UWSA1-1 Flashcards
What is this?
Diabetic nephropathy
When the glomerular sclerosis is nodular, it is described as a Kimmelstiel-Wilson (KW) lesion and is pathognomonic for DN. KW lesions consist of dense hyaline deposits and commonly arise from the glomerular arterioles. As the disease progresses, increased mesangial matrix proteins can lead to global glomerulosclerosis.
Diabetic glomerulosclerosis
pathophys
Diabetic nephropathy (DN) is a common complication of both type 1 and type 2 diabetes mellitus. Prolonged hyperglycemia in diabetes results in glycosylation of endothelial proteins, inflammation, and increased production of growth factors, collagen, and fibronectin. Over time, this results in mesangial expansion, glomerular basement membrane thickening, and glomerular sclerosis.
The first clinical sign of DN is albuminuria, which can progress to overt nephrotic syndrome (eg, peripheral edema, heavy proteinuria, fatty casts) and renal failure. The urine sediment is typically bland (ie, no red or white blood cells or casts).
Focal Segmental Glomerulosclerosis Histology
Focal segmental glomerulosclerosis causes nephrotic syndrome and is associated with foci of sclerosis and hyalinosis in some, but not all, glomeruli.
IgA Nephropathy Presenting symptoms
IgA nephropathy presents with recurrent hematuria associated with upper respiratory infections (synpharyngitic hematuria).
IgA Nephropathy Histology
Light microscopy demonstrates mesangial proliferation, and immunofluorescence demonstrates mesangial immune deposits composed of IgA.
Minimal Change Disease Presenting Features
Minimal change disease causes nephrotic syndrome and typically occurs in children.
Minimal Change Disease Histology
Light microscopy demonstrates normal glomeruli, but electron microscopy demonstrates diffuse effacement of podocytes.
Rapidly Progressive glomerulonephritis presenting features
Rapidly progressive glomerulonephritis causes nephritic syndrome and can occur as an end stage in multiple diseases (eg, Goodpasture syndrome, systemic lupus erythematosus).
Rapidly progressive Glomerulnephiritis Histology
light microscopy demonstrates glomerular crescents composed of proliferating parietal and inflammatory cells.
Cardiac Conduction Velocity Fastest to slowest
Paget Disease Pathophysiology
- Osteoclast dysfunction
- Excessive & disordered bone formation
Paget disease begins with the lytic phase, in which normal bone is resorbed by osteoclasts that are more numerous, are larger, and have many more nuclei (up to 100) than normal osteoclasts (5-10 nuclei). Bone turnover rates increase to as much as 20 times normal.
The second phase, the mixed phase, is characterized by rapid increases in bone formation from numerous osteoblasts. Although increased in number, the osteoblasts remain morphologically normal. The newly made bone is abnormal, however, with collagen fibers deposited in a haphazard fashion rather than linearly, as with normal bone formation. As the osteoclastic and osteoblastic activities of bone destruction and formation repeat, a high degree of bone turnover occurs.
In the final phase of Paget disease, the sclerotic phase, bone formation dominates and the bone that is formed has a disorganized pattern (woven bone) and is weaker than normal adult bone. This woven bone pattern allows the bone marrow to be infiltrated by excessive fibrous connective tissue and blood vessels, leading to a hypervascular bone state.
Paget Disease Clinical manifestations
- Often asymptomatic
- Bone pain & deformity
- Skull: headache, dizziness, hearing loss
- Spine: spinal stenosis, radiculopathy
- Long bones: bowing, focal enlargement, arthritis of adjacent joints
- Elevation in alkaline phosphatase
- X-ray: lytic or mixed lytic/sclerotic lesions; cortical & trabecular thickening
Paget disease of bone is characterized by excessive and disordered bone formation. It commonly involves the skull (eg, headache), spine (eg, radiculopathy, spinal stenosis), or long bones (eg, bone pain, bowing, arthritis of adjacent joints). Long-term complications of Paget disease include fracture, hearing loss, and malignant transformation leading to osteosarcoma.
Paget Disease Complications
- Fracture
- Excessive blood flow: high-output heart failure, vascular steal
- Malignant transformation (eg, osteosarcoma)
Cardiac stress test
coronary steal syndrome
Paget Disease AKA
Osteitis Deformans
Radiologic findings of Osteosacrcoma
Radiographic findings of osteosarcoma include destruction of the normal trabecular bone pattern, mixed radiodense (sclerotic) and radiolucent (lytic) areas, and periosteal new bone formation with lifting of the periosteum (Codman triangle). Adjacent soft tissue often demonstrates ossification in a “sunburst” pattern.
Avascular necrosis caused by
Avascular necrosis can be caused by long-term glucocorticoid use, autoimmune disorders (eg, systemic lupus erythematosus), or conditions that affect blood viscosity (eg, sickle cell disease).
