Ms Ii - Exam 3

Front 1

What does it mean when a tumor is well-differentiated?

Back 1

It resembles the surrounding tissue and has a good prognosis

Front 2

What transition will cancer cells undergo during metastasis?

Back 2

Epithelial --> Mesenchymal

Front 3

What happens to cell arrangement in cancer progression?

Back 3

Atypical hyperplasia: fairly normal arrangement; CIS: random alignment of cells; Invasive: loss of cell-cell contacts – these changes occur due to disruption of actin filaments

Front 4

What can necrosis in a tumor be associated with?

Back 4

A malignant tumor that has outgrown its blood supply

Front 5

What is the earliest stage that can be detected by mammography?

Back 5

Carcinoma in situ

Front 6

What is the progression from a normal breast to metastatic breast cancer?

Back 6

Normal breast --> atypical hyperplasia --> carcinoma in situ (stages 1-4/comedo) --> invasive breast cancer --> metastatic breast cancer

Front 7

What is the most common serum tumor marker used?

Back 7

PSA for prostate cancer

Front 8

What are the most common cancers in the US?

Back 8

Lung > breast/prostate > colon/rectum

Front 9

What differentiates between carcinoma, sarcoma, and teratoma?

Back 9

Carcinoma: derived from epithelial cells; Sarcoma: derived from mesenchymal cells; Teratoma: derived from germ cells

Front 10

What type of cancer is more common in WV when compared to other states?

Back 10

Cervical

Front 11

What are common metastatic sites?

Back 11

Melanoma --> Lungs; Prostate --> Bone; Colon --> Liver/Pancreas

Front 12

What is the most commonly mutated protein in cancers and what is this protein involved with?

Back 12

p53 – gatekeeper protein that provides a checkpoint in the cell cycle; high levels indicate dysfunction

Front 13

What is the first Cyclin to appear in G1 and what chain of events follows its production?

Back 13

Cyclin D1 --> it binds to cdk4 forming a complex that phosphorylates Retinoblastoma susceptibility protein (RB) --> RB phosphorylation causes its release from the transcription factor EF2 --> this activates EF2, allowing it to transcribe genes required for initiation of progression into S-phase

Front 14

What is the Abl gene and how does it cause cancer?

Back 14

It codes for a non-receptor tyrosine kinase which shuttles between the nucleus where it regulates gene transcription and the cytoplasm where it regulates the actin cytoskeleton and cell movement; Abl on chromosome 9 fuses with BCR on chromosome 22 to form the Philadelphia chromosome – Imatinib (Gleevac) diminishes Abl activity

Front 15

How does Ras function in tumor cells?

Back 15

A mutation causes Ras to be unable to self-hydrolyze its GTP to GDP, in effect keeping it in its activated state continuously; in this state it activates gene transcription through the MAP kinase pathway

Front 16

How does overexpression of growth factors often function in tumor cells?

Back 16

In conjunction with overexpression of growth factor receptors, allowing for an autocrine loop

Front 17

What defines growth factor receptors ascribable as oncogenes and what are some examples?

Back 17

Typically, transmembrane tyrosine kinase receptors that dimerize and trans-phosphorylate/activate upon stimulation by a ligand; Examples: EGFR, HER2/neu (Erb-2), FGFR, HGFT (Met)

Front 18

What defines oncogenes and what are the classic examples?

Back 18

An oncogene refers to a normal cellular gene (proto-oncogene) that when activated or overexpressed produces a dominant phenotype in spite of the presence of the normal allele;
Examples: growth factor receptors, growth factors, Ras, Abl, Src, Myc

Front 19

How do cancer cells increase their Cyclin levels?

Back 19

By amplification of their Cyclin genes

Front 20

Are most tumors that present clinically homogenous or heterogenous and what does this mean?

Back 20

Heterogenous: the progeny of the initial cancer cell can acquire different genetic damage over time

Front 21

What essential physiological changes are required for neoplasia?

Back 21

Tumor cells lack a requirement for growth signals; They are refractory to growth-inhibition signals (e.g. TGF-β); They are resistant to apoptosis (via inactivation of p53); They have defective DNA repair; They can replicate indefinitely; They initiated and sustain their own angiogenesis (secrete VEGF); Most tumors have the ability to invade and metastasize

Front 22

What compounds regulate the cell cycle and by what mechanism?

Back 22

G1: Cyclin D/cdk4; S: Cyclin E/cdk2; G2: Cyclin A/cdk2; M: Cyclin B/cdk1;
CDKs are constitutively present in the cell, but inactive --> Specific cyclins that activate the CDKs are produced for each phase of the cell cycle by complexing with them --> These complexes allow progression of the cell cycle

Front 23

How does RB cause cancer?

Back 23

By failing to suppress gene transcription; only happens in individuals who are homozygous for the mutated allele (Knudson’s two-hit hypothesis: need two mutations to cause RB); in people who are heterozygous for the RB mutation a “loss of heterozygosity” (LOH) will lead to RB

Front 24

What are BRCA1/2 involved in?

Back 24

DNA repair mechanisms (fixes double-stranded breaks) – BRCA1/2 are involved in breast cancer

Front 25

How can changes in the BCL-2 pathway lead to cancer?

Back 25

BCL-2 is an anti-apoptotic protein that protects mitochondria from the influence of death pathways; In B-cell follicular lymphomas BCL-2 is translocated from chromosome 18 to 14 (same place where Myc translocation takes place), leading to uncontrolled transcription of BCL-2 thus preventing lymphoid cells from dying

Front 26

In what genetic disease are APC mutations found?

Back 26

Familial Adenomatous Polyposis (FAP) --> leads to benign and malignant colon polyps

Front 27

What is the mechanism by which absence of APC leads to cancer?

Back 27

APC functions by destroying excess β-catenin; β-catenin is normally bound to E-cadherin, but translocates to the nucleus upon WNT stimulation of frizzled --> in the nucleus β-catenin activates the transcription factor TCF which in turn increases Myc and Cyclin D1 levels;

Front 28

In what syndrome does inheritance of a single mutated p53 gene cause a 25x greater risk for developing cancer in variety of locations by age 50?

Back 28

Li-Fraumeni syndrome

Front 29

What is the most important gene involved in cancer and how does it function?

Back 29

p53: normally prevents the propagation of cells with genetic damage; it does this by first halting the cell cycle (p53 is activated by ATM kinase after DNA damage has occurred) via p21 which inhibits CDKs --> this allows DNA repair enzymes (such as GADD45 induced by p53) to fix the damage --> if the damage is fixed p53 is degraded, if not, p53 induces apoptosis via the Bax gene

Front 30

What is Src and how does it cause cancer?

Back 30

It is a non-receptor tyrosine kinase that regulates cell cycle progression and the actin cytoskeleton; it also predisposes cells to undergo the epithelial-mesenchymal transition (EMT) seen in metastasis by altering the cytoskeleton and producing metalloproteinases for ECM degradation; Treated with Dasatinib and AZD0530 (clinical trials)

Front 31

What is the function of Myc and how does it cause cancer?

Back 31

It is a nuclear transcription factor involved in the cell cycle (Cyclin D2/histone deacetylation), cell movement, and cell adhesion; in tumor cells Myc is often upregulated – This is the cause Burkitt’s lymphoma (B-cell tumor) as a result of a chromosome 8 to 14 translocation (similar to BCR/Abl)

Front 32

What are some common tumor suppression genes?

Back 32

RB, p53, APC/β-catenin

Front 33

What is meant by the multi-hit hypothesis for carcinogenesis?

Back 33

Multiple genetic events are required to form a full blown tumor: mutations in DNA-repair enzymes (caretaker pathway) --> genomic instability --> mutations in tumor suppressor genes (gatekeeper pathway) --> activating mutations in oncogenes --> tumor cell

Front 34

What happens to tumor cells that lose expression of MHC-I?

Back 34

They become more susceptible to killing by NK cells (although NK cells are often not potent enough to cause complete destruction of the tumor – needs to be followed by a T cell response)

Front 35

What can tumor cells be transfected with in order to enhance tumor immunogenicity?

Back 35

B7 or GM-CSF

Front 36

How are monoclonal antibodies used in tumor cell destruction?

Back 36

By themselves, in binding to the tumor cells and activating NK cells; In a conjugated form with a toxin, causing ingestion of the toxin into the tumor cell; In a conjugated form with a radionuclide, causing death of the tumor cell and its neighbors by radiation

Front 37

How do heat-shock proteins enhance the immune response to tumors?

Back 37

They bind tumor antigens and carry them to dendritic cells where they can be degraded and presented on both MHC-I and MHC-II for T cell activation

Front 38

How can epithelial tumor cells evade tumor-infiltrating lymphocytes?

Back 38

By cleaving off their own surface receptor, MIC --> soluble MIC can then bind to NKG2D on tumor-infiltrating lymphocytes, causing the internalization of these NKG2D receptors --> this reduces the levels of NKG2D on the tumor-infiltrating lymphocytes, making them less effective

Front 39

How does the melanoma peptide vaccine (MAGE-1/-3) cause tumor destruction?

Back 39

It induces anti-melanoma CD8+ CTLs

Front 40

By what mechanisms can tumor cells be recognized by T cells?

Back 40

Mutated peptide is presented by MHC-I; Reactivated embryonic proteins are presented by MHC-I; Overexpression of normal cell proteins causes changes in density of self-peptide presentation

Front 41

Which immune cells are the most effective in controlling tumor cells?

Back 41

CD8+ CTLs

Front 42

By what mechanisms can tumors escape immune recognition?

Back 42

Tumor cells have low immunogenicity: lack of MHC, adhesion and co-stimulatory molecules; Antigenic modulation: endocytosis of antibodies against the tumor cells; Tumor-induced immune suppression: factors secreted by the tumor inhibit T cells

Front 43

What are two examples of tumors that are not neoplastic and what characterizes each?

Back 43

Choristoma: ectopic rest of normal tissue; Hamartoma: a mass of disorganized but mature specialized cells indigenous to a particular site – i.e. a choristoma is made up of elements not normally found at that site, whereas a hamartoma is made up of tissue that is normally found at that site

Front 44

What characterizes benign neoplastic lesions?

Back 44

Cohesive, expansile mass; remain localized to their site of origin; well-differentiated; slow growth

Front 45

What characterizes malignant neoplastic lesions?

Back 45

Invade adjacent structures/spread to distant sites; may be poorly differentiated or undifferentiated; may grow rapidly

Front 46

What is meant by the term direct seeding?

Back 46

Penetration of a tumor into a natural open space (e.g. peritoneal, pleural, pericardial cavities)

Front 47

What is a cancer called that has not invaded surrounding tissues yet?

Back 47

Dysplasia (carcinoma-in-situ)

Front 48

What is it called when one adult cell type is replaced by another due to environmental stress?

Back 48

Metaplasia (makes tissue much more susceptible to malignant transformation)

Front 49

What are some key morphologic features of malignant neoplasms?

Back 49

Pleomorphism (i.e. variation in size/shape); Hyperchromasia, increased nuclear/cytoplasm ratio, large nucleoli; Mitotic figures; Loss of cell polarity; Tumor giant cells; Necrosis

Front 50

What defines the term anaplasia?

Back 50

Lack of differentiation (i.e. it does not resemble comparable normal cells)

Front 51

What defines the term desmoplasia?

Back 51

The formation of an abundant collagenous stroma in response to tumor growth and invasion

Front 52

What is meant by the term clonality?

Back 52

The entire population of cells within a neoplasm arises from a single cell

Front 53

How does the spread of epithelial vs. mesenchymal malignancies differ, in general?

Back 53

Epithelial malignancies spread to lymphatics; Mesenchymal malignancies to the blood supply

Front 54

What suffix do embryonal tumors have associated with them?

Back 54

-blastoma (small, round, blue-cell tumor of children)

Front 55

What is a tumor called that originates from pluripotential stem cells and can differentiate into any type of tissue?

Back 55

Teratoma

Front 56

What are the terms used for benign and malignant mesenchymal neoplasms?

Back 56

Benign: -oma; Malignant: sarcoma

Front 57

What are the terms used for benign and malignant epithelial neoplasms?

Back 57

Benign: -oma; Malignant: carcinoma (e.g. adenoma vs. adenocarcinoma)

Front 58

What differentiates between T2 and T3, as well as N2 and N3?

Back 58

T2: larger, more invasive within the primary organ site; T3: larger/invasive beyond the margins of the primary organ site; N2: extensive regional lymph node involvement; N3: more distant lymph node involvement

Front 59

What are examples of serum tumor markers used in molecular diagnosis?

Back 59

Carcinoembryonic antigen (CEA): carcinomas and benign disorders; Alpha-fetoprotein: hepatocellular carcinoma and germ cell tumors; Human chorionic gonadotropin: trophoblastic and germ cell tumors; CA125: ovarian tumors; CA19-9: pancreatic and colonic cancers

Front 60

What are examples of prognostic/therapeutic molecules that affect breast cancer?

Back 60

Estrogen/progesterone receptors (receptor positive tumors have a better prognosis due to susceptibility to antiestrogen therapy); Overexpression of c-erb-B2 or HER2/neu protein (poor diagnosis)

Front 61

What are PSA and TTF1 used for?

Back 61

Determining site of origin for metastatic tumors; PSA: prostate; TTF1: lung, thyroid

Front 62

What antibodies are used to identify carcinomas vs. sarcomas?

Back 62

Carcinomas: Cytokeratin; Sarcoma: Vimentin; other antibodies used: lymphoma/CD45, glioma/GFAP

Front 63

What is immunohistochemistry used for in cancer?

Back 63

Categorization of undifferentiated malignant neoplasms, as well as leukemias/lymphomas; Determining the site of origin of metastatic tumors; Detection of prognostic/therapeutic molecules

Front 64

What are two techniques used in cytologic diagnosis of cancer?

Back 64

Fine-needle aspiration: used for readily palpable lesions (thyroid, lymph node); Cytologic smears (Pap smear, urine)

Front 65

What differentiates between grading and staging?

Back 65

Grade: level of differentiation; Stage: extent of spread

Front 66

What is measured in the TNM system?

Back 66

T: primary tumor size/extent of invasion; N: regional lymph node involvement; M: Metastases

Front 67

What is a retinoblastoma?

Back 67

Small, round, blue-cell tumor that occurs in the retina, usually in children, due to a defect in RB

Front 68

What is one of the most common syndromes that involve DNA repair mechanisms associated with mismatch repair and how can this be tested for?

Back 68

Hereditary nonpolyposis colorectal cancer (HPNCC) – tested for by looking at microsatellite instability (changes of simple sequence repeats in DNA)

Front 69

What does the loss of the VHL gene on chromosome 3 lead to?

Back 69

von Hippel Lindau Syndrome: hemangioblastomas of the brain/retina and renal cell carcinomas;
also pheochromocytomas, microcystic adenomas of the pancreas, cystic lesions of the epididymis, and endolymphatic sac tumors

Front 70

On what chromosomes are NF-1 and NF-2 found, respectively?

Back 70

NF-1: 17 (as in the # of letters in “von Recklinghausen”); NF-2: 22 (with bilateral eight nerve schwannomas)

Front 71

A mutation in what gene causes Familial Adenomatous Polyposis?

Back 71

APC gene on chromosome 5 – APC down-regulates β-catenin (involved in regulation of transcription factors and cell cycle genes); leads to innumerable polypoid adenomas of the colon

Front 72

What syndrome is associated with a germ-line mutation of p53?

Back 72

Li-Fraumeni syndrome (leads to multiple carcinomas and sarcomas)

Front 73

What is the most common target for genetic alteration in human tumors and what chromosome is it found on?

Back 73

p53 on chromosome 17

Front 74

How are familial cancers most often inherited and what are they mostly associated with?

Back 74

Autosomal dominant – defects in tumor suppressor genes

Front 75

On what chromosome is RB located and what transcription factor does it regulate?

Back 75

Chromosome 13; regulates E2F transcription factors

Front 76

Besides the increased risk for retinoblastomas, what other cancer is associated with RB?

Back 76

Osteosarcomas

Front 77

What symptoms are associated with cancer cachexia (wasting syndrome) and what is thought to cause it?

Back 77

Loss of body mass, weakness, anorexia, anemia – thought to be caused by production of TNF and other cytokines)

Front 78

What are some examples of neuromyopathic paraneoplastic syndromes?

Back 78

Peripheral neuropathies; Cerebellar cortical degeneration (Purkinje cell antibodies = ataxia); Limbic encephalitis; Lambert-Eaton myasthenic syndrome (antibodies to presynaptic terminals at neuromuscular junctions)

Front 79

What paraneoplastic syndrome is caused by 5-HIAA?

Back 79

Carcinoid Syndrome (seen with carcinoid tumors): flushing, diarrhea, heart disease

Front 80

What is Trousseau Syndrome?

Back 80

A hypercoagulable state associated with various carcinomas

Front 81

What paraneoplastic syndrome is seen in renal cell carcinomas?

Back 81

Polycythemia (~Erythropoietin)

Front 82

What are examples of paraneoplastic syndromes that are seen in lung cancer?

Back 82

Oat cell (small cell): Cushing’s syndrome (~ACTH), Hyponatremia (~SIADH); Squamous cell: Hypercalcemia (~Parathormone)

Front 83

What is meant by paraneoplastic syndromes?

Back 83

Symptom complexes in cancer-bearing patients that cannot be explained by the local or distant spread of the tumor nor by the elaboration of hormones indigenous to the tumor tissue

Front 84

What is the defect in Xeroderma Pigmentosum?

Back 84

A defect in nucleotide excision repair – leads to squamous carcinoma of the skin, especially due to UVB rays (since they cause the formation of pyrimidine dimers)

Front 85

What DNA repair defect causes increased susceptibility to DNA damage by ionizing radiation, oxygen free radicals, and DNA cross-linking agents?

Back 85

Defects in DNA repair by homologous recombination – e.g. Ataxia-telangiectasia, Bloom syndrome, Fanconi anemia

Front 86

What nonhereditary predisposing conditions are associated with cancer?

Back 86

Inflammatory diseases: ulcerative colitis, Crohn’s disease, Helicobacter pylori gastritis, viral hepatitis, chronic pancreatitis; Hyperplasia/Dysplasia/Metaplasia; Hepatic cirrhosis; Pernicious anemia; Solar keratosis; Leukoplakia (squamous hyperplasia of oral mucosa)

Front 87

What is hyperpigmentation of the skin called that is classified as a paraneoplastic syndrome?

Back 87

Acanthosis nigricans

Front 88

What paraneoplastic syndrome is associated with lung cancer (bronchogenic carcinoma)?

Back 88

Hypertrophic osteoarthropathy

Front 89

What are the most common types of cancer in males and females, respectively?

Back 89

Males: prostate>lung>colon/rectal; Females: breast>lung>colon/rectal

Front 90

What does Bavacizumab affect?

Back 90

Angiogenesis

Front 91

What cancer inducers are affected by Imatinib?

Back 91

C-kit, BCR-Abl, Platelet Derived Growth Factor (PDGF)

Front 92

Which drugs function at the level of the HER receptor (EGFR)?

Back 92

Cetuximab, Trastuzamab, Lapatinib, Erlotinib

Front 93

What does HER2 overexpression lead to?

Back 93

HER2 dimerizes with HER1,3,4 and provides signaling, leading to increased cell proliferation, increased cell migration, and resistance to apoptosis – overexpression of HER 2 will increase all these aspects and decrease patient survival rates

Front 94

What are the screening recommendations for breast cancer, colon cancer, cervical cancer, and prostate cancer?

Back 94

Breast: age 40; Colon: age 50; Cervical: 3 years after vaginal intercourse but no later than age 21; Prostate: age 50 (or 45 for high risk individuals – i.e. family history or African American)

Front 95

What is the major target for anti-cancer drugs?

