Random Missed Week 3 Flashcards
What are the 4 major dopaminergic pathways in the brain?
how do anti-psychotics affect these pathways?
- mesolimbic - cognition/behavior; hyperactivity ~ positive symptoms of schizophrenia
[where antipsychotics work to blcok D2 R]
- mesocortical - cognition/behavior; low activity ~ negative symptoms
- tuberoinfundibular - hypothalamus to pitutiary galnd and is responsible for the tonic inhibition of prolactin (arcuate nucleus of the hypothalamus secrete DA and bind to D2 on pituitary lactotrophs –> decrease prolactin secretion) - hyperprolactinemia, galactorrhea, menstrual irregularities
- nigrostriatal - substantia nigra to caudate and putamen; regulates voluntary movements; affected in parkinson’s; antipychotics disrupts this path and cause extrapyramidal effects and drug-induced parkinsonism
What is the hypothalamospinal tract?
Projects from the hypothalamus to the cilispinal center of the intermediolateral cell column (T1-T2) –> provide sympathetic innervation to the ipsilateral eye and face
Disruption of this tract typicall results in ipsilateral Horner Syndrome
Umbilical herninas:
Typical clinical presentaiton
What is one congenital abnormality seen?
Umbilical ring/congenital fascialopening for the umbilical cord, closes and forms the linea alba, a midline band of fibrous tissue
Umbilical hernias are caused by INCOMPLETE CLOSURE of the umbilical ring – allowing protrusion of bowel through the abdominal musculature.
Most are: reducible, asymptomatic, resolve sponteaneous within the first years of live
Associated with: Down’s , hypothyroidism, Beckwith-Wiedemann Syndrome
What part of N. meningitidis correlates with morbidity and mortality, especially in relation with sepsis?
LOS - lipooligosaccharide; acts as an endotoxin, and associated with many of the toxic effects of meningococal disease (LOS plasma levels correlate with disease manifestations and outcomes)
analygous to the lipopolysaccharide of enterig gram negative rods but lacks the repating O antigen of enteric LPS.
Meningococcal growth and lysis leads to release of outer membrane vesicles with membrane-attached LOS (same as LPS release with gram neg infections) –> LOS causes sepsis inducing a systemic inflammatory respones characterized by the production of TNF alpha, IL 1, IL 6, IL 8
What is the Kozak sewuence?
a consensus sequence that helps start translation in eukaryotes (located on mRNA) - helps initiate translation at the metioonine start codon AUG
Analogous to shine-dalgarno sequence in E. coli
(gcc)gccRccAUGG
R - adenin or guanine / purine 3 base pairs from the AUG plays an important role in the initiation process
anti-IgM negative
anti-IgG positive
to hep A
asymptomatic pt with previous infection to hAV
in children <6, HAv infectino is most often silent/subcliinica/anicteric/no jaundice
les freequencly could present as an acute, self-limited illness characterized by jaundice, malaise, fatigue, anorexia, nausea, vomiting and RUQ pain
Hep A- NO asymptopmatic viral carrier state, does not progress to chronic carrier, NO hepatits, no cirrhoss no HCC
What are causes of PKU
Mgmt?
PKU is most commonly caused by a deficiency in phenylalanine hydroxylase – restrict phenylalanine diet, and increase tyrosine diet
Other cause- BH4 cofactor deficiency; most likely due to dihydrobipterin reductance unable to reproduce BH4 (from BH2) after being used as a cofactor
[cofactor BH4 is used in the first 2 steps of phenylalanine metabolism]
What issues could problems with the urea cycle cause?
Mgmt?
What are important players?
Urea cycle is important to remove the extra nitrogen/ammonia from AA catabolism/metabolism;
The cycle takes place in part in the mitochondria and in part in the cytosol. Formation of urea is the final product to be excreted in the urine
Defects in any of the steps –> increase blood concentration of ammmonia –> central nervous system dysfuctnio.
SEvere defects manifest during ealry infancy and childhood, while midler defects may not manifest until adulthood
Tx: balancing dietar protien intake with protien ouput – protein restriction + meds tha provide alternative pathways for the removal of amonia from the blood
Key players: ordinarily, careless crappers are also frivolous about urination
Ornithine, carbomoyl phosphate, citruline, aspartate, arginosuccinate, fumarate, arginine, urea
What is a complication that could be seen with warfarin?
Primary anticoag effect of warfarin- inhibits the vitamin K dependent gamma carboxylation of clotting factors II, VII, IX, X (2,7,9,10)
Warfarin-induced skin necrosis –> transiet hypercoaguable state that occurs duirn ghte first few days of warfarin therapy:
Warfarin inhibits proteins C and S, which are natural anticoagulates present in blood –> vitamin K dependent cofactors continue procoag effect (2,9,10 esp)–> thrombosis and clot formation can interrupt blood flow to skin and lead to skin necrosis –> can lead to skin necrosis, particularly in patients with protein C or S deficiency – this complication is usually seen in the first few days of warfarin therapy
[pt should be given vitamin K and FFP to reverse the effects of coumadin]
*why a heparin bridge is commonly used when warfarin is initiated
H pylori treatment
H. pylri causes infection by downregulating somatostatin, which subsequently increases (through lack of inhibition) gastrin –> parietal cells –> acid release
Treatment given to H pylori to prevent the recurrence of a PUD.
Triple therapy: 2 antibiotics (amoxicillin, clarithromycin) + PPI (omperazole)
metoclopramide?
dopamine antagonist with prokinetic and antiemetic properties that can be used to treat gastrointestinal motility disorders (gastroparesis) and N/V
What are 3 common manifestations of sickle cell disease
most common AR disorder in AA
1. hemolysis- repeated sickling of RBC – permanet deformation and premature destruction; intra and extra vascular hemolysis –> INC indirect bilirubin, lactate dehydrogenase and DEC heptaglobin (binds circulating hb and reduces renal excretion of free hemoglobin, preventing tubular injury)
2. vasooclusive symptoms- pain due to hypoxic tissue injury; microvascular occlusions; dactylitis (hand-foot swelling syndrome! results from small infarctions in the bones of the extremities –> swelling, tenderness and warmth)
3. infections- infections with encapsulated organisms because of repated splenic infarcts cause functional asplenia
Diptheria toxin
Complications-
= AB EXOTOXIN
ADP-ribosylation is inhibited, inactives elongation factor 2
inhibits protein synthesis –> cell death
toxin acts locally, causing respiratory cell necrosis with formation of fibrous, coagulative exudates
(coalescing psedomembrane)
[A= active, active subunit of exotoxin transfers a ribose residue from the NAD to a histidine on the EF2; riboslylation inactivates –> inhibiting protein syntehsis]
Complications:
–> suffocation via obstruction from edema and pseudomembranes
systemically, predilection to brain and heart tissue –> myocarditis/HF and neurologic toxicity
Community acquired pneumo
common bugs-
#1: Strep pneumo (outer polysac cap prevents phagocytosis! no virulence without capsule; others include IgA protease, adhesins, pneumolysin)
H. influezae
Moraxella catarrhalis
Kplebsiella pneumo
S. Aureus
(atypical - C. pneumo, legionella)
What are endotoxins?
who are they produced by and consequnces?
Produced by gram-negative bacteria
consist mainly of LPS - structural component of the gram negative outer membrane, representing the somatic O antigenic determinats
LPS –> fever, hypotension, hemorrhage, DIC due to activation of the clotting system
(LOS in N. menigitis)
Describe the vascular supply of the upper abdomen?
Abdominal Aorta –>
first branch is the celiac truck @ T12
[supplies spleen, stomach, liver abdominal esophagus adn parts of the duodenum and pancreas]
SMA @ L1
IMA @ L3
-see image-
What agents should be used for motion sickness associated emesis?
For chemotherapy-induced emesis?
Motion sickness:
Antimuscarinics/anti-cholinergics such as scopolamine
Antihistamines - diphenyhydramine, meclizine, promethazine
Chemotherapy:
Serotonin (5Ht3) receptor antagonist - ondansetron, granisetron
[5HT3 R are located peripherally in the presynaptic nerve terminals of the vagus nerve in teh GI track, also present centrally in the chemoR trigger zone and the solitary nucleus and tract]
DA receptor antagonist - prochlorperazine, metoclopramine
Neurokinin 1 receptor antagonist - aprepitant fosaprepitant
How does PCP affect the body?
NMDA receptor ANTAGONIST
[can work secondarily to inhibit reuptake of NE, DA, and 5HT, and effects on sigma opiods R]
PCP is known to cause beliligerence, agitation, and loss of coordination, horizontal and vertical nystagmus and a consellation of cognitive sx that includes disorientaiton, poor judgement and memory loss
Can have dissociative and anesthetic effects but may also cause psychosis and server agitaiton leading to violent trauma==ataxia, horizontal and vertigal nystagmus and delirum could also be present
[NMDA agonist = glutamate, aspartate, D-cycloserine]
How would you tell the difference between the following cardiac conditions due to:
Untreated strep A
viral myocarditis/adenovirus, coxasckie B, parvovirus
T. Cruzi/chagas?
Untreated strep A –> acute rheumatic fever – immune-mediated dequela of an untreated group A strep pharyngeal infection; could lead tonew murmur; myocardia biopsy will show interstitial fibrosis with central lymphocytes and macrophages as well as scattered multinucleated giant cells = interstitial myocardial granuloma = ASCHOFF body is pathognomonic for ARF-related myocarditis
Viral myocarditis – lymphocytic interstitial infiltrate with focal necrosis of mycocytes; high in neutrophils??
