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By X. Rocko. Thunderbird School of Global Management.

Sideroblastic anemias are sometimes seen in alcoholics cheap lamisil 250mg online, in patients undergoing antituberculin therapy with isoniazid and pyrazinamide purchase 250mg lamisil free shipping, and in certain inflammatory and malignant disorders discount 250 mg lamisil free shipping. Sideroblastic anemia is treated with pyridoxine (vitamin B6) administered orally (preferred route) or parenterally generic lamisil 250 mg fast delivery. The endogenous cobalamins in humans are methylcobalamin and 5-deoxyadenosylcobalamin. Transport and absorption (1) In the stomach, dietary vitamin B12 complexes with intrinsic factor, a peptide secreted by the parietal cells. The intrinsic factor–vitamin B12 complex is absorbed by active transport in the distal ileum. The appearance of large macrocytic (megaloblastic) red cells in the blood is characteristic of this deficiency. Vitamin B12 is not synthesized by eukaryotic cells and is normally obtained from microbial synthesis. Therapeutic uses (1) Vitamin B12 is used to treat pernicious anemia (inadequate secretion of intrinsic factor with subsequent reduction in vitamin B12 absorption). Hypokalemia and thrombocytosis can occur upon conversion of severe megaloblastic anemia to normal erythropoiesis with cyanocobalamin therapy. Most folate is absorbed in the proximal portions of the small intestine and is transported to tissues bound to a plasma-binding protein. Folic acid requires reduction by dihydrofolate reductase to the active metabolite methyltetrahydrofolate. The cofactors of folic acid provide single carbon groups for transfer to various acceptors and are essential for the biosynthesis of purines and the pyrimidine deoxythymidylate. Catabolism and excretion of vitamin B9 is more rapid than that of vitamin B12; hepatic reserves are sufficient for only 1–3 months. Folic acid is used to correct dietary insufficiency (commonly observed in the elderly), as a supplement during pregnancy to decrease the risk of neural tube defects, during lactation, and in cases of rapid cell turnover, such as hemolytic anemia. Leucovorin may be used to reverse the effects of the folate antagonists (see Chapter 12) methotrexate, pyrimethamine, and trimethoprim. Hydroxyurea has been shown effective in reducing painful episodes by about 50%; the necessity of blood transfusions was also shown to be reduced. Hydroxyurea increases the production of fetal hemoglobin, which makes red cells resistant to sickling and reduces the expression of ad- hesion molecules such as L-selectin. The actions of pentoxifylline include increased erythrocyte flexibility and decreased blood viscosity. Myeloid growth factors are glycoproteins produced by many cells including fibroblasts, endo- thelial cells, macrophages, and immune cells that act to stimulate proliferation and differen- tiation of one or more myeloid lineage. Sargramostim is a recombinant protein essentially identical to the native protein. Its princi- pal action is to stimulate myelopoiesis in granulocyte–macrophage pathways as well as megakaryocytic and erythroid progenitor cells. Clinical uses (1) Reduce the duration of neutropenia and incidence of infection in patients receiving myelosuppressive chemotherapy or bone marrow transplantation (2) Mobilize peripheral blood progenitor cells prior to collection (3) For bone marrow graft failure c. Filgrastim is a recombinant protein that stimulates bone marrow production of neutrophils without increasing the number of basophils, eosinophils, or monocytes. Pegfilgrastin is filgrastin with a polypropylene glycol molecule added to the N-terminus. Its clinical uses are similar to those of sargramostim: reduction in the duration of neutrope- nia in patients on anticancer regimens and for patients with chronic severe neutropenia. It is used clinically to prevent severe chemotherapy-induced thrombocytopenia and to reduce the need for platelet transfusions following myelosuppressive chemotherapy for nonmyeloid malignancies. Commercial heparin contains 8–15 repeats of d-glycosamine-l-iduronic acid and d-glucosamine-d-glucu- ronic acid. Commercial preparations are derived from bovine lung or porcine intes- tinal extracts. The clotting factor is inactivated, and intact heparin is released and recycled in a catalytic man- ner. Pharmacologic properties (1) Heparin must be given parenterally (by slow infusion or deep subcutaneous injec- tion); it is not injected intramuscularly because of the potential for hematoma formation. The principal advantage of the low- molecular-weight heparins is a greater pharmacokinetic predictability that allows once- or twice-a-day subcutaneous dosing without the need for monitoring.