Avascular necrosis radiologic findings
Radiographic findings include the pathognomonic crescent sign, which indicates subchondral collapse at the femoral head
Osteoarthritis ragiographic findings
Osteophytes and joint-space narrowing
Osteoporosis Causes
Osteoporosis is common in older adults, and the risk is increased in patients with corticosteroid exposure (including inhaled corticosteroids)
Osteoporosis radiographic findings
X-ray would show trabecular thinning and possible fracture, rather than lytic/sclerotic lesions and new bone formation.
Secondary Hyperparathyroidism in CKD mechanism
Hypocalcemia and hyperphosphatemia in chronic kidney disease stimulate parathyroid hormone production (secondary hyperparathyroidism).
The resulting effects on bone, known as renal osteodystrophy, can include osteomalacia, osteitis fibrosa cystica, and adynamic bone disease. Patients usually have a known history of advanced renal disease.
Risendronic acid AKA
Risendronate
Risendronate indications
- help prevent osteoporosis
- treat Pagets disease of the bone
Risendronate MOA
Risedronate is a pyridine-based bisphosphonate that inhibits bone resorption caused by osteoclasts
Globus Sensation Description
Globus sensation is the feeling of a “lump in the throat” without accompanying physical, endoscopic, or radiologic findings of esophageal obstruction.
Globus sensation (also called globus hystericus and globus pharyngeus) is a common abnormal sensation of a foreign body, tightness, or fullness in the throat. It is often worse when swallowing saliva and may be alleviated with food or liquid. Globus is a functional disorder of the esophagus and by definition is not due to a structural abnormality or motility disorder. It is frequently associated with anxiety or other underlying psychological distress, but it also happens commonly in patients with no ongoing emotional symptoms.
Most individuals experience the globus sensation intermittently, although it can be persistent. Significant pain, dysphagia, vocal abnormalities, or systemic symptoms (eg, weight loss) are not typical for globus and suggest another condition.
Esophageal Webs Description
Esophageal webs are fragile mucosal folds that cause solid food dysphagia, usually in the mid to lower esophagus. They are most commonly seen in iron deficiency (Plummer-Vinson syndrome) and typically may be seen on barium swallow.
Pseudobulbar Palsy Description
Pseudobulbar palsy is caused by neurologic conditions such as multiple sclerosis and is characterized by dysarthria, dysphagia, dysphonia, and impaired movement of the tongue and facial muscles.
Substernal Goiter description
Substernal goiter occurs when one or both thyroid lobes grow into the thoracic cavity inlet. Most patients are asymptomatic, although rapid enlargement may compress the airway and lead to dyspnea, wheezing, or cough. Swallowing symptoms are less common due to the more posterior location of the esophagus.
Zenker Diverticula Description
Zenker diverticula are mucosal outpouchings caused by motor abnormalities of the esophagus (cricopharyngeus muscle Killians Triangle). They cause dysphagia, regurgitation, aspiration, and halitosis, and are typically diagnosed on barium swallow.
Synovial Fluid aspiration showing
Synovial fluid analysis will typically show numerous neutrophils with slender, needle-shaped monosodium urate crystals. The crystals are negatively birefringent (on polarized light microscopy: yellow when aligned parallel to slow ray and blue when aligned perpendicular).
Gout Synovial Fluid Aspiration
Synovial fluid analysis will typically show numerous neutrophils with slender, needle-shaped monosodium urate crystals. The crystals are negatively birefringent (on polarized light microscopy: yellow when aligned parallel to slow ray and blue when aligned perpendicular).
Gout Description
acute inflammatory monoarthritis, neutrophilic effusion, and numerous needle-shaped crystals has acute gout. Gout is a common disorder of uric acid metabolism characterized by episodic inflammatory arthritis; joint destruction can occur if the disease is left untreated
Gout Cause
Gouty arthritis is caused by precipitation of urate crystals in joints and is most common when uric acid levels are elevated or fluctuating (eg, initiation of diuretic therapy). Normally, the urate crystals have a protective coating of apolipoprotein E or B. When uric acid levels fluctuate or microtrauma occurs, bare urate crystals are shed and exposed to IgG antibodies. The subsequent antibody binding leads to neutrophil phagocytosis and release of inflammatory cytokines (primarily IL-1). This leads to infiltration by neutrophils and macrophages and subsequent inflammatory changes.
Characteristics of an osteoarthritic joint
Characteristic features of an osteoarthritic joint include degeneration of the articular cartilage, narrowing of the joint space, and bony outgrowths (osteophytes) at the articular margins.
Rheumatoid arthritis characterized by
Rheumatoid arthritis is characterized by immune-complex deposition, neutrophil accumulation in the synovial fluid, and perivascular inflammation of the synovial stroma. Synovial pannus formation
Acute septic arthritis synovial fluid features
Acute septic arthritis frequently affects the knee and may produce a neutrophilic effusion. However, synovial fluid would show microorganisms rather than numerous crystals.
Traumatic Joint Effusion Synovial fluid
Effusion in acute traumatic joint injury would usually be serosanguineous or frankly bloody. Crystals are not typically present in the joint fluid.
What is this?
