UWSA1-4 Flashcards
A 5-year-old boy comes to the office with periorbital edema and rust-colored urine for 2 days. His oral intake has been normal, but his parents are concerned that he is voiding less frequently than usual. Three weeks ago, he had a pustule on his face that subsequently developed an overlying, adherent, honey-crusted layer and resolved with antibiotics. The patient’s blood pressure is mildly elevated. Urinalysis is positive for protein and red blood cell casts. Which of the following characteristics best describes the bacteria involved in this patient’s condition?
This patient’s most likely diagnosis is acute poststreptococcal glomerulonephritis (PSGN). PSGN is an immune complex-mediated disease that occurs 1-3 weeks after a pharyngeal or skin infection (eg, impetigo) by Streptococcus pyogenes (group A Streptococcus or GAS). Deposition of streptococcal nephritogenic antigens within the glomerulus causes immune complex formation, which in turn triggers complement activation and inflammation.
GAS is a gram-positive, beta-hemolytic, bacitracin-sensitive bacterium that grows in chains. Gram-positive bacteria retain the crystal violet stain and appear purple. When GAS is plated on blood agar culture, GAS causes beta hemolysis (complete red cell lysis) and transparency in the normally red agar media. Bacitracin can be used to distinguish GAS from other streptococcal strains, with GAS being sensitive to bacitracin and most non-group A strains resistant.
Symptoms of PSGN typically include edema, gross hematuria, hypertension, and oliguria. The edema is commonly periorbital and can become generalized. Gross hematuria often presents as tea- or cola-colored urine, and urinalysis is positive for protein and blood. Serum abnormalities include a low C3 and mildly elevated creatinine. Antibody titers reflecting a previous GAS infection are helpful in diagnosis (Table). A biopsy is usually not indicated for diagnosis when the presentation is classic.
Strep Pyogenes features
GAS is a gram-positive, beta-hemolytic, bacitracin-sensitive bacterium that grows in chains. Gram-positive bacteria retain the crystal violet stain and appear purple.
When GAS is plated on blood agar culture, GAS causes beta hemolysis (complete red cell lysis) and transparency in the normally red agar media.
Bacitracin can be used to distinguish GAS from other streptococcal strains, with GAS being sensitive to bacitracin and most non-group A strains resistant.
Acute poststreptococcal Glomerulonephritits pathophysiology
PSGN is an immune complex-mediated disease that occurs 1-3 weeks after a pharyngeal or skin infection (eg, impetigo) by Streptococcus pyogenes (group A Streptococcus or GAS)
Deposition of streptococcal nephritogenic antigens within the glomerulus causes immune complex formation, which in turn triggers complement activation and inflammation.
Acute poststreptococcal Glomerulonephritits clinical features
Can be asymptomatic
Symptoms of PSGN typically include edema, gross hematuria, hypertension, and oliguria. The edema is commonly periorbital and can become generalized. Gross hematuria often presents as tea- or cola-colored urine, and urinalysis is positive for protein and blood. Serum abnormalities include a low C3 and mildly elevated creatinine. Antibody titers reflecting a previous GAS infection are helpful in diagnosis (Table). A biopsy is usually not indicated for diagnosis when the presentation is classic.
If symptomatic:
Gross hematuria (tea- or cola-colored urine)
Edema (periorbital, generalized)
Hypertension
Acute poststreptococcal Glomerulonephritits lab findings
Urinalysis: + protein, + blood, ± red blood cell casts
Serum:
↓ C3 & possible ↓ C4
↑ Serum creatinine
↑ Anti-DNase B (antideoxyribonuclease-B) & ↑ AHase (antihyaluronidase)
↑ ASO (antistreptolysin O) & ↑ anti-NAD (from preceding pharyngitis) (antinicotinamide-adenine dinucleotidase)
Staphylococcus aureus features
Staphylococcus aureus is a gram-positive, catalase-positive, coagulase-positive bacterium that grows in clusters.
Differentiating staph from strep
the catalase test is a particularly important test used to determine whether the Gram + cocci is a staphylococci or a streptococci.
Staph is catalase Positive
Strep is catalase Negative
Quelling Reaction
The Quellung reaction refers to capsule swelling that is evident on microscopy after a bacterium is exposed to its capsular antigens. Streptococcus pneumoniae, the most common cause of community-acquired pneumonia, is an example of a Quellung-reaction-positive bacterium.
Preceeding infections of Reactive Arthritis
Genitourinary infection: Chlamydia trachomatis
Enteritis: Salmonella, Shigella, Yersinia, Campylobacter, Clostridioides (formerly Clostridium) difficile
Reactive Arthritis symptoms
Asymmetric oligoarthritis
Enthesitis
Dactylitis
Ocular: conjunctivitis, anterior uveitis
Genital: urethritis, cervicitis, prostatitis
Dermal: keratoderma blennorrhagicum, circinate balanitis
Oral ulcers
Reactive arthritis risk factor
HLA B27
Reactive arthritis Pathophysiology
Genitourinary or gastrointestinal infection typically precedes the onset of symptoms by 2-6 weeks. The manifestations are caused by immune-complexes involving bacterial antigens. However, it does not represent disseminated infection, and joint aspirates are sterile (ie, it is a reactive, not infectious, arthritis).
Ankylosing Spondylitis description
Ankylosing spondylitis is a chronic disease affecting the axial skeleton and causes progressive stiffness and pain.
It is associated with HLA B27, but extra-articular symptoms are not prominent.
Disseminated gonococcal infection description
Disseminated gonococcal infection presents as
purulent arthritis (eg, knee, wrist, ankle)
or
as the triad of tenosynovitis, dermatitis, and non-purulent polyarthralgias.
Hypersensitivity Vasculitis
Hypersensitivity vasculitis is a drug reaction characterized by a purpuric rash.