Back 95

DNA: precursors, direct attack, replication enzymes

Front 96

How is extravasation caused in regard to anti-cancer drugs?

Back 96

When the anti-cancer drug leaks out or settles at the IV injection site, it can act as a vesicant and cause severe skin irritation and destruction

Front 97

What can be a complication of mucositis/stomatitis associated with anti-cancer drugs?

Back 97

Due to the myelosuppression associated with anti-cancer drugs, patients can develop fungal infections in their upper GI tract, thus worsening their mucositis/stomatitis

Front 98

What is done about the nausea and vomiting associated with anti-cancer drugs?

Back 98

It is treated with medication before the actual onset of symptoms since it is harder to beat once the patient is nauseous/vomiting

Front 99

What is the lowest value of blood counts after chemotherapy called?

Back 99

Nadir

Front 100

What common toxicities are associated with anti-cancer drugs?

Back 100

Tumor lysis syndrome: tumor cell contents are released causing hyperkalemia/ hyperphophatemia/increased uric acid (more common in leukemias/lymphomas); Myelosuppression; Nausea/Vomiting; Mucositis; Alopecia; Extravasation; Infertility; Secondary malignancies;

Front 101

What are the major problems with many anti-cancer drugs?

Back 101

The anti-cancer drugs not only affect cancer cells, but also normal cells that are rapidly dividing

Front 102

What is meant by Gompertzian growth of cancers?

Back 102

The initial growth phase is linear on log scale (i.e. high growth fraction/short doubling times); this is followed by a plateau growth phase (i.e. lower growth fraction/longer doubling times) – plateau phase possibly due to vascular needs that can’t be met

Front 103

For what cancer size is immunotherapy beneficent?

Back 103

Small tumor size (i.e. <105 cells)

Front 104

What are the primary treatment options for cancers?

Back 104

Surgery, radiation, chemotherapy, biotherapy

Front 105

How can anti-cancer drugs cause secondary malignancies?

Back 105

Besides attacking the cancer, they also act as mutagens, thus being able to cause secondary malignancies

Front 106

What is an important mechanism by which antibiotics work?

Back 106

They intercalate DNA, thus disrupting its normal functioning

Front 107

What are the pharmacokinetics associated with CTX?

Back 107

It is a pro-drug, activated by CYP450 to a phosphoramide mustard; CTX is detoxified by aldehyde dehydrogenase (ALDH) to a carboxy compound – besides being activated by CYP450, it is also dechloroethylated into dechloroethyl (neurotoxic) and chloroacetaldehyde (nephrotoxic)

Front 108

What is the mechanism of action of Cyclophosphamide (CTX) and what are its indications?

Back 108

Bifunctional alkylation of DNA, producing cross-links; Used as an anti-cancer drug and as an immunosuppressant

Front 109

What are the alkylating agents used in chemotherapy?

Back 109

Mechlorethamine, Cyclophosphamide, Ifosfamide, Melphalan, Chlorambucil, Busulfan, Carmustine, Lomustine, Streptozocin, Thiotepa, Dacarbazine, Procarbazine (non-classical)

Front 110

What differentiates adjuvant therapy from neo-adjuvant therapy?

Back 110

Adjuvant therapy: giving chemotherapy after surgery in order to prevent relapse;
Neo-adjuvant therapy: giving chemotherapy prior to surgery in order to reduce tumor burden

Front 111

What factors are cycle and dose rate determinants?

Back 111

Doubling time of the tumor; Time to recover from toxicity; Dosage regimen (low/high, intermittent/continuous); Subjective manipulation; Target (e.g. continuous for inhibiting angiogenesis and intermittent for drugs with cytotoxic effects)

Front 112

What anti-cancer drugs affect the winding/unwinding of DNA?

Back 112

Topoisomerase inhibitors

Front 113

What are the three classification mechanisms used for anti-cancer drugs?

Back 113

Chemical (not very useful); Cell cycle dependency: cycle independent (nonspecific), cycle specific (proliferation dependent), phase specific (only affects cells in a specific cell cycle phase); Mechanistic classifications (most useful clinically)

Front 114

By what mechanism do alkylating agents work?

Back 114

They covalently bind to the bases on DNA, causing mispairing/mutations/cross-linking/breaks

Front 115

How do the antimetabolite anti-cancer drugs function?

Back 115

They are structural analogs of endogenous precursor molecules for DNA/RNA biosynthesis; they interact with enzymes involved in nucleic acid biosynthesis, thus inhibiting predominantly DNA biosynthesis

Front 116

By what important mechanism do cancer cells become resistant to anti-cancer drugs?

Back 116

Alterations in drug transport (changes involving the p-glycoprotein transporter – MDR)

Front 117

What is the mechanism of action of Carboplatin and Cisplatin and what are their respective pharmacokinetics?

Back 117

They bind covalently to DNA; Carboplatin PK: 70% urine excretion; Cisplatin PK: inactivated by avid protein binding

Front 118

What is the mechanism of action of MTX?

Back 118

Inhibition of dihydrofolate reductase --> partially depletes reduced (activated) folates necessary for DNA synthesis; Metabolites inhibit purine (via AICAR) and thymidylate (via dTMP) biosynthesis

Front 119

What important toxicities are associated with Ara-C and what is its main indication?

Back 119

Myelosuppression; Mucositis; CNS and chest pain (mainly in elderly) – Ara-C is used mainly in leukemias

Front 120

What is the mechanism of action of Cytarabine (Ara-C) and what are its pharmacokinetics?

Back 120

MOA: inhibits DNA polymerase, incorporated into DNA, terminates DNA chain elongation;
PK: inactivated by cytidine deaminase; very short half-life (~10 min.)

Front 121

What antimetabolites are used in chemotherapy?

Back 121

Cytarabine (Ara-C), Fludarabine, Gemcitabine, Pentostatin, Cladribine, 6-MP, MTX, Pemetrexed, 5-FU, Capecitabine,

Front 122

What is special about the dosing calculation for Carboplatin?

Back 122

It is based on creatinine clearance

Front 123

What differentiates the toxicities associated with Carboplatin and Cisplatin?

Back 123

Carboplatin: myelosuppression, nausea/vomiting (n/v); Cisplatin: nephrotoxicity (incl. reduced GFR), ototoxicity, n/v – Cisplatin nephrotoxic/ototoxic effects are possibly irreversible

Front 124

What are the DNA binding agents used in chemotherapy?

Back 124

Carboplatin, Cisplatin, Oxaliplatin

Front 125

What important toxicities are associated with CTX?

Back 125

Myelosuppression; Immunosuppression; SIADH; Bladder toxicity (must keep pt hydrated)

Front 126

What toxicities are associated with MTX?

Back 126

Myelosuppression; Mucositis; Renal obstruction (prophylactic treatment with urinary alkalinization and hydration) – also, accumulation of MTX in third-space fluids (i.e. ascites or pleural effusions) prolongs its half-life

Front 127

What compound is given after high-dose MTX in order to “rescue” cells from toxicity?

Back 127

Reduced folate

Front 128

What are risk factors that predispose to B-cell lymphomas?

Back 128

Primary immunodeficiency syndrome; Autoimmune disorders; Acquired immunodeficiency disorders; Viral associations; Bacteria immune response associations

Front 129

What are the two different subtypes of CLL/SLL in regard to the stage at which the disease takes place?

Back 129

Naïve: takes place at the naïve B cell stage, lack somatic mutations, worse survival (~3 years);
Post-germinal center: takes place at the post-germinal center B cell stage, associated with memory B cells, possess somatic mutations, better survival (~7 years)

Front 130

What is the immunophenotype associated with CLL/SLL?

Back 130

Positive for CD5, CD19, CD20, CD22, CD23, occasional CD38 (worse prognosis);
Negative for CD10, Cyclin-D1

Front 131

What is the difference between Chronic Lymphocytic Leukemia (CLL) and Small Lymphocytic Lymphoma (SLL)?

Back 131

The majority of patients have CLL: a marrow disease in which blood with small round lymphocytes and smudge/basket cells are found; The minority has SLL: a spleen disease (white pulp) in which lymph node diffuse effacement with proliferation centers and paraimmunoblasts are seen – includes extranodal sites: skin, breast, ocular

Front 132

What characterizes the patient with CLL/SLL?

Back 132

Usually asymptomatic although fatigue, autoimmune hemolytic anemia, and infections are possible; also lymphadenopathy and hepatosplenomegaly; >50 years of age; 2:1 male:female

Front 133

What are the three categories of outcomes regarding B-cell lymphomas?

Back 133

Indolent (incurable, median survival >5 years): CLL/SLL, Follicular
Slowly aggressive (incurable, median survival = 3 years): Mantle cell
Aggressive (potentially curable): Diffuse large B-cell, Burkitt, Lymphoblastic

Front 134

What viral and bacterial infections are associated with B-cell lymphomas?

Back 134

EBV: Burkitt lymphoma, post-transplant lymphoproliferative disorders
Human herpes 8 – Kaposi sarcoma herpes virus: primary effusion lymphoma
Hepatitis C: Lymphoplasmacytic lymphoma with type II cryoglobulinemia
Helicobacter pylori: Extranodal marginal zone lymphoma

Front 135

What important CD markers are found in each of the three layers of the germinal centers?

Back 135

Pale center: CD10+; Mantle zone: CD5+; Marginal zone: CD10-/CD5-

Front 136

In hematopathology, what are the most common reasons for polyclonality and monoclonality, respectively?

Back 136

Polyclonality: reactive, infectious causes; Monoclonality: malignant causes (although it can be autoimmune) – Autonomy refers to growth/proliferation outside of normal regulatory pathways

Front 137

What chromosome translocations have been identified, in regard to B-cell lymphomas, which place oncogenes under Ig heavy chain gene promoter control on chromosome 14?

Back 137

Mantle cell lymphoma, t(11;14): overexpression of Cyclin-D1
Follicular lymphoma, t(14;18): overexpression of BCL-2
Burkitt lymphoma, t(8;14): overexpression of c-MYC

Front 138

What immunophenotype is associated with MCL?

Back 138

Positive for CD5, Cyclin-D1 (sets it apart from CLL/SLL!), CD19, CD20, CD22;
Negative for CD10, BCL-6, CD23

Front 139

What do 25-35% of Fl cases transform into?

Back 139

Diffuse Large Cell Lymphoma

Front 140

What is the immunophenotype of FL?

Back 140

Positive for BCL-6, CD10, CD19, CD20, CD22, and BCL-2: due to t(14;18)!
Negative for CD5 and Cyclin-D1

Front 141

How is FL graded?

Back 141

By counting centrocytes (lymphocyte with cleaved nucleus) and centroblasts (lymphocyte with large non-cleaved nucleus; counts are done per 40x high power field (HPF) –
Grade I: 0-5 centroblasts/HPF; Grade II: 6-15/HPF; Grade III: >15/HPF

Front 142

What are the classifications associated with follicle patterns in FL?

Back 142

Follicular (closest to normal lymph node morphology); Follicular and Diffuse; Minimally Follicular

Front 143

What are the differences between adult and pediatric Follicular Lymphoma (FL)?

Back 143

Adult: female>male, asymptomatic with large nodes; Pediatric: rare, male>>female, head and neck involvement, high-grade lymphoma, better prognosis

Front 144

What genetics are associated with MCL?

Back 144

The defect is almost always at the naïve B-cell stage; t(11;14) present: links IgH to Cyclin-D1; BCL-2 and MYC rearrangements are absent

Front 145

What is the prognosis for CLL/SLL?

Back 145

It is indolent and noncurable – Transformation can lead to Diffuse Large Cell Lymphoma (3%, known as Richter Syndrome); transformation can also lead to Paraimmunoblastic type and Hodgkin disease

Front 146

What sites in the body are involved in Mantle Cell Lymphoma (MCL)?

Back 146

Blood: small irregular lymphocytes; Bone marrow; Lymph nodes: nodular/diffuse patterns, proliferation centers absent (as opposed to CLL/SLL!); Spleen disease (white pulp); Extranodal disease

Front 147

What two specific extranodal diseases are seen with MCL and why?

Back 147

Lymphomatous Polyposis (GI tract); Waldeyer’s ring involvement (throat) – affected because they express the α4β7 homing receptor

Front 148

As a lymphoma becomes more aggressive, what happens to the sites of involvement?

Back 148

They become more extensive (i.e. they are more likely to affect other organs)

Front 149

What immunophenotype is associated with Burkitt’s lymphoma?

Back 149

Positive for CD10, BCL-6, CD19, CD20, CD22; Negative for CD5, BCL-1, CD23, CD34, TdT

Front 150

What morphological finds are associated with Burkitt’s lymphoma?

Back 150

Monotonous diffuse infiltrates of medium sized blasts with sharp lipid vacuoles; High mitotic and apoptotic counts; Starry-sky appearance

Front 151

What extranodal sites are commonly involved in Burkitt’s lymphoma?

Back 151

Endemic: jaw, facial bones; Sporadic: abdominal mass, breasts (in pre-adolescent girl); Immunodeficiency: lymph nodes and marrow – growth of these sites is extremely rapid

Front 152

What are the three clinical variants of Burkitt’s lymphoma?

Back 152

Sporadic: world-wide, children and young adults; Endemic: equatorial Africa, 4-7 years of age, virtually all EBV positive; Immunodeficiency associated: HIV/transplantation – EBV is a risk factor for Burkitt’s lymphoma

Front 153

What are the two major classifications of molecular profiling for Diffuse Large B-Cell Lymphoma and what is their prognostic significance?

Back 153

Germinal center type: better prognosis; Activated blood B-cell type: worse prognosis

Front 154

What immunophenotype is associated with Diffuse Large B-Cell Lymphoma?

Back 154

Positive for CD19, CD20, CD22, BCL-6; Negative for CD10, CD5, BCL-1

Front 155

What is the difference between primary and secondary Diffuse Large B-Cell Lymphoma?

Back 155

Primary: de novo, can happen in immunocompromised patients, better prognosis
Secondary: due to a transformation from another type of lymphoma, worse prognosis

Front 156

What characterized mature B cell lymphomas (TdT-) in children?

Back 156

They are usually aggressive (either large cell, Burkitt’s, or high-grade follicular)

Front 157

What morphology is associated with Diffuse Large B-cell Lymphoma?

Back 157

Large, transformed cells greater than 2x small lymphocyte size – the only important cytological feature is the plasmablastic type: found in oral cavity, associated with HIV/EBV, very aggressive

Front 158

What two diseases should be considered in a patient with an extremely large spleen?

Back 158

Chronic Idiopathic Myelofibrosis and Hairy Cell Leukemia

Front 159

What are the common sites of involvement of Lymphoplasmacytic Lymphoma?

Back 159

Lymph nodes (B-cells); Marrow (plasma cells); Blood (Rouleaux formation); Spleen;
rarely extranodal

Front 160

What is Waldenström Macroglobulinemia and what is it often associated with?

Back 160

Proliferation of lymphocytes/plasma cells accompanied by a monoclonal IgM spike leading to hyperviscosity of the blood – often associated with Lymphoplasmacytic Lymphoma (although it can also occur with non-Hodgkin lymphoma, rarely)

Front 161

How does the treatment of Hairy Cell Leukemia differ from that of other lymphomas?

Back 161

It requires a special treatment consisting of purine nucleoside analogs

Front 162

What sets Hairy Cell Leukemia apart from Mantle Cell Leukemia?

Back 162

It does not have the t(11;14) or BCL-1 rearrangement

Front 163

What immunophenotype is associated with Hairy Cell Leukemia?

Back 163

Positive for CD103, CD22, CD25, CD11c, Cyclin-D1 (like Mantle), CD19, CD20, TRAP stain;
Negative for CD5, CD10, CD23

Front 164

In which lymphoma is the red pulp of the spleen affected instead of the white pulp?

Back 164

Hairy Cell Leukemia – also presents with “hairy” lymphocytes, marrow involvement, but rarely lymph node involvement

Front 165

What is the key genetic factor for Burkitt’s lymphoma?

Back 165

t(8;14) involving c-MYC)

Front 166

What is different about the relapse rate for Burkitt’s lymphoma vs. other lymphomas?

Back 166

Relapse usually occurs very quickly; if the patient stays disease free for 2 years, they are considered cured (vs. 5 years for other lymphomas

Front 167

What lymphoma presents witth pancytopenia and monocytopenia?

Back 167

Hairy cell leukemia – monocytes are unable to compensate for the neutropenia because the lymphocytes secrete an inhibitory molecule to the monocytes

Front 168

What is the most common lymphoid tumor in African Americans?

Back 168

Plasma Cell Myeloma (second most common in Caucasians)

Front 169

What factors affect the prognosis for Plasma Cell Myeloma?

Back 169

Renal insufficiency means worse prognosis; Smoldering or indolent variant means better prognosis

Front 170

What immunophenotype is associated with Plasma Cell Myeloma?

Back 170

Positive for CD38, CD138; Negative for surface Ig, CD20 (Rituximab not effective)

Front 171

What is the most common Ig made by plasma cells in Plasma Cell Myeloma?

Back 171

IgG – followed by IgA (others are rare)

Front 172

What is needed to make a diagnosis of Plasma Cell Myeloma?

Back 172

Clinical, Pathologic, and Radiographic diagnosis – for the initial diagnosis, order both an SPEP and a UPEP so that diseased patients aren’t missed

Front 173

What is meant by the two-hit hypothesis of Plasma Cell Myeloma?

Back 173

People require both an antigenic stimulus and a mutagenic event to develop the disease

Front 174

What immunophenotype is associated with Lymphoplasmacytic Lymphoma?

Back 174

Positive for surface IgM, CD19, CD20, CD22; Negative for CD5, CD10, CD23

Front 175

What is the prognosis for Lymphoplasmacytic Lymphoma?

Back 175

Indolent, incurable; worse prognosis with advanced age and cytopenias; can transform to large cell lymphoma

Front 176

What clinical findings are associated with Plasma Cell Myelomas?

Back 176

Osteolytic lesions in flat bones (visible on x-ray); Bone pain; Hypercalcemia; Infections (due to decreased normal antibody production); Renal insufficiency/failure (damage to renal tubules); Anemia (marrow is packed with plasma cells)

Front 177

What are the cutaneous T-cell lymphomas?

Back 177

Mycosis fungoides/Sézary syndrome, Primary cutaneous anaplastic large cell lymphoma, Lymphomatoid papulosis

Front 178

What is the classical morphology associated with MF?

Back 178

T-cells with cerebriform nuclei (cerebriform cells); Epidermotropic T-cell infiltrates; Pautrier microabscesses (highly characteristic, but rare)

Front 179

What is the most common skin T-cell lymphoma and what characterizes it?

Back 179

Mycosis Fungoides (MF) – characterized by scaly skin eruptions (patches and plaques), which progress to generalized plaques over the years, which then become tumors; indolent course

Front 180

What cytokine-related symptoms can be seen at diagnosis with T-cell lymphomas?

Back 180

Hypercalcemia (due to osteoclast activating factor); Hemophagocytic syndromes

Front 181

How can T cell lymphomas be differentiated on a molecular level?

Back 181

Whether they are TdT+ or TdT-; TdT+ lymphomas are precursor or thymic T-cell derived lymphomas whereas TdT- lymphomas are peripheral or post-thymic derived lymphomas

Front 182

What distinguishes B cell and T cell lymphomas morphologically?

Back 182

T cell lymphomas are highly polymorphic whereas B cell lymphomas are not

Front 183

What are the extranodal based T-cell lymphomas?

Back 183

NK/T-cell lymphoma (nasal type), Enteropathy-type T-cell lymphoma, Hepatosplenic T-cell lymphoma, Subcutaneous panniculitis-like T-cell lymphoma

Front 184

How are T-cell lymphomas categorized?