- Endometrial glands within an endometrioma continue to proliferate and shed in response to pulsatile estrogen and progesterone. This cyclic shedding without an outlet can cause dysmenorrhea despite regular menses (eg, every 29 days). Over time, the shed cells and by-products of hemoglobin breakdown (eg, hemosiderin) can cause intraperitoneal inflammation, tissue fibrosis, and pelvic adhesions (eg, ovary adhered to the pelvic sidewall).
- Inflammation also recruits macrophages, which ingest the blood by-products and appear as pigmented, hemosiderin-laden macrophages.
Endometriosis Description
- An adherent adnexal mass and severe abdominal pain with menses (ie, dysmenorrhea) are most consistent with endometriosis. Endometriosis is characterized by the presence of endometrial glands and stroma in an extrauterine location, likely from a combination of cellular metaplasia and retrograde menstruation. The most common site for ectopic endometrial implants is the ovary; these implants can form a cystic ovarian mass that is composed of endometrial tissue and old blood (ie, an endometrioma).
- Endometrial glands within an endometrioma continue to proliferate and shed in response to pulsatile estrogen and progesterone. This cyclic shedding without an outlet can cause dysmenorrhea despite regular menses (eg, every 29 days). Over time, the shed cells and by-products of hemoglobin breakdown (eg, hemosiderin) can cause intraperitoneal inflammation, tissue fibrosis, and pelvic adhesions (eg, ovary adhered to the pelvic sidewall). Inflammation also recruits macrophages, which ingest the blood by-products and appear as pigmented, hemosiderin-laden macrophages.
Epithelial Ovarian Cancer possible presentation
Epithelial ovarian cancer can present as an adherent ovarian mass. However, microscopy typically reveals stromal invasion by atypical epithelial cells with enlarged nuclei. These tumors do not present with dysmenorrhea.
Granulosa-cell tumors histological features
- Granulosa cell tumors are sex cord stromal tumors; histologic findings include Call-Exner bodies, which are clusters of atypical granulosa cells that have scant cytoplasm and “coffee-bean” nuclei.
granulosa cell tumors menses
In addition, unlike endometriosis, those with granulosa cell tumors typically have irregular menses due to tumor secretion of estrogen and inhibin.
Mature cystic teratomas description
(ie, dermoid cysts) are benign ovarian germ cell tumors that can contain mesodermal, endodermal, and/or ectodermal tissue (eg, squamous epithelium, sebaceous glands).
Mature cystic teratomas menses
cysts are not typically associated with dysmenorrhea.
Mature Cystic Teratomas histology
Sertoli-Leydig cell tumors histology
Sertoli-Leydig cell tumors are rare sex cord stromal tumors composed of tubules of Sertoli cells alongside eosinophilic Leydig cells with prominent nucle
Sertoli-Leydig Cell tumors menses
These tumors secrete testosterone; therefore, patients typically have signs of virilization (eg, voice deepening, clitoromegaly) and irregular menses.
Sertoli-Leydig cell tumors secrete
Testosterone (androgens)
Teratogenic effects of ACE inhibitors and ARBs
Results in renal hypoplasia and dysplasia
↓
↓ fetal urine production
↓
Fetal compression
Mechanism of teratogenicity of ACE inhibitors and ARBs
ACE inhibitors and ARBs are highly teratogenic and contraindicated in pregnancy. Both medications decrease the activity of angiotensin II, which is critical for normal renal development and fetal urine production. ACE inhibitors prevent the conversion of angiotensin I to II, and ARBs block angiotensin II activity at the angiotensin II receptor type 1 (AT1). Use of either medication during pregnancy can cause fetal renal hypoplasia or dysgenesis and decreased fetal urine output.
Because fetal urine is the main component of amniotic fluid, fetal renal hypoplasia typically equates to low amniotic fluid levels (ie, oligohydramnios). Amniotic fluid is vital for fetal lung development, and normal levels typically protect against fetal compression; in contrast, chronically low levels can lead to pulmonary hypoplasia and limb compression or deformity (ie, Potter sequence). Low amniotic fluid levels also correspond with low fundal height and restriction of fetal movement that can contribute to severe fetal growth restriction.
Potter sequence pathophys
- Urinary tract abnormailty
- leads to oligohydramnios and sequence
Congenital CMV features
Congenital cytomegalovirus infection can cause fetal growth restriction, it is associated with microcephaly and periventricular intracranial calcifications
Fetal Posterior Urethral valves
- Fetal posterior urethral valves, membranes that obstruct the urethra, can cause decreased fetal urine output and resultant oligohydramnios. However, the backup of urine typically causes bilateral hydronephrosis (ie, large kidneys)
Importance of folic acid supplementation during pregnancy
Folic acid supplementation is recommended during pregnancy. Inadequate maternal folate levels can increase the risk for neural tube defects (eg, anencephaly, myelomeningocele)
Lead to polyhydramnios from neural tube defects and neuromuscular defects preventing adequate swallowing,
Fetal Alcohol Syndrome
Maternal alcohol use is teratogenic (ie, fetal alcohol syndrome) and may cause fetal growth restriction. However, it is not associated with abnormal fetal kidney development. Fetal ultrasound findings can include microcephaly and facial dysmorphia (eg, micrognathia)
Viral replication cycle and anti-viral therapy
Oseltamivir MOA
- Oseltamivir (Tamiflu) is a sialic acid analogue that inhibits the neuraminidases of the influenza A and influenza B viruses.