Viral Arthritis description
Viral arthritis causes symmetric, polyarticular disease. It is most common following parvovirus, hepatitis B, hepatitis C, rubella, and alphavirus infection.
Chromosome 15 genomic imprinting disorders
- Prader-Willi Syndrome
- Angelman Syndrome
Pathophysiology of Prader-Willi Syndrome
This child has Prader-Willi syndrome (PWS), a genomic imprinting disorder caused by the loss of paternally inherited alleles on chromosome 15q11-13. Within this region, certain genes are differentially imprinted and silenced depending on the parent of origin. Alleles that are maternally imprinted cannot be actively expressed unless there is a functional paternal copy. PWS can be caused by any genetic defect that results in the absence of this paternal contribution, most commonly microdeletions of the paternal 15q11-13 region or maternal uniparental disomy (ie, both chromosome 15s are inherited from the mother). This patient’s normal fluorescence in-situ hybridization (FISH) findings indicate that his condition is most likely due to maternal uniparental disomy.
Causes of prader-willi syndrome
Loss of paternally inherited allele from chromosome 15:
Paternal microdeletion
or
Maternal uniparental disomy
Clinical Features of Prader-Willi syndrome
Neonatal hypotonia
Hyperphagia/obesity
Short stature
Small hands & feet
Hypogonadism
Dysmorphic facies
Intellectual disability
Causes of Angelman Syndrome
Loss of maternally inherited allele from chromosome 15
Maternal microdeletion
Paternal uniparental disomy
S&S of Angelman syndrome
Epilepsy/seizures
Ataxic gait/tremors
Poor motor & language development
Inappropriate laughter/smiling
Intellectual disability
Celiac disease genetic implications
Celiac disease has a genetic component and is associated with the human leukocyte antigen
(HLA) DQ2 and DQ8 genotypes.
Celiac Disease Pathophysiology
Celiac disease (celiac sprue, gluten-sensitive enteropathy) is caused by dietary exposure to gliadins (a component of gluten) in wheat and related grains in susceptible individuals. This sensitivity to gluten can trigger autoimmune reactions in the gastrointestinal tract. In the small bowel, celiac disease causes marked villous atrophy in a background of diffuse enteritis. CD8+ T-cell lymphocytes infiltrate the small intestine surface epithelium, and a wide range of inflammatory cells (CD4+ T-cell lymphocytes, plasma cells, macrophages, eosinophils, and mast cells) take up residence in the lamina propria. Celiac disease has a genetic component and is associated with the human leukocyte antigen (HLA) DQ2 and DQ8 genotypes.
Celiac Disease S&S
This patient, with persistent diarrhea, bloating, and weight loss, has typical symptoms of celiac disease.
Celiac disease is often associated with dermatitis herpetiformis, which causes grouped vesicles, papules, and urticaria on the extensor surfaces of the elbows, knees, sacrum, and buttocks. The lesions are extremely pruritic and are caused by cross-reactivity of anti-gliadin IgA antibodies with transglutaminase at the dermal basement membrane. Skin biopsy will show microabscesses at the dermal papillary tips, which coalesce to form subepidermal blisters. Immunofluorescence staining for IgA confirms the diagnosis.
Dermatitis Herpetiformis
Celiac disease is often associated with dermatitis herpetiformis, which causes grouped vesicles, papules, and urticaria on the extensor surfaces of the elbows, knees, sacrum, and buttocks. The lesions are extremely pruritic and are caused by cross-reactivity of anti-gliadin IgA antibodies with transglutaminase at the dermal basement membrane. Skin biopsy will show microabscesses at the dermal papillary tips, which coalesce to form subepidermal blisters. Immunofluorescence staining for IgA confirms the diagnosis.
Celiac disease histology
In the small bowel, celiac disease causes marked villous atrophy in a background of diffuse enteritis. CD8+ T-cell lymphocytes infiltrate the small intestine surface epithelium, and a wide range of inflammatory cells (CD4+ T-cell lymphocytes, plasma cells, macrophages, eosinophils, and mast cells) take up residence in the lamina propria.
“Cobblestone mucosa and transmural inflammation” are characteristic of
Crohn disease
Identify
Polycystic Ovarian Syndrome Pathophysiology
polycystic ovary syndrome (PCOS), a common endocrine disorder in women that is associated with an elevated LH/FSH ratio and ovarian hyperresponsiveness to LH.
Because LH stimulates the ovarian theca cells to produce androgens, patients with PCOS usually have hyperandrogenism, which can be diagnosed clinically (eg, acne, hirsutism) or biochemically (ie, high testosterone level)
Elevated androgen levels and an unbalanced LH/FSH ratio both inhibit the maturation and release of a single dominant ovarian follicle (ie, ovulation). Therefore, patients with PCOS are typically anovulatory and develop multiple, smaller follicles that arrest in development. These follicles eventually degenerate and accumulate fluid, causing the classic appearance of bilaterally enlarged, polycystic ovaries.
Lesch-Nyhan Syndrome pathophysiology
Lesch-Nyhan syndrome caused by an X-linked recessive defect in hypoxanthine-guanine phosphoribosyltransferase (HGPRT). The HGPRT enzyme participates in the purine salvage pathway by catalyzing the conversion of hypoxanthine and guanine to inosine monophosphate and guanosine monophosphate, respectively. Deficiency of this enzyme causes decreased purine salvage, increased purine synthesis, hyperuricemia, and hyperuricuria.
Lesch-Nyhan Syndrome S&S
Characteristic features include self-mutilating behavior (eg, finger and lip biting), mild intellectual disability, involuntary movements (eg, dystonia), delayed motor development, nephrolithiasis, and gout. Parents may also report a “frost” on the skin under the affected child’s diaper due to hyperuricuria. Treatment with allopurinol decreases uric acid levels and therefore relieves symptoms related to gout and urolithiasis, but this treatment has little effect on neurological symptoms.
