Dr. Heart's High Yield

[Anonymous]

high yield Anatomy

ANATOMY
Embryology
Embryonic Period: Weeks 3-8, organ system development simultaneous
I. The Heart
A. Development (MESODERM)
1. Primitive heart tube
- pair of endocardial heart tubes (mesoderm) form within cardiogenic region
-EHT fuse during lateral folding to form primitive heart tube = endocardium
-surrounding mesoderm develops into myocardium and epicardium
-PHT forms five dilations (First Aid p. 94)
2. AP septum (aorticopulmonary)
-divides truncus arteriosus into aorta and pulmonary trunk
-neural crest cells migrate into truncal and bulbar ridges
-grow and twist in spiral, fuse to form AP septum
3. AV septum (atrioventricular)
-partitions AV canal into right and left AV canals
-dorsal and ventral AV cushions fuse to form AV septum
4. Atrial septum
-septum primum grows toward AV septum
-foramen primum between edges of septum primum and AV septum; obliterated when SP fuses with AV cushions
-septum segundum (crescent-shaped) forms to right of SP and fuses after birth with SP to form atrial septum
-foramen ovale is opening between upper and lower parts of SS; shunts blood from right atrium to left atrium
-functional closure soon after birth due to pressure changes; anatomical fusion incomplete in 25% of population; incidental (Image, see High-Yield Embryo)



5. IV septum (interventricular)
-muscular IV septum develops into floor of ventricle and grows toward AV septum; stops short to create IV foramen
-membranous IV septum forms following fusion of right and left bulbar ridges and AV septum; closes IV foramen
6. Aortic Arches (First Aid p. 92)
B. Congenital Anomalies
1. AP septal defects
a. Tetralogy of Fallot
-improper alignment of AP and AV septums
-overriding Aorta, Pulmonary stenosis, VSD (poor AV fusion), right ventricular hypertrophy (right-to-left shunting, cyanosis)
b. TGA (transposition of great arteries)
-AP septum fails to spiral
-right-to-left shunting, cyanosis
c. Persistent truncus arteriosus
-abnormal neural crest cell migration, incomplete development of AP septum
-usually accompanied by defect in IV septum
-cyanosis
2. Atrial septal defects
a. Patent foramen ovale
-foramen secundum defect, excessive resorption of SP or SS
-symptoms may manifest as late as age 30
-most common ASD
3. VSDs
a. Membranous VSD
-most common VSD
-fails to develop
-left-to-right shunting, pulmonary hypertension
-sx: excessive fatigue on exertion
4. Circulatory anomalies
a. Coarctation of aorta
-abnormally constricted inf. to ductus arteriosus
-increased BP in upper extremities, lack of femoral pulse, high risk of cerebral hemorrhage and bacterial endocarditis
b. PDA (patent ductus arteriosus)
-common in premature infants, mothers with rubella during pregnancy
-causes L>R shunting, O2 rich blood back into pulm. circulation
-can treat with indomethacin (prostaglandin synthesis inhibitor; I remember it by saying, Take yo’ PDA indo’, man! Also used for acute gout, as in stay indo’ or go-out)
II. The Lungs
A. Development
-laryngotracheal diverticulum forms in ventral wall of foregut
-tracheoesophageal septum divides foregut into esophagus and trachea
-distal end of LTD enlarges to form lung bud
-lung bud > 2 bronchial buds > primary, secondary, tertiary bronchi = bronchopulmonary segments
-4 stages
1. Glandular (Weeks 5-17)
-respiration not possible, premature fetuses cannot survive
2. Canalicular (Weeks 13-25)
-respiratory bronchioels and terminal sacs; vascularization increases
3. Terminal Sac (Weeks 24-birth)
-Type I and II pneumocytes, respiration possible
-Premature fetuses weeks 25-28 can survive
4. Alveolar (Birth-year 8)
-resp. bronchioles, terminal sacs, alveolar ducts and alveoli increase in number
B. Congenital anomalies
1. Tracheosophageal fistula
-abnormal communication b/t trachea and esophagus; malformation of septum
-sx: gagging and cyanosis after feeding, abd. distention after crying, reflux of gastric contents into lungs
2. Respiratory distress syndrome
-deficiency of surfactant
-common in premature infants, infants with diabetic mothers, fetuses with prolonged IU asphyxia
-tx: thyroxine and cortisol to mother
3. Pulmonary hypoplasia
-secondary to congenital diaphragmatic hernia (into pleural cavity) and bilateral renal agenesis
III. Liver
A. Development
-hepatic diverticulum (endoderm of foregut) forms in septum transversum (surrounding mesoderm, also plays part in development of diaphragm)
-HD sends hepatic cell cords into ST
-Cell cords surround vitelline veins, which form hepatic sinusoids
IV. Kidney
A. Development
-Intermediate mesoderm forms elevation along dorsal body wall = urogenital ridge
-portion of UG ridge, called nephrogenic cord, forms 3 sets of kidneys
1. Pronephros completely regresses
2. Mesonephros forms mesonephric (wolffian) duct
3. Metanephros develops from metanephric mesoderm and ureteric bud (outgrowth of mesonephric duct); becomes definitive adult kidney
-ascends during development from sacral region to adult location at T12-L3
B. Congenital anomalies
1. Renal agenesis - failure of ureteric bud to develop
2. Horseshoe kidney – inferior poles fuse, kidney trapped behind inf. mesenteric artery
3. Wilm’s tumor – malignant tumor in children, probably of embryonic origin, good prog
4. Urachal cyst – remnant of allantois, urine drainage from umbilicus
5. Pheochromocytoma – chromaffin cell tumor, generally along migratory path of neural crest cells
V. CNS
A. Development
1. Notochord induces overlying ectoderm to differentiate into neuroectoderm to form neural plate; notochord becomes nucleus pulposus
2. Neural plate folds to form neural tube
-some cells diff. into neural crest cells
-craniocaudal folding
3. Vesicles
B. Congenital anomalies
1. Spina bifida (high AFP levels)
2. Anencephaly (high AFP levels)
-1/1000 births
-most common serious birth defect in stillborns
3. Arnold-Chiari – herniation of cerebellum into foramen magnum
4. Dandy-Walker – hydrocephalus from atresia of foramena of Luschka and Magendie
5. Hydrocephalus – most commonly from stenosis of cerebral aqueduct
6. Fetal alcohol syndrome – most common cause of MR; microcephaly, heart disease
7. Craniopharyngioma – congenital cystic tumor, remnants of Rathke’s pouch
VI. Gut (ENDODERM & MESODERM)
A. Development
1. Foregut: celiac artery
-esophagus, stomach, liver, gallbladder, pancreas, upper duodenum
2. Midgut: superior mesenteric artery
-lower duodenum, jejunum, ileum, cecum, appendix, ascending colon, proximal 2/3 transverse colon
3. Hindgut: inferior mesenteric artery
-distal 1/3 of transverse colon, descending colon, sigmoid colon, upper anal canal
4. Lower anal canal = surface ectoderm (think squamous cell carcinoma)
B. Congenital anomalies
1. Esophageal atresia – malformed tracheoesophageal septum
2. Hypertrophic pyloric stenosis – hypertrophy of muscularis externa; projectile vomiting and small, palpable mass at right costal margin
3. Extrahepatic biliary atresia – incomplete canalization > occlusion of biliary duct; jaundice, pale feces, dark urine
4. Annular pancreas – ventral and dorsal pancreatic buds form ring around duodenum; obstruction
5. Duodenal atresia – failed recanalization; polyhydramnios, bile-containing vomit, stomach distention
6. Omphalocoele – midgut loop fails to return to abd. cavity; light gray sac at base of umbilical cord
7. Meckel’s diverticulum – remnant of yolk sac b/t umbilicus and ileum; drainage of meconium from umbilicus
8. Hirschsprung’s – failure of neural crest cells to form myenteric plexus in sigmoid colon and rectum; loss of peristalsis, fecal retention, abd. distention
VII. Other congenital anomalies
A. Head and neck
1. First arch syndrome – various facial anomalies
-lack of migration of neural crest cells into pharyngeal arch 1
-Treacher-*******, Pierre Robin
2. DiGeorge – pharyngeal pouches 3 & 4 fail to diff. into parathyroids and thymus; “first arch” facial anomalies with cardiovascular anomalies
3. Cleft palate and cleft lip (First Aid p. 94)
VIII. Skeletal System
A. Development
-lateral folding
-three sources: paraxial mesoderm, lateral plate mesoderm, neural crest cells
1. Paraxial mesoderm
-gives rise to somiteres 1-7 in head region
-gives rise to somites in postcranial region
a. dermatomes – give rise to dermis
b. myotomes – give rise to all skeletal muscles below head
c. sclerotomes – give rise to bones of axial skeleton
-abnormal induction results in spinal defects (scoliosis)
B. Congenital Anomalies (not any obvious ones relating directly to somite migration)
1. Caudal dysplasia
-refers to constellation of syndromes ranging from minor lesions of lower vertebrae to complete fusion of lower limbs
-is caused by abnormal gastrulation, in which migration of mesoderm is disturbed
-can be associated with various cranial anomalies:
a. VATER – vertebral defects, anal atresia, tracheoesophageal fistula, renal defects
b. VACTERL – similar to VATER, includes cardiovascular defects and upper limb defects
2. Sacrococcygeal teratoma
-arises from remnants of primitive streak (see below); normally degenerates
-derived from pluripotent cells, develop into various tissue types (hair, bone, nerve)
-more common in female infants, usually malignant, must be removed by 6 months
IX. Fetal Circulation
A. Pattern
Aorta > R, L umbilical arteries (deoxy) > Left umbilical vein (oxy) > ductus venosus > Inf. vena cava > Right atrium > foramen ovale > Left atrium > Left ventricle > Aorta
Right atrium > Right ventricle > Pulmonary artery > Ductus arteriosus > Aorta
B. Three main shunts
1. Ductus arteriosus: pulmonary trunk to aorta
2. Ductus venosus: bypass liver
3. Foramen ovale: right atrium to left atrium
C. Remnants (First Aid p. 92)
D. After first breath
1. Alveoli are oxygenated
2. Decreased pulmonary resistance (lungs expand)
3. Increased pulmonary blood flow
4. Increased left atrial pressure
5. Functional closure of foramen ovale
6. Ductus arteriosus closes via smooth muscle contraction within a few hours of birth
7. Ductus venosus closes within a few days, mechanism unknown
X. Embryonic Plate: Weeks 2-3 (First Aid p. 91)
A. Week Two
1. Embryoblast (bilaminar disk)
a. Epiblast
b. Hypoblast
c. Amniotic cavity
d. Yolk sac
2. Trophoblast (Placenta)
a. Syncytiotrophoblast
b. Cytotrophoblast