Chagas – intracellular protozoan parasite will be seen; distension of individual myofibers with intracellular trypanosomes
Describe the development of the testies:
The testicles develop in the fetal abdomen during organogeneisis
between weeks 8 and full term, they shlowly descend into the scrotum by passing from:
the abdomen through the DEEP INGUINAL CANAL –> inguinal canal [transversalis fascia opening, bounded by the trasversus abdominal musc laterally and the inferior epigastric vessels medially] –> passes anteromedially to exit the canal via the SUPERFICIAL INGUINAL RING [opening external oblique muscle aponeurosis above and medial to the pubic tubercle-> then it enters the scrotum
If this does NOT occur = cryptorchidism (increased risk for infertility an dtesticular CA)
If the testis is palpable medial to the deep inguinal ring, then it is already in the inguinal canal
What is achalasia?
motility disorder caused by reduced # of inhibitory ganglion cells in teh esophageal wall –> creates an imbalance favoring excitatory ganglion cells
- normal contraction of the upper esophageal sphincter
- DEC amplitude of peristalsis in the mid esophagus
- increased tone and incomplete relaxation at the LES
barium esophagram typically shows dilation of the esophagus with distal narrowing
What is the most common valve and underlying disease predisposing to IE?
mitral valve is the most commone valve affected by IE, in developed nations
MVP is the most common underlying valvular disease
[Rheumatic heart disease remains a frequent cause of IE in developing nations]
Microscopic deposits of platelets and fibrin occur spontenously in individuals with valvular dz secondary to endocardial injury from turbulent blood flow – deposits the become colonized by micro-organisms during episodes of bacteremi (ie-following dental extraction)
*rheumatic heart disease is the most important form of acquired heart disease in children and young adults in developing countries
what baldder issues could an MS pt see after an acute lesions of the spinal cord?
SPastic bladder – bladder hypertonia
bladder contractility is normal (little to no residual urine after emptying test), but distensibility is poor –> urinary frequency and urge incontinence
the bladder does not distenx/relax properly due to loss of descending inhibitory control from UMN
what could a flaccid bladder indicate?
typically occurs in teh setting of LMN lesion
patient will have large residual volume of urine after attempted emptying and will typically experience urinary incontinence at the end of the day (pressure from a full bladder) becomes greater than urinary sphincter pressure
What is HIV prophylaxis:
Pneumocystis pneumonia <200
TMP-smx
Histoplasma Capsulatum <150
itraconazole
Pneumocystis pneumonia and toxoplasmosis <100
TMP-smx
Mycobacterium avium complex <50
clarithromycin, azithromycin
how to distinguish MAC from extrapulmonary TB?
MAC grows well at high temps and exhibit optimum grow at 41 C
MAC more likely to cause marked anemia, hepatosplenomegaly, elevated alk phos and lactate deydrogenease levels
Explain angioedema in relation with ACE inhibitory therapy
rare and potentially serious side effect
Most commonly involved the tongue, lips or eyelids
laryngeal edema and difficulty breathing may also occur
Due to bradykining accumulation
[normally, ace is responsible for bradykinin breakdown - ACE inhibitors prevent bradykinin degradation, leading to increased levels – bradykinin is a potent vasodilator; and ultimately increases vascular permeability causing significant angioedema]
ACE inhibitors should be discontinued in patients who develop angioedema
The mechanism for clearing lung depends on the size of the particle
10-15 um –> trapped in teh upper respiratory tract
2.5 -10 um –> enter the trachea and bronchi and area cleard by mucocillary transport
finest particles <2 um –> reach the terminal bronchioli and alveoli and are phagocytosed by macrophages
What infection is the most common cause of aplastic crisis, in patients with SCD?
In pt with SCD and other hemolytic disorders, the most common viral cause of an aplastic crisis is infection of erythroid progenitor cells with parvovirus B19 - non enveloped single stranded DNA virus
How is the detrusor muscle regulated?
M3 cholingeric R
stimulation –> contraction
Inhibition –> relaxation and urinary retention
obturator nerve
arises from lumbar plexus and carries fibers from L2-L4 spinal segments
descends posteriormedial to the iliopsoas muslce and courases along the lateral aspect of the lessel pelvins before scending through the obturator canal –? the only major nerve that exits teh pelvis through this canal
supplies the obturator externus muslce and divides into the ant and pos branches supply the rest of the thigh adductor (adductor lungus, brevis, magnus)
ant division of the nerve gives off a aterminal cutaneous branch that provdies sensation over teh sital medial thigh
most comonly injured by compression due to pelvic trauma,surg or tumors (ie-bladder tumor)
pt present with weakness on thigh adduction and sensory loss in teh distal medial thig
What mediates cachexia?
Cachexia is a syndrome that encompasses anorexia, malaise, anemia, wt loss and generalized wasting due to underlying systemic dz
likely a manifesation of the lung neoplasm revealed on his chest symptoms
Tumor necrosis factor alpha (TNFalpha) cytokine that causes necrosis of some tumors in vitro and produces sz of cachezia in experimental animals
also caleld cachectin and is consdered a main mediator of paraneoplastic cachezi along with IL-1b and IL6
produced by macrophages in response to infection and some neoplastic cels
influences hypthalamus, leading to
appetite suppresion
INC BMR
bacterial infections, TNF alpha produces fever along with IL1, mediates sx of septic shock and causes hepatic release of acute phase reactants (C-reactive and fibrinogen)
What are the 4 different types of HTN disorders seen in pregnancy?
Chronic HTN - >140 / 90 prior to conception or before 20 weeks
Gestational HT: new onset HTN at > 20 weeks
NO end-organ damage or proteinuria
Pre-eclampsia: new onset HTN after 20 weeks PLUS
proteinuria or signs of end organ damage
- abnormal placental vasculature leads to placental hypoxia and ishcemia –> release of anti-angiogenic factors into materal circulation; inflammatory factors from hypoxic placenta –> endothelial injury –> endothelial damage increases permeability –> proteinuria*
- dysregulation of vascular tone –> elevated BP, which can cause end-organ damage (brain such as h/a, visual changes, liver - abdominal pain)*
Eclampsia: Preclampsia (htn + proteinuria or end organ damage) + new onset grand mal SEIZURES
what causes drug-induced parkinsonism?
–> extra-pyramidal sx
cogheel rigidity, resting tremor, masked facies adn bradykinesia (within first 3 months)
caused by D2 receptor blocakde in teh nigrostriatal pathway
(occurs more commonly w/first-generation anti-psychotic due to greater D2 blockade but can also occur with second-gen anti-psy)
treat wtih centrally acting anti-muscarinic agent trihexphenidyl, benztropine!
**donot use levopoda as it can precipitate psychosis
What gene is responsible for auto recessive polycycstic kidney disease?
common findings?
PKHD1 - gene for fibrocystin (chrome 16) [or pkd2 on chrom 4]
bilaterally enlarged, cystic fetal kidney, oligohydraminos (low amniotic fluid)
fibrocystin is found in the epithelial cells of both the rental tubule and bile ducts – deficiency leading to characteristic polycystic dilation of both structures
Age of presentaiton is determined by the severity
most severe - prenatal detection
oligohydraminos is present becuase amniotic fluid is composed of fetal urine and renal filtratin is severely impaired in ARPKD –> Potter sequnce; flattened facies, limb deformities, pulmonary hypoplasi
What is VACTERL association?
mesodermal defect
V = vertebral defects
A = anal atresia
C = cardiac defects
T & E = TE fistula
R= renal defects
L = limb defects
Von Hippel-Lindau disease:
rare, AD condition characterized by the presence of capillary hemangioblastomas in the retina and/or cerebellum
and congenital cyst and/or neoplasms in the kindey, liver and pancreas
pt are at risk for RCC - which can be bilateral
Von Recklinghausen’s diseaes is also know as?
