HIV, Environmental, and Nutritional Diseases Flashcards

Question

How can you differentiate the anemia of lead toxicity from iron deficiency?

Answer 1

Both are hypochromic and microcytic, but lead toxicity is associated with basophilic stippling of red cells and high red cell free protoporphyrin (or zinc protoporphyrin)

Answer 2

- Occurs only after CD4+ T cell activation -\> in most cases, virus activation results in T cell lysis - T cell activation: **-\>** kinase phosphorylates I kappa B, targeting it for enzymatic degradation **-\>** NFKB released, and travels to nucleus **-\>** NFKB binds gene promoter sequences, incl. the long-terminal-repeat sequences flanking the HIV genome

Answer 3

- HIV enters the body through mucosal tissues and blood, first infecting CD4+ T cells, dendritic cells, and macrophages, which carry the infection to the lymphoid tissues, where the virus may remain latent for long periods - Active viral replication is associated with more infection of cells and progression to AIDS, whose hallmark is profound immune deficiency, primarily affecting cell-mediated immunity -\> loss of CD4+ T cells, and impaired function in T cell survivors

Answer 4

- Initial infection of macros or dendritic cells may be important in the pathogenesis of HIV - Blood monocytes may be vehicles for HIV to be transported to various parts of the body, including the nervous system - In certain tissues, such as lungs and brain, as many as many as _10-50%_ of macrophages are infected

Answer 5

- Can infect and multiply in terminally differentiated, non-dividing macrophages - Dependent on viral vpr gen -\> the vpr protein allows nuclear targeting of the HIV pre-integration complex through the nuclear pore

Answer 6

- Infected macros bud relatively small amounts of virus from the cell surface, but contain large numbers of virus particles in their IC vacuoles - While macros allow viral replication, they are quite resistant to cytopathic effects of HIV, in contrast to CD4+ T cells -\> may be _RESERVOIRS OF INFECTION_ whose output remains largerly protected from host defenses - In late stages of HIV infection, when CD4+ T cell #'s decline greatly, macros may be important site of continued viral replication

Answer 7

- A microglial nodule: brain equivalent of a granuloma - Part of the explanation for this pt's impaired cognition (dementia)

Answer 8

- Perivascular macrophages, some forming multinucleated giant cells 1. They have viral proteins in them, identifiable by immunostains - Part of explanation for this patient's impaired cognition (dementia)

Answer 9

- Macrophages and microglia, cells in the central nervous system (CNS) that belong to the macrophage lineage - It is believed that HIV is carried into the brain by infected monocytes

Answer 10

- Remains obscure: b/c neurons not infected by HIV, and extent of neuropathologic changes often less than might be expected from severity of neurologic symptoms, most believe the neurologic deficit is caused indirectly by viral products and soluble factors produced by infected microglia - Included among the soluble factors are the usuals, i.e., IL-1, TNF, and IL-6. NO induced in neuronal cells by gp41 has been implicated - Direct damage of neurons by soluble HIV gp120 also postulated

Answer 11

- _Early period_ after primary infection, virus disseminates, and immune response to HIV develops, which often produces an acute viral syndrome - _Clinical latency_: viral replication continues, and CD4+ T-cell count gradually decreases until it reaches critical level, below which there is substantial risk of AIDS-associated diseases

Answer 12

- CTL response to HIV is detectable by 2 to 3 weeks after the initial infection, and peaks by 9 to 12 weeks - Marked expansion of virus-specific CD8+ T-cell clones occurs during this time, and _up to 10% of a patient's CTLs may be HIV specific at 12 weeks_ - The humoral immune response to HIV peaks at about 12 weeks

Answer 13

- Acute infection is characterized by infection of memory CD4+ T cells (expressing CCR5) in mucosal lymphoid tissues -\> death of many infected cells - B/c mucosal tissues are largest reservoir of T cells in body, and major site of memory T cells, this local loss results in considerable depletion of lymphocytes - Few infected cells are detectable in the blood and other tissues. - Mucosal infection is often associated with damage to the epithelium, defects in mucosal barrier functions, and translocation of microbes across the epithelium.

Answer 14

- Dendritic cells participate in the dissemination of the virus and development of host immune responses post-acute infection by capturing the virus in epithelia at sites of virus entry - Migrate into lymph nodes, and may pass HIV to CD4+ T cells via cell-cell contact in lymphoid tissues - _Viral replication be detected in the lymph nodes within days after first exposure to HIV_

Answer 15

- High numbers of HIV particles are now present in the patient's blood - Virus disseminates throughout the body, infecting CD4+ T cells, macrophages, and dendritic cells in peripheral lymphoid tissues - The extent of viremia, measured as _HIV-1 RNA levels_, in the blood is a useful surrogate marker of HIV disease progression and is of clinical value in the management of people with HIV infection.

Answer 16

- The period of time during which anti-HIV antibodies develop and become detectable 1. Infected individual mounts antiviral humoral and cell-mediated immune responses (developing virus-specific CD8+ CTLs) - Usually within 3-7 weeks of presumed exposure

Answer 17

- _CD8+ T cells_ detected in the blood at about the time viral titers begin to fall 1. This (and antiviral humoral) immune response partially control infection and viral production 2. Reflected by a drop in viremia to low, but detectable levels by about 12 weeks after primary exposure

Answer 18

- Clinical presentation of initial spread of the virus and host response -\> estimated 40-90% of individuals who acquire primary infection develop this syndrome - Typically occurs 3-6 weeks post-infection, and resolves spontaneously in 2-4 weeks - Clinically associated w/self-limited illness w/nonspecific symptoms: sore throat, myalgias, fever, weight loss and fatigue -\> flulike syndrome 1. Other clinical features, incl. rash, cervical adenopathy, diarrhea, and vomiting may also occur

Answer 19

- Level of steady-state viremia at the end of the acute phase; reflects equilibrium b/t virus and host response, and may remain fairly stable for many years - Predictor of rate of decline of CD4+ T cells, and progression of HIV disease 1. EX: in one study, only 8% of pts with viral load 36,270 copies developed AIDS in same time frame

Answer 20

- Because loss of immune containment is associated with declining CD4+ T cell counts, the three categories are based on T cell count: 1. CD4+ cells \>500 cells/uL 2. 200-499 cells/uL 3.

Answer 21

Blood CD4+ T cell counts

Answer 22

- Lymph nodes and spleen are sites of continuous HIV replication and cell destruction - Few or no clinical manifestations of HIV infection present

Answer 23

- Up to _2 billion_ CD4+ T cells killed per day - While majority of peripheral T cells do not harbor the virus, destruction of CD4+ T cells in lymphoid tissues continues during this phase, and # of circulating CD4+ T cells steadily declines

Answer 24

- Early in the course of disease, CD4+ T cells can be replaced almost as quickly as they are destroyed, but by the chronic stage, up to _10% of CD4+ T cells in lymphoid organs_ may be infected - Frequency of _circulating CD4+ T cells_ that are infected at any one time may be _less than 0.1%_ of the total CD4+ T cells

Answer 25

- Patients are either asymptomatic, or develop minor opportunistic infections, like: oral candidiasis (thrush), vaginal candidiasis, herpes zoster, mycobacterial TB, or autoimmune thrombocytopenia - Over a period of years, the continuous cycle of virus infection, T-cell death, and new infection leads to steady decline in # of CD4+ T cells throughout body, so host defenses begin to wane - Proportion of surviving CD4+ cells infected with HIV increases, as does the viral burden per CD4+ cell. Not unexpectedly, HIV RNA levels increase as the host begins to lose the battle with the virus

Answer 26

- This is herpes simplex virus - Can reactivate, most often around lips, and most often with vesicles

