By C. Givess. Regis University. 2018.

Despite the fact that sulfonamides have not long been used for the treatment of streptococcal infections cheap 15mg flexeril amex, sulfonamide resistance is common among present isolates of S purchase flexeril 15mg without a prescription. Thisisafurther interesting illustration of the nonreversibility of resistance in the absence of the selecting effect of the drug effective flexeril 15mg. The drug-resistant phenotypes do not seem to be at any disadvantage in competi- tion with their drug-susceptible relatives order 15 mg flexeril with amex. Detailed studies have shown that the folP in susceptible and highly resistant isolates differed by 13. Resistance to Sulfonamides in Campylobacter jejuni Sulfonamide resistance is commonly found in clinical isolates of C. It is mediated by chromosomal point mutations, but in a rather complicated pattern. The sulfonamide target gene folP was found to be very large compared to that of other bacteria and also quite similar to the corresponding gene of the peptic ulcer bacterium, Helicobacter pylori. The ensuing amino acid changes in the sulfonamide target enzyme, dihydropteroate synthase, mediated a distinct effect on the sulfonamide sensitivity of the enzyme. Resistance to Sulfonamides in Streptococcus pneumoniae In this pathogen, sulfonamide resistance is mediated by a dif- ferent type of chromosomal change. Originally, a spontaneous laboratory mutant of this bacterium was found to contain a six- nucleotide repeat in the sulfonamide target gene, folP, which in turn mediated an amino acid repeat of isoleucine and glu- tamic acid in the dihydropteroate synthase expressed from the gene. This could significantly alter the tertiary structure of the enzyme protein, which was later borne out by crystallographic studies. Finally, the ileu–glu repeat studied originally was also observed in a clinical isolate of S. Transformation experiments demonstrated that the duplication was sufficient to confer the sulfonamide resistance observed. Enzyme kinetic studies on the dihydropteroate syn- thase after removal of the repeat by site-directed mutagenesis, showed the Ki for sulfonamide to drop from 18 μ to0. The enzyme characteristics for the artificially mutated strain were identical to those of susceptible strains, demonstrat- ing that the duplication is sufficient for resistance. The fitness cost of resistance seems to be low, as reflected in the small increase in the Km value. The small but discernible increase indicates the absence of compensatory mutations. Still it could be enough for counterselecting resistant strains in the absence of the drug and might lead to an argument regarding the much-debated problem of drug resistance reversibility. Resistance to Sulfonamides in Pneumocystis jiroveci (carinii) This pathogenic organism is a fungus causing life-threatening pneumonia in immunosuppressed patients. Co-trimoxazole, the combination of sulfonamide (sulfamethoxazole) and trimethoprim, has been the drug of choice for the prophylaxis and treatment of this disease. The antipneumocystis effect of this drug combination is due primarily to the sulfon- amide component, since studies on the trimethoprim tar- get, dihydrofolate reductase, of this organism have shown trimethoprim to be a very poor inhibitor of this enzyme in it. There is thus the important question of whether the emergence of resistance mutations is the result of trans- mission between patients or arise and are selected within an individual patient under the pressure of sulfonamide or dap- sone treatment. Nucleotide sequencing could discern four different mutational patterns and identify as many as 14 amino acid changes in the development of resistance. At present, rifampicin (see Chapter 9) is the drug of choice for the treatment of leprosy. Plasmid-Borne Resistance to Sulfonamides Sulfonamide insusceptibility was one of the first antibiotic resis- tance traits found to be transferable (see Chapter 10). Since sulfonamide is a synthetic antibacterial agent, resistance by plasmid-mediated drug-degrading or drug-modifying enzymes was not to be expected. Instead, nonallelic, drug-resistant vari- eties of the chromosomal dihydropteroate synthase drug target enzyme were found to mediate high levels of sulfonamide resis- tance (Fig. Three types of plasmid-borne genes expressing such varieties are known: sul1, sul2, and sul3. These three genes differ among themselves (40% similarity at the amino acid level). The occurrence of these three plasmid-borne genes is the most common form of sulfonamide resistance among clinically isolated enterobacteria. Remarkably, only sul1andsul2 or both were long found in isolates of sulfonamide-resistant enterobacteria from various parts of the world. This is in contrast to trimethoprim resistance, described later in the chapter, at which more than 20 different plasmid- borne resistance genes have been found and characterized. The reason for this could be limited possibilities of configuration variation in the catalytic