NF1
inherited PERIPHERAL nervous system tumor
neurofibromas, optic nerve gliomas, Lisch nodules, cafe au lait spots
Sturge-Weber syndrome
encephalotrigeminal angiomatosis
rare congenital neurocutaneous disorder characterized by the presence of cutaneous facial angiomas as well as leptomeningeal angiomas
skin involvement in V1/V2
associated with mental retardation, seizures, hemiplegia, skull radipacities
“tram track” calcifications of skull radiographs
what is the process of T cell maturation –
Thymocytes are initally produced in the bone marrow but migrate from that location to mature during the FIRST TRIMESTER of genstation in the thymus; this is where TCR gene rearrangement, positive selection, negative selection and expression of exm markers and co-mol occurs
Pro T cells arrive at the thymus as double negatives (lack both CD4 and CD8)
TCR beta gene rearrangement occurs –> CD 4 and CD 8 expression occurs
@ thymic cortex, alpha genes rarrange to produce a functional alpha-beta TCR –> positive then negative selection occurs
positive selection - only T cells expressing a TCR that is able to bind to self MHC are allowed to survive; occurs in the thymic cortex and involved interactions of T cells with thymic cortical epithelial cells expressing self MHC – responsible for development of a T cell reertoire that can recognize self
Negative selection - process by which T cells possessing TCRs that bind with high affinity to self antigen or self MHC I/II, are eliminated by apoptosis.
occurs in thymic medulla, involved interaction with thymic medullary epithelial and dendritic cells
Drug of choice for acute status epilepticus?
IV benzodiazepines (lorazepam)
Work by enhancing the effects of gamma-aminobutyric acid (GABA) at the GABA-A receptor –> increased chloride influx and suppression of action potential firing
ligand-gated ion channel; allosteric attachment of bezos to GABA-A R –> influx of negatively charged chloride ion –> hyperpolarization of postsynaptic neuron and suppression of action potential firing (anticonvulsant effect)
Interferon-gamma
Who secretes it?
whats its role?
Produces primary by activated T lymphocytes and natural killer cells
Critical in immunity against viral and intracellular bacterial infections
Activates macrophages, inc MHC expresison, and promotes T helper 1 lymphocyte differentiation
interferong-gama assays are used for latent TB infection - by measuring the response of T lymphocytes when exosed to antigens uniqe to M. TB
Measure Cell-mediated immunity
can’t be used to distinguis active from latent infection
What enzymes are invovled in glycogen –> glucose-1-p
glycogen phosphorylase a goes form glycogen to glucose 1-p only in its active form
it is activated by phosphorylase KINASE
inactivate by phosphoprotein PHOSPHATASE
*PK is regulated differently in liver than in muscles
-glycogen in liver is used to maintain blood glucose levels during fasting, where as glycogen in muslce is used to provide energy for muscle contraction
IN the liver, PK is activated primaryly through the binding of E and glucago to a Gs protein coupled receptors which increase cAMP concentrations –> phosphorylation of PK (via protein kinase A)
Skeletal m. lacks glucago receptors, but muscle PK can sitll be phosphorylated in response to an E-induced INC in cAMP
Increased Ca2+ is MORE POWERFUL activator of muscle PK – release of SR calcium stores fllowing neuromusculear Ach stimulation allows for synchronization of skeletal muscl contratio and glycogen breakdown, providng eth energy necessary for anerboic m. contraction
riboflavin deficiency
can be seen in chronic alcoholics and severely malnourished
clinical sx: angular stomatitis, cheilitis, glossitis, seborrheic dermatitis, eye changes
Riboflavin = B2
key precursor to key constitutes of TCA and ETC
riboflavin –> FMN –> FAD
FADH –> FADH2
verrucous, skin-colored genital lesions
=condylomata accuminatum
bug?
where does it infect?
HPV, DS-DNA virus >100subtypes
Mostly type 6 and 11
infects basal epithelial cells through small breaks in teh skin or mucosal surfaces
redilection to STRATIFIED SQUAMOUS EPITHELIUM
(anal canal, vagina, cervix)
@ respiratory tract: true vocal cords only
- stratified squamous epithelium, proteicively lines anatomical areas that udnergo frequent friction and abrasion, including true vocal cords, cervix, anus*
- infants can acquire respiratoyr papillomatosis via passage through an HPV-infected birth canal*
Lansoprazole is what drug? MOA?
Proton pump inhibitor (think: omeprazole!)
blocks the final common pathway of gastric acid secretion from parietal cells which is stimulated by ACH, histamine and gastrin
Rentinal artery occlusion, blood traveling to…
internal carotid –> opthalmic artery –> central retinal artery
sx: acute, painless monocular vission loss
thromboembolic complications of atherosclerosis in the internal carotid are the most common cause of rentinal artery occlusion
PTSD first line treatment
trauma-focused cognitive behavioral therapy and anti-depressant medication-
selective serotonin reuptak einhibitor
Treatment for someone wtih dipthriae?
- diptheria antitoxin
- Penicillin or erythromycin
- DPT vaccine
Indirect inguinal hernias
more common than direct
tend to appear on the right side
due to failure of the processus vaginalis to obliterate, allowing abdominal contents to protrude through the deep inguinal ring
Can be detected by deep palpation of the external ring with the tip of the finger
Direct inguinal hernias
protrude through hesselbach’s triangle - weak spot of the anterior abdominal wall
bound by the rectus abdominis, inferior epigastric vessels and inguinal ligament
less prone to incarceration in comparisson to indrection due to their wide neck
uncommon for them to descend
best felt with the pup of the examiners finger on deep palpation
When does excretion of a substance reach its maximum state?
Excretion of a substnace is defined as the filtration plus the secretion minus the reabsorption
once carrier mediated secretion and reabsorption mechanisms are saturated, these processes are at their maximal state
Filtration itself does not require an enzyme or protein, so it does not show a maximal value; thus it cannot be saturated nor excreted
besides gas gangrene, what other symptom may accompany this bug?
Clostridium perfringenes, gram positive bacillus, responsible for 95% of gas gangren (clostridial myonecrosis), abundant in soil and can inoculate penetrating injury sites
sores germinate in ANAEROBIC environment into vegetative cells –> produce phospholipase toxin that attackes cell membranes (alpha toxin) –> extensive tissue damange, necrosis adn reduced blood supply to the affected area results with the diseaes can sometimes be felt on examination (crepitus) and may be visualized on radiographs (help distinguis gas gangrene from other necrotizing infections)
Tx: antibiotics and emergent debridement; overall poor prognosis and tissue loss is often considerable
It can also cause late-onset food poisoning that is characterized by transiet watery diarrhea (toxin formed when large # of clostridial spores are ingested), spores germinate and THEN begin to elaborate toxin (why its late onset)
Between Niemann-Pick and Tay-Sach’s, both cause cherry red spots in the macula, but which one does not have hepatosplenomegaly?
Tay-sach’s = NO hepatosplenomegy
Niemann-Pick - yes hepatosplenomegay
Tay-sach’s is deficient B-hexosaminidase A –> Gm2 accumulation in neurons
Niemann-Pick sphingomyelinase dificiency –> sphingomyelin accumulation within lysosomes results in cells that appear enlarged, foamy and cavuloated on electron microscopy
lip-laden foam cells accumulate in the liver and spleen and cause hepatosplenomegal –> progressive neuronal accumulation is responsible for hypotonia and neurologic degeneration
What is cutis aplasia and what syndrome could this be seen in?
What other clinical presentation is seen in this syndrome?
Cutis aplasia = focal skin defect of the scalp
seen in Patau syndrome
Pataus” trisomy 13 – phenotypic features reflect a defect in the fusion of prechordal mesoderm - an integral embryological structure affecting growth of the midface, eyes and forebrain
- holoprosencephaly, microcephaly, micropthalmia, cleft lip palate, omphalocele; abnl brain development, polydactyl and cutis aplaisa
usually meiotic nondisjunction
What is a fatal cause of hyperbilirubinemia in infants?
ABSENT liver conjucation enzymes (Crigler-Najjar syndrome type 1)
autosomal recessive disorder of bilirubin metabolism caused by a genetic lack of the UGT enzyme needed to catalyze bile glucuronidation
–> unconjugated hyperbilirubineia
Indirect bilirubin levels typically ~10-15
Because it is NOT conjugated - it is HIGHLY INSOLUBLE –> cannot be excreted; it tightly binds albumin and thus cannot be filtered by the glomerulus and not excreted –> deposits can cause kernicterus (bilirubin encephalopathy), potentially fatal condition characterized by severe jaundice and neurologic impairment as a child
substrates of CYP 450:
Anti-epileptics
Theophylline
Warfarin
OCPs
Cyclosporine
Statins
“Can alaways think when outdoors, son”
**be careful when using with either inducers- can increase the metabolism of the drug and thus decrease the therapeutic level - esp careful with warfarin! or inhibitors, that can decrease the metabolism of the drug and thus increase the potential for toxicity**
Inducers of CYP450 (8)
Chronic Alcohol use
St. John’s Wort
Phenytoin
Phenobarbital
Nevirapine
RIfampin
Griseofulvin
Carbamazepine
“chronic alcoholics steal phe-phen and never refuse greasy carbs”
= speed up metabolism
Inhibitors of CYP450
Acute alcohol abuse
Ritonavir
Amiodarone
Cimetidine
Ketoconazole
Sulfanamides
INH/isoniazid
Grapefruit juice
Quiidine
Macrolines (expect azithromycin)
AAA RACKS IN GQ Magazine
**decreaes metabolism of drugs
gliosis =?
proliferation of astrocytes in an area of neuro degeneration
leads to the formation of a glial scar which compensates for the voulme loss that occrs after neuronal death
glial scar
alendronate?