Antibiotics that inhibit prokaryotic protein synthesis at the 30s ribosomal subunit
tetracyclines (eg, doxycycline) and the aminoglycosides (eg, streptomycin)
Macrolide MOA
macrolide antibiotic that binds to the 50s prokaryotic ribosomal subunit and blocks the translocation step by preventing tRNA release from the donor site after peptide bond formation.
Chloramphenicol MOA
Chloramphenicol binds to the 50s prokaryotic ribosomal subunit and blocks peptidyltransferase action, thereby preventing new peptide bond formation.
Rifampin MOA
Rifampin blocks prokaryotic mRNA synthesis by bacterial RNA polymerase.
Typically used in combination with other antibiotics to minimize bacterial resistance, rifampin treats active tuberculosis and prevents meningitis caused by Neisseria meningitidis or Haemophilus influenzae.
Puromycin MOA
Puromycin is an aminonucleoside antibiotic that has a structure analogous to aminoacyl-tRNA. In prokaryotes, it leads to the premature release of unfinished polypeptide chains as polypeptidyl-puromycin derivatives.
Pilocarpine MOA
Muscarinic agonist
Atropine MOA
Muscarinic antagonist
Physostigmine moa
Acetylcholinesterase inhibitor
Phenylephrine MOA
alpha-adrenergic receptor agonist (α1 > α2)
What’s This?
peripheral blood smear shows macrocytosis and a hypersegmented neutrophil.
A 56-year-old woman comes to the office due to a 3-month history of excessive fatigue, along with progressive numbness in both feet. Her sleep is adequate, and she eats a normal diet. The patient has a history of hypothyroidism that was diagnosed following pregnancy 20 years ago. Her only current medication is levothyroxine, and she does not use alcohol. Physical examination shows mucosal pallor with a flat, shiny tongue. Neurologic examination finds diminished vibratory sensation in both feet. TSH level is normal. Peripheral blood smear is shown in the image below.
This patient has fatigue, peripheral neuropathy, and atrophic glossitis. The peripheral blood smear shows macrocytosis and a hypersegmented neutrophil. In addition, she has a history of autoimmune thyroiditis (the most common cause of hypothyroidism in developed countries). In light of her current symptoms, this patient most likely has pernicious anemia due to autoimmune destruction of gastric mucosa.
Over time, this damage results in chronic atrophic gastritis, causing profound hypochlorhydria and leading to a compensatory increase in serum gastrin levels (antral G cell gastrin secretion is inhibited by hydrochloric acid). In addition, the loss of intrinsic factor-secreting parietal cells leads to depletion of vitamin B12 stores and eventual deficiency.
Vitamin B12 deficiency causes hematologic (eg, macrocytic anemia) and neurologic (eg, peripheral neuropathy, combined degeneration of ascending and descending spinal tracts) manifestations. Pernicious anemia occurs most commonly in patients age >50, but it can be seen more frequently in younger patients with other autoimmune disorders.
Vitamin B12 Deficiency S&S
Vitamin B12 deficiency causes hematologic (eg, macrocytic anemia)
fatigue, peripheral neuropathy, and atrophic glossitis
and neurologic (eg, peripheral neuropathy, combined degeneration of ascending and descending spinal tracts) manifestations.
Pernicious Anemia Pathophysiology
Pernicious anemia is due to autoimmune destruction of gastric mucosa (parietal cells). Production of gastric acid is diminished, leading to a compensatory increase in gastrin release. Secretion of gastric intrinsic factor is also lost, leading to vitamin B12 deficiency.
Over time, this damage results in chronic atrophic gastritis, causing profound hypochlorhydria and leading to a compensatory increase in serum gastrin levels (antral G cell gastrin secretion is inhibited by hydrochloric acid).
In addition, the loss of intrinsic factor-secreting parietal cells leads to depletion of vitamin B12 stores and eventual deficiency. Vitamin B12 deficiency causes hematologic (eg, macrocytic anemia) and neurologic (eg, peripheral neuropathy, combined degeneration of ascending and descending spinal tracts) manifestations.
Pernicious anemia occurs most commonly in patients age >50, but it can be seen more frequently in younger patients with other autoimmune disorders.
Secretin mechanism of secretion
Secretin is produced by S cells of the duodenal mucosa in response to passage of gastric acid through the pylorus.
A 26-year-old man comes to the office due to a scrotal mass. He first noticed a painless mass in the scrotum 4 weeks ago while in the shower and thinks it may be getting larger. The patient has no history of abdominal or genital trauma. On examination, he has a left-sided scrotal mass that is palpable when he stands but disappears when he lies down. Light does not shine through the mass when a penlight is held behind it. Which of the following is the most likely diagnosis?
Varicoceles are dilations of the spermatic vein pampiniform plexus that are common in adults. They tend to arise on the left side as the left gonadal vein is one of the longest veins in the body and drains into the left renal vein at a perpendicular angle. The pressure within the left renal vein is also higher due to compression between the aorta and the superior mesenteric artery (“nutcracker effect”). This increased pressure in the left gonadal vein results in valve leaflet failure and retrograde blood flow toward the testis on standing. When the patient is recumbent, much of the blood returns to systemic circulation and the varicocele diminishes in size.
A varicocele can present as a vague fullness or as a large, compressible mass likened to a “bag of worms.” It does not transilluminate light. Some individuals are asymptomatic; others experience aching pain relieved with recumbency, testicular atrophy, or reduced fertility (due to blood stasis and/or increased scrotal temperature).
Varicocele Pathophysiology
Varicoceles are dilations of the spermatic vein pampiniform plexus that are common in adults. They tend to arise on the left side as the left gonadal vein is one of the longest veins in the body and drains into the left renal vein at a perpendicular angle. The pressure within the left renal vein is also higher due to compression between the aorta and the superior mesenteric artery (“nutcracker effect”). This increased pressure in the left gonadal vein results in valve leaflet failure and retrograde blood flow toward the testis on standing. When the patient is recumbent, much of the blood returns to systemic circulation and the varicocele diminishes in size.
