UWSA1-3 Flashcards
Pathogenesis of pulmonary arterial hypertension
PAH is more common in women than men and is often hereditary (eg, due to BMPR2 mutation). It may also occur sporadically or in the setting of connective tissue disease or HIV infection. The pathogenesis involves thickening of the smooth muscle medial layer and hyperplasia of the intimal layer of small pulmonary arteries and arterioles. Progressive intimal fibrosis takes place in a concentric, “onion skin” form with eventual development of plexiform lesions. Vascular resistance in the pulmonary arterial system is markedly increased, leading to elevated pulmonary arterial pressure.
To compensate for elevated pulmonary arterial pressure, right ventricular hypertrophy develops, often evidenced by right ventricular heave (detected by left parasternal lift) on physical examination. Over time, right-sided heart failure can occur with jugular venous distension, hepatomegaly, and peripheral edema.
Classification of pulmonary hypertension
Pulmonary arterial Hypertension mutation
BMPR2
Alveolar Hyaline membrane formation
Alveolar hyaline membrane formation occurs in acute respiratory distress syndrome, which typically occurs in the setting of acute illness or trauma
Describe varying uterine fibroids
pedunculated
intracavitary
Intramural
Submucosal
Subserosal
Heavy menses and irregularly enlarged uterus
This patient with heavy menses and an irregularly enlarged uterus likely has uterine leiomyomas (ie, fibroids). Fibroids are common benign tumors composed of uterine smooth muscle cells and fibroblasts. They commonly present in women in their 30s and 40s, and risk factors include African American race, early menarche, and nulliparity.
Although most leiomyomas are asymptomatic, some are associated with pelvic pressure and pain (due to pressure on neighboring structures) or with infertility/pregnancy loss (due to uterine cavity distortion). Heavy menstrual bleeding, the most common fibroid symptom, may result from impaired uterine contractility, increased uterine surface area, and ulceration of the endometrium over a submucosal fibroid. In addition, biochemical vasoactive growth factors expressed by the fibroids cause venous ectasia (dilation). During menstrual shedding, the large-caliber venules overwhelm normal hemostatic mechanisms (platelet aggregation, fibrin deposition, thrombus formation) that control menstrual blood loss. As a result, patients with fibroids, particularly submucosal or intracavitary fibroids, can have significant anemia and require blood transfusion.
Menses of endometrial cancer
Endometrial cancer can present with heavy vaginal bleeding and anemia; those with endometrial cancer typically have irregular, unpredictable menses caused by unopposed endometrial proliferation.
Endometrial polyps
Endometrial polyps are benign, intracavitary overgrowths of the endometrial stroma.
They typically cause intermenstrual bleeding (due to intermittent ulceration and necrosis)
Endometriosis
Endometriosis is the ectopic implantation of endometrial glands and stroma in the abdominopelvic cavity, which can cause pelvic pain, dysmenorrhea, or infertility. However, because the pathology is extrauterine, patients do not typically have heavy menses or uterine enlargement.
Ischemic colitis mechanism
Ischemic colitis is a common cause of lower gastrointestinal hemorrhage in the elderly. Typically, patients present with crampy abdominal pain, tenderness to palpation, and bloody stool. The two primary mechanisms that produce ischemic colitis are hypoperfusion secondary to diminished cardiac output (as seen in cardiac disease or prolonged shock) and occlusion of the bowel vascular supply (as seen with atheroma, thrombosis, or embolism). The weak lower extremity pulses in this patient indicate he likely has extensive atherosclerosis.
Ischemic Colitis histology
Histologic findings depend upon the cause and severity of the ischemia. Initially, mucosal hemorrhage, ecchymoses, and patchy necrosis are seen. If the ischemia persists and the injury extends down into the muscularis, the bowel wall thickens and becomes edematous. Frank blood may enter the bowel lumen. Finally, transmural infarction is observed, which may result in bowel perforation.
“cobblestone mucosa and transmural inflammation”
Crohns Disease
“Crypt abscesses and multiple pseudopolyps”
Ulcerative colitis
"”Macrophages with accumulated PAS-positive granules”
Whipples Disease
Osteogenesis imperfecta mutation
COL1A1 or COL1A2 genes
Osteogenesis imperfecta pathophysiology
This patient’s early-onset osteoporosis and ocular findings are suggestive of osteogenesis imperfecta (OI), a rare inherited disorder characterized by increased bone fragility. OI is most often caused by mutations in the COL1A1 and COL1A2 genes, which encode proteins that form type I collagen. This form of collagen is the predominant structural component of bones, tendons, ligaments, skin, and sclerae
osteogenesis imperfecta S&S
This patient’s early-onset osteoporosis and ocular findings are suggestive of osteogenesis imperfecta (OI), a rare inherited disorder characterized by increased bone fragility. OI is most often caused by mutations in the COL1A1 and COL1A2 genes, which encode proteins that form type I collagen. This form of collagen is the predominant structural component of bones, tendons, ligaments, skin, and sclerae.