Answer 27

- This is herpes simplex virus - Can reactivate, most often around lips, and most often with vesicles - Biopsy shows separation, usually at dermal-epidermal junction, w/_3 M giant cells_ (Multinucleated, with Molded nuclei, and Marginated native chromatin)

Answer 28

- This is herpes simplex virus - Can reactivate, most often around lips, and most often with vesicles - Biopsy would show separation, usually at dermal-epidermal junction, w/3 M giant cells (Multinucleated, with Molded nuclei, and Marginated native chromatin)

Answer 29

- Final phase of this disease is progression to AIDS - _Characterized by_ breakdown of host defense, dramatic increase in plasma virus, and severe, life-threatening clinical disease **-\>** after variable period, serious opportunistic infections, secondary neoplasms, or clinical neurologic disease (and dx w/AIDS) - Typically, _patient presents_ with long-lasting fevere (\>1 month), fatigue, weight loss, and diarrhea - In the absence of TX, most patients with HIV progress to AIDS after chronic phase lasting 7-10 years

Answer 30

_Exceptions_ to standard HIV/AIDS disease progression: 1. _Rapid progressors_: middle, chronic phase telescoped to 2 to 3 years after primary infection 2. _Long-term non-progressors_: untreated HIV-1–infected individuals asymptomatic for 10 years or more, with stable CD4+ T-cell counts and low levels of plasma viremia (usually about 5% to 15% of infected individuals 3. _Elite responders_: undetectable plasma virus ( about 1% of infected individuals

Answer 31

- To reduce the risk of disease progression - To prevent transmission of HIV

Answer 32

- Opportunistic infections: many of these represent reactivation of latent infections - The actual frequency of infections has been markedly reduced by the advent of highly active antiretroviral therapy (HAART), which relies on a combo of 3-4 drugs that block different steps in the HIV life cycle

Answer 33

- _Pneumocystis jiroveci_ (reactivation of prior infection): fungal pneumonia developed by 15-30% of untreated HIV-infected pts at some time during disease course - Alveoli fill up w/foamy exudate of cysts containing sm. organisms, and interstitium expanded w/edema and inflammatory infiltrate of lymphocytes/macros, creating alveolar-capillary block impeding gas exchange 1. Most characteristic symptom is dyspnea (like PE) 2. "" blood test abnormality is hypoxemia NOTE: clear space around exudate an artifact of tissue processing

Answer 34

- Pneumocystis cysts - Some with closely apposed surfaces in the center (like red blood cells), creating dark areas; others are ruptured and collapsed - Bronchoalveolar lavage fluid stained with methenamine silver stain

Answer 35

1. Candida (most common fungal infection) 2. Cytomegalovirus 3. Atypical and typical mycobacteria 4. Cryptococcus neoformans 5. Toxoplasma gondii 6. Cryptosporidium 7. Herpes simplex virus 8. Papovaviruses 9. Histoplasma capsulatum

Answer 36

- _Candidiasis_: most common fungal infect in pts w/AIDS - Infection of oral cavity, vagina, and esophagus are the most common clinical manifestations - Oral candidiasis (aka, thrush): white exudate that may resemble cottage cheese - In asymptomatic HIV-infected individuals oral candidiasis is a sign of immunologic decompensation, and it _often heralds the transition to AID_ **NOTE**: invasive candidiasis is infrequent in patients with AIDS, and usually occurs when there is drug-induced neutropenia or use of indwelling catheters

Answer 37

- One of the most common opportunistic infections in Memphis b/c hyper-endemic in MS river valley - Very similar to TB: caseating granulomatous infection if immunocompetent, but can be more diffuse pneumonia or disseminated if severely immunocompromised

Answer 38

- _Histoplasmosis_: small yeast forms, often in macrophages - Diffuse pattern pneumonia with numerous macrophages, but no discrete granulomas, and no necrosis

Answer 39

- Histoplasmosis: small yeast forms, often in macrophages - This high-power image shows many, small (3-5 micron) yeast forms in macrophages

Answer 40

- A virus that may cause disseminated disease, but, more commonly, affects eye and GI tract - Cytomegalovirus retinitis occurs almost exclusively in patients w/CD4+ T cell counts less than 50 per micro-L - GI disease, seen in 5% to 10% of cases, manifests as esophagitis and colitis, the latter associated with multiple mucosal ulcerations

Answer 41

Cytomegalovirus (CMV): simultaneous nuclear and cyto inclusions make the infected cells very large, hence name 1. Red cells 2. PNM's 3. Lymphocytes 4. Lg cells + basophilic nuclear inclusions with halos + granular, basophilc cytoplasmic inclusions

Answer 42

- This is an acid-fast stain showing mycobacterium TB - They tend to be dark red (evident here) and beaded (not evident here)

Answer 43

- Reactivation of latent pulmonary M tuberculosis, and outbreaks of primary infection, early in disease course 1. Infection may be confined to lung, or involve multiple organs - dissemination more common in pts w/very low CD4+ T-cell counts. Growing # of isolates resistant to multiple antimycobacterial drugs - Disseminated bac infection with atypical mycobacteria (chiefly, mycobacterium avium-intracellulare) late, in the setting of severe immunosuppression

Answer 44

- Cryptococcus neoformans meninges: reason for the headache 1. Lymphocytes and a few macros, and round, clear spaces containing faintly basophilic, round structures - Cryptococcus occurs in about 10% of AIDS pts. As in other settings with immunosuppression, meningitis is the major clinical manifestation of cryptococcus

Answer 45

- This is (cerebral) _toxoplasma gondii_, a frequent protozoal invader of the CNS in AIDS 1. Causes encephalitis, and is responsible for 50% of all mass lesions in the CNS - The large, granular mass in middle of the field is a cyst (latent infection reactivation), containing bradyzoites, a motile, quickly multiplying form of the protozoa 1. Active infection has tachyzoites outside the cysts (seen in this image too - very small) - The dark circle is a glial cell responding, and necrotizing

Answer 46

- Kwashiorkor: protein starvation with less inadequate carbohydrate nutrition - Lack of protein for lipoprotein synthesis causes lipid to accumulate in hepatocytes

Answer 47

- In malnourished children, protein energy metabolism presents as range of clinical syndromes, all characterized by dietary intake of proteins and calories inadequate to meet body's needs -\> marasmus and kwashiorkor are the 2 ends of the spectrum (w/considerable overlap) - _Somatic_ protein compartment (skeletal muscle) affected more severely in _marasmus_ - _Visceral_ protein compartment (visceral organs, esp. liver) affected more severely in _kwashiorkor_

Answer 48

- _Kwashiorkor_: protein depravation relatively more severe than total deficit in calories -\> seen in African children who have been weaned too early, and subsequently fed almost exclusively carb diet - _Hypoalbuminemia_ (severe depletion of the _visceral_ protein compartment) causes generalized edema, masking weight loss with fluid retention 1. Relative sparing of subcu fat and muscle mass - _Signs/symptoms_: flaky paint appearance, loss of hair color, enlarged, fatty liver (b/c reduced synthesis of carrier protein component of lipoproteins), and devo of apathy, loss of appetite, and listlessness 1. Vitamin deficiencies and secondary infections (immune deficiencies) also likely

Answer 49

- Kwashiorkor - Flaky paint appearance: alternating zones of hyperpigmentation, areas of desquamation, and hypopigmentation

Answer 50

- Often with chronic diarrheal states in which protein is not absorbed - Or in those with chronic protein loss due to conditions such as protein-losing enteropathies, the nephrotic syndrome

Answer 51

Cachexia (could also be anorexia - would need to know history)

