia • Gal-1-P Uridyl transferase Def. • Increase Gal-1-P will inhibits P-Glu Mutase, which interferes with glycogen syn and d degradationÆHypoglycemic. d ti ÆH l i • Excess converted to Galactitol via aldose reductase causes cataract. • More severe addition to above. Vomit/diarrhea/ liver/ lethragy/ MR. • Rx: avoid

• Type 1 (Non Classical) • Galactokinase def. • Galactosemia<< galactosuria (polydip & polyuria l i with ith UTI!!!!) UTI!!!!). • Excess converted to Galactitol via aldose reductase causes cataract. • Rx: avoid

Clinic Test

Galactose Connections

• Glu has –OH which can be reduced for a positive test in cases of excess Glu • Galactosuria and Fructosuria are urine pos test • If stool pos test = malasorption, osmotic diarrhea or inflammation • Also called reducing substance

• Babies need a lot of milk (rich lactose) because of baby uncoupling it’s ECT. • ÆUDP-Gal can reenter the pathways • If lactose intolerant: Soy milk

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Point upon wonder

Gluconeogenesis • A de novo synthesis of Glu from 3C and 4C precusors. • 4 irreversible steps • In both Mitochondria and Cytoplasm Cytoplasm. • Occur during fasting state, glycogen depleted. • Mainly in Liver, Kindney, Adrenal Cortex and intestinal epithelilium. • Provide Glu to brain and RBC.

• Why galactosemia Type 2 pt has hypoglycemia when we give them lactose? • C Comparing i G Galactose, l t why h F Fructose t can be given to baby at 6 months?

Gluconeogenesis • • • •

Regulation of Glyconeo.

Substrates are: Æglucogenic aa (protein fr muscle) ÆLactate (fr RBC and anaerobic exercise) ÆGlycerol 3 P (fr adipose tissue/ triacylglycerol)

Pyruvate carboxylase =RLS*******

+ Acetyl CoA

*Anapleurotic enz. *Biotin *mitochodria

PEPCK

+ Glucagon + Cortisol

*GTP *cytosol

F 1,6- BisPtase

+ ATP - AMP - F-2,6-BP (fr PFK2)

*Cytosol * inhibited by insulin, stim by glucagon.

G6Ptase

• Product: Glu

Gluconeogenesis

*In ER; liver only. (other tissue Glu with P grp prevent Glu exit cell)

Von Gierke: G6Ptase deficiency • • • • •

Æ severe fasting hypoglycemia ÆLactic acidosis ÆHyperLipidemia ÆHyperuremia Æshort stature

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Malate shuttle

Malate shuttle

• To bring NADH (product fr glycolysis) into mitochondria/ETC • T To bring bi OAA (f (fr pyruvateÆ t Æ OAA) into i t cytosol for gluconeogenesis

Viral Hepatitis vs. Alc Hepatitis

Pyruvate D.H. Complex

• Viral = lyses/ effects cell membrane • Æ AST to ALT is 1:1

• PyruvateÆ Acetyl CoA (Pyr D.H./ B complex)

• Alc = Lyses/effects cell mb and mitochondria mb • Æ AST to ALT is 2:1

• P PyruvateÆOAA t ÆOAA (PC is i in i mitochondria it h d i matrix, not in muscle) • Inhibited by: ATP, NADH, Acetyl CoA

B complex=PLAN F • • • • •

Why TCA??? • Intermediates in fasting/ liverÆ Glu

B1= TTP- decarboxylase B5=Lipoic acid- accepts acetyl grp B4=CoA- final acetyl aceptor B3=NAD- oxidizes FADH2ÆNADH B2=FAD- oxidizes Lipoic acidÆ FADH2

• Intermediates in fedÆ Fatty Acid • Intermediates also use for syn AA or converting one AA to another

• DZs!!!!!!

• Potentiate ATP product per Glu eat in!!!

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TCA

TCA

• In mitochondria • Cindy Is Kind So She Feeds Many O h Orphans • 4 irreversible steps

TCA Regulation Enzymes Stimulated Inhibited by by

Link to other pathways Comments

Citrate Synthase

ATP

Isocitrate ADP D.H.

ATP NADH

Major RLS

Alpha KG D.H.

Succinyl CoA ATP NADH

B complex RLS

• MalateÆGluconeogenesis • CitrateÆFA synthesis • Oxaloacetate and Alpha-KGÆ AA synthesis th i (Glutamate/GABA!!!!) (Gl t t /GABA!!!!) • Succinyl CoAÆHeme Synthesis • FumarateÆurea cycle • Alpha KGÆall transaminases AST & ALT

TCA Recap

TCA Connections

• In mitochondria= aerobic

• No specific Dzs • Problem with TCA is a major low energy state… • ÆNo ÆN ATP • Æ No Glu, AA, FA • ÆNo intermediates to other linked pathways

• Substrate: 1 Acetyl CoA + 3NAD + FAD +GDP GDP + Pi • Product: 2 CO2 + 3NADH + FADH2 +GTP + CoA • Net of 1 cycle of 1 Acetyl CoA= 12 ATPs

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Summary 5 pathways

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coursebook-1 - pass program

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