The severity of OI varies considerably, ranging from multiple fractures at birth to premature osteoporosis. Other manifestations include short stature, scoliosis, blue sclerae, hearing loss, increased skin and ligament laxity, and easy bruisability. The blue sclerae seen in patients with OI is caused by the decreased collagen content, which makes the sclerae abnormally thin and translucent and allows the underlying choroid to be seen. Blue sclerae are not diagnostic of OI; they can be seen in other rare disorders (eg, progeria, cutis laxa) and can be a normal finding in neonates.
Menkes Syndrome
Impaired intestinal copper transport can result in Menkes syndrome, an X-linked recessive disorder characterized by seizures, intellectual disability, skeletal abnormalities, and brittle hair. Although blue sclerae can be seen in this Menkes syndrome, this patient is female and lacks other findings consistent with this condition.
MCAD deficiency AKA
medium-chain acyl-CoA dehydrogenase deficiency
MCAD Deficiency Pathophysiology
Medium-chain acyl-CoA dehydrogenase deficiency results in hypoketotic hypoglycemia after prolonged fasting with nausea/vomiting, seizure and liver dysfunction likely triggered by decreased food intake in the setting of a viral illness (eg, low-grade fever, rhinorrhea)
Under normal circumstances, a prolonged fast will result in a decrease in insulin and an increase in glucagon, resulting in mobilization of stored energy. Glycogen is degraded during the first 24 hours of a fast. Gluconeogenesis is subsequently used to provide glucose, which is formed from metabolic intermediates (eg, glycerol, lactate, alpha-ketoacids) derived from the breakdown of protein and fatty acids.
Fatty acids are degraded during fasting to form ketone bodies, which may be used as an alternate source of energy by most tissues. Beta-oxidation is a four-step process that results in the sequential removal of two-carbon units (acetyl-CoA) from fatty acids. The first step is catalyzed by acyl-CoA dehydrogenase. When the amount of acetyl-CoA produced exceeds the capacity of the tricarboxylic acid (TCA) cycle, the excess acetyl-CoA is shunted into the production of ketone bodies (eg, acetoacetate, 3-hydroxybutyrate, acetone). In normal individuals, blood ketone levels are significantly increased within the first few days of a fast.
Acetyl CoA caboxylase is involved in
Acetyl-CoA carboxylase catalyzes the first step in fatty acid synthesis and is the major site of regulation of fatty acid synthesis
Glucose-6-phosphatase is involved in
Glucose-6-phosphatase dephosphorylates glucose-6-phosphate to free glucose, which is released into the circulation during glycogenolysis and gluconeogenesis.
Glucose-6-phosphatase deficiency (glycogen storage disease type I [Von Gierke disease]) results in fasting hypoglycemia and excessive accumulation of glycogen in the liver and kidneys
Glucose-6-phosphatase deficiency causes
Glucose-6-phosphatase deficiency (glycogen storage disease type I [Von Gierke disease]) results in fasting hypoglycemia and excessive accumulation of glycogen in the liver and kidneys
Glycogen phosphorylase deficiency
Glycogen phosphorylase is responsible for cleaving the alpha-1,4 glycosidic linkage between glucose residues in glycogen, thereby liberating glucose-1-phosphate. Deficiency of this enzyme in skeletal muscle results in glycogen storage disease type V (McArdle disease). This condition typically presents with exercise intolerance and muscle pain.
A 53-year-old woman is diagnosed with a metastatic brain tumor after developing new-onset, generalized tonic-clonic seizures. Several of her family members also have a history of cancer. The location of the primary tumor is determined and appropriate management is initiated. Further studies reveal that this patient is predisposed to malignancy as a result of a genetic alteration in a protein that functions to transduce signals from the cell membrane to the nucleus by activating other molecules. Which of the following proteins is most likely defective in this patient?