Answer 52

- Weight falls to _60% of normal_ for height, sex, age - Growth retardation, and loss of muscle (catabolism of _somatic protein_ compartment) 1. S_erum albumin normal_ (or slightly reduced) b/c visceral protein (more critical for survival) only marginally depleted 2. Subcu fat also mobilized as fuel, so extremities emaciated and head appears too large 3. Leptin low, which may stimulate hypothalamic-pituitary-adrenal axis to make high cortisol, contributing to lipolysis - Anemia, multiple vitamin deficiencies, and evidence of immune deficiency (esp. T-cell mediated) and concurrent infections

Answer 53

1. Growth failure: both 2. Wasting: both (marked in M) 3. Edema: K (sometimes mild) 4. Hair changes: K (common), M (less common) 5. Mental changes: K (very common), M (uncommon) 6. Dermatosis, flaky paint: K 7. Appetite: K- poor, M- good 8. Anemia: K (sometimes severe), M (less severe) 9. Subcu fat: K (reduced, but present), M (absent) 10. Face: K (may be edematous), M (drawn-in, monkey-like) 11. Fatty infiltration of liver: K

Answer 54

- Marasmus: starvation w/depravation of all nutrients in proportion - Anorexia nervosa: psychiatric disease with self-induced starvation due to obsession with thinness (and misperceived obesity) - Cachexia: state of profound loss of lean body mass and fat due to cytokines, esp. TNF (cancer is most common cause)

Answer 55

- Self-induced starvation -\> marked weight loss - Primarily in previously healthy young women who have devo'd obsession with body image and thinness - Highest death rate of any psychiatric disorder - _Amenorrhea_: result of less secretion of gonadotropin-releasing hormone, and less secretion of luteinizing hormone and follicle-stimulating hormone -\> considered a diagnostic feature - Major complication: increased susceptibility to _cardiac arrhythmia and sudden death_, from hypokalemia - _Other common findings_ due to decreased thyroid hormone release include cold intolerance, bradycardia, constipation, and *changes in the skin* (dry/scaly) and hair. Dehydration and electrolyte abnormalities freq present. *Bone density decreased* b/c low estrogen levels, like in postmenopausal osteoporosis. May also have anemia, *lymphopenia*, and hypoalbuminemia

Answer 56

- Excess body fat; most often defined in terms of BMI (weight in kg/height in m) - Recommended classification from NIH and WHO: 1. Normal weight: 18.5-24.9 kg/m(2) 2. Overweight: 25.0-29.9 3. Obesity: \> or = 30 4. Morbid obesity: \> or = 40 (aka, severe or extreme)

Answer 57

- Yes, the NIH and WHO cutoffs are derived from data collected on whites but in some populations, the level of risk in terms of body fat is reached at much lower BMI (South Asians) and in others a higher BMI (AA) when compared to whites - Current cutoffs for (South) Asians: 1. Overweight: 23-24.9 2. Obesity: \>25

Answer 58

- Increasing central adiposity is associated with increased risk of morbidity and mortality -\> _waist circumference_ should also be measured (+BMI) to assess abdominal obesity - Pts. with _abdominal obesity_ (aka, central adiposity, visceral android, or male-type obesity) are at increased risk for heart disease, diabetes, HTN, and dyslipidemia

Answer 59

- T2D, HTN, dyslipidemia, accelerated atherosclerotic CVD - Non-alcoholic fatty liver disease (steatohepatitis, steatosis, and cirrhosis), cholelithiasis (gallstones), cholecystitis (inflammation of gall bladder) - Osteoarthritis, obstructive sleep apnea, GERD, urinary stress incontinence, hypoventilation syndrome, depression, infertility - DVT, thromboembolus, chronic pro-inflammatory state - Cancers of colon, breast, esophagus, thyroid, kidney endometrium and gallbladder

Answer 60

- Eccentric thickening with loose atheroma containing cholesterol clefts and a fibrous cap producing severe stenosis (about 90%) of the lumen - Diagnosis: atherosclerosis

Answer 61

1. Diabetes mellitus 2. HTN 3. Dyslipidemia 4. Abdominal (male-pattern) obesity - Each of these speeds patient toward death via heart disease -\> _increases with age_ - Aka, obesity dyslipidemia syndrome, insulin resistance syndrome, or deadly quartet - Most prevalent in: Native Americans, Hispanics, AA, and European Americans

Answer 62

- Pro-inflammatory and pro-thrombotic - Associated with elevated levels of: 1. C-reactive protein (CRP) 2. IL-1 3. IL-6 4. IL-18 5. TNF 6. Plasminogen activator inhibitor-1

Answer 63

- Anti-inflammatory cytokine produced exclusively by adipocytes - Enhances insulin sensitivity, and inhibits many steps in the inflammatory process - Reduced in the metabolic syndrome - Very high levels in the blood (1,000x higher than other polypeptide hormones); lower in obese than lean people

Answer 64

1. Directs fatty acids (FA) to muscle for their oxidation 2. Decreases influx of FA to liver & total hepatic TG content 3. Decreases glucose production in liver, causing increase in insulin sensitivity and protection against metabolic syndrome

Answer 65

- Circulates as complex of 3, 6, or more aggregates of monomeric form - Binds two receptors, AdipoR1 and AdipoR2, found in many tissues, including the brain, but most highly expressed in skeletal muscle and liver, respectively - Binding of adiponectin to its receptors triggers signals that activate cAMP-dependent protein kinase (protein kinase A), phosphorylating and inactivating acetyl coenzyme A carboxylase, a key enzyme required for FA synthesis

Answer 66

- Metabolic syndrome responds to diet, leading to weight loss, with additional benefit from specific diets: 1. Mediterranean: high in fruits, veggies, nuts, whole grains, and olive oil 2. Dash diet: low in sodium 3. Diet of foods with lower glycemic index, replacing refined grains with whole grains, etc.

Answer 67

- Yes: practical, regular, moderate daily minimum of 30 minutes, like brisk walking - May be beneficial beyond its effect on weight loss by more selectively removing abdominal fat, at least in women - Liposuction reduces amt of subcutaneous fat, which changes abdominal - superficial adipose tissue ratio and might affect potential of metabolic syndrome by means of its separate parameters and clinical manifestations (from PubMed)

Answer 68

- Metabolic syndrome is associated with insulin resistance, T2D, and hormonal changes -\> _increases in insulin and insulin-like growth factor-1 (IGF-1) stimulate cell proliferation and inhibit apoptosis_, which may contribute to tumor growth - Hyperinsulinemia (HI) -\> decreased IGFBP-1 and 2 (IGF binding protein), increasing the bioavailability IGF-1, which promotes cell proliferation, and decreases apoptosis (effect enhanced by decreased adiponectin) 1. HI also leads to increased estrogen bioavailability, decreased sex-hormone binding globulin, and increased ovarian androgen

Answer 69

- Non-alcoholic fatty liver disease: consistently associated with insulin resistance and metabolic syndrome (having at least 2 of: HTN, dyslipidemia, abdominal obesity, T2D) - Insulin resistance (T2D) results in the accumulation of triglycerides in hepatocytes by at least three mechanisms: 1. Impaired oxidation of fatty acids (FA) 2. Increased syn/uptake of FA 3. Decreased hepatic secretion of very-low-density lipoproteins (VLDL) cholesterol

Answer 70

- Gall bladder with thickened, inflamed wall (_cholecystitis_), containing bile, pus, gallstone, and debris - Two main types of gallstones: 1. Cholesterol stones - contain crystalline cholesterol monohydrate (80% of stones in the West) 2. Pigment stones - _Bile formation is the ONLY significant pathway for the elimination of excess cholesterol from the body_ -\> when cholesterol concentrations exceed solubilizing capacity of bile (supersaturation), cholesterol can no longer remain dispersed and crystallizes out of solution