B. Week Three
1. Gastrulation
-establishes three germ layers: ectoderm, mesoderm, endoderm (trilaminar disk by day 21); give rise to all tissues and organs
-primitive streak first indication
-all derived from epiblast



Gross Anatomy
1. Direct hernia: leaves abdominal cavity medial to inferior epigastric vessels
Indirect hernia: leaves abdominal cavity lateral to inferior epigastric vessels
Femoral hernia: protrusion of abdominal viscera through femoral ring into femoral canal
Lumbar puncture: needle into lumbar cistern between spinous processes L3/L4 or L4/L5 Pericardiocentesis: wide bore needle inserted through 5th or 6th intercostal space near sternum. Careful not to puncture internal thoracic artery

2. Thyroid C5 Duodenum T12-L1
Sternal notch T2 Kidneys T12-L3
Bifurcation of trachea T4-T5 Conus medularis L1-L2 adult, L3 newborn
Heart: Base T6-T9 Umbilicus L4
Apex 5th left intercostal space

3. Knee: 1. Patellar ligament- damage to femoral nerve or spinal cord L2-L4. Loss of patellar reflex 2. MCL- tear also tears medial meniscus. Passive abduction of extended leg at knee joint. 3. LCL- passive adduction of extended leg at knee joint. 4. ACL- anterior drawer sign. 5. PCL- posterior drawer sign. 6. Terrible triad- MCL, medial meniscus and ACL tears.

Hip: 1. Posterior dislocation- head of femur moves posterior to the iliofemoral ligament. Presents with lower limb that is flexed at hip joint, adducted, medial rotated and shorter than opposite limb. 2. Fracture of neck of femur presents laterally rotated and shortened.

Shoulder: 1. Dislocation- may be anterior or posterior. If anterior then axillary nerve may be damaged. 2. Separation- results in a downward displacement of clavicle.

Clavicle: 1. Fracture- most common at medial 1/3. Results in upward displacement of proximal fraagment and downward displacement of distal fragment

4. Brachial Plexus: 1. Axillary n- dislocation of shoulder, abduction (deltoid) and lateral rotation (teres minor) are compromised. 2. Long thoracic n- winging of scapula (serratus anterior). 3. Radial n- wrist drop (extensors of forearm). 4. Median n- ape hand (thumb muscles) and flexors of forearm if damage is at elbow or above. 5. Ulnar n- claw hand and radial deviation of hand, loss of some flexors if at elbow or above.

5. Peripheral nerves: 1. Common peroneal n- foot drop (tibialis anterior m) and inversion (peroneus muscles). 2. Deep peroneal n. entrapment- Compression of anterior compartment muscles of the lower leg by ski boot or athletic shoes that are too tight. Causes pain in the dorsum of the foot that radiates to the space between the first two toes.

6. Hands: 1. Carpel Tunnel Syndrome- compression of median nerve by inflammation, weakend flexion and abduciton and opposition of thumb, loss of extension of index and middle fingers, sensory loss of index, middle and half of ring fingers and palmar part of thumb. 2. Cubital tunnel syndrome- sorry I was not able to find this one. 3. Dupuytren’s contracture- progressive fibrosis of palmar aponeurosis, pulls digits into marked flexion at MCP joints.

7. Blood-testes barrier: There is a barrier that exists between the blood vessels that supply the testes (branches of the testicular artery and vein) and the duct system in which spermatozoa are produced and transported. The testis is derived partly from celomic mesoderm and partly from intermediate mesoderm with the blood vessels migrating in around the duct system.

8. Abdominal arteries: 1. Celiac trunk(CT)-FOREGUT-left gastric a., splenic a., hepatic a. 2. Superior messenteric a.(SMA)- MIDGUT- part of duodenum through proximal 2/3 of transverse colon. 3. Inferior mesenteric a.(IMA)-HINDGUT- distal 1/3 of transverse colon to upper rectum

Collaterals: 1. Internal thoracic a. to superior epigastric a. to inferior epigastric a. 2. Superior pancreaticoduodenal a.(from CT) to inferior pancreaticoduodenal a. (from SMA) 3. Middle colic a. (from SMA) to left colic artery (from IMA) 4. Marginal a. (from SMA and IMA) 5. Superior rectal a. (from IMA) to middle rectal a. (from internal iliac a.)

9. Bone: 1. Metaphysis: between epiphysis and diaphysis. 2. Epiphysis: growth plate responsible for linear bone growth. 3. Diaphysis: long part of bone responsible for annular bone growth.


(Add histology and neuroanatomy 1-2)
Neuroanatomy

3. Hearing
-Unlike other sensory systems, the central auditory pathways have bilateral representation of
sounds (sound from 1 ear reaches auditory cortex in both hemispheres).
-Pathway
-first neruons in spiral ganglion synapse in cochlear nucleus
-second neurons synapse bilaterally in superior olivary nuclei
-third neurons travel in the lateral lemniscus to synapse in the inferior colliculus
-fourth neurons then synapse in the medial geniculate nucleus
-the fibers then go to the transverse temporal gyrus of the cortex
-Conduction and nerve deafness
-Weber test (forehead)
-lateralizes to the affected ear with conduction deafness and to the unaffected
ear with nerve deafness
-Rinne test (mastoid process)
-distinguishes between better bone or air conduction of sound

4. Extraocular muscles (see First Aid pg. 111 and table 10.1 pg. 118 in Basic Clinical Neuroanatomy)
-Movements and innervation
-Medial Rectus – CN III – adduction (in)
-Superior Rectus – CN III – elevation (after abduction) (up)
-Inferior rectus – CN III – depression (after abduction) (down)
-Inferior oblique – CN III – elevation and adduction (up and in)
-Superior oblique – CN IV – depression and adduction (down and out)
-Lateral rectus – CN VI – abduction (out)
-Lesions
-CN III – eye turned down and out, ptosis, mydriasis
-CN IV – eye slightly up and in – diplopia going down stairs – tilting head away from the
affected side to correct the diplopia
-CN VI – eye deviates medially (abductor paralysis)

5 and 6. Chemical synapse, neurotransmitters, receptors, second messengers, effects BRS phys. 13-18
-Chemical synapse (BRS phys pg. 13-14)
-Presynaptic cell
-action potential – depolarization of presynaptic terminal – Ca2+ enters
presynaptic terminal – release of neurotransmitter into cleft
-Postsynaptic cell
-neurotransmitter binds to receptors causing a change in permeability to ion
-inhibitory neurotransmitters hyperpolarize – excitatory depolarize
-Receptor types (BRS phys pg.35-38)
-alpha 1 receptors – excitatory – epi and norepi – IP3 and increase intracellular Ca2+
-alpha 2 receptors – inhibatory – inhibit adenylate cyclase and decrease cAMP
-beta 1 receptors – excitatory – epi and norepi – activate adenylate cylcase – cAMP
-beta 2 receptors – relaxation – epi and norepi – activate adenylate cyclase – cAMP