A varicocele can present as a vague fullness or as a large, compressible mass likened to a “bag of worms.” It does not transilluminate light. Some individuals are asymptomatic; others experience aching pain relieved with recumbency, testicular atrophy, or reduced fertility (due to blood stasis and/or increased scrotal temperature)
“nutcracker effect”
The pressure within the left renal vein is also higher due to compression between the aorta and the superior mesenteric artery
Varicocele S&S
A varicocele can present as a vague fullness or as a large, compressible mass likened to a “bag of worms.” It does not transilluminate light. Some individuals are asymptomatic; others experience aching pain relieved with recumbency, testicular atrophy, or reduced fertility (due to blood stasis and/or increased scrotal temperature).
What is a hydrocele?
Hydroceles are peritoneal fluid collections that accumulate between the parietal and visceral layers of the tunica vaginalis. Hydroceles can be small or quite large, with pain increasing with the mass size. Although communicating hydroceles can change in size with positional changes, the fluid within a hydrocele is easily transilluminated
Varicocele description
Varicoceles are dilations of the spermatic vein pampiniform plexus that enlarge with standing and regress with lying down. Patients may be asymptomatic or experience aching pain relieved with recumbency, testicular atrophy, or reduced fertility.
Acanthosis nigracans
acanthosis nigricans, a reactive skin condition characterized by brown to black, velvety thickened plaques that tend to arise in flexural regions such as the axillae or back of the neck.
Acanthosis nigricans is most commonly associated with benign conditions such as insulin resistance or obesity. However, it can also signal the presence of malignancy within the gastrointestinal (GI) tract (eg, stomach, liver) or lungs. When acanthosis nigricans appears suddenly, spreads quickly, or involves the mucous membranes or palms and soles, the likelihood of malignancy increases. It has been postulated that malignancy and hyperinsulinemia cause acanthosis nigricans by influencing growth factor production.
Adrenal insufficiency presentation
Adrenal insufficiency can present with fatigue and weight loss, and it is associated with hyperpigmentation due to increased secretion of ACTH and melanocyte-stimulating hormone in response to inadequate cortisol levels.
Peutz-Jeghers syndrome
rare autosomal dominant disease characterized by pigmented mucocutaneous macules (eg, perioral pigmentation) and hamartomatous polyps in the GI tract. Progressive growth can lead to malignant transformation.
Atrophic glossitis associations
may be associated with a number of nutritional deficiencies, including iron, vitamin B12, folate, and other nutrients.
A 42-year-old woman is evaluated for several months of dyspnea. The patient reports being diagnosed with a cardiac murmur in her early adolescence, which was attributed to mild valvular insufficiency. She has been asymptomatic until recently, when she started having progressive dyspnea on exertion, fatigue, and occasional paroxysmal nocturnal dyspnea. The patient has no other medical problems. Examination reveals a grade III/VI holosystolic murmur at the apex that radiates to the axilla. Echocardiogram shows thickened, redundant mitral valve leaflets with posterior leaflet prolapse and severe mitral regurgitation. Mitral valve replacement is performed with a mechanical valve, and the postoperative course is uncomplicated. Which of the following is indicated for long-term management of this patient?
Mechanical prosthetic valves are thrombogenic, and patients are at risk of valve thrombosis and systemic thromboembolic complications. In patients with mechanical mitral valve replacement, long-term anticoagulation with a vitamin K antagonist (eg, warfarin) is recommended to reduce the risk of thromboembolic complications.
Vitamin K is essential for the gamma-carboxylation of coagulation factors II, VII, IX and X. It is converted into an “inactive” form during the process and reactivated by the enzyme vitamin K epoxide reductase. Warfarin competitively inhibits this enzyme, depleting the body of biologically active vitamin K. This interferes with the vitamin K-dependent synthesis of active clotting factors.
Glycoprotein IIb/IIIa inhibitors list
(eptifibatide,
abciximab,
tirofiban)
P2Y12 receptor blockers list
clopidogrel, ticagrelor, prasugrel
PCSK9 inhibitor list
Alirocumab is a monoclonal antibody against PCSK9 (increases availability of LDL receptors on hepatocyte membranes, resulting in increased LDL clearance from the circulation.)
A 64-year-old man comes to the office with a 6-week history of back pain. The pain is severe at times, is not related to activity, and often wakes him from sleep. The patient has no history of spinal trauma. On further questioning, he reports mild weight loss and occasional pinkish hematuria. Examination reveals an enlarged prostate with a hard nodule. Laboratory studies are notable for mild anemia and a markedly elevated prostate-specific antigen level. Biopsy and subsequent imaging confirm adenocarcinoma of the prostate with evidence of bony metastases in the lumbar spine. The patient declines orchiectomy but is willing to consider leuprolide therapy. Long-term treatment with this medication would result in which of the following?
Most prostate cancers are androgen-dependent. Androgen deprivation therapy, either by surgical orchiectomy or pharmacologic suppression of testosterone production, can slow progression of the disease and relieve symptoms (eg, bone pain).
Leuprolide is a gonadotropin-releasing hormone (GnRH) analog. It has agonist properties when administered in a pulsatile fashion and can cause a rise in LH and testosterone release on initial administration. However, continuous GnRH effect, whether from a GnRH infusion or long-term leuprolide use, suppresses pituitary LH release (Choice E) and leads to reduced production of testosterone by Leydig cells. The lower levels of circulating testosterone produce a clinical effect similar to surgical orchiectomy.
Antiandrogen therapies
Flutamide MOA
Flutamide, a nonsteroidal agent used in the treatment of prostate cancer, acts as a competitive testosterone receptor inhibitor.