- Newly formed virus particles initially remain attached to cells and respiratory tract mucins through hemagglutinin binding of glycoconjugate receptors.
- Neuraminidase cleaves the terminal sialic acid residues on these receptors, allowing for the release of attached virions from infected cells and subsequent viral spread.
- Neuraminidase inhibitors force the newly synthesized virions to remain adherent to the host cell surface, ultimately forming viral aggregates that are unable to infect new host cells.
- Through this mechanism of action, oseltamivir can shorten the course of influenza A and B infections when taken within 48 hours of symptom onset.
Oseltamivir Clinical use
Influenza A or B
Penicillin MOA
penicillins, which interact with transpeptidase (penicillin-binding protein), inhibit peptidoglycan cell wall synthesis
Fluoroquinolones MOA
Fluoroquinolones inhibit DNA gyrase and topoisomerase, which participates in supercoiling.
Aminoglycosides MOA
Aminoglycosides bind to bacterial ribosomes, inhibiting protein synthesis primarily by binding to the aminoacyl site of 16S ribosomal RNA within the 30S ribosomal subunit
Amantadine MOA
- Amantadine prevents viral assembly and also inhibits viral release through interactions with the viral M2 protein.
- Amantadine is no longer used due to resistance.
Ribavirin MOA
- Ribavirin inhibits viral RNA polymerase activity and RNA fragment initiation and elongation, leading to viral protein synthesis inhibition.
- It is used in chronic hepatitis C infection and in some cases of respiratory syncytial virus infection.
Ribavirin Clinical use
It is used in chronic hepatitis C infection and in some cases of respiratory syncytial virus infection.
Trypsinogen activation
Trypsinogen: Enterokinase in the duodenal brush border cleaves this pancreatic protease, activating it to trypsin. Trypsin then cleaves and activates other pancreatic proenzymes such as proelastase and procarboxypeptidase.
DNA laddering description
The appearance of DNA fragments in multiples of 180 base pairs on gel electrophoresis is known as DNA laddering. This finding is a sensitive indicator of apoptosis, a process of programmed cell death that can occur when regulating factors (eg, interleukins) are withdrawn from proliferating cells. Laddering arises from the action of specific endonucleases during karyorrhexis. These endonucleases cleave DNA at internucleosomal linker regions, which occur at 180-base pair intervals in the genome.
A hallmark feature of some cancer cells is their ability to evade programmed cell death, particularly the intrinsic (mitochondrial) pathway of apoptosis.
Follicular B-cell lymphoma pathogenesis
The appearance of DNA fragments in multiples of 180 base pairs on gel electrophoresis is known as DNA laddering. This finding is a sensitive indicator of apoptosis, a process of programmed cell death that can occur when regulating factors (eg, interleukins) are withdrawn from proliferating cells. Laddering arises from the action of specific endonucleases during karyorrhexis. These endonucleases cleave DNA at internucleosomal linker regions, which occur at 180-base pair intervals in the genome.
A hallmark feature of cancer cells is their ability to evade programmed cell death, particularly the intrinsic (mitochondrial) pathway of apoptosis. A well-established mechanism by which malignant lymphoid cells avoid apoptosis is via overexpression of BCL2, an antiapoptotic protein. In fact, most follicular B cell lymphomas are associated with a t(14;18) translocation that leads to BCL2 overexpression.
Follicular B-cell lymphoma genetics
- most follicular B cell lymphomas are associated with a t(14;18) translocation that leads to BCL2 overexpression and apoptosis evasion
- BCL2 is an antiapoptotic protein of the mitochronidal (intrinsic pathway).
Warburg Effect
Malignant cells can undergo high rates of glycolysis to produce the macromolecules necessary to sustain rapid cellular growth (Warburg effect).
Bronchial parasympathetic control
Acetylcholine stimulates muscarinic M3 receptors on bronchial smooth muscle, activating the Gq-phospholipase C-IP3 pathway, which increases intracellular calcium and triggers muscle contraction (bronchoconstriction)
Examples of inhaled antimuscarinics
- Ipratropium
- Tiotropium
Inhaled muscarinic agonist
Methacholine is an inhaled muscarinic agonist that can help diagnose asthma as it promotes bronchoconstriction (methacholine challenge).
Methacholine challenge
- Cholinergic agents activate muscarinic receptors on bronchial smooth muscle, leading to increased muscle contraction intensity (bronchoconstriction).
- Methacholine is an inhaled muscarinic agonist that can help diagnose asthma as it promotes bronchoconstriction (methacholine challenge).
Edrophonium MOA
Edrophonium is a short-acting acetylcholinesterase inhibitor that can be used to support the diagnosis of myasthenia gravis (Tensilon test).
