By Z. Zakosh. Vanguard University.

Included system aticreviews and m eta-analyses ofskeletalm uscle relaxants inpatients with m usculoskeletal conditions Tim e period covered and F unding A uth or sources used inliterature source and M eth od of C h aracteristics of Y ear A im s search Eligibility criteria Exclusioncriteria role appraisal identified articles VanTulder Systematicreview of th rough O ctober2001 R andomiz ed Studies of U niversity of Independently 27 studies excluded 48 tadacip 20 mg amex erectile dysfunction clinics, 49 effectiveness of (M EDL IN E order tadacip 20 mg with visa erectile dysfunction doctor visit,EM BA SE)or controlled trials and ch lormez anone Toronto and assessed by two 2003 skeletalmuscle 2002 (C och rane L ibrary) double-blind and botulinum VU U niversity reviewers using 30 trials of2884 patients relaxants inth e controlled clinical toxin M edical criteria (11-item included (14 ofth ese treatmentofback M EDL IN E,C och rane L ibrary, trials ofpatients with C enter instrument) studies did notmeetour pain EM BA SE nonspecificlow back A msterdam recommended by inclusioncriteria because painreceiving th e C och rane Back th ey were non-English or skeletalmuscle R eview G roup. Included system aticreviews and m eta-analyses ofskeletalm uscle relaxants inpatients with m usculoskeletal conditions A uth or Population Y ear ch aracteristics M ainR esults A dverse events Internalvalidity VanTulder A cute orch roniclow A llstudies h ad atleasttwo criteria forwh ich itwas N onbenz odiaz epines versus placebo G O O D. M eanquality score 6 (range 3- (11 studies,pooled relative risks) 2003 degrees;age,race and 9,scale 0-11). Skeletal Muscle Relaxants Page 92 of 237 Final Report Update 2 Drug Effectiveness Review Project Evidence Table 2. Included system aticreviews and m eta-analyses ofskeletalm uscle relaxants inpatients with m usculoskeletal conditions Tim e period covered and F unding A uth or sources used inliterature source and M eth od of C h aracteristics of Y ear A im s search Eligibility criteria Exclusioncriteria role appraisal identified articles M eta-analysis N ibbelink A ssess th e Time period covered not C ontrolled clinical Studies outside A uth ors N otreported 20 double-blind 70 th erapeutic clear studies ofpatients th e U nited States employed by randomiz ed trials of1153 1978 response of with skeletalmuscle (3 studies) M erck. N ot patients (434 cyclobenz aprine N otclearwh atmeth ods used spasm treated with because of reported if cyclobenz aprine,280 compared to to identify relevantstudies, cyclobenz aprine, differences in funderh eld diaz epam,439 placebo) diaz epam and butappears to include diaz epam,or protocoland data data. Skeletal Muscle Relaxants Page 93 of 237 Final Report Update 2 Drug Effectiveness Review Project Evidence Table 2. N o evaluationfor 70 14% musculoskeletal G lobalresponse: C yclobenz aprine and diaz epam placebo h eterogeneity. Insufficientdetailof 1978 strain,10% idiopath ic, significantly betterth anplacebo,no significant Drowsiness: 39% vs. N otclearif 8% postoperative,6% differences betweencyclobenz aprine and Dry mouth : 24% vs. H ead-to-h ead trials ofskeletalm uscle relaxants inpatients with spasticity W ith drawals Type of Interventions Screened orlostto A uth or Study, Dose Exclusion Eligible follow-up Y ear Setting Duration Eligibility C riteria C riteria Enrolled A nalyz ed PopulationC h aracteristics Bass R andomiz ed A : Tiz anidine titrated to Patients with N otreported N otreported 18 with drew or Initialintervention: Tiz anidine vs. H ead-to-h ead trials ofskeletalm uscle relaxants inpatients with spasticity A uth or M eth od ofO utcom e A ssessm entand Y ear Tim ing ofA ssessm ent O verallR ating O utcom es Bass Spasms: 6 pointordinalscale F A IR. Durationofcontractures: N o significantdifferences between M uscle strength : N otclearh ow rated treatments C lonus: N otclearh ow rated R esolutionofclonus: 14/29 (48% )vs. H ead-to-h ead trials ofskeletalm uscle relaxants inpatients with spasticity A uth or F unding Source and Y ear A dverse events R ole O th ercom m ents Bass Tiz anidine vs. H ead-to-h ead trials ofskeletalm uscle relaxants inpatients with spasticity W ith drawals Type of Interventions Screened orlostto A uth or Study, Dose Exclusion Eligible follow-up Y ear Setting Duration Eligibility C riteria C riteria Enrolled A nalyz ed PopulationC h aracteristics C artlidge R andomiz ed A : Baclofen30 mg/day Spasticity,oth er N otreported N otreported 3 A ge range (years): 22-61 79 crossovertrial for2 weeks and 60 eligibility criteria F emale gender: 19/40 1974 mg/day for2 weeks unclear N otreported 37 R ace: N otreported U. B: Diaz epam 15 40 U nderlyingconditionmultiple sclerosis: 34/40 Single center mg/day for2 weeks and Baseline A sh worth score 3 or4 inatleast1 