Back 184

By their clinical presentation: leukemic/disseminated, nodal, cutaneous, extranodal

Front 185

What are the leukemic/disseminated T-cell lymphomas?

Back 185

All of the ones ending on leukemia: T-cell prolymphocytic leukemia, Large granular lymphocytic leukemia, Aggressive NK cell leukemia, Adult T-cell leukemia/lymphoma

Front 186

What are the nodal based T-cell lymphomas?

Back 186

Angioimmunoblastic T-cell lymphoma, Peripheral T-cell lymphoma, Anaplastic large cell lymphoma

Front 187

Which factors indicated a worse prognosis for a patient with MF?

Back 187

>60 years of age; Increased LDH; Large T-cell transformation

Front 188

How is a key aspect of ATLL diagnosis?

Back 188

Clonal HTLV-1 integration – (immunophenotype is similar to that of MF)

Front 189

What are the four clinical variants of ATLL and what characterizes each?

Back 189

Acute (survival 2wks-yr): most common, constitutional symptoms, leukemic phase with eosinophils, skin rash/generalized adenopathy/hepatosplenomegaly, hypercalcemia (can be lethal); Lymphomatous (2wks-yr): adenopathy without leukemic phase, hypercalcemia less common;
Chronic (>2yrs): skin lesions, no hypercalcemia, increased WBC, 25% of cases progress to acute;
Smoldering (>2yrs): normal WBC, skin/lung disease, no hypercalcemia, 25% of cases progress

Front 190

What is characteristic of the morphology of ATLL and what are the sites of involvement?

Back 190

High nuclear:cytoplasmic ratio lymphocytes; Flower cells (or cloverleaf cells=polylobated nuclei); Sites of involvement: lymph nodes, spleen, blood, marrow, extranodal (50%: commonly skin with rare Pautrier-like microabscesses)

Front 191

Which T-cell lymphoma is associated with Human T-cell Leukemia Virus-1 (HTLV-1) and what characterizes this lymphoma?

Back 191

Adult T-cell leukemia/lymphoma (ATLL) – has a long latency and requires a “second hit”; mostly endemic to Japan, Caribbean, and Central Africa

Front 192

What clinical signs are seen with Sézary syndrome?

Back 192

Erythroderma, lymphadenopathy, circulating tumor cells, pruritus, alopecia, palmar/plantar hyperkeratoses

Front 193

What distinguishes Sézary syndrome from MF?

Back 193

Sézary syndrome will have >1000 MF-type cells/μL – morphologically, Sézary syndrome can also have Lutzner cells (small) and classical Sézary cells (large); there is very little bone marrow involvement; immunophenotype is similar to MF, but there is an increased CD4:CD8 blood ratio

Front 194

What is the clinical staging of MF?

Back 194

Stage I: confined to skin; Stage II: enlarged lymph nodes (but negative!); Stage III: histologically positive lymph nodes; Stage IV: visceral dissemination

Front 195

What are the histologic grades of lymph node involvement?

Back 195

Grade I (no involvement): dermatopathic, cerebriform cells; Grade II (early involvement): partial architectural effacement; Grade III (extensive involvement): complete architectural effacement

Front 196

What immunophenotype is associated with MF?

Back 196

Positive for CD2, 3, 4, 5, HECA; Negative for CD7, 8, ALK – MF is of peripheral epidermotropic T-cell origin

Front 197

What characterizes the morphology of Anaplastic large cell lymphoma?

Back 197

Hallmark cells: large cell, kidney bean/horseshoe nucleus, eosinophilic Hoff region, abundant cytoplasm, concentrate around vessels

Front 198

What immunophenotype is associated with Peripheral T-cell lymphoma, NOS?

Back 198

Not very specific, but CD4+>>CD8+ – Peripheral T-cell in origin

Front 199

What is characteristic of the morphology of Peripheral T-cell lymphoma, NOS?

Back 199

Cells with clear cytoplasm (!); Polymorphous; Inflammatory background; Hemophagocytosis

Front 200

What is the most common T-cell lymphoma and how does it present?

Back 200

Peripheral T-cell lymphoma, NOS: presents with eosinophilia, pruritus, hemophagocytic syndromes, lymph node and extranodal tissue involvement – aggressive but potentially curable

Front 201

How does ALK affect the prognosis of Anaplastic large cell lymphoma?

Back 201

The prognosis is worse if cells are ALK negative

Front 202

How do cells in Anaplastic large cell lymphoma become ALK positive?

Back 202

Due to t(2;5) where the ALK gene is translocated beside the Nucleophosmin gene; since Nucleophosmin is transported to the nucleus, ALK will also be found in the nucleus, thus causing it to stain positive – ALK gene codes for a tyrosine kinase receptor of the insulin superfamily

Front 203

What immunophenotype is associated with Anaplastic large cell lymphoma?

Back 203

Positive for CD2, CD4, CD30(!), ALK-1(!); Negative for CD3, 5, 7, 8, EBV

Front 204

What is the cell of origin of ATLL and what is the usual cause of death with this disease?

Back 204

CD4+ peripheral T-cell – Cause of death is usually infectious or hypercalcemia

Front 205

Which T-cell lymphoma is ALK-protein positive and what characterizes it?

Back 205

Anaplastic large cell lymphoma: generally a childhood disease, presents with lymphadenopathy and marrow disease, extranodal infiltrates are common (e.g. skin)

Front 206

What are the two types of Anaplastic large cell lymphoma?

Back 206

Primary systemic type: involves lymph nodes, marrow, and extranodal sites; Primary cutaneous type: involves skin

Front 207

What are characteristic features of Hodgkin lymphoma?

Back 207

Reed-Sternberg (RS) cells with possible T-cell rosettes; Non-neoplastic inflammatory background

Front 208

What immunophenotype is associated with NLPHL?

Back 208

L&H cell B-cell immunophenotype (i.e. doesn’t stain like a RS cell): positive for CD45, CD20, BCL-6 and negative for CD15, CD30; Also, rosettes of CD3-positive T-cells are seen around the L&H cells

Front 209

What describes the lymph nodes in NLPHL?

Back 209

Total to partial effacement with nodular to nodular-diffuse pattern

Front 210

What is the RS cell variant seen in NLPHL?

Back 210

L&H cells (aka popcorn cells); they are seen in a background of non-neoplastic lymphocytes

Front 211

What clinical features are associated with NLPHL?

Back 211

5% of Hodgkin lymphoma; Predominantly males, 30-50 years; Not associated with EBV; Frequent relapses, but rarely fatal; Sites of involvement are commonly the lymph nodes (extranodal is rare)

Front 212

What sets Nodular Lymphocyte Predominant Hodgkin Lymphoma (NLPHL) apart from the classical type?

Back 212

Although there are RS cells present, NLPHL has a non-Hodgkin phenotype

Front 213

What clinical features are commonly found with Hodgkin lymphoma?

Back 213

Lymph node in origin (often cervical nodes); Localized disease at presentation; Seen in younger adults; Generally excellent outcomes

Front 214

What is particular about the incidence of Hodgkin lymphoma and how does this differ from other lymphomas?

Back 214

The incidence is stable whereas with other lymphomas the incidence is rising (due to the increased number of immunocompromised patients)

Front 215

What do all Hodgkin lymphomas have in common?

Back 215

Reed-Sternberg cells (present in nodular lymphocyte predominant and classical types)

Front 216

What is a key difference between Hodgkin and non-Hodgkin lymphoma?

Back 216

In non-Hodgkin lymphoma malignant cells are in the majority (may have rare Reed-Sternberg cells); In Hodgkin lymphoma there are just a few malignant cells (Reed-Sternberg cells)

Front 217

What is the age distribution of Classical Hodgkin lymphomas?

Back 217

Bimodal: 15-35 years and late in life

Front 218

What causes almost all Classical Hodgkin lymphomas in developing countries and immunosuppressed patients?

Back 218

Latent Type II EBV infection

Front 219

What cytokines/chemokines are associated with Classical Hodkin lymphomas?

Back 219

Interleukins; GM-CSF, Lymphotoxin-a; TGF-β (leads to broad bands of fibrosis); Eotaxin (leads to the classic background of eosinophils)

Front 220

What stage disease does Classical Hodgkin lymphoma usually present as?

Back 220

Stage I/II: localized with a large mass; at higher stages, when the bone marrow becomes involved, large nodules (dark purple) may be seen in the marrow

Front 221

What are common sites of involvement with Classical Hodgkin lymphomas?

Back 221

Non-axial lymph nodes: cervical, mediastinal, axillary – a lot of patients will have a classic mediastinal mass

Front 222

What are the morphologic findings of Classical Hodgkin lymphomas?

Back 222

Multinucleated RS cells, mononuclear Hodgkin cells (variants), mummified cells (large pyknotic cells), T-cell rosettes, collagenous fibrosis

Front 223

What clinical signs are associated with Classical Hodgkin lymphomas?

Back 223

Peripheral lymphadenopathy (1-2 nodal regions); B symptoms (40%); Mononucleosis is associated with an increased risk

Front 224

What is the survival associated with NLPHL?

Back 224

Stage I/II: 80% survival; Stage III/IV: unfavorable; 3-5% of cases transform to Large Cell Lymphoma

Front 225

What immunophenotype links together the Classical Hodgkin lymphomas?

Back 225

Positive for CD15, CD30, and negative for CD45 (although they differ in clinical features, RS cell features, cellular background, and EBV rate)

Front 226

What are the genetics associated with NLPHL?

Back 226

There is a high rate of on-going VDJ somatic mutations; cell of origin is the germinal center B-cell (centroblastic stage) – same goes for Classical Hodgkin lymphomas

Front 227

What are the clinical findings associated with Mixed Cellularity Classical Hodgkin lymphoma?

Back 227

2nd most common subtype; Adult males, no bimodal distribution; Stage III/IV disease; B symptoms common; High EBV rate (75%) so more prevalent in HIV and developing countries

Front 228

What describes the cellular background of Lymphocyte Depleted Classical Hodgkin lymphoma?

Back 228

It is very hypocellular although RS cells are still present

Front 229

What characterizes Lymphocyte Depleted Classical Hodgkin lymphoma?

Back 229

Rare; Adult males; Stage III/IV disease; 80% B symptoms; EBV rate > 95% so seen in HIV and developing countries

Front 230

What are the sites of involvement and growth pattern of Lymphocyte Rich Classical Hodgkin lymphoma?

Back 230

Sites of involvement: mainly lymph nodes; Growth pattern: nodular (commonly) or diffuse;
Cellular background consists predominantly of small lymphocytes with few or absent eosinophils and PMNs

Front 231

What characterizes Lymphocyte Rich Classical Hodgkin lymphoma?

Back 231

Rare; 60 years median age; Mostly males; Stage I/II disease; B symptoms are rare; Similar clinically to NLPHL

Front 232

What is an unusual characteristic of the cellular background associated with Mixed Cellularity Classical Hodgkin lymphoma?

Back 232

It can present with histiocytes/macrophages and possible granuloma-like clusters (don’t confuse with cat scratch disease)

Front 233

How do sites of involvement and growth pattern differ between the Mixed Cellularity type and the Nodular Sclerosis type?

Back 233

In Mixed Cellularity lymph node involvement is common but it rarely is a mediastinal disease; The growth pattern in Mixed Cellularity is diffuse and not nodular as seen with Nodular Sclerosis

Front 234

Which Classical Hodgkin lymphoma subtype is associated with Lacunar variant RS cells and what characterizes this disease?

Back 234

Nodular Sclerosis Classical Hodgkin lymphoma: 70% of cases, young adult, 40% B symptoms, 10-40% EBV rate

Front 235

What are common sites of involvement with Nodular Sclerosis Classical Hodgkin lymphoma and what distinguishes the growth pattern?

Back 235

Sites of involvement: mediastinal disease, bulky disease, spleen/lung; Growth pattern: forms collagen bands around nodules (thus it is called the nodular sclerosis type)

Front 236

What are the goals in the various phases of drug development?

Back 236

Phase 1: pharmacokinetics (measured in all phases) and dose-depend safety; Phase 2 (open label): safety and therapeutic benefit (efficacy); Phase 3 (blinded controls, larger population): safety and efficacy; Phase 4: post-marketing surveillance

Front 237

Which resources at WVU assist in setting up clinical trails?

Back 237

Clinical Trials Research Unit (MBRCC) and Office of Research Compliance

Front 238

What is CITI training?

Back 238

Collaborative Institute Training Initiative – required for all WVU investigators engaged in human research

Front 239

What approval is required for human drug development clinical trials on a local level and what does it consist of?

Back 239

IRB approval (committee decision); they look at the investigators (expertise, CITI training, conflict of interest), background (what’s known about the drug), experimental design, risk/benefit (checked by Data Safety Monitoring Board), consent form (written at 6th grade level; risks, potential side effects, voluntary participation/withdrawal, alternatives, fate of data, compensation for participants), HIPPA

Front 240

What are the three key principles regarding US Government guidelines for human subject research?

Back 240

Beneficence (benefit/risk); Justice (equitable subject selection); Respect for persons (informed consent)

Front 241

What is listed in the US Pharmacopedia Drug Information (USP DI) for Health Care Professionals?

Back 241

Accepted and unaccepted off-label uses for FDA-approved drugs

Front 242

What is the only step needed to be performed for generic drug development?

Back 242

Companies have to prove pharmaceutical and bioequivalence to the innovator’s drug (i.e. pharmacokinetics for oral solids)

Front 243

What does it mean when a cell stains positive for non-specific esterase (NSE)?

Back 243

It is a monocyte

Front 244

What characterizes AML, M4 (myelomonocytic)?

Back 244

1/4 of AML, intermediate disease; Marrow failure; >20% blasts; >20% PMNs; >20% Monocytic; Cell of origin: PMN-monocyte split precursor; MPO-SSB/NSE positive; Immunophenotype: CD13, CD33, CD34 (for myeloblasts), CD14, CD4, CD11b/c, CD36 (for monoblasts)

Front 245

What category is M3?
Promyelocytic leukemia (has

Back 245

been classified)

Front 246

What characterizes AML, M2 (myeloid with maturation)?

Back 246

1/3 of AML, intermediate disease; Marrow failure; >20% blasts; >10% maturing neutrophils; <20% monocytes; Neutrophil dysplasia; MPO-SSB positive/NSE negative; positive for CD13, CD33, CD34, CD15 (more mature), cMPO

Front 247

What characterizes AML, M1 (myeloid without maturation)?

Back 247

Not as rare, aggressive disease; Marrow failure; >20% blasts; <10% maturing neutrophils; MPO-SSB positive/NSE negative; Immunophenotype: positive for CD13, CD33, CD34, cMPO

Front 248

What characterizes AML, M0 (myeloid with minimal differentiation)?

Back 248

Rare, poor prognosis; Marrow failure; >20% blasts, no Auer rods; Myeloid in origin; MPO-SSB/NSE negative; Immunophenotype: positive for CD13, CD33, CD34

Front 249

What does it mean when a cell stains positive for periodic acid-Shiff (PAS)?

Back 249

It is an RBC or a megakaryocyte

Front 250

What is the difference between myelodysplasia and acute myeloid leukemia (AML)?

Back 250

AML has greater than 20% blasts in blood or marrow (unless there are specific cytogenetic changes – e.g. t(8;21), t(15;17), inv(16))

Front 251

What does it mean when a cell stains positive for myeloperoxidase (MPO-SSB) or Sudan Black B (SBB)?

Back 251

It is a neutrophil

Front 252

What does the presence of an Auer Rod indicate?

Back 252

A myeloid malignancy (AML)

Front 253

What characterizes AML, M5a (Monoblastic) and M5b (Monocytic)?

Back 253

M5a (young people), M5b (adults); Not very common; Swelling of gingiva, bleeding; >20% blasts; >20% monocytic; <20% PMNs; no Auer rods; MPO-SSB negative/NSE positive; Immunophenotype: positive for CD13, CD33, CD14, CD4, CD11b/c, CD36

Front 254

What characterizes AML, M7 (Megakaryoblastic)?

Back 254

Rare, all ages; Associated with mediastinal germ cell tumors (males) and Down syndrome; Presents with bleeding gums and skin involvement; >20% megakaryoblasts; Myelofibrosis (dry tap); PAS-positive/NSE-punctate/MPO-SSB-negative; Immunophenotype: positive for CD13, CD33, CD41, cCD61

Front 255

What characterizes AML, M6b (Pure Erythroid)?

Back 255

Very rare, very poor outcome, all ages; >80% erythroid cells; No myeloblast increase; PAS-positive, MPO-SSB/NSE negative; Immunophenotype: positive for Glycophorin A, Heme A –
Must consider B12/folate deficiency!

Front 256

What characterizes AML, M6a (Erythroleukemia)?

Back 256

Rare, poor outcome, adults; Anemia with normoblastemia; >50% erythroid cells of all maturing stages; >20% of non-erythroid cells are blasts; PAS positive, Iron ± ringed sideroblasts, MPO-SSB-positive myeloblasts, NSE negative; Immunophenotype: positive for CD13, CD33, Glycophorin A, Heme A;

Front 257

What characterizes AML, inv(16) with CBF-beta/MYH11?

Back 257

More common, usually younger people; M4 morphology, but blasts can be <20%; Auer rods may be present, atypical eosinophils, increased monocytes, decreased mature PMNs; MPO-SSB positive/NSE weak positive; Immunophenotype: positive for CD13, CD33, cMPO, CD14, CD4, CD11b/c, CD64 – good response with Cytarabine

Front 258

What characterizes Precursor T Lymphoblastic Leukemia/Lymphoma?

Back 258

Young adults; 10% have leukemia/80-85% have lymphoma; Mediastinal mass is common;
Genetic translocations are common (TCR genes); MPO-SSB negative/NSE punctate; Immunophenotype: positive for TdT, CD1a/2/3/4/5/7/8; Prognosis similar to B cell ALL

Front 259

What is the prognosis for Precursor B Lymphoblastic Leukemia/Lymphoma?

Back 259

Pediatric: good cure rate; Adult: not as good; Prognostic parameters that are associated with a good prognosis are hyperdiploid, young age, low-normal WBC, initial response to therapy

Front 260

What characterizes Precursor B Lymphoblastic Leukemia/Lymphoma?

Back 260

Children; 80-85% have leukemia/10% have lymphoma; Mediastinal mass is rarely seen;
MPO-SSB negative/NSE punctate; Immunophenotype: positive for TdT, HLA-DR, CD19, CD10, CD22; Genetics (e.g. hypo- vs. hyperdiploidity) are important in prognosis

Front 261

What percent of acute leukemias are myeloid and what are the associated clinical pictures of AML and ALL?

Back 261

70% are AML; AML: adults (mean=60), variable Auer rods, CD13, CD33, CD34, MPO, NSE;
ALL: children (under 6), TdT positive, CD19/22 (B cell), cCD3/CD2 (T cell)

Front 262

What are causes of therapy-related AMLs?

Back 262

Alkylating agents/radiation therapy (e.g. for breast cancer): starts as MDS with subset going to AML, Multidrug Resistance Glycoprotein (MDR-1) presence common;
Topoisomerase II inhibitor therapy (e.g. with Etoposide treatment): presents as AML without prior MDS, usually monocytic in origin (M4/M5), cytogenetics can be 11q23 and other translocations

Front 263

What characterizes AML, 11q23 with MLL translocation?

Back 263

Less common, infants/children; Can be therapy-related; DIC common; Often involvement of skin/gingiva (i.e. monocytic); Involves MLL 11q23 and one of many other genes; M5 morphology (sometimes M4), monocytic with monoblasts/promonoblasts; MPO-SSB negative/NSE positive; Immunophenotype: positive for CD13, CD33, CD14, CD4, CD11b/c, CD36

Front 264

What translocations are associated with t(8;21), t(15;17), inv(16), and 11q23?