Phenylephrine MOA
Phenylephrine is a potent alpha-1 receptor agonist that promotes contraction of vascular smooth muscle (vasoconstriction).
Considerations of Benzodiazepine metabolism
- Slower benzodiazepine metabolism and elimination in the elderly increase the likelihood of adverse effects such as confusion, anterograde amnesia, ataxia, and falls
- Benzodiazepines are metabolized in the liver and then excreted in the urine. Most benzodiazepines are metabolized via CYP-mediated hepatic oxidative reduction (phase I) followed by glucuronide conjugation (phase II).
- Elderly individuals have reduced oxidative reduction, resulting in slower elimination of many drugs metabolized by the liver.
- However, certain benzodiazepines (lorazepam, oxazepam, temazepam) undergo only glucuronide conjugation, which tends to be relatively preserved in the elderly and those with liver disease.
- In addition, elderly individuals have an increased volume of distribution of lipid-soluble drugs (decreased total body water and mass; increased body fat) as well as decreased renal function, which also contribute to prolonged elimination time of drugs.
Benzodiazepine in the elderly adverse effects
Slower benzodiazepine metabolism and elimination in the elderly increase the likelihood of adverse effects such as confusion, anterograde amnesia, ataxia, and falls
Benzodiazepine tolerance
Tolerance is associated with the length and extent of benzodiazepine use. Prolonged exposure decreases the GABA receptor’s affinity for the drug, resulting in less GABA activity and the necessity for increased dosages to achieve the same effect
Anticholinergic Toxicity
7 main symptoms
Central nervous involvement causes confusion, visual hallucinations, psychosis, and seizure. Coma and respiratory failure can develop in severe cases.
Jimson Weed
Jimson weed seeds (Datura stramonium). Jimson weed is an easily obtained drug of abuse that contains a number of anticholinergic toxins, including atropine, hyoscyamine, and scopolamine. Toxicity may also be seen with excess intake of pharmacologic anticholinergics, such as antihistamines (eg, hydroxyzine, diphenhydramine), antipsychotics (eg, chlorpromazine, olanzapine), antispasmodics (eg, dicyclomine, hyoscyamine), and cyclic antidepressants (eg, amitriptyline, desipramine).
Cocaine Toxicity
Cocaine toxicity is characterized by increased energy, tachycardia, and hypertension; vasoconstriction can result in myocardial ischemia and chest pain. Although tactile hallucinations of formication (ie, sensation of bugs crawling on skin) can occur, patients with cocaine intoxication are typically diaphoretic
To determine the causal mutation, blood was collected from the affected children, DNA was extracted from peripheral leukocytes, and the fibroblast growth factor receptor (FGFR) gene was analyzed. Both affected offspring were found to be heterozygous for the same mutation in the FGFR gene. Which of the following is the most likely explanation for this unaffected couple having children with the disorder?
Germline mosaicism
Types of mosaicism
- Somatic Mosaicism
- Germline Mosaicism
- Combined Mosaicism
Mosaicism description
- Mosaicism is defined as the presence of multiple, genetically different cell lines within the body. Typically, mosaicism results from a mutation during the first stages of embryonic development. The earlier the mutation occurs, the more daughter cells that are affected.
- Mosaicism can be classified as germline, somatic, or both.
- Germline mosaicism involves only oocytes or spermatocytes and should be considered when a genetic mutation is identified in the offspring but not in the parents.
- The likelihood that future offspring will be affected by the same mutation depends on the proportion of mutant to wild-type germ cells in the mosaic parent. The presence of 2 affected children in a family suggests that the number of mutant germ cells in the mosaic parent is high.
Fish Oil Consumption recommended for
Fish oil supplementation is often recommended for those patients with refractory hypertriglyceridemia
Diabetic patients routine examinations
- Individuals with diabetes mellitus should inspect their feet daily for signs of trauma or infection.
- Neurologic evaluation of Achilles tendon reflex, vibration sense, and pain and temperature sensation should be performed periodically (yearly) on diabetic patients
What is this?
Acute promyelocytic leukemia
Acute Promyelocytic Leukemia Histological Features
Auer rods are azurophilic, needle-shaped cytoplasmic inclusions formed by the fusion of primary granules found in myeloblasts and promyelocytes. The rods can be seen on peripheral blood smears and bone marrow aspirates of patients with acute myeloid leukemia, particularly acute promyelocytic leukemia (APL).
Burkitt Lymphoma Histology
Tumor cells classically have round nuclei with basophilic cytoplasm containing prominent lipid vacuoles.
Chronic Myeloid Leukemia Histology
Peripheral blood smear shows leukocytosis with many mature and immature myeloid cells.
Acute Lymphoblastic Leukemia Histology
- High nuclear to cytoplasmic ratio and immature chromatin
- Peripheral blood smear typically demonstrates anemia, thrombocytopenia, and lymphoblasts.
Follicular Lymphoma Histology
The peripheral blood smear will often show malignant cells with notches or clefts (centrocytes).