Answer 71

1. Female 2. 40's 3. Fertile 4. Overweight (fat, if it helps you remember)

Answer 72

- Condition: Raynaud phenomenon - Cause: exaggerated vascular response to cold with abnormal vasoconstriction of digital arteries 1. Vasoconstriction (white), deoxygenation causing cyanosis (blue), reperfusion causing hyperemia (red); doesn't always have to have all of these phases - Epi: very common (5% of US population), but more common in females and young adults - Treatment: warm hands - Prognosis: usually benign, except in minority of patient who have scleroderma with it

Answer 73

- Irregular-shaped areas of erosion - Osteoarthritis

Answer 74

- Continually increased pressure on cartilage in weight-bearing joints causes pressure atrophy, progressing to injury and necrosis - The knee suffers a concentration of pressure per unit area higher than any other weight-bearing joint

Answer 75

- Clusters of tumor cells invading fibrous and adipose tissue -\> diagnosis = breast cancer - Possible mechanisms: 1. Fat tissue produces excess **estrogen**, associated with risk of breast, endometrial, and some other cancers 2. Obese people often have increased levels of insulin and **IGF-1** in their blood 3. Fat cells produce hormones, adipokines, that may stimulate cell growth. **Leptin**, more abundant in obese people, seems to promote cell proliferation 4. Fat cells may also have direct and indirect effects on other tumor regulators, incl. mammalian target of rapamycin (**mTOR**) and AMP-activated protein kinase 5. Obese people often have chronic low-level **inflammation**

Answer 76

- Stellate (star-shaped) tan-white lesion surrounded by yellow fat - Breast resection (lumpectomy) - Diagnosis: breast cancer

Answer 77

- One study estimated: 1. 34,000 new cases of cancer in men (4%) and 2. 50,500 in women (7%) were due to obesity - The percentage attributed to obesity was as high as 40% for some cancers, particularly endometrial cancer and esophageal adenocarcinoma

Answer 78

- Secreted from endocrine cells in the ileum and colon - Acts centrally by stimulating POMC/CART neurons in the hypothalamus, causing decrease in food intake (similar to amylin) - Plasma levels are low during fasting, and increase shortly after food intake 1. IV administration reduces energy intake, and its levels generally increase after gastric bypass 2. By contrast, levels of PYY generally decrease in ppl w/Prader-Willi syndrome (loss of imprinted genes on chromosome 15q11-q13), disorder marked by hyperphagia and obesity - These observations have led to ongoing work to produce PYYs for the treatment of obesity

Answer 79

- Alterations in the gut microbiome are the focus of new research b/c diet has marked effects on the bacterial makeup of the colon - Bacterial flora can have large effects on the ability of the host to break down certain dietary constituents (e.g., fiber) and absorb nutrients, as well as on epithelial integrity and inflammation - In response to these changes, expression of gut factors such as PYY that feedback on central appetite centers may also be altered

Answer 80

- A peptide secreted with insulin from pancreatic beta cells that reduces food intake and weight gain - Being evaluated for treatment of obesity and diabetes - Acts centrally by stimulating POMC/CART neurons in the hypothalamus, causing decrease in food intake (similar to PYY)

Answer 81

- Total # of adipocytes established in childhood and adolescence (childhood obesity important), and is higher in obese than lean individuals - In adults, estimated 10% of adipocytes are renewed annually, regardless of level of individual's body mass, but # remains constant -\> #'s are tightly controlled, and loss of fat mass occurs through shrinking of existing adipocytes - _Difficulty maintaining weight loss_ from dieting not well understood, but appears to be _related to homeostatic mechanisms keeping body fat constant_ w/time -\> unless lowered caloric intake and/or energy expenditure maintained, body weight returns to pre-diet levels

Answer 82

- Omega-3-FA's, which may be protective against atherosclerosis (ex: eskimos who eat high fat diet, but have low incidence of atherosclerosis) - Avg. US adult consumes 3:1 ratio of saturated to polyunstaruated FA's. But, lowering this ratio to 1:1 causes 10-15% reduction in serum cholesterol level within weeks - Given strong association of hypercholesterolemia and atherosclerosis, low fat diet might lower risk (or _substitution_ of "good fats") 1. Note: recent studies have shown that omega-3 _supplements_ do not lower risk of CVD

Answer 83

- In addition to leptin and adiponectin, adipose tissue produces cytokines like: 1. TNF, IL-6, IL-1, and IL-18, chemokines, and steroid hormones 2. Increased production creates chronic pro-inflammatory state marked by _high levels of circulating C-reactive protein_ - May be more than a one-way street -\> emerging evidence suggests immune cells, esp. tissue macros, have important roles in regulating adipocyte function - Adipose tissue participates in control of energy balance and metabolism, functioning as a link between lipid metabolism, nutrition, and inflammatory responses

Answer 84

- Cerebral toxoplasmosis or primary CNS lymphoma: accurate interpretation of CT and MRI is critical because the treatments are different - In 50-80% of cases, these appear similar and require careful interpretation: 1. _Primary CNS lymphoma_: typically sub-ependymal spread, and more frequently is a solitary lesion 2. _Toxoplasmosis_: tends to be scattered throughout basal ganglia and at corticomedullary junction, and is multi-focal (86%) - _Ependyma_: thin epithelium-like lining of ventricular system of brain and central canal of spinal cord. One of four types of neuroglia in CNS, and is involved in the production of cerebrospinal fluid (CSF)

Answer 85

- JC virus: a human papovavirus (assoc. with neoplasms in animals, and important cause of CNS infection in HIV+) -\> causes: 1. Progressive, multifocal leukoencephalopathy: due to infection of oligodendrocytes (myelin-making cells of the CNS) - Large, circular, hyperbasophilic cell in upper right corner is an infected cell - The larger, granular cells with long, pink tails are reactive glial cells

Answer 86

Mucocutaneous ulcerations involving the mouth, esophagus, external genitalia, and perianal region ## Footnote

Answer 87

- Persistent diarrhea, which is common in untreated patients with advanced AIDS, is often caused by infections with protozoans such as: 1. Cryptosporidium, isospora belli, or microsporidia - These patients have chronic, profuse, watery diarrhea with massive fluid loss - Diarrhea may also result from infection with enteric bacteria, such as: 1. Salmonella, shigella, and M. avium-intracellulare

Answer 88

- Proliferation of spindle-shaped cells, creating slit-like vascular spaces -\> _Kaposi Sarcoma_ (KS) - Patients with AIDS have a high incidence of certain tumors, esp. Kaposi, B-cell lymphoma, cervical cancer in women, and anal cancer in men - Estimated _25-40%_ of untreated HIV-infected individuals will eventually develop a malignancy - _Reversible_, if immune function improved (so NOT really a malignant tumor)

Answer 89

Kaposi sarcoma

Answer 90

- Some pts. w/advanced disease given ART devo a paradoxical clinical deterioration during recovery period of the immune system, despite increasing CD4+ T-cell counts and decreasing viral load - Basis not understood, but postulated to be a poorly regulated host response to high antigenic burden of persistent microbes - One of several new complications assoc. w/HIV-infection and tx that have emerged

Answer 91

- Include: 1. Lipoatrophy: loss of facial fat 2 Lipoaccumulation: excess fat deposition centrally 3. Elevated lipids 4. Insulin resistance 5. Peripheral neuropathy 6. Premature cardiovascular kidney and liver disease

Answer 92

- Non-AIDS morbidity far more common than classic AIDS-related morbidity - Major causes are: _cancer, and accelerated CV, kidney, and liver disease_ - Mechanism for these non-AIDS related complications is not known, but persistent inflammation and T-cell dysfunction may play a role

Answer 93

Lead, mercury, arsenic, and cadmium

Answer 94

- _Children_: CNS defects (b/c more permeable blood-brain barrier) 1. Absorb more than 50% of lead ingested from food, while adults absorb about 15%; main source of exposure is lead-based paint in older homes - _Adults_: Peripheral neuropathy - _Both_: Interferes with remodeling of cartilage, and causes anemia by interfering with hemoglobin synthesis