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The ■ The H is that category membership for one 0 H0 is that liking/disliking is independent of gender cheap 250 mg lamisil mastercard. The H0 is that the frequencies in the categories of one variable are ______ of those of other variable order lamisil 250mg amex. Below are the frequencies for people who are f 15 f 15 o e e satisfied/dissatisfied with their job and who do/don’t work overtime 250 mg lamisil overnight delivery. The two-way 2 is used when counting the ______ with which participants fall into the ______ of two variables generic lamisil 250mg otc. Describing the Relationship in a Two-Way Chi Square A significant two-way chi square indicates a significant correlation between the vari- ables. To determine the size of this correlation, we have two new correlation coeffi- cients: We compute either the phi coefficient or the contingency coefficient. If you have performed a 2 3 2 chi square and it is significant, compute the phi coefficient. Think of phi as comparing your data to the ideal situations shown back in Table 15. The larger the coefficient, the closer the variables are to forming a pattern that is perfectly dependent. Remember that another way to describe a relationship is to square the correlation coefficient, computing the proportion of variance accounted for. If you didn’t take the square root in the above formula, you would have 2 (phi squared). This is analogous to r2 or 2, indicating how much more accurately we can predict scores by using the relationship. The other correlation coefficient is the contingency coefficient, symbolized by C. This is used to describe a significant two-way chi square that is not a 2 3 2 design (it’s a 2 3 3, a 3 3 3, and so on). For example, in our handedness study, N was 50, df was 1, and the significant 2 was 18. To graph a one-way design, label the Y axis with frequency and the X axis with the categories, and then plot the fo in each category. For a two-way design, place frequency on the Y axis and one of the nominal variables on the X axis. The only other type of nonparametric procedure is for when the dependent variable involves rank-ordered (ordinal) scores. First, sometimes you’ll directly measure participants using ranked scores (directly assigning participants a score of 1st, 2nd, and so on). Second, sometimes you’ll initially measure interval or ratio scores, but they violate the assumptions of parametric procedures by not being normally distributed or not having homogeneous variance. Then you transform these scores to ranks (the highest raw score is ranked 1, the next highest score is ranked 2, and so on). Either way, you then compute one of the following nonparametric inferen- tial statistics to determine whether there are significant differences between the condi- tions of your independent variable. The Logic of Nonparametric Procedures for Ranked Data Instead of computing the mean of each condition in the experiment, with nonparamet- ric procedures we summarize the individual ranks in a condition by computing the sum of ranks. In each procedure, we compare the observed sum of ranks to an expected sum of ranks. To see the logic of this, say we have the following scores: Condition 1 Condition 2 1 4 5 8 ©R 5 18 ©R 5 18 Here, the conditions do not differ, with each containing both high and low ranks. When the ranks are distributed equally between two groups, the sums of ranks are also equal (here, ©R is 18 in each). Our H0 is always that the populations are equal, so with ranked data, H0 is that the sums of ranks for each population are equal. Thus, the ©R 5 18 observed above is exactly what we would expect if H0 is true, so such an outcome supports H0. But say the data had turned out differently, as here: Condition 1 Condition 2 1 2 3 4 ©R 5 10 ©R 5 26 Condition 1 contains all of the low ranks, and Condition 2 contains all of the high ranks. Because these samples are different, they may represent two different popula- tions. With ranked data Ha says that one population contains predominantly low ranks and the other contains predominantly high ranks.