7. Blood supply to brain (see First Aid pg. 112, BRS Path pg. 356-357)
-Embolism – most frequently to middle cerebral artery leading to contralateral paralysis,
motor defects, sensory defects, aphasias
-Thrombosis – from atherosclerosis of carotids, vertebral and basilar aa., and middle cerebral aa.
-Hemorrhage – hypertension and coagulation disorders – most often in basal ganglia, pons,
frontal lobe, cerebellum

8. Basal Ganglia (globus pallidus, caudate, putamen) (First Aid pg. 109)
-initiation of voluntary movements and control of postural adjustments
-Pathology of the basal ganglia
-Negative signs: akinesia, bradydinesia, abnormal postural adjustments
-Positive signs (dyskinesia at rest): hypertonicity (rigidity), tremors, chorea, athetosis,
ballismus
-Huntington disease – degeneration of striatal neurons (putamen and caudate)
-Parkinson disease – degeneration of the dopamine neurons in the substantia nigra
-Tardive dyskinesia – exposure to manganese and drugs – hypersensitivity to dopamine agonists
-Hemiballismus – lesions in contralateral subthalamic nucleus

9. Pituitary associations
-Optic chiasm sits on top of pituitary – bilateral hemianopsia
-Sits in the sella turcica - local pressure effects hypopatuitarism

10. Brain MRI and CT
-Abcess or cysticercosis CT and MRI – ring enhancing lesion
-Multiple sclerosis MRI – multiple focal areas of demyelination (plaques) in brain and spinal cord
-Huntington’s disease – atrophy of the caudate nucleus, putamen, and frontal cortex – looks like
ventricles have enlarged

11. Pupillary light reflex - doesn’t involve cortex
-Direct response – afferent pathway is optic nerve of eye tested – efferent pathway is CN III
to the eye tested
-Consensual response – afferent pathway is optic nerve of eye tested – efferent pathway is
CN III of opposite eye
-Accomodation – pupils constrict, eyes converge, lense more convex – depends on CN III
and visual association cortex

[Anonymous]

Behavioral Science
Epidemiology/Biostatistics

1. The five leading causes of death are heart disease, cancer, cerebrovascular disease, COPD and accidents/adverse effects. These are the same in whites and blacks. Blacks have a greater death rate than the general population and also have increased mortality risk with most diseases.

2. Leading causes of cancer:
Men: Lung, prostate, colon/rectal, pancreas, non-Hodgkin’s lymphoma
Women: Lung, breast, colon/rectal, pancreas, ovary

3. Prevalence of common psychiatric disorders:
Alcoholism: 70% of the population drinks, 12% heavily. Men:women = 2:1. Low incidence among Jews and Orientals. High among urban blacks and indians. 10% lifetime prevalence.
Drug abuse: 5% lifetime prevalence. M>F. By definition, it must impair social/occupational functioning to be drug abuse.
Bullemia/Anorexia nervosa: >90% are female.
Schizophrenia: 1% lifetime prevalence. Increased in urban and low S/E groups.
Major depression: 17% lifetime prevalence. 10X more frequent than bipolar disorder.
Depression(dysthymia): W:M 2-3:1; 6% lifetime prevalence.

4. Morbidity = sick rate
Mortality = death rate
5. HIV transmission
45-60% homosexual/bisexual men
20-25% IV drug users
13% heterosexuals
<1% perinatal
6. Types of studies:
Randomized clinical trial: Investigator assigns individuals to study and control groups by a random process (syn: controlled clinical trial)
Cohort: Study begins by identifying individuals with and without a factor being investigated. These factors are identified with and without knowledge of which individuals have or will develop disease (e.g. – identify people on NSAIDS and not on NSAIDS and see which develop PUD later)
Case control: Identify those with disease(case) and without disease(control) without knowledge
of exposure of subjects to factors being investigated (e.g. – identify post menopausal subjects with and without breast cancer and see how many are nulliparous).
7. Standard deviation : measures the spread of data (how far in general it is from the mean).
p-value: probability of obtaining data at least as extreme as that obtained in the investigation’s sample set if the null hypothesis were true. (The smaller the p-value, the larger your confidence interval)
mean: sum of measurements/number of measurements
median: half of the data values occur above, half below the median.
Mode: most frequently occurring data value.
8. You can change a test’s criteria to make it more sensitive(fewer false negatives) or specific(fewer false positives)

(Add epi, neruophysiology, psych 1-2)

Psychiatry

3. Diseases associated with personality types.
· There is only one specific conditioned shown to be convincingly associated with a particular personality trait – coronary artery disease appears more common in people who are more hostile.
· It is hypothesized that it is connected to the adrenalin surge that accompanies angry outbursts.
4. Clinical features and treatment of phobias.
· Phobia disorders are the most common psychiatric disorder.
· More than 12% have a phobic disorder in some circumstances.
· Only 1% is significantly disabling.
· Many begin in young women (15-30) from stable families.
· Relief occurs with escape, thus reinforcing the avoidance pattern – a vicious cycle.
· One of the best studied and most debilitating is agrophobia. This is a combination of multiple anxieties: fears of open/closed spaces, crowded places, unfamiliar places, being alone. In general it is a loss of sense of security. Depression is common and most patients also have panic attacks (panic disorder with agrophobia).
· Other phobia: public speaking, public bathrooms (males), animals, storms, needles, etc.
· Most phobias, social or specific are more frequent among women.
· Treatment:
-b-blockers can be used before public speaking.
-Mild tranquilizers can be used temporarily to confront the phobia.
-SSRIs and MAOIs are effective for generalized social phobias.
-Agrophobia, with or without panic attacks, can be treated with anti-anxiety medications (TCAs, MAOIs, alprazolam).
-Cognitive-behavior therapy is essential. Exposure is the key treatment: systematic desensitization-graded exposure; flooding – face feared object directly; or implosion – thinking about it.
5. Clinical features of child abuse.
· There are 4 classic types of child abuse: emotional, neglect, physical, and sexual abuse.
· Emotional abuse is the most common and often overlooked.
· Neglect is the most under-reported and can include physical, emotional, and educational neglect.
· One third of abusers have been abused themselves.
· Children who are particularly at risk are the ADHD, conduct disorders, difficult temperaments, low birth weight, and sick children.
· Younger children are more likely to be physically abused.
· Mothers are more likely to abuse prepubertal children, while fathers adolescents.
· Some of the typical symptoms:
Sleep disorders, developmental delays, antisocial behavior, poor self-esteem, runaway, lying, stealing, fire starting, drug and alcohol abuse, borderline PD, dissociation (multiple personalities). See First Aid for the physical symptoms.
6. Clinical features of common learning disorders.
· Rule out: hearing/vision loss, language difficulties, poor attendance.
· When aptitude tests (measures potential to learn) are greater than achievement tests consider a learning disorder.
· Dyslexia – difficulty reading
Seems to be reading the book, but later becomes clear the child is guessing at simple words and looking at pictures.
· Dyscalcula – great difficulty in math.
Everything is rote memorization and not understanding.
· Mental retardation (<18 years old, ¯ IQ – less than 2 standard deviations, ¯ functioning)
Mild IQ 50-70 85% Usually recognized when enter school; most self sufficient
Moderate IQ 35-50 10% Learn simple skills; supported lifestyle
Severe IQ 20-35 4% Simple speech; supported care
Profound IQ <20 1% Significant neurological damage, complete care required
· Down syndrome and fragile X syndrome are the number one and two causes, respectively, of mental retardation. Social causes produce most of the mild retardation (e.g. environmental deprivation, abuse, neglect). Fetal alcohol syndrome is the number one cause of mental retardation.
7. Therapeutic applications of learning theories.
· Classical Conditioning – behavior are built from stimulus-response connections. Behavior is built up out of, and linked to, simple reflexes by association. Usually they are associated because they occur close together in time.
· Classical Conditioning has four components: Unconditional Stimulus - food (UCS), Unconditional Response – salivation (UCR), Conditioned Stimulus - bell (CS), and Conditioned Response – salivation (CR).
· Reinforcement – pairing of CS & UCS ® develops the effectiveness of the CS to elicit the CR. Irregular pairing most effective.
· Extinction – deleting the UCS will eventually lead to stopping of CR.
· Pavlovian A conditioning – UCS is positive (pleasurable); Pavlovian B conditioning – UCS is unpleasant
· An example: A child comes to the physician’s office for a shot (UCS). She cries when she gets the shot from the nurse (UCR). The next month she sees the same nurse (CS) and starts to cry (CR). In time if the sight of the nurse is not followed by a shot the conditioned response (crying) will stop – extinction.
· Other examples – Alcoholism and Antabuse, Food aversion in children with cancer, treatment of phobias.
· Operant Conditioning – feature behavior is contingent upon the consequences (reinforcement) of that original behavior. A person’s behavior, ideas, and personality are the products of the “histories of reinforcement” experienced by that person throughout life.
· Behavior that is not part of the individual’s natural repertoire can be learned through reward or punishment.
· Positive reinforcement is a positive stimulus that increases the rate of behavior.
· Negative reinforcement (escape) is the removal of an aversive stimulus that increases the rate of behavior. An example would be a child who increases his study behavior to avoid losing television privileges.
· Punishment is an aversive stimulus aimed at reducing an unwanted behavior.
· The pattern or schedule of reinforcement affects how quickly a behavior is learned or disapears.
-Fixed ratio schedule
-Fixed interval schedule
-Variable-ratio schedule (best one)
-Variable interval schedule
8. Problems associated with the physician-patient relationship.
· Factors that increase patient compliance
-Good physician-patient relationship
-Feeling ill
-Older physician
-Short period spent in the waiting room
-Written instructions for taking medication
-Acute illness
-Simple treatment schedule
-One behavioral change at a time
9. Management of the suicidal patient.
· Ask – should patient be hospitalized. Be conservative.
· Identify and treat psychiatric or medical conditions.
-Treat depression vigorously.
-If determinedly suicidal, use ECT (electroconvulsive therapy) instead of waiting for medication response.
· Develop an alliance with the patient.
-Allow to express anger, feelings of hopelessness.
-Try to understand why the patient wants to die.
· Suicidal patients are often ambivalent about death.
-Point this out to them, show them the evidence of their desire to live.
-Make plans with/for patient.
· Try to reduce social isolation.
-Involve family/significant others.
-Involve community resources.
· Suicidal potential can change rapidly – reassess frequently.
· Many depressive suicides occur within 36 hours of discharge – don’t lose contact with patient.
· Don’t minimize the seriousness of a suicide attempt.
· Don’t explain away the patient’s symptoms.
· Don’t agree to hold a suicide plan in confidence.
· Many patients with severe depression do not have the energy to commit suicide. The risk of suicide increases as depression begins to diminish and energy to act on suicidal impulses returns with treatment.
10. Addiction: risk factors, family history, behavior, factors contributing to relapse.
· Genetic evidence for alcoholism: 4 times the normal risk if one parent, 60% risk if both parents are alcoholics.
· Type 1 alcoholics – adult onset; gradually escalating consumption, male and females; modest family history; 75% of alcoholics.
· Type 2 alcoholics – adolescence and early adulthood; risk taking and anti-social characteristics; primarily male; very resistant to treatment; strong family history; 25% of alcoholics.
· Other predictive, inherited biological features are associated with alcoholism (particularly in males):
-Resistant to intoxication – very high risk of developing alcoholism.
-Subnormal rise of cortisol after drinking.
-Subnormal release of epinephrine following stress.
· Alcohol stimulates the release of dopamine producing euphoria. Over time natural levels of dopamine fall unless stimulated by alcohol – very reinforcing. Natural dopamine levels may take months or years to recover.
· The majority of alcoholics die 15 years early – usually form heart disease or cancer.
· 6% life-time prevalence of drug abuse in the U.S. and males > females in all age groups.
· Abusers are not all alike but do have some common features:
-Marked depression and anxiety.
-Increased dependency needs.
-Low self-esteem.
-Familial associations with antisocial personality.
-Dysfunctional family
-A chronic course resistant to treatment.
-Drug use to treat psychiatric illnesses are modestly abused but more commonly chronic abuse produces emotional problems.