Back 264

t(8;21): M2 with AML/ETO1; t(15;17): M3 with PML/RARα;
inv(16): M4eo with CBF-beta/MYH11; 11q23: M5 with MLL

Front 265

What characterizes AML, M3 (Acute Promyelocytic Leukemia)?

Back 265

t(15; 17) with PML/RARα (retinoic acid receptor); Any age; DIC common; Lost of Auer rods (bundles of kindling – Faggot cell); >20% blasts + promyelocytes; MPO-SSB strong positive/NSE weak positive; Immunophenotype: positive for CD33, cMPO, negative for CD34 (since there are promyelocytes, not blasts); Treatment with all trans-retinoic acid (differentiating agent) and subsequent anthracycline (consolidation)

Front 266

What characterizes AML, t(8;21) with AML1/ETO?

Back 266

Most common cytogenetic change; Younger patients; M2 morphology, but blasts can be <20%; Variable PMN dysplasia with Auer rods, increased eosinophils; MPO-SSB positive/NSE negative; Immunophenotype: positive for CD13, CD33, CD34, cMPO – good response with Cytarabine

Front 267

What is a key difference between the treatment of AML and ALL?

Back 267

In AML a maintenance regimen is not normally given

Front 268

What cytogenetics will be associated with about 30% of adult ALL patients?

Back 268

t(9;22) – 190kd BCR/Abl

Front 269

What cytogenetics are associated with Acute Promyelocytic Leukemia?

Back 269

t(15;17)

Front 270

What are B symptoms?

Back 270

Fever, nightsweats, weight loss ( >10%/6 months) – they imply a worse prognosis

Front 271

What are the cytogenetics associated with AML prognosis?

Back 271

Good prognosis: t(8;21), t(15;17), inv16; Poor prognosis: -5, -7, trisomy 8, complex karyotype, prior MDS ; Intermediate prognosis: normal karyotype (largest subgroup)

Front 272

What finding is diagnostic of acute myeloid leukemia?

Back 272

Auer rod in cytoplasm

Front 273

What is the major determinant for long-term disease survival in adults with AML?

Back 273

Cytogenetics

Front 274

How does age of onset differ between AML and ALL?

Back 274

AML: mostly an adult disease (40% long-term survival); ALL: mostly a childhood disease

Front 275

What is an abnormal feature of a bone marrow slide?

Back 275

Homogeneity

Front 276

What is a common site for a bone marrow biopsy?

Back 276

Posterior iliac crest

Front 277

What age group is mostly associated with CML?

Back 277

Young adults

Front 278

What stages are associated with lymphoma?

Back 278

Stage 1&2: involved lymph nodes on one side of diaphragm; Stage 3: involved lymph nodes on both sides of diaphragm; Stage 4: marrow involvement

Front 279

What percent of patients with Multiple Myeloma will relapse after treatment?

Back 279

~95% (it is considered incurable)

Front 280

In what disease are “punched-out” lytic lesions of the skeletal system found?

Back 280

Multiple myeloma (due to local accumulations of plasma cells)

Front 281

What mutation is thought responsible for the overgrowth of myeloid cells in Polycythemia Vera, Essential Thrombocytosis, and Myelofibrosis?

Back 281

A mutation in just another kinase (JAK2) which causes it to become constitutively activated

Front 282

What are the three phases of CML?

Back 282

Chronic: minimal blasts; Accelerated: 10-19% blasts; Blast phase: >20% peripheral blasts

Front 283

What is the pathogenesis of CML?

Back 283

t(9;22) – 210, 230kd BCR/Abl

Front 284

What are the WHO classifications of ALL and which is most common?

Back 284

Precursor B-cell ALL (most common); Precursor T-cell ALL; Burkitt (mature B-cell) ALL

Front 285

What percent of patients receiving an allograft bone marrow transplant will have bacterial infections?

Back 285

85-90% - patients will receive prophylactic antibiotics, antifungals (early post-transplant), and antivirals (since Herpes simplex and CMV will reactivate – CMV can come from donor or host)

Front 286

What are the chances of finding a sibling HLA matched donor?

Back 286

25%

Front 287

What are the most important HLA subclasses that need to be typed?

Back 287

A, B, C, DR (chromosome 6); done through gene sequencing – HLA-C is not important in cord blood transplants

Front 288

What are the two most common reasons to go through an autologous bone marrow transplant?

Back 288

Multiple Myeloma and Hodgkin’s Lymphoma – autologous = patient’s own stem cells rescue immune system after chemotherapy

Front 289

How does therapy differ for patients over the age of 50?

Back 289

They do not receive ablative therapy or radiation, but rather get reduced intensity immunosuppressive treatments (non-ablative)

Front 290

What is the difference between bone marrow, peripheral blood, and cord blood grafts regarding allografts?

Back 290

Bone marrow: mid stem-cell/T-cell dose, 20-25 days for engraftment, mid chances of GVHD; Peripheral blood: high stem-cell/T-cell dose, 10-14 days for engraftment, mid chances of GVHD; Cord blood: low stem-cell/T-cell dose, 30-40 days for engraftment, low chances of GVHD

Front 291

What are the most common reasons to have an allogeneic bone marrow transplant?

Back 291

Leukemia, aplastic anemia, refractory lymphoma – patients have abnormal bone marrow

Front 292

Reactivation of what virus is seen in almost all autologous transplant patients?

Back 292

Varicella zoster – prophylactic Acyclovir

Front 293

What types of infections are common in the first 14 days after transplant?

Back 293

Gram positive/negative, fungal (Candida), Herpes simplex

Front 294

What happens to the innate and acquired immune systems after an autologous transplant?

Back 294

The innate comes back quickly, whereas the acquired immune system takes 6-12 months to recover

Front 295

What organs are affected most in Graft vs. Host disease?

Back 295

Skin, GI tract, liver – about 50% of patients will be affected by GVHD

Front 296

What is the key difference between Graft vs. Tumor effect and GVHD?

Back 296

Graft vs. Tumor occurs through direct cell contact, whereas GVHD occurs via an APC

Front 297

What is the most common teratoma of childhood?

Back 297

Sacrococcygeal teratomas: girls>boys, 75% benign/10% malignant, mostly seen in younger infants

Front 298

What morphology is associated with neuroblastoma?

Back 298

Wide size range; Soft, gray, brain-like tissue: may show necrosis, cystic softening, hemorrhage and calcification; Small primitive cells (neuroblasts): can be seen as Homer Wright pseudorosettes or ganglion cell differentiation

Front 299

What are neuroblastic tumors derived from and where do they occur most frequently?

Back 299

Derived from primordial neural crest cells; Occur mostly in the abdomen (adrenal medulla and sympathetic ganglia) but also in other sites like the posterior mediastinum

Front 300

What genetic markers are associated with small, round, blue cell tumors of childhood?

Back 300

Ewing sarcoma/PNET: CD99 expression; Rhabdomyosarcoma: Myo D1 expression; Burkitt lymphoma: t(8;14); Lymphoblastic lymphoma: TdT+; Wilms tumor: chromosome 11 (WT1 gene); Retinoblastoma: 13q14 (RB) deletion/mutation

Front 301

What is the differential for a small, round, blue cell tumor?

Back 301

Neuroblastoma, Lymphoma, Rhabdomyosarcoma, Ewing sarcoma/PNET

Front 302

What malignancy is associated with Down Syndrome?

Back 302

Leukemia

Front 303

What is the leading cause of death from disease in children 4-14 years of age?

Back 303

Malignant neoplasia (top three: leukemia, CNS tumors, lymphoma)

Front 304

What are the two peaks of incidence associated with teratomas?

Back 304

Within first 2 years: congenital; Late adolescence: slow growing

Front 305

What are the benign pediatric tumors?

Back 305

Hemangioma, Lymphangioma, Fibrous tumors, Teratomas

Front 306

How does histologic maturity of teratomas relate to its biologic behavior?

Back 306

Mature: benign, well-differentiated cystic lesions; Immature: lesion of indeterminate malignant potential; Malignant: mixed with another germ cell tumor component

Front 307

What are the stages of neuroblastoma?

Back 307

1: localized tumor;
2A: localized with incomplete gross excision, ipsilateral lymph nodes negative;
2B: : localized with incomplete gross excision, ipsilateral lymph nodes positive;
3: unresectable unilateral tumor infiltrating across the midline:
4: metastasis to distant lymph nodes

Front 308

What do the letters in WAGR syndrome stand for?

Back 308

Wilms’ tumor; Aniridia; Genital anomalies (e.g. hypospadias); mental Retardation

Front 309

What is the function of the WT1 gene?

Back 309

Encodes a transcription factor expressed in the kidneys and gonads of the developing fetus – found on chromosome 11

Front 310

What syndromes/malformations are associated with an increased risk for Wilms’ tumor?

Back 310

WAGR syndrome, Denys-Drash syndrome, Beckwith-Wiedemann syndrome

Front 311

What is the most common primary renal tumor of childhood and what age of diagnosis is associated with it?

Back 311

Wilms’ tumor (nephroblastoma); diagnosed between ages 2-5

Front 312

How does DNA ploidy affect the prognosis of neuroblastoma?

Back 312

Diploid is unfavorable (this is the opposite for most diseases)

Front 313

What is meant by stage 4S regarding neuroblastoma?

Back 313

Localized primary tumor (1, 2A, 2B) with dissemination limited to skin/liver/bone marrow – limited to infants < 1year of age

Front 314

What is the clinical presentation associated with neuroblastoma?

Back 314

<2 years of age: large abdominal mass, fever, possible weight loss; >2 years of age: possible metastatic disease, bone pain, respiratory symptoms, GI complaints – neonates can present as “blueberry muffin babies” (stage 4S)

Front 315

How does age of the child affect prognosis of neuroblastoma?

Back 315

< 1 year: excellent prognosis; 1-5 years: intermediate prognosis (depending on tumor stage); >5 years: very poor prognosis

Front 316

What biologic markers are associated with neuroblastoma?

Back 316

Catabolites of catecholamines: VMA, HVA; Serum neuron specific enolase; N-myc amplification

Front 317

What syndrome is associated with a gene on 11p15.5 (“WT2 gene”) and what are the clinical findings?

Back 317

Beckwith-Wiedemann syndrome: enlargement of body organs, macroglossia, hemihypertrophy, omphalocele, adrenal cytomegaly

Front 318

What is the prognosis for Wilms’ tumors?

Back 318

With chemotherapy, radiotherapy, and surgery, survival is 90% - diffuse anaplasia is considered unfavorable (50% 2-year survival)

Front 319

What does anaplasia in a Wilms’ tumor correlate with?

Back 319

Underlying p53 mutations and resistance to chemotherapy – found in 5% of Wilms’ tumors

Front 320

What is the morphology of a Wilms’ tumor?

Back 320

Triphasic pattern containing blastema, stroma, and epithelial cells

Front 321

What is the clinical presentation of Wilms’ tumor?

Back 321

Large abdominal mass; also hematuria, pain in abdomen, intestinal obstruction, hypertension, pulmonary metastasis

Front 322

What does the presence of nephroblastomatosis imply an increased risk of?

Back 322

Wilms’ tumor (nephroblastomatosis refers to the presence of a normal tissue at an abnormal time; also known as nephrogenic rests)

Front 323

What tumors are children with Beckwith-Wiedemann at increased risk for?

Back 323

Wilms’ tumor, hepatoblastoma, adrenocortical tumors, rhabdomyosarcomas, pancreatic tumors

Front 324

What gene, found in the same chromosomal region as WT1, is associated with aniridia?

Back 324

PAX6 (both are located on 11p13) – if a patient has a deletion restricted to PAX6, they will not be at increased risk for a Wilms’ tumor

Front 325

What clinical findings are found with Denys-Drash syndrome?

Back 325

Gonadal dysgenesis and nephropathy – due to germline abnormalities of the WT1 gene (dominant negative missense mutation)

Front 326

Which bacteria, normally found in the gut, are a common cause of UTIs?

Back 326

E. coli

Front 327

What is the classical explanation of why certain cells stain Gram+ and others Gram-?

Back 327

Gram+ cells have a very thick cell wall

Front 328

What cell arrangements are often seen with Streptococcus and Staphylococcus, respectively?

Back 328

Streptococcus: chain-like; Staphylococcus: grape-like

Front 329

What terms describe the shapes of bacteria and what are examples associated with each?

Back 329

Cocci (speherical): Streptococcus, Staphylococcus; Bacillus (rods): Bacillus anthracis, E. coli;
Vibrio (curved): Vibrio cholerae; Spirochete (spiral): Treponema pallidum, Borrelia burgdorferi

Front 330

Why is the difference between eukaryotic and prokaryotic ribosomes important?

Back 330

Prokaryotes have 70S ribosome (vs. 80S in eukaryotes); the 70S ribosome differs in DNA sequence which makes it vulnerable to attack by Gentamycin and Neomycin

Front 331

How do Mycoplasma bacteria differ from other bacteria?

Back 331

They do not have peptidoglycan, but do have sterols in their cell membrane

Front 332

Which bacteria, normally found in the gut, can cause “gas gangrene” in wounds?

Back 332

Clostridium perfringens

Front 333

What are the main classifications of microbes based on?

Back 333

Cellular with nuclear membrane: parasites, fungi, yeasts; Cellular without nuclear membrane: bacteria; Not cellular: viruses, prions

Front 334

What are some examples of microbes that are commensal and how do they help?

Back 334

E. coli: vitamin K; various bacteria: vitamin B12; lactobacilli: acidify vagina and prevent Candida albicans overgrowth – most importantly, commensal bacteria compete with pathogenic species for colonization

Front 335

What size range is associated with microbes?

Back 335

Bacteria: 0.2 μm (Mycoplasma) – 700 μm (Thiomargarita);
Viruses: 20 nm (polio) – 200 nm (smallpox)

Front 336

What is a key difference in the peptidoglycan between Gram+ and Gram- bacteria?

Back 336

Gram+ bacteria use (Gly)5 between the two peptides forming the cross-link; Gram- bacteria use a L-DAP instead of a L-lysine connecting the D-ala forming the isopeptide bond

Front 337

Which antibiotics block synthesis of the tetrapeptide precursor of cell wall synthesis?

Back 337

Fosfomycin (for UTIs), cycloserine (for TB)

Front 338

What is the mechanism of action of Bacitracin?

Back 338

It blocks peptidoglycan precursor synthesis by blocking regeneration of the lipid carrier (BP)

Front 339

What is the mechanism of action of Vancomycin?

Back 339

It blocks the glycosyltransferase (blocks chain polymerization); it does so by binding to the terminal D-ala/D-ala structure

Front 340

What is the mechanism of action of Penicillin?

Back 340

As a structural analog of the D-ala/D-ala dimer, it inhibits the transpeptidase reaction by forming a covalent complex with them

Front 341

What external reactions are involved in the biosynthesis of cell wall?

Back 341

Glycosyl transfer (polymerization of NAG/NAM structures) --> transpeptidase cross-linking --> carboxypeptidase removes a terminal D-ala on one of the peptides

Front 342

What cytoplasmic reactions are involved in the biosynthesis of cell wall?

Back 342

NAG --> NAM --> NAM with L-ala/D-glu/L-DAP --> NAM with L-ala/D-glu/L-DAP/D-ala/D-ala --> switch terminal UDP for bactoprenol (BP) --> attach NAG --> attach (Gly)5 in Gram+ --> flip entire structure to outside of cell wall

Front 343

What is the major component of bacterial cell walls and what does it consist of?

Back 343

Peptidoglycan: composed of alternating glycans (NAG/NAM) with attached peptides (D-ala, L-DAP, D-glu, L-ala)

Front 344

How does lysozyme affect peptidoglycan?

Back 344

It cleaves the β1-4 linkage between NAG and NAM

Front 345

Between which peptides does cross-linking take place?

Back 345

D-ala / L-DAP; forms an isopeptide bond utilizing a COOH or NH2 from the R group instead of one from the normal backbone structure; cross-link occurs between tetrapepide and pentapeptide

Front 346

What additional cell wall structure is found in Gram-, but not in Gram+ bacteria?

Back 346

LPS (is attached to the peptidoglycan via periplasm and an outer membrane, which are not found in Gram+ bacteria)

Front 347

What is the key component in LPS that causes it to be an endotoxin?

Back 347

Lipid A (binds TLR-4 causing fever, inflammation, shock)

Front 348

What are the components of Lipopolysaccharide (LPS)?

Back 348

Conserved portion: Lipid A connected to a short polysaccharide part called the core;
Highly variable portion: long polysaccharide part called the O-antigen/O-polysaccharide

Front 349

What are the antitumor antibiotics?

Back 349

Doxorubicin, Epirubicin, Idarubicin, Mitoxantrone, Actinomycin D, Bleomycin

Front 350

What is the active metabolite of Irinotecan and how is it excreted?

Back 350

Irinotecan is converted by carboxyesterases to SN-38 (100-1000x more active); SN-38 is glucoronidated and excreted in the bile; CYP3A4 also metabolizes Irinotecan, but forms inactive metabolites

Front 351

What is the mechanism of action of Irinotecan?

Back 351

Stabilization of a ternary complex between topoisomerase I and dsDNA, inducing single strand breaks, thus preventing cells from entering mitosis (G2 arrest)

Front 352

What are the topoisomerase I inhibitors?

Back 352

Irinotecan, Topotecan

Front 353

What toxicities are found with Doxorubicin?

Back 353

Cardiac problems: acute arrhythmias and chronic CHF (keep lifetime dose <550 mg/m2); Vesicant; Radiosensitizer; May make patient’s fluids/tissues red

Front 354

What important pharmacokinetics are associated with Doxorubicin?

Back 354

It has a large volume of distribution; Elimination is via bile, so bilirubin levels must be checked

Front 355

What is the most common antitumor antibiotic and what is its mechanism of action?

Back 355

Doxorubicin; MOA: free radical formation, topoisomerase II interaction (!), DNA intercalation

Front 356

What are the mechanisms of action of 5-Fluorouracil (5-FU)?

Back 356

Inhibition of thymidylate synthase (= decreased thymidine); Incorporation into RNA and DNA leading to apoptosis – some S phase specificity

Front 357

What are important toxicities associated with 5-FU and what drug is used in association with 5-FU?

Back 357

Toxicities (continuous infusion): mucositis, diarrhea, hand-and-foot syndrome (paresthesias, redness --> pain --> peeling --> resolution); Toxicities (daily bolus): myelosuppression; Drug interactions: Leucovorin (folinic acid) stabilizes/prolongs binding of 5-FU to thymidylate synthase

Front 358

What compound causes deactivation of 5-FU?

Back 358

Dihydropyrimidine dehydrogenase (DPD); 5-FU has a short half-life (min.) – DPD deficiency often results in lethal toxicity

Front 359

What important toxicities are associated with Vincristine?

Back 359

Neuropathies: decreased DTR --> paresthesias --> autonomic dysfunction; SIADH; Photosensitivity; NOT myelosuppression (sets it apart) – If accidentally given intrathecal, it is almost always lethal

Front 360

What is characteristic of the metabolism of signal transduction inhibitors?

Back 360

They are all metabolized by CYP3A4

Front 361

What are the signal transduction inhibitors used in chemotherapy?

Back 361

Dasatinib, Erlotinib, Imatinib, Lapatinib, Sorafenib, Sunitinib, Temsirolimus

Front 362

What sets Ixabepilone apart from Paclitaxel and Docetaxel?

Back 362

Although it has a similar MOA as Paclitaxel/Docetaxel, it is less susceptible to MDR/P-gp and may therefore work on vinca/taxane/anthracycline resistant cells

Front 363

What important toxicities are associated with Paclitaxel and Docetaxel, respectively?