center of dihydropteroate synthase. The sulfonamide-resistant enzyme must be able to distinguish between its normal substrate p-aminobenzoic acid and the struc- turally very similar sulfonamide (see 3-1 and 3-2). The folP gene is marked on the large circular chromosome representing the chromosomal sulfonamide- sensitive dihydropteroate synthase. Plasmid-borne genes for sulfonamide resistance, sul, express dihydropteroate synthases that are insusceptible to inhibition by sulfonamides. Minimum inhibitory concentrations for sul- fonamides are given for the different plasmid-mediated dihydropteroate synthases. In particular, sul2showsasharp acuity in its ability to distinguish between normal substrate and sulfonamide. In a study from the early 1990s, a large number of sulfonamide-resistant clinical isolates of enterobacteria from different parts of the world were shown to harbor either sul1 or sul2 or both as plasmid-borne genes mediating sulfonamide resistance. In addition to being borne on plasmids, the three sul genes have further genetic mechanisms available for their rapid spread. Regarding sul1, for example, it is almost always located in an integron of the Tn21 type (Chapter 10) together with other resistance genes. The sul3 observed later is mediated by a composite transposon with flanks of known insertion sequences (Chapter 10). As mentioned, the two resistance genes sul1ad sul2 occurred in about the same frequencies among clinical isolates of sulfonamide-resistant enterobacteria. Furthermore, it was seen that the relative frequency of sul2 had increased and that it was now to be found mostly on large transferable plasmids (Chapter 10) together with many other resistance genes. The explanation of this unexpected phenomenon could be that sul2 had become associated with other resistance genes and then been selected via the use of other antibacterial agents. This is an important interpretation, since it bears on the spread of resistance by linkage between different resistance genes. Another, location of sul2, found relatively recently, is on the chromosome of Haemophilus influenzae. Methotrexate and aminopterin cannot be used as antibacterial agents, however, since they are not selective for bacteria. At the methylation reaction the tetrahydrofolate is oxidized and its rereduction by dihydrofolate reductase is inhibited by trimethoprim. The selective action of trimethoprim on bacterial dihydrofolate reductase, leaving mammalian enzymes untouched, allows the clinical use of trimethoprim as an antibac- terial drug inhibiting bacterial dihydrofolate reductases at very low concentrations.

In laboratory practice generic 15mg flexeril visa, most analytes are reported Clinical chemistry/Calculate/Significant figures/2 with two significant figures 15mg flexeril with amex. B The Henderson–Hasselbalch equation can be used to determine the pH of a buffer containing a weak acid and a salt of the acid flexeril 15mg line. A glycerol kinase method for triglyceride calls for a result for the patient’s serum before applying the serum blank in which normal saline is substituted ratiometric formula to calculate concentration discount 15 mg flexeril free shipping. A The acceptable range for quality control results is deviations usually set at the 95% confidence interval. This is Chemistry/Evaluate laboratory data to assess defined as the range between –1. Chemistry/Evaluate laboratory data to assess validity/ If a control is assayed 100 times, 68 out of 100 results Accuracy of procedures/Quality control/1 would fall within +1 s and –1 s of the mean. Two consecutive controls greater than 2 s above 100 results fall within ±3 s of the mean. A Rejecting a run when three consecutive controls fall the mean between 1 and 2 s or when a trend of four increasing C. Four controls steadily increasing in value but less or decreasing control results occurs would lead to than ±1 s from the mean frequent rejection of valid analytical runs. One control above +1 s and the other below –1 s control limits are four consecutive controls above or from the mean below 1 s (41s) to detect a significant shift, and a cusum result exceeding the ±2. When controls deviate in opposite directions, the difference should exceed 4s before the run is rejected. One of two controls within a run is above +2s Answers to Questions 20–24 and the other control is below –2s from the mean. The R4S rule is applied only to controls within a run Chemistry/Evaluate laboratory data to recognize (Level 1 – Level 2), never across runs or days. Two consecutive controls are both beyond –2s Ninety-five percent of the results fall within ±2s of the from the mean. B The R4s rule is applied to two control levels within Accuracy of procedures/Quality control/2 the same run. The R4s rule detects random error standard deviation from the mean (error due to poor precision). Two consecutive controls in the same run are control results either increase or decrease in the same each greater than ±4s from the mean direction; however, this is not cause for