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Other individuals alesse 0.18 mg visa, called Down syndrome preservation of chromosome number and structure is mosaics buy alesse 0.18mg low price, have a mixture of normal cells and cells with accomplished through the replication of the entire set of three copies of chromosome 21 cheap alesse 0.18 mg with amex, resulting in a milder chromosomes just before mitosis purchase alesse 0.18 mg free shipping. Zygotes that Sex cells cheap alesse 0.18 mg line, such as eggs and sperm, undergo a differ- receive a full extra set of chromosomes, a condition ent type of cell division called meiosis. This reduction in the number of chromosomes within sex cells is accomplished during two rounds of cell division, called meiosis I and meiosis II. During meiosis I, a cell with 46 replicated chromosomes divides to form two cells that each contain 23 replicated chromosomes. Normally, the meiosis I division separates the 23 pairs of chromo- somes evenly, so that each daughter cell contains one chromosome from each chromosome pair. During meiosis II, the two daughter cells containing 23 replicated chro- mosomes divide to form four daughter cells, each con- taining 23 non-replicated chromosomes. Chromosome pairs may fail to separate during meiosis I, or a replicated chromosome may fail to separate during meiosis II. Meiosis produces four daughter cells, each with half the normal number of chromosomes. Non-sex cells in humans are called diploid (meaning “double the number”) since they contain the full number of normal chromosomes. Human diploid cells normally each have 46 chromosomes, and haploid cells normally each have 23 chromosomes. Alterations in chromosome number Two kinds of chromosome number alterations can occur in humans: aneuploidy, an abnormal number of chromosomes, and polyploidy, more than two complete sets of chromosomes. During normal meiosis, chromosomes are distributed evenly among the four daughter cells. Sometimes, however, an uneven number of chromosomes are distributed to the daughter cells. As noted in the pre- vious section, chromosome pairs may not move apart in meiosis I, or the chromosomes may not separate in meio- Figure 1. The result of both kinds of mistakes (called nondis- junction of the chromosomes) is that one daughter cell receives an extra chromosome, and another daughter cell zygote is missing a chromosome, the condition is called does not receive any chromosome. When an egg or sperm that has undergone faulty If the zygote survives and develops into a fetus, the meiosis and has an abnormal number of chromosomes chromosomal abnormality is transmitted to all of its cells. If the zygote has an extra Examples of aneuploidy include trisomy 21, also chromosome, the condition is called trisomy. If the known as Down syndrome, and trisomy 13, also called GALE ENCYCLOPEDIA OF GENETIC DISORDERS 233 Angelman syndrome gene Huntington fragile X syndrome disease Maternal age and prenatal diagnosis GALE ENCYCLOPEDIA OF GENETIC DISORDERS 237 (Photo Researchers, Inc. Final height the fetus, has led to diagnosis of the condition before in adults with CCD is usually shorter than expected given birth. More unusual complications associated with CCD include (curvature of the spine), bone fragility, deafness, cleft palate, and a small jaw. The diagnosis of CCD is typically made by the doc- Children with CCD may be screened for deafness. The Surgery may be performed to remove the baby teeth and clavicular hypoplasia may only be seen on x rays. Orthodontic procedures may be required to align the The multiple dental anomalies in CCD are also quite spe- teeth. Identification of a mutation may confirm the initial diagnosis, or allow diagnosis before birth. CCD is not expected to affect life expectancy in In a few cases, recognition of the features of CCD by most cases and most diagnosed persons enjoy good over- ultrasound imaging, a technique that produces pictures of all health. Therefore, they have a 25% risk with National Organization for Rare Disorders (NORD). As the infant grows, a delay in developmental milestones becomes apparent around the time that walking and talking should occur. Mental retar- dation in the mild to moderate range is found in all patients with CS. A small number of patients will have Coffin-Lowry Syndrome I A common test used to detect color blindness.