Back 363

Paclitaxel: acute anaphylaxis, myelosuppression, peripheral neuropathy; Docetaxel: myelosuppression, peripheral neuropathy, fluid retention

Front 364

How are Paclitaxel and Docetaxel metabolized?

Back 364

By CYP3A4 and 28C (Paclitaxel only) – they are easily cleared from the CNS thus reducing the effects there; this can lead to increased relapse rates in the brain

Front 365

What is the mechanism of action of Paclitaxel and Docetaxel?

Back 365

Promotes microtubule assembly and then inhibits depolymerization, thus stabilizing the microtubules in their non-functional state

Front 366

What important toxicities and drug interactions are associated with Irinotecan?

Back 366

Myelosuppression; n/v; Diarrhea: early (treated with atropine), late (treated with loperimide) – Drug interactions: CYP3A4 inducers/inhibitors

Front 367

What are the mitotic inhibitors used in chemotherapy?

Back 367

Vincristine, Vinblastine, Vinorelbine, Paclitaxel, Docetaxel, Ixabepilone

Front 368

What is the mechanism of action of Vincristine and what is its half-life?

Back 368

Binds tubulin, thus inhibiting microtubule formation (i.e. M phase specific = mitotic arrest) – it’s half-life is long (>20 hrs)

Front 369

What is the mechanism of action of Temsirolimus?

Back 369

It binds to FKBP-12 and inhibits mTOR (like Sirolimus) --> this leads to growth arrest

Front 370

What is the mechanism of action of Tamoxifen and what are its important toxicities?

Back 370

Competitive estrogen antagonist (mostly G2 specific) – Toxicities: menopausal symptoms, thromboembolism, flare reaction, ocular/endometrial/uterine cancer

Front 371

What are the estrogen receptor modulators used in chemotherapy?

Back 371

Fulvestrant, Tamoxifen, Toremifene

Front 372

What are the two subclassifications of anti-estrogen therapies and what characterizes each?

Back 372

Receptor modulators: used pre- or post-menopausal, toxicities include blood clots / uterine cancer;
Aromatase inhibitors: used post-menopausal, toxicities include osteoporosis / fractures

Front 373

What pharmacological class is Vorinostat and what is its mechanism of action?

Back 373

Histone deacetylase inhibitor – MOA: inhibits HDAC1,2,3,6 which catalyze removal of acetyl groups from histones and transcription factors --> cell cycle arrest and/or apoptosis

Front 374

What pharmacological class is Bortezomib and what is its mechanism of action?

Back 374

It is a proteasome inhibitor – MOA: reversible inhibitor of ubiquitin proteasome pathway

Front 375

What is the pharmacologic class of Arsenic Trioxide and Tretinoin

Back 375

They are differentiating agents

Front 376

What two signal transduction inhibitors are competitive inhibitors of ATP on the tyrosine kinase Bcr-Abl and how do they differ?

Back 376

Imatinib and Dasatinib – Dasatinib has activity in Imatinib-resistant cell lines

Front 377

Which signal transduction inhibitors are associated with the EGFR/ErbB-1/ HER1 tyrosine kinases and what differentiates between them?

Back 377

Erlotinib and Lapatinib – Erlotinib: causes cell cycle arrest and inhibition of angiogenesis, and is associated with a rash (no rash = no efficacy); Lapatinib has a dual action on ErbB-1 and ErbB-2, making it useful in HER-2 positive breast cancer

Front 378

Which signal transduction inhibitors are used for renal cell cancer and what is characteristic of them?

Back 378

Sorafenib and Sunitinib – both are multi-kinase inhibitors causing inhibition of proliferation and antiangiogenesis; since they affect multiple tyrosine kinase inhibitors, they have more extensive toxicities associated with them

Front 379

What is particular about the pharmacokinetics of Tamoxifen?

Back 379

It is metabolized by several CYP450 enzymes (3A, 2C, 2D6); however, in order to achieve maximal efficacy, Tamoxifen must be metabolized by CYP2D6 to highly active metabolites; since ~10% of Caucasians do not have CYP2D6, this can cause problems; Inhibitors of CYP2D6 should also be avoided

Front 380

What important toxicities are associated with Leuprolide?

Back 380

Hot flashes, reduced libido, impotence, gynecomastia

Front 381

What is the mechanism of action of Leuprolide?

Back 381

`It is a GnRH agonist --> causes an initial surge of LH/FSH from the pituitary, temporarily increasing the levels of testosterone (~ 1 week) --> ultimately secretion of LH/FSH is decreased by continuous receptor stimulation – used to treat prostate cancer (also breast/ovarian cancer)

Front 382

What are the androgen receptor antagonists, used in chemotherapy and for what specific cancer are they important treatment options?

Back 382

Bicalutamide, Flutamide – used in prostate cancer

Front 383

What is the mechanism of action of Anastrozole and what toxicities are associated with it?

Back 383

MOA: blocks aromatase conversion of androgens to estrogens in peripheral tissues; Toxicities: menopausal symptoms, vaginal dryness/bleeding, GI effects, osteoporosis

Front 384

What are the aromatase inhibitors used in chemotherapy?

Back 384

Aminoglutethimide, Anastrozole, Letrozole, Exemestane

Front 385

What is special about the outer membrane of Gram- bacteria?

Back 385

It is a permeable barrier that confers resistance to antibiotics; they get their nutrients through porins found in the outer membrane

Front 386

What is the importance of efflux pumps?

Back 386

They pump out all sorts of substances (including antibiotics)

Front 387

Why are siderophores highly diverse between bacteria?

Back 387

If a bacterium were to produce a siderophore that is recognized by other bacteria, it will allow those bacteria to make use of its siderophore, in effect reducing its own iron levels

Front 388

How does iron accumulation occur in bacterial cells?

Back 388

Bacteria secrete siderophores which scavenge Fe3+; once it finds iron, a periplasmic binding protein brings the siderophore to the permease, where its transport across the membrane is powered by the hydrolysis of ATP (ABC transporters)

Front 389

How does lactose get into bacterial cells?

Back 389

The accumulation of lactose is driven by the proton-motive force

Front 390

What functions are associated with the cytoplasmic membrane of bacteria?

Back 390

Energy production (H+-linked ATPase, respiratory chain with cytochromes); Transport;
Secretion (e.g. of proteins); Signaling (chemoreceptors)

Front 391

Which bacteria are neither Gram+ nor Gram-?

Back 391

Mycoplasmas: don’t have cell walls; Mycobacteria: have thick, waxy cell walls that require a special acid-fast stain (AFB)

Front 392

\What structural component of group A strep is used for adhesion to eukaryotic target cells?

Back 392

M protein (“adhesin” protein)

Front 393

What is a purpose of pili/fibriae found in Gram- bacteria?

Back 393

They have terminal proteins that are used to attach to eukaryotic cell components

Front 394

What is the purpose of capsule on Gram+ and Gram- bacteria?

Back 394

Protect against phagocytosis and protect against drying out – capsule is a slime consisting of polysaccharides

Front 395

What has to happen for flagella to continue in a swimming motion and not change into the “tumble”?

Back 395

The concentration of chemoattractants has to continuously increase so that it can stimulate the flagella into not reversing its motion

Front 396

What is the period called that occurs before exponential growth takes place?

Back 396

Lag phase

Front 397

What are ways of determining bacterial growth curves?

Back 397

Serial dilutions followed by plating; Spectrophotometry (measures turbidity)

Front 398

What is chocolate agar?

Back 398

Agar that contains lysed RBCs – used to grow certain types of bacteria

Front 399

What protein is present in bacteria that can clear blood agar?

Back 399

Hemolysin (this is a virulence factor for bacteria)

Front 400

What is the purpose of the molecular syringe (type III secretion apparatus) associated with certain bacteria?

Back 400

It allows the bacteria to insert certain small molecules into the host cells it’s trying to invade

Front 401

Besides adhesion to cells, what other function is associated with pili?

Back 401

Conjugation/mating between bacteria: transfer of DNA

Front 402

What is the difference between ccw rotation and cw rotation of the flagellar bundle?

Back 402

ccw: smooth swimming; cw: “tumble” (reorients itself)

Front 403

What is an important purpose of flagella?

Back 403

Chemotaxis

Front 404

What propels flagella?

Back 404

Proton-motive force

Front 405

What compounds can be used as alternate electron acceptors?

Back 405

Nitrate, DMSO, fumarate

Front 406

What is the best way to kill spores?

Back 406

Combination of heat and water (steam, as in an autoclave)

Front 407

What can certain bacteria undergo in conditions of nutrient limitation?

Back 407

Sporulation (can be done by certain Gram+ bacteria: Clostridia, Bacillus)

Front 408

What are examples of “rich media”?

Back 408

Digests of meat, yeast cultures, milk proteins, sometimes with blood added

Front 409

What is the difference between a prototroph and an auxotroph?

Back 409

Prototroph: a bacterial strain that has the same nutritional requirements as the wild-type strain from which is was derived; Auxotroph: a mutant organism that requires some nutrient not required by the organism from which it was derived

Front 410

What are the enzymes that convert superoxide and hydrogen peroxide, respectively?

Back 410

Superoxide: superoxide dismutase (SOD); Hydrogen peroxide: catalase – these enzymes are missing in obligate anaerobes

Front 411

What happens when a pair of oxygen’s takes one, two, or three electrons?

Back 411

One: formation of superoxide; Two: formation of hydrogen peroxide; Three: formation of hydroxyl radical (most damaging due to its rapid reaction rate – no enzymes can detoxify this)

Front 412

406. What factor increase is seen with 10 generations of exponential growth?

Back 412

1,000x (e.g. a population that doubles every 20 minutes will see a 1,000x increase in 3.5 hours)

Front 413

What are requirements for a bacterial growth medium?

Back 413

Water, carbon (e.g. glucose), nitrogen (NH4+, or an amino acid), inorganic ions (sulfate, phosphate, K/Mg/Fe, trace metals), oxygen

Front 414

What are the different categories of bacteria associated with how they handle oxygen?

Back 414

Obligate aerobes: must have oxygen (Pseudomonas, Mycobacterium tuberculosis);
Obligate anaerobes: cannot have oxygen (Clostridium, Bacteroides);
Facultative anaerobes: will respire if oxygen is present, but ferment if not (E. coli, Staph. aureus)

Front 415

Urban dwellers take prescribed medications more faithfully (T/F)?

Back 415

F

Front 416

What is the best way to end a visit with a patient?

Back 416

“Is there something else you need today”?

Front 417

What factor has been shown to positively influence proper adherence to medications?

Back 417

Physician job satisfaction

Front 418

Older people (over 60) are more likely to take their medications (T/F)?

Back 418

T

Front 419

The more medications, the least likely they will be taken properly (T/F)?

Back 419

F

Front 420

A lower educational background promotes compliance (T/F)?

Back 420

F

Front 421

Females are more likely to follow physicians’ prescribing advice (T/F)?

Back 421

F

Front 422

Why has the nomenclature changed from compliance to adherence?

Back 422

Because compliance indicates that the patient should yield to a doctor’s opinion when in fact there should be a more equal doctor-patient relationship

Front 423

What is the percentage of people with hypertension who regularly take their medication?

Back 423

76% (has better adherence rate than most medications)

Front 424

Smokers are more compliant with medications (T/F)?

Back 424

F

Front 425

What are some physician factors influencing adherence?

Back 425

Number of patients seen per week (the more, the worse); Scheduling of follow-up appointments (the more, the better); Physician specialty (more specialized = less adherent); Number of tests ordered (the more, the better); Physician willingness to answer questions (the more, the better)

Front 426

At what level does the average American read?

Back 426

8th grade level (20% 5th grade or lower) – 1 in 5 American are functionally illiterate

Front 427

What percent of Emergency Department patients misunderstand their diagnosis, treatment, or follow-up instructions?

Back 427

78% (34% misunderstood follow-up instructions)

Front 428

What are factors related to compliance with treatment for hypertension?

Back 428

Other concurrent heart disease; Belief that medications are necessary for good health; Personal perceptions and social circumstances; Females are more likely to comply with “diet” changes than with “lifestyle” changes; Educations and female gender do make a difference with diet

Front 429

What is a factor that has a neutral influence on patient adherence to physician recommendations?

Back 429

The seriousness of the problem being treated

Front 430

What is the primary site of metabolism for recombinant drugs and why?

Back 430

Kidney – since they are small, the drugs can leak through the glomerulus; however, when they are reabsorbed in the nephron, they are degraded by local proteases

Front 431

What is the nomenclature used for MoAb?

Back 431

Common suffix is “mab”; Antibody source: u = human, o = murine; xi = chimeric

Front 432

What problems are associated with MoAb use?

Back 432

Cross-reactivity with normal tissues; Antigenic modulation (receptor internalization); Development of anti-mouse antibodies by patient (can only give one dose); Tumor heterogeneity in antigen expression; Tumor lacks adequate blood supply; Lack of direct toxicity; Lack of host accessory effectors

Front 433

What is particular about the half-life of monoclonal antibodies (MoAb) and what is the most important organ for clearance?

Back 433

Half-life is long; Liver and reticuloendothelial system are most important organs for clearance

Front 434

What two drugs are interleukins and how do they differ?

Back 434

Aldesleukin (IL-2): stimulates the immune system, severe toxicities associated with it (e.g. hypotension), only used as a last resort; Denileukin (fusion protein of diphtheria toxin fragments and IL-2): targets delivery of toxin to cells expressing an IL-2 receptor, used to destroy cells in some leukemias/lymphomas

Front 435

What is Alpha interferon used for and what toxicities are associated with it?

Back 435

Leukemias, lymphomas, melanomas, myelomas – toxicities: flu-like symptoms, n/v, weight loss

Front 436

What are the biologic effects of interferons?

Back 436

Antiproliferative; Immunomodulatory; Differentiation (monocytes --> macrophages); Antigen expression (increased Ig expression on lymphocytes); Oncogene expression (reduced)

Front 437

What are the nonspecific immunostimulants?

Back 437

BCG; Levamisole

Front 438

How does the effectiveness of treatment compare when looking at biologic response modifiers, between continuous SC infusion and bolus IV?

Back 438

Continuous SC is far more effective than bolus IV

Front 439

What are compounds called that modify the host’s biologic response to tumor cells?

Back 439

Biologic Response Modifiers

Front 440

What is the mechanism of action of Trastuzumab and what are some of its toxicities?

Back 440

MOA: binds to HER2 receptor leading to cell cycle arrest, and acts as a mediator of antibody-dependent cell-mediated cytotoxicity via natural killer cells and monocytes; Toxicity: hypersensitivity, CHF (especially in combination with Doxorubicin – signs may be delayed)

Front 441

What is the mechanism of action of Filgrastim and Pegfilgrastim and what are some of their toxicities?

Back 441

MOA: they are G-CSF and thus stimulate multiple stages of neutrophil production as well as increase the activity of individual neutrophils; Toxicity: bone pain, hyperuricemia

Front 442

What are the established roles of neutrophil-related growth factors?

Back 442

Prevention (not treatment) of neutropenic fever following “standard-dose” chemotherapy; Acceleration of hematopoietic recovery following “high-dose” chemotherapy; Generation of autologous peripheral blood progenitor cells; Treatment of chronic neutropenic states

Front 443

What are the indications for EPO?

Back 443

Anemia secondary to renal failure, malignancy, or chemotherapy

Front 444

Besides causing hematopoiesis, what negative side-effects are associated with EPO?

Back 444

Cancer-related angiogenesis (via VEGF), promotion of cancer cell migration; also hypertension, thrombotic events, and seizures

Front 445

What is the mechanism of action of Tositumomab?

Back 445

MOA: it is murine IgG conjugated with Iodine131, which binds to CD20 on B-cells, leading to complement-dependent toxicity, antibody-dependent cellular toxicity, and direct toxicity of radioactivity (to the bound cell and adjacent cells)

Front 446

What is the mechanism of action of Gemtuzumab and what are some of its toxicities?

Back 446

MOA: it is humanized IgG conjugated with the toxin calicheamicin, which becomes internalized after CD33 binding on leukemic cells (causes dsDNA breaks); Toxicities: myelosuppression

Front 447

441. What is the mechanism of action of Bevacizumab and what are some of its toxicities?

Back 447

MOA: binds to VEGF, thus inhibiting tumor-related angiogenesis; Toxicities: hypertension, proteinuria, problematic wound healing (since it inhibits angiogenesis)

Front 448

What is the mechanism of action of Cetuximab and what are some of its toxicities?

Back 448

MOA: binds to EGFR (ErbB-1/HER1), and in effect competitively inhibits EGF/TGF-α binding, thus blocking signaling for tumor cell growth, angiogenesis, and metastasis; Toxicities: Acneform rash (like Erlotinib), infusion reactions

Front 449

What is the mechanism of action of Rituximab and what are some of its toxicities?

Back 449

MOA: binds to CD20 on B-cells (CD20 regulates cell cycle), and causes B cell lysis; Toxicities: Infusion reactions, risk of acute death – Rituximab is used for B-cell non-Hodgkin’s lymphoma

Front 450

What is the difference between Filgrastim and Pegfilgrastim and what drug interactions are associated with them?

Back 450

Pegfilgrastim is pegylated, thus substantially increasing its half-life (since it cannot be filtered out at the glomerulus); Both drugs should not be used concomitantly with cycle-specific chemotherapy (e.g. with 5-FU) since it can worsen myelosuppression

Front 451

What is the mechanism of action of Sargramostim and what are its toxicities?

Back 451

MOA: since it is a GM-CSF, it has the same MOA as Filgrastim; Toxicities: also similar to Filgrastim, but includes myalgias

Front 452

What is Oprelvekin and what is its mechanism of action?

Back 452

IL-11; MOA: stimulates multiple stages of megakaryopoiesis and thrombopoiesis

Front 453

At what point can diagnostic techniques be used to detect a cancer?

Back 453

At about 109-1010 cells

Front 454

Where and how does bacterial DNA replication occur?

Back 454

It occurs at a site on the DNA called the OriC; initially, levels of DnaA increase and bind around OriC à this causes DnaB/DnaC to bind as well, which functions as the helicase that separates the two DNA strands – DNA replication is bidirectional!

Front 455

How does expression of the lac operon occur?

Back 455

Under normal conditions, a gene found upstream from the lac operon, called lacI, is transcribed and produces a protein that binds to the operator region, thus inhibiting transcription of the operon – when lactose (or a structurally similar molecule) binds with the inhibitor protein (from lacI), it will dissociate from the operator region allowing transcription of the lac operon to take place

Front 456

What does the lac operon consist of?

Back 456

3 genes cotranscribed into 1 mRNA: lacZ (β-galactosidase, converts lactose à glucose/galactose), lacY (lactose permease, brings lactose into the cell), lacA

Front 457

What does the bacterial RNA polymerase consist of and what gives it its specificity?

Back 457

Core enzyme: 2 α-units, one β, and one β`; the protein Sigma (σ) is the specificity factor that directly recognizes the promoter site

Front 458

How does control of pyrimidine synthesis occur within bacteria?

Back 458

The catalytic subunits that are responsible for the formation of pyrimidines are bound by regulatory subunits which respond to nucleotide binding (i.e. if the level of CTP increases, it will inactivate ATCase so that other pyrimidines can be formed instead, in order to maintain a healthy balance in pyrimidine synthesis)

Front 459

How do bacteria prevent multiple initiations at OriC?

Back 459

By methylation of the origin

Front 460

Where is chromosome replication regulated?

Back 460

At the initiation step – once initiation occurs, replication occurs at the same rate (it is constant); what differs between different bacteria is how long it takes to initiate replication (i.e. if doubling time is 20 min., that means replication is initiated every 20 min. – says nothing about the speed of DNA elongation)

Front 461

What is the difference between DNA polymerase I and III?