Answer 95

- Major source of exposure is contaminated fish - Developing brain highly sensitive to methyl mercury, which accumulates in the CNS - Exposure of fetus to high levels of mercury in utero may lead to Minamata disease: characterized by cerebral palsy, deafness, and blindness

Answer 96

- Naturally found in soil and water, and is a component of some wood preservatives and herbicides - Excess arsenic interferes with mito ox phos, and the function of a variety of proteins - Also causes toxic effects in the GI tract, CNS, and CV system; long-term exposure causes skin lesions and carcinomas

Answer 97

- Nickel-cadmium batteries and chemical fertilizers can contaminate soil - Excess cadmium causes obstructive lung disease and kidney damage

Answer 98

Smoking ## Footnote

Answer 99

- Contains more than 2000 compounds - Among these are _nicotine_, responsible for tobacco addiction, and potent carcinogens: 1. Polycyclic aromatic hydrocarbons 2. Nitrosamines 3. Aromatic amines

Answer 100

- About 90% of lung cancers occur in smokers; smoking cessation reduces the risk of lung cancer. - Smoking is also associated with an increased risk of cancers of the: 1. Oral cavity, larynx, esophagus 2. Stomach 3. Bladder, and kidney 4. Some forms of leukemia

Answer 101

- Smokeless tobacco use is an important cause of _oral cancers_ (tobacco companies moving into this business perceived as a continued public health threat) - Tobacco consumption interacts with alcohol in _multiplying the risk_ of oral, laryngeal, and esophageal cancer - Tobacco consumption _increases the risk_ of lung cancers from occupational exposures to asbestos, uranium, and other agents

Answer 102

- Tobacco use is an important risk factor for development of: atherosclerosis and MI, peripheral vascular disease, cerebrovascular disease - In the lungs, in addition to cancer, it predisposes to emphysema, chronic bronchitis, and chronic obstructive disease (COPD) - Maternal smoking increases the risk of abortion, premature birth, and intrauterine growth retardation

Answer 103

- Nicotine damages vascular endothelial cells, causing inflammation via IL-8, LTB4, and TNF, attracting neutrophils - Inactivation of anti-proteases, i.e., alpha-1-antitrypsin, reduces efficacy in "cleaning up" ROS made by elastas from neutrophils -\> tissue damage - Increased alveolar macrophage elastase and metalloproteinases in lungs may cause emphysema

Answer 104

- Emphysema in lung tissue: abnormal, permanent enlargement of airspaces due to destruction of the walls between alveoli

Answer 105

- Intoxication, accidents, murder, suicide - Pancreatitis, gastritis (erosive, hemorrhagic and ulcerative) - _Liver disease_ (steatosis, hepatitis, cirrhosis) - Alcoholic cardiomyopathy, peripheral neuropathy - _Fetal alcohol syndrome_ - Cerebral atrophy, cerebellar degeneration - Cancer of the mouth, larynx, esophagus, breast, liver

Answer 106

- Drowsiness at 200 mg/dL. Stupor (300 mg/dL) and coma, with possible respiratory arrest, at higher levels - Yes: rate of metabolism affects the blood alcohol level 1. Chronic alcoholics can tolerate levels up to 700 mg/dL, partially explained by accelerated ethanol metabolism caused by 5- to 10-fold induction of liver CYPs

Answer 107

- Oxidized to acetaldehyde by alcohol dehydrogenase, _CYP 450 system_, and catalase - Acetaldehyde converted to acetate in mito, and utilized in respiratory chain - _Oxidation by alcohol dehydrogenase depletes NAD_, leading to accumulation of fat in the liver and metabolic acidosis

Answer 108

- Most (80-85%) is taken up in bone and developing teeth; competes with Ca, and binds phosphates, w/half-life in bone of 20-30 years - 5-10% remains in the blood, and the rest is distributed in the soft tissues

Answer 109

- _Lead lines_: excess lead interferes with normal remodeling of calcified cartilage and primary bone trabeculae in the epiphyses in children, causing _increased bone density_ - These may also occur in the gums, where excess lead causes hyperpigmentation - Lead _inhibits the healing of fractures_ by increasing chondrogenesis and delaying cartilage mineralization

Answer 110

- Excreted via the kidneys - Acute exposures may cause damage to the proximal tubules

Answer 111

- _Main effects_: fatty liver, alcoholic hepatitis, and cirrhosis (which leads to portal hypertension and increases risk for devo of hepatocellular carcinoma) - Can cause bleeding from gastritis and gastric ulcers, peripheral neuropathy (thiamine deficiency), alcoholic cardiomyopathy, and acute/chronic pancreatitis - _Major risk factor for cancers of oral cavity, larynx, and esophagus_ -\> risk is greatly increased by concurrent smoking or use of smokeles tobacco

Answer 112

- Estimated more than 10 million chronic alcoholics live in US, and alcohol consumption is responsible for more than _100,000 deaths annually_ - _\>50% from accidents_ involving drunk driving and alcohol-related homicides and suicides - About 15,000 _(15%) a consequence of cirrhosis_ of the liver

Answer 113

- After consumption, ethanol absorbed unaltered in the stomach and small intestine, and distributed to all of the tissues and fluids of the body in direct proportion to blood level - Concentration of _80 mg/dL in blood_ constitutes legal definition of drunk driving in US 1. For avg person, this is about three standard drinks, i.e., about three (12 ounce) bottles of beer, 15 ounces of wine, or 4 to 5 ounces of 80 proof distilled spirits

Answer 114

- Tan-yellow color instead of the typical red-brown - Steatosis

Answer 115

- Hepatocytes distended with clear cytoplasm due to lipid dissolved out during processing - _Steatosis_ 1. Common causes: alcohol, obesity, uncontrolled diabetes

Answer 116

Normal liver

Answer 117

1. Shunting of substrates away from catabolism and toward lipid biosynthesis b/c generation of excess reduced nicotinamide-adenine dinucleotide (NADH) from metabolism of ethanol by alcohol dehydrogenase and acetaldehyde dehydrogenase 2. Impaired assembly and secretion of lipoproteins 3. Increased peripheral catabolism of fat

Answer 118

- In addition to steatosis, there is acute neutrophilic inflammation, and some dying or dead hepatocytes with pyknotic nuclei - _Steatohepatitis_

Answer 119

Normal liver

Answer 120

- **Acetaldehyde** (major metabolite of ethanol) induces lipid peroxidation and acetaldehyde-protein adduct formation, which may disrupt cytoskeleton and membrane function - **Alcohol directly** affects cytoskeleton organization (e.g., Mallory-Denk bodies), mito function and membrane fluidity - **ROS** generated via oxidation of ethanol by microsomal ethanol oxidizing system react w/and damage proteins and membranes - **Cytokine-mediated inflammation** & cell injury major feature of alcoholic hepatitis & alcoholic liver disease - **TNF** considered to be main effector of injury; IL-1, IL-6 and IL-8 may also contribute.

