838 Final Exam Study Guide A.pdf

838 Final Exam Bone and joint disorders: arthri/s, osteoporosis Parathyroid gland: - Typically, 4 glands per thyroid Parathyroid hormone (PTH) regulates the body’s calcium and phosphorus. Parathyroid gland contains adipose, Chief cells and Oxyphil cells o Chief cells: More abundant, produces PTH o...

838 Final Exam Bone and joint disorders: arthri/s, osteoporosis Parathyroid gland: - Typically, 4 glands per thyroid Parathyroid hormone (PTH) regulates the body’s calcium and phosphorus. Parathyroid gland contains adipose, Chief cells and Oxyphil cells o Chief cells: More abundant, produces PTH o Oxyphil cells: Less abundant, unknown funcKon. Start to appear aMer puberty. Parathyroid hormone (PTH): - Released by the parathyroid gland, travels through the blood and has major acKon on the bone and kidney. - Binds to Type-I or Type-II PTH receptors. o Type I- binds PTH and PTH-related pepKde (PTHrP) o Type II- binds only PTH - PTH release is sensiKve to small changes in calcium concentraKon in the body. o PTH on bone: PTH mobilizes calcium from bone o PTH on kidney: PTH enhances renal reabsorpKon of calcium o PTH also causes producKon of calcitriol (vitamin D3) which leads to an increase in intesKnal absorpKon of calcium. PTH indirectly increases intesKnal absorpKon of calcium. - NegaKve feedback loop available incase calcium is too high (can shut down PTH release) - Calcium in the blood is monitored by Ca2+ Sensing Receptor (CaSR) a type of GPCR which is expressed on the surface of many cells (Kidney, Brain, Thyroid C cells). The ligand to this GPCR is calcium and it was the first receptor found to bind to an ion instead of an organic molecule. - Major effect of PTH on phosphate à promotes phosphate excreKon by inhibiKng sodium-dependent phosphate transport in the proximal tubule. Calcitriol (Vitamin D3): - ProducKon is regulated at the kidneys by PTH - Calcitriol is the primary hormone responsible for enhancing Ca2+ uptake from the small intesKne o Facilitates renal reabsorpKon of Ca2+ o Helps mobilize Ca2+ out of bone Fibroblast Growth Factor-23 (FGF-23): - Regulates serum phosphate homeostasis, vitamin D metabolism, bone mineralizaKon. 838 Final Exam Calcitonin: - Released by C cells of thyroid Acts directly on osteoclasts by blocking bone resorpKon induced by hormones like PTH and Vitamin D Has acKons that are opposite the acKons of PTH o Released when plasma Ca2+ increases Bone structure: - - - CorKcal (compact) o Located on the outside of the bone o Accounts for 80% of skeletal mass o Gives strength to the bone o Slowly remodeled Trabecular (cancellous) o Located on the Inside of the bone o Accounts for 20% skeletal mass o Rapidly remodeled 2 Cells in the bones (Osteocytes): o Osteoclasts § Responsible for breaking down the bone (bone-dissolving) § Do not contain PTH hormone receptors § FormaKon requires M-CSF (macrophage colony-sKmulaKng factor) and other signals § Secretes acid and proteases which dissolves hydroxyapaKte matrix and collagen o Osteoblasts § Responsible for building the bone (Bone-forming) § Under the influence of PTH and vitamin D3. • Contain PTH receptors • Secretes osteocalcin, osteonecKn, enzymes, collagen fibers, proteoglycan which form Osteoid formaKons § Concentrates calcium/phosphate into vesicles, an enzyme is secreted which allows calcium/phosphate to precipitate into hydroxyapaKte crystals which then interact with the osteoid formaKons to form the matrix of the bone. Bone remodeling: - PTH effect on osteoblasts causes osteoprotegrin (OPG) and RANK-L to have a direct effect on osteoclasts to differenKate. 838 Final Exam VDR (Vitamin D receptor) is member of steroid receptor superfamily of DNA-binding nuclear receptors - Primary targets: intesKnes and bone Most essenKal acKon: sKmulate acKve intesKnal calcium transport in the duodenum Deficiency causes bone mineralizaKon defects (rickets) Related to calcium and phosphate delivery to sites of mineralizaKon problems - Vitamin D is a prohormone which is produced on our skin when we have exposure to UVB. 7-dehydrocholesterol is stored on the skin (Dermis) and is converted to vitamin D3 by UVB. Transported to the liver and converted to 25-hydroxyvitamin D3. Finally, converted to 1, 25-hydroxyvitamin D3 in the kidney. Calcium Homeostasis Disorders Primary hyperparathyroidism - One or of the parathyroid glands become overacKve – too much PTH