= Fosmax
bisphosphaonates, chemically structure to pyrophosphate and attach to hydroxyapatite binding sites on bony surfaces, preferentially bindg in areas of increased bone turnover
MOA of digoxin
positive inotropic agent
provides SYMPTOMATIC relief in patients with acute decomponsated heart failure due to left ventircular systolic dysfunction
alos has anti-adrenergic effect (via increased parasympathetic tone) with slowing of conduction through the AV node - help improve cardiac function in pt with rapid ventricular rate
Directly INHIBITS NA/K/ATPase pump –> DEC of sodium efflux – increase of sodium inside, then decreases the Na+/Ca2+ exchanger — decreasing efflux of calcium from the cells
INC intracellular calcium –> binding to troponin C and sbsequent actin-myosin cross-bridge formation and myocyte contractino, resulting in imporved myocute contractility and LVSF
antiphospholipid antibody syndrome?
Disorder characterized by the presence of antiphospholipid antibodies in the setting of venous or arterial thromboembolism OR reccurent pregnancy loss.
- may be primary or secondary to other AI dz such as SLE –
suggestive with prolonged aPTT and negative rapid plasma reagin (RPR) -
act to produce hypercoagulable state due to activation of phospholipid dependent coa pathways
these antibodies can cause false-positives results on ontreponemal serologic syphilis test by reacting iwth cardiolipi (dominant antigen used in these test)
Subacute/dequervain granulomatous thyroiditis
onset following a viral illness, painful thyroid enlargement w/transiet hyperthyroid symptoms
– painful enlargement of the thyroid gland (cross-reactive??) —>
elevated T4, suppressed TSH and DEC radioiodine uptake
INC ESR and CRP
DEC radioiodine uptake
Histo: early neutrophilic infiltrate with microabscesses fomration –> lymphocytic inflammatory infiltrate with macrophages and multinucleated giant cells (granulmatous!!)
self-limited (<6 weeks)
Where do the lowest osmolarity occur in the kidney?
Distal convoluted tubule
Highest @ bottom of loop of henele and end of collecting tubule
*ADH acts on the collecting ducts - increasing their permeability to water; in the presence of ADH, the collecting ducts contain the most concentrated fluid in the nephron - while the thick ascending limb of the loop of henle adn distal convoluted tubule contain the most dilute fluid
Arteriolar vasodilators…
lower bp by reducing systemic vascular resistance
LIMITED by subsequent stimulation of baroreceptors with resulting reflex sympathetic activation –> increased HR, contractility and cardiac output – > sympathetic stimulation of the renin-angiotensin-aldosterone axis results in sodium and fluid retention with peripheral edema
offsets the BP lowering effects of these drugs and limited their long-term efficacy
What could be causing bladder outlet obstruction?
dynamic component - smooth muscle tone in the bladder neck, prostate capsule and prostatic urethra
Fixed component - structural effects of the enlarged prostate
What does the mullerian factor give rise to?
fallopian tubes, uterus, cervix and upper vagina by 20 weeks of age
Mullerian agenesis = MRKH syndrome = vagina agenesis
variable uterine development, no upper vagina and could be described as “short vagina” primary amenorrhea since they have no/hypoplastic uterus
NL: ovaries (which secrete estrogen normally and thus pt has regular development of secondary sexual characteristics)
Describe reassortment
reassormbent aka rearrangement
when viruses with segmented genomes (ie -influenza virus) exchange genetic material - genetic shift; mixing of genomic semented in segmented viruses tha tinfect the same host cell.
*segmented genome is key to allow for this genetic shifts through rearragement to occur
can leads to PANDEMICS!
ie) H1N1
typical presentaiton of pituitary adenomas-
1 Prolactinoma- increased levels of prolactin suppress GnRH –> release LH, FSH from pituitary (amenorrhea & galactorrhea, decreased testicular testosterone production, decreased libido, decread fertility),
non-functional adenomas could present with mass effect –> bitemporal hemianopia, hypotituitarism, h/a
Functional:
How does ACTH affect the size of the adrenal gland?
ACTH is a major trophic hormone of the zona fasciculata and reticularis –> HYPERPLASIA, whereas the zona glomerulosa is primary regulated by angiotensin II.
Prolonged ACTH stimulation casues hyperplasia of the zona fasiculata and reticularis, resulting in excessive cortisol production –> cushing syndrome
What is the role of Golgi Tendon in a muscle fiber?
golgi tendon circut is a negative feedback system that regulates and maintains muscle tension
when a muscle exerts too much force, GTO inhibit contraction (via Ibsensory axons that are in contact with inhibitory interneurons in teh spinal cord –> synapse with the alpha motor neurons that innervate the same muscle) of the muslce causing sudden muscle relaxation
this prevents damage to the musculoskeletal system
dont confuse with deep tendon reflexes (whats tested in clinical setting) - which is due to muscle spinde/sintrafusal muscle fibers, that are connected in parallel (not in series) with extrafusal fibers
What do the following areas functions?
A =Frontal eye field, found near the caudal end of the middle frontal gyrus to the precentral gyrus, brodmann areas 6 and 8
B = Brocas, motor, nonfluent aphasia, responsible for all communicative motor planning; pt could communicate meaninfully but broken; difficult writing and signing; have insight to their expressive language difficulties; can understand and follow command
C =precental gyrus, primary motor cortex can cause slurred speech/dysarthria due to paresis/paralysis of the skeletal muscles involved with movements of the mouth, tongue, larynx
D = postcentral gyrus, primary somatosensory cortex; sensation loss in the corresponding are of the contralateral body
E = cauda superior temoral gyrus / broadmann 22 = wernicke; sensory/receptive aphasia – fluent aphasia; speech flows readily but it is meaningless; word salsad; pt lack insight to their problem
F = visual cortez; cortical blidness or visual impairment that can make reading and writing difficult; spoken speech would be unaffected
how many words should a 2 year old know?
50 - 200 word vocabulary, and be able to string 2 word phrases together
what controls fibroblast migration and proliferation during the healing process?
multiple growth factors include:
Platelet-drvived growth factor (PDGF)
Transofrming Growth factor B (TGF-b) - also critical for stimulating connective tissue synthesis and remodeling of the extracellular matrix; usually decreases to limit the amt of collagenous scar tissue
What contributes th Hep C multiple subgenotypes?
Variant straints differ primarily at hypervariable genomic regions, such as those found in teh sequences ecoding its 2 envelop gylocprotiens
There is NO PROOFREADING 3’->5’
Familial hypocalciruic hypercalemia:
Autosomal dominant, benign disorder in which pt have a defective Ca-sensing R in parathyroid and kindeys (membrane bound R to bound to a G protein) –> higher calcium levels are required to suppress the secretion of PTH –> raises the set point of calcium-induced regulation of PTH secretion; pt with FH have mild asymptomatic hypercalcemia, reduced urinary excretion of calicum and high nl / mildly elevated PTH
what is the effect of cortisol/prednisome treatment on the immune system?
- inhibition of phospholipase A2 –> no arachodonic
- inhibits IL2
- inhibits release of histamines from mast cels; dec vasodilation and vascular permeability
- dec eosinophils
- Neutrophilia - due to dec wbc adhesion/demargination!
–> increase risk for infection; good for autoimmune and inflammatory conditions
what immune response do the following elicit:
polysac capsule vaccine?
conjugated toxoid vaccine?
The polysac capsule provokes an antibody-mediates B cell immune response and is primary antigenic constitue of vaccines against encapsulated bacteria; vaccines containing polysac are ineffective in children <2 years old due to their immature humoral immunity; there for a …
polysa that is conjugated with a carrier protein is used to amplify the pt humor response agasint the poly sac through T-cell recruitment –> t-cell dependent antigen
Immunogenicity is increased as a result of T-cell dependent stimulation of B lymphocytes and production of memory B lymphocytes
Vitiligio is due to…
Characterized by the partial or complete loss of epidermal melanocytes
significant correlation btwn vitilgio and AI disorders
Which class of antiarrhythmic agents are known to prolong qt?
which of those drugs has the lowest risk?
Class II and class IA antiarrthmic agents cause lengthening of the cardiac action potential, which manifest as QT interval prolongation on ECG.
Amiodarone is associated with a very low risk of torsades de pointes and other proarrhythmias.
Transthyretin
protein tetramer produced in the liver, acts as a carrier of thyroxine and retinol
mutations in the TTR gene can increase teh tendency of TTR to misfold, producing an amyloid protein that infiltrates the myocardium –> infiltrative cardiomyopathy
stomach ulcer vs erosion?
LAYERS: mucosa, muscularis mucosa, submucosa, muscularis propria, serosa
Erosions = do not extend full through the muscularis mucosa [short-term; curling ulcers, cushing ulcers, smoking, alcohol, NSAIDS-via inhibition of prostaglandin synthesis….]