Back 461

DNA Pol. I: replaced RNA primer with DNA; DNA Pol. III: extension of DNA on leading and lagging strands

Front 462

What is the purpose of negative supercoiling?

Back 462

It favors processes like transcription and replication

Front 463

What is the mechanism of action of DNA gyrase and which class of antibiotics uses this mechanism to our benefit?

Back 463

It puts negative supercoils into DNA by causing ds-DNA breaks and subsequently reforming them in a different configuration – Fluoroquinolone antibiotics (e.g. Ciprofloxacin) trap bacterial DNA gyrase while it is bound to ds-DNA, leading to ds-breaks in the bacterial DNA, thus killing the organism

Front 464

How does the level of cAMP determine whether the lac operon is transcribed?

Back 464

cAMP will associate with CRP and dimerize; this complex then binds to a promoter region and subsequently recruits RNA polymerase to initiate transcription of the lac operon – cAMP levels will be low when glucose is present so that the lac operon is not transcribed

Front 465

What is the purpose of translational repression?

Back 465

It prevents overproduction of regulatory proteins – for example, S20 is a regulatory protein involved in the assembly of the 16S ribosome from rRNA; S20 has a high affinity for rRNA and will bind to it if present; however, if rRNA is not present, S20 will bind to its own mRNA transcript and inhibit its translation; in this fashion it prevents its own overproduction

Front 466

How do rapidly dividing bacteria speed up their production of proteins?

Back 466

They produce more ribosomes (individual ribosomes do not work faster)

Front 467

What structures are involved in the peptidyl transferase reactions?

Back 467

RNA only – there are no ribosomal proteins found near the active site

Front 468

What does attenuation cause?

Back 468

Conditional termination of transcription after initiation has taken place (e.g. tryptophan operon)

Front 469

What is the main function of two-component regulatory systems?

Back 469

Sensing small molecules outside the cell (i.e. signal molecules); when the sensor kinase component binds the signal molecule, it dimerizes and self-phosphorylates à the phosphorylated forms then phosphorylates a cytoplasmic response regulator à this response regulator then dimerizes and becomes active, which allows it to bind to DNA to activate or repress transcription

Front 470

What is the purpose of a complementation test?

Back 470

To see whether two different mutations affect the same gene; if the mutations are on the same gene, no growth will occur since neither organism containing the mutation is able to compensate for the other’s disability; however, if the mutations are on different genes, the organisms will be able to grow by using the non-mutated form from their respective partner

Front 471

What is an example of a common mechanism for suppression of a mutation?

Back 471

In the case of a nonsense mutation (creation of a stop codon), one copy of the gene used for tRNA synthesis can mutate to read the stop codon as though it were specific for the amino acid that was mutated in the first place (thus generating a functional protein)

Front 472

What does the term reversion mean?

Back 472

A change in phenotype from mutant (e.g. frameshift leading to a nonsense mutation in a gene required for histidine synthesis) back to wild-type

Front 473

What is characteristic of the treatment for a Mycobacterium tuberculosis infection?

Back 473

Combination therapy is necessary since using any of the drugs alone rapidly leads to resistance

Front 474

What is the importance of the fact that DNA uses thiamine instead of uracil?

Back 474

Thiamine has an extra methyl group; this allows it to be distinguished from a deaminated cytosine (which is very similar to uracil), thus reducing errors in DNA synthesis

Front 475

Which factors are responsible for the low rate of mutations seen in DNA?

Back 475

Base complimentarity; Proofreading function by DNA polymerase (exonuclease domain); Mismatch repair (parental DNA strand is marked by methylation)

Front 476

What is the key difference between a plasmid and a chromosome?

Back 476

Plasmids don’t contain any genes essential for viability

Front 477

Why is the effect of a mutation in bacterial DNA never masked (i.e. always expressed)?

Back 477

Prokaryotes are haploid, so changes in DNA sequence can’t be compensated for by a second copy of the chromosome (as with diploid eukaryotes)

Front 478

In what situations can a mutant genotype still present with wild-type phenotype?

Back 478

If the mutation is silent or a substitution is accepted; if the mutation affects an intron (not as common in prokaryotes); if the mutation is suppressed: a second mutation compensates for the first

Front 479

What is the use of conditional mutations in the study of phenotype?

Back 479

They are most important in studying essential functions, since dead is a phenotype (e.g. making a protein temperature-sensitive and studying its effects on phenotype at various temperatures)

Front 480

How do the bacteria in the gut differ between a normal individual and one with IBD?

Back 480

The person with IBD has a much greater variety of microbes present, whereas the healthy individual has only a couple of classes of bacteria present

Front 481

What side effect, associated with β-lactams, is only found in Penicillins that are penicillinase resistant (e.g. Oxacillin, Nafcillin)?

Back 481

Neutropenia and interstitial nephritis (!)

Front 482

What adverse effects are associated with Tetracyclines?

Back 482

Discoloration of teeth in children; Hepatotoxicity in pregnancy (Aminoglycosides are also class D in pregnancy!); Photosensitivity

Front 483

What adverse effects are associated with Vancomycin?
Vancomycin (prevented by giving an antihistamine and slowing the IV infusion rate)

Back 483

Ototoxicity (auditory >> vestibular); “Red-Man” syndrome: histamine release due to rapid IV infusion of

Front 484

What important adverse effects are associated with Aminoglycosides?

Back 484

Nephrotoxicity and ototoxicity (both components of the 8th nerve) – can measure plasma levels

Front 485

What unique side-effect is associated with Ceftriaxone?

Back 485

Biliary sludging (reversible, do not treat!)

Front 486

]What does it mean when an antibiotic is cell cycle independent?

Back 486

The antibiotic can kill the cell regardless of the phase it is in; this means that killing of the cells is only dependent on the amount of drug that’s available (concentration dependent), and not on how long the drug is present (time independent)

Front 487

What side effects are associated with β-lactams?

Back 487

Non-allergic ampicillin/amoxicillin rash; Seizures (with high CNS levels); Increased Na/K levels (since these ions are often part of the drug preparation) – however, β-lactams are safe in pregnancy

Front 488

Which type of antibiotic (cell cycle dependent/independent) would best be given as a single bolus dose?

Back 488

Cell cycle independent, since it is concentration dependent and will kill the cells without regard for time – cell cycle dependent drugs should be given as a continuous infusion (if possible)

Front 489

What are examples of cell cycle dependent and independent antibiotics?

Back 489

Dependent: β-lactams, since they are bactericidal during cell wall synthesis; Independent: Aminoglycosides, since they inhibit protein synthesis which occurs throughout the cell cycle

Front 490

What does it mean when an antibiotic is cell cycle dependent?

Back 490

The antibiotic is only effective at a certain stage of the cell cycle, so that means killing of the cell is dependent on how long the drug is around (time dependent), but not on how much of the drug is around (concentration independent), since that won’t affect how many cells are at a certain stage

Front 491

What adverse effects are associated with Metronidazole?

Back 491

Mutagenic; Alcohol intolerance (council patient not to drink)

Front 492

What is the association between β-lactams and the CSF?

Back 492

They cannot cross the BBB, and they are actively pumped out; however, with CSF inflammation, β-lactams can cross due to increased capillary permeability

Front 493

How do blood levels differ between aqueous, procaine, and benzathine Pen G, when given IM?

Back 493

Aqueous will be rapidly absorbed and peaks high, early; Benzathine does not peak high, but has a very sustained level of release over a long time period; Procaine is an intermediate form

Front 494

What adverse effects are associated with Sulfonamides?

Back 494

Skin rash (can become Stevens-Johnson syndrome); Acute hemolytic anemia (with G6PDH deficiency); Kernicterus (bilirubin deposition in basal ganglia, affects newborns, not recommended in 3rd trimerster)

Front 495

What adverse effect is associated with Chloramphenicol?

Back 495

Bone marrow dysfunction: anemia, low incidence of pancytopenia (potentially fatal)

Front 496

What adverse effects are seen with Macrolides?

Back 496

GI disturbances (irritation and blockade of small bile ducts); Prolonged QT (like Quinolones) – cannot put a patient on Quinolone/Macrolide if they are taking a CCB

Front 497

What adverse effects are associated with Quinolones?

Back 497

CNS effects (HA, insomnia, agitation, seizures – i.e. not indicated in a patient with epilepsy);
Connective tissue disorders (should be avoided in children, tendonitis/tendon rupture);
Prolonged QT; Photosensitivity; Dysglycemia (hyper > hypo)

Front 498

\What adverse effect is seen with Minocycline (Tetracycline)?

Back 498

Vertigo (reversible)

Front 499

What adverse effect are associated with Clindamycin?

Back 499

Diarrhea, C. difficile colitis

Front 500

What drug is known to compete with the efflux pump responsible for pumping Penicillin out of the CSF as well as into the urine?

Back 500

Probenecid (not an abx)

Front 501

What is the main indication for Vancomycin?

Back 501

MRSA/MRSE – since they are resistant to β-lactams

Front 502

What combination of drugs should be avoided with Cephalosporins?

Back 502

Potential nephrotoxins: Aminoglycosides, Vancomycin

Front 503

What administration of Penicillins is contraindicated?

Back 503

Intrathecal administration since it can cause seizures

Front 504

What problem can arise when giving a patient on Spironolactone a Penicillin salt preparation?

Back 504

Hyperkalemia, since Spironolactone in K sparing and the Penicillin salt contains K (!)

Front 505

Which antibiotics show synergism with the Aminoglycosides?

Back 505

Aminopenicillins and Anti-pseudomonal Penicillins (micro lecture also included 2nd/3rd gen. Cephalosporins in this list) – there is in virto in activation of Aminoglycosides by Penicillins, so they should not be given through the same

Front 506

How do amoxicillin and ampicillin differ?

Back 506

Amoxicillin has better oral absorption and less diarrhea

Front 507

How does excretion differ between Penicillins and penicillinase-resistant Penicillins?

Back 507

Penicillins undergo active renal excretion at the PCT, so renal status should be taken into consideration; penicillinase-resistant Penicillins do not undergo urinary excretion (they have a much longer half-life)

Front 508

What is the key difference between Penicillin G and V?

Back 508

Penicillin V is a semisynthetic antibiotic which has an added portion to its structure that gives it acid stability (increases bioavailability)

Front 509

What does the common nucleus of Cephalosporins consist of?

Back 509

7-aminocephalsporanic acid: contains a β-lactam ring and a 6-membered dihydrothiazine ring

Front 510

What are the extended-spectrum pens?

Back 510

Antipseud pens: ticarcillin, piperacillin

Front 511

What are the broad-spectrum pens?

Back 511

Amino-penicillins: ampicillin, amoxicillin; their hydrophobic amino group facilitates their penetration through the outer membrane of Gram- bacteria (e.g. E. coli)

Front 512

How Methacillin antibiotics inhibit β-lactamase?

Back 512

Their R-group contains two methoxy groups that sterically inhibit the action of β-lactamase (these drugs are also called antistaph pens)

Front 513

What are the different Penicillins and what distinguishes between them?

Back 513

Penicillin G: found in different formulations (aqueous, procaine, benzathine); Penicillin V: oral administration; Methicillin: effective in Class A β-lactamase producers, includes nafcillin and oxacillin

Front 514

What does the common nucleus of Penicillins consist of?

Back 514

6-aminopenicillanic acid: contains a β-lactam ring and a 5-membered thiazolidine ring

Front 515

What are the two main classes that antibiotics are divided up in, and what are the subdivisions associated with them?

Back 515

Small molecular: chemotherapeutic agents (synthetic chemical origin, sulfonamide), antibiotic agents (microbial origin, penicillin G), semisynthetic antibiotics (chemically modified antibiotic, methicillin); Large molecular: peptide antibiotics (microbial origin, not commercialized, bacteriocins)

Front 516

What is the difference between narrow-spectrum and broad-spectrum antimicrobials?

Back 516

Narrow: primarily effective against one class of microbes (e.g. Gram+, penicillin G);
Broad: effective against multiple classes of microbes (e.g. Gram+/Gram-, amoxicillin)

Front 517

What is the difference between bacteriostatic and bactericidal antimicrobials?

Back 517

Bacteriostatic: inhibits bacterial multiplication (e.g. sulfanilamide); Bactericidal: kills bacteria (e.g. penicillin G and other β-lactam antibiotics)

Front 518

What is the difference between 1st, 2nd, 3rd generation Cephalosporins?

Back 518

1st gen. (e.g. cephazolin): used for Gram+ bacteria that have PBP-3 (penicillin-binding protein-3);
2nd gen. (e.g. cefoxitin, cephamycin): used in OB/GYN for anaerobe coverage, better than 1st gen. against Gram-, but less effective against Gram+, some cross BBB;
3rd gen. (e.g. ceftriaxone): even better for Gram- but worse for Gram+, crosses BBB, used in combination or alone, restricted for use on bacteria resistant to 1st/2nd gen. drugs

Front 519

Which Penicillin binding proteins (PBPs) are found in microbes and which antibiotics bind to them?

Back 519

PBP1: binds Penicillins; PBP2a: doesn’t bind any commercial β-lactam antibiotic (MRSAs); PBP3: binds Cephalosporins

Front 520

What is meant by the terms R, MDR, and XDR in regards to drug resistance?

Back 520

R: resistant to a single antibiotic, or a single class; MDR: resistant to drugs from two or more classes; XDR (extended drug resistance): MDR and R to fluroquin or amikacin (assoc. with TB)

Front 521

Which Cephalosporin is considered 4th generation by some?

Back 521

Cefepime: effective against Gram- and Gram+

Front 522

What characterizes the pharmacodynamics of Streptomycin?

Back 522

It is bactericidal for aerobic Gram- bacteria; OM active transport is required; Bacterial resistance is mediated by enzymatic mechanisms; Toxicities include ototoxicity and nephrotoxicity (!)

Front 523

What uses are associated with Doxycycline?

Back 523

Contraindicated in pregnancy (hepatotoxic) and young children (discolors developing teeth)

Front 524

What pharmacodynamics are associated with Tetracyclines (e.g. Doxycycline)?

Back 524

They are bacteriostatic, but dose-dependent (i.e. high-dose is bactericidal) and organism-dependent; They are broad-spectrum; Do not take oral formulations with milk (!), since bivalent cations (Ca2+, Mg2+) will chelate the Doxycycline and prevent its absorption

Front 525

What does Tetracycline activity and resistance center around?

Back 525

Membrane pumps that either pull Tetracycline into the cell or pump it out

Front 526

How does the mechanism of action differ between that of Tetracyclines and Aminoglycosides?

Back 526

Tetracyclines also inhibit proteins synthesis at the 30S ribosome subunit, but they do so by preventing tRNA to mRNA binding (vs. preventing tRNA to 30S binding for Aminoglycosides)

Front 527

How does Gentamycin differ from Streptomycin?

Back 527

Gentamycin is much more broad-spectrum

Front 528

What are the uses of the Aminoglycosides?

Back 528

In combination with β-lactams: Gentamycin has a 4x synergy with 4th gen. Penicillins or 2nd/3rd gen. Cephalosporins (synergy occurs because Gentamycin causes membrane damage which allows the pens/cephs to enter more easily)

Front 529

What is the therapeutic use of Methacillin?

Back 529

Sepsis, endocarditis, and meningitis caused by susceptible S. aureus strains

Front 530

What is the mechanism of action of the Aminoglycosides?

Back 530

Streptomycin: inhibits protein synthesis by preventing binding of tRNA to the bacterial 30S ribosome subunit

Front 531

What is the oral formulation of Methacillin?

Back 531

Dicloxacillin

Front 532

What uses are associated with Macrolides?

Back 532

Substitute for Penicillins in pen allergic patients; covers major bacterial causes of walking pneumonia (e.g. Mycoplasma pneumoniae)

Front 533

What are the most overprescribed antibiotics?

Back 533

Cephalosporins (followed by Fluoroquinolones)

Front 534

Which Fluoroquinolone does affect S. pneumoniae?

Back 534

Moxifloxacin

Front 535

What are the uses of Ciprofloxacin?

Back 535

UTI, STD, RTI (not useful when caused by S. pneumoniae, but good for hospital acquired RTIs)

Front 536

What pharmacodynamics are associated with Ciprofloxacin?

Back 536

Dose-dependent bactericidal for Gram+/-; excellent bioavailability except in CSF

Front 537

What is the mechanism of action of Fluoroquinolones (e.g. Ciprofloxacin)?

Back 537

Interferes with topoisomerase II and IV

Front 538

What are examples of extended spectrum Macrolides?

Back 538

Clarithromycin, Azithromycin

Front 539

How does Tigecycline differ from other Tetracyclines?

Back 539

It is refractory to the influx/efflux pumps required for Tetracycline activity and resistance

Front 540

What pharmacodynamics are associated with Macrolides?

Back 540

Bacteriostatic (but bactericidal in high doses) for selected Gram+/Gram-;

Front 541

What is the mechanism of action of the Macrolides (e.g. Erythromycin)?

Back 541

Binds to the 50S subunit and causes early peptide chain release

Front 542

What new drug is part of the Glycopeptide classification?

Back 542

Dalbavancin

Front 543

What elicits the strength of an antibiotic?

Back 543

Its killing curve: the steeper the slope, the more effective it is

Front 544

In Dilution AST, what is meant by the MIC and MBC?

Back 544

MIC: first test tube, in a serial-dosage test, that is not cloudy with bacteria (dose is bacteriostatic);
MBC: first test tube that shows almost no growth when plated on a Petri dish (dose is bactericidal) – MBC dosage is important in immunocompromised patients who can’t finish off the remaining bacteria left by the MIC dose (also in patients with endocarditis and osteomyelitis)

Front 545

What is the purpose of Dilution AST?

Back 545

Antibiotic susceptibility test – determines which antibiotics will be effective against a certain bug isolated from a patient and grown in culture

Front 546

What uses are associated with Sulfamethoxazole?

Back 546

In combination with Trimethoprim, which is a non-competitive inhibitor dihydrofolate reductase (same metabolic pathway) – both can be used at low doses to minimize adverse effects; it is formulated as co-trimoxazole (TMP/SMX, Bactrim, Septra) and used for UTI

Front 547

What pharmacodynamics are associated with Sulfamethoxazole?

Back 547

Bacteriostatic; Broad-spectrum; Adverse reactions are common (fever/rash/photosensitivity)

Front 548

What is the mechanism of action of Sulfonamides (e.g. Sulfamethoxazole)?

Back 548

Competitive inhibitor of PABA in folate synthesis (tetrahydrofolate is required for deoxynucleotide synthesis, bacteria cannot absorb folate but must synthesize it) – perhaps the only antibiotic that functions by inhibiting intermediate metabolism of bacteria

Front 549

What is the mechanism of action of the Glycopeptides (e.g. Vancomycin)?

Back 549

Blocks cell wall transpeptidization by binding to the D-ala/D-ala terminus of the peptidoglycan pentapeptide thus preventing the incorporation of NAG/NAM subunits into the peptidoglycan matrix (compare to the β-lactams which inhibit the enzyme DD-transpeptidase, and thus prevent peptidoglycan cross-linking)

Front 550

What pharmacodynamics are associated with Vancomycin?

Back 550

Bactericidal (like β-lactams); Narrow-spectrum: Gram+; rapid infusion toxicity: hypotension; must monitor oto/renal functions

Front 551

What uses are associated with Vancomycin?

Back 551

MRSA caused sepsis but also used orally for C. dif intestinal toxicosis

Front 552

If an object contains 1x106 bacteria and an disinfectant is applied that kills 90% of the bacteria every 10 min., how many will be left after 40 minutes?

Back 552

Every 10 minutes, 10% of the original number will be left, so after the first 10 min, 1x105 bacteria are left; the exponent decreases by 1 every 10 minutes, so after 40 min. there will be 1x102 left (i.e. 100)

Front 553

What is an example of “cidal-static” antagonism?