Prevention of androgen-receptor binding blocks the stimulatory effect of androgens on the primary tumor and metastases.
Melanocytes embryology
During the first three months of embryonic development, precursor melanocytes migrate from the neural crest to the dermis and then the epidermis. Once established in the epidermis, the precursor cells differentiate into melanocytes. Identifiable melanosomes appear within the melanocytes of the fetal epidermis by eight to ten weeks of gestational age.
Germ cells embryology
Originating from the tissues of the posterior yolk sac, primordial germ cells similarly migrate to the gonadal ridge during the fifth and sixth weeks of embryonic development. (Like melanocytes, germ cells may stray from the migration route and take up residence in different organs or tissues, which accounts for the development of melanocytic and germ cell tumors in unusual locations.) As oogonia, the germ cells undergo numerous mitoses and then meiosis, finally arresting as primary oocytes in meiotic prophase. As undifferentiated spermatogonia, the germ cells proliferate in the basal compartment, with some giving rise to primary spermatocytes.
A pediatric cardiologist is consulted about a 2-week-old boy with a suspected congenital heart defect. The patient struggles while feeding, developing tachypnea, tachycardia, and transient cyanosis. The boy’s postnatal course was complicated by a seizure during the first week. Physical examination shows low-set ears and increased distance between the eyes. Karyotype analysis reveals a partial deletion on chromosome 22. Disturbed development of which of the following cardiac structures most likely occurred in utero?
Conotruncal (outflow tract) defects are common in infants with DGS and include persistent truncus arteriosus, tetralogy of Fallot, and interrupted aortic arch. In utero, a wall normally divides the single truncal root into a separate pulmonary artery and ascending aorta. Persistent truncus arteriosus occurs when this septum does not form, leading to branching of the aorta, pulmonary arteries, and coronary arteries from a single arterial trunk. This defect can lead to cyanosis and heart failure if it is not surgically corrected.
Digeorge Syndrome Pathogenesis
DiGeorge syndrome (DGS) is caused by a chromosome 22q11.2 deletion and results in failed development of the third and fourth pharyngeal pouches during week 4 of embryogenesis.
Consequently, individuals with DGS have defective T cell-mediated immunity due to an absent or hypoplastic thymus (absent thymic shadow), tetany or seizures secondary to absent parathyroid glands (hypocalcemia), and defects in the heart and great vessels.
DiGeorge Syndrome S&S
Conotruncal cardiac defects
Abnormal facies
Thymic aplasia/hypoplasia
Cleft palate
Hypocalcemia (seizures or tetany)
A 2-year-old boy is brought to the office due to recurrent otitis media and pneumonia. His most recent pneumonia episode required intubation and mechanical ventilation. During that admission, Pneumocystis jiroveci was identified on bronchoscopy. Neither the patient’s parents nor his two older siblings have evidence of an immunodeficiency disorder. The patient’s HIV test is negative. Flow cytometry demonstrates a lack of CD40ligand expression on CD4 lymphocytes. Which of the following serum concentrations are most likely low in this patient?
IgA and IgG and IgE
Activated CD4 cells express CD40 ligand (CD40L), which stimulates B cells to undergo class-switch recombination. Defects in CD40L signaling prevent B cells from producing significant amounts of immunoglobulin other than IgM (hyper-IgM syndrome), leading to recurrent sinopulmonary, gastrointestinal, and opportunistic infections
The 5 major types of immunoglobulin are distinguished by different amino acid sequences in their heavy chain (alpha, delta, epsilon, gamma, mu). Unstimulated B cells constitutively express mu and delta heavy chains and generate only IgM and IgD. In order to generate other immunoglobulin types, B cells must undergo costimulation by CD40 ligand (CD40L), which is expressed on the surface of activated CD4 cells.
Binding of CD40L to CD40 triggers activated B cells to undergo class-switch recombination, which replaces the mu heavy chain with alpha, epsilon, or gamma depending on concurrent cytokines released by the activated CD4 cell. This leads to the production of IgA (alpha heavy chain), IgE (epsilon heavy chain), or IgG (gamma heavy chain).
Because CD40L is required for B cells to class-switch from IgM to other major immunoglobulin types, defects in CD40L signaling result in elevated IgM and no significant IgA, IgE, or IgG. This rare disorder is called hyper-IgM syndrome and is characterized by recurrent sinopulmonary, gastrointestinal, and opportunistic (eg, Pneumocystis jiroveci) infections. Although interaction between B and T cells is impaired in this condition, overall B and T cell quantities tend to be normal.
Hyper IgM syndrome
An error in CD40 signaling from t cells to b cells
The 5 major types of immunoglobulin are distinguished by different amino acid sequences in their heavy chain (alpha, delta, epsilon, gamma, mu). Unstimulated B cells constitutively express mu and delta heavy chains and generate only IgM and IgD. In order to generate other immunoglobulin types, B cells must undergo costimulation by CD40 ligand (CD40L), which is expressed on the surface of activated CD4 cells.
Binding of CD40L to CD40 triggers activated B cells to undergo class-switch recombination, which replaces the mu heavy chain with alpha, epsilon, or gamma depending on concurrent cytokines released by the activated CD4 cell. This leads to the production of IgA (alpha heavy chain), IgE (epsilon heavy chain), or IgG (gamma heavy chain).
DNA Methylation
DNA methylation refers to the addition of methyl groups to nucleotide residues (often adenine and cytosine) by the enzyme DNA methyltransferase. In eukaryotes, cytosine-guanine dinucleotide repeats (CpGs) in the promoter region of genes are preferentially methylated as part of the epigenetic code – a heritable form of gene regulation not reliant on changes in the genetic code itself. The methylation of cytosine residues in CpGs prevents transcription factors from binding to the promoter, effectively silencing transcription of genes not required by terminally differentiated somatic cells. It can also be pathologic; an example includes malignancies in which selective methylation downregulates tumor suppressor genes.