[Anonymous]

BIOCHEMISTRY

DNA/RNA/Protein

1. Molecular biology tools and techniques:
a. Cloning – introduction of pieces of DNA into a vector in order to permit amplification. Many methods of cloning exist. Commonly, total cellular DNA is cleaved, and each piece is inserted into a vector. The library of vectors is introduced into bacteria or another replication host. A bacteria which has a vector will then replicate, making many copies of the DNA in that vector, hence, a clone. (Lippincott page 404)
b. cDNA libraries – complementary DNA libraries are made by reverse transcribing (making DNA from RNA) all of the mRNA in a cell. The DNA copies are replicas of mRNA without introns. These can be used as probes, primers, or many other uses.
c. PCR-see page 146-biochemistry.
d. Restriction length fragment polymorphism—within the natural sequence of many genes are restriction sites, specific sequences cleaved by restriction enzymes. Many of these sites are polymorphic. That is, they contain differences which render them susceptible or perhaps not susceptible to cleavage at that particular site. These differences can be used to identify genes, or match DNA from different samples, as in forensics.
e. Sequencing – The major method of sequencing is the Sanger dideoxy nucleotide method. An elongation reaction is carried out using a primer just upstream of the portion to be sequenced. The mixture includes radioactive nucleotides except one of the nucleotides (A,T,G,or C) is dideoxy. That is, it does not have an oxygen at the 2 or 3 position of the ribose sugar. When one of the dideoxy bases is incorporated into the growing chain, elongation is stopped. A reaction is run containing dideoxy nucleotides of each base. For instance, one reaction contains all of the nucleotides but the adenosines are dideoxy. The results are then run on a gel. The sequence can be read by observing which bases were the terminating base at each position on the sequence.
2. Transcriptional regulation
a. The operon model – This model is related to the regulation of gene transcription (making RNA from genes) in certain environments. For instance the Lac operon consists of regulatory proteins that control production of proteins necessary to degrade lactose. These are only needed when lactose is present.
b. Eukaryotic transcription—Eukaryotic transcription is controlled by regions of DNA called promoters upstream from the material of the genes. Transcription factors bind to promoters, and help recruit RNA Polymerase II, which binds the TATA box, located approx. 25 bases upstream from the transcription start site. Another sequence, the CAAT box, is located approx. 40 bases upstream from the TATA box. Enhancer regions are other regions of DNA that bind specific protein that aid in transcription of certain gense. These regions can be located upstream, within the gene, within introns, close, or far from the transcription start site. Before a gene is transcribed a large complex of proteins is formed in the promoter region. The need for this large complex of proteins helps in gene regulation.
c. Role of steroid hormones – Steroid hormones cross membranes and travel directly to the nucleus of target cells. Bound to their respective receptors, steroid hormones act like transcription factors or enhancer binding proteins. They bind to hormone response elements near the genes they regulate and either enhance or inhibit transcription of those genes.
3. Translation (Protein synthesis)
a. Translation of mRNA occurs in the cytosol on ribosomes. Ribosomes can be free floating or attached to the ER membrane. Three nucleotides on mRNA encode for on amino acid. The start site is AUG on the RNA. This codes for methionine. Each amino acid is attached to a specific tRNA, which recognized the codon for that particular amino acid. Translation happens in three steps: initiation, elongation, and termination.
i. Initiation: Initiation involves assembling two ribosomal subunits, the mRNA, GTP, the tRNA with the first amino acid, and initiation factors that facilitate the whole process. The ribosome recognizes specific sequences on the mRNA and assembles the machinery. In bacteria, the first amino acid is N-formyl-methionine, while in eukaryotes it is normally methionine. The first tRNA with the appropriate amino acid is in the P-site of the ribosome, and the next tRNA with its appropriate amino acid arrives to the A-site. A peptide bond is formed between the two amino acids. Initiation factors aid in the setting up of the complex.
ii. Elongation: Elongation factors help the ribosome move down the mRNA with energy derived from GTP hydrolysis. tRNAs are attached to their amino acids using energy from ATP by specific synthetases for each amino acid and tRNA combination. Each time the ribosome moves down the mRNA, the nascent polypeptide is moved into the P-site, making room in the A-site for a new tRNA/amino acid pair.
iii. Termination: Termination occurs when the ribosome meets a termination sequence. Release factors cause the new peptide to be released from the ribosomes, and cause the dissociation of the ribosome complex.
b. Post translational modification of proteins occurs depending on the final destination and function. Modifications include trimming of proteins to active forms. Insulin for example, is synthesized as a zymogen and cleaved to the active molecule. Covalent alterations are also added to some proteins. These include glycosylation with different sugars, phosphorylation, hydroxylation, or association with coenzymes.
4. Acid-base titration curve of amino acid and proteins
a. Protons will dissociate from weak acids at a certain pH, depending on the strength of the bond of the dissociable hydrogen. This pH is called the pKa of the acid. The Henderson-Hasselbach equation relates the relative amount of acid and base at a given pH to the pKa of an acid.
b. Amino acids, since they have a carboxyl group, are weak acids. The pKa of most carboxyl groups is around 2, and the pKa for most amino groups of amino acids is around 9. They are referred to as pKa1 and pKa2 respectively. Some amino acids with an acidic or basic side chain have an additional pKa for the side chain hydrogen ion. See page 12 in Lippincott for examples of titration curves.
c. Proteins have titration curves as well. However, the carboxyl group and the amino group are the main titratable acids, as well as titratable side chains.
d. Titratable side chains include the acidic amino acids, aspartate and glutamate, basic amino acids arginine, lysine and histidine. The pKa of histidine is 6.0, so at physiologic pH it is not ionized.
5. Role of SH2 domains
a. The role of SH2 domains is simple: they bind phosphotyrosine. They are normally found in proteins involved in signal transduction. By binding to phosphotyrosine, they allow signals to be passed from one molecule to another. For instance, some receptors, when bound to a ligand, have tyrosine kinase activity. When these tyrosines are phosphorylated, and SH2 domain of another protein can bind to the cytoplasmic phosphotyrosine. The signal can be passed to other proteins and eventually to the nucleus.