Back 553

Giving Penicillin and Tetracycline together: the Tetracycline will prevent growth which will make the effects of Penicillin (i.e. killing bacteria that are synthesizing new cell walls) useless

Front 554

What are examples of Clavulenic acid drugs?

Back 554

Clavulanate, Sulbactam, Tazobactam

Front 555

What is an example of a suicide molecule and what is its mechanism of action?

Back 555

Clavulenic acid: has a high affinity for β-lactamases produced by various microbes, which they irreversible bind and inactivate, thus allowing other β-lactam antibiotics to do their job undisturbed – these are not effective on MRSA since their resistance is based on PBPs, not β-lactamase

Front 556

How are the S and R breakpoints used?

Back 556

By looking at the killing curve for a particular microbe/antibiotic combination and finding the concentration of antibiotic that is necessary to kill 80% of the microbe; if this concentration falls before the predetermined S breakpoint, the microbe will be susceptible; if it falls between the S and R breakpoints, it will be intermediate; and if it falls after the R breakpoint, it will be resistant

Front 557

What is the use of breakpoints regarding Dilution AST?

Back 557

It determines the SIR: is a bacterial isolate Susceptible, Intermediate, or Resistant to a particular antibiotic

Front 558

Why are Bactrim/Septra used prophylacticly in females with recurrent UTIs?

Back 558

The normal vaginal secretions are acidic and will cause ion trapping of the drugs; this will ensure that an infection in the making will be killed before changing the vaginal pH

Front 559

How do Fluoroquinolones cause possible CNS effects?

Back 559

Through their effects on GABA inhibition (also true for NSAIDs)

Front 560

Which substances can cause a decreased absorption of Fluoroquinolones?

Back 560

Antacids containing vitamins (Zn, Mn, Mg, Fe) and milk; this applies to Tetracyclines as well; administer the drugs 2-4 hours apart

Front 561

Because of their mechanism of action of inhibiting DNA gyrase (Topo II) and Topo IV, are Fluoroquinolones cell cycle specific?

Back 561

NO! – effective in static cultures

Front 562

What is the current drug of choice for chronic bacterial prostatitis?

Back 562

Fluoroquinolones

Front 563

What are the two most common Fluoroquinolones?

Back 563

Ciprofloxacin (Cipro), Levofloxacin (Levaquin)

Front 564

What should patients be counseled to do when taking Bactrim/Septra and why?

Back 564

Maintain proper hydration since irreversible renal impairment can occur due to crystalluria (really only a problem in patients with renal disease)

Front 565

Which enzymes are inhibited by Sulfonamides and Trimethoprim, respectively?

Back 565

Sulfonamides: Dihydropteroate synthetase (PABA --> folic acid), enzyme not present in humans;
Trimethoprim: Dihydrofolate reductase (folic acid --> tetrahydrofolic acid), enzyme present in humans, but antibiotic has a much higher affinity for the bacterial enzyme than the human form

Front 566

What is the absorption/excretion associated with Sulfonamides/Trimethoprim (Bactrim/Septra)?

Back 566

Oral absorption, renal excretion (good for UTI)

Front 567

Why is Trimethoprim not effective in bacterial prostatitis?

Back 567

Although it was thought to be effective due to ion trapping in the prostate fluid, the pH of this fluid in bacterial prostatitis is much higher, diminishing the ion trapping effect and reducing effectiveness of the drug

Front 568

What is the danger of giving theophylline with Fluoroquinolones?

Back 568

Theophylline levels can be increased due to decreased hepatic catabolism (can lead to a decrease in cAMP degradation which can have cardiac effects, such as prolonged QT); Theophylline may also potentiate the GABA inhibition effects already caused by the Fluoroquinolones

Front 569

What are some of the indications for Tetracyclines?

Back 569

Rickettsial infections; Mycoplasma pneumoniae; Chlamydiae; Acne

Front 570

What is special about the elimination of Doxycycline (part of Tetracyclines class)?

Back 570

It does not undergo renal clearance

Front 571

What is the mechanism associated with increased insulin release seen in patients taking Fluoroquinolones?

Back 571

Fluoroquinolones bind to a sulfonylurea receptor and cause closure of K channels --> this leads to depolarization of the cell, which will cause Ca channels to open --> the influx of Ca is the stimulus for insulin release (under normal circumstances this process is initiated by glucose influx into the cell, raising the ATP/ADP ratio)

Front 572

What characterizes the glucose dysregulation seen with Fluoroquinolones?

Back 572

Initial hypoglycemia due to increased insulin release; followed by hyperglycemia due to some unknown mechanism; the hyperglycemia can be exacerbated by glucocorticoid steroids –
people most prone to dysglycemia are diabetics with renal impairment receiving insulin/oral hypoglycemics

Front 573

Why are the Aminoglycosides ototoxic and what other drugs are known to exacerbate these effects?

Back 573

The half-life of the drug is much longer in otic fluid – ototoxicity is exacerbated by loop diuretics! (Furosemide) and Vancomycin

Front 574

In what class of bacteria is Metronidazole effective?

Back 574

Anaerobes

Front 575

What is a key difference between Clindamycin and Chloramphenicol?

Back 575

Clindamycin does not get into the CNS

Front 576

What potentially fatal side effect is associated with the hepatic elimination of Chloramphenicol?

Back 576

Gray baby syndrome: pre-mature babies/neonates have undeveloped hepatic conjugation and renal elimination which can lead to toxicity; these toxicities include vomiting, decreased respiration, green color of loose stools, hypothermia, cyanosis, and possibly death

Front 577

What is special about the distribution of Chloramphenicol?

Back 577

It has a uniquely high CSF distribution

Front 578

Which antibiotics have a mechanism of action that involves interfering with the bacterial 50S ribosomal subunit?

Back 578

Macrolides (Erythromycin, Azithromycin, Clarithromycin), Clindamycin: steric inhibition;
Chloramphenicol: direct inhibition

Front 579

What factors can exacerbate the nephrotoxicity seen with the Aminoglycosides?

Back 579

Hydration status, Indomethacin, Vancomycin, some β-lactams

Front 580

What drug is used for the treatment of Legionnaires disease?

Back 580

Azithromycin (Macrolide abx)

Front 581

Although Macrolides are associated with GI disturbances, when a patient ceases to take the drugs and the GI effects continue, what underlying problem should be taken into consideration?

Back 581

Pseudomembranous colitis due to C. difficile

Front 582

Which class of antibiotics is rapidly bactericidal and has a post-antibiotic inhibitory effect?

Back 582

Aminoglycosides – can be given once daily since it is cell cycle independent and because of its post-antibiotic effect (peak-trough regimen)

Front 583

What is the mechanism of action of Metronidazole?

Back 583

Pro-drug; active metabolite reacts with functional groups of DNA and protein causing DNA strand breaks (causes mutagenicity, thus contraindicated in 1st trimester)

Front 584

What adverse effects are associated with Metronidazole?

Back 584

HA, urine discoloration, mutagenicity, alcohol – “Antabuse” reaction

Front 585

How can antibiotics be responsible for lowered plasma contraceptive levels?

Back 585

By killing some bacteria in the intestine, bacterial deconjugation of eliminated contraceptives is reduced; this means that less contraceptive is reabsorbed after bile elimination

Front 586

By what process can plasmids be transformed into bacteria that are not typically transformable?

Back 586

Through electroporation (add plasmid to bacteria and pass a current at high voltage through them)

Front 587

Where do antibiotic resistance genes come from?

Back 587

Often from soil microorganisms (they have them to protect themselves)

Front 588

What are the two general types of phages?

Back 588

Lytic (virulent): always kill the host cell; Lysogenic (temperate): may go through lytic cycle, but can sometimes form a lysogen (dormant prophage becomes part of bacterial chromosome) – if a phage that contains a gene encoding for a toxin becomes a lysogen, it can confer the toxic gene to the bacteria, thus increasing its virulence

Front 589

Genes associated with what function are often carried in bacteriophages?

Back 589

Genes that encode for toxins (transfer process is called specialized transduction)

Front 590

What is the case in an Hfr strain of bacteria?

Back 590

Hfr stands for high frequence of recombination – in an Hfr strain the F plasmid has integrated itself into the bacterial chromosome, meaning that the entire chromosome is transferred during conjugation

Front 591

How does bacterial conjugation occur?

Back 591

The donor cell and recipient join via a pilus (the donor cell must contain the F plasmid in order to form the pilus); the plasmid in the donor cell is then nicked and transferred in its single-stranded form; once it enters the recipient, strand replication will occur and the plasmid is reformed

Front 592

By what mechanisms does multiple drug resistance occur?

Back 592

De novo mutations; Plasmid acquisition

Front 593

What are the three different mechanisms for bacterial gene transfer?

Back 593

Transformation: transfer of “naked” DNA (no protein coat); Transduction: DNA carried by a bacterial virus (phage); Conjugation: requires direct cell-cell contact where a plasmid is sent through a pilus

Front 594

Which bacterial gene transfer mechanism plays a major role in drug resistance transfer?

Back 594

Conjugation

Front 595

What characterizes transformation?

Back 595

Bacteria lyse in stationary phase releasing their contents; DNA from lysed bacteria is bound by specific surface proteins and is transported into other cells through the membrane; once inside, if the DNA is a chromosomal gene it will undergo homologous recombination only if the cell it entered is of the same species (if it is a different species, this cannot occur); however, if the DNA is a plasmid, it can cross species barriers – this mechanism can be used to transfer useful traits

Front 596

What does generalized transduction refer to?

Back 596

When a phage goes through the lytic cycle, instead of packaging its own DNA, it packages a part of the host DNA

Front 597

What are the locations on Salmonella’s genome called where the Type III secretion apparatuses are found?

Back 597

Pathogenicity islands (large AT heavy regions)

Front 598

How does Salmonella typhimurium get to its target organs?

Back 598

It adsorbs to and travels through the gut epithelium (via a Type III secretion apparatus); once inside Peyer’s patches it uses macrophages to travel in the body (again via the Type III secretion apparatus); eventually it grows in the spleen and liver

Front 599

By what mechanism does Salmonella switch between the production of different flagellins?

Back 599

Normally, a promoter sequence allows for transcription of H2 flagellin along with a repressor for H1 flagellin --> the promoter sequences is flanked by transposable elements and can become inverted --> when this occurs, the promoter becomes inactive and transcription of H2 and the H1 repressor is halted --> this in effect allows for the transcription of H1 and the switch is complete

Front 600

What is meant by antigenic variation?

Back 600

Use of alternative structural proteins to form identical structures (this allows the micro be form a protein that is not cross-reactive, i.e. the immune system doesn’t respond to it yet) – e.g. flagellin protein in Salmonella

Front 601

What are transposable elements?

Back 601

DNA segments that can move to other sites – a transposon is a type of complex transposable element (these can be capable of moving antibiotic resistance genes)

Front 602

What are the modified smooth muscle cells that surround capillaries?

Back 602

Pericytes

Front 603

What two factors are important in maintaining blood pressure?

Back 603

RAAS and [Na]

Front 604

What is a common cause of malignant hypertension and what sign is associated with this disease?

Back 604

Cause: renal failure; Sign: Retinal hemorrhages and exudates with or without papilledema

Front 605

What causes hypertension in patients?

Back 605

95% is idiopathic (essential hypertension); 5% is malignant (death in ~2 years)

Front 606

What are the three patterns of arteriosclerosis and what describes each?

Back 606

Arteriolosclerosis: hardening of the arteries by hyaline deposits or blood vessel hyperplasia ; Monckeberg medial calcific sclerosis: calcification of the internal elastic lamina;
Atherosclerosis: thickening of the intima with fatty streaks and plaques

Front 607

Where do 90% of berry aneurisms occur?

Back 607

In the anterior circulation --> cause subarachnoid hemorrhage

Front 608

Which blood vessels are most easily penetrated by tumors and inflammatory processes?

Back 608

Veins

Front 609

What complication is problematic with arteriovenous malformations (AVM)?

Back 609

The pressure of the arterial system is transmitted directly to the venous system, causing hemorrhage

Front 610

What are the layers of a blood vessel from the inside outwards?

Back 610

Tunica intima (single layer of endothelial cells) --> Internal elastic lamina --> Tunica media (smooth muscle) --> External elastic lamina --> Tunica adventitia (connective tissue with nerve fibers and vasa vasorum)

Front 611

What are the principle points of physiologic resistance to blood flow?

Back 611

Arterioles

Front 612

What type of arteriolosclerosis is characteristic of malignant hypertension?

Back 612

Hyperplastic arteriolosclerosis: “onion-skinning” of the blood vessel

Front 613

What clinical signs are associated with a thoracic aneurism?

Back 613

Respiratory difficulties; Difficulty swallowing; Persistent cough; Pain caused by erosion of bone; Cardiac disease

Front 614

What characterized syphilitic (luetic) aneurisms?

Back 614

Tertiary stage shows predilection for small vessels; Inflammation begins in the aortic adventitia, particularly the vasa vasorum; Ischemic injury of the tunica media

Front 615

Where do abdominal aneurysms usually occur?

Back 615

Below the renal arteries but above the bifurcation of the aorta; a resulting thrombus can clog nearby arteries (renal, mesenteric, etc.)

Front 616

What terms describe the morphology of different aneurysms?

Back 616

Saccular (spherical): involve only a portion of the wall, partially/completely filled with thrombus;
Fusiform: involve a long segment of the vessel (e.g. large segment of the aorta)

Front 617

What is a mycotic aneurism?

Back 617

An aneurism caused by infection of a major artery that weakens the vessel wall

Front 618

What is the difference between true and false aneurysms?

Back 618

True: bound by arterial wall components (atherosclerotic, syphilitic, congenital, left ventricular);
False: breach of vascular wall (hematoma, post-MI rupture, leak at anastomosis of vascular graft)

Front 619

Which humoral factors are involved in blood vessel constriction and dilation, respectively?

Back 619

Constriction: Angiotensin II, Catecholamines, Thromboxane, Leukotrienes, Endothelium;
Dilators: Prostaglandins, Kinins, NO

Front 620

What neural factors are associated with blood vessel constriction and dilation, respectively?

Back 620

Constriction: α-adrenergic; Dilation: β-adrenergic

Front 621

What is the major morphologic characteristic of benign nephrosclerosis?

Back 621

Hyaline arteriolosclerosis: seen in elderly patients, hypertensive patients, and diabetics

Front 622

What are the main categories of causes associated with vasculitis?

Back 622

Direct invasion of vascular walls by infectious pathogens; Immune-mediated mechanisms; Physical and chemical injury (irradiation, mechanical trauma, toxins)

Front 623

Which disease is associated with weakening of pulses in the upper extremities (“pulseless disease”)?

Back 623

Takayasu Arteritis: females<40, granulomatous vasculitis, mainly affects aorta and pulmonary arteries, adventitial mononuclear infiltrate to intense mononuclear inflammation in the media, coldness/numbness of fingers, ocular disturbances – involves HLA-A24/B25/DR2

Front 624

What signs and symptoms are associated with Giant Cell Arteritis?

Back 624

Fever, fatigue, weight loss; Facial pain or HA along the course of the superficial temporal artery; Diplopia to transient/complete vision loss – diagnosed by vessel biopsy and histologic confirmation

Front 625

Which arteries are principally involved in Giant Cell Arteritis?

Back 625

Temporal, vertebral, ophthalmic arteries (medical emergency); can also be associated with a thoracic aortic aneurysm

Front 626

Which diseases are associated with AECA?

Back 626

Lupus; Kawasaki disease

Front 627

Which diseases are associated with particular forms of ANCA?

Back 627

c-ANCA: Wegener’s granulomatosis; p-ANCA: Microscopic polyangiitis, Churg-Strauss

Front 628

What antibodies are commonly found in the serum of a patient with vasculitis?

Back 628

Anti-neutrophil cytoplasmic antibodies (ANCA); Anti-endothelial cell antibodies (AECA)

Front 629

What distinguishes Type A and Type B aortic dissections?

Back 629

Type A: involves ascending aorta (and possible descending as well); Type B: involves only the descending aorta (distal to subclavian artery)

Front 630

What clinical presentation is associated with vasculitis?

Back 630

Fever, myalgias, arthralgias, malaise

Front 631

What are some complications associated with an aortic dissection?

Back 631

Cardiac tamponade, aortic insufficiency, MI, extension of dissection into great arteries of neck, rupture (=most common cause of death) – 65-75% survival

Front 632

What clinical signs are associated with Kawasaki Disease?

Back 632

Erythema of palms and soles, skin rash with desquamation and enlargement of cervical lymph nodes; 20% may develop cardiac sequelae – necrosis and inflammation affects entire thickness of vessel wall; ASA and IV γ-globulin have reduced fatalities to 1%

Front 633

What clinical picture is seen with Buerger’s disease?

Back 633

Adult smoker; severe pain with skin lesions

Front 634

What is Buerger’s disease also known as and what characterizes it?

Back 634

Thromboangiitis obliterans: segmental, thrombosing, acute and chronic inflammation of the medium/small arteries (usually tibial/radial arteries, but can extend to associated nerves/veins)

Front 635

What causes Wegener’s granulomatosis and what clinical signs are associated with it?

Back 635

c-ANCA; Seen mostly in adults; Associated with upper respiratory lesions and renal lesions

Front 636

What pathology is associated with Wegener’s granulomatosis?

Back 636

Acute necrotizing granulomas of the upper/lower respiratory tracts; Necrotizing/granulomatous vasculitis of small/medium-sized vessels; Focal necrotizing/crescentic glomerulitis

Front 637

What clinical signs are associated with Microscopic Polyangiitis?

Back 637

Hemoptysis, abdominal pain, muscle weakness/pain, hematuria/proteinuria, palpable purpura, leukocytoclasia (infiltration of the media with neutrophils) – skin biopsy is diagnostic, p-ANCA will be positive in 70% of cases, caused by immunologic reaction (remove offending agent)

Front 638

What is the key difference between PAN and Microscopic Polyangiitis?

Back 638

In PAN the medium-size arteries are involved, whereas with Microscopic Polyangiitis the smaller vessels (arterioles, capillaries, venules) are involved – both are segmental transmural necrotizing inflammations

Front 639

Which systemic vasculitis presents as a segmental transmural necrotizing inflammation?

Back 639

Polyarteritis Nodosa (PAN): fibrous thickening of vessel wall, lumen may be thrombosed, all stages of activity may exist in different vessels or in the same vessel

Front 640

What is the clinical picture of PAN?

Back 640

Young adult, remittent/episodic with long symptom-free intervals, Hepatitis B association (30%), hypertension, melena (due to vascular lesions in GI tract), peripheral neuritis – no association with ANCA, Tx with corticosteroids and cyclophosphamide

Front 641

What characterizes Kawasaki Disease?

Back 641

Mucocutaneous lymph node syndrome in young children (may result from immune reaction); Kawasaki may lead to arteritis of the coronary arteries (which can lead to MI)

Front 642

What is thrombophlebitis and what causes it?

Back 642

Venous inflammation with possible thrombus formation (can lead to pulmonary embolism) most commonly in the deep leg veins; can be caused by cardiac failure, neoplasia, pregnancy, obesity, prolonged bed rest, and genetic hypercoagulability syndromes

Front 643

How do cavernous hemangiomas differ from capillary hemangiomas?

Back 643

They are less common; Less well circumscribed; Involve deeper structures; May not regress – there is an association with von Hippel-Lindau disease (genetic condition involving tumors in vascular rich parts of the body)

Front 644

What is a capillary hemangioma?

Back 644

Largest single type of vascular tumor; found in infants, usually fade with age

Front 645

What is angiomatosis?

