By U. Shakyor. Syracuse University.

Three types of switch mechanisms commonly occur: replication errors that turn expression on or off order fluticasone pills in toronto, gene conversion into fixed expression sites generic fluticasone 500 mcg without a prescription, and invertible promoters that change the direction of transcription discount 100 mcg fluticasone visa. REGULATORY SWITCHES BY REPLICATION ERRORS OF SHORT REPEATS Short, repeated nucleotide sequences often lead to high error rates during replication. Repeats have recurring units typically with 1–5 bases per unit. Short, repeated DNA sequences probably lead to replication errors by slipped-strand mispairing (Meyer 1987; Levinson and Gutman 62 CHAPTER 5 1987; Charlesworth et al. Errors apparently arise when a DNA polymerase either skips forward a repeat unit, causing a deletion of one unit, or slips back one unit, producing a one-unit insertion. Gene expression can be turned on or off by insertions or deletions. Inserted or deletedrepeats within the coding sequence cause frameshift mutations that prevent translation and production of a full protein. For example, the eleven opacity genes of Neisseria meningitidis influence binding to host cells and tissue tropism. These genes each have between eight and twenty-eight CTCTT repeats, which can disrupt or restore the proper translational frame as the number of repeats changes (Stern et al. The limited repertoire of eleven genes and the crude on-off switching suggest that variable expression hasmore to do with altering cell tropism than with escape from host immunity (Fussenegger 1997). On-off switches can also be created by short repeats in transcriptional control regions. Bordetella pertussis controls expression of two distinct fimbriae by transcriptional switching (Willems et al. Fimbriae are bacterial surface fibers that attach to host tissues. Particular cells pro- duce both, only one, or neither of thefimbrialtypes. Sequencesofabout 15 C nucleotides in the transcriptional promoters of each of the two genes influence expression. The actual length of the poly-C sequence varies, probably by slipped-strand mispairing during replication. The length affects transcription of the attached gene. Thus, by the stochas- tic process of replication errors, the individual loci are turned on and off. Again, this sort of switching may have more to do with tissue tropism than with escape from immune recognition. GENE CONVERSION Some pathogens store many variant genes for a surface antigen, but express only one of the copies at any time. For example, there may be a single active expression site at which transcription occurs. Occa- sionally, one of the variant loci copies itself to the expression site by gene conversion—a type of intragenomic recombination that converts the target without altering the donor sequence. The genome preserves the archival library without change, but alters the expressed allele. The spirochete Borrelia hermsii has approximately thirty alternative loci that encode an abundant surface lipoprotein (Barbour 1993). There GENERATIVE MECHANISMS 63 is a single active expression site when the spirochete is in mammalian hosts (Barbour et al. The expression site is changed by gene con- version to one of the variant archival copies at a rate of about 10−4–10−3 percell division (Stoenner et al. A small number of antigenic variants dominate the initial parasitemia of this blood-borne pathogen. The host then clears these initial variants with antibodies. Some of the bacteria from this first parasitemia will have changed antigenic type. Those switches provide new variants that cause a second parasitemia, which is eventually recognized by the host and cleared. The cycle repeats several times, causing relapsing fever. The protozoan Trypanosoma brucei has hundreds of alternative loci that encode the dominant surface glycoprotein (Barry 1997; Pays and Nolan 1998). Typically, each cell expresses only one of the alternative loci. Switches in expression occur at a rate of up to 10−2 per cell divi- sion (Turner 1997). The switch mechanism is similar to that in Borrelia hermsii—gene conversion of archival copies into a transcriptionally ac- tive expression site. Thus, this parasite can also change expression by switchingbetween transcription sites. It is not fully understood how different transcription sites are regulated. A promoter region between the two genes controls transcription. Thepromoter triggers transcrip- tion in only one direction, thus expressing only one of the two variants. Occasionally, the promoter flips orientation, activating the alternative gene. The ends of the promoter have inverted repeats, which play a role in the recombination event that mediates the sequence inversion. Salmonella uses a similar mechanism to control flagellum expression (Silverman et al. Moraxella species use a different method to vary pilin expression (Marrs et al. The variable part of the pilin gene has alternate cassettes stored in adjacent locations. Inverted repeats flank the pair of alternate cassettes, causing the whole complex occasionally to flip orientation. The gene starts with an initial constant 64 CHAPTER 5 region and continuesintoone of the cassettes within the invertible com- plex. When the complex flips, the alternate variable cassette completes the gene. Several bacteriophage use a similar inversion system to switch genes encoding their tail fibers, which determine host range (Kamp et al. Fussenegger (1997) reviews other invertible-sequence mechanisms. These low-diversity switches provideonlyalimitedadvantage against immunity because, even if the switch rates were low, an infection would soon contain all variants at appreciable abundance. Thus, these switch mechanisms may serve mainly to generate alternative attachment vari- ants.