Genetic Errors

1. Inherited hyperlipidemias--
Type Increased lipoprotein class Increased Lipid
I Chylomicrons Triglycerides
IIa LDL Cholesterol
IIb LDL and VLDL Cholesterol and triglycerides
III Remnants Triglycerides and cholesterol
IV VLDL Triglycerides
V VLDL and chylomicrons Triglycerides and cholesterol

2. Glycogen and lysosomal storage diseases are covered in First Aid.
3. Porphyrias --
a. Porphyrias are defects of porphyrin metabolism, leading to buildup of toxic metabolites. Porphyrins are ring structures. An example in heme without the iron. Many defects exist in many different steps in the pathways. They are classified depending on clinical and biochemical properities. Five main types exist:
i. congenital erythropoietic porphyria
ii. erythrohepatic porphyria
iii. acute intermittent porphyria
iv. porphyria cutanea tarda
v. mixed porphyria
b. Manifestations include light sensitivity, vesicles that heal when scarring, anemia. Pathogenesis is not well understood.
c. The clinical picture is someone with light sensitivity, so they only go out at night. They have weird fluorescing molecules in their bodies, so their teeth fluoresce (porphyrin rings.) Because of defects in heme synthesis and metabolism, anemia can be a problem, so they want to drink blood. Some say that vampire legends came from people with porphyrias. Interesting eh?

4. DNA repair defects (First Aid p. 149)
Disease Features Type of repair defect
Xeroderma pigmentosum (skin sensitivity to UV light) Skin tumors, photosensitivity, cataracts, neurological abnormalities Nucleotide excision repair defects, including mutations in helicase and endonuclease genes
Cockayne syndrome Reduced stature, skeletal abnormalities, optic atrophy, deafness, photosensitivity, mental retardation Defective repair of UV-induced damage in transcriptionally active DNA; considerable etiological and symptomatic overlap with xeroderma pigmentosum and trichothiodystrophy
Fanconi anemia Anemia; leukemia susceptibility; limb kidney, and heart malformations; chromosome instability As many as eight different genes may be involved, but their exact role in DNA repair is not yet known
Bloom’s syndrome (radiation) Growth deficiency, immunodeficiency, chromosome instability, increased cancer incidence Mutations in the reqQ helicase family
Werner syndrome Cataracts, osteoporosis, atherosclerosis, loss of skin elasticity, short stature, diabetes, increased cancer incidence; sometimes described as “premature aging” Mutations in the reqQ helicase family
Ataxia-telangiectasia (x-rays) Cerebellar ataxia, telangiectases*, immune deficiency, increased cancer incidence, chromosome instability Normal gene product is likely to involved in halting the cell cycle after DNA damage occurs
Hereditary nonpolyposis colorectal cancer Proximal bowel tumors, increased susceptibility to several other types of cancers Mutation in any of four DNA mismatch repair genes
*Telangectases are vascular lesions caused by the dilatation of small blood vessels. This typically produces discoloration of the skin.Reference: Medical Genetics p. 39

5. Triplet repeat diseases.
Disease Description Repeat sequence Normal & Abnormal range Parent in which expansion usually occurs Location of expansion
Huntington disease Loss of motor control, dememtia, affective disorder CAG 6 to 34; 36 to >100 More often through father Exon
Spinal and bulbar musculaar atrophy Adult-onset motor-neuron disease associated with androgen insensitivity CAG 11 to 34; 40 to 62 More often through father Exon
Spinocerebellar ataxia (type 1, 2, 3, 6) Progressive ataxia and other type specific symptoms CAG Varies with type More often through father Exon
Dentatorubral-pallidoluysian atrophy/Haw River syndrome Cerebellar atrophy, ataxia, myoclonic epilepsy, choreoathetosis, dementia CAG 7 to 25; 49 to 88 More often through father Exon
Myotonic dystrophy Muscle loss, cardiac arrhythmia, cataracts, frontal balding CTG 5 to 37; 100 to >1000 Either parent, but expansion to congenital form through mother 3’ Untrans-lated region
Friedreich’s ataxia Progressive limb ataxia, dysarthria, hypertrophic cardiomyopathy, pyramidal weakness in legs GAA 7 to 22; 200 to 900 or more Disorder is autosomal recessive, to disease alleles are inherited from both parents Intron
Fragile X syndrome (FRAXA) Mental retardation, large ears and jaws, macro-orchidism in males CGG 6 to 52; 200 to >2,000 Exclusively through mother 5’ Untras- lated region
Fragile site FRAXE Mild mental retardation GCC 6 to 35; 200 or more More often through mother Unknown
Reference: Medical Genetics p. 83
6. Inherited defects in amino acid metabolism.
Name Prevalence Mutant gene product Chromosomal location
Phenylketonuria (PKU) 1/10,000 Phenylalanine hydroxylase 12q24
Tyrosinemia (type 1) 1/100,000 Fumarylacetoacetate hydrolase 15q23-25
Maple syrup urine disease 1/180,000 Branched-chain "-ketoacid decarboxylase (multiple subunits) Multiple loci
Alkaptonuria 1/250,000 Homogentisic acid oxidase 3q2
Homocystinuria 1/340,000 Cystathionine $-synthase 21q2
Oculocutaneous albinism 1/35,000 Tyrosinase 11q
Cystinosis 1/100,000 Unknown 17p
Cystinuria 1/7,000 SLC3A1 (type 1) 2p
Reference: Medical Genetic p.138


Metabolism

1. Glycogen synthesis: regulation, inherited defects.
A. Regulation: In the well fed state, Glycogen synthetase is allosterically activated by glucose 6-phosphate, as well as by ATP, a high energy signal in the cell. An elevated insulin level results in overall increased glycogen synthesis.
Glucagon (in the liver) and Epinephrine (muscle and liver) bind cell membrane receptors and stimulate adenylate cyclase then cAMP. Glycogen synthetase is then phosphorylated by cAMP-dependent protein kinase which inhibits the production of glycogen. (Lippincott’s Biochem p. 142-145)
B. Inherited defects: Glycogen storage diseases- First Aid p. 150
2. Oxygen consumption, carbon dioxide production, and ATP production for fats, proteins, and carbohydrates.
A. Oxygen consumption occurs in the mitochondrial matrix. Cytochrome oxidase uses oxygen as the final electron acceptor and converts it to H2O.
B. Carbon dioxide production results from reactions in several pathways including the TCA cycle and the Hexose Monophosphate Pathway (HMP). One molecule of CO2 (and one NADH) is produced in the conversion of Pyruvate to Acetyl-CoA by pyruvate dehydrogenase. Two molecules of CO2 are produced in the TCA cycle for every molecule of Acetyl-CoA. One molecule of CO2 (and one NADPH) is also produced by the conversion of 6-Phosphogluconate to Ribulose 5-phosphate in the HMP.
C. ATP production
Fats are broken down through Triacylglycerol degradation into fatty acids which are then broken down to Fatty Acyl CoA and then Acetyl-CoA which then enters the TCA cycle. Each Acetyl-CoA produces 3NADH, 1FADH2, 2CO2, 1GTP which is equal to 12ATP/acetyl CoA.
Proteins are broken down to amino acids which enter the TCA cycle at different points. Refer to p.244 Fig. 22.22 in Lippincott’s Biochem for the metabolism of specific amino acids and associated genetic deficiencies.
Carbohydrates are broken down to monosaccharides, the most common of which is D-glucose. Aerobic metabolism of glucose produces 38 ATP via malate shuttle, 36 ATP via G3P shuttle. Anaerobic glycolysis produces only 2 ATP per glucose molecule.
3. Amino acid degradation pathways (urea cycle, tricarboxylic acid cycle). Refer to Lippincott’s Biochem Figure 21.11, p.237 and Figure 22.2, p.244.
4. Effect of enzyme phosphorylation on metabolic pathways.
Enzyme Enzyme Activity when Phosphorylated Description
Glycogen phosphorylase Active Degrades glycogen
Glycogen synthase Inactive Synthesizes glycogen
Pyruvate kinase Inactive Converts Phosphoenolpyruvate (PEP) to Pyruvate
Pyruvate dehydrogenase Inactive Converts Pyruvate to Acetyl-CoA
Acetyl CoA carboxylase Inactive Converts Acetyl CoA to Malonyl CoA in triglyceride synthesis
Hormone sensitive lipase Active Breaks triglyceride into a fatty acid and a diglyceride