Answer 121

- _Mallory-Denk bodies_: tangled skins of deranged cytoskeletal cytokeratin intermediate filaments 1. Inclusion found in cytoplasm of liver cells 2. Damaged intermediate filaments 3. Most common in alcoholic hepatitis (65% prevalence) and alcoholic cirrhosis (51% prevalence)

Answer 122

- Abnormal, nodular architecture -\> cirrhosis - _Cirrhosis_ is a distinctive form of liver fibrosis w/regenerative nodules of hepatocytes, not properly connected to hepatic arterial supply, portal veinous circulation or biliary system, and surrounded by fibrous tissue

Answer 123

- Round-oval nodules of regenerative hepatocytes completely surrounded by fibrous tissue, characteristic of cirrhosis

Answer 124

- 15 years (but only about 15% of alcoholics get it) - Differentiate based on HISTORY

Answer 125

- Trabeculae (right side) and glandular structures of cells that look like hepatocytes, but with bigger nuclei, less cytoplasm, and bile in some of the glandular structure lumens - _Hepatocellular carcinoma_ (liver cancer; complication of alcoholic liver disease): cause of death in 3-6% of cases of alcoholic liver disease

Answer 126

- Rounded, variegated, green, brown, and tan mass with background cirrhosis - _Hepatocellular carcinoma_

Answer 127

1. Specific dysmorphic facial features 2. Growth retardation 3. CNS abnormalities: wide range of neurobehavioral problems, incl. impairment of self-regulation, cognition, and adaptive functioning

Answer 128

- 2011 US survey (pregnant women 15-44): 1. Cigarette use: 17.6% 2. Alcohol use: 9.4% (2.6% binge drinking, 0.4% heavy drinking) 3. Ilicit drug use 5%

Answer 129

- Antineoplastic agents - Anticoagulants - Menopausal hormone therapy preparations and oral contraceptives - Acetaminophen - Aspirin

Answer 130

- Menopausal hormone therapy _increases risk of breast and endometrial cancers and thromboembolism_, and does not appear to protect against ischemic heart disease - Oral contraceptives have protective effect against endometrial and ovarian cancers, but _increase the risk of thromboembolism and hepatic adenomas_ (adenoma is a benign tumor of epithelial tissue with glandular origin)

Answer 131

- Overdose of acetaminophen may cause _centrilobular liver necrosis_, leading to liver failure -\> early treatment with agents that restore GSH (glutathione) levels may limit toxicity - Aspirin blocks production of thromboxane A2, which may produce _gastric ulceration and bleeding_

Answer 132

- Sedative-hypnotics (barbiturates, ethanol) - Psychomotor stimulants (cocaine, meth, ecstasy) - Opioid narcotics (heroin, oxycodone) - Hallucinogens - Cannabinoids (marijuana)

Answer 133

- Metabolized to _NAPQI_ (N-acetyl-p-benzoquinoneimine) via hepatic P450 system - With very large doses, excess NAPQI leads to hepatic centrilobular necrosis

Answer 134

- Most commonly used analgesic in the US -\> toxicity is common, and responsible for \>50,000 ED visits/year - In US, it is the cause of about 50% of acute liver failure cases, with 30% mortality - Intentional overdose is the most common cause of acetaminophen toxicity in UK, but unintentional OD most common in US, representing almost 50% of total intoxication cases

Answer 135

- Window between usual dose (0.5gm) and toxic dose (15-25gm) large, and drug is ordinarily very safe - Toxicity begins with: nausea, vomiting, diarrhea, and sometimes shock, w/evidence of jaundice in a few days - Overdoses can be treated in early stages (w/in 12 hrs) by admin of N-acetylcysteine, restoring GSH levels 1. If serious overdose liver failure ensues, starting w/centrilobular necrosis that may extend into entire lobules, liver transplant only hope for survival

Answer 136

- Can induce myocardial ischemia via coronary artery vasoconstriction + enhancing platelet aggregation and thrombus formation (Norepi/dopa reuptake inhibitor) - Cigarette smoking potentiates cocaine-induced coronary vasospasm -\> dual effect of cocaine, causing increased myocardial O2 demand by sympathomimetic action, and, decreasing coronary blood flow, sets stage for myocardial ischemia that may lead to MI - Cocaine can also precipitate lethal arrhythmias by enhanced sympathetic activity, disrupting normal ion (K+, Ca 2+, Na+) transport in myocardium - Toxic effects are not necessarily dose related, and fatal event may occur in first time user w/typical mood-altering dose

Answer 137

- Delta-9-tetrahydrocannabinol: distorts sensory perception and impairs motor coordination, with acute effects generally clear in 4-5 hours - With continued use, these changes may progress to cognitive and psychomotor impairments, such as inability to judge time, speed, and distance, a potential cause of automobile accidents

Answer 138

- Laryngitis, pharyngitis, bronchitis, cough and hoarseness, and asthma-like symptoms have all been described, along with mild, but significant airway obstruction - Marijuana cigarettes also contain a large number of carcinogens that are also present in tobacco

Answer 139

- A large number of studies have characterized the endogenous cannabinoid system, which consists of the cannabinoid receptors CB1 and CB2, and the endogenous lipid ligands known as endocannabinoids - This system participates in the regulation of the hypothalamic-pituitary-adrenal axis, and modulates the control of appetite, food intake, and energy balance, as well as fertility and sexual behavior

Answer 140

- May injure cells directly or indirectly by generating _free radicals_ from water or molecular oxygen - Damages DNA -\> rapidly dividing cells like _germ cells, and those in bone marrow and GI tract_ very sensitive to radiation injury - DNA damage that is not adequately repaired may result in mutations that predispose affected cells to _neoplastic transformation_ - May cause _vascular damage and sclerosis_, resulting in ischemic necrosis of parenchymal cells, & replacement by fibrous tissue

Answer 141

- Wide range of structural changes in chromosomes related to double-stranded DNA breaks, incl. deletions, translocations, and fragmentation - Mitotic spindle often becomes disorderly; there may be polyploidy & aneuploidy, or apoptosis - Nuclear swelling, condensation/clumping of chromatin and disruption of nuclear membrane may be noted - Giant cells w/pleomorphic nuclei, or \>1 nucleus may appear, and persist for years after exposure - At extremely high doses of radiant energy, markers of cell death, i.e., nuclear pyknosis & lysis, appear quickly

Answer 142

- Low power view of ileum resected for obstruction caused by radiation therapy for uterine cervical squamous cell carcinoma - Note the sharp border between the normal ileum (arrow 1) and the injured ileum - The radiation-injured part is totally replaced by fibrous scar tissue (even the muscle layer above arrow 2) - The epithelium is gone (arrow 3)

Answer 143

- Abnormal, pleomorphic, _radiation-injured cells_ - Radiant energy may induce cytoplasmic swelling, mito distortion, and degeneration of ER; plasma membrane breaks and focal defects may be seen - Histologic constellation of cellular pleomorphism, giant-cell formation, conformational changes in nuclei, abnormal mitotic figures creates _similarity b/t radiation-injured cells and cancer cells_, a problem plaguing the pathologist when evaluating irradiated tissues for the possible persistence of tumor cells

Answer 144

- Artery (former) obliterated by radiation injury (junction of what used to be tunica intima and media arrowed) - Vascular changes and interstitial fibrosis prominent in irradiated tissues. _In immediate postirradiation period, vessels may show only dilation_ - With time, or higher doses, a variety of degenerative changes appear, including endo cell swelling and vacuolation, or _even necrosis and dissolution of walls of small vessels_ (e.g., venules or capillaries) -\> affected vessels may rupture or thrombose - Still later, endo cell proliferation and collagenous hyalinization and thickening of intima seen, resulting in _marked narrowing or even obliteration of vascular lumens_. At this time, increase in interstitial collagen in irradiated field becomes evident, leading to scarring

Answer 145

- A condition in which the patient binges on food, then induces vomiting - More common than anorexia nervosa, and generally has a better prognosis -\> estimated to occur in 1-2% of women and 0.1% of men, w/avg. onset at 20 y/o - Primarily in previously healthy young women who have developed an obsession with body image and thinness - Major complication an increased susceptibility to cardiac arrhythmia and sudden death from hypokalemia

