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Terms in this set (126)

Henoch-Scholein purport
Path: IgA immune complexes-mediated (type III hypersensitivity) vasculitis. Generally follows upper respiratory or minor infections.
Clinical manifestation:
1. palpable purpura
2. arhtralgias
3. abdominal pain, intussusceptions
4. renal disease similar to IgA nphropathy (hematuria)
-usually made clinically
confirmed by skin biopsy showing IgA deposition in blood vessels.

deposition of these complexes in the walls of small vessels and the renal mesangium leads to recruitment of neutrophils and lymphocytes as well as activation of complement via the alternative/lectin pathway.

resulting inflammation leads to the organ dysfunction and palpable purport found in HSP The condition is self limited and resolves as the circulating immune complexes clear. Treatment is supportive unless specific complications (eg, intussusception) occur.

a. antibody dependent cellular cytotoxicity type II hypersensitive is part of the body's defense against viral and parasitic infections. Antibodies bound to antigens on the surface of infected cells are recognized by th eFc receptors on the effector cells (eg, NK, neutrophils and eosinophils) that then destroy the infected cells by releasing cytolytic granules

delayed hypersensitivity type IV are T-cell and macrophage mediated response. They occur in response to Mycobacterium TB infections and in certain allergic reactions, such as contact dermatitis and transplant rejection

a palpable skin rash is commonly seen with disseminated Nessiera infections (miningococcemia or disseminated gonococcus). Unlike the purport of HSP, which is generally limited to the lower extremities, the rash of disseminated Neisseria begins with petechiae on the trunk and spreads over the entire body. patients also have a fever, hypotension and tachycardia

IgE depended degranulation occurs in atopic and anaphylactic reactions type I hypersensitivity. IgE on the surface of mast cells and basophils binds the offering allergen and triggers degranulation with relate of histamine, serotonin and other vasoactive substances.
Hep B infection progresses through two phases
1. proliferative: the entire vision and all related antigens of the episomal HBV DNA are present. ON the hepatocyte cell surface, viral HBsAg and HBcAGg are expressed in conjunction with MHC class I molecules. This expression serves to activate the cytotoxic CD 8 T lymph, which respond by destroying the infected hepatocytes. Note that the vision itself doesn't have a cytopathic effect
2. integrative : the HBV DNA is incorporated into the host genome of those hepatocytes that survived the immune response. Infectivity ceases and liver damage tapers off when the antiviral antibodies appear and viral replications stops. The risk of hepatocellular carcinoma, however, remains elevated because ofHBV dan that has been integrated into the host genome

a. HBV has no direct cytotoxic effect
b. host antibody HBsAb neutralizes HBV infecitivty by binding to the viral surface antigens HBsAg and preventing the antigen from interacting with hepatocyte receptors. Note that this neutralization occurs before the virus enter the hepatocyte, and therefore wouldn't be associated with hepatocellular damage.

c. antigen antibody complexes cause some of the early symptoms of HBV infections (eg, arthralgia, arthritis and urticaria) as well as some of the choir complications (eg, immune complex glomerulonephritis, cryoglobulinmeia, vasculitis). These complexes are not responsible for hepatocellular damage.

d. the pathogenesis of autoimmune hepatitis not hep B infection ivvloves antigen mimicry with genratio not self antigen receogzign CD 4 T lymph that damage hepatocytes
Dude has trigeminal neuralgia (tic douloureux), a neuropathic disorder the typically presents with episodic, severe, unilateral, electric shock like pain in the distribution of CN V. Symptoms are often triggered by innocuous stimuli such as shaving or washing the face

First line treatment: carbamazepine - a neuroleptic medication that inhibit neuronal high-frequency firing by reducing the ability of Na channels to recover from inactivation. Adverse effects are:
1. bone marrow suppression ,which may lead to anemia, agranulocytosis, and thrombocytopenia (thus CBC should be monitored periodically)

Ketamine, felbamate and memantine are examples of medications that block NMDA receptors. Ketamine is used as a general anesthetic agent, felbamate is anticonvulsant and memantine may be effective in treatment of Alzheimer dementia.

SSRI (eg, fluoxetine, sertraline) are typically used to treat depression, anxiety and PTSD. Side effects may include headache, wroesenign anxiety/agitaiton, and insomnia

Ethosuximide blocks T-type Ca channels and decreases calcium current in thalamic neuron. This anticonvulsant is the agent choice for absence seizures. Major side effects include GI symptoms and drowsiness

Various anti seizure medications (eg, bento and barbiturates) act on GABA-A receptor to increase chloride conductance; however, carbamazepine doesn't significantly affect chloride channels.

Donepezil is an AChesterase inhibit that can be used to treat Alzheimer dementia. Side effects are generally related to increased cholinergic activity, which includes GIT symptoms and symptomatic bradycardia.
clinical features of cardiac tamponade
-etiology: malignancy/radiation therapy, infection , drugs and connective tissue disae (eg, SLE and RA)
-C/Ps: beck's triad (JVD, hypotension, diminished heart sound). Pluses paradoxes (abnormally large inspiratory decrease in systolic BP > 10 mm Hg)
-Diagnosis: ECG (low voltage QRS complexes, electrical alternates) and chest x-ray (enlarged water bottle shaped heart, clear lungs)

This patient presentation of hypotension, tachycardia, jugular venous distention with clear lungs and pulses paradoxes (manifesting as loss of palpable pulse during inspiration) is consistent with cardiac tamponade.
- this is most likely d/t patient's recent viral illness causing viral pericarditis with significant pericardial fluid accumulation.

Normally there is a <10 mm Hg decrease is systolic blood pressure during inspiration. pulses paradoxes refers to an abnormal exaggerated decrease in systolic blood pressure of over 10 mm Hg on inspiration, a common finding in patients with large pericardial effusions causing tamponade.

Inspiration causes an increase in systemic venous return, resulting in increased right heart volumes. Under normal conditions, this results in expansion of the right ventricle into the pericardial space with little impact on the left side of the heart.

However, in conditions that impart expansion into the pericardial space (eg, cardiac tamponade), the increased right ventricular volume that occurs with inspiration leads to bowing of the intraventricular septum toward the left ventricle. This leads to decrease LV end diastolic volume and forward stroke volume, with a resultant decrease in systolic pressure during inspiration.

In acute MI, presentations include substernal discomfort, diaphoresis and/or dyspnea, and can progress to cariogenic shock (hypotension, tachycardia, JVD and pulmonary edema). patients can have weak or undetectable peripheral pulses; however, pulses paradoxes is typically not seen.

Acute viral myocarditis can lead to severe LV systolic dysfunction and present with acute CHF and cariogenic shock. Patients with severe LV failure can have pulses alternates - a variation in pulse amplitude with alternate beats. Pulses paradises is typically not seen.

Pulses paradoxes can also occur in patients with asthma, COPD and constrictive pericarditis. Constrictive pericarditis is caused by scarring and loss of elasticity of the normal pericardial sac: it takes several weeks to months to develop and only rarely occurs after recurrent episodes of acute pericarditis

the intimal stage of septic shock is hyper dynamic circulatory state with lowered systemic vascular resistance and increased CO (warm shock). weak pulses and pulses paradoxes would not be expected

In tension pneumothorax, breath sounds are typically absent on the affected side with hype resonance to percussion. Other features include tachypnea, tachycardia, hypotension, distended neck veins, and tracheal deviation to the contralateral side,
Features of drugged induced LE
C/Ps: abrupt onset symptoms 9fever/fatigue, arthralgia/arthritis, rash, serosistis). Predilection for slow acetylators
Labs: anti-histone antibodies (95%) and anti-dsDNA antibodies (rarely seen more specific for SLE)
Implicated drugs: procainamdie, hydrazine, isonizadi,minocylcine, TNF-alpha inhibitors (eg, etanercept)

The drugs above are metabolized via phase II acetylation in the liver. hepatic expression on N-acetyltransferase is genetically determined, and patients with a slow acetylator phenotype are greater risk for developing DILE. Patients who are slow aceytlators are also predisposed to isoniazid induced peripheral neuropathy d/t increased drug concentrations.

Liver hydrolysis is a phase I reaction in which a compound is clveaed by adding water (eg, esterase or amides enzymes). Phase I metabolism usually priced phase II conjugation metabolism

Liver hydroxylation is a phase I oxidation transformation catalyzed by P450. Addition of the hydroxyl group reduces lipid solidity and facilitates excretion.

Liver sulfate conjugation is a phase II metabolic pathway that biotransform drugs into more polar compounds that are more water soluble easily excreted

certain drugs are hydrolyzed by plasma esterase, which rapidly cleave ester links after the drug enters the circulation. This rapid inactivation allows for short duration of these medications. many drugs used in anesthesia (eg, succinylcholine,teraciane, remifentanil) are metabolized by plasma hydrolysis.

A few drugs are not metabolized in the body. They are excreted in the urine mostly unchanged and are still pharmacologically active.
anti fungal targets
1. Griseofulvin: mitosis
2. DNA and RNA synthesis: Pyrimidines (eg, flucytosine) the only agent in this calls of anti fungal, is converted to 5-fluorouracil within the fungal cell wall and interferes with fungalRNA and protein synthesis.
3 Cell wall: echinocandins (eg, caspofungin, micafungin) inhbit the synthesis of glucan, a component of the fungal cell wall
4. Cell membrane: amphotericin B & nystatin bind ergosterol (polyenes) in fungal cell membrane,s creating pores and causing cell lysis (via leakage of K). Azoles (eg, ketoconazole, fluconazole, itraconazole, voriconazole) inhibit synthesis of of ergosterol.

Of these agents, only polyenes (amphotericin B, nystatin) depend on the amount of ergosterol incorporated into fungal cell membrane in order for them to work.

An organism that decreases the amount of ergosterol in its cell membrane would likely become resistant to polyenes.
-amphotericin B is a systemic anti fungal active against Candidia, Aspergillus, Cryptococcus, Histoplasma, Blastomyces and Coccidiodes.
-nystatin is used topically; oral candidiasis is the main indication for its use ("swish and swallow")

cyclosporin is an immunosuppressant used in transplant recipients to prevent rejection. It decreases the synthesis of IL-2, thereby inhaling T cell proliferation.

Flu cytosine is used in combination with amphoteric B primarily for the treatment of cryptococcal meningitis in patients with HIV> It is a nucleotide analog that competitively inhibits RNA synthesis in fungal cells.

Griseofulvin interacts with fungal cell microtubules, inhibit mitosis. It accumulates in keratin-containing tissues and is used to treat dermatophyte infection (eg, microsporum, epidermophyton and trichophyton)
amyloid is abnormally folded (insoluble) fibrillar protein that deposits in the extracellular space of tissues. When stained in Congo red and viewed under polarized light, these deposits have a characteristic of apple green birefringence d/t to their beta-sheet structure

Amyloid deposition can affect multiple organs system, such as those involved in plasma cell tumors (eg, amyloid light chain protein (AL)) and chronic inflammatory disease (eg, amyloid-associated protein (AA)).

However, in Alzheimer disease, amyloid deposits are seen exclusively in brain tissue. these deposits contain beta-amyloid (A-beta), which formed by cleavage of amyloid precursor protein ( a transmembrane glycoprotein).

Early in the disease, neuritic (senile) plaques can be found in the medial temporal lobe (eg, hippocampus, amygdala, entorhinal cortex) and are composed of central ABeta core surrounded by dystrophic neuritis. Beta deposition can also occur in the media/adventitia of cerebral vessels (amyloid antipathy) and may cause vessel wearing with intracranial hemorrhage.

Huntington, atrophy of the caudate and microscopy reveals intranuclear inclusions containing aggregates of hungtington protein

Parkinson has intracellular eosinophilic inclusions composed of alpha-synuclein (lewy bodies).

Pick (frontotemporal dementia) silver stationing shows round cytoplasmic inclusions contiatning aggregates of tau protein (Pick bodies)

Neuritic plaques and amyloid antipathy is not seen in pseudo dementia

Vascular dementia typically present its sudden/stepwise cognitive decline in patients with cardiovascular risk factors and ischemic stroke.
Within the zone of autoregulation, increase in coronary blood flow are primarily mediated by the relative myocardial hypoxia that occurs during times of increased work.

At baseline levels of activity, the myocardium extracts over 70% of the available oxygen from the blood it receives. When the oxygen demand increases, increased blood flow is required because the percent oxygen extraction from hemoglobin cannot be significantly increased (i.e., resting O2 extraction is already near maximal). Thus, increased myocardial oxygen requirements during exercise can only be achieved from a corresponding increase in coronary blood flow.

Local factors influencing coronary blood flow:
-autonomic nervous system neurotransmitter
-mechanical shear stress
-NO (endothelium derived relaxation factor)

There are numerous local factors that are important in influencing coronary blood flow. Of these adenosine and NO are the most important factors involved in coronary blood flow auto regulation

-Adenosine, a product of ATP metabolism, acts as a vasodilatory element in the small coronary arterioles.
-NO is created by and released from endothelial cells in the coronary vasculature. It is synthesized from arginine and oxygen by endothelial nitric oxide synthase (eNOS), and is released from coronary endothelium in response to neurotransmitters (eg, ACh and NE), platelet products (i.e., serotonin, adenosine diphosphate), thrombin, histamine, bradykinin and endothelin. NO is also released in response to pulsatile stretch and flow shear stress in the coronary arteries. It is the major regulators flow-mediated vasodilation in large arteries and pre arteriolar vessels.
-NO acts within the vascular smooth muscle cells via a soluble guanylate cyclase enzyme to increase production of cyclic GMP and cause smooth muscle relaxation.

NE is a neurotransmitter released from sympathetic neurons. Alpha-1 receptors cause construction of blood vessels. Alpha 2 are centrally located and cause inhibitor of the sympathetic system. Beta-1 receptors cause excitation of the heart. Beta-2 receptors (not stimulated by NE) cause vasodilation. despite these these effects nervous input generally has very little effect on coronary blood flow.

Each is a NT released from parasympathetic neurons. It acts on muscarinic receptors to affect an inhibitory influence on the heart. As stated, nervous input has very little effect on coronary blood flow.

Angiotensin II is a very powerful vasoconstrictor that acts to regulate systemic, not local, blood pressure

Histamine is a potent vasodilator released primarily from mast cells when there is tissue damage. It increases capillary permeability, leading tot local edema.

Serotonin is produced by gut neuroendocrine cells, platelets, and serotonergic neurons in the CNS. Little is known about its vasoactive affects; it has been shown to have both vasoconstrictor and vasodilator effects.
Patient has Conn syndrome - a very common cause of secondary HTN. Primary hyperaldosteronism secretes high amount of mineralocorticoids from bilateral nodular hyperplasia of the adrenal zona glomerulosa or an aldosterone producing adrenal adenoma.

The main effect of aldosterone is to stimulate the absorption of sodium and excretion of potassium and hydrogen ions in the renal collecting tubules.

Aldosterone secretion from the glomerulosa is normally regulated by angiotensin II and potassium levels. Overpoduciton of aldosterone can result in sodium retention, hypertension and feedback suppression of the RAAS system (i.e., very low renin activity).

Some patients also develop metabolic alkalosis and hypokalemia , which can exacerbated by increased distal bubble sodium delivery (eg, diuretics, increased sodium intake).

Clinical presentations: muscle weakness, cramps, occasionally rhabdomyolysis and cardiac arrhythmias.

a/b. overactivity chromaffin and extra adrenal paraganglion cells will give you pheochromocytoma a catecholamines secreting tumors. Typical presentation is severe hypertension. But it is also associated with tachycardia and symptoms of catecholamines excess (eg, sweating, palpitations, headaches).

c. JG cells will give you hypertension but also high renin levels. This is typically seen in renal artery stenosis with decreased renal blood flow.

d/f. zona fasciculate and reticular will give cushing and hyperandrogegism, respectively. Cushing syndrome can cause hypertension and hypokalemia but is usually associated with weight gain and Cushingoid body habits (eg, central obesity and moon face).
Most available antidepressant medications affect serotonin or both serotonin and NE at the synapse. SSRIs are used as first line antidepressants that work by blocking the 5HT transporter. This prevents the normal reuptake of serotonin in the presynaptic neuron, resulting in increased availability of serotonin in the synaptic space.