secreKon Causes Hypercalcemia Most common cause: chief cell adenomas Treat with surgery Hypoparathyroidism - Parathyroid glands are not producing enough PTH Caused by injury or neck surgery Calcium decreases, phosphate increases Treat with calcium/vitamin D supplements, PTH therapy (Natpara), dietary changes 838 Final Exam Medullary Carcinoma (Thyroid) - ProducKon of excess calcitonin - Causes hypercalcitoninemia (high calcitonin) 20% have geneKc associaKon (mulKple endocrine neoplasia MEN- 2A/MEN-2B) o Hereditary mutaKons in RET proto-oncogene Treat with thyroid surgery Osteoporosis - Bone resorpKon > bone deposiKon Metabolic disorder Most common in women aMer menopause Risk factors: small and thin body type, postmenopausal age, smoking, poor diet, low dietary calcium intake. Estrogen deficiency à increased bone turnover and enhanced resorpKon (can result in osteoporosis) Most important eKologic factor: gonadal steroid deficiency Treatment of Osteoporosis: - - Bisphosphonates: MOA: induce osteoclast apoptosis, suppress bone resorpKon o Risedronate o Alendronate o Ibandronate o Zoledronic acid o Pamidronate PTH derivaKves: MOA: sKmulated new bone formaKon o TeriparaKde (Forteo) o Consists of first 34 AA of PTH Osteomalacia - Defect in mineralizaKon of the bone caused by vitamin D deficiency (less likely), phosphate deficiency, inherited alkaline phosphatase deficiency, drugs In children = rickets Rarely vitamin D deficiency 838 Final Exam Male Reproduc/ve Disorders Male - Wolffian duct o Sertoli cells – anK-Mullerian hormone o Leydig cells – testosterone o DHT- responsible for phenotypic male development Female - Mullerian duct Absence of anK-Mullerian hormone, testosterone and DHT - The male reproducKve fetus may not differenKate correctly. - Blood-tesKs barrier: impermeable barrier between tubes of tesKs and intersKKal fluids. 838 Final Exam - TesKs are not at the proper temperature so it will What hormone is key in the regulaKon of T synthesis? - LH - Estrogen is present in the testes – some testosterone is aromaKzed by adipose Kssue. 5-α-reductase type I and II – liver and skin 5-α-reductase type II – reproducKve Kssues TheoreKcally, what effect would a drug have if it selecKvely blocked 5-a reductase type I, Type II or both? - Blocking Type I will be good for Male paoern baldness 838 Final Exam - If SHBG increases, then biologically acKve T will decrease. - FSH directly sKmulates Sertoli cells – starts making mature sperm LH helps make high levels of testosterone, so sperm formaKon occurs. ~90-day transport- 90 days for sperm to mature. Seminal vesicles are necessary to keep sperm viable. 838 Final Exam - - - What is there was damage to seminiferous tubule? o This has the Sertoli cells – Not able to make sperm. What is there was damage to Leydig cells? o There is less intratesKcular Testosterone – Not able to make sperm. What is male having elevated estradiol? o More negaKve feedback – decrease test and sperm What is fasKng/anorexia/calorie reducKon? o LepKn is potent sKmulator of GnRH which will downregulate the whole process and ulKmately less sperm Chronic illness? o Same process Meds that affect downregulaKon and negaKve effects of ferKlityo Chronic opioids o CorKcosteroids o 2nd gen anKpsychoKcs o Things that cause these symptoms: LUTS: Lower urinary tract symptoms BPH: Benign prostaKc hypertrophy Prostate cancer 838 Final Exam - Age + Androgens = BPH T types of cells in the prostate: - GnRH blockers will cause ED, loss of libido, flushing, nausea, tesKcular atrophy, decreased muscle mass ect…. - Lowers DHT- A and B Lowers T – A Lowers LH- A Both will reduce the size of prostate – But A is stronger but more side effects. 838 Final Exam InferKlity: - Red ones are to know. 838 Final Exam Female Reproduc/ve Disorders Menstrual cycle: 1. 2. 3. 4. 5. 6. 7. 8. 9. 10. 11. 12. 13. 14. 15. 