Back 645

Multiple angiomas involving large segments of various organs

Front 646

What signs/symptoms are associated with lymphangitis?

Back 646

Dilated lymphatics filled with exudate (due to group A β-hemolytic strep); Painful subcutaneous red streaks extending along the course of lymphatics with painful enlargement of regional lymph nodes

Front 647

What causes SVC and IVC syndromes and what signs are associated with them?

Back 647

SVC syndrome: neoplasia compressing SVC, associated with dusky cyanosis, dilation of veins;
IVC syndrome: neoplasia or thrombi, associated with edema of the legs, distension of superficial collateral veins of the lower abdomen and massive proteinuria

Front 648

What two clinical tests can be done to check for thrombophlebitis?

Back 648

Trousseau sign; Homan sign: passive dorsiflexion of the foot elicits sharp calf pain

Front 649

What is the Raynaud phenomenon?

Back 649

Ischemic attacks of the extremities: cold-induced vasoconstriction of digital arteries, precapillary arterioles, and cutaneous arteriovenous shunts (color changes: white --> blue --> red)

Front 650

What clinical picture is associated with Raynaud phenomenon?

Back 650

Median age: 14 years old; may have family history; atrophy of skin, subcutaneous tissues, and muscles – must exclude secondary Raynaud phenomenon in case it is due to other diseases (e.g. SLE, atherosclerosis, Buerger’s)

Front 651

What causes varicose veins?

Back 651

Prolonged, increased intraluminal pressure (e.g. due to long periods of standing, obesity, pregnancy) causes loss of vessel wall support, especially in the superficial veins of the upper/lower legs of people over 50 years of age

Front 652

What benign, painful tumor is often found under the finger nails?

Back 652

Glomus tumor (glomangioma): arises from modified smooth muscle cells of the glomus body

Front 653

What is angiosarcoma?

Back 653

Malignant endothelial neoplasm found mostly in older adults; can be due to arsenic, Thorotrast, PVC, and radiation exposure – poor outcome

Front 654

Which blood vessel abnormality is an intermediate between hemangioma and angiosarcoma?

Back 654

Hemangioendothelioma

Front 655

What virus are 95% of Kaposi’s sacromas associated with?

Back 655

Herpesvirus 8 (HHV-8)

Front 656

What are the four types of Kaposi’s sarcoma?

Back 656

Classic/European: not associated with HIV; African/endemic: lymphadenopathy, aggressive; Transplant/immunosuppressed-associated: aggressive; AIDS-associated: most common

Front 657

What is Bacillary Angiomatosis?

Back 657

Vascular proliferation due to opportunistic infections (Bartonella family) in immunocompromised people – also known as Cat Scratch Fever and Trench Fever

Front 658

What are the vascular ectasias and what diseases are they associated with?

Back 658

Nevus flammeus (birthmark/port-wine stain): Sturge-Weber syndrome; Spider telangiectasia: pregnancy and cirrhosis; Hereditary hemorrhagic telangiectasia: Osler-Weber-Rendu disease

Front 659

What is a pyogenic granuloma?

Back 659

Lobular capillary hemangioma: polypoid rapidly growing exophytic red nodule attached by a stalk (can develop after trauma)

Front 660

What are capillary lymphangiomas?

Back 660

Network of endothelium-lined lymph spaces (absence of blood cells); seen with Turner syndrome

Front 661

What characterizes LDL?

Back 661

Originate from membrane surface of cells; Composed of triglycerides (9%) and cholesterol (60%); Normally removed from the blood by receptor-mediated uptake into the liver and other tissues; Closely associated with coronary artery disease (CAD)

Front 662

What side effects are associated with statins?

Back 662

Muscle damage (rhabdomyolysis and myalgias); Acute renal failure; Increased serum liver transaminases (liver failure is rare); Bloating, diarrhea, constipation

Front 663

How does limiting cholesterol biosynthesis by HMG CoA reductase reduce LDL?

Back 663

A reduction in cholesterol biosynthesis leads to a decrease of intracellular cholesterol levels available for bile acid synthesis; As a compensatory mechanism, the liver upregulates its LDL receptors, thus removing LDL from the blood – IDL and VLDL remnants are also removed

Front 664

How do HMG CoA reductase inhibitors function?

Back 664

The inhibits the rate-limiting step in cholesterol biosynthesis; also, they modify endothelial function, inflammatory responses, plaque stabilization, thrombus formation, and reduce plaque formation

Front 665

What is the “gold standard” drug class for lowering plasma cholesterol?

Back 665

HMG CoA reductase inhibitors (i.e. –statins)

Front 666

Which has a greater impact on cardiovascular events, increased LDL or reduced HDL?

Back 666

Reduced HDL

Front 667

What characterizes HLD?

Back 667

Produced in liver; Composed of triglycerides (8%) and cholesterol (17%); Transport cholesterol from periphery to liver; Inversely correlated with CAD

Front 668

What are the risk factors for coronary artery disease for LDL, HDL, and total cholesterol levels?

Back 668

LDL<130; HDL>40; Total cholesterol<200

Front 669

What characterizes chylomicrons?

Back 669

Originate in the small intestine; Composed of dietary triglycerides (90%) and cholesterol (3%); Chylomicron triglycerides are broken down by lipoprotein lipase leaving a cholesterol-rich chylomicron remnant which is taken up by the liver

Front 670

What characterizes VLDL?

Back 670

Originate in the liver; Composed of triglycerides (55%) and cholesterol (dietary/de novo – 16%); Metabolism of triglycerides by lipoprotein lipase converts VLDL to LDL

Front 671

What is the mechanism of action of Cholestyramine and Colestipol?

Back 671

They are ion exchange resins that bind to bile acids in the small intestines preventing their reabsorption --> increased conversion of liver cholesterol to bile acids --> de novo synthesis can’t keep up --> upregulation of liver LDL-receptors --> decrease in plasma LDL

Front 672

What is the function of fibric acid derivatives (e.g. Clofibrate)?

Back 672

Lower triglycerides by stimulating lipoprotein lipase activity to break down plasma triglycerides from lipoproteins (especially from chylomicrons and VLDL)

Front 673

Which drug appears to reduce plaque volume?

Back 673

Synthetic HDL

Front 674

What kind of drug is Anaretrapib?

Back 674

It is an investigational drug that functions as a CEPT inhibitor (CEPT mediates the transfer of cholesterol esters and triglycerides between lipoproteins); it is supposed to markedly increase HDL and decrease LDL

Front 675

What is the mechanism of action of Ezetimibe?

Back 675

It inhibits the uptake of cholesterol in the intestinal lumen by acting at the brush border to reduce cholesterol transport across the cell wall – can be used in combination with statins (e.g. Vytorin)

Front 676

How does Colesevelam differ from other bile acid binding drugs?

Back 676

It is a hydrogel polymer, causing it to have less incidence of GI disturbances and it does not appear to reduce absorption of acidic drugs as do the resins

Front 677

What side effects are associated with the bile acid binding products?

Back 677

Significant GI disturbances (constipation/steatorrhea); Bind certain acidic and hydrophobic drugs in the GI tract inhibiting their absorption (e.g. digitoxin, phenobarbital, tetracyclines); They can also inhibit intestinal absorption of fat-soluble vitamins

Front 678

What contraindications are associated with statins?

Back 678

Pregnancy and lactation; Liver disease and cholestasis

Front 679

What drug interactions are associated with statins?

Back 679

Some statins are metabolized by CYP3A4, so inhibitors of 3A4 should be avoided (e.g. cyclosporine, amiodarone, ketoconazole, erythromycin, HIV protease inhibitors); also concurrent use of statins with Gemfibrozil can increase the risk of myopathy

Front 680

Which CYP enzymes are responsible for the metabolism of common statins?

Back 680

3A4: Lovastatin, Simvastatin; Partial 3A4: Atorvastatin, Fluvastatin; Partial 2C9/2C19: Rosuvastatin, Fluvastatin; NOT metabolized by CYP enzymes: Pravastatin

Front 681

What side effects are associated with Clofibrate?

Back 681

Increased risk of gallstones, increased risk of mortality – not prescribed much anymore

Front 682

Which combination therapy has the most potential for lowering LDL/triglycerides while raising HDL?

Back 682

Statin/Niacin

Front 683

What side effects are associated with Niacin?

Back 683

Intense flushing and itching; Hepatotoxicity; GI disturbances – an extended release formula (Niaspan) has fewer side effects

Front 684

What is the mechanism of action of Niacin (Vitamin B3)?

Back 684

It decreases the breakdown of triglycerides in adipose tissue by inhibiting lipolysis; this decreases the supply of FFAs for the synthesis of VLDL which will in turn decrease the formation of LDL; it also increase HDL

Front 685

What is Omacor used for?

Back 685

Reduce triglycerides and increase survival post-MI; It is an Omega-3 polyunsaturated fatty acid preparation

Front 686

What is the mechanism of action of Fenofibrate?

Back 686

Similar to Gemfibrozil but functions by inhibiting AcCoA carboxylase; this decreases fatty acid synthesis and increases LDL uptake by the liver – used to reduce CAD in patients with DM-II

Front 687

What is the mechanism of action of Gemfibrozil?

Back 687

Stimulates lipoprotein lipase on the endothelium (lowering triglycerides); Inhibits the synthesis of apolipoprotein B (a carrier molecule for VLDL, IDL, and LDL) thus decreasing plasma LDL;
It also increases HDL modestly

Front 688

What are the main major arteries in which atherosclerosis is a clinical concern?

Back 688

Aorta, carotid a., iliac a. (for medium-sized arteries: coronary a., popliteal a.)

Front 689

Where in the plaque do lymphocytes accumulate?

Back 689

In the shoulders of the plaque

Front 690

What happens with small-artery atheromas?

Back 690

Ischemic injury

Front 691

What is a key characteristic of atherosclerosis in regard to the vessel wall?

Back 691

Intimal lesions and weakening of the underlying media

Front 692

What are some less common consequences of atherosclerosis?

Back 692

Sudden cardiac death, Mesenteric occlusion, Chronic ischemic heart disease, Ischemic encephalopathy, Large artery atheromas, Aneurysms

Front 693

What are the most dangerous plaques?

Back 693

Thrombus plaques

Front 694

How does a normal artery progress to a plaque?

Back 694

Either directly or via a fatty streak

Front 695

What is the difference between stenosis and occlusion?

Back 695

Occlusion is by definition a 100% closure of the vessel, whereas stenosis is by definition less than 100% closed off

Front 696

What is the difference between an eccentric and a concentric plaque?

Back 696

Eccentric plaques take up one side of the vessel, whereas concentric plaques go around the entire vessel

Front 697

What is a major concern with fibrous plaques in the aorta?

Back 697

Thinning of the tunica media leading to aneurysm

Front 698

What accumulates into class III lesions?

Back 698

Oxidized LDL and cholesterol – potentiated by hypercholesterolemia

Front 699

Which segment of aorta is far more susceptible to aneurysmal dilatation due to atherosclerosis?

Back 699

Abdominal aorta

Front 700

What are the key characteristics of atherosclerosis in regard to plaque formation?

Back 700

Intimal thickening and lipid accumulation

Front 701

What do derivatives of cigarette smoking in circulation lead to?

Back 701

Accelerated plaque formation

Front 702

What causes fatty steaks to form around ostia (entrance from one vessel into the next)?

Back 702

Turbulence – these fatty streaks are called adaptive thickenings (they do not disturb blood flow)

Front 703

What is contained within fatty streaks?

Back 703

T lymphocytes; Extracellular lipid (in smaller amounts than in plaques) – fatty streaks are present in all people over age 10

Front 704

What is a key difference between class III and IV lesions?

Back 704

Class IV lesions (atheromas) have a core of extracellular lipid whereas Class III lesions have small extracellular lipid pools

Front 705

How do foamy macrophages end up inside plaques?

Back 705

Circulating monocytes invade into tissues, including plaques, where they differentiate into macrophages (these macrophages take up LDL and become foamy)

Front 706

What are the American Heart Association atherosclerosis classification categories?

Back 706

I: initial lesion of isolated foam cells; II: fatty streaks; III: intermediate lesion (raised, causes stenosis); IV: Atheromas (introduce an extracellular matrix of lipids); V: fibroatheromas (progressive fibrous cap formation with smooth muscle); VI: complicated lesions (thrombus deposition, ulceration)

Front 707

Which AHA classification categories have the ability to stop progressing?

Back 707

I and II

Front 708

Where do fibrous plaques cause the greatest frequency of disease?

Back 708

Lower abdominal aorta > Coronary a. > Popliteal a. > Internal carotid aa. > Circle of Willlis

Front 709

What are the three principle microscopic components of atherosclerotic plaques?

Back 709

Cells: smooth muscle cells, macrophages, leukocytes (recruited by VCAM-1); ECM: collagen, elastic fibers, proteoglycans; Intracellular- and extracellular lipid

Front 710

Which cell in a plaque is most responsible for causing pathogenesis?

Back 710

Smooth muscle cell (especially the ones recruited from the media by PDGF)

Front 711

How can neovascularization of a plaque be problematic?

Back 711

If it receives its blood supply from the lumen of the main vessel and from the vasa vasorum, the pressure in the vessel can become a problem and cause hemorrhaging of the plaque, weakening the fibrous cap

Front 712

How does LDL become oxidized?

Back 712

Through its exposure to free radicals (antioxidants may help stem the development of raised lesions)

Front 713

What factors are responsible for the pathogenesis of atherosclerosis?

Back 713

Endothelial injury, Inflammation, Lipids, Smooth muscle cells

Front 714

What are modifiable risk factors of atherosclerosis?

Back 714

Hyperlipidemia, HTN, cigarette smoking, Diabetes Mellitus; also Lipoprotein A, trans-fat intake, Chlamydia pneumoniae, excessive alcohol intake

Front 715

What are the constitutional risk factors of atherosclerosis?

Back 715

Age (older), sex (male), genetics (e.g. homocystinuria)

Front 716

What is the term used when a thrombus creates a new lumen?

Back 716

Recanalization

Front 717

What is the most feared complication of an atherosclerotic plaque?

Back 717

Superimposed thrombosis (due to disrupted lesions leading to the exposure of highly thrombogenic substances – i.e. smooth muscle cells, etc)

Front 718

What is found in the “shoulder” of atherosclerotic plaques?

Back 718

Macrophages, Smooth muscle cells, T-lymphocytes

Front 719

What is located deep to the fibrous cap?

Back 719

Necrotic core containing a disorganized mass of lipids – if the cap thins and the core is exposed, a thrombus can form

Front 720

What variables can make atherosclerosis worse?

Back 720

Neovascularization at the periphery of lesions; Dystrophic calcification (increased risk of coronary events)

Front 721

What layer is always the one that thickens in atherosclerosis?

Back 721

Intima (NOT the media or adventitia)

Front 722

What vessel wall layer is affected by Mönckeberg Medial Calcific Sclerosis?

Back 722

Media – as opposed to the intima in atherosclerosis

Front 723

What are the two key determinants of the early stages of atherosclerosis?

Back 723

Serum cholesterol concentrations; Smoking

Front 724

What should risk-factor evaluation and prevention start in regards to atherosclerosis?

Back 724

Childhood

Front 725

What players in atherosclerosis can produce PDGF?

Back 725

Platelets attached to damaged endothelium; Smooth muscle cells recruited into plaque; Macrophages – PDGF causes smooth muscle cells to migrate into the plaque

Front 726

Can atherosclerosis be initiated without endothelial damage?

Back 726

Yes, for example through VCAM-1 induction

Front 727

What are mimickers of vasculitis and how do they present?

Back 727

Subacute bacterial endocarditits (SBE): new heart murmur, splinter hemorrhages, unusually high fever; Infection: liver dysfunction (Hep C), drug abuse (HIV, Hep C, cocaine), high risk sexual activity (HIV); Cancer: history of cancer; Cholesterol emboli: necrosis of lower extremity digits

Front 728

What is the treatment for PAN?

Back 728

Prednisone and Cyclophosphamide (Cytoxan)

Front 729

What is associated with PAN?

Back 729

Hepatitis B (PAN occurs within six months of Hep B infection) – patients are ANCA negative

Front 730

What signs should be suspect of PAN?

Back 730

Men in 40s/50s; Palpable purpura; Peripheral neuropathy; Glomerulonephritis: red cell casts, proteinuria – should biopsy active site for diagnosis (angiogram: beating with aneurysms)

Front 731

What are the clinical features of Polyarteritis Nodosa (PAN)?

Back 731

Mononeuritis multiplex: transient wrist drop/foot drop; Focal necrotizing glomerulonephritis; Palpable purpura; Arthralgias; Myalgias; Abdominal claudication; Abnormal liver tests; MI; Seizure, stroke; Jaw claudication; Testicular pain; Retinal hemorrhage – basically anywhere you find medium/small vessels

Front 732

What is the only way to confirm the diagnosis of Giant Cell Arteritis and what is the treatment?

Back 732

Temporal artery biopsy (big piece), should also have high ESR; Treatment: Prednisone (immediately), Aspirin (helps prevent blindness)

Front 733

What symptoms are associated with Giant Cell Arteritis (Temporal Arteritis)?

Back 733

Superficial temporal headache (can’t wear hat/glasses/comb hair), jaw claudication, diplopia, blindness: acute or transient (amaurosis fugax), polymyalgia rheumatica (pain/stiffness in proximal muscle groups), fever or cough (can present by themselves), weight loss, fatigue

Front 734

What types of vasculitis are associated with large, medium, and small vessels, respectively?

Back 734

Large: Takayasu’s Arteritis, Giant Cell Arteritis; Medium: PAN, Kawasaki’s disease, Buerger’s disease, CNS vasculitis; Small: Hypersensitivity vasculitis, Cryoglobulinemia, Henoch-Schönlein Purpura, Wegener’s Granulomatosis, Microscopic Polyangiitis, Churg-Straus Vasculitis

Front 735

What is claudication?

Back 735

Attacks of lameness and pain (mainly in the calf muscles) upon exertion – caused by ischemia

Front 736

What signs should be suspect of vasculitis?

Back 736

Multisystem disease, unexplained constitutional signs/symptoms, palpable purpura, gangrene, claudication, Raynauld’s, livedo reticularis, glomerulonephritis, mononeuritis multiplex, myalgias/arthralgia/arthritis, intestinal angina, testicular pain

Front 737

What clinical manifestations are associated with Wegener’s granulomatosis regarding the lungs and kidneys?

Back 737

Upper respiratory tract symptoms: sinusitis, nasal discharge, epistaxis, nasal ulcerations, nasal septum perforations, saddle-nose deformity, oral ulcers, otitis media, subglottic stenosis (stridor); Lower respiratory tract symptoms: asymptomatic, chronic cough, alveolar hemorrhage, pneumonitis, respiratory insufficiency, pleuritis;
Renal symptoms: Pauci-immune necrotizing glomerulonephritis (i.e. no immune-complex deposition), asymptomatic, active urine sediment: hematuria, pyuria, proteinuria, casts

Front 738

What is the treatment associated with Wegener’s?

Back 738

Generalized/Limited WG: Prednisone, Cytoxan; Milder WG: MTX or Cyclosporin –
Patients on Cytoxan or with severe respiratory infections should be given Bactrim to protect against Pneumocystis Carinii

Front 739

What are the protein targets associated with c-ANCA and p-ANCA?

Back 739

c-ANCA: proteinase 3; p-ANCA: myeloperoxidase

Front 740

What clinical manifestations besides lung/renal are associated with Wegener’s?

Back 740

Weight loss, fatigue, fever, proptosis (retro-orbital pseudotumor), palpable purpura, ulcers, subcutaneous nodules, vesicles, joint/muscle pains, mononeuritis multiplex (not as common), pericarditis – positive c-ANCA