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Active-control trial: A trial comparing a drug in a particular class or group with a drug outside of that class or group 250mcg fluticasone amex. Allocation concealment: The process by which the person determining randomization is blinded to a study participant’s group allocation buy fluticasone 500 mcg visa. Applicability: see External Validity Before-after study: A type nonrandomized study where data are collected before and after patients receive an intervention discount fluticasone 500mcg otc. Before-after studies can have a single arm or can include a control group. Bias: A systematic error or deviation in results or inferences from the truth. Several types of bias can appear in published trials, including selection bias, performance bias, detection bias, and reporting bias. Bioequivalence: Drug products that contain the same compound in the same amount that meet current official standards, that, when administered to the same person in the same dosage regimen result in equivalent concentrations of drug in blood and tissue. Black box warning: A type of warning that appears on the package insert for prescription drugs that may cause serious adverse effects. It is so named for the black border that usually surrounds the text of the warning. A black box warning means that medical studies indicate that the drug carries a significant risk of serious or even life-threatening adverse effects. Food and Drug Administration (FDA) can require a pharmaceutical company to place a black box warning on the labeling of a prescription drug, or in literature describing it. Blinding: A way of making sure that the people involved in a research study — participants, clinicians, or researchers —do not know which participants are assigned to each study group. Blinding usually is used in research studies that compare two or more types of treatment for an Proton pump inhibitors Page 93 of 121 Final Report Update 5 Drug Effectiveness Review Project illness. Case series: A study reporting observations on a series of patients receiving the same intervention with no control group. Case study: A study reporting observations on a single patient. Case-control study: A study that compares people with a specific disease or outcome of interest (cases) to people from the same population without that disease or outcome (controls). Clinical diversity: Differences between studies in key characteristics of the participants, interventions or outcome measures. Clinically significant: A result that is large enough to affect a patient’s disease state in a manner that is noticeable to the patient and/or a caregiver. Cohort study: An observational study in which a defined group of people (the cohort) is followed over time and compared with a group of people who were exposed or not exposed to a particular intervention or other factor of interest. A prospective cohort study assembles participants and follows them into the future. A retrospective cohort study identifies subjects from past records and follows them from the time of those records to the present. Combination Therapy: The use of two or more therapies and especially drugs to treat a disease or condition. Confidence interval: The range of values calculated from the data such that there is a level of confidence, or certainty, that it contains the true value. The 95% confidence interval is generally used in Drug Effectiveness Review Project reports. If the report was hypothetically repeated on a collection of 100 random samples of studies, the resulting 100 95% confidence intervals would include the true population value 95% of the time. Confounder: A factor that is associated with both an intervention and an outcome of interest. Controlled clinical trial: A clinical trial that includes a control group but no or inadequate methods of randomization. Control group: In a research study, the group of people who do not receive the treatment being tested. The control group might receive a placebo, a different treatment for the disease, or no treatment at all. Convenience sample: A group of individuals being studied because they are conveniently accessible in some way. Convenience samples may or may not be representative of a population that would normally be receiving an intervention. Crossover trial: A type of clinical trial comparing two or more interventions in which the participants, upon completion of the course of one treatment, are switched to another. Direct analysis: The practice of using data from head-to-head trials to draw conclusions about the comparative effectiveness of drugs within a class or group. Results of direct analysis are the preferred source of data in Drug Effectiveness Review Project reports. Dosage form: The physical form of a dose of medication, such as a capsule, injection, or liquid. The route of administration is dependent on the dosage form of a given drug. Various dosage Proton pump inhibitors Page 94 of 121 Final Report Update 5 Drug Effectiveness Review Project forms may exist for the same compound, since different medical conditions may warrant different routes of administration. Dose-response relationship: The relationship between the quantity of treatment given and its effect on outcome. In meta-analysis, dose-response relationships can be investigated using meta- regression. Double-blind: The process of preventing those involved in a trial from knowing to which comparison group a particular participant belongs. While double-blind is a frequently used term in trials, its meaning can vary to include blinding of patients, caregivers, investigators, or other study staff. Double-dummy: The use of two placebos in a trial that match the active interventions when they vary in appearance or method of administrations (for example, when an oral agent is compared with an injectable agent). Effectiveness: The extent to which a specific intervention used under ordinary circumstances does what it is intended to do. Effectiveness outcomes: Outcomes that are generally important to patients and caregivers, such as quality of life, responder rates, number and length of hospitalizations, and ability to work. Data on effectiveness outcomes usually comes from longer-term studies of a “real-world” population. Effect size/estimate of effect: The amount of change in a condition or symptom because of a treatment (compared to not receiving the treatment). It is commonly expressed as a risk ratio (relative risk), odds ratio, or difference in risk. Efficacy: The extent to which an intervention produces a beneficial result under ideal conditions in a selected and controlled population. Equivalence level: The amount which an outcome from two treatments can differ but still be considered equivalent, as in an equivalence trial, or the amount which an outcome from treatment A can be worse than that of treatment B but still be considered noninferior, as in a noninferiority trial. Equivalence trial: A trial designed to determine whether the response to two or more treatments differs by an amount that is clinically unimportant.