In contrast to eukaryotes, the methylation of adenine and cytosine residues in prokaryotic DNA helps the cell distinguish its DNA from foreign DNA. Unmethylated foreign DNA is destroyed as part of a cellular defense mechanism. Adenine residues may also be methylated shortly after DNA replication, allowing mismatch repair enzymes to distinguish between old and new strands.
Chromosomal DNA is isolated from a malignant cell and subjected to restriction endonucleases, yielding a large number of DNA fragments. These DNA fragments are then separated by gel electrophoresis and their nucleotides are sequenced. One of the DNA fragments is found to have a region rich in cytosine-phosphate-guanine (CpG) dinucleotide repeat sequences. Further analysis reveals that most of the cytosine residues have been methylated to 5-methylcytosine. Which of the following statements regarding this DNA fragment is most accurate?
Low transcriptional activity due to methylation
An 18-year-old man comes to the emergency department with severe right groin pain and difficulty bearing weight on the right lower extremity. He has had no fever or trauma. The patient was hospitalized 6 months ago for a similar pain in his proximal humerus but was discharged without a definitive diagnosis. On physical examination, he appears to be in pain but there is no visible abnormality of his lower extremities or hips. He also has nontender hepatosplenomegaly. A radiograph of the proximal right femur reveals marked osteopenia with cortical collapse. Following an extensive workup, an enzyme deficiency is found to be the cause of his presentation. Which of the following enzymes is most likely deficient in this patient?
β-Glucocerebrosidase
Gaucher
disease
Gaucher Disease inheritance
Autosomal recessive
Gaucher Disease Accumulated substrate
Glucocerebroside
Gaucher Disease Key features
Hepatosplenomegaly
Pancytopenia
Bone pain/osteopenia
Fabry Disease Inheritance pattern
X-linked recessive
Fabry disease deficiency
α-Galactosidase A
Fabry Disease Accumulated substrate
Globotriaosylceramide
Fabry Disease Key features
Angiokeratomas
Peripheral neuropathy
Glomerulopathy
Tay-Sachs Disease inheritance pattern
Autosomal Recessive
Tay-Sachs Disease deficiency
β-Hexosaminidase A
Tay-Sachs Disease accumulated substrate
GM2 (ganglioside)
Tay-Sachs disease key features
Macular cherry-red spot
Progressive neurodegeneration
Niemann-Pick disease inheritance pattern
Autosomal recessive
Niemann-Pick disease deficiency
Sphingomyelinase
Niemann-Pick disease accumulated substrate
Sphingomyelin
Niemann-Pick disease key features
Macular cherry-red spot
Progressive neurodegeneration
Hepatosplenomegaly
Krabbe disease deficiency
Galactocerebrosidase
Krabbe disease accumulated substrate
Galactocerebroside & psychosine
Krabbe disease key features
Progressive neurodegeneration
Peripheral neuropathy
Optic atrophy
Metachromatic leukodystrophy deficiency
Arylsulfatase A
Metachromatic leukodystrophy accumulated substrate
Cerebroside sulfate
Metachromatic leukodystrophy key features
Progressive neurodegeneration
Peripheral neuropathy
Metachromatic leukodystrophy inheritance pattern
Autosomal Recessive
Krabbe Disease Inheritance pattern
Autosomal Recessive
Neiman-Pick Disease inheritance pattern
Autosomal recessive
The most common lysosomal storage disease
Gaucher Disease
Description of Gaucher Disease
Gaucher disease is the most common lysosomal storage disorder. It is an autosomal recessive condition resulting from β-glucocerebrosidase deficiency. Accumulation of the glycolipid glucocerebroside in lysosomes of macrophages results in the cardinal finding of “wrinkled tissue paper” on microscopy. These Gaucher cells are found throughout the body. In addition, accumulation of lipid-laden macrophages in the liver and spleen leads to hepatosplenomegaly. The enlarged spleen breaks down blood cells faster than they are produced, resulting in anemia, thrombocytopenia, and leukopenia (pancytopenia). Blood cell production may also be impaired from bone marrow infiltration.
The pathologic lipid accumulation also triggers the release of lysosomal proteolytic enzymes and inflammatory mediators that are destructive to bone. Affected patients have osteopenia, collapse of the bony cortex, and bone infarction. The compromised vascular supply of the bone can present as bone pain crises and later progress to pathologic fractures and avascular necrosis (osteonecrosis). This patient’s clinical and radiographic findings are suggestive of avascular necrosis.
“wrinkled tissue paper”
Gaucher Disease
Accumulation of the glycolipid glucocerebroside in lysosomes of macrophages results in the cardinal finding of “wrinkled tissue paper” on microscopy. These Gaucher cells are found throughout the body.
Fabry disease description
Fabry disease, a disorder of α-galactosidase A deficiency, can initially present with severe extremity pain. Deposition of globotriaosylceramide in nerve tissue causes a peripheral neuropathy that manifests as a burning sensation.
Metachromatic leukodystrophy description
Metachromatic leukodystrophy is caused by a deficiency of arylsulfatase A, an enzyme responsible for metabolism of the myelin glycolipid cerebroside sulfate.
Accumulation of this substrate causes central and peripheral nervous system demyelination, leading to neurologic regression, seizures, and ataxia.
von Gierke disease description
Glucose-6-phosphatase deficiency causes von Gierke disease, an autosomal recessive glycogen storage disorder that presents in infancy. Typical features include hepatomegaly, hypoglycemia, and lactic acidosis
Tay-Sachs disease & Nieman-Pick Disease descriptions
Tay-Sachs disease (hexosaminidase A deficiency) and Niemann-Pick disease (sphingomyelinase deficiency) present in infancy with neurologic degeneration and cause death in early childhood secondary to respiratory infection and failure. Funduscopic examination reveals a characteristic, cherry-red macular spot.