Ulcer= penetrate the mucosal layer, and extend into the submucosa layers (iner circumferential and outer longitudinal smooth muscle layers)
clinical presentation of herpes ingentials?
systemic sx - fever, myalgia
inguinal lymphadenopathy
itchy, painful, vesicular genital rash, on the genitalia or buttocks occurs in stages - vesicles, ulcers and then crusting
genital HSV lies dormat in teh sacral dorsal root ganlgia, and can be activates to cause recurrent genital lesions - tends to be localized and les severe due to humoral immunity from prior infection
[vs syphillis, usually a single painless lesion/chancre after initial infection; HPV exclusively infects the epithelial cells, predisposing to the development of cervical and vuvlar CA, warts are the most common skin manifestation]
Cilostazol, dipyridamole, milrione, inamrinone are selective phosphodiesterase enzyme inhibitors…how do they function
Phosphodiesterase III inhibitor; INC cAMP in platelets, resulting in inhibition of platelet aggregation; vasodilators (systemic and venous dilation) –> decrease BP, limiting the use of milrinone in pt with severe hypotension
decrease the rate of degradation of cAMP in cardiac tissue – increased cAMP promote calicum influx into the caridac myocytes, which in turn increase myocardial contractility (positive inotorpy)
ocassionaly used as an IOTROPIC agen in pt with refractory HF due to LVS dysfunction
Describe the following gas anesthetics properties:
Drugs with DEC solubility in blood = ___ induction and recovery times.
Drugs with INC solubility in lipids = ____ potency
= 1 /MAC
Describe the following gas anesthetics properties:
Drugs with DEC solubility in blood = low blood/gas partition coefficenct = RAPID induction AND recovery times= LOW POTENCY
Drugs with INC solubility in lipids = INC potency
= 1 /MAC (minimal alveolar concentration)
recombination vs reassortment vs phenotypic mixing
Recombinations refers to gene exchange that occurs through the crossing over of 2 DS-DNA molecules –> progency can have recombined genomes with traints not present simultaneously in either parent virus
Reassortmetn describes the mixing of genome segments in segmented viruses that infect the same host cells (such as influenza virus!!)
–> can result in sudden alterations in surface antigens of the viral progeny
Phenotypic mixing when a host cell is co-infected with 2 viral strains and progency virons contian parental genome from one strain and nucleocaspid (or envelop ) from proteins from anotehr strain. progeny could aquire additional traits but since the genome is left uncahnged, subsequent progeny would not retain these traints
What is pleiotropy?
Instances where multiple phenotypic manifestations result from a single genetic mutation.
Most syndromic genetic illnesses exhibit pleiotropy
Granulosa ovarian tumors-
describe its histology and gross appearance:
Sex-cord stromal tumors of the ovary that secrete estrogen and can cause endometrial hyperplasia
Call-exner bodies - cells arranged in a microfollicular or rosette pattern are seen on microscopy
On gross pathology, the tumor apepars yellow due to the lipid content in theca cells
how does SCD cause anemia?
HbS is caused by a single point mutation at the 6th AA position of the beta chain, that replaces a glutamic acid (negatively charged molecule) with valine (a nonpolar amino acid) – this change promotes hydrophobic interactions aong the Hb molecule that results in Hb polymerization and erythrocyte sickling.
This is increased in states of low O2, high altitude, acidosis, and dehydration.
how does P)1, % saturation of Hb and total O2 content change in:
CO poisoning
Anemai (low Hb)
Polycythemia (high Hb)
CO poisoning: decrease % saturation of Hb and total )2
Anemai (low Hb): NL % saturation (nothing is wrong with the Hb), DEC O2 content
Polycythemia (high Hb): NL % saturation, INC O2 content
PO2 is the DISSOLVED oxygen in the plasma and is unrelated to hmoglobin function - thus arterial O2 will remain unchanged in all of these conditions
How does methemoglobin change the oxygen delivery in the blood?
Nitrates cuase poisoning by inducing the conversion of heme iron (nl reduced for Fe2+/ferrous) to the oxidized ferric (Fe3+) –> methemoglobin
With iron in the oxidized ferric state, methemoglob in unable to bind oxygen
The affinity of any residual ferrous iron in the hb tetramer is INCREASED!! causing a leftward shift of the oxygen-dissociaiton curve.
The partial pressure of oxygen in the blood, which represents the amount of oxygen dissolved in plasma is left unchagned!
What are common medications to avoid in older adults?
Anti-cholinergics: First gen antihistamines, GI antispasmodics
CV: anithrombotics (dipyridamole, ticlopidine), alpha blockers (orthostatic hypotension), central alpha agonist, anti-arrythmics
CNS: TCA, anti-psychotics, barbiturates, benzos
Endocrine: sliding-scale insulin, sulfonylureas
Pain: indomethacin, muscle relaxants, meperidine
What is the pathway of nl vitamin D metabolism:
UV light converts 7-dehydrocholesterol to vit D2, D3 (also dietary intake as D2, D3-cholecalciferol)
@ liver w/25-hydroxylase–> 25, hydroxyvitamin D
@ kidney with 1-alpha-hydroxylase –> 1,25 dihydroxyvitamin D
[neg feedback Ca2+, pos feedback PTH]
What is tachyphylaxis?
Tachyphylaxis is a phenomenon observed with teh overuse of alpha adrenergic agonist (and nitroglycerine)
Alpha adrenergic agonist are effective decongestants because they are able to vasoconstrict prominent vessels of the nasal mucosa.
Phenylephrine, xylometazoline and oxymetazoline are used as topica preparations for the treatment of allergic rhinitis and common cold associated with congestion and rhinitis
Tachyphylaxis = rapidly declining effect after a few days of use. It occurs because of decreased production of endogenous NE from the nerve terminasl due to a negative feedback mxn –> relative vasodilation (since there was removal of the vasoconstriction), subsequent edema and congestion –> exacerbates teh nasal congestion symptoms
–> REBOUND RHINORRHEA (nasal congestion withouth cough, sneezing or postnasal drip) - rhinorrhea MAY OR MAY NOT BE PRESENT< but is associated with teh use of topical decongestants for greater than 3 days…the use of adrenergic agonist should be stopped to allow for the restoration of nl NE feedback pathways
What do the superficial inguinal nodes drain?
Anal canal (below pectinate line), skin below umbilicus (except popliteal territory), scrotum
Drain nearly all the cutaneous lymph from the umbilicus to the feet, including the external genitalia and anus (up to dentate line)
EXCEPTIONS: testes (drains directly to the para aortic), glans penis and the cuteaneous portions of hte posteiror calf.
These nodes drain into the deep inguinal lympho nodes
What do the para-aortic lympho nodes drain?
Testes, ovaries, kidneys and uterus
What do the popliteal lymph nodes drain?
Dorsolateral foot, posterior calf
What do the internal iliac lympho nodes drain?
Lower rectum to anal canal (above pectinate line), bladder, vagina (middle third), prostate
What is the pathogenesis behind achondroplasia?
Achondroplasia is due to a point mutation in the FGFR3 gene –> exaggerated inhibition of chondrocyte proliferation, leading to prevention of endochondral ossification in the long bones
–> clinical features: rhizomelia (proximal limb shortening), brachydactyl (shortened fingers), midface hypoplasia, frontal bossing, macrocephaly; normal torso length
**disporportionate shortening (vs GH deficiency)
vs flat bones grwo via intramembranous (NOT endochondral ossification), defined as DIRECT DEPOSITION of new bone created by osteoblast on top of formed bone – thus flat bones remain unaffected in achondroplasia
90% are new mutations
10% are inherited (AD)
needed for harm = ?
needed to harm = number of ppl who must be treated before an adverse event occurs
1/attributable risk (aka: absolute risk inc)
Atributable risk:
- calculate the AE rates in tx and placebo
- attributable risk = event rate tx - event rate in placebo
* for every X patients treated with tx drug, 1 will experience an adverse event.*
mneumonic for lower leg and food nerve/actions:
PED
TIP
PED = Peroneal Everts and Dorsiflexes
if injured, pt has a foot dropPED
–> foot is inverted and planterflexed
TIP = Tibial Inverts and Plantarflexes
if injured, pt can’t stand on TIPtoes
–> foot is everted
what is clasp-knife spacsticity?
what type of injury?
Initial resistance to passive extension followed by sudden release of resistance
UMN lesions, results from a LACK OF UMN INHIBITION on the spinal strech reflex arc
UMN lesions can affect any part of the pyramidal motor system - including corticospinal tracts of the spinal cord, medulla, pons, midbrain, internal capsule, precentral gyrus
Pt with internal capsule stroke commonly have pure motor weakness affecting the contralateral arm, leg and lower face
Hemolytic disease of hte newborn?
Most commonly occurs from maternal sensitization of Rh antigens during a prior pregnancy with an Rh(D)+ fetus. In subsequent Rh(D)+ pregnancies, maternal anti-Rh(D) IgG antibodies cross the placenta and cause a severe autoimmune hemolytic anemia in the fetus and life-threatening hydrops fetalis (generalized edema)
+ direct Coombs test = AI hemolysis
profound anemia, jaundice, stimuation of immature, nucleated erythrocytes nd persistent extramedullary hematopoiesis in the liver, spleen and other tissues
Why is there no vaccine to Neisseria G.?
no lasting immunity or vaccine because of the ability of these bacteria to modify their OUTER MEMBRANE PROTEINS by the process of antigenic variation
*alos, repeated Neisseria infections can be caused by terminal complement deficiencies leading to an inability to form the MAC
Toxicity of Nitroprusside?