The receptor activities are the primary MOA of antipsychotics used mainly to treat schizophrenia and other psychotic disorders and to augment antidepressants int the treatment of mood disorders. Potent antagonism of D2 is the mech of action of first generation antipsychotics such as haloperidol. Second-generation antipsychotics have comparatively less affinity for D2 and additional property of 5HT2 receptor antagonism, which underlies their lower risk of extrapyramidal side effects. An antipsychotic would be appropriate monotherapy for MDD without psychotic feature.

Block of Na, resulting in stabilization of neuronal membranes, is the MOA of some anti epileptic drugs (eg, carbamazepine). These drugs also have a role as a mood stabilizers in bipolar disorder but are not a primary treatment of unipolar MDD

Inhibition of monoamine oxidase is used to treat resistant to SSRI depression. These drugs are not used as first line therapy d/t their dietary restriction and risk of serious adverse events (eg, HTN crisis, serotonin syndrome)

Benz work to potentiate the effect of endogenous GABA, the major inhibitory neurotransmitter in tehCNS, by facilitating the increase frequency of chloride channel opening in the GABA A receptor. They have sedative hypnotic anxiolytic anticonvulsant and muscle relaxant properties but it is not first line treatment for depression
Bitch has panhypopituitarism with failure of lactation, central hypothyroidism and adrenal insufficiency. In setting of a recent delivery, this is most likely d/t ischemic necrosis of the pituitary gland (Sheehan syndrome).

During pregnancy, the pituitary enlarges d/t estrogen induced hyperplasia of the alctotrophs. However, the blood supply to the pituitary doesn't increase proportionally. As a result, the enlarged pituitary is vulnerable to ischemia in case of systemic hypotension d/t permpartum hemorrhage (which this patient likely experienced given her low hemoglobin).

The most common manifestation of Sheehan syndrome is failure of lactation d/t prolactin def. It also commonly causes hypocortisolism and hypothyroidism. Manifestations of thyroid deficiency may take a few weeks to develop d/t the long circulation half-life thyroxine (5-7 days) and peripheral conversation of the T4 into T3. Cortisol def manifests rapidly however, with nausea, postural hypotension , fatigue and weight loss.

Pituitary apoplexy is d/t sudden hemorrhage into the pituitary, usually in setting of a preexisting pituitary adenoma. It usually presents with acute severe headache, opthalmoplagia and altered sensorium.

Lymphocytic hypphsiitsi is the most common inflammatory ocndiotn of the pituitary and typically occurs during late pregnancy or the early postpartum prediod. In contrast to Sheehan syndrome, the presentation is acute with severe headaches and visual field defects.

Primary pituitary cancer is extremely rare, although the pituitary is prone to metastases d/t its rich vascular supply. These patients typically present with tumor mass effects (eg, headache, bitemporal hemianopsia).

Non-malignant infiltrative lesions such as sarcoidosis and histiocytosis X daily involve the supresellar region, where they compress the hypothalamus and pituitary stalk. This disrupt the normal hypothalamic dopaminergic suppression of of prolactin secretion, leading to increased prolactin levels and possible galactorrhea. Central diabetes insidious may also be seen with resulting hypernatremia.
Ectopic pregnancy occurs when a fertilized ovum implants outside of the uterus. Most common site is the ampulla of the fallopian tube, which appear as an adnexal mass on ultrasound. Ask factors include tubal pathology such as previous infection or surgery (eg, tubal ligation).

Pregnancy after permanent sterilization is extremely rare, but one third cases are ectopic if implantation occurs An ectopic pregnancy may become life threatening as the embryo and trophoblastic tissue proliferate. This growth will compromise the blood supply to the surrounding tissues, which can result in rupture and profuse intra abdominal bleeding.

A ruptured ectopic pregnancy is managed surgically by removing the pregnancy an achieving homeostasis. Dilation and curettage of the uterus may be performed either to stop uterine bleeding or confirm whether the pregnancy is intrauterine or ectopic.

IN an ectopic pregnancy, the uterine specimen will reveal decidualized endometrium ONLY, consistent with dilated coiled endometrial glands and vascularized edematous storm. these changes occur in the luteal phase of the menstrual cycle, under influence of progesterone, as the endometrium prepares for implantation. Embryonic trophoblastic tissue will e absent from the uterus.

The finding of atypical endometrial cells that form glands would suggest endometrial adenocarcinoma, a malignancy that typically occurs in postmenopausal women and manifests with vaginal bleeding.

A molar pregnancy or spontaneous aboriton may present with vaginal bleeding. Uterine curettage may show enlarged chorionic villi and avascular edematous storm. IN contrast, intrauterine chorionic villi are absent in ectopic pregnancy.

An inflammatory endometrial infiltrate would suggest endometritis, an infection of the decidua, which presents with uterine tenderness, fever, and tachycardia. An ectopic pregnancy is not an infectious process

Straight, short endometrial glands and compact storm are found in the early proliferative phase of the menstrual cycle. This microscopic appearance would be observed 4-7 days after the onset of menses.
Patient has dysentery by Shigella. The bacteria is transmitted via fecal oral and is never a component of the intestinal flora. People who are at risk are children, men who have sex with men and adults in skilled nursing facilities.

It is non lactose fermenting organism that produce acid (not gas) during glucose fermentation (in contrast to E.coli). Furthermore, Shigella species are non-motile and do no produce H2S (In contrast to Salmonella)

Mucosal invasion is the essential pathogenic mechanism for infection. It infiltrates the M cells that overlie Peyer's patches. After cell entry, it is able to lyse its containment vacuole and enter the cytosolic compartment. It then can induce apoptosis of the host cell and spread to adjacent cells via protrusions created during shot cell actin polymerization. Shigella invasion triggers a robust host inflammatory response that is largely mediated by neutrophils.

Some stars have shiga toxin that messes with the 60S ribosomal subunit, halting cellular protein synthesis. However, shiga toxin plays a minor, nonessential role in the disease process as notoxigenic strains also cause shigellosis.

Intestinal colonization is not necessary as transmission of as few as 10-100 organism is sufficient to cause disease. If Shigella is slated from a stool culture, an active infection is taking place.

Proliferation in lymph nodes is more characteritiscs of Salmonella type and Yersinia entercoliticia (grows at low temp like Listeria) can gain access to lymphatics and proliferate in the mesenteric lymph nodes. Y enterocolitica can cause inflammation and enlargement of the lymphoid tissue around the appendix an detrital ileum ("pdseudoappedicitis"), leading to right lower quadrant pain that can be confused with acute appendicitis.

Shigella infections rarely case bacteremia, as the bacterium is readily phagocytose and destroyed after entering the blood stream. Enteric bacteremia is more likely to be cased by E coli, S phi (typhoid fever), Klebsiella and Proteus
B-cell precursors proliferate and mature in the bone marrow. They then leave and go to the lymphoid organs and peripheral tissues, where they are exposed to antigens.

On first exposure to a new antigen, a clone of B-cells becomes activated. Some activated B-cells differentiated into short lived plasma cells that release antigen specific IgM through a T-cell independent process.

However, most activated B cells migrate to lymphoid follicles located in the lymph node cortex where they form germinal centers that are the site of B-cell proliferation during the immune response. A portion of these activated B cell form long lived memory cells that remain dormant in the lymph node until the next encounter with the same antigen, but the majority transform into antibody secretin plasma cells.

Isotope switching (from IgM to other types of immunoglobulins) also occur in the germinal centers later in the primary response, providing activated B-cells the ability to produce antigen-specific antibodies of differing isotopes.

Heavy chain constant region are isotope-specific and distinguish the 5 isotopes (IgM, G, A, E and D), while the variable regions are antigen specific.

Light chains are antigen-specific and do not determine isotope. Isotope switching first requires interaction of the CD40 receptors on activated B-cells with the CD40 ligand (CD154) expressed by activated T-cells. Afterward, isotope switching can occur through genetic rearrangement of the heavy chain constant regions. This process is regulated by T-cell cytokines such as IL-2, 4, 5, 6 and IFN-y. After the primary immune response, subsequent encounter with the same antigen generate a predominantly IgG response (or IgA in the case of mucosal response).

Negative selection and tolerance refers to the deletion of T-cell clones that strongly bind to self-MHC antigens such that an immunologic unresponsiveness to self antigen is selected. This process occurs in the fetal thymus. Peripheral tolerance develops by means of T-cell anergy, which is the functional inactivation of T-cells that a re reactive to self antigens.

VDJ = heavy chains. VJ = light chain occur via DNA rearrangement. After undergoing Ig gene rearrangement, each B-cell makes antibodies of a single specificity. an enormous variety of different Ig molecules can potentially be produced through rearrangement. Recombination of these regions occurs during B-cell maturation within the bone marrow. Later on, during the primary immune response, affinity maturation occurs in the germinal centers through the process of somatic hypermutation.

The primary immune response to a new antigen initially results in plasma cells that only produce IgM. Isotope switching later occurs in the germinal center of lymphondes and requires interaction of the CD40 receptor on B cells with the CD154 expressed by activated T-cells. IgG is the main serum Ig of the secondary response.
Ammonia is generated from metabolism of amino acids and is converted to urea by the urea cycle.

The combination of bicarb, ammonia and ATP is catalyzed by carbamoyl phosphate synthetase (rate limiting enzyme in the urea cycle).

Carbamoyl phosphate combines with ornithine to form citrulline in a reaction catalyzed by ornithine transcarbamylase.

Citrulline enters the cytosol and is converted to arginosuccinate, and then arginine. The conversion of arginine to ornithine by arginase completes the urea cycle by releasing a urea molecule.

N-acteylglutamate serves a regulator of the urea cycle through citation of carbamoyl phosphate syntehatase I.

This patient has OTC def, the most common urea cycle disorder. Def results in excess carbamoyl phosphate, which stimulates pyrimidine synthesis. As an intermediate product in the this pathway, orotic acid accumulates and results in increased urinary orotic acid.

Patients also have hyper ammonia d/t impaired ammonia excretion, chi is a metabolic emergency. Ammonia is neurotoxic and causes episodes of vomiting and confusion/coma. Tachypnea also occur d/t cerebral edema from ammonia buildup, resulting in central hyperventilation and respiratory alkalosis. Metabolic decompensation is often triggered by illness (eg, viral upper resp. infection, acute otitis media), fasting or increased protein intake.

a/c: defects in carbamoyl phosphate synthetase I and N-acetylglutamate synthetase also result in hyperammonemia, levels of carbamoyl phosphate are low and orotic acid is not elevated in the urine.

Hypoxanthine-guanine phosphoribosyltransferase def (Lesch-Nyhan syndrome) results in hyperricemia because purines cannot be salvaged from degraded DNA. Rate kidney stones and self mutilation are the classic clinical manifestations.

Uridine monophosphate synthetase (UMPS) is part of the pyrimidine synthesis pathway. UMPS def leads to orotic acid buildup (similar to OTC def) but not hyperammonemia. Characteristics influence megaloblastic anemia and delayed growth.
Patient has scarlet fever, caused by Group A step that produced pyrogenic exotoxins. Scarlet fever is most often associated with step pharyngitis, which begins acutely after an incubation period of 1-5 days. Clinical symptoms are:
-fever, malaise, abdominal pain and sore throat
-pharynx is typically erythematous, swollen and possibly covered with gray white exudate
-tongue have inflamed red papillae with an appearance similar to that of a red strawberry.

After 1-2 days, a rash appears on the neck, armpit an groin that subsequently generalized the rest of the body. Rash begins as scarlet spots or blotches, giving a boiled lobster appearance. As the rash progresses and becomes more widespread, it begins to resemble a sunburn with goose pimples ("sandpaper-like" rash). The cheeks commonly appear flushed, giving the area around the mouth a pale appearance in comparison (circumoral pallor). Toward the end of the first week, desquamation begins and is most pronounced in the armpits, groin and tips of the fingers ad toes.

As with any strep upper resp. infection, scarlet fever can predispose to acute rheumatic fever and glomerulonephritis. Treatment with penicillin V can prevent development of rheumatic fever, although its role in preventing glomerulonephritis is uncertain.

Aplastic anemia can complicate parvovirus B19 infection in patients with sickle cell anemia or immunocompromised.

Coronary artery aneurysm its the most dreaded complication of Kawasaki disease, which can present with fever, strawberry tongue, and a rash. However, tonsillar exudates are typical of bacterial disease, and this patient lack of other manifestation of Kawasaki disease (eg, bilateral conjunctival injection)

Encephalitis can be cause by measles (acutely), acute disseminated encephalomyelitis (during recovery), and subacute sclerosing panencephalitis (years later).

Orchitis is one of the most common complicates of mumps. Mumps characteristically presents with fever malaise, headaches, and myalgia followed by the development of parotitis within 48 hours.
Patient is under vaccinated and has septic arthritis caused by H. influenzae B (Hib), secondary to hematogenous dissemination following his recent episode of otitis media.

H influenza is a small pleomorphic, gram neg coccobacillus that is part of the normal flora of the URT.

It is blood loving organism that requires both X factor (hematin) and V factor (NAD) to grow. Because these factors are found within erythrocytes, optimal concentrations are present only in lysed blood agar (chocolate agar).

H. influenza can be either encapsulated or unencapsulated (zontypble) w/ encapsulated strains divided into 6 serotypes (a-f) based on the poly saccharide structure of the capsule. Type B capsular material consists of a ribose and ribitol phosphate polymer called polyribitol phosphate (PRP).

It is the only serotype that contains pentose monosaccharides rather than hexose sugars as the carbohydrate component of the capsule. The PRP capsule prevents phagocytosis and intracellular killing of neutrophils, allowing the organism to invade the vasculature, persist in the bloodstream, and spread hematogenously to distant sites. Antibodies against the type B capsule provide immunity by promoting opsonization and complement fixation.

H. influenza type B used to be a major cause of severe, invasive infections including epiglottis, meningitis and bacteremia. However, since the advent of the conjugate Hib vaccine, most H influenzaeinfections are do non-type B strains that cause noninvasive disease such as sinusitis, bronchitis, otitis media and conjunctivitis.

B. there are no strains of H influenza known to produce an exotoxin of any kind.

FImbriae are not present in this bacteria. These are proteinaceous projections from bacterial cells mediate attachment to target issues during the process of establishing infection. This mehod of attachment to tart tissues during the process of establishing infection. This method of attachment is used by N. gonorrhoeae, N. meningititidis and E. coli.

Hemolysis are not secreted by H influenza

Hyaluronidase a enzyme used by bacteria to digest extracellular ground substance and enhance their ability to spread. Hyalurondiase is not produced by H influenza. It is produced by staphylococci, group A strep, and Clostridium difficile most notably.
Vasospasm occurs in 20-30% of patients with subarachnoid hemorrhage (SAH) caused by ruptured intracerebral aneurysm such as a berry aneurysm. Symptoms of cerebral vasospasm include:
-altered mental status (his confusion)
-focal neurological deficits (this patient's weakness of right arm and leg)

Etiology: substances generated by the degradation of subarachnoid blood clots.

Symptoms manifest no earlier than three days after the hemorrhage, and most frequently occur seven to eight days following SAH.

DOC: Calcium channel blocker (eg, Nimodipine). This drug is identified as a cerebral selective drug. MOA is unknown. Might be vasodilation or neural protectant.

Bet-adrenergic blocker (eg, metoprolol) would decrease HR and PB. No role in treatment of SAH or intrecerebral vasospasm.

Central sympatholytics (eg, methyldopa and clonidine) stem alpha-2A receptors to decrease generalized sympathetic outflow. This would decrease blood pressure in addition to decreasing both alpha and beta sympathetic stimulation. They do not play a role in vasospasm following SAH therapy, however it is useful in intracranial hemorrhages such as those caused by HTN.

ACE inhibitors (captopril and enalapril) decrease BP and cardiac hypertrophy by inhibiting the cover sion of Angiotensin I to Angiotensin II. They are useful in HTN, prevention of diabetic nephropathy, and in HF with systolic dysfunction. Major side effects are cough and angioedema.

Thiazide diuretics are presently the first line of treatment for essential HTN in the outpatient setting.

Osmotic diuretics such as mannitol are part of the treatment for increased intracranial pressure, IN SAH, vasospasm, not ICP, is the main problem.