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Type I error: A conclusion that there is evidence that a treatment works discount generic fluticasone canada, when it actually does not work (false-positive) buy discount fluticasone online. Type II error: A conclusion that there is no evidence that a treatment works purchase 250 mcg fluticasone amex, when it actually does work (false-negative). Validity: The degree to which a result (of a measurement or study) is likely to be true and free of bias (systematic errors). Variable: A measureable attribute that varies over time or between individuals. Variables can be • Discrete: taking values from a finite set of possible values (e. Washout period: [In a cross-over trial] The stage after the first treatment is withdrawn, but before the second treatment is started. The washout period aims to allow time for any active effects of the first treatment to wear off before the new one gets started. Statins Page 114 of 128 Final Report Update 5 Drug Effectiveness Review Project Appendix B. Search strategy Searches on Medline, Medline-In Process amd Cochrane Central Register of Controlled Trials were repeated in May-June of 2009 and gave additional citations that were reviewed and incorporated when they met eligibility criteria. Database: Ovid MEDLINE(R) <1996 to January Week 4 2009> Search Strategy: -------------------------------------------------------------------------------- 1 lovastatin. Methods used to assess quality of studies Study quality was objectively assessed using predetermined criteria for internal validity, which were based on a combination of the US Preventive Services Task Force and the National Health 1, 2 Service Centre for Reviews and Dissemination criteria. All included studies, regardless of design, were assessed for quality and assigned a rating of “good,” “fair,” or “poor”. Studies that have a fatal flaw were rated poor quality. A fatal flaw was the failure to meet combinations of criteria that may be related to indicate the presence of bias. An example would be inadequate procedures for allocation concealment combined with important differences between groups in prognostic factors at baseline and following randomization. Studies that meet all criteria were rated good quality; the remainder were rated fair quality. As the fair-quality category was broad, studies with this rating varied in their strengths and weaknesses: The results of some fair-quality studies were likely to be valid, while others were only possibly valid. A poor-quality trial was not valid; the results were at least as likely to reflect flaws in the study design as a true difference between the compared drugs. Criteria for assessing applicability (external validity) are also listed, although they were not used to determine study quality. Does the systematic review report a clear review question and clearly state inclusion and exclusion criteria for primary studies? A good-quality review focuses on a well-defined question or set of questions, which ideally refer to the inclusion/exclusion criteria by which decisions are made about whether to include or exclude primary studies. These criteria would relate to the four components of study design, indications (patient populations), interventions (drugs), and outcomes of interest. A good-quality review also includes details about the process of decision-making, that is, how many reviewers were involved, whether the studies were examined independently, and how disagreements between reviewers were resolved. Is there evidence of a substantial effort to find all relevant research? If details of electronic database searches and other identification strategies are given, the answer to this question usually is yes. Ideally, search terms, date restrictions, and language restrictions are presented. In addition, descriptions of hand-searches, attempts to identify unpublished material, and any contact with authors, industry, or research institutes should be provided. The appropriateness of the database(s) searched by the authors should also be considered. For example, if only MEDLINE is searched for a systematic review about health education, then it is unlikely that all relevant studies will be located. Is the validity of included studies adequately assessed? If the review systematically assesses the quality of primary studies, it should include an explanation of the basis for determining quality (for example, method of randomization, whether outcome assessment was blinded, whether analysis was on an intention-to-treat basis) and the process by which assessment is carried out (that is, how many reviewers are involved, whether the assessment is independent, and how discrepancies between reviewers are