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The work and liver function test findings were within neuroexcitation can range from irritability cheap alesse 0.18 mg with mastercard, confu- normal limits order alesse 0.18 mg visa. In fact alesse 0.18 mg generic, high tissue duced acute CNS toxicity or drug interaction was concentrations are achieved with oral ciprofloxacin alesse 0.18mg discount, suspected cheap 0.18 mg alesse with visa, and all his medications were discontin- especially in the prostate and urinary tract. Diabetic gastroparesis is seen in long-standing se- (A) Ciprofloxacin can displace GABA from its re- vere diabetes. Graumlich DRUG LIST PENICILLINS PAGE Cefonicid 532 Amoxicillin 530 Cefoperazone 531 Ampicillin 530 Cefotaxime 532 Carbenicillin 530 Cefotetan 531 Cloxacillin 529 Cefoxitin 531 Dicloxacillin 529 Cefpodoxime 532 Mezlocillin 530 Cefprozil 532 Nafcillin 529 Ceftazidime 531 Oxacillin 529 Ceftibuten 532 Penicillin G 528 Ceftizoxime 532 Penicillin V 529 Ceftriaxone 532 Piperacillin 530 Cefuroxime 532 Ticarcillin 530 Cephalexin 532 CEPHALOSPORINS Cephapirin 532 Cephradine 532 Cefaclor 532 CARBAPENEMS, CARBACEPHEMS, AND Cefadroxil 532 MONOBACTAMS Cefamandole 533 Cefazolin 532 Aztreonam 534 Cefdinir 532 Imipenem-cilastatin 534 Cefepime 531 Loracarbef 534 Cefixime 532 Meropenem 534 Cefmetazole 531 526 45 -Lactam Antibiotics 527 INTRODUCTION MECHANISMS OF RESISTANCE A number of antibiotics produced by fungi of the genus A number of microorganisms have evolved mecha- Cephalosporium have been identified. These antibiotics nisms to overcome the inhibitory actions of the - called cephalosporins contain, in common with the lactam antibiotics. In addition to the numerous resistance: inactivation of the -lactam ring, alteration penicillins and cephalosporins in use, three other classes of PBPs, reduction of antibiotic access to PBPs, and of -lactam antibiotics are available for clinical use. Bacterial These are the carbapenems, the carbacephems, and the resistance may arise from one or more than one of these monobactams. They block a critical The most important mechanism of resistance is hy- step in bacterial cell wall synthesis. Many bacteria (Staphylo- coccus aureus, Moraxella [Branhamella] catarrhalis, MECHANISM OF ACTION Neisseria gonorrhoeae, Enterobacteriaceae, Haemophilus influenzae, and Bacteroides spp. The - cross-linking of adjacent peptidoglycan (murein) strands lactamases evolved from PBPs and acquired the capacity by a transpeptidation reaction. In this reaction, bacter- to bind -lactam antibiotics, form an acyl enzyme mole- ial transpeptidases cleave the terminal D-alanine from a cule, then deacylate and hydrolyze the -lactam ring. The -lactam antibiotics structurally resemble the Efforts to overcome the actions of the -lactamases terminal D-alanyl-D-alanine (D-Ala-D-Ala) in the pen- have led to the development of such -lactamase in- tapeptides on peptidoglycan (murein) (Fig. Bacterial transpeptidases covalently bind the -lactam They are called suicide inhibitors because they perma- antibiotics at the enzyme active site, and the resultant nently bind when they inactivate -lactamases. The intact the -lactamase inhibitors, only clavulanic acid is avail- -lactam ring is required for antibiotic action. Chemical inhibition of -lactamases, lactam ring modifies the active serine site on transpep- however, is not a permanent solution to antibiotic tidases and blocks further enzyme function. Enzymes re- ing proteins (PBPs) function as transglycosylases and sistant to clavulanic acid include the cephalosporinases carboxypeptidases. When -lactam antibiotics inactivate An additional mechanism of antibiotic resistance in- PBPs, the consequence to the bacterium is a structurally volves an alteration of PBPs. Resistant bacteria, usually weakened cell wall, aberrant morphological form, cell gram-positive organisms, produce PBPs with low affin- lysis, and death. The development of muta- tions of bacterial PBPs is involved in the mechanism O for -lactam resistance in Streptococcus pneumoniae, S Enterococcus faecium, and methicillin-resistant S. Some gram-negative bacteria employ a third mech- N anism of resistance, namely, one that reduces antibiotic O COOH access to PBPs. Gram-positive organisms have an ex- posed peptidoglycan layer easily accessible to -lactam -lactam ring Thiazolidine ring antibiotics (Fig. In contrast, gram-negative organ- isms have an outer membrane surrounding the peptido- 6-aminopenicillanic acid glycan layer. In susceptible gram-negative 528 VI