Antidote-
Nitroprusside is a short acting nitro drug that works by inc cGMP which leads to the direct release of NO
used for HTN Emergencies
Metabolized in the blood to release NO and cyanide ions –>
Can cause cyanide toxicity and release cyanide
[cyanide is a potent mitochondrial toxin that binds Fe3+ in cytochrome C oxidase, inhibiting the ETC and halting aerobic respiration in the cell - presents iwth altered metnal stuatus, seizures, CV collapse, lactic acidosis and BRIGHT RED VENOUS BLOOD - seen on arterial blood gas and funduscopy]
Cyanide is normally metabolized by rhodanese, that transers a sulfur mol to cyanide to form thiocyanate –> less toxic and excreted in urine
GIVE: Sodium thiosulfate, sodium nitrite and hydroxycobalamin
Risk factors for neural tube defects?
Failure of neural tube closer AT 4 WEEKS gestation results in NTDs
First trimester use of valproate is a 10-20X risk factor due to impaired folate metabolism, folate anatagonist (methotrexate, trimethoprim-sulfamethoxazole) but this can be greatly reduced with periconceptional folate/Vit B9
How does lithum affect the kidneys?
Use of this tx could lead to –> lithium induced nephrogenic diabetes insipidus
Lithium therapy reduces the ability of hte kidneys to concentrate urine primarily by antagonizing the action of vasopressin (ADH, AVP), in the collecting tubules and ducts
What do the following receptors sense?
Central chemoreceptors?
Peripheral chemoreceptors?
Pulmonary stretch R?
Medulla respiratory center controls depth and rate based on input from the following receptors:
Central CR:
Loc - medulla
stimuated by - dec pH of surrounding CSF, mainly increased PaCO2 (H+ doesn’t readily diffuse through bbb)
Peripheral CR
Loc - carotid and aortic bodies
Sense - senseing arteria PaO2 and stimulated by hypoxemia, increased in PaCO2, H+ (but central chemo R are more important to increases in repiration due to hypercapnia)
Pulmonary stretch R, include myelinated and unmeylinated C fibers in the lungs and airways
R - regl duration of inspiration depending on the degree of lung distension - Hering Breuer reflex and act predominately to protect the lung from hyperinflation
** in healthy individuals, major drive for breathing is PaCO2, oxy with pp >70 mmHg has relatively small effect
BUT in pt with long standing COPD, dec sensistivity to PaCO2 and pH (remember they are hypercapnic!), pt are profoundly hypoxemic –> ARTERIAL Pa)2 becomes a significant contributor to the respiratory drive
What is the pathophys behind GERD?
GERD sx: heartburn, regur, dysphaia + nocturnal cough, hoarseness
Gastroesophageal junction incompetence is the primary pathophysiologic mxn responsible for GERD -> comonly caused by transiet lower esophageal sphincter relaxation resulting in the reflux of acidic gastric contents back into the esophagus
Irritation of the esophageal mucosa –> inflammatory reaction with epithelial regeneration
mucosal erythema/edema can be observed macroscopically in the distal esophagus and erosions/ulcerations may develop in severe cases
Characteristic histological finidings include: basal zone hyperplasia, elongation of the lamina propria, papillae, scattered eosinophils and neutrophils
What can lead to pill induced esophagitis?
Tetracycline antibiotics
Potassium Chloride
Bisphosphanates
What are the cytokine mediators of systemic inflammatory response, such as in sepsis?
TNF-alpha (secreted by activated macrophages)
@ high concentrations, causes symptoms of septic shock
IL, 1 and IL 6
Wiskott-Aldrich Syndrome:
WATER
*Wiskott-Aldrich: Thrombocytopenic purpura/Thrombocytopenia, Eczema, Recurrent infections*
inc risk of Autoimmune disease and malignancy.
Mutation in WAS gene (X-linked recessive) –> T cells unable to reorganize actin cytoskeleton; combined B lymphocyte and T-lymphocyte disorder
INC risk of pyogenic infections because pt can’t mount a humoral response to encapsualted organisms
T cell deficits –> INC infections of opportunistic pathogens
clinical pres: dec/nl IgG, IgM; INC IgE and IgA, small and numerous platelets
INC after 6 months, when maternal IgG and IgA have waned
TX: HLA-matched bone marrow transplant
how does the haversian system communicate?
Central canal is encricled by multiple oncetric lamellae of bony matrix that each contain lacunae filled with osteocytes and extraceullar bone fluid
Delicate canaliculi radiate from each lacuna to create a reticular netowrk with adjaccent lacunae and the cytoplasmic porcesses of the osteocytes lie within these cancailculi
The cytoplasmic processes send signals to and exchange nutrients and waste products with the osteocytes within the neighboring lamellae via gap junctions
Osteocytes serve to maintain the structure of the mineralized matrix and control the short-term release and deposition of calicum
*the plasma calcium concentration directly dictates the metabolic activity of the osteocytes; can also sense stress and sense signals to modulate the activity of surface osteoblast
while PTH and calcitonin indirectly influence their metabolic activity
How would one diecide which benzo to use?
Which are short acting?
Which are prefered for elderly pt or pt with hepatic dz?
Based on 2 pharmacokinetic factors:
Drug’s half-life (related to the desired length of clinical effect)
Extent of hepatic metabolism
Short acting: ATOM
alprazolam, triazolam, oxazepam, midazolam
For decreased hepatic function: LOT
Lorazepam, oxazepam, temazepa
What is the most common of the carpal bone fractures?
Scaphoid fractures are the most common fractured carpal bone and is prone to avascular necrosis and non union owning to retrograde blood supply (radial artery)
Fractures frequently results from falls onto an outstretched hand that casues direct axial compression or wrist hyperextension
sx: persistent wrist pain and tenderness in teh ANATOMICAL SNUFF BOX
dislocation of what carpal bone could lead to acute carpal tunnel syndrome?
lunate
What is actue compartment syndrome?
when increased pressure within a fascial compartment compromises blood circulation within that space
Develops after significant trauma, and particularlyy long-bone fractures of the leg and forearm
What is dupuyren’s contracture?
It is a slow progressive fibroproliferative dz of the palmar fascia
Nodules form on the fascia, eventually resulting in contractures that draw the fingers into flexion
What heart condition, that can cause cyanosis, is improved by squating?
Cyanotic spells that improve by squating, prominent right ventricular impulse and systolic murmur is consistent with Tetrology of Fallot
What are the 4 distinct anatomica abnormalities associated with TOF and what is it due to?
abnormal neural crest cell migration leads to anterior and cephalad deviaiton of the infundibular septum during embryologic development –> malaligned VSD and an overriding aorta
Ventricular septal defect
Overriding aorta over the right and left ventricles
Right ventricular outflow tract (RVOT) obsturction
Right ventricular hypertropy
cyanosis could occur due to right-to-left shunt
What is alternative splicing?
what is splicing?
What type of RNA is present in each
Process by which different combinations of DNA coding regions/exons are selectively included or excluded from a MATURE messenger RNA (mRNA) –> allows for DNA contained in a single gene to code for a functionally diverse group of proteins
A single gene can code for various unique proteins by selectively including or excluding different DNA coding regions/exons into mature mRNA
VS: splicing, which is a post-transcriptional modificaiton that removes noncoding DNA regions/introns from PRECURSOR-mRNA (pre-mRNA) – process is driven by a large protein complex = splicesome, comprised of a small nuclear ribonucleoproteins (snRNPs)
Thromboangiitis obliterans (Buerger’s disease)
vasculitis of medium and small-sized arteries, primarily tibial and radial arteries
Seen typically in heavy smokers (note hypersensitivity to injected tobacco extract), males under <40 y/o
Segmental thrombosing vasculities often extends into contiguous veins and nerves (feature rarely seen in other types of vasculities)–> inflammatory process may eventually encase all three structures - arteries, veins, nerves in fbrous tissues
Condition may result from direct endothelial cell toxicity from tobacco products or from hypersensitivity to them
More common in israel, Japan and India vs US and Europe
Calf, foot or hand intermittent claudication may be seen as well as superficial nodular phlebitis and cold sensitiivty (Raynaud’s phenomenon)
Severe distal pain, even at rest can result from neural invovlement; later complications include ulcerations and gangrene of the toes, feet and fingers
Tx: smoking cessation
What is the function of eosinophils?