rejection until D. Trends are systematic errors consecutive controls (affecting accuracy) linked to an unstable reagent, calibrator, or instrument condition. For example, loss Chemistry/Evaluate laboratory data to assess of volatile acid from a reagent causes a steady pH validity/Accuracy of procedures/Quality control/2 increase, preventing separation of analyte from 23. Recalibrate, then repeat controls followed by can be evaluated by repeating abnormal patient selected patient samples if quality control is samples. If the average difference between results acceptable before and after recalibration is > 2s, then all samples B. Prepare fresh standards and recalibrate Chemistry/Evaluate laboratory data to take corrective action according to predetermined criteria/Quality control/3 228 Chapter 5 | Clinical Chemistry 25. B Data between ±2 and ±3s must be included in current target limits calculations of the next month’s acceptable range. Using control results from all shifts on which the “out-of-control” situations a frequent occurrence. A Although calcium has the lowest s, it represents the Chemistry/Apply principles of laboratory assay with poorest precision. Relative precision operations/Quality control/2 between different analytes or different levels of the same analyte must be evaluated by the coefficient 26. For example, when comparing the precision of the level 1 control to the level 2 control, A. The method mean for comparison of precision and accuracy among level 1 is at the center of the y axis and mean for level laboratories? Which plot will give the earliest indication of a Answers to Questions 30–31 shift or trend? Results are out problems/Quality control/2 of control when the slope exceeds 45° or a decision 31. Te matrix is similar to the specimens being dynamic linear range of the assay, and can be used tested for multiple analytes. Te concentration of analytes reflects the clinical is determined from replicate assays by the user‘s range method, not the “true” concentration of the analyte. Analyte concentration must be independent of Out-of-control results are linked to analytic the method of assay performance rather than to the inherent accuracy Chemistry/Apply principles of basic laboratory of the method. Kurtosis temperature, evaporation, light exposure, and Chemistry/Evaluate laboratory data to recognize bacterial contamination. Day 9 plotting control data is that trends can be identified Chemistry/Evaluate laboratory data to recognize before results are out of control and patient data problems/Quality control/3 must be rejected. In this case, corrective steps should have been implemented by day 7 to avoid the delay 34. Referring to the Levy–Jennings chart, what and expense associated with having to repeat the analytical error is present during the second analysis of patient samples. Kurtosis in the assay conditions that affect the accuracy of all results, such as a change in the concentration of the Chemistry/Evaluate laboratory data to recognize calibrator; change in reagent; a new lot of reagent problems/Quality control/3 that differs in composition; or improper temperature 35. What is the first day in the second half of the setting, wavelength, or sample volume. Day 19 This means that four consecutive controls are greater Chemistry/Evaluate laboratory data to recognize than ±1s from the mean. D An R4s error is defined as the algebraic difference +2s between two controls within the same run. C The minimum requirement for frequency of quality control for a general chemistry analyte (based upon +2s the Clinical Laboratory Improvement Act, 1988) is two levels of control assayed every 24 hours. Two controls every 8 hours are required for blood gases, automated hematology, and 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 point-of-care glucose testing to comply with College of American Pathology requirements. A Student’s t test is the ratio of mean difference to the standard error of the mean difference 37. Tree levels assayed within 24 hours variables and should be high in any method Chemistry/Apply principles of basic laboratory comparison. Which of the following statistical tests is used to compare the means of two methods? Linear regression analysis Chemistry/Evaluate laboratory data to assess the validity/Accuracy of procedures/Statistics/2 232 Chapter 5 | Clinical Chemistry 39. Two freezing point osmometers are compared by Answers to Questions 39–41 running 40 paired patient samples one time on each instrument, and the following results are 39. A The F test determines whether there is a statistically obtained: significant difference in the variance of the two sampling distributions. Assuming the samples are Standard collected and stored in the same way and the analysis Instrument Mean Deviation is done by a technologist who is familiar with the Osmometer A 280 mOsm/kg 3. The F test is calculated by dividing the variance (s )2 If the critical value for F = 2. Precision cannot be evaluated statistically when the two instruments) is accepted.