Note: not a complete table- add enzymes as needed

5. Rate limiting enzymes in different metabolic pathways: First Aid p. 155
6. Sites of different metabolic pathways (What organ? Where in the cell?).
-Organ sites (First Aid 99 p 156):
-Liver: Most represented, including gluconeogenesis; fatty acid oxidation (b-oxidation); ketogenesis;
lipoprotein formation; urea, uric acid & bile acid formation; cholesterol synthesis.
-Brain: Glycolysis, amino acid formation.
-Heart: Aerobic pathways (e.g., b-oxidation and Krebs cycle)
-Adipose tissue: Esterification of fatty acids and lipolysis
-Muscle: fast twitch: Glycolysis; slow twitch: Aerobic pathways
-Cell sites (First Aid 99 p 154):
-Mitochondria: b-oxidation, acetyl-CoA production, Krebs cycle.
-Cytoplasm: Glycolysis, fatty acid synthesis, HMP shunt, protein synthesis (RER), steroid synthesis (SER).
-Both: Gluconeogenesis, urea cycle, and heme synthesis
7. Fed state versus fasting state: forms of energy used, direction of pathways.
-See liver diagrams for both states on page 159 of First Aid 99.
-Fed (Absorptive) state (BRS Biochemistry p 4):
-Glucose is oxidized by various tissues for energy or is stored as glycogen in liver and muscle. In liver, glucose is also converted to triacylglycerols, which are packaged in VLDL and released into the blood. Fatty acids of the VLDL and chylomicrons are stored in adipose tissue. Absorbed amino acids are used by various tissues to synthesis proteins, produce nitrogen-containing compounds, and produce energy.
-Fasting state (BRS Biochemistry p 7):
-With decreasing blood glucose level, the liver is stimulated by glucagon to supply glucose (glycogenolysis & gluconeogenesis) and ketones to the blood. The liver uses amino acids from muscles and fatty acids and glycerol from adipose tissue.
-Prolonged Fasting (BRS Biochemistry p 9):
-Muscles: ¯ use of ketones & * oxidation of fatty acids for primary energy source.
-Brain: *use of abundant ketones instead of glucose.
-Liver: ¯ gluconeogenesis & spares muscle proteins.

8. Tyrosine kinases and their effects on metabolic pathways (insulin receptor, growth factor receptors)
-Insulin Receptor (Lippincott p 273):
-Insulin binding activates receptor tyrosine kinase activity in the intracellular domain of the b-subunit.
-Tyrosine residues of the b-subunit are autophosphorylated.
-Receptor tyrosine kinase phosphorylates other proteins, such as the insulin receptor substrate (IRS).
-Phosphorylated IRS promotes activation of other protein kinases and phosphatases, leading to the biological actions of insulin (see Topic 13 below).
-Insulin-like Growth Factor Receptor (BRS Physiology p 249):
-The IGF receptor has tyrosine kinase activity like the insulin receptor

9. Anti-insulin hormones (e.g., glucagon, GH, cortisol).
-Considered “counterregulatory hormones” because they oppose many actions of insulin (Lippincott p 275):
-Glucagon: Acute, short-term regulation by stimulating hepatic glycogenolysis and gluconeogenesis.
-Epinephrine: Acute, short-term regulation by promoting glycogenolysis and lipolysis, inhibiting insulin secretion, and inhibits the insulin-mediated uptake of glucose by peripheral tissues.
-Cortisol: Long-term management by stimulating gluconeogenesis and lipolysis.
-Growth Hormone: Long-term management by stimulating gluconeogenesis and lipolysis.

10. Synthesis and metabolism of neurotransmitters.
-Acetylcholine (Correlative Neuroanatomy p 30):
-ACh is synthesized from acetyl-CoA and choline by the enzyme choline acetyltransferase in the presynaptic cholinergic nerve terminal.
-ACh is broken down after release into the synaptic cleft by the enzyme acetylcholinesterase.
-Choline is taken back up into the presynaptic nerve terminal to be converted back into ACh.
-Catecholamines (Correlative Neuroanatomy p 30):
-Phenylalanine®tyrosine®DOPA®dopamine®norepinephrin e®epinephrine (First Aid 99 p151).
-Tyrosine is converted to DOPA by tyrosine hydroxlyase.
-DOPA is converted to dopamine by DOPA decarboxylase.
-Dopamine is hydroxlyated to NE and NE is converted to epinephrine by phenylethanolamine-N-methyltransferase.
-Dopamine and NE are inactivated by both MAO (presynaptic nerve terminal) and COMT (postsynaptic).
-Serotonin (Correlative Neuroanatomy p 32): Synthesized from the amino acid tryptophan.

11. Purine/pyrimidine degradation:
-Purine (G, A) degradation (BRS Biochemistry p 265):
-First phosphate and ribose are removed; then the nitrogenous base is oxidized.
-Guanine is degraded to xanthine and adenine to hypoxanthine, which is then oxidized to xanthine by xanthine oxidase (this enzyme requires molybdenum).
-Xanthine is oxidized to uric acid by xanthine oxidase.
-The kidneys excrete uric acid, which is not very water-soluble.
-Pyrimidine (C, U, T) degradation (BRS Biochemistry p 267):
-Unlike the purine rings, which are not cleaved in human cells, the pyrimidine ring can be opened and degraded to a highly soluble structures, such as b-alanine and b-aminoisobutyrate.
-The carbons produce CO2 and the nitrogens produce urea.

12. Carnitine shuttle: function and inherited defects.
-Function (Lippincott p 182):
-The carnitine shuttle transports the acyl group from cytosolic fatty acyl CoA molecules across the inner mitochondrial membrane, which is impermeable to CoA, returning it to mitochondrial CoA molecules.
-The newly formed mitochondrial fatty acyl CoA molecules can then undergo b-oxidation.
-Inherited defects:
-The congenital absence of a carnitine acyltransferase in skeletal muscle, or low concentrations of carnitine due to defective synthesis, result in an inability to use long-chain fatty acids as a metabolic fuel, causing myoglobinemia and weakness following exercise.

13. Cellular/organ effects of insulin secretion (Lippincott p 273 and BRS Biochemistry p 154).
-Liver: * glycogen synthesis; ¯ glucose production by inhibiting gluconeogenesis & glycogenolysis; * triacylglycerol synthesis & conversion to VLDL.
-Muscle: * glycogen synthesis; * glucose uptake by increasing the number of glucose transporters.
-Adipose tissue: ¯ triacylglycerol degradation & * triacylglycerol synthesis; * glucose uptake by increasing the number of glucose transporters.
-Most tissues: * entry of amino acids into cells & * protein synthesis.
-Insulin does NOT significantly stimulate the transport of glucose into tissues such as liver, brain, & RBCs.

14. Effect of uncouplers on oxidative phosphorylation (Lippincott p 71).
-Compounds that increase the permeability of the inner mitochondrial membrane to protons can uncouple electron transport and phosphorylation.
-The energy produced by the transport of electrons, without a proton gradient, is released as heat rather than being used to synthesize ATP.
-2,4-dinitrophenol, a lipophilic proton carrier that readily diffuses through the membrane, is an uncoupler.
-Aspirin in high doses (as well as other salicylates) is an uncoupler. This explains the fever that accompanies the toxic overdoses of these drugs.
-Uncoupling is different that just inhibiting electron transport, like cyanide does.