Nitrates such as nitroglycerin and isosorbide mononitrate are used as vasodilators primarily for the treatmenet of anti pectoris.
This patient is experiencing pleuritic chest pain d/t acute lower lobe bacterial pneumonia.

Pleuritic chest pain is characterized by sharp, localized, often severe pain that is exacerbated by coughing, breathing or changing position. It can result from any condition that causes inflammation of the pleura (eg, infection, pulmonary embolism, uremia). The pleura is dived into the segments as follows:
-Visceral pleura: The visceral (pulmonary) pleura covers all surfaces of the legs, including the surfaces within the pulmonary fissures. The visceral plea doesn't carry pain fibers.
-Parietal pleura: Forms the outer boundary of the pleural space and can be subdivided as follows:
a. costal pleura: covers the thoracic wall, including the ribs, sternum, intercostall spaces, costal cartilages and sides of the thoracic vertebrae.
b. mediastinal pleura: covers the mediastinum
c. diaphragmatic pleura: covers the surface of the diaphragm located within the thoracic cavity
d. cervical pleura: extends with the apices of the lung into the neck.

The phrenic nerve, which is derived from the C3-C5 nerve roots, delivers motor innervation to the diaphragm and carries fibers from the diaphragmatic and mediastinal pleura. Irritation of the pleura in either area will cause a sharp pain worsened by inspiration that will be refereed to the C3-C5 distribution at the bas e of the neck and over the shoulder, Sensory innervation of the remainder of the parietal pleura are accomplish by the intercostal nerves and typically felt closer to the source of the pain.

The spinal accessory nerve is motor innervation of the SCM and traps.

The long thoracic nerve is the winged scapula causing lesion by the serrates anterior

The vague nerve is parasympathetic to the viscera of the best and the foregot.
Cholesteatomas are collections of squamous cell debris that form a round, pearly mass behind the tympanic membrane in the middle ear.

They can occur congenitally or may develop in adults as either an acquired primary lesion or secondary to infection, trauma, or surgery of the middle ear.

Primary cholesteatomas are a result of chronic negative pressure in the middle ear causing retraction pockets in the tympanic membrane that become cystic; as the squamous cell debris accumulates, a cholesteatoma is formed.

Secondary cholesteatomas occur after squamous epithelium migrates to or is implanted in the middle ear ("skin in the wrong place").

Cholesteatomas most commonly cause painless otrrhea. They also can produce lytic enzyme and are often discovered when they erode through the auditory ossicles, causing conductive hearing loss. If a mass grows sufficiently large, it can erode into the vestibular apparatus or facial nerve, causing vertigo or facial palsies.

Cholesterol granulomas can form in the middle ear after hemorrhage but are much less common than cholesteatomas. They appear as bluish-black gelatinous material behind the tympanic membrane. Despite what the name implies, cholesteatomas do not contain any lipid or cholesterol components.

A facial nerve neuroma can grow in the middle ear as the facial nerve courses through this territory. However, it would present with unilateral facial paralysis.

Squamous cell carcinoma is the most common malignant tumor of the ar canal. It typically appears as ulcerated plaque or nodule. The most common symptom is local or regional pain.

Granulomatous disease of the ear can occur but is uncommon and usually develops in conjunction with a systemic disease, such as sarcoidosis, granulomatosis with polyangiitis, or Langerhans cell histiocytosis.
Chediak-higashi syndrome is an AR inherited disease that can affect the CNS, skin color and immune system.

Neurologic defects associated with this condition include: nystagmus, peripheral and cranial neuropathies.

Immunodeficiency in this syndrome results from a defect in neutrophil phagosome lysosome fusion. This causes abnormal giant lysosomal inclusion that are visible on light microscopy of a peripheral blood smear. The immunodeficiency leads to recurrent pyogenic infections most commonly caused by Staph and Strep.

Abnormal melanin storage in melanocytes causes partial oculocutaneous albinism.

a. neutrophils in patients with CGD are unable to kill catalase-producing organisms, d/t the deficiency of NADPH oxidase.

Phenylketonuria is caused by def of phenylalanine hydroxyls. Impaired conversion of phenylalanine to tyrosine leads to CNS abnormalities. The patients have features of albinism and musty body odor.

DiGeroge syndrome is an immunodeficiency resulting from a delation on chromosome 22 leading to maldevelopment of the 3rd and 4th pharyngeal pouches. It is characterized by thyme and parathyroid phypoplasia, abnormal facies and cardiac defects. Thyme hypoplasia causes T cell defect that manifests with recurrent viral, fungal and protozoal infections.

Wiskott-Aldrich syndrome is an X-lniked disorder characterized by immunodeficiency, eczema and thrombocytopenia. The immunodeficiency present in Wiskott-Aldrich syndrome is a combined B-lymphocyte and T-lymphocyte disorder

Albinism is a genodermatosis that results from defects in the production of melanin by melanocytes. In this disease melanocytes are normal in number location; it is the production of the pigment itself that is defective. Complete albinisms is manifest by white hair, blue eyes and pink or white skin and results from a complete absence of tyrosinase.
Benzo work at the GABAa, is the main NTs in the CNS and synthesized from glutamate using glutamate decarboxylase.

GABAa receptor complex consists of 5 subunits and central chloride ion channel, with different binding sites for GABA and various drugs (eg, benzodiazepines, barbiturates). Bentos act by biding to the bento binding site, which allosterically modulates the binding of GABA, resulting in an increased frequency of chloride ion channel opening.

The influx of Cl ions into the neurons causes neuronal hyperpolarization and inhibitor of the action potential.

a. GABAb receptors mediate their actions using G proteins. The skeletal muscle relaxant baclofen is an example of a drug that works as a GABAb receptor agonist. Benz work at the GABA receptor.

Benzos do not alter GABA metabolism. Certain anti-epileptic medications including valproic acid and vigabatrin, function to reduce gaba catabolism.

Benzodiazepines do not function through direct activation of GABAa receptor. Instead, they work as positive allosteric modulators that promote an increased frequency of channel opening in response to GABA stimulation.

Benzodiazepines do not function through the blockage of GABAa receptor lumen. Examples of drugs that directly block the lumen of ion channels include amiloride (which affects epithelial sodium channels in the distal portions of the nephron) and verapamil (a calcium channel blocker).

Prolonged benzos usage has been shown to cause down regulation of GABAa receptors and may be one of the mechanisms by which benzodiazepine tolerance develops.
HIV is an RNA virus that coverts RNA genome into cDNA with the help of a viral RT. Once in cDNA, the viral genome can be incorporated into the host cell genome by viral integrase. The HIV cDNA genome is referred to as a provirus once it has been integrated into the host cell genome.

Zidovudine (AZT) is a nucleoside RTase inhibitor used to treat HIV infection. It competitively binds to RTase and is incorporated into the viral genome as a thymidine analog. However, AZT has an aside group in place of the Oh group normally found on the 3' end of thymidine. Because of a free 3' hydroxyl group is required for new nucleotides to be added to replicating DNA, the aside group on AZT prevents DNA chain elongation.

a. inhibition of nucleoside phosphorylation is not an effect of AZT. In fact, nucleoside reverse transcriptase inhibitors (including AZT) must be phosphorylated within the host cell to form the functional triphosphate moiety. Non-nucleoside reverse transcriptase inhibitors can allosterically bind to and inactivate reverse transcriptase without being phosphorylated.

b. the enzyme thymidylate synthase catalyzes the conversion of deoxyuridine monophosphate (dUMP) to deoxythymidine monophosphate (dTMP). N5, N10-methylene THF is methyl donor in this reaction and is converted to DHF in the process. THF is then regenerated from DHF by dihydrofolate reductase. Methotrexate is a chemotherapeutic agent the inhibits DNA synthesis by inhibiting DHF reductase (i.e., folate dependent uracil methylation).

d. in dsDNA, A goes with T and G goes C. These bases bind via H-bond. Some chemotherapeutic agents, like the anthracyclines daunorubicin and doxorubicin, intercalate between the bases, causing defective base pairing and splitting of the DNA strands. Transcription and replication failure and mutagenesis ultimately result.

e. integration of viral DNA into the host genome is mediated by integrate, a retroviral enzyme that is inhibited by raltegravir an integrate inhibitor.
Pentad of TTP-HUS (thrombocytopenia thrombotic purpura-hemolytic uremic syndrome):
1. fever
2. neurologic symptoms
3. renal failure
4. anemia
5. thrombocytopenia

These share common clinical pathologic features including:
-platelet activation in arterioles and capillaries
-diffuse microvascular thrombosis (most commonly affecting the brain, kidneys and heart)
-microangiopathic hemolytic anemia with schistocytes

Unlike DIC, in which coagulate cascade activation leads to prolongation in coagulation studies (PT and activatedPTT), TTP is almost always characterized by normal PT and PTT.

a. focal segmental glomerulosclerosis, including its collapsing variant, commonly manifests as heavy proteinuria.

b. crescentic or rapidly progressive glomerulonephritis typically presents with macroscopic hematuria, HTN and progressive renal failure. It is classified as anti-glomerular basement membrane (with hemoptysis in Goodpasture syndrome), immune complex mediated (eg, systemic lupus erythematous), or pace-immune (with pulmonary, upper respiratory and kidney involvement in granulomatosis with polyangiitis).

c. PSGN is typically in childhood that can follow strep pharyngitis and lead to increased coke colored urine output and periorbital edema

d. hence-schonlein purport is typical a childhood disease with nonthrombocytopenic palpable purport and arthritis; IgA nephropathy commonly presents with recurrent hematuria and low grade proteinuria following an upper respiratory tract infection. Both diseases have similar histopathologic findings with IgA deposition in the mesangium.

Acute tubular necrosis d/t ischemia (eg, prolonged hypotension), nephrotoxins (eg, antibiotics), or pigment deposition (eg, myoglobinuria) generally presents with rising creatinine and muddy brown granular casts on urinalysis.
Patient has CF because:
-recurrent pneumonia
-digital clubbing
-bilateral absence of vas deference

CF patients have serious lung and pancreatic complications depending on the severity of the mutation. Regardless of lung and pancreas function, virtually all adult men with CF have azoospermia and infertility. Although spermatogenesis is usually normal, almost all males with CF are unable to secrete semen d/t congenital bilateral absence of vas deferens. CFTR mutations are likely responsible for abnormal development of Wolffian structures, resulting in vagal genesis and defective sperm transport.

A diagnosis of CF can be based on elevated sweat chloride levels. If the sweat chloride test is equivocal, measurement of nasal transepithelial potential difference and genetic testing for CFTR mutations should be performed to confirm the diagnosis.

b. although primary ciliary dyskinesia (eg, Kartagener syndrome) can cause recurrent pulmonary infections and digital clubbing, infertility in Kartagener syndrome is usually d/t immotile spermatozoa. Abnormal nasociliary motility is a nonspecific finding that is seen most commonly in patients with primary ciliary dyskinesesia and in some CF patients (from abnormally thick mucus).

Low serum alpha-1 antitrypsin is associated with AAT def and not with CF. AAT def is typically associated with panacinar emphysema and chronic liver disease. Infertility is not seen in these patients

d/f: FSH, LH and testosterone levels are suavely normal in patients with CF. A low testosterone level in setting of decreased FSH and LH is seen in hypogonadotropic hypogonadism (eg, Kallmann syndrome)

e. primary humoral deficiencies usually manifest as recurrent upper and lower respiratory tract infections d/t impaired antibody production. However, most patients with selective IgA def are asymptomatic.
Time after MI and predominant light microscopic changes:
0-4 hours: no visible changes
4-12: wavy fibers with narrow, elongated myocytes
12-24: myocyte hypereosinophilia with pyknotic (shrunken) nuclei
1-3ds: coagulation necrosis (loss of nuclei and striations) and prominent neutrophilic infiltrate.
3-7ds: disintegration of dead neutrophils and myofibers. Macrophage infiltration at border areas
7-10ds: robust phagocytosis of dead cells by macrophages. Beginning formation of granulation tissue at margins
10-14ds: well developed tissue with neovascularization
2weeks-2months: progressive collagen deposition and scar formation

Sudden cardiac death 12 days after an MI is most likely d/t ventricular arrhythmias originating from the infarcted myocardium.

The microscopic diagnosis of MI depends on the presence of necrotic myocardium, with areas of acute inflammation and necrosis separated from viable myocardium. After the initial event, several characteristic microscopic changes occur in the infarcted zone in a specific temporal sequence with some overlap in different stages. During the second week after MI, the damaged tissue is replaced by granulation tissue and neovascularization is found in the infarct zone.

a. increased collagen deposition and decreased cellularity in the zone of infarcted myocardium generally become evident beginning at 2 weeks post infarction. Fibrosis continues during weeks 2-8, resulting in a dense collagenous scar at about 2 months post infarction.

b. prominent interstitial neutrophil infiltration is found t the border zone of infarcted myocardium 1-3 days after MI onset. This acute inflammatory infiltrate becomes increasingly prominent over the next few days after receding around days 5-7.

Edema and wavy myocyte fibers with normal appearing nuclei can be detected in infarcted myocardium by light microscopy approximately 4-12 hours following MI.

Cytoplasmic hypereosinophilia is a characteristic finding of early MI and occurs 12-24 hours after onset.

Macrophage phagocytosis of infarct myocardium begins at about 3 days post infarction. The macrophages become laden with degenerating myoglobin pigment and hemosiderin (not foam cells, which are indicative of extensive lipid engulfment). By day 10, the accumulated macrophages begin to be replaced by granulation tissue.

Infarcted myocardium usually appears normal under light microscopy up to 4 hours after the onset of MI.
Patient's valve is d/t dystrophic calcification affecting an aging aortic valve. Dystrophic calcification is considered a hallmark of cell injury an death, occurring in all types of necrosis (eg, coagulative, fat, caseous, liquefactive) in the setting of normal calcium levels.

Grossly, dystrophic calcium deposits are seen as fine, gritty, white granules or clumps. On hematoxylin and eosin staining, these deposits typically appear as dark-purple, sharp-edged aggregates. Deposits that develop lamellate outer layers are described as psammoma bodies.

Dystrophic calcification in aged (or damaged) cardiac valves is thought to be the result of endothelial and fibroblast death secondary to chronic hemodynamic stress ( can be accentuated by valvular abnormalities) or atherosclerotic inflammation. Subsequent release of cellular degradation products into the valvular interstitial then promotes calcification and thickening of the valve leaflets and annulus. These changes are often benign in elderly adults (aortic sclerosis); however, overtime, progressive valvular stiffening can lead to outflow obstruction (calcific aortic stenosis).

b. extracellular amyloid deposition occurs in patients with amyloidosis. Amyloidosis can cause restrictive cardiomyopathy and HF, but it is not directly associated with calcification of the aortic valve.

c. hypercalcemia is associated with metastatic calcification affecting normal tissues and organs. IN this process, calcium deposition typically occurs in more alkaline tissues involved in acid excretion, such as kidneys, lungs, systemic arteries and gastric mucosa.

d. Intracellular hemosiderin accumulations common in patients who have hemolytic anemia or who undergo frequent blood transfusions. It is not directly associated with calcification of the aortic valve.

Pathologic cell hypertrophy of left ventricular cardiomyocytes (i.e., left ventricular hypertrophy) can occur as the result of severe aortic stenosis.
S. aureus can cause right sided endocarditis in IV drug users. These bacteria settles on the valve leaflets d/t blood flow turbulence at these sites. They can cause perforation in the heart valves, rupture the chord tendineae, and send septic emboli to the lung (with right heart endocarditis) or to the brain and systemic circulation (with left heart endocarditis). This patient with fever is an IVDU with holosystolic murmur that increases inspiration (likely tricuspid regurgitation) and multiple lung opacities (likely septic emboli).

a. candida endocarditis is rare and typically a severe manifestation of candidemia, with septic emboli to the brain, extremities and GIT tracts. Patients who are IVDUs, have prosthetic heart valves, or have indwelling lines are at increased risk of infection.

b. cultured negative endocarditis d/t Bartonella, Coxiella, Mycoplasma, Histoplasma Chlamydia or HACEK (Haemophilius, actinobacillus, cardibacteriu, eikenella, and kingella), among others, would be much less likely than S. aureus endocarditis

c/d/e/h: S. pneumonia and K. pneumonia typically cause pneumonia; Klebsiella can also lead to UTIs. Nocardiosis typically affects the lung (cavitary lesions), brain (brain abscess), or skin and is seen mostly in immunocompromised patients. Peptostreptococcus causes anaerobic infections (dental, cutaneous, intraabdominal).

g. S. bovis now known as S. galolyticus is part of the normal flora of the colon and bacteremia or endocarditis caused by these guys is associated with colon cancer (happens in about 25% of the cases)

I. S. viridian is the most common etiologic agent in subacute bacterial endocarditis following dental work. SBE occurs most frequently in patients with preexisting valvular abnormality (eg, rheumatic heart disease, congenital heart malformations). The presentation is typically sub acute (over weeks rather than days).
Train of four (TOF) stimulation is used during anesthesia to assess the degree of paralysis induced by NMJ blocking agent. A peripheral nerve is stimulated 4 times in quick succession and the muscular response is recorded. the heigh of each bar represent the strength of each with; higher bars indicate the activation of increasing number of individual muscle fibers (myocytes).