Ras
Ras function
Ras is an oncoprotein (ie, protein encoded by a proto-oncogene) component of the MAP-kinase signal transduction system. It is present in an inactive (GDP-containing) or an active (GTP-containing) form. The phosphorylated, active Ras protein transmits a stimulus from the receptor on the cell surface into the nucleus, promoting mitogenesis. Up to 20% of all human tumors contain mutated Ras proteins that have reduced GTPase activity (leading to less GTP degradation); as a result, these mutated Ras proteins remain in an excited GTP-containing state (gain of function), stimulating neoplastic growth through continuous pathologic activation of the mitogenic signaling pathway.
BRAF gene type
Proto-oncogene (1-hit gain of function)
Ras signal transduction
ABL gene type
Proto-oncogene (1-hit gain of function)
Non-receptor tyrosine kinase
ERBB2 AKA
HER2
ERBB2 gene type
Proto-oncogene (1-hit gain of function)
Receptor tyrosine kinase
AKA HER2
ERBB1 AKA
EGFR
ERBB1 gene type
Proto-oncogene (1-hit gain of function)
Receptor Tyrosine kinase
AKA EGFR
MYC gene type
Proto-oncogene (1-hit gain of function)
Transcription factor
RAS gene type
Proto-oncogene (1-hit gain of function)
GTP binding protein
BRCA 1 gene type
Tumor suppressor gene (requires 2-hit loss of function)
DNA Repair gene
BRCA 2 gene type
Tumor suppressor gene (requires 2-hit loss of function)
DNA repair gene
APC/β-cateinin gene type
Tumor suppressor gene (requires 2-hit loss of function)
WNT signaling pathway
TP53 gene type
Tumor suppressor gene (requires 2-hit loss of function)
Genomic Stability
RB gene type
Tumor suppressor gene (requires 2-hit loss of function)
(G1/S transition inhibitor) GTP
WT1 gene type
Tumor suppressor gene (requires 2-hit loss of function)
Urogenital differentiation
VHL gene type
Tumor suppressor gene (requires 2-hit loss of function)
Ubiquitin ligase component
INR interpretation
When the INR is higher than the recommended range, it means that your blood clots more slowly than desired, and a lower INR means your blood clots more quickly than desired
Features of a Lineweaver-Burke Plot
In this example, rifampin use will increase CYP2C9 concentration within hepatocytes. This increaseinenzyme concentration leads to an increase in hepatic warfarin metabolism and a corresponding rise inVmax. Because the y-intercept in a Lineweaver-Burke plot is 1/Vmax, an increase in Vmax would lowerthey-intercept. Enzyme induction increases the expression of an enzyme but does not change its affinity for substrate (Km), so the x-intercept (-1/Km) would remain unchanged.
A 68-year-old man on warfarin therapy after a mechanical valve replacement develops a rapid decrease in INR after starting rifampin. Rifampin induces synthesis of CYP2C9, a cytochrome P450 enzyme in hepatocytes, leading to increased warfarin metabolism. Which of the following plots most likely represents the change in CYP2C9 enzyme kinetics with regard to warfarin metabolism? (Solid line, original state; dashed line, change in kinetics)
In this example, rifampin use will increase CYP2C9 concentration within hepatocytes. This increaseinenzyme concentration leads to an increase in hepatic warfarin metabolism and a corresponding rise inVmax. Because the y-intercept in a Lineweaver-Burke plot is 1/Vmax, an increase in Vmax would lowerthey-intercept. Enzyme induction increases the expression of an enzyme but does not change its affinity for substrate (Km), so the x-intercept (-1/Km) would remain unchanged.
Histology of pulmonary carcinoid Tumor
Pulmonary carcinoid tumor arises from enterochromaffin (Kulchitsky) cells in the bronchial epithelium. It is composed of uniform, polygonal cells with eosinophilic cytoplasm and granular (ie, salt and pepper) chromatin
Lung mass expressing Chromogranin and Synaptophysin
This patient has a lung mass expressing neuroendocrine markers (eg, chromogranin, synaptophysin), consistent with a pulmonary neuroendocrine tumor (NET). The spectrum of pulmonary NETs ranges from carcinoid (well differentiated) to small cell carcinoma (poorly differentiated). In this young nonsmoker, carcinoid tumor is most likely.
Pulmonary carcinoid tumor arises from enterochromaffin (Kulchitsky) cells in the bronchial epithelium. It is composed of uniform, polygonal cells with eosinophilic cytoplasm and granular (ie, salt and pepper) chromatin. The tumor typically forms in proximal airways and grows endobronchially, explaining its frequent presentation with obstruction (eg, unilateral wheezing, recurrent pneumonia) or tumor bleeding (eg, hemoptysis).