- Parasitic defense - stimualted by IL-5, produced by Th2 and mast cells
parasite binds the Fc receptors on IgG and IgE antibodies located on eosinophil cell surface –> eosinophil degranulation and release of cytotoxic proteins (major basic protein) and reactive oxygen intermediates, substances that damage and destry Ab-bound parasites; example of antibody-depedent cell-mediates cytotoxicity, which is also used by macrophages, neutrophils and NK cells
Eosinophils can phagocytose parasitic antigens and present them in associattion with MHC Class II molecules to stimulate helper T lymphocytes
- Type I hypersensitivity reactions: eosinophils also synthesize prostaglandins, leukotrienes and cytokines that contribute to the inflammatory seen in the LATE-PHASE type I hypersen and chornic allergic reactions
What compromises a major part of the normal vagina flora?
What can occur if this normal flora was changed?
What are some triggers for this change?
Gram-positive lactobacilli comprise a major part of vaginal flora and exist in balance with other colonizers at a normal vaginal pH of 3.8 to 4.5
Changes to vaginal flora and epithelial injury can lead to overgrowth of yeast, most commonly candida
Common triggers: antibiotic use, high estrogen levels (pregnancy), systemic corticosteroid use, uncontrolled DM, any other cause of immunosuppression, including HIV
What are small nuclear ribonucleoproteins (snRNPs)?
snRNPs are important components of the splicesome, a molecule that removes introns from pre-mRNA during processing within the nucleus, by clearing the 5’ end of introl 1 splice donor site and joing that end to the branch point…the freeded 3’ OH exon 1 then forms a phosphodiester bond with the 5’ phosphate at the splice acceptor site –> joining exons 1 and 2.
Defective snRNPs assembly –> impaired splicesome function and degeneration of anterior horn cells in the spinal cord/ lower motor neurons
A protein important for the assembly of snRNPs is encoded in the survival motor neuron 1 gene (SMN1) and mutations to this gene could lead to spinal muscular atropy (sx: delayed motor development, flaccid paralysis)
What are RNA molecules that can carry out functions withouth first being translated inot proteins?
Non-coding RNAs
include: small nuclear RNA (snRNA - made by RNA pol II), ribosomal RNA and transfer RNA
What are P bodies?
Once mRNA is finalized [transcription, post-transcriptional processing before leaving the nucleus - c’ cap, poly A tail, intro splicing] the mRNA leaves the nucleus bound to specific packaging proteins –> it can then associate with ribosomes to undergo translations but certain mRNA sequences instead associated with proteins that are found in P bodies.
P bodies are distinct foci found with eukaryotic cells that are invovled in mRNA regulation and turn over. They play a fundamental role in translation repression and mRNA decay
include numerouns proteins that are invovled in mRNA quality control and microRNA-induced mRNA silencing; could also fxn ans a form of mRNA storage as certain mRNAs are incorporated into P bodies later to be translated.
What is the role of prostacyclin?
Prostacyclin aka prostaglandin I2, is produced from prostaglanding H2 by prostacyclin synthase in vascular endothelial cells
When secreted, it vasodilates, inhibits platelet aggregation and increases vascular permeability.
Function sof prostacyclin oppose those of thormboxane A2 – these two work in concert to ensure vascular homeostasis
How does FAS work?
Part of the TNF receptor family
Fas R initiate the EXTRINSIC pathway of apoptois through a cytoplasmic component know as the death domain
Upon binding Fas ligand (FasL), the receptors trimerize, allowing their death domains to form a binding site for an adapter protein caleld Fas-associated death domain (FADD). Receptor-bound FADD then stimualtes the activation of initiator caspases 8 & 10 that beign an activation cascade culminating in the activation of executioner caspases 3&6 –> these initiate the terminal processes of apoptosis, including cleavage of DNA, fragmentation of the nucleus, organelle autodigestion and plasma membrane blebbing.
Fas R is expressed on T-lymphocytes and pays a role in the pathogenesis of numerous dz including CA and AI.
Fas-FasL interaction is necessary in thymic medullary negative selection. Mutations in Fas INC numbers of circulating self-reacting lymphocytes due to failure of clonal deletion
After Fas crosslinks with FasL, multiple Fas molecules coalesce, forming a binding site for a death domain–containing adapter protein, FADD. FADD binds inactive caspases, activating them –> cell death
**autoimmunity!**
Blood flow is directly proportional to…
the vessel radius raised to the fourth power.
Resistance to blow flow is inversely proportional to the vessel radius raised to the power of 4!
R = [viscosity*length] / r^4
Factitious disorder vs malingering?
Facitious disorder is the intentional falsification or inducement of symptoms with the goal to assume sick role; pt deceptively produce signs and symptoms of a medical or psychiatric illness or induce injury to obtain attention an dreceive protracted care. These pt are aware of their symptoms and conceal their attemps to simulate or cause them but they lack conscious awareness of why they do it. The presentation is often episodic and more likely to occur in women and health care workers; when an individual falsifies illness in someone else (ie -child), the dx is factitious disorder imposed on another
Requires the absence of obvious rewards (such as in malingering)
VS
Malingering is the falsification or exaggeration of symptoms to TO OBTAIN EXTERNAL INCENTIVES (secondary gain - financial benefits, time off work)
What are the two primary defects in the pathophysiolog of type 2 diabetes?
- defective insulin secretion from pancreatic beta cells
- insulin resistance in peripheral tissues
Insulin resistance is caused by a number of genetic (insulin receptor and post-receptor mutations) and environmental (lack of physical activity, obsesity). INC BMI is very commonly associated with insulin resistance and DM2. VISCERAL FAT correlated much more strongly with insulin resistance than subcutaneous fat –> measurement of waist circumference or waist to hit ratio is an effective indirect assessmetn of visceral fat, esp in pt with only mild or moderate elevations of BMI.
A wasit circumference >102 cm (40 in) in mend adn > 88 cm (35 in) in women is associated with a higher risk for insulin resistance, diabetes and coronary artery disease
Insulin resistance:
suppresses gluconeogenesis
promoates glycogen synthesis in the liver –> GLUCAGON EXCESS
dyslipidemia - high triglyceride, low HDL
NO CHANGE to LDL levels due to insulin resistance
Dec uptake in skeletal muscle –> reduced glucose oxidation in muscle and glycogen synthesis
(glut 4 in skeletal muscle and adipose tissue req insulin)
ketone formation is not seen normally
Methylated DNA? Histone methylation?
Histone Acetylated?
Template strand cytosine and adenine are methylated in DNA replication, which allows mismatch repair enzymes to distinguish between old and new strands in prokaryotes.
DNA methylation at CpG islands represses transcription
Histone methylation is usually reversibly represses DNA transcription, but can activate it in some cases depending on methylation location.
X-bar is an example; heterochrome DNA – typically found at the periphery of the nucleus
Methylation = Mute
DNA acetylaiton Relaxes DNA coiling, allowing for transcription
Acetylation = Active
likely euchormatic = active DNA
Tricyclic antidepressant overdose:
Overdose of TRI-Cyclic Anti-D = TRI-C
Tri-C’s: Convulsions, Coma, Cardiotoxicity (arrhythmias); also respiratory depression, hyperpyrexia.
Confusion and hallucinations in elderly due to anticholinergic side effects (use nortriptyline).
Treatment: *NaHCO3 to prevent arrhythmia.*
What would a nicotinic blockade (diplopia and dysphagia) and muscarinic blockade (ie - dry mouth) suggestive of?
Classic presentaton: diplopia, dysphagia, dysphonia
develop within 12-36 hours of consumption
Food poisoning with clostridium botulinum toxin!
highly potent preformed neurotoxin that inhibits acetylcholine release from presynaptic nerve terminals at the neuromuscular junction (NMJ), preventing muscular contraction.
This can be partially overcome by high-rate repetitive nerve stimulation, which explains compound muscle action potential( CMAP) facilitation.
Statin’s MOA:
HMG-COA Reductase competitve inhibitors (prevent conversion of HMG-CoA to mevalonic acid)
*rate limiting step of cholesterol biosynthesis –> decrease liver cholesterol synthesis leads to increased hepatic clearance of LDL from the circulation by LDL receptors; thus after mediating endocytosis of LDL particles, the receptors are returned to the cell surface for reuse - allowing intrahepatic cholesterol to remain at normal levels while blood levels are kept low
–> enhanced hepatic LDL receptor reclying and increased LDL clearance from the circulation
Statin-induced myopathy (myalgia, elevated creatine kinase = myonecrosis) is the most common complication of statin use (esp when used with fibrates or niacin) –> rhabdomyolysis
Other: hepatotoxicity -INC LFTS
Juvenile hemangioma:
Strawberry-type capillary hemangioma
lesions consisit of unencapsulated aggregates of closely packed, think-walled capillaries
strawberry angiomas are benign adn quiet common, occuring in 1/200 births - may be multiple and can be found in the skin, subcutaneous tissues, oral mucous membranes or lips
Capillary hemangiomas may also occur in the liver, spllee and kidneys
these are present at birth and origianlly grow in proportion to the child - lesions regress sponteneously at or before puberty; usually by age 7.
What are proteosomes?
Proteasomes act as recyling centers for proteins, breaking down misfolded, damaged and cytotoxic proteins into their component building blocks for reuse in new proteins –
Proteasome inhibitions (bortezomib, boronic acid-containing dipeptide) results in the accumulation toxic intracellular proteins
Proteosomes regulate the balance of pro and antiapoptotic proteins, and their inhibition leads to an excess of proapototic proteins –> iduce apoptosis of the malignant cells (ie- plasma cells in multiple myeloma)
What is the number needed to treat?