How to differentiate Tay-Sachs disease & Nieman-Pick Disease
accumulated substrate
Niemann-Pick includes hepatosplenomegaly and Tay-Sachs does not
The histology for diagnosing Tay-Sachs disease and Niemann-Pick disease also differs. Niemann-Pick disease’s histological diagnosis is most notable for its lipid laden macrophages. In other words, under the microscope and histology slides, doctors can see a patient’s macrophage with an unusual large amount of lipids inside them, known as foam cells. Unlike Niemann-Pick disease, Tay-Sachs disease is notable for its lysosomes with onion skin for histology – literally, the lysosomes in the cells look like onions with multiple circular peel layers in it!
A 34-year-old man is brought to the emergency department after several episodes of coffee ground emesis. The patient says his mouth feels dry and that he becomes dizzy on standing. He has recently taken ibuprofen for a back injury sustained several weeks ago. Blood pressure is 90/60 mm Hg and pulse is 120/min. His skin is cool and clammy, and there is mild epigastric tenderness. Increased levels of which of the following molecules are most likely to be seen within the vascular smooth muscle of this patient?
Ip3
This patient with coffee ground emesis, orthostatic hypotension, and tachycardia likely has a brisk upper gastrointestinal hemorrhage due to excessive ibuprofen use. His sympathetic tone has increased in an effort to prevent circulatory failure from hypovolemia, causing vasoconstriction (eg, cool, clammy skin) and tachycardia. The 2 major mediators of the sympathetic response are epinephrine and norepinephrine. These catecholamines function by stimulating adrenergic cell surface receptors.
The adrenergic receptor responsible for arteriolar constriction and increasing blood pressure is the alpha-1 receptor. This receptor functions via the phosphatidylinositol second messenger system. When a catecholamine binds to the alpha-1 receptor, Gq protein becomes stimulated and activates phospholipase C. Phospholipase C then releases inositol triphosphate (IP3) and diacylglycerol (DAG) from membrane phospholipids. IP3 liberates calcium stored in the endoplasmic reticulum and DAG activates protein kinase C, ultimately leading to smooth muscle contraction.
SAM
S-adenosylmethionine (SAM) is produced by condensation of methionine with ATP. SAM functions as a methyl group donor in several reactions requiring methyl transfer. In the adrenergic system, SAM is required for the conversion of norepinephrine to epinephrine by the enzyme phenylethanolamine-N-methyltransferase. This enzymatic reaction predominantly occurs in the adrenal medulla and is upregulated by cortisol.
A researcher develops a particular mouse lineage that carries a human tumor necrosis factor-alpha transgene with a modified 3′ region from a human globin gene. As a result, the mice develop symmetric polyarthritis and intestinal inflammation.
Which of the following medications would most directly counteract these inflammatory changes?
Infliximab
TNF-alpha function
Tumor necrosis factor-alpha (TNF-alpha) is a cytokine produced by activated macrophages and T cells in response to inflammatory stimuli (eg, infection, injury). TNF-alpha stimulates signaling pathways (eg, nuclear factor–κB) that lead to local and systemic inflammatory reactions through the following mechanisms:
Local: Increased expression of adhesion molecules on endothelial cells, leading to recruitment of leukocytes (eg, neutrophils, macrophages). Stimulation of phagocytosis
Systemic: Induces fever (prostaglandin-mediated effect), acute phase responses (eg, elevated C-reactive protein), anorexia/cachexia, and increased leukocyte production. Triggers release of additional pro-inflammatory cytokines (eg, IL-1, IL-6)
Excessive TNF-alpha
Excessive TNF-alpha activity is implicated in the pathogenesis of a variety of chronic inflammatory conditions (eg, rheumatoid arthritis, Crohn disease) and is an important target for therapeutic agents (eg, TNF-alpha inhibitors).
TNF-alpha inhibitors
Infliximab and adalimumab are monoclonal antibodies that bind TNF-alpha and prevent it from associating with its cell-surface receptors, thus blocking proinflammatory effects.
Another TNF-alpha inhibitor is etanercept, a recombinant TNF-alpha receptor fusion protein that acts as a decoy receptor, binding TNF-alpha and keeping it away from functional receptors.
Imatinib moa and clinical use
Imatinib inhibits BCR-ABL1 tyrosine kinase, the abnormal gene product associated with chronic myeloid leukemia.
Natalizumab MOA and clinical use
Natalizumab, a monoclonal antibody against integrin, interferes with leukocyte adhesion and subsequent migration into tissue. Natalizumab can be used to treat multiple sclerosis and Crohn disease,
but is associated with increased risk of progressive multifocal leukoencephalopathy.
Tacrolimus moa and clinical use
Tacrolimus decreases T-cell activation and proliferation by inhibiting calcineurin and blocking transcription of IL-2. It is used to prevent rejection following solid organ transplantation and to treat severe atopic dermatitis.
Cox-1 vs Cox-2
Stable angina AKA
Angina pectoris
Stable angina features
This patient has stable angina (ie, angina pectoris), which is characterized by chest pain that develops with exertion and resolves within 1–2 minutes of rest. Stable angina can progress to acute coronary syndrome (ie, unstable angina or myocardial infarction), which is caused by occlusion of the coronary vasculature, typically by a thrombus. The thrombus arises secondary to increased platelet deposition and clotting factor activity at the site of a disrupted atherosclerotic plaque.
Patients with stable angina should be started on aspirin to reduce the occurrence of adverse cardiovascular events. Aspirin impairs prostaglandin synthesis by irreversibly inhibiting cyclooxygenase-1 (COX-1) and cyclooxygenase-2 (COX-2). COX-1 is expressed in most tissues and regulates normal cellular processes (eg, gastric protection, platelet function). By inhibiting COX-1 in platelets, aspirin prevents the synthesis of thromboxane A2 (TXA2), a potent stimulator of platelet aggregation and vasoconstriction. This helps reduce the risk of occlusive thrombus formation.