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Third-generation cephalosporins are sensitive to another class of b-lactamase order lamisil 250 mg on-line, the cephalosporinases (genes are generally located on chromosomes as opposed to plasmids) generic lamisil 250mg on line. They are used in treatment of streptococcal infections as well as infections Chapter 11 Drugs Used in Treatment of Infectious Diseases 257 caused by E lamisil 250 mg generic. Ceftriaxone is used for sexually trans- mitted infections caused by gonorrhea purchase 250 mg lamisil free shipping, as well as in empiric therapy for commu- nity-acquired meningitis. Adverse effects and drug interactions (1) Cephalosporins most commonly cause hypersensitivity reactions (2%–5%); 5%–10% of penicillin-sensitive persons are also hypersensitive to cephalosporins. Aztreonam (Azactam) (1) Aztreonam is a naturally occurring monobactam lacking the thiazolidine ring that is highly resistant to b-lactamases. Vancomycin (Vancocin, Vancoled) (1) Vancomycin is a tricyclic glycopeptide that binds to the terminal end of growing pepti- doglycan to prevent further elongation and cross-linking; this results in decreased cell membrane activity and increased cell lysis. Rapid infusion may cause anaphylactoid reactions and ‘‘red neck’’ syndrome (flushing caused by release of histamine). Bacitracin (1) Bacitracin inhibits dephosphorylation and reuse of the phospholipid required for accep- tance of N-acetylmuramic acid pentapeptide, the building block of the peptidoglycan complex. Cycloserine (Seromycin) (1) Cycloserine is an amino acid analogue that inhibits alanine racemase and the incorpo- ration of alanine into the peptidoglycan pentapeptide. Daptomycin (Cubicin) (1) Daptomycin is a bactericidal agent that binds to and depolarizes the cell membrane resulting in loss of membrane potential and rapid cell death. Fosfomycin (Monural) (1) Fosfomycin inhibits the enzyme enolpyruvate transferase and therby interferes down- stream with the formation of bacterial cell wall specific N-acetylmuramic acid. Structure and mechanism of action (1) Aminoglycosides are amino sugars in glycosidic linkage to a hexoseaminocyclitol. Transport across the inner membrane requires active uptake that is dependent on electron transport (gram- negative aerobes only), the so-called energy dependent phase I transport. This ‘‘freezes’’ the initiation complex and leads to a buildup of monosomes; it also causes translation errors. Selected drugs and their therapeutic uses (1) The role for aminoglycosides has decreased substantially due to their narrow spectrum of activity and toxicity, and the availability of other agents. Adverse effects (1) Aminoglycosides have a narrow therapeutic index; it may be necessary to monitor se- rum concentrations and individualize the dose. Tetracyclines (tetracycline [Sumycin], oxytetracycline [Terramycin], demeclocycline [Declo- mycin], doxycycline [Vibramycin], minocycline [Minocin], tigecycline [Tygacil]) a. Structure and mechanism of action (1) Tetracyclines are derivatives of naphthacene carboxamide. Resistance to one tetracycline confers resistance to some, but not all, congeners. Doxycycline is excreted almost entirely via bile into the feces and hence is the safest tetracycline to administer to individuals with impaired renal function. Spectrum and therapeutic uses (1) Tetracyclines are active against both gram-negative and gram-positive organisms, but the use of these agents is declining because of increased resistance and the develop- ment of safer drugs. They are also used in combination regimens for elimination of infections caused by Helicobacter pylori. Chapter 11 Drugs Used in Treatment of Infectious Diseases 261 (4) Tigecycline, a derivative of minocycline, has a broad spectrum of activity and has activ- ity against many tetracycline-resistant organisms. Children age 6 months to 5 years receiving tetracycline therapy can develop tooth discolorations. Pharmacologic properties (1) Chloramphenicol is absorbed rapidly and distributed throughout body fluids. Therapeutic uses (1) Chloramphenicol is a broad-spectrum antibiotic used to treat most gram-negative organisms, many anaerobes, clostridia, chlamydia, mycoplasma, and rickettsia. How- ever, because of the potential for severe and sometimes fatal adverse effects, use of this agent is limited to the treatment of infections that cannot be treated with other drugs; these infections include typhoid fever (although resistance is increasingly a problem), meningitis due to H. Adverse effects (1) Chloramphenicol causes dose-related bone marrow suppression, resulting in pancyto- penia that may lead to irreversible aplastic anemia. Also, chloramphenicol causes hemolytic anemia in patients with low levels of glucose 6-phosphate dehydrogenase. This syn- drome results from the inadequacy of both cytochrome P-450 and glucuronic acid con- jugation systems to detoxify the drug. Elevated plasma chloramphenicol levels cause a shocklike syndrome and a reduction in peripheral circulation; the incidence of fatalities is high (40%).

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