When a non depolarizing NMJ blocker (eg, vecuronium) is administered, competitive inhibition of postsynaptic ACh receptors at the motor endplate prevents some of these fibers from activating, decreasing the strength of the twitch. TOF stimulation shows a progressive reduction in each of the 4 responses (fading pattern) as a result of less acetylcholine being released with each subsequent impulse (d/t the additional affect of presynaptic acetylcholine receptor blockade)

In contrast, depolarizing blockers (eg, succinylcholine) initially function by preventing depolarization of the motor endplate and show equal reduction of all 4 twitches during TOF stimulation (phase 1 blockade). The responses remain equal because the presynaptic ACh receptor stimulation helps to mobilize presynaptic ACh vesicles for release. Persistent exposure to succinylcholine response in eventual transition to phase II blockade as the ACh receptors become desensitized and inactivated (i.e., functionally similar to non depolarizing blockade).

Succinylcholine is commonly administered for reaped-sequence intubation d/t its rapid onset (<1 minute). The duration of action is determined by its metabolism by plasma cholinesterase and is typically <10 mins. However, some patients are homozygous for an atypical plasma cholinesterase, which breaks down succinylcholine more slowly. In these patients, the paralysis can last four hours and they must be painted on mechanical ventilation until spontaneous respiration resumes.

a. Dantrolene relaxes skeletal muscle by reducing the release of Ca from the ssarcoplasmsc reticulum. Dnatrolene is used to treat malignant hyperthermia and neuroleptic malignant syndrome. It is not routinely used as an NMJ blocking agent.

b. bentos are effective for station, but they have no direct action at the NMJ and do not provide sufficient muscle paralysis to facilitate intubation.

c/e. Pancuronium and tubocurarine are non depolarizing NMJ blockers. Unlike depolarizing nmj drugs, these agents do not function in distinct phases and their TOF responses always display a fading pattern. Neostigmine administration reverses non depolarizing NMJ blockade.
This patient most likely have a patent ductus arterioles (PDA). The ducts arterioles is an embryonic derivative of the 6th aortic arch that allow sfetal blood to pass directly from the pulmonary artery to the proximal descending aorta (bypassing the pulmonary circulation). This vessels usually closes shortly after birth secondary to decreased prostaglandin E2 (PGE2) levels and increased oxygen concentration.

potency of the ducts after birth results in a left-right shunt that can cause left ventricler volume overload and symptoms of heart failure (eg failure to thrive, respiratory distress).

PE will show continuous machinery like murmur and palpable thrill over the left infraclavicular region d/t to turbulent blood flow through the PDA.

Pharmacologic closure of PDA can be achieved by PGE2 synthesis inhibitor (eg, indomethacin) in premature infants. However, older patients usually require surgical ligation or percutaneous PDA occlusion.

Bulbus cordis forms the beginning of the ventricular outflow tract in the embryonic heart. This structure forms the smooth portion of the left and right ventricles adjacent to the aorta and pulmonary artery, respectively.

The primitive atrium receives blood from the sinus venous in the embryonic heart and transmits it to the primitive ventricle. The primitive atrium forms the rough portions of the left and right atria.

The sinus venous is an embryologic structure within the heart that receives blood from the venue cave. IN adults, this structure forms the smooth portion of the right atrium, known as the sinus venarum.

1st aortic arch: part of maxillary artery
2nd aortic arch: hyoid artery and stapedial artery
3rd aortic arch: common carotid artery, proximal internal carotid artery
4th aortic arch: on left (aortic arch) on right (proximal right subclavian artery)
6th: proximal pulmonary arteries. on left (ductus arterioles).
The following disorders and their CVS developmental defects

Down = endocardial cushion defects (eg, osmium premium atrial septal defects, regurgitant atrioventricular valves)

DiGeorge = Tetralogy of Fallot and Interrupted aortic arch

Friedrich ataxia = hypertrophic cardiomyopathy

Kartagener syndrome = situs inverses

Marfan = cystic medial necroses (eg, aortic dissection, aneurysm). Mitral valve prolapse

Tuberous sclerosis = valvular obstruction d/t cardiac rhabdomyomas

turner = aortic coarctation and bicuspid aortic valve.

This patient most likely has congenital coarctation of the aorta, which typically affects the region of the aorta just distal to the left subclavian artery. Although traditionally classified into pre ductal and post ductal types, the signs and symptoms of aortic coarctation depend more on the age of presentation, which varies according to the severity of the stenosis.

Severe coarctation usually presents in infancy with differentials cyanosis affecting the lower extremities as long as the ductus arterioles remain patent. On ductal closure, these neonates can develop signs of heart failure and shock. More moderate can develop signs of heart failure and shock.

More moderate stenosis often presents in childhood or adolescence with symptoms of lower extremity claudication (eg, pain and cramping its exercise), BP discrepancy between he upper and lower extremities, and delayed or diminished femoral pulses Continuous murmur and pulsatile intercostal collateral scan also develop secondary to restricted circulation.

Congenital aortic coarctation occurs in up to 10% of patients with Turner syndrome (45 XO)

DiGeorge is associate with interrupted aortic arch, a mor extreme anomaly than aortic coarctation in which the aortic arch is atretic or a segment of the arch is absent. Affected patients have poor lower extremity pulses, but respiratory distress, variable cyanosis and signs of CHF will also develop during the first days of life.

Down is associated with endocardial cushion defects that result in osmium premium atrial septal defects and regurgitant atrioventricular valves.

Friedrich ataxia is marked by spinocerebellar degeneration with predominantly spinal ataxia. This can produce difficulty walking, but femoral pulses are not affected. This AR condition is associated with hypertrophic cardiomyopathy.

Kartagener syndrome, cilia are immotile d/t a micro tubular dyne arm defect. Infertility, recurrent sinusitis, and cronchiectasiss occur as a result. This syndrome is associated with situs inversus.

Marfan syndrome is associated with cystic medial necrosis of the aorta, which may result in aortic dissection and aortic valve incompetence. Mitral valve prolapse can also occur d/t the same degenerative process.

Tuberous sclerosis is an AD syndrome characterized by cutaneous angiofibromas (adenoma sebaceous), seizures, and mental retardation. Pathological lions include CNBS hamartomas and benign neoplasms, renal and other visceral cysts, and cardiac rhabdomyomas.
Patient has a history of paroxysmal atrial fibrillation and ischemic stroke off anticoagulation is likely suffering from a recurrent embolic stroke complicated by seizure. Stroke is one of the the most common causes of seizure, which occurs d/t to the release of excitotoxic neurotransmitters in the ischemic brain region.

The clinical manifestations of partial (focal) seizure depend on the anatomic brain region in which the seizure activity occurs. This patient's intimal right arm numbness/paresthesias were likely caused by a simple partial seizure originating in the left primary somatosensory cortex (post central gyrus). This brian region is responsible for processing all somatic sensory modaiteis (eg, touch, temp/pain, vibration/proprioception) of the contralateral body.

The patient subsequently develop right sided convulsion d/t spread of the seizure along the lateral brain convexity to the primary motor strip (pre central gyrus). The seizure then became seoncdarily generalized to involve both cerebral hemispheres, causing tonic clonic convulsions.

The frontal eye field is the region of the cerebral cortex that controls horizontal eye movement. Activation of the left frontal eye field during seizure would cause the eyes to deviate horizontally to the right. After the seizure, the patient's eyes may temporarily deviated to the left d/t postictal neuroinhibztion.

Broca is located in the posterior inferior frontal gyrus of the dominant (usually left) hemisphere and is responsible for controlling expressive speech/language. A seizure originating from Broca area would likely result in octal speech and vocalizations.

Sensory speech (Wernicke) area is located in the posterior superior temporal gyrus of the dominant hemisphere and is responsible for language comprehension. A seizure originating from the temporal lobe of the cerebral cortex would likely result in auditory hallucinations.

The primary visual cortex in the occipital lobe is responsible for processing visual information from the contralateral homonymous visual fields. A seizure originating from the left primary visual cortex would likely result in visual hallucinations affecting the right homonymous visual fields.
The transition form point 1 to point 2 on the graph shows the loading of O2 into partially deoxygenated hemoglobin.

At very low pO2, the Hb molecule is fully deoxygenated and binding of the first O2 is relatively difficult ( as indicated by the early flatness of the curve).

As pO2 increases, O2 binds to 1 of the 4 heme moieties on the hemoglobin molecule, causing the oxygen binding affinity of the other Hb subunits to increase (steepening of the curve). Additional O2 molecules bind as the PO2 increases. As Hb become saturated with oxygen, very little additional binding occurs, and the curve levels out.

In the peripheral tissue, the release of O2 from Hb is enhanced by increased pCO2 and the resultant decrease in pH (Bohr effect). This effect occurs d/t the histidine side chains found on the alpha and beta hemoglobin subunits. As the tissue release CO2, the majority is converted by erythrocyte carbonic anhydrase to bicarb and Hydrogen ion. While bicarb is shifted out of the erythrocytes in exchange for Cl ions found in the plasma, the hydrogen ions remain within the erythrocytes. The hydrogen ions are buffered by the histidine residues on Hb and in the process, help stabilize the deoxygenated form of Hb and decrease its affinity to oxygen.

When deoxygenated blood enters the alveolar capillaries of the lung, the rise of pO2 increases the binding of O2 to Hb and causes the release of H and CO2 from Hb (Haldane effect). As bicarb shifts back into the erythrocytes in exchange for Cl, carbonic anhydrase converts H and bicarb back into the CO2 and water. The CO2 is then excreted through the lungs.

Erythrocytes contain a higher concentration of chloride ions in venous blood than in arterial blood d/t the chloride shift. However, neither Cl nor phosphate is transported in Hb.

Heme is NOT released from Hb in the context of oxygen loading or dissociation. However, it is released during normal destruction of aged RBCs in the spleen.

In the lungs, higher pH, lower temp and decreased concentration of 2,3-DPG shift the oxygen dissociation curve to the left, increasing the affinity of Hb to oxygen.
HPV (1-4): skin warts (verruca vulgarism)
HPV (6, 11): genital warts (condylomata acuminatum)
HPV (16,18): cervical, vaginal, vulvar and anal neoplasia

SCC most common type of cervical cancer, arises from the squamocolumnar junction of the endocervix. CIN is carcinoma in situ and precedes SCC. CIN represents a wide spectrum of dysplastic changes of the cervical epithelium that occur under the influence of HPV infection. CIN is usually transient in young healthy women. However, patients with persistent HPV infection or untreated high grade CIN are at risk of invasive cervical cancer.

DNA from high risk strains (i.e., 16, 18 and 31_ is integrated into the human cell genome, leading to over expression of viral oncogene E6 and E7.
-E6 binds to protein p53 and increases its degradation
-E7 binds to RB1 and displaces transcript factors normally bound by pRB, the tumor suppressor protein product of RB

Risk factors are related to risk of acquiring HPV infection:
-skin to skin contact
-sexual contact
-multiple sex partners
-unprotective sex (lack of barrier contraceptive)

BFG:null parity, early menarche and obesity increase the risk endometrial cancer. These factors are associated with increased estrogen stimulation of the endometrium.

C: FH of breast cancer is a risk factor for developing breast malignancy. Breast cancer is not associated with cervical cancer, as the latter is usually d/t a persistent, oncogenic HPV infection.

D: plants wart is usually caused by HPV 1-4; these strains are not typically carcinogenic and are not associated with cervical dysplasia and invasive cervical cancer.

H. douching is a risk factor for arterial vaginosis by disturbing the vaginal ecosystem, resulting in overgrowth of Gardnereall vaginalis.
This guy has nephrotic syndrome characterized by edema and marked proteinuria (over 3.5 g/day). With the underlying malignancy, this patient most likely have membranous glomerulopathy. Up 85% of cases are idiopathic. It is also the most common causes of nephrotic syndrome in adults. The remainder occur secondary to the following things:
1. systemic disease: DM, said tumors (lung/colon), and immunologic disorder s(such as SLE)
2. Certain drugs - gold, penicillamine and NSAIDs
3. Infections - hep B, hep C, malaria and syphilis.

His biopsy shows uniform, diffuse thickening of the glomerular capillary wall on light microscopy without an increase in cellularity, are consistent with a diagnosis of membranous glomerulopathy.

EM will reveal thickening caused by irregular, dense deposits lead between the basement membrane and the epithelial cells. These protrusions resemble "spikes" when stained with silver.

IF microscopy reveals that these granular deposits contain IgG and C3

d. membranoproliferazive glomerulonephritis, shows large hyperceullalr glomeruli (hence, "proliferative"). In membranous glemerulopathy, diffuse thickening of the capillary wall is seen without the increase of cellularity.

Berger is painless hematuria in children and young adults a few days after an upper respiratory infection. IgA deposits mesangium are found in IF.

Minimal change disease is the most common cause of nephrotic syndrome in children. NO abnormalities are found on light or IF microscopy. However, effacement of the foot processes of podocytes are seen on EM.
Aldosterone is a steroid hormone. In HF, aldosterone is produced in the myocardium and acts locally, leading to fibrosis and myocardial hypertrophy. The resulting cardiac remodeling worsens left ventricular dysfunction in HF patients.

Spironolactone is an aldosterone antagonist with mild diuretics effects. By competitively inhibiting aldosterone, spironolactone effectively blocks aldosterone's detrimental cardiac effects.

It has a potassium-sparing effects, which can lead to hyperkalemia.
It is structurally similar to androgens and exerts an anti-androgenic effect by acting as an androgen receptor antagonist and inhibiting testosterone synthesis. The resulting effects can include unilateral or bilateral gynecomastia, decreased libido, and impotence.

c. eplerenone is a new and more selective aldosterone antagonist that produces fewer endocrine side effects.

a. carvedilol is a nonselective beta/alpha1 blocker used to treat HF. S/Es are fatigue, hypotension and bradycardia.

b. dofetilide is a class III antiarrhthmic used to maintain sinus rhythm in patients with afib. Risks include serious ventricular arrhythmias and conduction disturbances.

d/e. hydrazine is a direct vasodilator often used in combination with isosorbide denigrate for treatment of HF. Common side effects include tachycardia and orthostatic hypotension.

f/i: metolazone and torsemide are diuretics used to control edema in patients with HF. Neither has a significant antiandrogenic effect.

G. Rivaroxaban is a factor Xa inhibitor used to reduce the risk of cardioembolic stroke in patients atrial fibrillation. Excess bleeding is the primary risk.
This patient's symptoms and biopsy finding are suggestive of acute serum sickness, a condition caused by tissue deposition of circulating immune complexes (type III hypersensitivity).

Most common manifestations include fever, pruritic skin rash and arthralgia that begin 7-14 days after exposure to an antigen.

Lymphadenopathy and proteinuria may also occur in some patients.

Histology: small vessel vasculitis with fibrinoid necrosis and intense neutrophil infiltration. Deposition of IgG and/or IgM complement fixing antibodies result in localized complement consumption and hypocomplementemia (decrease serum C3 levels).