resolved). Authors Statins Page 119 of 128 Final Report Update 5 Drug Effectiveness Review Project may have used either a published checklist or scale or one that they designed specifically for their review. Is sufficient detail of the individual studies presented? It is usually considered sufficient if a paper includes a table giving information on the design and results of individual studies or includes a narrative description of the studies. If relevant, the tables or text should include information on study design, sample size for each study group, patient characteristics, interventions, settings, outcome measures, follow-up, drop-out rate (withdrawals), effectiveness results, and adverse events. The authors should attempt to synthesize the results from individual studies. In all cases, there should be a narrative summary of results, which may or may not be accompanied by a quantitative summary (meta-analysis). For reviews that use a meta-analysis, heterogeneity between studies should be assessed using statistical techniques. If heterogeneity is present, the possible reasons (including chance) should be investigated. In addition, the individual evaluations should be weighted in some way (for example, according to sample size or according to inverse of the variance) so that studies that are thought to provide the most reliable data have greater impact on the summary statistic. Controlled Trials Assessment of Internal Validity 1. Was the assignment to the treatment groups really random? Adequate approaches to sequence generation: Computer-generated random numbers Random numbers tables Inferior approaches to sequence generation: Use of alternation, case record number, birth date, or day of week Not reported 2. Adequate approaches to concealment of randomization: Centralized or pharmacy-controlled randomization Serially-numbered identical containers On-site computer based system with a randomization sequence that is not readable until allocation Inferior approaches to concealment of randomization: Use of alternation, case record number, birth date, or day of week Open random numbers lists Serially numbered envelopes (even sealed opaque envelopes can be subject to manipulation) Statins Page 120 of 128 Final Report Update 5 Drug Effectiveness Review Project Not reported 3. Were the groups similar at baseline in terms of prognostic factors? Were outcome assessors blinded to treatment allocation? Was the patient kept unaware of the treatment received? Did the article include an intention-to-treat analysis or provide the data needed to calculate it (that is, number assigned to each group, number of subjects who finished in each group, and their results)? Did the article report attrition, crossovers, adherence, and contamination?

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Ramirez-Amador V buy generic fluticasone online, Anaya-Saavedra G cheap fluticasone 100mcg line, Calva JJ purchase fluticasone without a prescription, et al. HIV-related oral lesions, demographic factors, clinical staging and anti-retroviral use. Ramos H, Pagliari C, Takakura CF, Sotto MN, Duarte MI. Pruritic papular eruption associated with HIV-etiopatho- genesis evaluated by clinical, immunohistochemical, and ultrastructural analysis. Efficacy and safety of etanercept in psoriasis/psoriatic arthritis: an updated review. Rothengatter S, Sehr T, Gholam P, Durani H, Hartmann M. Skin diseases and sexually transmitted diseases in HIV- infected patients on HAART compared to a non-infected population – results of a retrospective study. Severe cutaneous reactions associated with the use of hiv medications. The relationship between HIV infection and atopic dermatitis. Frühsymptome der HIV-Erkrankung an Haut und Schleimhäuten. Cutaneous tumors in immunodeficient patients: pathogenetic aspects and treatment strategies. Springer, Berlin, Heidelberg, New York, London, Paris, Tokyo 1999. In: Korting HC, Callies R, Reusch M, Schlaeger M, Sterry W (Hrsg. Syphilis – Leitlinie der DSTDG zur Diagnostik und Therapie. Use of infliximab to treat psoriatic arthritis in HIV-positive patients. Effect of HAART on natural history of AIDS-related opportunistic disorders. A review of drug patch testing and implications for HIV clini- cians. Current role of thalidomide in HIV-positive patients with recurrent aphthous ulcerations. Severe acquired immunodeficiency in homosexual males, manifested by chronic perianal ulcerative herpes simplex lesions. Atazanavir plasma concentrations vary significantly between patients and corre- late with increased serum bilirubin concentrations. Pruritus in HIV-1 disease: therapy with drugs which may mod- ulate the pattern of immune dysregulation. Feasibility and Effectiveness of Indicator Condition-Guided