A newborn boy is in the neonatal intensive care unit for management of prematurity. He was delivered vaginally at 26 weeks gestation due to premature labor and preterm rupture of membranes. The patient is intubated and has an umbilical arterial catheter in place. The medical team is preparing to place another catheter through the umbilical vein. To reach the inferior vena cava and right atrial junction, the umbilical venous catheter most likely passes through which of the following structures?
Ductus venosus
Describe fetal blood flow
In utero, blood flows from the placenta into the fetus via the umbilical vein. The blood then flows to the fetal liver, where it may be diverted into the inferior vena cava (IVC) via the ductus venosus. The ligamentum teres and ligamentum venosum are the remnants of the umbilical vein and ductus venosus in adults, respectively.
The umbilical vessels are commonly used for central vascular access and resuscitation of a critically ill neonate. These procedures take advantage of the fact that complete closure of the ductus venosus does not occur until approximately 1 week after birth, although this structure is closed functionally within hours of birth. An umbilical venous catheter passes through the umbilical vein and ductus venosus until the tip reaches the IVC at the junction of the right atrium.
Umbilical vessel structure
Azygous vein
Foramen ovale
In the fetus, the foramen ovale allows blood to pass from the right atrium directly into the left atrium, bypassing the lungs. Lung inflation at the time of birth decreases right heart pressure relative to left heart pressure, causing closure of the foramen ovale. The foramen ovale is obliterated in most adults, with the fossa ovale as its remnant.
Identify
A 53-year-old man who recently emigrated from Russia comes to the office due to several months of productive cough with occasional hemoptysis. Medical history is significant for tuberculosis and chronic bronchitis. The patient has smoked a pack of cigarettes per day for the past 20 years. Tuberculin skin testing yields 15 mm of indurated erythema. Bronchoalveolar lavage fluid is cultured, and microscopic examination of the cultured organism is shown in the image below:
Culture of this patient’s bronchoalveolar lavage fluid shows a conidial head consistent with Aspergillus fumigatus, a fungus ubiquitous in the environment (eg, soil) worldwide.
In culture, Aspergillus has a characteristic microscopic morphology, with conidial heads (fruiting structures) that project from septate hyphae on exposure to air. The conidial head is composed of a supportive conidiophore (hyphal stalk) and terminal vesicle with radiating phialides that bear infectious conidia (spores). The conidia disseminate in the air and spread the organism.
Inhalation of conidia may lead to pulmonary disease in certain individuals. In patients with a history of tuberculosis, Aspergillus can colonize preexisting lung cavities. Multiplication of fungal elements within these cavities can lead to formation of an aspergilloma (ie, fungus ball), which may cause chronic cough and occasional hemoptysis (due to eroded blood vessels). Treatment includes antifungal therapy and surgical excision.
colonize preexisting lung cavities
Aspergillus (fungus ball=aspergilloma)
Actinomyces israelii description
Actinomyces israelii is a bacterium that colonizes the mouth and classically causes cervicofacial abscesses following trauma (eg, tooth extraction). Gross examination of fluid drained from infected sites typically shows yellow “sulfur” granules, which are microscopically composed of aggregates of branching, gram-positive rods.
Candida albicans description
Candida albicans is a yeast that typically causes mucocutaneous infections in immunocompetent hosts. Widespread disease occurs only in immunocompromised patients, and microscopic examination would show budding yeast and pseudohyphae
Mycobacterium histology
Reactivation of latent Mycobacterium tuberculosis infection may cause cough and hemoptysis, but culture would grow acid-fast bacilli (appear pink-purple with acid-fast stain).
Pneumocystis jiroveci
Pneumocystis jirovecii is a ubiquitous fungal organism that causes opportunistic pneumonia in HIV-positive patients with CD4 counts < 200/mm3. Microscopic examination of sputum or bronchoalveolar lavage fluid shows cup- or disc-shaped organisms; it cannot be cultured.
A colony of bacteria resistant to gentamicin and a colony resistant to ampicillin are mixed on an agar plate containing both antibiotics. Bacterial growth is noted after incubation for 24 hours. The same experiment is then repeated with the addition of deoxyribonuclease (DNAse) to the agar plate. The enzyme is functional in the culture medium but is not able to penetrate the bacterial cell membrane. During this second experiment, no bacterial growth is observed. Which of the following is the most likely mechanism of bacterial survival in the first experiment?
Transformation
Mechanisms of bacterial gene transfer
Transformation
Conjugation
Transduction
Transformation
Direct uptake of naked DNA from the environment
Conjugation
One-way transfer of chromosomal or plasmid DNA
Donor cell F factor DNA codes for sex pilus
Bacteria that lack F factor serve as recipient cells
Transduction
Transfer of DNA by bacteriophage:
- Generalized transduction: Packaging of random bacterial genes into virion during lytic infection
- Specialized transduction: Packaging of specific bacterial genes near the viral insertion site during lysogenic infection
Transposons
Transposons mediate the transfer of genetic information from one location in the genome to another (eg, from a plasmid to chromosomal DNA).
This process is not directly responsible for organism-to-organism genetic transfer, but moving a gene from chromosome to plasmid readies it for conjugative transfer.
A 39-year-old male complains of facial puffiness in the morning. He is HIV positive. Laboratory evaluation reveals proteinuria (3.5 g/day). Renal biopsy shows glomerular epithelial cell enlargement and vacuolization, as well as varying degrees of glomerular capillary wall collapse. Many renal tubules show cystic dilation and are filled with proteinaceous material. This patient most likely suffers from which of the following?