Effects of IL-2
IL-2 exerts strong proinflammatory effects on most lymphocyte-derived cells, as follows:
- CD4 cells: IL-2 acts in an autocrine manner to increase proliferation of activated CD4 lymphocytes and induce differentiation into type 1 and type 2 helper subtypes. These cells then secrete cytokines (eg, interferon gamma, tissue necrosis factor alpha, interleukin-4) that drive the inflammatory response. IL-2 also stimulates the generation of long-lasting memory cells.
- CD8 cells: IL-2 also promotes the clonal expansion of CD8 cells and stimulates activated CD8 cells to increase cytotoxic killing via the release of perforin, granzymes, and proinflammatory cytokines.
- NK cells: IL-2 stimulates the clonal expansion of NK cells and dramatically enhances their cytotoxic killing.
- IL-2 also exerts potent anti-inflammatory effects via stimulation of regulatory T (Treg) cells. Treg cells constitutively express the IL-2 receptor, which allows them to rapidly activate and proliferate in areas of inflammation (where IL-2 levels are high). Treg cells downregulate the immune response via the expression of surface molecules (eg, CTLA-4) and anti-inflammatory cytokines (interleukin-10, TGF-beta). Therefore, they serve as an important counterbalance to runaway immune activation
Cell junctions and Cadherins
What are Cadherins?
- Cadherins are calcium-dependent adhesion molecules that bind epithelial cells together within tissues. Cadherin molecules on epithelial cells bind to cadherin molecules on adjacent cells to form adherens junctions and desmosomes.
- Cadherins (eg, desmogleins, desmocollins, E-cadherin) are adhesion molecules that bind epithelial cells together within tissues. They are transmembrane proteins that interact intracellularly with intermediate proteins (catenin, plakoglobin, desmoplakin), which facilitate binding to intermediate filaments (keratin) or microfilaments (actin) within the cytoplasm.
- Externally, cadherin molecules on epithelial cells bind to cadherin molecules on adjacent cells to form adherens junctions and desmosomes. Interactions between the extracellular domains of adjacent cadherins are calcium-dependent; removing calcium from the extracellular fluid will cause dissociation of cadherin-mediated junctions, leading to loss of cell-cell adhesion.
Cell junctions
Molluscum contagiosum histology
Microscopy will show epidermal hyperplasia along with molluscum bodies, large eosinophilic cytoplasmic inclusions made of virus particles. Molluscum bodies can also be identified in the material expressed from the umbilicated lesions.
Molluscum contagiosum clinical features
Molluscum contagiosum is characterized by firm, flesh-colored papules on the skin and mucous membranes. The papules are often pruritic and have umbilicated centers containing white, curd-like material. Molluscum contagiosum is caused by a poxvirus (MC virus) and is transmitted through direct contact or fomites. In children, lesions commonly appear on the eyelids, face, or trunk. In adults, sexual transmission may lead to lesions on the trunk and anogenital region. HIV-positive or otherwise immunocompromised individuals may have a prolonged course with widely distributed papules, facial involvement, and lesion counts numbering in the hundreds.
Microscopy will show epidermal hyperplasia along with molluscum bodies, large eosinophilic cytoplasmic inclusions made of virus particles. Molluscum bodies can also be identified in the material expressed from the umbilicated lesions.
Basal cell Carcinoma gross histology
typically forms slow-growing papules, often with ulceration or a rolled border
Basal cell carcinoma Histology
Histopathology shows nests or strands of basaloid cells with hyperchromatic nuclei. The cells at the periphery often display parallel alignment (palisading).
What is this?
Basal Cell Carcinoma
what is this?
Verruca Vulgaris
What is Verruca Vulgaris?
Verruca vulgaris (common warts) due to human papillomavirus causes non-umbilicated, skin-colored or pink papules or growths.
Biopsy is characterized by undulating epidermal hyperplasia with enlarged nuclei and cytoplasmic vacuolization (koilocytosis) forming perinuclear halos.
Verruca Vulgaris Histology
Biopsy is characterized by undulating epidermal hyperplasia with enlarged nuclei and cytoplasmic vacuolization (koilocytosis) forming perinuclear halos.
Cryptococcus Neoformans Histology
- Microscopic assessment will show budding encapsulated yeast
- Thick polysaccharide capsule
- India ink
Posterior Knee Dislocation
At risk for popliteal artery injury and tibial nerve
Bartholin Cyst
The greater vestibular (Bartholin) glands drain into the Bartholin duct. Blockage of a Bartholin duct leads to mucus accumulation and cyst formation. Infection of the cyst can result in a labial abscess, a painful unilateral labial mass occasionally accompanied by purulent vaginal discharge.
Herpes Zoster Pathophysiology
- herpes zoster (shingles).
- Although most commonly seen in adults age >50, herpes zoster can occur in children, especially those with primary varicella infection (chicken pox) in the first year of life.
- Herpes zoster results from reactivation of latent varicella zoster virus (VZV).