Answer 146

- Extreme weight loss, fatigue, muscle atrophy, anemia, anorexia, and edema -\> mortality generally a result of atrophy of diaphragm and o/respiratory muscles - 50% of cancer pts, most commonly GI, pancreatic and lung, and responsible for 30% of cancer deaths

Answer 147

- Mediators secreted by tumors and during chronic inflammation reactions contribute to devo: 1. _Proteolysis-inducing factor_: glycosylated polypeptide excreted in urine of weight-losing pts w/pancreatic, breast, colon, & o/cancers 2. _Lipid-mobilizing factor_: increases FA oxidation, and pro-inflammatory cytokines like TNF (aka, cachectin) and IL-6 - Proteolysis-inducing factor + pro-inflammatory cytokines cause skeletal muscle breakdown via NFKB-induced activation of ubiquitin proteasome pathway, promoting degradation of skeletal muscle structural proteins like myosin heavy chain by upregulating the expression of several muscle-specific ubiquitin ligases - Other data implicate acquired abnormalities of the myofibril dystrophin-glycoprotein complex (figure), the same membrane complex that is defective in several forms of muscular dystrophy

Answer 148

- Thirteen vitamins are necessary for health; distinction between fat- and water-soluble vitamins is important 1. Fat soluble: A, D, E, K -\> more readily stored in the body, but may be poorly absorbed in fat malabsorption disorders, caused by disturbances of digestive functions 2. Water-soluble: all the others - Can be synthesized endogenously: 1) vitamin D from precursor steroids, 2) vitamin K and biotin by the intestinal microflora, and 3) niacin from tryptophan, an essential amino acid

Answer 149

- Maintenance of normal vision (esp. in reduced light) - Regulation of cell growth and differentiation (esp. epithelial mucus -secreting cells) - Regulation of lipid metabolism - Enhancing immunity to infection, esp in kids w/measles - Vitamin A is the name given to a group of related compounds that include retinol (vitamin A alcohol), retinal (vitamin A aldehyde), and retinoic acid (vitamin A acid), which have similar biologic activities

Answer 150

- Bile - Pancreatic enzymes - Some level of antioxidant activity in the food

Answer 151

- Generally ingested as retinol ester or β-carotene (which is converted to retinol) and absorbed in intestine - Transported in chylomicrons to liver for esterification & storage; uptake in liver via apolipoprotein E receptor - \>90% of body's vitamin A reserves stored liver, mainly in perisinusoidal stellate (Ito) cells - In healthy persons who consume an adequate diet, reserves are sufficient to meet body's demands for at least 6 months

Answer 152

- Before release, retinol binds to specific _retinol-binding protein_ (RBP), synthesized in the liver - Uptake of retinol/RBP in peripheral tissues dependent on cell surface receptors specific for RBP - After uptake, retinol binds cellular RBP, and RBP is released back into the blood - Retinol may also be stored in peripheral tissues as retinol ester or may be oxidized to form _retinoic acid_, which has important effects on epithelial differentiation and growth

Answer 153

- Synthesis of _rhodopsin_ from retinol: 1) oxidation to all-trans-retinol, 2) isomerization to 11-cis-retinal, 3) covalent association w/7-transmembrane rod protein opsin - Photon of light causes isomerization of 11-cis-retinal to all-trans-retinal, which dissociates from rhodopsin, and induces conformational change in opsin, triggering nerve impulse via neurons from retina to brain - During dark adaptation, some of the all-trans-retinal is reconverted to 11-cis-retinal, but most is reduced to retinol and lost to the retina

Answer 154

- Four: _rhodopsin_ in the rods, the most light-sensitive pigment and therefore important in reduced light, and _three iodopsins_ in cone cells, each responsive to specific colors in bright light

Answer 155

Squamous metaplasia of mucus-secreting epithelium into a keratinizing epithelium

Answer 156

- Activation of retinoic acid receptors (RARs) by their ligands (retinoic acid) causes the release of corepressors and the obligatory formation of heterodimers with another retinoid receptor, known as the retinoic X receptor (RXR) - Both RAR and RXR have three isoforms, α, β, and γ. The RAR/RXR heterodimers bind to retinoic acid response elements located in the regulatory regions of genes that encode receptors for growth factors, tumor suppressor genes, and secreted proteins

Answer 157

- Retinoic X receptor (RXR), believed to be activated by 9-cis retinoic acid, can form heterodimers with other nuclear receptors, such as nuclear receptors involved in drug metabolism, the peroxisome proliferator-activated receptors (PPARs), and vitamin D receptors - PPARs are key regulators of fatty acid metabolism, including fatty acid oxidation in fat tissue and muscle, adipogenesis, and lipoprotein metabolism -\> PPAR + RXR are ligand-activated transcription factors that decrease triglycerides and increase HDLs

Answer 158

- Beneficial effect of vitamin A in diarrheal diseases may be related to the maintenance and restoration of the _integrity of the epithelium of the gut_ - The effects of vitamin A on infections also derive in part from its ability to _stimulate the immune system_ - Infections may reduce the bioavailability of vitamin A by inhibiting retinol binding protein (RBP) synthesis in the liver through the acute-phase response

Answer 159

- Tx of _acute promyelocytic leukemia_: all-trans-retinoic acid induces differentiation and apoptosis of acute promyelocytic leukemia cells by binding a PML-RARα fusion protein that characterizes this form of cancer - A different isomer, 13-cis retinoic acid, has been used with some success in the tx of _childhood neuroblastoma_ - _NOTE_: retinoids also used clinically for the tx of skin disorders like severe acne and some forms of psoriasis

Answer 160

- One of the earliest manifestations is impaired vision, esp. in reduced light (night blindness) - **EYE**: Xerophthalmia (dry eye), buildup of keratin debris in small opaque plaques (_Bitot spots_), then destruction of cornea (keratomalacia), and blindness - **EPITHELIUM**: upper respiratory passage and urinary tract undergoes squamous metaplasia. Loss of mucociliary epi of airways predisposes to secondary pulmonary infections, and desquamation of keratin debris in urinary tract predisposes to renal/urinary bladder stone - **IMMUNE** deficiency

Answer 161

- Maintenance of adequate plasma levels of _Ca and phosphorus_ to support metabolic functions, bone mineralization, and neuromuscular transmission - Required for prevention of bone diseases, i.e., _rickets_ (in children whose epiphyses have not already closed), _osteomalacia_ (in adults), and hypocalcemic _tetany_ (a convulsive state caused by insufficient EC concentration of ionized Ca, which is required for normal neural excitation and the relaxation of muscles)

Answer 162

- Primary source: endogenous syn from precursor, 7-dehydrocholesterol, in photochemical rxn that requires _solar or artificial UV light_ in range of 290-315 nm (UVB radiation) -\> syn of cholecalciferol (aka, vitamin D) - Under usual conditions of sun exposure, about 90% of required vit D endogenously synthesized in skin. Ppl with dark skin generally have lower level of vitamin D production b/c of melanin pigmentation - Dietary sources, like _deep-sea fish, plants, and grains_, contribute the remaining required vit D, and depend on adequate intestinal fat absorption. In plants, vit D is present in a precursor form (ergosterol), which is converted to vitamin D in the body

Answer 163

1. Photochemical syn from 7-dehydrocholesterol in skin and absorption from foods/supplements in gut 2. Vit D binding to plasma α 1 -globulin (D-binding protein or DBP), and transport into the liver 3. Conversion of vit D into 25-hydroxycholecalciferol (25-OH-D) in the liver via action of 25-hydroxylases, including CYP27A1 and other CYPs 4. Conversion of 25-OH-D into 1,25-dihydroxyvitamin D, [1α,25(OH) 2 D 3], the most active form of vitamin D, by the enzyme 1α-hydroxylase in the kidney