Carcinoid tumors may secrete vasoactive mediators (eg, serotonin, vasoactive intestinal peptide), which can provoke episodes of cutaneous flushing and secretory diarrhea (ie, carcinoid syndrome). Pulmonary carcinoid tumors produce lower mediator levels than their midgut counterparts, so florid carcinoid syndrome is quite rare.
Small cell lung carcinoma is another pulmonary NET that arises in the proximal airways; however, it occurs almost exclusively in older smokers, grows invasively to infiltrate the basal lamina (eg, metastases, weight loss), and can cause a variety of paraneoplastic syndromes (eg, Lambert-Eaton syndrome).
Medullary Thyroid Carcinoma Histology
Renal cell carcinoma Histology
Pheochromocytoma Histology
Lung Squamous Cell Carcinoma Histology
Gram positive vs Gram negative bacteria structure
Internal Ribosome Entry Site
Eukaryotic translation is initiated when the small ribosomal subunit binds the 5’ cap of mRNA and scans for the methionine start codon (AUG) within the Kozak consensus sequence. Ribosomal binding to the 5’ cap is facilitated by a family of proteins known as eukaryotic initiation factors (eIFs).
During programmed cell death (apoptosis), the activation of caspases results in eIF degradation, leading to interruption of translation. As a result, many of the proteins necessary for apoptosis are translated using an alternative method known as internal ribosome entry. With this method, a distinct nucleotide sequence called the internal ribosome entry site (IRES) attracts the eukaryotic ribosome to mRNA and allows translation to begin in the middle of the mRNA sequence. IRESs are usually located in the 5’ untranslated region, the segment of mRNA located directly upstream from the translation start codon
Thiazolidinedione MOA
Thiazolidinediones (TZDs) (eg, pioglitazone) are oral antidiabetic medications that exert their glucose-lowering effects by decreasing insulin resistance. They activate peroxisome proliferator-activated receptor gamma (PPAR-γ), a nuclear receptor that modulates genes involved in lipid and glucose metabolism. Important proteins that are upregulated by TZDs include:
glucose transporter-4, an insulin-responsive, transmembrane glucose transporter expressed in adipocytes and skeletal myocytes that increases glucose uptake by target cells
adiponectin, a cytokine secreted by fat tissue that lowers triglyceride levels by inducing differentiation of preadipocytes into insulin-responsive adipocytes and stimulating fatty acid oxidation
Because TZDs do not promote pancreatic beta-cell insulin release, they do not cause hypoglycemia. The main side effects are fluid retention (with possible worsening of congestive heart failure) and weight gain.
A 46-year-old woman with type 2 diabetes mellitus comes to the clinic for a follow-up appointment. She was diagnosed with diabetes 5 years ago and has been treated with metformin. Over the last year, her glycemic control has worsened despite good compliance with diet, exercise, and medication. Laboratory results show a fasting glucose level of 185 mg/dL and hemoglobin A1c of 8.0%. After discussing medication options, the patient agrees to the addition of an oral antidiabetic medication that induces differentiation of preadipocytes into adipocytes and increases glucose transporter-4 expression on the adipocyte cell membrane. Which of the following agents was most likely chosen for this patient?
Pioglitazone
Thiazolidinediones (TZDs) (eg, pioglitazone) are oral antidiabetic medications that exert their glucose-lowering effects by decreasing insulin resistance. They activate peroxisome proliferator-activated receptor gamma (PPAR-γ), a nuclear receptor that modulates genes involved in lipid and glucose metabolism. Important proteins that are upregulated by TZDs include:
glucose transporter-4, an insulin-responsive, transmembrane glucose transporter expressed in adipocytes and skeletal myocytes that increases glucose uptake by target cells
adiponectin, a cytokine secreted by fat tissue that lowers triglyceride levels by inducing differentiation of preadipocytes into insulin-responsive adipocytes and stimulating fatty acid oxidation
Adverse effects of Thiazolidinediones
main side effects are fluid retention (with possible worsening of congestive heart failure) and weight gain
Acarbose MOA
Acarbose is an intestinal brush border alpha-glucosidase inhibitor that decreases postprandial hyperglycemia by reducing gastrointestinal absorption of polymeric glucose
SGLT-2 Inhibitors
Sodium-glucose cotransporter-2 inhibitors (eg, canagliflozin, dapagliflozin) act in the kidney to decrease reabsorption of filtered glucose.