Testing for HIV: Results from HIDES I (HIV Indicator Diseases across Europe Study). Topical tacrolimus for effective treatment of eosinophilic folli- culitis associated with human immunodeficiency virus infection. Oral hairy leukoplakia: clinicopathologic features, pathogenesis, diag- nosis, and clinical significance. The effect of baseline CD4 cell count and HIV-1 viral load on the effi- cacy and safety of nevirapine or efavirenz-based first-line HAART. Walling DM, Etienne W, Ray AJ, Flaitz CM, Nichols CM. Persistence and transition of Epstein-Barr virus geno- types in the pathogenesis of oral hairy leukoplakia. Male circumcision and risk of HIV infection among heterosexual African American men attending Baltimore sexually transmitted disease clinics. Cutaneous malignancy and human immunodeficiency virus disease. Adverse drug interactions and reactions in dermatology: current issues of clinical relevance. Cutaneous manifestations of HIV in the era of HAART: an institu- tional urban clinic experience. HIV-1-associated Neurocognitive Disorder (HAND) and Myelopathy CHRISTIAN EGGERS, THORSTEN ROSENKRANZ HIV-1-associated neurocognitive disorder (HAND) Terminology, etiology and epidemiology In 2007 an international panel (Antinori 2007) devised three categories of HAND in order of descending severity: HIV-1-associated dementia (HAD), HIV-1-associated mild neurocognitive disorder (MND), and HIV-associated asymptomatic neurocog- nitive impairment (ANI) (“Frascati criteria”). This replaces the older terms HIV ence- phalopathy, AIDS dementia complex, and HIV-associated cognitive motor complex. Table 1: The classification system of HAND (“Frascati criteria”) (Antinori 2007) HIV-associated asymptomatic Neuropsychological testing with impairment (≥1 standard neurocognitive impairment deviation) in cognitive function in ≥2 functional domains*. HIV-1-associated dementia Marked acquired impairment in cognitive functioning. Marked interference with day-to-day functioning (work, home life, social activities). For all categories, delirium must be excluded, and there must be no alternative plausible cause. Cognitive domains are: verbal/language; attention/working memory; abstraction/executive; memory (learning; recall); speed of information processing; sensory-perceptual, motor skills The primary cause of HIV-1-associated neurocognitive disorder (HAND) is an infection of the CNS caused by HIV. If untreated, there is a high level of replication of HIV in the macrophages and microglial cells of the brain. Neural cells have not consistently been shown to be infected. However, different immunopathological mechanisms lead to structural damage of these cells with subsequent neurocogni- tive impairment (NCI). With respect to viral replication and viral quasispecies, the CNS is partially independent from the hematolymphatic compartment (Eggers 2003, Eggers 2013), and this may lead to “viral excape” with direct clinical consequences (Canestri 2010, Peluso 2012). A recent autopsy study on patients with advanced HIV infection found aspects of Alzheimer’s pathology and unspecific histological changes as equally associated with HAND as the classical HIV pathology (Everall 2009). As the life expectancy of HIV+ individuals in the developed world now comes close to that of the general population (May 2014), the prevalence of HAND has risen to 628 Interdisciplinary Medicine 20-50% (Sacktor 2002, Heaton 2010). With ART, the prevalence of severe cases has decreased while that of the minor variants has increased (Heaton 2011). Among indi- viduals in the WHO/CDC clinical stage A, however, a slight to moderate impairment is more frequent than in the pre-HAART-era. Longitudinal cohort observations have shown that many patients with asymptomatic neurocognitive impairment (ANI), even with suppressed plasma viral load, will eventually develop symptomatic NCI (Cole 2007, Grant 2014). Patients who were diagnosed and treated early after infec- tion had a low prevalence of NCI (Crum-Cianflone 2013). A study of treated subjects with initially low but increasing CD4 T cell counts showed some improvement of cognitive function, but this remained worse than that of an HIV-negative control group (Mc Cutchan 2007). Frequent subjective complaints of reduced cognitive performance with and without objective correlates on formal neuropsychological testing have been found in many patients with longstanding suppression of plasma viral load (Simioni 2010). HAND is associated with a shortened survival (Sevigny 2007) and with poor medication adherence (Albert 1999). It is generally accepted that HAND, in untreated patients, at least in its more severe stages, is a treatable condition.

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