16. Hypothalamus GnRH PulsaKle fashion PulsaKle fashion LH FSH Estrogen Inhibin Inhibin FSH LH Mid-cycle LH OvulaKon GnRH Corpus luteum Progesterone 838 Final Exam Pregnancy: Menopause: 838 Final Exam Pathophysiology of menstrual disorders Amenorrhea: - Primary amenorrhea: Never menstruated by age 16 - Secondary amenorrhea: 838 Final Exam PCOS: PolycysKc ovary syndrome Dysmenorrhea: 838 Final Exam PALM-COEIN: Pathophysiology of inferKlity: Ovulatory: 838 Final Exam Tubal: Other (Hypothyroidism and HyperprolacKnemia) Pathophysiology of common disorders of pregnancy: GestaKonal diabetes: 838 Final Exam Ectopic pregnancy: GestaKonal hypertension vs pre-eclampsia/eclampsia: 838 Final Exam Infec/ous disease: Host Aoributes: - Immune status Sex Age History/personal choices/hygiene NutriKonal status Microbiome Presence of disease or medicaKons Environmental aoributes: - Vectors Insects and other carriers that transmit infecKous agents ZoonoKc hosts Animals that harbor infecKous agent and oMen act to amplify the infecKous agent Climate Living condiKons/populaKon density Access to health care services Availability of nutrients 838 Final Exam Host Defenses Against InfecKons Innate Immune System - Non-specific immune response Rapid response; mulKple mechanisms to protect host from infecKon Present at birth Consists of barriers o Physical and chemical AcKvaKon of inflammatory cells and proteins Neutralize organisms, recruit phagocyKc cells AcKvaKon of adapKve immune system Induce response through humoral and cell-mediated immunity Physical and chemical barriers: - - - Skin o Squamous epithelial cells o Sebaceous and sweat glands Mucous membranes o Mouth, pharynx, esophagus, and lower urinary tract o ProtecKve layer of mucus Not all pathogens entering the human body will cause disease since humans are protected by normal flora and their immune systems Innate immune response- inflammatory response: - - - Paoern recogniKon receptors (PRRs) o AcKvated through sensing of pathogen-associated molecular paoerns (PAMPs) o SKmulates acKvaKon of a pro-inflammatory cascade o Do not require prior contact with organism to be acKvated Signs of inflammaKon o Increased blood supply o Decreased pH Pro-inflammatory cytokines o Histamine, bradykinin o Interleukin-1 (IL-1), interleukin-6 (IL-6), tumor necrosis factor, interferon-γ Innate Immune System- Complement System - - 2 pathways can acKvate the complement system o Classic pathway o AlternaKve pathway Both pathways form C3 convertase – an enzyme that cleaves C3 component Eventually creates a membrane aoack complex (MAC) which has C5-C9 and causes Cell lysis. 838 Final Exam AdapKve Immune System - Acquired immunity or anKgen-specific immunity AnKgen must first be recognized and processed Rapid increase of T and B lymphocyte clones Each clone has the same anKgen receptor as the original and fights the same pathogen ProtecKve Immunity - Occurs aMer iniKal exposure to a pathogen (via infecKon or vaccinaKon) Memory lymphocytes and pathogen-specific anKbodies are generated and allows a rapid response to infecKon InfecKve EndocardiKs (IE) - - An infecKon caused by bacteria that enter the bloodstream and seole in the heart lining Right sided endocardiKs effects: o Pulmonary valve o Tricuspid valve LeM sided endocardiKs effects: o AorKc valve o Mitral valve Most common causes of IE are gram posiKve bacteria: - Viridans group streptococci Staphylococcus aureus Coagulase-negaKve Staph (S. epidermidis, etc) Enterococci (E. faecalis, E. faecium) Most common risk factors - Presence of a prostheKc valve (highest risk) Previous endocardiKs (highest risk) Congenital heart disease IV drug use (IVDU) 838 Final Exam - VegetaKon of the bacteria is marker for IE. 838 Final Exam MeningiKs - MeningiKs – inflammaKon of subarachnoid space or CSF due to viral, bacterial, or fungal infecKon Meninges – 3 separate membranes that surround the brain and cerebrospinal fluid (CSF) o Dura mater, arachnoid, and pia mater Causes of meningiKs: - - Neonates – translocaKon of vaginal flora during birth o Group B streptococci (Streptococcus agalacKae), E. coli Adults o Streptococcus pneumoniae o Neisseria meningiKdis o Haemophilus influenzae Elderly, immunocompromised, or pregnant paKents o Food-borne pathogen– Listeria monocytogenes Inflammatory response to meningiKs: - AbnormaliKes in cerebral blood flow Cerebral edema Cerebral hypoperfusion Brain herniaKon (medical emergency) Clinical ManifestaKons of Bacterial MeningiKs - Rapid onset fever, headache, neck sKffness or pain Nausea/vomiKng Photophobia Confusion/lethargy Signs of herniaKon: coma, papilledema, bradycardia, respiratory depression, hypertension Pneumonia - Acute infecKon of the lung Kssue InflammaKon of lung parenchyma AccumulaKon of inflammatory exudate in airways Types of Pneumonia: o Community-acquired pneumonia (CAP) § OutpaKent or ≤ 48 hours of hospital admission o Hospital-acquired pneumonia (HAP) § > 48 hours aMer hospital admission § Staphylococcus