Sulfonylureas MOA
Sulfonylureas (eg, glyburide) and meglitinides (eg, repaglinide) bind to and close the ATP-sensitive K+ channel in the pancreatic beta-cell membrane, inducing depolarization and L-type calcium channel opening. The increased Ca2+ influx stimulates insulin release.
Meglitinides MOA
Sulfonylureas (eg, glyburide) and meglitinides (eg, repaglinide) bind to and close the ATP-sensitive K+ channel in the pancreatic beta-cell membrane, inducing depolarization and L-type calcium channel opening. The increased Ca2+ influx stimulates insulin release.
Same mechanism as sulfonylureas but with less affinity and are shorter-acting so carry less risk of post-prandial hypoglycemia
Meglitinides examples
repaglinide
Clinical manifestations of Crohns Disease
Crohn disease is a chronic, idiopathic, inflammatory condition that classically presents with abdominal pain, diarrhea, and low-grade fever. Aphthous ulcers of the mouth, as in this patient, may also be observed. Bowel obstruction, fistulae, or perianal disease (eg, fissures, abscesses) eventually develops in most individuals due to transmural inflammation of the intestinal wall. Although any area of the gastrointestinal tract may be affected, the most frequently involved site is the terminal ileum.
Most common area afflicted in Crohns Disease
Although any area of the gastrointestinal tract may be affected, the most frequently involved site is the terminal ileum.
What is this?
Aphthous ulcers of the mouth found in Crohns Disease
Area most afflicted in Celiac Disease
distal duodenum and proximal jejunum
Chronic Atrophic Gastritis vs Chronic Antral Gastritis
Chronic atrophic gastritis is characterized by chronic inflammation of the gastric body/fundus due to autoimmune parietal cell destruction, whereas chronic antral gastritis is typically associated with Helicobacter pylori infection.
List of CYP 450 Inhibitors
- Antibiotics (eg, metronidazole, macrolides, TMP-SMX)
- Azole antifungals
- Amiodarone
- Cimetidine
- Grapefruit juice
leads to ↑ Warfarin effect
(↑ bleeding risk)
List of CYP 450 Inducers
- Carbamazepine
- Phenytoin
- Phenobarbital
- Rifampin
- St. John’s wort
↓ Warfarin effect
(↓ in efficacy)
aPTT coagulation pathway
Intrinsic
Pt measures which coagulation pathway
Intrinsic
Warfarin primarily affects which coagulation pathway
Intrinsic PT
Heparin affects which coagulation pathway
Extrinsic aPTT
High INR interpretation
When the INR is higher than the recommended range, it means that your blood clots more slowly than desired
Lactulose Treatment of Hepatic encephalopathy
in cirrhosis, NH3 metabolism is reduced in the liver leading to increased systemic NH3 levels which cause Neuropsychiatric abnormalities (sleep disturbances and mood changes)
When Txed with Lactulose, it is converted to lactic and acetic acid which decreases the colon pH favoring the formation of NH4+ which is not absorbed and can be secreted reducing overall levels of NH3 and symptoms improve
S&S of Hepatic encephalopathy
In a patient with severe liver dysfunction; the acute onset of confusion; sleep disturbances; and jerky, involuntary hand movements with dorsiflexion (ie, asterixis) are concerning for hepatic encephalopathy. (caused by reduced NH3 metabolism in the liver and increased systemic NH3
Crystalloid infusion
Crystalloid infusion is useful in the fluid resuscitation of hypovolemic individuals but would likely only exacerbate the edema and ascites in a cirrhotic patient
portacaval shunting
Immediate portacaval shunting would likely worsen the hepatic encephalopathy because it would redirect the ammonia-rich portal blood into circulation without any hepatic processing
α1 stimulation change in second messenger
Increased IP3
Bone structure haversian system
Laryngeal Nerves
Pathway of the Left Recurrent Laryngeal nerve
Branches of the Left Vagus and loops under the aortic arch between aorta and pulmonary arteries
Pathway of the Right Recurrent Laryngeal nerve
Branches of right Vagus and loops under the Right subclavian near the branchpoint from the right Brachiocephalic
Coccidioides immitus infection
Coccidioides immitis is a dimorphic fungus that grows as a mold in the environment but converts to spherule form within host organisms. It is classically contracted by people in the San Joaquin Valley in California (“Valley Fever”), but it is also endemic in southern Arizona, New Mexico, and Texas, as well as parts of Mexico and South America. Infection occurs when a host inhales arthroconidia from the soil. Once within the host, the arthroconidia convert to multinucleate spherules (sporangia), which produce numerous endospores capable of forming new spherules.