Answer 164

1. _Hypocalcemia_ stimulates secretion of parathyroid hormone (PTH), augmenting the conversion of 25-OH-D into 1,25-dihydroxyvitamin D by activating 1α-hydroxylase 2. _Hypophosphatemia_ directly activates 1α -hydroxylase , increasing the production of 1,25-dihydroxyvitamin D 3. Through a _negative feedback_ mechanism, increased levels of 1,25-dihydroxyvitamin D down-regulate its own synthesis through inhibition of 1α-hydroxylase activity

Answer 165

- Binds a _high-affinity nuclear receptor that associates w/RXR_ -\> heterodimeric complex binds vit D response elements in regulatory sequences of vit D target genes - Receptors for 1,25-dihydroxyvitamin D are present in most cells of the body -\> in small intestine, kidneys, and bones, signals transduced via these receptors regulate plasma levels of Ca and phosphorus - Also appears to act through mechanisms that don't require transcription of target genes. A_lternative mechanisms_ involve binding of 1,25-dihydroxyvitamin D to membrane-associated vit D receptor (mVDR), leading to activation of protein kinase C & opening Ca channels

Answer 166

- Contributes to the mineralization of osteoid matrix and epiphyseal cartilage in both flat and long bones - Stimulates osteoblasts to synthesize Ca-binding protein, osteocalcin, involved in the deposition of Ca during bone devo

Answer 167

1. Stimulation of intestinal calcium absorption 2. Stimulation of calcium reabsorption in the kidney 3. Interaction with PTH in the regulation of blood calcium.

Answer 168

- Stimulates intestinal _absorption of Ca in the duodenum_ through the interaction of 1,25-dihydroxyvitamin D with nuclear vitamin D receptor and the formation of a complex with RXR - Complex binds to vit D response elements, activating the transcription of _TRPV6_ (a member of the transient receptor potential vanilloid family), which encodes a critical _calcium transport channel_

Answer 169

- Increases calcium influx in distal tubules of the kidney via increased expression of _TRPV5_, a member of the transient receptor potential vanilloid family - TRPV5 expression _also regulated by PTH_ in response to hypocalcemia

Answer 170

- Vit D maintains Ca and phosphorus at supersaturated levels in plasma - Parathyroid glands have a key role in the regulation of EC Ca concentrations -\> they have a Ca receptor that senses even small changes in blood Ca concentrations - In addition to effects on Ca absorption in intestine and kidneys, both 1,25-dihydroxyvit D and PTH enhance expression of RANKL (receptor activator of NF-κB ligand) on osteoblasts: 1. **RANKL** binds its receptor (RANK) in prosteoclasts, inducing differentiation of these cells into mature osteoclasts -\> via secretion of HCl and activation of proteases like cathepsin K, osteoclasts dissolve bone and release Ca and phosphorus into circulation

Answer 171

- When hypocalcemia occurs due to vit D deficiency, PTH production is elevated, causing: 1. Activation of renal 1α-hydroxylase, increasing the amount of active vitamin D and calcium absorption 2. INC resorption of Ca from bone by osteoclasts 3. Decreased renal Ca excretion 4. INC renal excretion of phosphate (by increased synthesis in bone of **fibroblast growth factor 23** (FGF-23), a _phosphatonin_ (gp of agents that block phosphate absorption in the intestine and phosphate reabsorption in the kidney) - While a normal serum level of Ca may be restored, hypophosphatemia persists, impairing mineralization of bone. INC production of FGF-23 may be responsible for tumor-induced _osteomalacia_ and some forms of _hypophosphatemic rickets_

Answer 172

- Macrophages - Keratinocytes - Tissues like breast, prostate, and colon - _NOTE_: low levels of 1,25-dihydroxyvitamin D (\<20 ng/mL) are associated with a 30%-50% INC in the incidence of colon, prostate, and breast cancers

Answer 173

- Activity of **CYP27B** located in the mitochondria - Pathogen-induced activation of TLRs in macros causes INC expression of vit D receptor and CYP27B, leading to local syn of 1,25-dihydroxyvit D and activation of vit-D-dependent gene expression in macros - _Recent clinical trial_: vit D supplements INC lymphocyte counts, altered circulating levels of multiple cytokines and chemokines, and enhanced clearance of Mycobacterium tuberculosis from sputum

Answer 174

- Megadoses of orally administered vitamin can lead to hypervitaminosis - _Children_: may take the form of metastatic calcifications of soft tissues such as the kidney - _Adults_: causes bone pain and hypercalcemia - Toxic potential of vitamin D is so great that in sufficiently large doses it is a potent rodenticide

Answer 175

Think back to first semester.

Answer 176

- Alveoli are filling up with a foamy (more foamy than PE fluid, for example) exudate of cysts that contain small organisms and interstitium is inflamed - Alveolar exudate and interstitial inflammation create an alveolar-capillary block impeding gas exchange, _causing dyspnea and hypoxemia_ - **Pneumocystis jiroveci pneumonia** - NOTE: this is an HIV+ patient

Answer 177

- _Symptoms_: insidious onset of dyspnea, fever, & non-productive cough - _Signs_: tachypnea with no rales or rhonchi (can be striking, up to 30 RR -\> pt. will have difficulty defining exactly when started) - _Chest x-ray_: symmetric bilateral hazy interstitial (this is important) infiltrates, which become dense alveolar infiltrates; may initially come back clear - **Dr. Cross comments:** 1. Can be sick week or 2 before coming to clinic, so not a sudden onset illness (fatal, if not treated) 2. Known AIDS patient: if CD4 if hypoxemic, you put them in the hospital

Answer 178

- Large cells with basophilic nuclear inclusions and granular cytoplasmic inclusions (and halos) - _Cytomegalovirus (CMV)_: there are immunostains for confirming dx of CMV and pneumocystis (unrelated -\> common for these pts to have more than one type of infection) - CMV in AIDS patients usually disseminated - CMV enteritis common in AIDS patients -\> diarrhea - CMV retinitis common in AIDS patients -\> visual impairment

Answer 179

- MCV is a _reactivation agent_ (pt. already has it), not a primary infection: 80-90% of people have had it, and not gotten that sick with it b/c it is an _opportunistic infection_ that makes those that are immunosuppressed ill - CMV pneumonia very rare (but exists in cancer & AIDS pts) -\> in bronchoscopy/respiratory specimens to dx, there may be CMV reactivating, but doesn't mean it's causing the pneumonia - CMV _colitis/retinitis_ much more common than PNA when AIDS is very advanced, and CD4+ counts are very low - CMV _treatment pretty toxic_ for these pts (and can cause many terrible symptoms, including bone marrow suppression), and these pts are already bone marrow suppressed

Answer 180

- _Macrophages_ - Macros bind microbes coated w/Abs or complement and phagocytose and destroy them, serving as effector cells of humoral immunity - They also respond to signals from CD4 T cells, improving their ability to destroy these phagocytosed microbes, serving as effector cells of cellular immunity, which is depressed in patients with HIV/AIDS - _NOTE_: this was a clicker question, so there clearly could be better responses, but this was the best of those he listed

Answer 181

- HIV/AIDS - _Note_: there is now an opt-out test, so no longer have to ask for permission -\> tell them you are going to do the test, unless they refuse 1. You can say: "We test everyone for HIV b/t the ages of 15 and 64; we are going to test you today, unless you refuse"

Answer 182

- D = 10 million virions/mL, 10 cells/cu mm, 10 years of infection - **Dr. Cross comments**: 1. _Key is CD4 count_: at 200, pts are still pretty healthy, but this guy is sick, so his CD4 must be really low (i.e., 10, in this case) 2. Goal of treatment to get viral load _undetectable_ 3. Viral load hard to use to tell how long pt. has had HIV: may not always be as high as 10 million, but rather only be 50,000; can kind of fizzle out with advanced states