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Not only is the task of preventing calamities impossible buy cheap flexeril 15 mg online, you can easily ruin most of your present moments if you try order 15mg flexeril mastercard. If you check your car’s engine before leaving for work each day order flexeril 15 mg without prescription, if you scrimp and save every possible penny for retirement buy generic flexeril 15mg line, if you never eat ice cream because of the fat content, if you overprotect your children because you worry that they’ll get into trouble, if you wash your hands every time you touch a doorknob, if you never take a risk, then what will your life be like? Because bad things don’t happen to them on most of those worry days, they feel like their worrying has paid off. But worry by itself has never in the history of humans prevented anything from happen- ing. Find out how to embrace uncertainty, which can make life both interesting and exciting. When you find yourself feeling anxious, ask yourself whether your worry is an attempt to control the unpredictable. They scan the newspaper for financial information that may possibly help them know when to sell at just the right moment. Yet, as the past few years have shown, there are no guarantees in the stock market. Of course, take reasonable precau- tions regarding your health, family, finances, and well-being, but when worry about the future invades the present enjoyment of your life, it has gone too far. When you become anxious, try to be patient and kind with yourself and say to yourself, Chapter 13: Mindful Acceptance 207 ✓ Okay, I’m feeling anxious. In the example of Jeanine that follows, Jeanine’s contrasting reactions, first with impatience and then with patience, provide an illustration of how you, too, can turn your impatience into patience. Frequently, she arrives about five minutes early, but once a month or so, traffic backs up, and she’s a few minutes late. The impatient Jeanine: Traffic is at a standstill, and anxiety churns in Jeanine’s stomach and builds. Sweating and clutching the steering wheel, she begins tracking the ways that she can change lanes and get through a bit faster. She visualizes her boss noticing her tardiness and the others at her office looking up at her. The patient Jeanine: Traffic is at a standstill, and anxiety churns in Jeanine’s stomach. She notices and accepts the anxiety in her body, thinking, “I may be late, but most every morning, I am on time or early. Like building muscles by lifting weights, you can build the patience muscles in your mind a little at a time. Bookstores and libraries display hun- dreds of books about how to pump up your self-esteem. In fact, overly positive self- esteem causes more anxiety, as well as a host of other ills. Similarly, most positive human characteristics and qualities turn into negatives when they reach extreme levels. But excessive courage can make a person reckless, excessive generosity can make a person an easy mark for the dishonest, excessive focus on work can leave insufficient room for pleasure, and exces- sive trust can turn someone into a dupe. Perhaps our upcoming description of self-esteem as similar to a balloon may help you understand the shocking dangers of too much investment in ego and self-esteem. Inflating and deflating the self-esteem balloon We think of self-esteem like a balloon. If your self-esteem is quite low, you probably spend time judging yourself harshly and negatively. Your energy probably suffers, and you may feel quite anxious about your perceived deficiencies. Too much ego or self-esteem, however, is like a balloon that’s tightly stretched and so full of air that it’s about to explode. If your self-esteem balloon is too full of itself, those threats can appear especially ominous. On the other hand, a balloon with just the right amount of air is pretty tough to break. The balloon with the right amount of air doesn’t worry so much about crashing or bursting. In a sense, both the deflated balloon and the one close to the bursting point worry plenty about their own state: their condition, worth, and vulnerability. The key to having just the right amount of ego — air in the balloon — is to have less concern with yourself (along with more concern for others) and less worry about how you stack up against others. When you can accept both your positive and negative qualities without being overly concerned for either, you’ll have the right amount of air in your ego balloon, but that isn’t always so easy to do. It takes a solid focus on learning, striving, and working hard — though not to excess. Chapter 13: Mindful Acceptance 209 The seductive power of positive thinking In the 1950s, self-help gurus began a movement Hardly. Today, school achievement lags sig- by encouraging everyone to pump up their self- nificantly behind where it was in 1960. School violence is cles were written on the topic of self-esteem in much higher than 50 years ago, and the rates professional journals; however, in the past ten of depression and anxiety among today’s youth years alone, more than 8,000 such articles have are higher than ever. An incredible number of recent research tion, literally thousands of self-help books have studies show a strong link between the over- promoted the unquestioned value of nurturing abundant focus on the self and violence, poor self-esteem. The self-esteem movement now school achievement, and emotional problems permeates parenting magazines, school cur- of all sorts. It seduced a gen- to be bad for you, but studies suggest that an eration of parents, teachers, and mental-health overly inflated self-esteem is even worse. The workers into believing that the best thing that answer appears to lie in having less focus on they could do for kids was to pump up their self- the almighty self. So has more than a half-century of promot- ing self-esteem (also known as ego) paid off? Appreciating your imperfections All too often, anxious people feel that they must be perfect in order for others to like and accept them. Kelly always wears exactly the right fashionable clothes, the right colors, and her accesso- ries always match. She always knows just what to say, never stumbling over a single word or swearing. Does she seem like someone you’d like to hang out at a pool with on a summer weekend? Picture that person in your mind and recall some of the good times that you’ve spent together. Think about how much you appreciate this person and how your life has been enriched by the relationship.

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