Coccidioidomycosis most commonly causes asymptomatic infection or mild pneumonia with pleural effusion. A rash and symmetric arthralgias can develop. Rarely, C immitis infection can cause formation of a thin-walled cavity in the lung; in such a case, the patient may have hemoptysis in addition to fever and cough.
What is this?
Histopathology is characterized by an intense, lymphoplasmacytic infiltrate with the formation of germinal centers and destruction of thyroid follicles.
Hürthle cells (enlarged, metaplastic epithelial cells with prominent nucleoli and abundant eosinophilic cytoplasm) are commonly seen surrounding atrophic follicles.
Hurthle Cells
(enlarged, metaplastic epithelial cells with prominent nucleoli and abundant eosinophilic cytoplasm) are commonly seen surrounding atrophic follicles.
Hashimoto thyroiditis histology also includes intense, lymphoplasmacytic infiltrate with the formation of germinal centers and destruction of thyroid follicles.
Follicular adenoma histology
Follicular adenoma causes a painless, unilateral neck mass; histologic findings include numerous neoplastic follicles separated from the surrounding normal thyroid tissue by an intact capsule.
Follicular carcinoma histology
Follicular carcinoma shows relatively uniform cells in small follicles, nests, or sheets; it is distinguished from follicular adenoma by capsular and vascular invasion.
Graves Disease histology
Graves disease presents with a diffusely enlarged thyroid associated with hyperthyroidism, exophthalmos, and pretibial myxedema. The thyroid follicular epithelium is tall and crowded, with hyperactive reabsorption causing scalloping around the edges of the colloid.
What does this patient most likely have on physical exam?
Atrial septal defect is associated with a widely split and fixed S2
In the normal individual, PO2 levels are lowest in the deoxygenated blood of the superior vena cava, right atrium, and right ventricle. After oxygenation in the pulmonary vasculature, blood PO2 is high in the left atrium, left ventricle, and aorta. In an individual with an atrial septal defect (ASD), the normally low PO2 readings of the right atrium (and right ventricle) are increased because of the shunting of oxygenated blood from the left atrium to the right atrium. Based on the PO2 readings provided above (including a low superior vena cava PO2, moderate right atrial and right ventricular PO2, and high left atrial and left ventricular PO2), this individual has an ASD.
The left-to-right shunt of ASD causes right ventricle overload during diastole and an increase in pulmonary blood flow. Larger left-to-right shunts tend to limit respiratory variation secondary to a delay in pulmonic valve closure. As a consequence, S2 (the sound of the semilunar valves closing) is widely split and fixed. Because the blood flow across the ASD is low velocity and minimally turbulent, it does not cause an audible murmur. However, several other murmurs are associated with ASD, including a midsystolic pulmonary flow or ejection murmur (secondary to increased flow across the pulmonic valve), a diastolic rumble (secondary to increased flow across the tricuspid valve), and a low-pitched diastolic murmur (secondary to pulmonic regurgitation).
Describe X-linked recessive inheritance
With a carrier mother
50% of male children from a carrier mother will be affected, whereas 50% of female children will be carriers.
With an affected father
All daughters are carriers
All sons are Unaffected
What is the Gower Sign?
a physical exam finding in muscular dystrophy
Duchenne muscular dystrophy S&S
Patients with Duchenne muscular dystrophy develop normally at first, crawling and walking at the appropriate age milestones. Symptoms typically present at age 3-5, with progressive muscle weakness and generalized difficulty with physical activity.
Affected boys often use their hands to support the body as they rise from the floor, a maneuver termed Gower’s sign. This reflects the progression of the disease; the proximal lower extremity musculature is the first to be affected, with the distal and upper extremities affected later. Patients are often wheelchair bound by age 12 and usually die by the fourth decade of life due to respiratory insufficiency or cardiomyopathy.
A 40-year-old man comes to the office due to food “sticking” in his throat. He has also had cough, nocturnal regurgitation, and difficulty belching. The patient has no other medical problems and takes no medications. He has a 20-pack-year smoking history and occasionally drinks beer. Vital signs are normal. Examination shows no palpable neck masses. The trachea is midline. The oropharynx is clear. The lungs are clear to auscultation and percussion. Heart sounds are normal. The abdomen is soft and nontender with no organomegaly. Barium study findings are shown below.
Achalasia (Greek for “does not relax”) is an esophageal motility disorder characterized by the absence of esophageal peristalsis in the distal esophagus and incomplete relaxation of a hypertensive lower esophageal sphincter. Achalasia is caused by degeneration of inhibitory ganglion cells in the esophageal wall.