aureus § Pseudomonas aeruginosa o VenKlator-associated pneumonia (VAP) § > 48 hours aMer endotracheal intubaKon 838 Final Exam Acute pneumonia occurs when: - - Defect in host defenses o Pulmonary defenses: § Changes in airflow § Epiglows and cough reflex § Cilia and mucus § Alveoli o Ex: Impaired cough reflex or cell-mediated immune dysfuncKon InfecKon with virulent microorganism Exposure to large inoculum Pathogens reach lungs by: - Direct inhalaKon of infecKous respiratory droplets AspiraKon of oropharyngeal contents Hematogenous spread (infecKon elsewhere can be carried to the lungs) Clinical ManifestaKons of Pneumonia: - Fever, cough (usually producKve), tachypnea, tachycardia, x-ray (infiltrates). Sepsis and SepKc Shock - Clinical syndrome characterized by a dysregulated inflammatory response to infecKon Leading cause of morbidity and mortality in the U.S. SepKc shock = sepsis + hypotension requiring vasopressor support to maintain MAP >65 mmHg AND lactate >2 mmol/L Predicted mortality of 40% 838 Final Exam Pathophysiology of Sepsis - Hemodynamic alteraKons o VasodilaKon causes hypotension and hypoperfusion due to nitric oxide released from endothelial cells in response to bacterial endotoxin o DistribuKve shock produces imbalances in blood flow and hypoperfusion of some organs o Vascular and mulKorgan dysfuncKon o Organ failure from microvascular injury by local and systemic inflammatory responses to infecKon o Decreases in the number of funcKonal capillaries, resulKng in an inability to extract oxygen maximally o AggregaKon of neutrophils and platelets may also reduce blood flow o Complement system components are acKvated, aoracKng neutrophils, and releasing locally acKve substances (prostaglandins and leukotrienes) o Toxins may arise from a lipopolysaccharide outer membrane component of gram- negaKve bacteria (endotoxins) or from proteins synthesized and released by bacteria (exotoxins) o CD4 cells get sKmulated to secrete cytokines with either inflammatory (type 1 helper T cell) or anK-inflammatory (type 2 helper T-cell) properKes § SKmuli include organism, microbial inoculum, and site of infecKon Clinical ManifestaKons of Sepsis - Systemic response to infecKons: tachycardia, tachypnea, alteraKons in body temperature and leukocyte count Specific organ system dysfuncKon o Cardiovascular dysfuncKon o Respiratory dysfuncKon o Renal dysfuncKon o HepaKc dysfuncKon o Hematologic dysfuncKon InfecKous diarrhea - “GastroenteriKs” refers to bacterial or viral infecKons that affect both the stomach and small/large intesKnes. Causes of infecKous diarrhea: - - Most cases are due to viral pathogens o Rotavirus, norovirus, astrovirus Environmental factors: o Person-to-person transmission o Fecal-oral spread of Shigella or Rotavirus Water-borne transmission o Cryptosporidium, Vibrio cholerae Food-borne transmission o Salmonella or S. aureus food poisoning 838 Final Exam Secretory diarrhea (watery diarrhea): superficially aoach to enterocytes in the small bowel lumen - - Symptoms: combinaKon of diarrhea, vomiKng, and abdominal pain Pathogens include: Vibrio cholerae, Enterotoxigenic E. coli (ETEC), rotavirus, norovirus, protozoa (Giardia, Cryptosporidium) Some of these pathogens release enterotoxins, which are proteins that increase cyclic adenosine monophosphate (cAMP) producKon, causing dramaKc efflux of water and secreKon of electrolytes by intesKnal villi, leading to profuse watery diarrhea May progress to dehydraKon and vascular collapse unless vigorous volume and electrolyte resuscitaKon is given Inflammatory diarrhea: bacterial invasion of the mucosal lumen resulKng in cell death - Symptoms: fever, crampy, lower abdominal pain, & diarrhea which may contain visible mucus Pathogens include: EIEC, Shigella, Salmonella, Campylobacter, Entamoeba histolyKca Hemorrhagic diarrhea: EHEC produces 2 Shiga-like toxins; A subunit of Shiga toxin catalyzes the destrucKve cleavage of ribosomal RNA and halts protein synthesis, leading to cell death. - Shiga toxin can enter systemic circulaKon and is phagocytosed by neutrophils, and in turn endocytosed by target epithelial cells à vascular damage and possible pro-thromboKc state preceding hemolyKc-uremic syndrome Broad spectrum of clinical disease: asymptomaKc infecKon; watery (non-bloody diarrhea); hemorrhagic coliKs (blood, inflammatory diarrhea); hemolyKc-uremic syndrome (characterized by anemia and renal failure)