- On resolution of the primary infection, immunity develops and VZV retreats to the dorsal root ganglion of cutaneous sensory nerves, where it remains in a latent state.
- Risk factors for reactivation of latent VZV include age, trauma, malignancy, and immunosuppression.
Shingles S&S
Herpes zoster manifests clinically with a prodrome of neuropathic pain that is typically unilateral and isolated to one dermatome. Crops of grouped vesicles with underlying erythema subsequently erupt in that same dermatome accompanied by severe pain.
What is this?
Atopic Dermatitis
Atopic Dermatitis Pathophysiology
- Affects infants and young children and is frequently associated with a family history of atopy (eg, asthma, food allergies, allergic rhinitis).
- Infants typically experience eruptions on their cheeks and diaper area; flexural surfaces are often involved in older children.
Measels rash features
- is rarely seen in the United States due to current immunization practices.
- The viral exanthem associated with measles begins on the head and face and spreads downward to involve the trunk and lower extremities.
- The pathognomonic lesions are red/blue Koplik spots on the buccal mucosa.
What is Nummular Eczema?
- Nummular eczema most commonly occurs in the setting of xerosis.
- Use of harsh soaps and exposure to environmental irritants can exacerbate the condition.
- Nummular eczema presents with pruritic, coin-shaped, erythematous patches.
Psoriasis rash feautres
- Psoriasis causes well-demarcated, erythematous plaques with overlying silvery scale on the extensor surfaces of the extremities.
- It is more commonly seen in adults and appears to be triggered by environmental factors such as smoking, weather changes, and stress.
Receptor vs non-receptor Tyrosine Kinases
- These receptors are transmembrane proteins that have a ligand-binding extracellular region, a hydrophobic transmembrane region, and an intracellular (cytoplasmic) domain with inducible tyrosine kinase activity.
- Ligand binding to the extracellular portion of a tyrosine kinase receptor causes dimerization of 2 identical receptor subunits.
- Each subunit phosphorylates the other, causing a conformational change in the intracellular domains of the tyrosine kinase receptor dimer.
- This conformational change exposes each subunit’s catalytic domain, and phosphorylation of tyrosine residues on target proteins ensues.
- The difference comes in whether the receptor has intrinsic tyrosine kinase activity or if there is a cytoplasmic tyrosine kinase that binds to and dimerizes receptor to continue downstream signalling
PLC-IP3 Pathway
Identify
Sildenafil MOA
selective phosphodiesterase-5 inhibitor (eg, sildenafil)
prevents breakdown of cGMP which leads to increased relaxation
How does Sildenafil help with Erectile Dysfunction
The photomicrograph above depicts a hematoxylin- and eosin-stained transverse section of the penis.
selective phosphodiesterase-5 inhibitor (eg, sildenafil). Local release of nitric oxide during sexual stimulation increases the activity of soluble guanylate cyclase in smooth muscle cells.
Simultaneous inhibition of phosphodiesterase-5 further augments intracellular cyclic guanosine monophosphate (cGMP) concentrations.
cGMP mediates relaxation in the smooth muscle cells that surround the cavernous venous sinuses of the corpora cavernosa (area B).
Through this mechanism, phosphodiesterase-5 inhibitors facilitate vascular congestion, causing the corpora to become engorged and sustaining the erection.
Corpus Spongiosum function
Maintains patency of urethra
Visual Pathways
Right Anopia
No vision in right eye
Sever right optic nerve
Bitemporal hemianopia
Sever optic chaisma
no lateral visual fields
Binasal Hemianopia
No vision in medial fields
Sever optic tract lateral to optic chaisma
Left homonymous hemianopia
No Left sided vision
Sever right optic tract proximal to optic chaisma
Left homonymous inferio quadrantanopia
left pie on the floor
sever right dorsal optic radiation
Left homonymous superio quadrantanopia
Left Pie in the sky
Sever right meyer loop
Craniopharyngiopharyngiomas
Craniopharyngiomas are slow-growing suprasellar tumors arising from remnants of Rathke’s pouch. They have a bimodal age distribution with one peak in childhood and another peak in adults (age 50-75).
Individuals typically present insidiously with headaches, signs of pituitary dysfunction (eg, growth failure in children), and visual disturbances. Bitemporal hemianopia often occurs due to tumor compression on the central portion of the optic chiasm.
Neuroimaging classically reveals a calcified mass in the suprasellar region.
Exocrine pancreas secretions
The exocrine pancreas secretes approximately 1 L of fluid, which consists of an aqueous portion and an enzymatic portion, into the duodenum daily. The acinar cells primarily contribute to the enzymatic portion and the ductal cells are responsible for producing the aqueous portion.
Pancreatic exocrine secretions contain fixed concentrations of sodium and potassium that are virtually identical to those of plasma. Levels of bicarbonate and chloride, however, vary with the pancreatic flow rate, which increases in response to the hormone secretin. During low flow, the ductal cells secrete an isotonic solution containing low bicarbonate concentrations and higher chloride concentrations. During high flow, the pancreas secretes an isotonic solution that is high in bicarbonate and low in chloride.