30 mg/day for2 weeks lowerlimb Priormuscle relaxantuse: N otreported 4 weeks intervention,4 weeks crossover C orston R andomiz ed A : Tiz anidine upto 24 Patients with N otreported N otreported 0/10 (0% ) Tiz anidine vs. H ead-to-h ead trials ofskeletalm uscle relaxants inpatients with spasticity A uth or M eth od ofO utcom e A ssessm entand Y ear Tim ing ofA ssessm ent O verallR ating O utcom es C artlidge Spasticity: A sh worth scale F A IR. U rinary frequency (improvementinpooled scores): +2 vs. H ead-to-h ead trials ofskeletalm uscle relaxants inpatients with spasticity A uth or F unding Source and Y ear A dverse events R ole O th ercom m ents C artlidge Baclofenvs. Skeletal Muscle Relaxants Page 100 of 237 Final Report Update 2 Drug Effectiveness Review Project Evidence Table 3. H ead-to-h ead trials ofskeletalm uscle relaxants inpatients with spasticity W ith drawals Type of Interventions Screened orlostto A uth or Study, Dose Exclusion Eligible follow-up Y ear Setting Duration Eligibility C riteria C riteria Enrolled A nalyz ed PopulationC h aracteristics Eyssette R andomiz ed A : Tiz anidine titrated to Patients age 18-70 N otreported N otreported 14/100 (14% ) Tiz anidine vs. H ead-to-h ead trials ofskeletalm uscle relaxants inpatients with spasticity A uth or M eth od ofO utcom e A ssessm entand Y ear Tim ing ofA ssessm ent O verallR ating O utcom es Eyssette Spasticity: 1 (absent)to 5 (spontaneous) F A IR. H ead-to-h ead trials ofskeletalm uscle relaxants inpatients with spasticity A uth or F unding Source and Y ear A dverse events R ole O th ercom m ents Eyssette F requentside effects: N otreported 73% ofpatients onbaclofen 73 Tiz anidine (n=50): 15 drowsiness,14 dry mouth ,8 fatigue,6 orth ostatich ypotension,7 insomnia priorto study entry, 1988 Baclofen(n=50): 10 drowsiness,12 fatigue,10 muscularweakness,9 disturbance ofaffect,8 proportionineach vomiting interventiongroupnot reported. H ead-to-h ead trials ofskeletalm uscle relaxants inpatients with spasticity W ith drawals Type of Interventions Screened orlostto A uth or Study, Dose Exclusion Eligible follow-up Y ear Setting Duration Eligibility C riteria C riteria Enrolled A nalyz ed PopulationC h aracteristics G lass R andomiz ed A : Dantrolene 100 mg N otreported N otreported N otreported 5 with drew Demograph ics notreported 82 crossovertrial qid 1974 62 11 C linicalconditions ofpatients enrolled not U. Inpatients eligible,39% C VA ,18% 16 spinalcord injury,12% M S,4% C P,4% Single center C : Dantrolene 100 mg miscellaneous (proportions notreported for qid + diaz epam 5 mg each interventiongroup) qid D: Placebo 4 2-week intervention periods H oogstraten R andomiz ed A : Tiz anidine titrated, M ultiple sclerosis Severe cardiac N otreported 5 Baseline ch aracteristics notreported foreach 74 trial range 12-24 mg/day patients with stable insufficiency, interventiongroup 1988 C rossover spasticity for>2 diastolicblood N otreported 14 M eanage (years): 55 B: Baclofentitrated, month s,K urtz ke pressure >110, F emale gender: 6/16 N eth erlands range 15-60 mg/day expanded disability severe 16 R ace: N otreported status score 4-7 h ypotension, Single center 2-3 weeks titration ch ronic A verage K urtz ke EDSS score:6. H ead-to-h ead trials ofskeletalm uscle relaxants inpatients with spasticity A uth or M eth od ofO utcom e A ssessm entand Y ear Tim ing ofA ssessm ent O verallR ating O utcom es G lass R esistance to passive stretch : 1-6 scale F A IR. A mbulation: A mbulationIndex interventiongroups Spasticity/tone: A sh worth scale,patient self-report(0-5 scale) R eflexes/clonus M uscle strength Efficacy: -3 to +3 scale Tolerance: -3 to +3 scale Skeletal Muscle Relaxants Page 105 of 237 Final Report Update 2 Drug Effectiveness Review Project Evidence Table 3. H ead-to-h ead trials ofskeletalm uscle relaxants inpatients with spasticity A uth or F unding Source and Y ear A dverse events R ole O th ercom m ents G lass W ith drawal(adverse event): 3/16 vs. N ot clearwh y 46/62 eligible patients were notentered into study. N otclearif patients wh o with drew from one interventionreceived oth erinterventions. H ead-to-h ead trials ofskeletalm uscle relaxants inpatients with spasticity W ith drawals Type of Interventions Screened orlostto A uth or Study, Dose Exclusion Eligible follow-up Y ear Setting Duration Eligibility C riteria C riteria Enrolled A nalyz ed PopulationC h aracteristics M edici R andomiz ed A : Tiz anidine titrated, O utpatients with H eartdisease, N otreported 2 death s and 3 Tiz anidine vs. H ead-to-h ead trials ofskeletalm uscle relaxants inpatients with spasticity A uth or M eth od ofO utcom e A ssessm entand Y ear Tim ing ofA ssessm ent O verallR ating O utcom es M edici N eurologicexam: K urtz ke meth od F A IR. F unctionalassessmentofdisability: 43% Pedersenscale Patientglobalassessmentofclinicalch anges: N o significant Patientself-assessmentofdisability: M ild, differences betweeninterventions (raw data notreported) moderate,severe,very severe Ph ysicianglobalassessmentofclinicalch anges: N o significant Ph ysicianglobalassessmentofclinical differences betweeninterventions (raw data notreported) ch anges:W orse,no ch ange,improvement, G lobalassessment/ph ysician(good to excellent):60% vs. H ead-to-h ead trials ofskeletalm uscle relaxants inpatients with spasticity A uth or F unding Source and Y ear A dverse events R ole O th ercom m ents M edici Tiz anidine vs. Skeletal Muscle Relaxants Page 109 of 237 Final Report Update 2 Drug Effectiveness Review Project Evidence Table 3.