[Anonymous]

Microbiology
Microbiology

1. Principles of bacteriologic lab tests -- specific culture growth requirements:
(pg. 192, 1999 First Aid).
2. Dermatologic manifestations of bacterial and viral infections:
a. Primary Syphilis -- painless chancre
b. Secondary syphilis -- maculopapular rash, condylomata lata (flat topped papules -- located at the anus and in skin folds where heat and moisture exist).
c. Rocky Mountain Spotted Fever -- stage 1: erythema chronicum migrans (a red rash that spreads, leaving a clear center -- bulls-eye rash).
d. Menningococcemia --intravascular multiplication of N. meningitidis in the blood can result in a petechial rash (minute hemorrhagic spots the size of a pin that do not blanch when pressed). The rash can enlarge if the organisms multiply in the blood to the leading to fulminant meningoccemia (Waterhouse-Friderichsen syndrome--bilateral hemorrhage into the adrenals).
e. Herpes Zoster (varicella zoster) Virus -- vesicular rash (chicken-pox) that appear on the back of the head and ears then spread to the face, neck, trunk, and extremities. The distinguishing feature from other rashes (small pox) is that lesions will be at different stages (whereas small pox lesions are concentrated on the extremities and are all in the same stage). The lesion are very pruritic (itchy).
f. Coxsackievirus --Coxsackie A: herpangina -- fever, sore throat, and small red-based vesicles over the back of the throat. Hand-foot-mouth disease -- (coxsackie A-16) eruptions of small pearly, gray vesicles on the fingers, toes, palms, and soles often accompanied by painful vesicles and ulceration of the buccal mucous membranes and the tongue with slight fever; disease lasts 4 to 7 days.
3. Common sexually transmitted diseases: (pg. 191 1999 First Aid)
4. Viral Gastroenteritis in the pediatric and adult population:
a. Rotavirus -- Group A: cause most infantile disease (most between 6 - 24 months) -- 30-60% of infantile diarrhea. Occurrence is during the winter months (SW to NE spread). Diarrhea, vomiting, and fever for 5-7 days.
Group B: associated with large epidemic of severe diarrhea (3-5 days) in Adults in China.
b. Enteric Adenovirus (serotypes 40 & 41) -- 2nd most common cause of diarrhea in children.
Symptoms consist of prolonged diarrhea lasting 5-12 days, vomiting and fever.
c. Norwalk virus -- most common cause of outbreaks of gastroenteritis reported to the CDC.
Epidemics of vomiting and diarrhea in older children and adults, associated with shellfish,
food or water.
5. Common causes of community-acquired and nosocomial pneumonia: (pg. 190 First Aid)
6. Infections that cause congenital/neonatal complications: ToRCHeS -- all of these organisms can cross the blood-placenta barrier.
a. Toxoplasma gondii -- can cause chorioretinitis, blindness, seizures, mental retardation,
microcephaly, encephalitis, and stillbirth if infections is acquired early in gestation.
b. Rubella (Rubivirus) -- risk is greatest with infection early in fetal development. Heart: PDA,
VSD, and pulmonary artery stenosis. Eye: cataracts, chorioretinitis. CNS: mental
retardation, microcephaly, deafness.
c. CMV -- most common viral cause of mental retardation. Also cause microcephaly, deafness,
seizures.
d. Herpes -- neonate is often infected during delivery. Manifestations vary -- vesicular lesions
or CNS involvement.
HIV
e. Syphilis -- high rate of mortality (still-birth, spontaneous abortion, and neonatal death).
Survivors will go on to develop Early of Late congenital syphilis.
1. Early: occurs w/in 2 years and is like severe adult secondary syphilis -- widespread
rash and condyloma latum. "Snuffles" -- mucous membrane involvement with
runny nose.
2. Late: similar to adult tertiary syphilis except cardiovascular involvement rarely
occurs.
7. Parasites that frequently cause disease in the U.S.
a. Entamoeba histolytica - flask-shaped ulcer in large intestine - amoebic liver abcesses (liver paste)
b. Trichomonas vaginalis - strawberry cervix, twitching motility STD
c. Giardia lamblia - non-bloody diarrhea, malabsorption, trophozoite is “old man with moustache”
d. Cryptosporidium parvum - diarrhea in immunocompromised
e. Toxoplasma - acutely like mono. In utero - hydrocephalus, chorioretinitis, brain calcifications
also in immunocompromised
f. Pneumocystis carinii - immunocompromised
g. Enterobius vermicularis (Pinworm)
h. Ascaris lumbricoides - lives in intestine, pathology in lungs; Toxocara canis (dog Ascaris)
8. Parasites that cause disease more commonly outside U.S.
a. Trypanosoma brucei - Africa - sleeping sickness, Winterbottom’s sign
b. Trypanosoma cruzi - S. America - reduviid bug, Chaga’s disese, arrhythmias, CHF
c. Leishmania tropica (Asia) and mexicana (C. and S. America) - sandfly, cutaneous ulcers
1. L. braziliensis (C. and S. America) - also mucocutaneous involvement
2. L. donovani (Asia and S. America) - visceral involvement
d. Plasmodium malariae (least common), falciparum (most common, most deadly), vivax and ovale (both have latent liver phase) - Anopheles mosquito
e. Chlonorchis sinensis - SE Asia - cholangiocarcinoma
f. Paragonimus westermani - SE Asia - causes hemoptysis, CNS involvement in 1%
g. Schistosomas - all cause liver granulomata, cirrhosis
1. S. haemotobium - Africa - adults in bladder-squamous cell carcinoma, no Katayama fever
2. S. japonicum - SE Asia - adults in superior mesenteric vein, Katayama fever
3. S. mansoni - all but developed world - adults in inferior mesenteric vein, Katayama fever
h. Onchocerca volvulus - Africa and S. America - black fly, river blindness
i. Wucheria bancrofti/Brujia malayi - Aedes/Culex mosquitos, elephantiasis
*Note: All other parasites seen worldwide, but can easily be avoided
9. Herpes Simplex (HSV-1) encephalitis is the most common cause of viral encephalitis
a. Brain tissue swelling, cell death (medial temporal lobe lesion)
b. Fever, focal neurological abnormalities, mental status changes
c. Treat with Acyclovir (one of the few treatable viral encephalitides)
10. Tests for diagnosis of viral infections
a. Culture (gold standard) - examine for cytopathic effect (CPE) - takes a few days to two weeks
1. Can add red cells to check for hemagglutinins
2. 100% specificity (for showing a virus is there, not specific ID), poor sensitivity
3. Without antigen detection (shell vial technique) can only make presumptive ID of virus
b. Antigen detection - can do on cell specimens from patient or on culture (shell vial technique)
1. Immunofluorescence assay - Ab labeled w/ fluorescing compound - use UV microscope
2. ELISA, immunoperoxidase - Ab labeled w/ enzyme that changes substrate color
c. Serology for IgG (four-fold rise of two specimensis diagnostic), IgM - single result is diagnostic
d. DNA probes/PCR
e. Electron microscopy for ID of viral particles - expensive, insensitive
11. Know the microscopic appearance of organisms - too difficult to summarize here, easier to see
12. Fever patterns - a. Roseola (HHV-6) - very high fever for 3-5 days, comes down w/ a rash for 1-3 days
b. Plasmodia - spiking fevers- P. malariae (q 72 hrs.); vivax, ovale (q 48 hrs.), falciparum (varies)
c. Brucellosis - undulant fever - fever increases to peak in evening, declines to normal by morning