Serum sickness can occur following administration of antigenic heterologous proteins such as chimeric monoclonal antibodies (eg, rituimab and infliximab) or nonhuman IGs (eg, venom antitoxins). A serum sickness like reaction is also associated with the use of certain nonprotein drugs (eg, penicillin, cofactor, and TMP-SMX).

a. anergy to cutaneously applied Candida antigens would be indicative of depressed cell mediated immunity. Cell mediated immunity is involved in the pathogenesis of type IV (delayed) hypersensitivity.

c. serum IgE levels are typically found in atopic individuals prone to IgE mediated (type I) hypersensitivity. Type I reactions cause vasodilation and tissue edema and inflammatory infiltration; NOT vasculitis with fibrinoid necrosis

Deposition of IgA containing immune complexes is involved in pathogenesis of Henoch-Schonlein purpura in pediatric patients. IgA doesn't play an important role type III hypersensitivity

Serum sickness causes release of C5a (a neutrophil chemoattractant) complement fragment at sites of immune complex deposition. This lead to neutropenia d/t extensive neutrophilic marginalization and tissue infiltration. In addition, infliximab and other TNF-alpha inhibitors can also cause neutropenia.

Mild thrombocytopenia can be associated with serum sickness d/t platelet consumption at the site of active vascular inflammation. However,rsevere thrombocytopenia is unlikely.
Clinical features of fibromyalgia:

Symptoms - widespread musculoskeletal pain, fatigue, impaired attention and concentration, psychiatric disturbances (eg, depression, anxiety), symptoms lasting for more than 3 months.

PE: multiple tender points at characteristic locations. Absence of joint or muscle inflammation

Labs: normal acute phase reactants (eg, ESR, CRP) and other inflammatory markers.

Fibromyalgia is a chronic disorder that is characterized by widespread musculoskeletal pain in association with fatigue and neuropsychiatric disturbances (eg, paresthesias, poor sleep, depression, difficulty concentrating).

It its most common in women age 20-55. Examination often shows tenderness at characteristics locations in the soft tissues and at bony prominences.

The diagnosis can be made in patients with chronic pain and fatigue for over 3 months in the absence of physical or lab findings suggestive of an inflammatory etiology (eg, synovial swelling, elevated erythrocyte sedimentation rate or C-reactive protein) or other chronic pain syndrome.

The price etiology of fibromyalgia is unknown, but it likely involves abnormal central processing of painful stimuli. Possible contributing actors including genetic predisposition and physical or emotional stressor. Although exercise can temporarily exacerbate the pain of fibromyalgia, gradual incremental aerobic exercise is proven to reduce pain and improve function.

Treatments: TCAs and SNRIs modify processing pain signals and can also be considered in patients with more severe or refractory symptoms.

Ankylosing spondylitis is a chronic inflammatory disease of the axial skeleton characterized by progressive pain and stiffness of the spine, sacroiliitis, and positive serology for HLA-B27 in the majority of patients.

Dermatomyositis is an autoimmune condition the causes bilateral proximal muscle weakness associated with violaceous eruption on the eyelids and knuckles, and elevated creatinine kinase levels.

Polymyalgia rheumatic is an inflammatory disorder that affects patients over 50 and causes subacute pain and stiffness in the shoulder and hips, weight loss, fever and malaise. The patient's age, soft tissue tenderness and neuropsychiatric symptoms are not consistent with PMR but are typical of fibromyalgia.

RA causes symmetric inflammatory polyarhtirtis. It typically presents with pain and morning stiff ness of the metacarpophalangeal and proximal interphalanageal joints. the affected joints are warm, swollen and tender on palpation.
The ovaries suspended posterolaterally to the uterus by the utero-ovarian ligament and receives blood supply through the vessels that travers the infundibulopelvic (IP) ligament (eg, suspensory ligament of the ovary). The IP ligament also houses the ovarian nerve plus. Rotation of the ovary around the IP ligament results in ovarian torsion.

The main risk factor for torsion is the presence of a large ovarian mass (eg, cyst, neoplasm). the weight of mass causes the ovary to twist and occlude the ovarian vessels and nerves.

When blood flow to the ovary is completely blocked, the tossed ovary becomes edematous and ischemic. A patient with ovarian torsion will typically present with sudden onset of unilateral pelvic pain and nausea and sometimes vomiting and fever. Pelvic ultrasound is the first line diagnostic test and may show decreased or no blood flow to the ovaries.

a/c: the mesosalpinx is the portion of the board ligament that connects the fallopian tubes to the pelvic sidewall. The broad ligament is a wide sheet of peritoneal tissues that encapsulates the reproductive organs anteriorly and posteriorly and attaches the uterus to the pelvic sidewalls bilaterally, making torsion of the ovary around the ligament (including mesosalpinx) anatomically impossible.

d. the round ligament maintains the ante flexion of the uterus. It runs from the lower aspect of the uterus through the inguinal ring to the labia major and is not connected to the ovaries. During pregnancy, a woman may experience intermittent sharp pain d/t irritation from sudden movement of the stretching round ligament.

e. the uterosacral ligaments connect the posterior aspect of the uterus to the anterior portion of the sacrum. these ligaments hold the uterus in an anteverted or retroverted position; loss of this support contributes to uterine prolapse into the vagina. they do not involved in the position or vascular supply of the ovaries.
Dude has anal squamous cell carcinoma given the duration of pain, itching and rectal bleeding gin addition to the visible ulcerative mass (anal cancers are ulcerative in over 50% of cases).

Anogenital SCC and they precursors, squamous intraepithelial lesion, have been linked to HPV. The HPV 16 and 18 serotypes are the guys that are strongly correlated with invasive carincoma.

Immunodeficiency states increase host susceptibility to HPV infection and more severe infection HIV-positive men who have sex with men are at increased risk of developing anal squamous cell carcinoma (anal intercourse is hypothesized to be related), and HIV positive women are more prone to developing cervical SCC.

a. adenoviruses can cause severe upper respiratory illnesses, pneumonia and disseminated infection in immunosuppressed patients

b/e: HIV patients often experience reactivation of latent EBV infection. EBV replication in such patients is associated with certain lymphomas and with oral fairly leukoplakia, which typically manifests as white plaques on the lateral tongue margins (this patient's white buccal plaques on initial diagnosis were more likely thus d/t Candida).

c. C. trachoma's causes lymphogranuloma venereum, characterized by ulcerative or vesicular lesion on the external genitalia follows y significant regional lymphadenopathy. Proctitis with tenesmus and bloody discharge can be seen with both LGV and anal carcinoma; however, LGV has a less indolent clinical course, and painful lymphadenopathy is a cardinal feature

d. HIV positive patients with less than 100 CD4 cell count are at significantly increased risk of developing CMV infection, which most frequently causes retinitis in AIDS patients. CMV involvement of the GIT typically manifests as esophageal ulcers or colitis, not anal masses.

f. although AIDS increases the prevalence of HSV-2 infection and the frequency of symptomatic genital herpes recurrences, HSV-2 is not typically associated with anogenital carcinoma. A large, hard mass in not characteristic of herpetic session (classically painful vesicles or ulcers).
Characteristic of gram negative rods.

Lactose fermenters (pink colonies)
-Fast fermenter are: KEE (Klebsiella, E. coli and enterobacter)
-Slow fermenter are: CS (Citrobacter and serratia)

Lactose nonfermenters (white colonies)
-Oxidase positive: pseudomonas aeruginosa
-Oxidase negative
1) No H2S = shigella
2) H2S (black color) = Salmonella and Proteus

Gram negative bacilli account for 5% of all community-acquired pneumonia. However, they are responsible for the majority of cases of nosocomial pneumonias and have a high mortality rate.

Pneumonia caused by gram negative rods is rare in health individuals and usually occurs in patients with immunocompromisation (especially neutropenia) and impaired host defenses (eg, infants, the elderly, alcoholics).

The patient's pneumonia is most likely caused by Klebsiella, a gram negative lactose fermenting bacillus. The presence of a thick capsule is seen as a clear zone on gram stain and also causes the carahceristic mucoid growth in culture. Klebsiella pneumonia classically affects alcoholics.

The pathophysioogicla mech involves colonization of the oropharynx followed by micro aspiration of upper airway secretions. As the aspiration usually occurs while supine, the upper lobes are commonly affected.

Hallmark of Klebsiella pneumonia is thick, mucoid, blood tinged sputum (currant jelly sputum) and lung tissue necrosis with early abscess formation.

a/d: Chlamydia pneumonias and Mycoplasma pneumonias are common causes of atypical community acquired pneumonia. These organisms are not visible on gram stain and do not grow on conventional cultures.

c. legionella pneumoophila is a gram neg bacillus that can cause pneumonia, general following aerosolization from a contaminated water supply. HOWever, it is not encapsulated organisms and does not produce mucoid colonies.

P. aeruginosa commonly causes a nosocomial infection that is generally seen in patients with structural lung disease, immunocompromisation or intensive care hospitalization.

S. aureus can cause pneumonia,. but it is gram positive and so is S. pneumoniae.
For a person in th upright position, regional differences in ventilation (V) and perfusion (Q) occur vertically in the lungs d/t the effects of gravity.

The "slinky effect" on lung ventilation
-End expiration: pleural suction fixes lung apex while gravity pulls down. Alveoli are stretched open more at apex than the base.
-End inspiration: Lugn elastically expand during inspiration so that alveoli are of similar size. Alveoli expand more at the base than the apex, thus ventilation increases from apex to base.
-Thus ventilation increases from the apex to base because gravity acts to stretch the lung downward from the apex, which is effectively fixed to the pleural cavity by the low intrapleural pressure. As a result, at end expiration, alveoli at the apex are expanded more than those at the base. During inspiration, a smaller amount of air id directed to the l uno apex since the alveoli there are more distended and less compliant.

Regional variance in perfusion of the lungs is also determined by gravity and can be dived into 3 zones based on the continuity of blood flow:

Zone 1) doesn't occur in the lung under normal physiologic conditions but would be found at the apex. IN this zone, alveolar pressure is greater than arterial pressure which is greater than venous pressure. The arterial pressure is low in this region as the heart must pump blood uphill against the force of gravity. Because arterial pressure is low than alveolar pressure, the pulmonary capillaries are collapsed and there is no blood flow (i.e., zone 1 represents alveolar dead space). These regions can form when there is low pulmonary arterial pressure (eg, hemorrhage) or high alveolar pressure (eg, positive pressure ventilation).

Zone 2) is found in the higher areas of the lung. Here the arterial pressure > alveolar pressure > venous pressure, because alveolar pressure is greater than venous pressure, the pulmonary capillaries are initially obstructed near the venous end of the capillary bed. However, as arterial pressure rises during systole, capillary pressure becomes high enough to overcome alveolar pressure. For this reason, blood flows through zone 2 in a pulsatile fashion.

Zone 3) is found in the lower areas of the lung. Here, the arterial pressure > venous pressure > alveolar pressure. Arterial venous pressure are both greater than alveolar pressure, and therefore blood flows continuously through the pulmonary capillaries. When a person lies supine, the differences in lung perfusion are negated as gravity then affected the lung equally form apex to base. In spin individual, the lung is entirely composed of zone 3 blood flow.

Although both ventilation and perfusion increases from apex to base, perfusion increases to a MUCH greater degree. Thus, as one moves down the lung from the apex to the base, the V/Q ratio progressively decreases from around 2.5 to about 0.6.
Clozapine indications: Treatment-resistant schizophrenia. Schizophrenia associated with suicidal tendency.

Adverse effects:
-Metabolic syndrome

The second generation antipsychotic clozapine is the only antipsychotic that has consistently shown superior efficacy in treatment resistant schizophrenia and schizophrenia associated with persistent suicidality.

Clozapine has affinity for multiple dopamine and serotonin receptors, but the precise pharmacological mech responsible for its superiority is unknown.

Clozapine binds loosely and transiently to D2 receptors, causing significant fewer extrapyramidal symptoms compared to first generation antipsychotics.

NEUTROPENIA and the potential for life threatening agrunolcytosis are the major adverse effects of clozapine, which happens in about 1% of patients. Thus guidelines require enrollment in a centralized program that regularly monitors the patient's absolute neutrophil count.

Treatment should be interrupted if neutropenia is suspected to be clozapine induced and the absolute neutrophil count is <1000.

Seizures, myocarditis and metabolic syndrome are other important adverse effects that require provider vigilance.

Clozapine plasma levels can be checked after an initial target dose is reached, but further dosage adjustments are usually based on clinical response. Clozapine levels are not regularly monitored.

c/g: Thyroid function tests and creatinine should be monitored in patients taking lithium d/t this drug's potential to adversely affecting the thyroid and kidney.

d. although physicians should be alert to the development of CVS symptoms suggestive of myocarditis, routine ECGs are not required. Among the second generation antipsychotic, ziprasidone is most often noted for causing a prolonged QT interval.

e. LFT may be mild elevated with use of many psychotropic medications, inclusion antipsychotics and anticonvulsants; however, routine monitoring of LFT are not required with clozapine.

Prolactin levels are not routinely monitored. Among the second generation antipsychotics, risperidone has been associated with a greater risk of prolactin elevation.
Acute cholecystitis is caused by gallstone obstruction of the cystic duct in more than 90% of cases.

Ingestion of fatty foods then stimulates contraction of the gallbladder against the impacted stone, resulting in severe cocky pain.

Mechanical disruption of the gallbladder mucosa and release of inflammatory mediators (eg, lysolecithin, prostaglandins) cause the obstructed gallbladder to become inflamed and edematous.

As blood supply to the distended organ becomes compromised, secondary bacterial infection frequently develops. Potential complications include gangrene and perforation, with subsequent formation of a pericholecystic abscess or generalized peritonitis.

US is the PREFERRED intimal imaging test of the diagnosis of acute cholecystitis; however, nuclear medicine hepatobiliary scanning (i.e., cholescintigraphy) can be an alternate means when US is INCONCLUSIVE.

During a hepatobiliary scan, a radio tracer is administered IV and is preferentially taken up by hepatocyte and excreted into bile.

IN patients with a patent cystic duct, the gallbladder will be seen as the radio tracer accumulates and concentrates within. In acute or chronic cholecystitis, the radio tracer will be taken up by the liver with progressive excretion into the common bile duct and proximal small bowel, but the gallbladder will not be visualized d/t the obstruction.

a. distended duodenal upper GIT series would be suggestive of small-bowel obstruction (as seen with gallstone ileum).

b. the presence of echogenic structures within the gallbladder on US can be suggestive of acute cholecystitis in the setting of fever and abdominal pain, but it is not DIAGNOSTIC. Cholelithiasis can also cause more benign biliary colic, or be an incidental asymptomatic finding in the setting of other abdominal pathology. US findings more specific for acute cholecystitis include gallbladder wall thickening, pericholecystic fluid, and a positive sonographic Murphy sign.

d. mild increases in serum aspartate and alanine aminotransferase levels can occur in acute cholecystitis, but they are not specific and do not aid in the diagnosis.

e. most patients have insufficient calcium in their gallstones to be visualized on an abdominal X-ray.
Levodopa have 2 of the same outcomes in the periphery and brain.
1. Gets metabolized into 3-OMD by Catechol-O-methyl transferase
2. Gets metabolized into dopamine by DOPA decarboxylase

These two outcomes are targets for Parkinson treatments.
-Entacapone & Tolcapone inhibits Catechol-O-methyl transferase to inhibit the conversion of Levodopa into 3-OMD. The ladder drug (eg, tolcapone) can cross the BBB and work on the COMT in the brain
-Carbidopa inhibits DOPA decarboxylase PERIPHERALLY because it cannot cross the BBB.