An inflammatory infiltrate composed mainly of lymphocytes and eosinophils develops around the nitric oxide–producing neurons in the myenteric (Auerbach) plexus. These neurons, responsible for esophageal smooth muscle relaxation, are preferentially destroyed, while excitatory cholinergic neurons responsible for smooth muscle contraction are relatively spared. This creates an imbalance favoring increased lower esophageal tone and impaired sphincter relaxation, resulting in a functional obstruction at the gastroesophageal junction. Patients typically experience dysphagia, regurgitation of undigested food, heartburn, weight loss, and difficulty belching. Barium esophagram shows dilation of the esophagus with narrowing of the distal esophagus, which has been compared to a “bird’s beak” (as seen in the image).
Achalasia Pathophysiology
Achalasia is caused by degeneration of inhibitory ganglion cells in the esophageal wall.
An inflammatory infiltrate composed mainly of lymphocytes and eosinophils develops around the nitric oxide–producing neurons in the myenteric (Auerbach) plexus. These neurons, responsible for esophageal smooth muscle relaxation, are preferentially destroyed, while excitatory cholinergic neurons responsible for smooth muscle contraction are relatively spared. This creates an imbalance favoring increased lower esophageal tone and impaired sphincter relaxation, resulting in a functional obstruction at the gastroesophageal junction.
Achalasia (Greek for “does not relax”) is an esophageal motility disorder characterized by the absence of esophageal peristalsis in the distal esophagus and incomplete relaxation of a hypertensive lower esophageal sphincter.
Achalasia S&S
Patients typically experience dysphagia, regurgitation of undigested food, heartburn, weight loss, and difficulty belching.
Barium esophagram shows dilation of the esophagus with narrowing of the distal esophagus, which has been compared to a “bird’s beak” (as seen in the image)
G6PD deficiency pathophysiology
Hemolytic anemia due to oxidative stress (infection, sulfa drugs, fava beans, nitrofurantoin)
glucose-6-phosphate dehydrogenase (G6PD) catalyzes the production of NADPH for glutathione metabolism. Loss of G6PD function lowers intracellular levels of reduced glutathione, which increases erythrocyte susceptibility to oxidative injury.
Most patients are asymptomatic until oxidative stimuli (eg, nitrofurantoin) overwhelm the reductive potential of older erythrocytes, resulting in hemoglobin oxidation, denaturation, and precipitation. Precipitated hemoglobin makes erythrocytes less deformable and results in intravascular hemolysis in small capillaries and extravascular hemolysis in the reticuloendothelial system.
G6PD histology
Peripheral blood smear often shows signs of reticuloendothelial macrophage pruning such as bite cells (removal of precipitated hemoglobin from the erythrocyte membrane) and blister cells (resealing of the erythrocyte membrane edges after the “bite”). The precipitous decline in hemoglobin triggers the release of young erythrocytes (reticulocytes) from bone marrow, leading to reticulocytosis.
Identify
Identify
Broca Area (motor speech)
A 63-year-old man is brought to the emergency room due to acute-onset neurologic deficits. The patient’s symptoms started shortly after waking up this morning. He has a history of hypertension and hyperlipidemia, and has smoked a pack of cigarettes daily for the past 40 years. His father had a stroke at age 60. Neuroimaging shows an infarction involving the territory marked by the asterisk in the image below.
Which of the following findings is most likely present on this patient’s neurologic examination?
Agrammatic Speech
Wernicke’s area lesion
Lesions in Wernicke area (caudal superior temporal gyrus, Brodmann area 22), however, typically result in receptive (sensory) aphasia with impaired comprehension. Patients classically lack insight into their problem. Wernicke aphasia is also known as fluent aphasia because speech flows readily but is meaningless (“word salad”)
A 31-year-old man comes to the emergency department due to fever, dysuria, urinary frequency, and pelvic pain. His symptoms began a week ago and have become progressively worse. The patient has no associated genital lesions or urethral discharge. He has a history of HIV and is on appropriate antiretroviral therapy. His temperature is 38.8 C (102 F), blood pressure is 135/85 mm Hg, and pulse is 96/min. Abdominal examination is unremarkable. There is exquisite tenderness anteriorly on digital rectal examination. Laboratory evaluation shows leukocytosis. A transverse T1-weighted MRI image of the pelvis is shown below. Which of the following is the most likely site of infection in this patient?