The NNT = number of pt that need to be treated with a medicaiton to avoid a negative outcome in one patinet. It is calculated by dividing 1 / absolute risk reduction
Lower NNT values represent more beneficial treatments
absolute risk reduction = percentage indicating the actual difference in event rate between control and treatment
Why does cardiac tamponade cause pulsus paradoxus?
inspiration causes an increase in systemic venous return –> increase right heart volumes.
Normally, this results in expansion of the right ventricle into the pericardial space with little impact on the left side of the heart. BUT, in conditions that impair expansion into the pericardial sac - increased right ventricular volume that occurs with inspiration leads to bowing of the interventricular septum towards the left ventricle –> decrease in left ventricular LV end diastolic volume and forward stroke with a resultant decrease in systolic pressure during inspiration.
Remember, pulsus paradox is an abnormal exaggerated decrease in systolic blood pressure >10 mmHg on inspiration - seen in:
CAPOT: COPD, asthma, pericarditis, OSA, Tamponade
SLE autoantibodies
In SLE, autoantibodies bind autoantigens and form immune complexes that deposit on vessel walls –> IC deposition leads to complement activation and resultant tissue inflammation and injury
In acute phase - fibrinoid necrosis of the vessel wall
In chronic phase - fibrosis and narrowing of lume
Commonly seen autoantibodies in SLE:
- ANA - antinuclear antibodies, virually in all SLE pt as wel as pt with other connective tissue disorders; test is sensitive but not specific
- Anti-DS DNA - highly specific to SLE; only about 60% of SLE pt have high anti-dsDNA titers thus absense of anti-dsDNA antibodies does not rule out dx
- Antibodies against small nuclear ribonucleoproteins (anti-snRNPs) aka anti-SMITH antibodies, are present in about 20-30% of SLE patients and also highly specific to SLE; absence does not rule out dx
What is rheumatoid factor?
It is an IgM directed against the Fc fragmetn of self IgG found in patients with rheumatoid arthritis
Also found in other collagen tissue disorders
Who typically presents with anti-centromere antibodies?
majority of pt with CREST syndrome
HOw does the serratus anterionr help facitate arm elevation?
Pulls the lower end of the sacpula forward = sacuplar rotation
What is the most commonly fractured bone?
The clavicle; the majority occur in young childrne
The clavical is the point of origin or insertion fo numerous muslces including:
Deltoid, pectoralis major, subclavius, sternohyoid, trapezius, SCM
Action of the SCM:
upward traction of the medial fragmetn of the patient’s fractured clavicle
if clavical is fractured it pulls it superiorly and posterioly
What coudl you give levodopa with to preven its dedegration?
PD is typically treated with levodopa (immediate precursor of dopamine), which is able to cross the BBB. Levodopa is administered with DOPA decarboxylase inhibitors (carbidopa) and sometimes catechol-O-methyltransferase inhibitors (entacapone or tolcapone - prevents peripheral methylation) to reduce the peripheral metabolism of levodoa, resulting in increased levopoda bioavailability to the brain
Dopamine is the NT that is absent in the nigrostriatum of pt with PD BUT dopamine itself cannot be administered direclty due to its inability to cross the BBB but levodopa CAN cross…yet it is rapidly metabolized in the periphery to dopamine (via DOPA decarboxylase) and 3-O-methyldopa (via COMT) thus only a small percentage of levodopa actually reaches the brain
How does B1 receptor act?
stimulation of B1-adrenergic receptors causes Gs protein GTP binding –> activation of adenylyl cycalse and increased cAMP in the target cells
IN cardiac myocytes, increased cAMP causes calcium channel activation and increased calcium concentration, facilitating binding of actin-myosin complex with troponin C and increased myocardial contractility (positive inotropic effect)
Increased cAMP also causes a rise in heart rate by increasing Na+ and Ca2+ channel activation in pacemakers (positive chronotropic effect)
In vasculature, mild vasodilation
–> increased in cardiac contractility, dec in systemic vascular resistance withouth significant change in arterial blood pressure –> increase cardiac output can improve symptoms and end-organ perfusion in pt with severe left ventricular systolic dysfunction and cardiogenic shock
Example of B1 agonist = doubutamie
tamoxifen and raloxifen:
Selective estrogen receptor modulators SERMS
interact with estrogen receptor and have agonist or antagonist activity depending on the tissue
In breast tissue, tamoxifen has anti-estrogenic effect and is used for adjuvant treatmetn of estrogen receptor positive breast cancer; reduces the risk of recurrent cancer as well as estrogen dependent beign breast leasions
Both act as partial estogen recepto agonist in bone and can cause an increase in bone mineral density after menopause
Tamoxifen has favorable effects on serum lipids with a decrease in total and LDL choelsterol and not significant changes in HDL. Serum triglycerides may increase in some patients
BUT in endometrial tissue, it has stimulatory effect and can lead to the development of endometrial hyperplasia and endometrial CA
OTHER AEs: hot flashes, venous thromboemolism
RISK IS NOT SEEN WITH RALOXIFENE!
partial vs complex seizures…what is the treatment?
Partial seziures = simple sizures, there is no associated impairment of consciousness during or after the event
Complex seizures are characterized by loss of memory during the event and a postictal state
Both can be effectively treated with carbamazepine (also used for generalized tonic-clonic seizures, mood stabilizer in bipolar and treat trigeminal neuralgia)
BLOCKS voltage-gated sodium channels in cortical neurons –> stablizes channes in an inactivated state – fewere Na channes = less available for the propagation of an abnormal action potential
AEs: bone marrow suppression (anemia, agranulocytosis, thrombocytopenia…), hepatotoxic (monitor LFTs regularly), SIADH associated with use
blood supply and venous supply of the hindgut.
Hidgut = 1/3 distal transverse colon, descending colon, sigmoid colon and rectum
Receive arterial blood from the IMA, branch from the aorta
Structures are drained by the inferior mesenteric vein, which doe snot course with the IMV. it drains into the splenic vein which then drains into the portal vein
C diff pathogenesis
Intestinal overgrowth (rf: abx, hospitalization, advanced age, PPI) –> toxin production
Enterotoxin A –> watery diarrhea
Cytotoxin B –> colonic epithelial cell necrosis and fibrin deposition
Clinical pres: fever, abdominal pain, watery diarrhea, leukocytosis (ranges from mild diarrhea to fulminant colitis - toxic megacolon)
Characteristic white/yellow pseudomembranes on sigmoidoscopsy
dx: PCR detection of toxin genes in stools
Tx: metronidazole or oral vancomycin
What is the qualifiers for bipolar I disorder?
pt with one or more lifetime manic episodes are diagnosed with bipolar I dz…
DIGFAST:
Distractibility, Impulsivity/indiscretion, Grandiosity, Flight of ideas, Activity increase, Sleep decrease, Talkativeness
Manic episodes an occur with or withouth psychotic features (ie-delusions, hallucinations)
Delusions, if present, are often mood congruent but can also be mood incongruent - msot bipolar I patients will experience both major depressive and manic episodes but depressive episodes are not required for dx.
Patent ductus arterosus (PDA)
Vascular connection between the main pulmonary artery and the aorta that normally obliterates after birth
Clinical features vary depending on size
continuous machinelike murmur (left to right shunting) with no signifcant sx
Large PDAs can present anytime during childhood with progressive pulmonary hypertension and reversal of the shunt to right to left; characteristic continuous murmur decreases as the pulmonary pressure rises and ultimately disappears.
–> HF, cyanosis (eisenmenger syndrome)
**cyanosis and clubing are most pronounced in the lower extremities ** differential cyanosis and clubing
becuase the PDA delievers unoxygenated blood distal to the left subclavian artery
How does coarctation of the aorta present?
most commonly located juxtaductal region just distal to the left subclavian artery
typically presents in children and adults as a BP discrepancy and pulse delay between the upper and lower extremiteis
In neonates, severe coarctation can present with HF, esp once the ductal tissue collapses; if the ductus arterisus remains patent, deoxygenated blood can bypass the coarctation and cause differential cyanosis in infancy. However, infants with severe coarctation are unlikely to survive withouth surgical correction
Eisenmenger syndrome?
reversal of shunt flow from left to right –> right to left.
Differential clubbing and cyanosis withouth blood pressure or pulse discrepancy are pathognomonic for a large patent duct arteriosus complicated by Eisenmenger syndrome. Severe coarctation of the aorta can cause lower extremity cyanosis.
Right to left shunting in patients with large septal defects and tetralogy of fallot results in whole-body cyanosis
How is PAH and inulin excreted by the kidney
Inulin and mannitol - no tubular areabsorption or secretion
Filtration amt = excreted amt
Glucose, sodium and urea
net tubular reabsorption
excreted amt << filtered amount
PAH and creatinint
net tubular secretion
Excreted amt >> filtered amt