Levodopa is the immediate precursor of dopamine, a NT that is absent in nigrostriatum of patients with Parkinson disease. Dopamine itself cannot be administered directly because it cannot cross the BBB, but levodopa can. It is rapidly metabolized in the peripheral tissues to dopamine (via DOPA decarboxylase) and 3-O-methyldopa (via COMT). Thus, only a small percentage of levodopa reaches the brain. Therefore, levodopa is typically administered with carbidopa, a peripheral DOPA decarboxylase inhibitor, but even then only about 5-10% of levodopa actually reaches the brain

Entacapone is COMT inhibitor that increases bioavailiabity of levodopa by inhibiting its peripheral methylation. Combining levodopa with entacapaone helps increase the plasma half-life of levodopa, producing a more stable levodopa plasma concentrations and prolonging the therapeutic effect of each dose. COMT inhibitors are currently used to treat Parkinson disease patients with motor fluctuations who are experiencing end of dose "wearing off" periods with levdopa/carbidopa therapy, as they are otherwise ineffective.

b. dopamine agonist (eg, bromocriptine, pramipexole, ropinirole) preferentially stimulate dopa 2 receptors

c. amantadine likely enhances the effect of endogenous dopamine by increasing dopamine synthesis/relase and inhibiting the reuptake of dopamine

d. anticholinergics such as trihexyphenidyl and benztropine inhibit central muscarinic receptors. these drugs are mainly used for drug induced parkinsonism, but patients with tremor as the predominant symptom also respond well.

e. Acetylcholinesterase inhibitors (eg, donepezil, rivastigmine) increase the amount of acetylcholine in the CNS. These drugs are commonly used in patients with dementia to increase cholinergic activity in the prefrontal cortex. However, they should be used cautiously in patients with Parkinson disease as higher levels of Ach in the basal ganglia can exacerbate symptoms.
This patient was given an SSRI. History suggests an intentional overdose, and she has serotonin syndrome that gives the following clinical features:
-neuromuscular excitation (hyperreflexia, clonus, myoclonus, rigidity and terror)
-autonomic stimulation (hyperthermia, tachycardia, diaphoresis and vomiting/diarrhea)
-altered mental status (agitation and confusion)

This syndrome most commonly occurs when SSRIs are given with other serotonergic agents such as MAOIs or triptans. It may also occur with a single agent if an excess dose is taken. However, a multitude of other meds have been implicated in precipating serotonin syndrome, and it may be difficult to obtain an adequate medicate history in patients with altered mental status. Therefore, it is important to maintain a high index of suspicion.

TRYPTOPHAN is a precursor of serotonin, and metabolism occurs by the enzymes TRYPTOPHAN HYDROXYLASE and AMINO ACID DECARBOXYLASE

a. Glutamic acid is the precursor for GABA
b. histidine is precursor for histamine that plays a role in allergic (atopic) reaction
c. methionine is a precursor or intermediate in the synthesis of cysteine, carnitine, taurine and lecithin.
d. tyrosine is precursor for thyroxine, dopamine, epinephrine, NE and melanin.

-supportive care including airway maintenance, hydration and temp maintenance.
-Pharmacologic therapy: serotonin receptor antagonists such as CYPROPHEPTADINE, which is the first generation histamine antagonist with nonspecific 5-HT, and 5-HT2 receptor antagonistic properties

a. short-acting antiHTNs (eg, esmolol, nitroprusside) can be used to treat HTN associated with serotonin syndrome. Antihypertensive agents with longer half-lives, such as propranolol, should be avoid d/t the risk of developing hypotension and shock

b. haloperidolis a anti-dopaminergic agent used primarily for treatment of psychosis. An adverse reaction associated with antipsychotic meds is neuroleptic malignant syndrome, which presents with symptoms similar to serotonin syndrome

c. Flumazenil is th antidote for benzo overdose, not serotonin syndrome. Bento themselves are frequently used for treating serotonin syndrome, and can help relieve agitation as well as mild reduce HR and BP

e. Naloxone is the antidote for narcotic overdose
Midline fusion of neural folds creates the neural tube during the 3rd week of fetal life. The neural tube is a structure that is connected to the amniotic cavity by opening at the ends known as anterior and posterior neuropores. Failure of neuropore closure by 4 weeks gestation leads to neural tube defects (NTDs).
-Anterior NTDs include anencephaly (complete absence of the brain) and encephalocele (protrusion of neural tissue through the cranial defect).
-Posterior NTDs include
1. spina bifida occult
2. meningocele - present as cystic mass at the lower spine that is covered with skin and sometimes a tuft of hair.
3. meningomyelocele - is a cystic mass where portions of the spinal cord and caudal equine within the protruding meningeal sac.

Folate (B9) supplementation reduces risk of NTDs and is recommended for all women of childbearing age because the neural tube develop during the time when most women are unaware of their pregnancy.

Prenatal valproate use for bipolar or epilepsy is associated with a 10 to 20 fold increased risk of NTDs d/t impaired folate metabolism. Other risk factors include maternal use of folate antagonists (eg, methotrexate, TMP-SMX)

a. antenatal steroid therapy (eg, betamethasone) reduces the incidence of neonatal respiratory distress syndrome in premature infants.

b. Although chronic alcohol consumption can result in folate consumption (and therefore NTDs), it is more commonly associated with fetal alcohol syndrome. However, fetal alcohol syndrome is unlikely in the absence of short palpebral fissure, a thin vermilion border and smooth philtrum.

c. Lithium an valproate are first line drugs for acute mania. If valproate cannot be substituted by another drug to control a mood or epilepsy disorder, the lowest effective dose should be prescribed during pregnancy. Lithium use in pregnancy is also not recommended d/t toits association with increased incidence of Ebstein anomaly (ASD, atrialized ventricles and messed up valves)

d/e. Uncontrolled HTN and tobacco use can cause fetal growth restriction, premature delivery and placental abruption. Tobacco use, HTN and antiHTN medicates are not associated with NTDs
The electrical impulses in the myocardium are normally generated by the SA node at the rate of 60-100 bpm. These impulses are then transmitted through the conduction system to the ventricles, which depolarize from apex to base and from endocardium to epicardium.

cells throughout the conduction system possess pacemaker ability. The SA node, however, normally stifles impulse generation by other cells in the conduction systems it is able to fire more rapidly. Should impulse conduction from the SA node be interrupted, the pacemaker activity of cells in other regions of the conduction system will be unmasked. The location of the pacemaker can be identified on ECG, which reflects the sequence of cardiac depolarization:
-P: atrial depolarization
-QRS: ventricular depolarization
-T: ventricular depolarization

AV nodal cells an become pacemakers when conduction between the SA and AV nodes is impaired. This can occur in complete (3rd degree) AV block , in which SA node impulses cause atrial contraction while impulses generated by the AV node cause ventricular contraction. on ECG, the atria and ventricles depolarizes independently of each other (AV dissociation). QRS complexes are narrow since ventricular depol proceeds normally. The AV node produces HR of 45-55 bpm.

a. when electrical impulses are generated by the SA node, the HR is normal. The ECG shows P waves synchronized with each QRS complex and normal ventricular depol

c,d,e. When electrical impulses are generated below the AV node and His bundle, the HR can slow to as few as 20 ppm. The ECG also shows prolonged, abnormal shaped QRS complexes d/t aberrant impulse conduction through the ventricles.
Drug resistance is associated with prolonged use of highly active antiretroviral therapy (HAART), a regimen that includes inhibitors of HIV RT and protease.

The development of such drug resistance has been attributed to high mutation rate of the HIV genome and the selective pressure exerted by antiretroviral drugs.

Pol gene mutations are responsible for the emergence of HIV protease variants that are resistant to standard protease inhibitors. The pol gene mutations are also transcriptase that render the enzyme resistant to standard nucleoside and non-nucleoside RTIs.

a. The humoral immune response against HIV is comprised of neutralizing Abs directed against the epitopes of folded viral envelop glycoproteins. Frequently emerging after the primary infection are new HIV-1 "escape mutants" that are no longer susceptible to host antibody neutralization. Because structural glycoproteins are encoded for the HIV-2 env gene, viral evasion of humoral immunity is more likely to occur secondary to a mutation of the env gene.

b. activation induced apoptosis can occur in uninfected CD4 cells as they respond to MHC class II-associated HIV peptides on the surfaces of infected cells. Abnormal intracellular signals transducer by HIV might also prime the infected CD4 T cells for apoptosis. Hypothetically, a reduction in CD4 T cell apoptosis could result if mutations in the HIV genome either changed the MHC class II antigenic peptides on the infected cells or reduced the host intracellular caspase activation. However, it is unclear to what extent these alterations actually occur. Moreover, no direct association between these alterations and pol gene mutations has been established.

c. reduced viral replication is not likely to be associated with high rate of genomic mutations in HIV, as the replication rate is generally positively correlated with the mutation rate.

d. HIV-1 possesses the intrinsic ability to mutate rapidly. During both intimal and chronic infection mutations can develop in the HIV-1 epitopes recognized by CD8+ cytotoxic T cells. As a result, cell-mediated immune (CMI) responses may quickly become inadequate to control HIV. However, a specific linkage between such CMI epitope evolution an pol gene mutations has not been established.
At lower doses, the quantity of drug glucuronide formed is directly proportional to the dose administered (i.e., as more of the drug is administered, more drug-glucuronide is produced). Because a fixed proportion of drug is converted to the metabolite, this early portion of the graph represents first-order kinetics.

As the active sites of glucuronosyltrransferase become saturated, the drug-glucuronide rate doesn't continue to rise with increasing doses of the substrate drug. At this point (2 on the graph), the kinetics change from first to zero order kinetics and the graph levels out to a zero slope. With zero order kinetics, a constant amount of drug is metabolized an eliminated per unit of time regardless of its concentration or dose

Zero- and first-order kinetics can also be represented graphically by showing the decrease in drug concentration over time after a single dose. Zero order metabolism is indicated by a straight line with negative slope (fixed amount eliminated per unit of time), whereas first order kinetics manifest as an exponential decay curve (fixed proportion eliminated per unit of time).

a. After point 3, the curve remains flat, indicating that a constant amount of drug is metabolized per unit of time regardless of the dose. As higher doses are administered, the proportion that is converted to the metabolite becomes smaller.

b. bioavailability (the fraction of unchanged drug that reaches the systemic circulation) usually decreases with oral administration d/t incomplete absorption and first pass metabolism. It can be calculated using graphs of plasma drug concentration versus time; however, this information is not provided.

c. at point 2, biotransformation (i.e., metabolism) of drug begins to switch from first order to zero order kinetics d/t enzyme saturation. However, drug metabolism doesn't stop.

e. before point 1, drug metabolism proceeds via first order kinetics. Therefore, the drug metabolization rate increases as higher doses are administered.
Most colon adenocarcinomas develop from preexisting adenomatous polyps (adenomas). Colon adenomas usually occur in patients 50-0 y.o and are considered premalignant. It is hypothesized that 10 years on average, is required for malignant transformation of adenoma. Early detection and decision of adenomatous polyps is, therefore, an effective prophylaxis for colon adenocarcinoma.

The malignant potential of adenomatous polyps determined by the following:
1. size of the polyp: <1cm - unlikely to undergo malignant transformation; >4cm = 40% risk of malignancy
2. histologic appearance: villous adenomas are more prone to be malignant than tubular adenomas
3. degree of dysplasia.

The transformation of normal mucosal cells into malignant ones is caused by a series of gene mutations called the adenoma to carcinoma sequence:
1. progression from normal mucosa to small polyp. The intimal appearance of small adenomatous polyps is attributed to mutation of the APC tumor suppressor gene
2. increase the size of the polyps. Mutation of K-ras protooncognee is thought to facilitate this sep by leading to uncontrolled cell proliferation.
3. Malignant transformation of adenoma into carcinoma requires mutation of two genes: p53 and DCC.

Increase the size of adenomatous polyps (and therefore, increase in their malignant potential) is attributed to K-ras protoconcogene mutation. Tai gene normally encodes for a protein that regulates cell cycle by stimulating and inhibiting it as necessary. Mutation of K-ras cauaews it to become the oncogene K-ras, which encodes for a protein that has lost its ability to inhibit the cell cycle, but can still stimulate it. Thus, unregulated cell proliferation ensues.
Water deprivation results in ADH release from the posterior pit. ADH stimulates V2 receptors on principal cells in the renal collection ducts, activating a cAMP second-messenger G-protein system that leads to insertion of endosomes containing aquaporin 2 into the apical cell membrane.

Aquaporin 2 is a water channel that spans the luminal membrane, enhancing the water permeability of the principal cells. When ADH feels are low, aquaporin 2 accumulates within pits along the luminal membrane and is returned to cell cytoplasm through endocytosis.

In the presence of high ADH, the tubular fluid osmolarity follows this patter.

-in the proximal tubule (choice A), water is reabsorbed along with electrolytes. The tubular fluid in this segment remains isotonic with plasma (300) whether the final urine is concentrate or diluted

-in the descending limb of the loop of Henle, free water is drawn out of the tubules into the renal interstititum and the tubular fluid becomes hypertonic (>300, typically reaching 122 when ADH is high

-electrolytes, but not water, are reabsorbed in the thin ascending limb of the loop of Henle. The tubular fluid becomes hypotonic (<300). the thick and think ascending limbs ar primary region of urine dilution, achieved mainly through NaCl reabsorption

-the distal convoluted tubule is relatively impermeable to water, so the tubular fluid remains hypotonic. Reabsorption of solutes continues to occur; thus, fluid in the distal tubule is the most dilute (lowest osmolarity, approaching 100)

- in the presence of ADH, the collecting duct is highly permeable tow water. Water leaves the tubular fluid driven by the high osmolarity of the medullary interstitum and hypertonic urine is formed (up to 1200 mOsm/L). The CD system is the primary region of urine concentration through the mechanism of DH mediated water absorption.
GIT ulcers are defined as breaches of alimentary tract mucosa that extend through the muscular mucosal into the submucosa (or beyond). Those specifically designated as peptic ulcers are chronic lesions in areas exposed to acid/peptic juices, most commonly in the proximal duodenum, astral stomach and dastroesophageal junction. Patients may present with epigastric discomfort, early satiety, and a positive fecal occult blood test.

Almost all peptic ulcers are d/t either Helicobacter pylori infection or use of NSAIDs. The vast majority of ulcers occur within the first part of the duodenum; however, multiple or refractory ulcers beyond the duodenal bulb may be seen in patients with gastronome (non-beta islet cell tumor of the pancreas)

Duodenal ulcers are very rarely malignant and do not require biopsy. Conversely, gastric ulcers can be malignant (eg, mucosa-associated lymphoid tissue lymphoma, gastric adenocarcinoma) and must be biopsied for confirmation.

Gastric ulcers caused by H pylori infection are associated with an increased risk of gastric cancer, but duodenal ulcers related to this infection do not lead to a higher risk of duodenal carcinoma.

Esophageal adenocarcinoma can appear as an ulcerated/exophytic lesion in the lower one third of the esophagus and typically results from Barrett's esophagus, chronic GIT reflux, obesity and/or smoking. Esophageal squamous cell carcinoma appear as plaque like thickening of the mucosa in the upper 2/e of the esophagus that may become ulcerated. Major risk factors include smoking, alcohol consumption and caustic injury.

cd: carcinomas of the distal colon tend to be annular lesions that results in "napkin-ring" contraction of the bowel, with heaped-up edges and and ulcerated central region. Risk factors include advanced age, hereditary (eg, FAP) or sporadic colon cancer in the family , and inflammatory bowel disease.
The lip and palate form doing the fifth-sixth week of embryonic development through a series of scions:

1. the first pharyngeal arch splits into the upper maxillary province and the lower mandibular prominence
2. fusion of the 2 medial nasal prominences form the midline inter maxillary segment. The inter maxillary segment will beomce the philtrum of the upper lip, the 4 medial maxillary teeth and primary palate.
3. the left and right maxillary prominences then fuse with the midline inter maxillary segment to form the upper lip and primary palate. If one of the maxillary prominences fails to fuse with inter maxillary segment, a unilateral cleft lip will occur. If both maxillary prominences fail to fuse with the inter maxillary segment, bilateral cleft lip results.

a. failure of the medial nasal prominence to fuse and form the inter maxillary segment is associated with severe midline defects, such as holoprosencephaly
c. during the 7th-8th week of embryonic development, the maxillary prominences give rise to palatine shelves. The thin sheets of tissue that comprise the palatine shelves grow medially and fuse into the secondary plate. Fusion of the secondary palate with the posterior aspect of the primary palate form the complete palate. Failure of any of these process can lead to clef palate. The presence of cleft lip increases the risk of cleft palate, but either can occur in isolation

d. the orbits normally arises from the sides of the face and rotate medially. However, excessive tissue from the frontal nasal prominence could result in orbital hypertelorism (wide-set eyes) in addition to a broad forehead and wide nasal bridge

e. micrognathia is characterized by hypoplasias of the mandibular prominence. In Pierre-Robin sequence, the sever micrognathia results in the posterior display meant of the tongue (glossoptosis) and prevents fusion of the secondary palate (cleft palate).
Listeria monocytogenes is a facultative intracellular, gram +, that produces a very narrow zone of beta hemolysis on blood agar, resembling pattern produced by group B strep.
-immotile at 37 c but has tumbling motility at 22 c, a fact that can be used to identify potential Listeria isolates.
-It can multiple at temp as low as 4c, which allows the bacteria to contaminate refrigerated food (eg, meats, unpasteurized milk, soft cheese, raw vegetables).