Delivery of acidic chyme to the duodenum stimulates mucosal endocrine cells (S cells) to release secretin, which in turn stimulates secretion of bicarbonate by the pancreatic ductal cells. As secretion of bicarbonate increases, luminal chloride concentration decreases. A chloride-bicarbonate exchanger on the apical surface of ductal cells helps maintain this inverse relationship.
Acute Stress disorders features
- Anxiety associated with intrusive memories, nightmares, and arousal (sleep difficulty, poor concentration, exaggerated startle) is consistent with acute stress disorder (ASD).
- Avoidance of external reminders (outside traffic noises), impaired concentration, and negative mood are also characteristic of the disorder.
- Symptoms must last for >3 days and <1 month following trauma exposure.
- Patients typically have some form of intrusive re-experience (distressing memories, nightmares, flashbacks) and are preoccupied with negative thoughts about their role in the traumatic event.
- They may have dissociative experiences such as forgetting details of the event or feeling detached from reality.
Differential Diagnoses of Psychotic Disorders
Accurate diagnosis of primary psychotic disorders requires attention to the time frame and extent of psychotic symptoms.
A new screening test is positive for disease X in 250 out of 1,000 affected patients and in 100 out of 1,000 healthy controls. The screening test is then applied to a population where the disease prevalence is 10,000/100,000. How many false positives would be expected per 100,000 individuals in this population?
The screening test was incorrectly positive for disease X in 100 out of 1,000 healthy controls, corresponding to a false positive rate (FPR) of 10% (100/1,000). Note that this also means that the test correctly identified 900 out of the 1,000 healthy individuals as being healthy, corresponding to a specificity of 90% (900/1,000). The FPR, which is equal to (1 – specificity), is a characteristic of the screening test and does not change with disease prevalence (similar to sensitivity and specificity). In a population of 100,000 with a disease prevalence of 10,000/100,000, 10,000 will have the disease and 90,000 will not. When the same FPR is applied to these 90,000 healthy individuals, there will be 90,000 × 10% = 9,000 false positives per 100,000 individuals.
The solution can also be visualized using a 2 x 2 (contingency) table. Starting with a hypothetical population of 100,000 individuals, the prevalence of diseased individuals is given as 10,000; this is the total number of diseased individuals (last row in second column). Therefore, the total number of healthy (non-diseased) individuals is 100,000 – 10,000 = 90,000 (last row in third column). The screening test is falsely positive in 100 out of 1,000 non-diseased controls, so there will be 9,000 false positive test results for the 90,000 non-diseased patients.
The rest of the table can be completed as follows: The number of non-diseased patients who test negative is 90,000 – 9,000 = 81,000. The screening test is positive in 250 out of 1,000 diseased patients (sensitivity = 250/1,000 = 25%), so for 10,000 diseased patients, there will be 2,500 positive test results and 10,000 – 2,500 = 7,500 negative test results (second and third rows in second column).
Relative Risk equation
Relative risk is calculated as the risk in exposed subjects divided by the risk in unexposed subjects.
Left side of table descriptor
Predictor (like exposure to risk factor or test result)
Top of Table descriptor
Outcome (like diseased or not)
Number Needed to Treat Equation
What is this?
PML radiography
Toxoplasmic encephalitis radiography
MRI of the brain typically shows multiple ring-enhancing lesions.
A 19-year-old woman comes to the hospital due to 4 days of severe abdominal pain and nausea. She has also had reddish-brown discoloration of her urine but no dysuria or increased urinary frequency. Her boyfriend adds that she has become restless and irritable and has had several aggressive outbursts since she began to feel unwell. The patient had a similar episode at age 13 but has not had any symptoms since. She recently started taking combined oral contraceptives but takes no other medications. Her temperature is 37 C (98.6 F), blood pressure is 120/70 mm Hg, and pulse is 110/min and regular. On examination, she is anxious and her abdomen is soft with mild generalized tenderness on deep palpation. She has no skin rash. Which of the following conversions is most likely impaired in this patient?
A
Acute Intermittant Porphyria S&S
Typical clinical findings during an acute AIP attack include severe vague abdominal pain, nausea and vomiting, motor/sensory neuropathy, and neuropsychiatric manifestations (eg, insomnia, agitation).
A classic feature is port-wine colored urine that darkens on exposure to light and air (oxidation of excess PBG).
Cutaneous findings and photosensitivity are absent (as they are typically a result of porphyrinogen accumulation), and patients are symptom-free between attacks.
AIP is the second most common porphyria after porphyria cutanea tarda (PCT), caused by uroporphyrinogen decarboxylase (UROD) deficiency. UROD deficiency can be congenital or acquired (exposure to aromatic hydrocarbons, estrogen supplementation, hepatitis C). Cutaneous photosensitivity is the cardinal manifestation (Choice C).
Porphyria Cutanea Tarda features
rare disorder characterized by painful, blistering skin lesions that develop on sun-exposed skin (photosensitivity)