CHEMOTHERAPY Porin LPS Peptidoglycan Periplasm Cytoplasmic membrane A B FIGURE 45. The outer membrane contains lipopolysaccharides (LPS) and porins with narrow, restrictive channels that function as barriers to antibiotic permeability. Drug efflux mechanisms are associated penicillins (G and V), antistaphylococcal (penicillinase- with multiple drug resistance, including resistance to - resistant) penicillins, aminopenicillins, and antipseudo- lactam antibiotics. Natural penicillins have therapeutic ef- Widespread use of -lactam antibiotics exerts selec- fects limited to streptococci and a few gram-negative tive pressure on bacteria and permits the proliferation organisms. A comparison of current antibi- ant) penicillins treat infections caused by streptococci ograms with those from previous decades shows an and staphylococci but do not affect MRSA. The amino- alarming increase in bacterial resistance to -lactam an- penicillins are effective against streptococci, enterococci, tibiotics. The antipseudomonal penicillins retain activity against streptococci and possess additional ef- PENICILLINS fects against gram-negative organisms, including various The penicillins are a large group of bactericidal com- Enterobacteriaceae and Pseudomonas. The struc- Natural Penicillins ture common to all penicillins is a -lactam ring fused with a thiazolidine nucleus (Fig. The antimicrobial Penicillin G (benzylpenicillin) is an acid-labile com- activity of penicillin resides in the -lactam ring. Consequently, penicillin G is most appropriate or -lactamases results in the formation of penicilloic for intramuscular or intravenous therapy. Addition of tributes to most tissues and serosa-lined cavities, al- various side chains (R) to the basic penicillin molecule though low concentrations appear in breast milk and 45 -Lactam Antibiotics 529 cerebrospinal fluid.

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The major adverse effect associated with vancomycin Sodium colistimethate cheap alesse 0.18 mg with visa, the parenteral preparation buy cheap alesse 0.18mg online, binds therapy is ototoxicity cheap 0.18 mg alesse with visa, which may result in tinnitus buy generic alesse 0.18mg online, high- less to tissue and is excreted faster than the free base purchase alesse 0.18mg free shipping. More commonly, the intravenous infusion of van- Clinical Uses comycin can result in chills, fever, and a maculopapular With the advent of potent broad-spectrum antibiotics, skin rash often involving the head and upper thorax such as the quinolones and third-generation cephalo- (red man syndrome). Red man syndrome is associated sporins, the indications for the use of the polymyxins, with increased levels of serum histamine. In combination with neomycin, polymyxin B can be used as a bladder irrigant to reduce the risk of catheter- associated infections, although this use remains contro- THE POLYMYXINS versial. It also can be used as topical therapy in external The polymyxins are a group of antibiotics produced by otitis caused by P. Polymyxin B (Aerosporin) and co- listin (polymyxin E, Coly-Mycin) are used in the treat- Adverse Effects ment of bacterial diseases. Colistin and polymyxin B can cause extreme nephro- toxicity when used parenterally, and any preexisting re- Structure and Mechanism of Action nal insufficiency will potentiate the nephrotoxicity The polymyxins are polypeptide antibiotics that contain caused by these antibiotics. These antibi- Neurotoxicity is a rare adverse reaction that can be otics accumulate in the cell membrane and probably in- recognized by perioral paresthesia, numbness, weak- teract with membrane phospholipids. These drugs may pre- fatty acid portion of the antibiotic penetrates the hy- cipitate respiratory arrest both in patients given muscle drophobic portion of the membrane phospholipid and relaxants during anesthesia and in persons with myas- the polypeptide ring binds to the exposed phosphate thenia gravis. A pediatric nurse is found to be colonized with ANSWERS MRSA in her nares during an outbreak inves- 1. The may undergo culture investigation of their skin flora best strategies to eradicate her nasal carriage and orifices to determine the source of infection. Bacitracin oint- (C) Bacitracin ointment application to her nasal ment has been used with limited success and may passages be an option, along with strict handwashing and iso- (D) Polymyxins lation precautions. Polymyxins are effective topical (E) A month-long furlough from patient care agents for gram-negative infections. In