Intracellular bacteria are protected against circulating immune factors such as Abs and complement but must develop survival mechanism in order for them to survive inside of macrophages, such as:
-fusion of phagosomes with lysosomes (eg, salmonella and Tb)
-inhibiting phagolysossome acidification (Tb)
-or escaping from the phagosome into the cytosol (eg, Literal and Shigella).

Listeria is able to lyse the vacuolar membrane through the action of Listeriolysin O, a pore forming toxin that is selectively activated within codified phagosomes.

In healthy people, Listeria infection stimulates the production of cytokines (IFy, TNF-b, IL-12) that induce cell mediated immune redone leading to macrophage activation and killing of intracellular Listeria. However, in pateitnets that are immunocompromised, elderly and pregnant woman, the organism survives and can cause serious infections. Neonates can acquire Listeria transplacentally or during delivery; they are especially vulnerable to developing meningitis and septicemia because their cell mediated immunity is not yet fully developed.

b. eosinophil activities are important against helminths
c. Paitents with pure humoral immune defects (eg, X-linked agammaglobulinemia of Bruton) are at increased risk of bacterial infections by STrp and Staph but have normal responses to infection combated by cell mediate immunity (eg, lister, virus and fungi)
d. Mast cells contribute to defuse against parasites and play an important role in allergic response. They do not confer immunity to intracellular pathogens
e. patients with inherited def of the terminal complement components (eg, C5b-C9( are unable to form the membrane attack complex and are predisposed to recurrent Neisseria infections.
Hb electrophoresis is used to determine if the patient's new husband also has sickle cell trait. Abnormal Hb moves at a slower speed than normal d/t to the replacement of the glutamic acid by valine. The husband's test result combines with the maternal family history will determine the risk that future offspring will inherit sickle cell anemia

a. chorionic villi are part of the placenta and as such are fetal tissue. Once fetal DNA is obtained, DNA sequencing can be performed to evaluate for sickle cell mutation. This can be performed at 10-14 weeks gestation. However, it is relatively invasive and carries a risk of miscarriage, spotting/bleeding, infection, and other complications. CVS is not helpful to a patient who wishes to determine her risk prior to conception

b. it is not necessary to perform maternal Hb electrophoresis as it has been establish from this patient's history that she has sickle cell trait

c. Northern blot use electrophoresis to separate RNA by size, followed by the application of a DNA probe to detect a specific RNA molecule. This allows for the quantification of the RNA expression of specific genes. Hemoglobin electrophoresis is a more appropriate test for SCD as it involves the separation of protein (eg, hemoglobin) rather than RNA

e. Karyotype is a visual analysis of all the chromosome in a cell ordered by size and stained to reveal chromosomal banding. SCD results form a single nucleotide mutation, not form an abnormality in overall chromosome structure. Disorders d/t chromosomal abnormalities include Klinefelter syndrome (47, XXY) and Turner syndrome (45, XO) and trisomy disorder.
This patient has xeroderma pigmentosum, which literally means pigmented dry skin.
-decreased ability to repaired DNA following damaged by UV light.

Clinical manifestation:
-erythema, scaling and subsequent hyper pigmentation and lentigo formation on light-exposed areas.
-Later, the skin of affected areas shows atrophy, telangiectasia, and intermingling areas of hypo and hyperpigmentations.
-skin malignancies, including SCC, basal cell carcinoma and malignant melanoma, develop as early as 5-6 years of life.

Normally the region of DNA damaged by UV radiation are excised and replaced. In xero pigmentosum, the genes that code for various DNA repair enzymes are abnormal. IMparimtn of DNa repair results d/t defects in excision of abnormal nucleotides or defects in replacement of nucleotides following excision

other diseases associated with impaired DNA repair include:
-Fanconi (AR, hypersensitivity to DNA cross linking agents)
-Bloom syndrome (AR, hypersensitivity to UV damage and chemotherapeutic agents)

a. The Rb gene is responsible for regulation of the cell cycle. The abnormal Rb protein loses its ability to arrest the cell cycle in the G1 phase. Mutation is associated with retinoblastoma and osteosarcoma
b. mutation of fas protein is found in many types of cancer. Fas codes for a G-protein that regulates signal transduction. Abnormal was stimulates, signal transduction leading to unregulated cell division, inhibited apoptosis and decreased cell adhesion. These predispose to malignancy and metastasis
d. abnormalities in mismatch repair are found in patients with HNPCC aka Lynch syndrome.
Lynch syndrome (HNPCC) is an AD disease caused by defective DNA mismatch repair.

DNA replication occurs with a high degree of fidelity because mismatched nucleotides are repaired through the proofreading activity of DNA pol delta and epsilon. However this proofreading functionality is not infallible; base substations and small insertion and deletion mismatches occur d/t errors in base pairing every 10^6 bases on average.

Function of the DNA mismatch repair system to fix these errors shortly after the daughter stands are synthesized. The mismatch repair system involves several genes, including MSH2 and MLH1, with code for component of the human MutS and MutL homoglos. Mutatons of these 2 genes account for around 90% of cases of lynch syndrome

Mismatch repair begins with MutS homolog deleting a mmistmatch on the new created daughter strand, which is distinguished from the parent by occasional nicks in the phosphodiester bonds.

Mute homolog is then recruited, and the resulting complex slides along the DNA molecule until 1 of the taught strand nicks in encounters. At this point, exonuclease 1 is loaded onto and activated by the repairs complex.

The daughter strand is then degraded backward past the initial mismatch point, leaving a variable gap of ssDNA that is stabilized by ssDNA-binding protein. The complex then dissociated while DNA pol delta load the 3' end of the discontinuity and begins synthesizing a new daughter strand segment.

Finally, DNA ligase I seals the raining nick to complete the repair process.

b. exposure to UV light can cause pyrimidine (usually thymine) dimers to form d/t covalent joining of adjacent pyrimidines. Pyrimidine dimers interfere with DNA replication and are removed by nucleotide excision repair

c/d: several types of insults can alter the DNA bases. For example, NO can deaminase C, A and G. There are also spontaneous changes, such as deamination of C to U and the constant low level loss of purines via thermal disruption. Glycosylases are enzymes that detect and remove abnormal bases from DNA, creating an empty sugar phosphate residue that is subsequently removed and replaced by the correct nucleotide (base excision repair).

e. exposure to ionizing radiation causes double stranded DNA breaks that are repaired by end joining repair mechanism. Non homologs end going, the main mechanism in primates, is more prone to cause mutations than homologous recombination.
This patients weight gain, dry skin, hair loss and constipation accompanied by bradycardia are most likely d/t hypothyroidism.

Lithium, a mood stabilizer used in treatment of bipolar disorder and unipolar depression ,interferes with normal thyroid functioning through multiple mechanisms, including decreasing thyroid hormone synthesis and release.

Hypothyroidism and goiter are the most common thyroid abnormalities in lithium treated patients. Periodic measurement of the serum TSH level is recommended for patients on long term lithium therapy. When hypothyroidism develops, it can be treated with T4 and doesn't necessarily require lithium discontinuation.

Long term lithium therapy is also associated with adverse effects on renal function (nephrogenic diabetes insidious and less frequently, chronic tubulointerstitial neprhopathy), requiring regular monitoring of blood lithium levels and renal function (i.e., BUN and creatine). Lithium use during pregnancy has ben associated with Ebstein anomaly of the tricuspid valve, but the absolute risk is small.

a. carbamazepine is used to treat manic episodes and maintenance. It can also be use to treat partial and generalized seizures as well as its most famous indication TRIGEMINAL NEURALGIA. Side effects: agranulocytosis, hyponatremia (SIADH) and neural tube defects.

b. citalopram is an SSRI used as an antidepressant. side effects is sexual dysfunction.

c. clozapine is a second generation antipsychotic indicated for treatment-refractory schizophrenia. It is associated with agranulocytosis that requires regular monitoring of the absolute neutrophil count. Although clozapine can cause weight gain and constipation, it is not an initial treatment for mood disorders and would not explain all of this patient's symptoms (eg, dry skin and hair loss)

d. lamotrgine is indicated for depressive episodes, maintenance. Focal seizure. serious side effect is the deadly steven johnson syndrome.

f. risperidone is second generation antipsychotic that can cause weight gain and symptoms of hyperprolactinemia (eg, galactorrhea, amenorrhea). It is not associated with hypothyroidism.

g. Trazodone, an antidepressant, is most commonly sued to treat depression related insomnia du/t its sedating effects. It is associate wth the are but serious side effects of priapism (prolonged painful erection).

h. valproate indicated for depressive episodes and their maintenance. Main is absence, generalized tonic clonic and myoclonic seizure. Side effects are hepatoxcity and neural tube defects.
Lab abnormalities in cirrhosis:

Indicators of liver function: Impaired biosynthetic capacity (elevated PT and hypoalbuminemia). Impaired transport and metabolic capacity (elevated bilirubin).

Indicators of liver injury: markers of hepatocyte injury (elevated AST > ALT). Markers of cholestatiss (elevated ALP and GGT)

Others: thrombocytopenia (d/t splenic sequestration and of platelets)

Alcohol-associated hepatic injury evolves through he stages of alcoholic steatosis (reversible), alcoholic hepatitis (reversible), and alcoholic cirrhosis (irreversible).

Lab findings in cirrhosis reflect both hepatocellular/biliary injury and loss of hepatic function Hepatocyte injury causes a release of intracellular enzymes and an increase in serum transaminases; biliary injury is reflected by increases in ALP and GGT.

Although these lab studies are indicative of ongoing hepatobiliary injury, they do not provide information on the liver's functional reserve, a key determinant of prognosis in patients with cirrhosis.

Serum albumin levels and PT are better indicators of liver's biosynthetic function, and its ability to transport and metabolize organic anions is reflected by serum bilirubin level.

Hypoalbuminemia, elevated bilirubin, and prolonged PT are signs of inadequate liver function (eg, liver failure) and indicate a poor prognosis in cirrhotic patients. For this reason, they are included in multiple scoring systems used to assess the severity liver failure and need for transplantation.

a. AST indicates hepatocellulalr injury and relate ion intracellular enzymes into the blood. AST is classically elevated to more than 2 times the level of SLT in alcoholic liver disease. Transaminase elevation do no reflect liver function and do not predict outcomes; these enzymes can be transiently elevated by a number of self-limited processes.

b. fibrinogen is a coagulation factor and an acute phase protein. Liver fibrinogen synthesis is increased in response to infection or acute inflammation and diminished in liver failure. Therefore, low fibrinogen levels would be expected in liver failure.

When the ALP is elevated, serum GGT measurement can differentiate whether the cause is biliary disease or an alternate cause such as bone disease. GGT elevations are more specific biliary injury

The BT is measurement of platelet function (not liver synthetic function) and is often prolonged in severe alcoholic liver disease, although with a fair degree of variance. Thrombocytpoenia in alcoholism develops d/t both direct toxic effects of alcohol and the bone marrow and hypersplenism with splenic sequestration of platelets.
This patient has CREST syndrome:
Raynaud phenomenon
Esophageal dysmotility
Telangiectasia aka spider angioma

is a limited variant of systemic sclerosis with skin disease that primarily affects the face, forearms and fingers.

The pathogenesis of systemic sclerosis involves chronic autoimmune inflammation, vascular endothelial injury resulting in chronic ischemic tissue damage (eg, fingertip ulcers), and excessive activation of fibroblasts leading to progressive tissue fibrosis.

Esophageal dysmotility is a result of atrophy and fibrous replacement of the muscular in the lower esophagus. The esophageal body and the lower esophageal sphincter become atonic and dilated, resulting symptoms of GERD (eg, heartburn, regard and dysphagia). This increase the risk of Barrett's esophagus and fibrous stricture formation.

a. sliding hiatal hernia is characterized by herniation of gastroesophageal junction and a portion of the stomach through the esophageal hiatus, which predisposes patients to GI reflux.

c. increased gastric acid production occurs with gastronomes, gastrin secretin gneuroendocirne tumors of the small intestine/pancreas that often present with multiple or medically refractory peptic ulcers.

d. Achalasia is an esophageal motility disorder characterized by failed relaxation of the lower esophageal sphincter resulting in food retain, dilation of the esophageal body and symptoms of solid liquid dysphagia

e. diffuse esophageal spasm is characterized by periodic, uncoordinated, simultaneous contractions of the lower esophagus d/t impaired inhibitory innervation within the esophageal myenteric plexus. Patients typically have liquid/solid dysphagia and chest pain d/t inefficient propagation of food into the stomach.
Juvenile pilocytic astrocytomas usually arise in the cerebellum, brainstem, hypothalamic region or optic pathways.

Microscopically, pilocytic astrocytomas are well differentiated neoplasms comprised of spindle cells with hair like glial processes that are associated with micro cysts. these cells are mixed with Rosenthal fibers and granular eosinophilic bodies.

b. GBMs occur dos often in the subcortical white matter of the cerebral hemisphere When a tumor in the frontal cortex spreads across the corps callous into the contralateral hemisphere, it creates the appearance of a bilateral symmetrical lesion, here the term "butterfly glioma." GBMs are composed of poorly differentiated, often pleomorphic astrocytic cells with marked nuclear atypia and brisk mitotic activity. Necrosis is an essential diagnostic feature, and prominent microvascular proliferation is common.

c. medulloblastoma (primitive neuroectodermal tumor) is the second most common posterior fossa tumor in children. ON microscopic examination cells are small and poorly differentiated, with scant cytoplasm and little storm. A high mitotic index is common. Classic Homer-Wright rosettes can be seen in one fifth of cases

d. ependymomas account for 10% of posterior fossa tumors in children. Intracranial lesions usually occur infratentiorially, arising from the roof too the fourth ventricle in children, while spinal ependymomas typically occur in adults. histologically, ependymal pseudo rosettes with glial fibrillar acidic protein (GFAP)-positive processes tapering toward blood vessels characterize ependymomas.

e. Neuroblastomas are the most common extra cranial solid tumors occurring in children. Undifferentiated neuroblastoma are small, round, blue cell tumors. A neuritic process also called neuropil, is apathy pathogonomic feature of neuroblastoma cells. NSE< chromagranin, snaptophysin and S-100 immunohistochemical stains are usually positive. More than 90% of patients have elevated urianry levels of homovanillic acid (HVA) and/or vanillylmandelic acid (VMA). The most important biologic marker is MYCN (N-MYC) of chromosome 2.
this patient is experiencing vertigo d/t vestibular dysfunction. Vertigo is a sensation of motion when no motion is present or an exaggerated sense of motion for a given bodily movement.

It must be distinguished from other sensations that are often described by patients using similar terminology, such as imbalance, light headedness and syncope.

Vertigo resulting from vestibular dysfunction tends to be sudden onset, interfere with waking and cause nausea and vomiting. Typical causes of vestibulopathy include Meziere's disease, perilymphatic fistulas, benign positional verge, labyrinthitis, and acoustic neuromas.

a. disease of the posterior column of the spinal cord can occur in syphilis (i.e., tabes dorsalis) and vitamin B12 def. Typical symptoms include ataxia, decreased proprioception and vibratory sense and hyporeflexia. this patent's normal neurologic exam makes this unlikely

b. vagal nerve damage can present as hoarseness, dysphagia, abnormal GI motility and tachycardia. However, dysfunction would not cause vertigo.

c. Optic tract dysfunction will result in visual problems. Vision deficits do not typically cause vertigo, but may cause people to feel unsteady on their feet.

e. cerebellar dysfunction presents as ataxia, imbalance, incoordination, and nystagmus. Patients with cerebellar dysfunction will be unable to perform tandem walk d/t their imbalance.

f. the frontal cortex controls executive functions and response inhibitor. Damage to the frontal cortex results in frontal release symptoms, such as personality change, inability to organize or plan and disinhibition.
Statins are the first line therapy for hypercholesterolemia and are useful in primary and secondary prevention of acute coronary events.