Answer: C
This patient has acute bacterial prostatitis. Acute prostatitis is most commonly caused by enteric organisms similar to those found in urinary tract infection (eg, Escherichia coli, enterococci). The prostate is normally sterile but may become contaminated by reflux of urine from the bladder or urethra. Affected patients classically present with constitutional symptoms such as fever, chills and malaise, in addition to urinary symptoms such as dysuria and urinary frequency.
The above MRI shows a cross-section of the male pelvis with the prostate visible just posterior to the pubic symphysis. Digital rectal examination typically reveals a tender, boggy (swollen, spongy) prostate. Other structures that may be palpated on digital rectal examination include:
Anterior: Bladder (if full), perineal body, bulb of penis (male)/uterine cervix (female)
Lateral: Ischiorectal fossa
Posterior: Sacrum, coccyx
Identify
(Choices A and B) On MRI scan, the pubic ramus and pubic symphysis (bone) appear dark, while the cartilage of the symphyseal joint appears gray.
Choice C The above MRI shows a cross-section of the male pelvis with the prostate visible just posterior to the pubic symphysis
(Choices D and E) The anal canal and the levator ani muscle, respectively, are seen in the posterior midline of the image provided.
In animal experiments, the effects of various substances on the glomerular filtration rate (GFR) and renal plasma flow (RPF) are studied. Mean arterial pressure (MAP) is kept constant. In the figures below, convergent arrowheads represent arteriolar constriction, while divergent arrowheads represent arteriolar dilation. Which of the following figures signifies an increase in GFR and a decrease in RPF?
These experiments analyze the effect that changes in afferent or efferent arteriolar resistance will have on the GFR and RPF. For a single nephron, RPF can be related to MAP and the total vascular resistance (TVR) in the afferent and efferent arterioles as follows:
RPF = MAP / TVR
In this case, TVR in the nephron equals the resistance in the afferent arteriole (Rafferent) plus the resistance in the efferent arteriole (Refferent). Therefore, for RPF to decrease when MAP is held constant, Rafferent and / or Refferent must increase. Likewise, a decrease in either of these values will cause an increase in RPF.
The GFR can be estimated using the starling equation as follows:
GFR = (PGC – PBS) – (pGC – pBS)
This equation determines whether the net hydrostatic pressure (P) and the net oncotic pressure (p) favors flow of fluid from the glomerular capillaries (GC) to Bowman’s space (BS). If all else is held equal, this equation shows that an increase in hydrostatic pressure in the glomerular capillaries will favor increased filtration and an increase in GFR. Constriction of the afferent arteriole will reduce steady state hydrostatic pressure in the glomerular capillary (PGC) thereby decreasing the filtration of fluid from the plasma into Bowman’s space and decreasing GFR. Constriction of the efferent arteriole will increase Refferent, increase the steady state PGC and increase the GFR. In summary, constriction of the efferent arteriole will increase GFR and decrease RPF.
Picornaviridae
MHC class II pathway
Coded for by the HLA-D region, major histocompatibility complex (MHC) class II molecules are located primarily on antigen-presenting cells (eg, macrophages, dendritic cells, B cells). Each MHC class II molecule is a heterodimer composed of an alpha and beta chain. The invariant chain brings these chains together to form a stable complex in the endoplasmic reticulum. The MHC-invariant complex then passes through the Golgi apparatus and enters an endocytic compartment in which the invariant chain is proteolytically degraded and an extracellular peptide is inserted between the alpha and the beta chains. This newly formed MHC class II–peptide complex travels to the cell surface, where it is expressed and recognized by CD4+ helper T cells.
Common physical exam findings of chronic iron deficiency
Whats this?
Koilonychia (chronic iron deficiency)
Oral glucose challenge
This patient has normal glucose levels following an oral glucose challenge (eg, <140 mg/dL). Although she has an appropriate insulin response to the glucose load, her fasting insulin levels are elevated. Elevated baseline insulin levels are highly suggestive of insulin resistance, which occurs when peripheral tissues (eg, adipose, skeletal muscle, liver) are unable to respond properly to normal levels of insulin. In this condition, pancreatic beta cells attempt to compensate by secreting larger amounts of insulin to maintain blood glucose values within the normal range. Insulin resistance plays a major role in the pathophysiology of type 2 diabetes mellitus. Insulin resistance in the setting of normal or mildly elevated glucose levels is a frequent finding before overt diabetes mellitus develops. Over time, most prediabetic patients develop progressive loss of beta cell function, which eventually results in inadequate levels of insulin to compensate for the insulin resistance.