the treatment of uncomplicated urinary tract in- from patient care responsibilities is unlikely to erad- fection caused by gram-negative bacteria, the ther- icate her nasal colony. Trimethoprim, which exhibits broad-spectrum (A) Teicoplanin activity, with sulfamethoxazole is active against (B) Bacitracin most aerobic and facultative gram-positive and (C) IV vancomycin gram-negative organisms. A urine culture in an asymptomatic female patient as triple antibiotic, which has gram-positive and with an indwelling Foley catheter comes back with gram-negative spectra. Intravenous antibiotics are not indicated un- (A) Start IV vancomycin to cover enterococci less this evolves into a deeper soft tissue infection. It is not unusual to get colonized by hospital (C) Initiate a quinolone like levofloxacin with flora, especially with an indwelling Foley catheter. If broad-spectrum coverage for UTIs the patient does not have any clinical evidence of in- (D) Discontinue use of the Foley catheter if possi- fection, it is not necessary to start therapy with van- ble and obtain follow-up cultures if she develops comycin or for that matter, any antibiotic. Entero- symptoms coccal UTI can still be treated with penicillins, but (E) Watchful waiting they are increasingly resistant to penicillins and even 5. Since susceptibility data are still pend- investigational and not used in the United States for ing, neither vancomycin nor the new drug linezolid is parenteral therapy? Watchful (D) Bacitracin waiting may not be effective because these patients (E) Linezolid may go on to develop complicated UTIs. The emergence of resistant pneumo- should be considered in resistant gram-positive in- coccal meningitis: implications for empiric therapy. Last year he underwent partial resection of With a chronic indwelling Foley catheter, he most his colon to treat ischemic bowel disease. His examination revealed temperature 104°F ued, and specific therapy with vancomycin should (40°C), heart rate 110 beats/minute, respiratory rate be initiated. He denied any cough or clear because findings on chest radiographs take headache, abdominal pain, or change in bowel or time to evolve, and film may remain negative at bladder function except that his urinary output has initial presentation. Pertinent points in Discontinue his central line and initiate treatment his examination included a supple neck and a cen- with IV nafcillin. Heart sounds were normal, without any his infection is not clear initially, and his presenta- murmurs, and he reported diffuse nonspecific vague tion, without any localizing features, gives rise to the abdominal discomfort without any localization or possibility of a line infection. His laboratory findings were 2 quently do not reveal any evidence of infection, but WBC 29,000/mm, hemoglobin 13 g/dL, platelets high-grade bacteremia (3 of 4 bottles) with gram- 300,000.

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Imantinib mesylate (Gleevec) is a rationally designed The drug produces remissions in 15% of patients inhibitor of the tumor-specific bcr-abl kinase generic alesse 0.18mg mastercard. The with renal cell carcinoma 0.18mg alesse free shipping, with median durations of re- Philadelphia chromosome generic alesse 0.18 mg fast delivery, present in nearly all patients mission of 18 to 24 months cheap 0.18 mg alesse fast delivery. The bcr-able kinase is therefore a verse effect is severe hypotension in as many as 85% of unique drug target in leukemic cells discount alesse 0.18mg free shipping, and imantinib se- patients, which may lead to myocardial infarctions, pul- lectively and potently inhibits this kinase. This hypotension is thought CML patients are achieved with high frequency and to be due to a capillary leak syndrome resulting from very low toxicity, and this compound may become a extravasation of plasma proteins and fluid into ex- front-line agent for treating this cancer. Patients drug resistance has already been observed in the clinic with significant cardiac, pulmonary, renal, hepatic, or as a result of mutations in the bcr-abl kinase, and this CNS conditions should not receive therapy with magic bullet does not appear to be curative for CML aldesleukin. Extension of the use of imantinib to other tu- and vomiting, diarrhea, stomatitis, anorexia, altered mor types with overexpression of c-kit kinase or mental status, fevers, and fatigue. CELLULAR GROWTH FACTORS Herceptin Filgrastim The introduction of herceptin (Trastuzumab) into clin- Filgrastim (Neupogen) is a human recombinant granu- ical