Immunology

1. Some Immunologic Tests – ELISA – see above
a. Coombs test – anti-Ig Ab is added to red cells to look for agglutination
· Direct - looks for Ab bound to rbc’s
· indirect – looks for Ab in serum – serum added to naked rbc’s, then anti-Ig added
b. Complement-fixation tests – utilize Ig’s ability to fix complement to look for various antigens
2. Immune complex diseases (Type III hypersensitivity)
a. Serum sickness – circulating foreign Ag leads to Ab formation and deposition of Ag-Ab complexes (in arteries, glomeruli, synovia) that activate complement to cause tissue damage (arthritis, rash, fever)
b. Arthus reaction – vasculitis from Ag injection into skin – Ag-Ab complexes form at injection site
c. SLE – DNA-anti-DNA complexes in kidneys, vessels to cause glomerulonephritis, vasculitis
d. Post-streptococcal GN – Strep Ag deposits in kidney, Ab binds (Arthus-type reaction)
III. Human antibodies exhibit an enormous range (~108) of specificity’s. The genetic basis for this involves several factors:
A. VDJ recombination
1. the heavy chain of the immunoglobulin is made up of a variable (V), diversity (D), and junctional/joining (J) segment.
2. The gene possesses greater than 200 V, 20 D, and 6 J coding sequences.
3. During B cell development the sequences between the V, D, and J sequences are removed via recombination to provide for a single open reading frame.
4. Heavy chain recombination precedes light chain rearrangement.
5. The light chains can utilize either the kappa or lambda genes for generation of a functional Ig protein.
6. Light chain possesses V and J segments: No D
7. During B cell development, the sequence between the V segment (more than 100 coding sequences) and the J segment (1 or more J segments, depending on the light chain) is removed via recombination to provide for a single open reading frame.
B. Class switching
1. Only the heavy chain
2. The isotype is defined by those sequences (known as the constant region, i.e. codes for IgG, IgM etc.) that are invariable and downstream of the VDJ recombination.
3. Isotype switching utilizes recombination to remove such constant region sequences so as to allow the VDJ sequence to be placed upstream of different C regions.
C. Affinity maturation
1. After the B cells have been activated and class switched, a portion are found that migrate to the spleen and lymph nodes. Two things happen:
a) rapid proliferation, every 6-12 hours=1 division
b) B cells sustain somatic mutation at Ig chains.
2. Aim of this process is to create Ig with higher affinity for antigen
3. Those B cells that lose affinity for antigen are eliminated.
IV.
A. Immune system evasion and antigenic variation
1. Inhibition of complement activation
a) Capsules with sialic acid residues that prohibit alternative pathway activation
b) Group B and Group A streptococcal C5a-ase
2. Presence of antiphagocytic factors
a) Capsular polysaccharide
b) M-proteins
3. Genetic variation of surface proteins
a) Pilli of GC
4. Inhibit phagolysosome fusion- mycobacteria
5. Scavenge reactive oxygen species- glycolipid of M. leprae
6. Block killing- hemolysins of L monocytogenes
V. Immune deficiencies
A. Transient physiologic hypogammaglobulinemia occurs in infants between the ages of approximately 3 and 6 months. Although infants born with adult levels of placentally transferred IgG, a low level of IgG results from:
1. The disappearance of maternal antibody which has a half life of 22-28 days
2. The infants low early rate of synthesis of secretable immunoglobulins
B. Congenital agammaglobulinemia (Bruton’s disease) is a sex-linked (male) disorder that affects infants between the ages of 5 and 6 months. These patients have an apparently normal thymus and CMI.
1. Clinical features include:
a) Recurrent pyogenic infections
b) digestive tract disorders
2. Cause—may occur in the transition from pre-B to B cells and involves the loss of a tyrosine kinase gene. The pre-B cells are normal
3. Diagnosis is made by noting the absence of tonsils (on examination), germinal centers (on lymph node biopsy), and B cells (on peripheral smear) Serum immunoglobulins levels of less that 10% also suggest the disease.
4. Treatment—passive transfer of adult serum immunoglobulin can be administered prophylactically to diminish infections.
C. Dysgammaglobulinemia. Patients of varying age present with a selective immunoglobulin class deficiency.
1. Diagnosis—Most patients have decreased IgA levels with 1:600-800 of those patients having levels of less than 5mg/dl
2. Immunologic features include:
a) Loss of mucosal surface protection
b) Failure of IgA bearing cells to differentiate into secreting plasma cells, although their numbers are normal
c) increased susceptibility to autoimmune disease
D. Congenital thymic aplasia (DiGeorge syndrome) is characterized by hypocalcemia, tetany and an absence of T cells
1. Cause—Not hereditary. It is caused by unknown intrauterine injury to the third and fourth pharyngeal pouches that occurs between the third and sixth weeks of gestation
2. Clinical Features:
a) Thymus and parotid glands are not developed
b) Depressed CMI permits opportunistic infections (Candida, Pneumocystis, viruses)
c) Apparently normal germinal centers, plasma cells, and serum immunoglobulin
3. Treatment—These patients die early
a) Vaccination with live vaccines (measles) is contraindicated
b) The transplantation of fetal thymic tissue is experimental and may be complicated by a graft-versus-host reaction.
E. Chronic mucocutaneous candidiasis is a highly specific T cell disorder that is characterized by an absence of immunity to Candida. Patients have apparently normal T cell absolute numbers and functions. Approximately 50% of patients with this disorder also have endocrine dysfunctions (hypothyroidism)
F. Wiskott-Aldrich syndrome is a sex-linked (male) disorder occurring mainly in children. The syndrome has three main features 1) thrombocytopenia (bleeding), eczema, and recurrent infections. An increased incidence of lymphoreticular malignancies or lymphomas occur.
1. Immunologic features include:
a) Depressed CMI and a low serum IgM level, but normal IgG and IgA levels
b) Poor response to bacterial capsular polysaccharide antigens.
2. Cause—May be an absence of specific glycoprotein receptors on T cells and platelets.
3. Treatment—Bone marrow transplantation may be effective
G. Severe combined immunodeficiency disease (SCID) is a rare disorder characterized by a genetic defect in stem cells that results in the absence of the thymus gland and t and b cells. Affected children are extremely susceptible to infections and have a very short life span.

1. Immunologic features—A deficiency in the enzyme adenosine deaminase (ADA) occurs in 50% of patients. This deficiency results in the accumulation of toxic deoxyadenosine triphosphate (DATP), which inhibits ribonucleotide reductase and prevents DNA synthesis. A mutation in the g chain of the IL-2 receptor gene is found in other patients with SCID
2. Treatment—Gene therapy with ADA is experimental
H. Chronic granulomatous disease (CGD) results from a genetic defect in the nicotimamide adenine dinucleotide phosphate (NADPH) oxidase system in neutrophils. Patients are susceptible to infections by age 2 years, especially organisms of low virulence.
1. Immunologic features—Neutrophils bactericidal activity (respiratory burst) is defective because of depressed NADPH oxidase, superoxide dismutase activity and decreased hydrogen peroxide levels
2. Diagnosis is based on failure of neutrophils and macrophages to reduce a nitroblue tetrazolium dye
3. Treatment with IFN-g has been successful
I. Absence of spleen can be due to surgical removal after a trauma, treatment of certain hematologic diseases or as a result of infarction in sickle cell disease.
1. Increased susceptibility to encapsulated organisms such as Streptococcus pneumoniae
2. The spleen is required for induction of protective humoral immune responses to the thymus-independent capsular polysaccharide antigens of such organisms.
VI. MHC/HLA serotypes. Class I antigens are found on all nucleated cells (3 gene loci: HLA-A, HLA-B, and HLA-C). Class II antigens are found on immunologic effector cells (e.g. macrophages, B cells, activated epithelial cells; 3 gene loci: HLA-DP, HLA-DQ, and HLA-DR)
1. Familial inheritance
a) Many alleles of class I and class II molecules are present at each locus on chromosome 6.
b) Haplotypes from both parents are inherited and expressed codominantly.
2. Disease associations
a) DR4 Rheumatoid arthritis
b) DR3, DR4 IDDM
c) DR3 Sjogren’s syndrome
d) B27 ankylosing spondylitis
3. Transplant compatibility
a) Matching the donor and recipient at the HLA locus improves graft acceptance
b) Both the donor and recipient are typed for HLA profiles using DNA sequence analysis of the HLA genes or more than 200 specific anti-HLA antisera
c) HLA antigens on allographs stimulate recipient CD4+ T cells while respond by secreting cytokines and by inducing adhesion molecules
(1) IL-2 activates CD8+ T cells to a state of cytotoxicity, thus releasing effector molecules such as perforins
(2) IFN-g activates monocytes/macrophages to expresses delayed type hypersensitivity, resulting in increased lysosomal activity, phagocytosis, respiratory burst and release of TNF-a
(3) Activated selectins, integrins, intercellular adhesion molecules (ICAM) and vascular cell adhesion molecules (VCAM) promote leukocyte extravasion into the graft bed.
d) Acute rejection
(1) Within weeks
e) Chronic rejection
(1) Episodic bouts of rejection, occurring months to years after transplantation
f) Hyperacute rejection
(1) Within minutes—graft never takes because of pre-existing sensitivity
VII. Allergies
A. Common antigens
1. Penicillin
2. Procaine
3. Insect venom
4. Pollen
5. Molds
6. Foreign serum
7. Fungal spores
8. House dust
9. Animal dander
B. Antigen-IgE-mast cell complex
1. Excess IgE antibody is produced and binds avidly via its FC domain to its receptor on the surface of mast cells and basophils
2. When antigen is reintroduced into the sensitized host, it binds to and aggregates several cell-bound IgE antibody molecules, forming the complex
3. The resulting membrane perturbation causes degranulation of the mast cells and release of histamine, leukotrienes, serotonin, bradykinin, etc.
4. These agents rapidly contract smooth muscle, increase vascular permeability and secretions, change coagulability, and induce hypotension
C. Mechanism of immunotherapy
1. A hyposensitive state is achieved by repeated injection of the agent into subliminal doses
2. Parenteral exposure favors the synthesis of IgG which combines avid