MOA: inhibiting HMG-COA reductase, the rate limiting enzyme in the synthesis of cholesterol. It lowers cholesterol, LDL and TAGs levels.

Primary side effects:

Statin associated myopathy is usually characterized by mild muscular pain and resolves with discontinuation of the medication. However, some patients will develop severe myopathy with striking elevation in CK levels and occasional rhabdomyolysis. The risk of severe myopathy is increased when statins are given concurrently with vibrate (especially gemfibrozil), which impair the hepatic clearance of statins and lead to excessive blood levels. An increased risk of statin myopathy is also likely with concurrent use of niacin or ezetimibe, but to a lesser extend.

a. concurrent use of bile acid sequestrates with statins doesn't increase the risk of myopathy. However, bile acid sequestrates can reduce GI absorption of statin

d. vibrates can increase drug levels of ezetimibe but this don'ts have significant impact on its side effects, which are generally mild and not dose related. Ezetimibe doe not alter the pharmacokinetics of vibrates and doesn't substantially influence their adverse effects.

e/f. the primary adverse effects of niacin include flushing, hyperglycemia and hepatotoxicity. There are no significant interactions with the concurrent use of niacin and ezetimibe or gemfibrozil.
Atherosclerosis is a chronic inflammatory and fibroproliferative disease. Endothelia cells, vascular smooth muscle cells (VSMCs), and leukocytes play an important role in the development and progression of this disease.

The process is initiated by chronic hemodynamic stress and hyperlipidemia, which cause ENDOTHELIAL CELL INJURY.

Leads to expression of surface vascular cell adhesion molecules (VCAMs) that all adherence and migration of MONOCYTES and T lymph into the intima. The infiltrating leukocytes and dysfunctional endothelium release cytokines and growth factors (eg, platelet-derived growth factor, fibroblast growth factor, endothelia 1, IL-1) that promote MIGRATION AND PROLIFERATION of VSMCs within the intima.

VSMCs are also stimulated to synthesized EXTRACELLULAR MATRIX PROTEINS (eg, collagen, elastin, proteoglycans) that form the fibrous cap typical of mature atheroma. Disruption of the fibrous cap with luminal thrombosis (ATHEROSCLEROTIC PLAQUE RUPTURE) has catastrophic clinical consequences and is responsible for the majority of acute coronary syndrome cases and sudden cardiac death.

a. endothelial cell dysfunction is the earliest pathophysiologic change that precedes the formation of atherosclerotic lesions. Endothelial injury results in increased lipid permeability, leukocyte (monocytes, T cells) and platelet recruitment, and migration and proliferation of VSMC from media to the intra. However, the VSMCs are directly responsible for the synthesis of new collagen and extracellular matrix

b. fibroblasts are found infrequently in the tunica initma of BVs and are not significantly involved in atherosclerosis pathogenesis

c/e: activated macrophages and T lyme secrete growth factors that recruit VSMCs reasonable for forming the fibrous cap, but they are not directly responsible for the dense deposition of extracellular matrix and collagen. macrophages also produce matrix metalloproteinases and tissue factors that degrade the extracellular matrix, causing the formation of large, soft lipid rich core with thinning of the fibrous cap Such vulnerable plaques have an increased chance for rupture.
Temporomandibular disorder (TMD) is characterized by a constellation of symptoms that may include unilateral facial pain that worsens with jaw movement, headache and ear discomfort.

Symptoms can originate from temporomandibular joint (TMJ) derangement, pathologic contraction of the muscle of mastication and/or hypersentitivy of the nerves that supply the jaw

The mandibular nerve is the largest branch of the trigeminal nerve and contains both motor and sensory components. It supplies sensation to the TMJ and manidublar teeth as well as the floor of the mouth, inside of the cheeks, anterior tongue, and much of the skin of the lower part of the face. The motor fibers innervate the muscle of mastication (medial and lateral pterygoid, master, temporals), muscles of the floor of the mouth (i.e., mylohyoid), tensor vili palatine and the ensor tympani in the middle ear.

As a result, patient with TMD involving the mandibular nerve can have both jaw pain and otological symptoms.

a. cervical spine disease causes neck pain, referred pain to the shoulder and arms, and upper extremity motor weakness

b. facial nerve, which is primarily responsible for facial expression, carries somatic signal from the external auditory canal and the pinna but is not involved in the sensory innervation of the TMJ or the middle ear.

d. maxillary division of the trigeminal nerve carries mainly sensory fibers from the cheek, nares, upper lip and teeth, the pharyngeal palate and the maxillary sinuses.

e. the vestibulocochlear nerve provides auditory and position sense but is unrelated to the TMJ and not involved in TMD
Symptoms of digoxin toxicity:
-cardiac: life treating arrhythmias
-GI: anorexia, nausea, vomiting and abdominal pain
-Neurologic: color vision alterations, confusion, fatigue, weakness

Patient has aFib and CHF is having digoxin toxicity. Although calcium channel blockers and metal blockers are the preferred treatment for patients with aFib with rapid ventricular response, digoxin is a common second line treatment that is particularly useful in patients with underlying systolic cardiac dysfunction. Its major effects are:
1. increased vagal tone, causing slowing of conduction through the AV node (rate control affect)
2. Na-K-ATPase inhibition, causing increased intracellular sodium and calcium (increases cardiac contractility)

Digoxin has a narrow therapeutic index, making toxicity relatively common. Symptoms of digit intoxication are fairly nonspecific and include nausea, abdominal pain, fatigue, dizziness, confusion, blurred vision nd abnormal color perception.

Toxicity can cause a wide range of cardiac arrhythmias, including brady cardia and junctional escape beats d/t increased AV nodal block.
-hypokalemia can precipitate toxicity by increasing digoxin binding to Na-K-ATPase. However, ELEVATED POTASSIUM is a sign of digoxin toxicity as inhibitor of the pump increases extracellular potassium.

a. amiodarone can cause pulmonary toxicity, thyroid dysfunction, cardiac arrhythmias, elevated liver enzyme and visual disturbances. However, it doesn't cause hyperkalemia

b. acute aspirin overdose presents with vertigo, tinnitus, vomitng and diarrhea, whereas severe intoxication can lead to coma, hyperpyrexia, pulmonary edema and death

d/f: beta blocker and/or calcium blocker overdose usually cause profound bradycardia and hypotension (absent in the patient), In addition,nausea and vomiting are more common in digoxin overdose than in beta blocker overdose, which typically causes bronchospasm and hypoglycemia.

E: furosemide overdose causes volume depletion, along with electrolyte abnormalities such as hypokalemia and hypomagnesemia.

g. spironolactone can cause hyperkalemia, gynecomastia, impotence and decreased libido

h. Valsartan is an angiotensin II receptor blocker. Overdose usually causes hypotension, renal failure and hyperkalemia.
Deglutition (swallowing) is a complex process that involves 3 phases:
1. In the voluntary oral phase, the food bolus is collected in the back of the mouth and lifted upward to the posterior wall of the pharynx.
2. This initiates the pharyngeal phase, which consists of involuntary pharyngeal muscle contractions that propel the food bolus to the esophagus.
3. During the esophageal phase, food stretches the walls of the esophagus, stimulating just above the site of distention and moving the food downward. Relaxation of the lower esophageal sphincter (LES) follows, allowing the food bolus to enter the stomach.

Abnormal spasm or diminished relaxation of the CRICOPHARYNGEAL MUSCLE during swallowing is thought the be the underlying mechanism of Zener diverticulum formation.

This process results in early oropharyngeal dysphagia with a feeling of food obstruction at the level o f the neck and coughin/chocking. Increased oropharyngeal intraluminal pressure eventually results in herniation of the pharyngeal mucosa through a zone of muscle weakness (false diverticulum) in the posterior hypo pharynx (Killian triangle).

1. halitosis/regurgitation.
2. pulmonary aspiration of diverticular contents may also lead to recurrent pneumonia.

-As diverticulum enlarges, it may become palpable as a lateral neck mass, and dysphagia can worsen d/t luminal narrowing caused by extrinsic esophageal compression.

d. degenerative changes of the myenteric plexus with impaired LES relaxation result in achalasia. Barium swallow typically shows esophageal dilation with esophagogastric junction narrowing giving the characteristic "bird's beak" appearance.

c. mucosal tears around the gastroesophageal junction can be caused by increased intraluminal pressure in the stomach during prolonged or recurrent tretchign/vomiting (Mallory-Weiss syndrome).

d. retention cysts form d/t accumulation of trapped secretions following obstruction of a gland's duct. Chronic rhino sinusitis frequently causes mucus retention cysts in the maxillary sinus.

e. mediastinal lymphadenitis (eg, d/t Tb, fungal infections)) can cause scarring/traction of the mid portion of the esophagus, resulting in the formation of true diverticular (i.e., containing all gut wall layers).
S. pneumonias is the most common cause of CA pneumonia.

However, alcoholics has a significantly increased risk of aspiration pneumonia (infection with oral flora) because alcohol intoxication impairs the gag and cough reflexes.

Alcoholics with poor oral hygiene have increased numbers of oral bacteria, further increasing this risk. In addition, alcohol may impair the phagocytic and/or bactericidal action of alveolar macrophages, predisposing to infection.

Pulmonary infections in alcoholics patients very commonly include anaerobic oral flora (bactericides, prevotella, fusobacterium and peptostreptococcus) admixed with aerobic bacteria. Necrotizing infections and lung abscesses may result.

This patient's CT shows a lung abscess that can be identified by presence of air fluid levels. Of antibiotics choices given, CLINDAMYCIN has the most activity against oral anaerobes and also covers aerobic Gram-positive organisms such as S. pneumoniae). Similar to macrolide, lindamycin works primarily by being to 50s ribosomal subunit in bacteria and disrupting protein synthesis.

b. vanco is active only against gram positive bacteria and aren't very good against anaerobes.

c/e: Klebsiella is a common pathogen in alcoholics with aspiration pneumonia and can also cause mono microbial lung abscess. However, lung abscesses are most recently caused by polymicrobial infection involving anaerobes. Ciprofloxacin and cefazolin have poor coverage against anaerobic organisms.

d. metronidazole has excellent coverage against anaerobes but doesn't cover aerobic organisms. Adequate covers against both aerobic strep and anaerobes is essential for successful treatment of lung abscesses.
Patient is having peri-infarction pericarditis that improve with supportive measures, those with sufficient or persistent symptoms are typically treat with aspirin in combination with colchicine.

Acetylsalicylic acid - is an NSAID that irreversibly inhibits COX-1/2 by acetylation, preventing the conversion of archindonic acid to prostaglandins, prostacyclin and thromboxane.

COX-1 acetylation inhibits generation of TXA2, in platelets (antithrombotic effect).

COX-2 acetylation blocks prostaglandin production in inflammatory cells (eg, activated lymphocytes and neutrophils), resulting in anti-finlammatory, antipyretic and analgesic effects.

a. tylenol is an analgesic and antipyretic agent that reversibly inhibit COX primarily in the CNS. It lacks the anti-inflammatory properties d/t its weak inhibition of COX in peripheral tissue.

c. budesonide is a glucocorticoid agent with potent anti-inflammatory activity. Corticosteroids reduce COX-2 expression and decrease synthesis of arachidonic acid via phospholipase A2 inhibition.

d. Celecoxib is a selective COX-2 inhibitor that provides anti-inflammatory benefits without interfering with the physiological functions of COX1. In contrast to to non selective NSAIDs, selective COX2 inhibitors have no significant effect on platelet function and are associated with lower incidence of GI bleeding. However, selective COX2 inhibitor is associated with an increased in thrombosis.

e. colchine exerts its anti inflammatory effects by inhibiting polymerization of beta-tubulin into microtubules, preventing migration and activation neutrophils.

f,g,h: diclofena, ibuprofen and indomethacin are NSAIDs that reversibly inhibit COX1/2
ACALCULOUS CHOLECYSTITIS: is acute inflammation of the gallbladder in the absence of gallstones.

-Most commonly occur in critically ill patients and is associated with high mortality. Pathology, gallbladder stasis and ischemia, which cause inflammation of and injury to the gallbladder wall.

-fever, RUQ pain, positive Murphy's sign, leukocytosis and mild elevation in LFT.
-PE: jaundice and palpable RUQ mass.

Diagnostic study of choice is an ultrasound, which may show signs of acute cholecystitis (eg, an edematous and enlarged gallbladder) and no gallstones

a. choledochal cysts are congenital dilations of the common bile duct that typically present during childhood (age <10) with recurrent abdominal pain and jaundice

b. chronic cholecystitis results from repeated mild attacks of acute cholecystitis, which leads to thickening of the gallbladder wall. Ultrasound typically demonstrates a shrunken, fibroses gallbladder

c. Liver fluke infection usually affects individuals from endemic areas (eg, southeast asia) and presents acutely with fever, RUQ pain, jaundice and eosinophilia. Infection of the biliary tree is associated with the formation of brown pigment gallstones, not acute calculus cholecystitis.

e. pigment gallstones are categorized as black (typically secondary to intravascular hemolysis) or brown (typically secondary to biliary infection).

f. porcelain gallbladder is usually found incidentally on abdominal radiograph as a rim of calcium deposits outlining the gallbladder. The condition associated with chronic cholecystitis and may increase the risk of gall bladder carincoma.
Patient has excessive VIP secretion, most likely from a VIPoma that results in (WDHA):
-watery diarrhea

VIP stimulates HCO3 and Cl secretion via binding the secondary messenger cAMP causing sodium, chloride and water secretion into the bowel (secretory diarrhea)

Somatostatin (octreotide) decreases the production of many GI hormones (eg, VIP, gastrin, glucagon, cck), its inhibitor of vip production by this lipoma is responsible for the resolution of this patient's symptoms

a. cck causes increased secretion of pancreatic enzymes and bicarb, gallbladder contraction and inhibitor of gastric emptying. It however doesn't cause WDHA syndrome. It is produced by I cells of the proximal small bowel mucosa in repose to fatty acid and amino acids.

b. gastric is produced by G cells in the stomach mucosa. It stimulates gastric acid production and growth of the gastro mucosa. Gastronomes classically cause intra table peptic ulcer disease (Zolliner_ellison syndrome).

c. Gherkin is produced in the stomach and regulates food intake. Levels increase in fasting states and fall after eating. Antagonist of gherkin are being investigated as drug targets.

d. glucagonoma ins apnacreatic aha cell tumor the thypersecretes glucagon and can cause secondary DM and necrolytic migratory erythema of the skin.

Motion is produced by duodenal mucosa na stimulates smooth muscle contract in the upper git. antibiotic erythromycin acts as agonist at motion receptors in the stomach and duodenum, contributing to the drug's GI side effects.
the qrs complex duration is typically slightly reduced during exercise in response to the increase in cardiac conduction velocity the accompanies faster HRs. However, this patient's QRS duration is normal at rest and prolonged at near maximal HR. This suggests that the drug used to treat his afib lengthens the qrs duration in a rate dependent manner, which is consistent with a drug exhibiting strong use dependence such as flecainide.

Flecainide is class 1c antiarrhthmic that is typically used to treat supra ventricular tachycardias such as those caused by afib.

Class 1c binds strongly to the fast sodium channels responsible for phase 0 depol of cardiac myocytes, blocking the inward sodium curren and prolonging qrs complex.

They are the slowest of the class 1 agents to dissociated fro Na channel. This results in a phenomenon known as use dependence, in which their sodium blocking effects intensity as HR increases d/t less time between AP for the medication to dissociate form receptor

a. selective beta 1 blockers such as atenolol od not significantly affect qrs duration. However, their use during exercise ECG testing can limit the max hr that is achieved

b. digoxin can cause false positive st segment depression during exercise egg testing as well as slower the max achievable hr. it doesn't significantly affect qrs duration

c. dofetilide is a class iii natiarrhthmic drug that blocks the outward potassium current during repeal. as a result, it increases qt interval duration but doesn't affect qrs duration. class III cents demonstrate reverse use dependence (the slower the hr, the more qt interval is prolonged).

e. verapamil class iv is a Ca channel blocker that slows the SA and AV nodal conduction. It also increases coronary blood flow and reduces myocardial oxygen demand, which can mask ischemia during stress testing. verapamil doesn't affect qrs duration.