practice for the treatment of breast cancer marks a locyte colony–stimulating factor (rG-CSF) produced major advance in the use of monoclonal antibody can- using recombinant DNA technology. Herceptin is a humanized antibody di- sor hematopoietic cells in the bone marrow by binding rected against the HER-2 antigen that is overexpressed to specific receptors that stimulate cellular proliferation on the tumor cell surface in approximately 25% of and differentiation into neutrophils. HER-2/neu/erbB2 overexpres- some neutrophil functions, including phagocytosis and sion marks an aggressive estrogen receptor–negative antibody-dependent killing. Therefore, a therapeutic agent Filgrastim is used to accelerate recovery of neu- selective for this target is particularly valuable. Herceptin use is associated with in- adverse reaction being mild to moderate bone pain sec- fusion- related hypotension, flushing and bronchocon- ondary to stimulation of bone marrow proliferation. Herceptin appears to sensitize patients to cardiotoxic- ity, an important concern in patients also receiving Sargramostim doxorubicin. Sargramostim (GM-CSF, Leukine, Prokine) is a human recombinant granulocyte and macrophage colony– Iressa stimulating factor that stimulates the production and po- tentiates the function of both granulocytes and macro- Iressa (ZD1839) is an orally active tyrosine kinase in- phages from hematopoietic progenitor cells. It is used to hibitor selective for the epidermal growth factor (EGF) accelerate bone marrow repopulation after high-dose receptor tyrosine kinase. Iressa is undergoing clinical chemotherapy, radiation therapy, and bone marrow trans- trials in the treatment of various solid tumors, including plantation. Adverse effects associated with sargramostim head and neck cancer, breast cancer and non-small cell use include bone pain (similar to that of filgrastim), fa- lung cancer. The major A summary of the principal clinical uses of most of side effects include diarrhea and skin rash. Bone mar- the drugs mentioned in this chapter can be found in row toxicity has not been a dose-limiting problem. The nitrogen mustard with the broadest spectrum account for the fact that differences in the spectrum of antitumor activity in its class is of antitumor activity and clinical indications differ (A) Ifosfamide for agents within the same class. Ifosfamide also has (B) Cyclophosphamide a broad spectrum of antitumor activity although it is (C) Mechlorethamine not as broad as that of cyclophosphamide. The effectiveness of chemotherapy in human cancer was the use of melphalan is limited because a substituted phenyl which agent in trophoblastic choriocarcinoma in ring in the molecule reduces its reactivity. The long-term complete remissions of tro- (A) Chlorambucil phoblastic choriocarcinoma in women was the first (B) Thiotepa demonstration of the curative potential of (C) Methotrexate chemotherapy in human cancer. Which class of drugs bind avidly to tubulin and mission in patients with primary brain tumor, the cause arrest of cells in metaphase? The mechanism of action of nitrogen mustards (C) Alkylating agents is to form covalent bonds with adjacent guanine (D) Antiestrogens residues and inhibit DNA replication and transcrip- (E) Antimetabolites tion. The patient man breast cancer cells that contain estrogen recep- inquires about her chances for remission. Interferon alfa-2b has been somewhat of a disap- known as interferons were capable of containing vi- pointment as an anticancer drug. However, it has ral infections led to the hope that they would have proved useful in the treatment of which of the fol- many beneficial results, including anticancer activity. Pharmacogenetic determinants of anti- tion, differences in the toxicity profile, duration of cancer drug activity and toxicity. Receptor tyrosine kinases as rational tar- Vinorelbine for treatment of advanced non-small cell gets for prostate cancer treatment: Platelet-derived lung cancer. Case Study Treatment of Leukemic Meningitis 15-year-old girl moves into your neighborhood ANSWER: Immediately arrange for an evaluation of Aand makes an appointment to see you. She consider administering methotrexate 12 mg in- tells you that she has been doing well, but recently trathecally every day for 4 days. With such a regi- she has had frequent severe headaches, and her men, subsequent evaluations of the CSF often indi- mother said she has stumbled a couple of times dur- cate no leukemic cells present.

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