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The amino acid sequence of the M6 serotype revealed repeats in three regions of the protein (Hollingshead et al effective 20mg tadacip erectile dysfunction doctors raleigh nc. Region 1 has five repeats of 42 bp order tadacip 20mg free shipping erectile dysfunction following radical prostatectomy, each repeat con- taining two nearly identical 21 bp repeats; region 2 has five 75 bp re- peats; and region 3 has two repeats of about 81 bp. In regions 1 and 2, the two outermost repeats vary slightly in sequence from the three identical repeats in the interior. Sequence analysis of variant M proteins suggests that mutations oc- cur by generating both gains and losses of the duplications. These mu- tations probably arise by intragenic recombination between the DNA repeats, but may be created by slippage during replication. Slippage mutations over repeated DNA lead to gain or loss in the number of re- peats and occur at frequencies much higher than typical replication er- rors (Charlesworth et al. The repeats of the M protein are multi- ples of 3 bases; thus changes in repeat number do not cause frameshift GENERATIVE MECHANISMS 61 mutations. Some of the repeats vary slightly in base composition, so recombinations can alter sequence composition as well as total length. Fussenegger (1997) reviews several other cases of bacterial cell-wall proteins that have repeated sequences, most of which occur in multiples of 3 bp. Repeats are often associated with binding domains for other proteins or polysaccharides (Wren 1991), so perhaps the ability to gen- erate variable-length domains provides an advantage in attachment to host tissues or in escape from host immunity. Other mutational mechanisms besides repeats may increase local mu- tation rates(Ripley 1999). For example, when double-stranded DNA splits to be replicated, the complementary bases on a single strand may bind to each other to form “hairpin” structures. Caporale (1999) suggests that certain ge- nomic regions, such as antigenic sites, may have DNA base compositions that promote higher mutation rates. Apart from the well-known case of repeats and replication slippage, no evidence at present associates antigenic sites with higher replication errors. But this would certainly be an interesting problem to study fur- ther. One could, for example, focus on associations between mutation rate and nucleotide sequence. Comparison would be particularly inter- esting between epitopes that evolve rapidly and conserved regions of antigenic molecules that evolve slowly. Such comparison may help to identify aspects of nucleotide composition that promote higher error rates in replication. Three types of switch mechanisms commonly occur: replication errors that turn expression on or off, gene conversion into fixed expression sites, and invertible promoters that change the direction of transcription. 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.

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Preliminary studies of neutralization kineticsprovidesomecluesabouthow anti- body binding affects fitness 20 mg tadacip visa erectile dysfunction nerve. Different mechanistic models of neutraliza- tion could be transformed into a family of mathematical models for neu- tralization kinetics 20mg tadacip with mastercard impotence and depression. Those models would clarify predicted response to EXPERIMENTAL EVOLUTION: INFLUENZA 229 experimental manipulation under different assumptions, allowing bet- ter tests of the mechanistic assumptions. In addition, models would sug- gest how changes in different aspects of neutralization would affect viral fitness. The more sensitive steps in neutralization would be under more intense selective pressure for change, suggesting a testable prediction for which amino acid sites would be most likely to respond during ex- perimental evolution. These studies would link molecular mechanisms, kinetic consequences, and evolutionary forces. Experimental Evolution: CTL Escape 14 CTL pressure favors amino acid substitutions in pathogen epitopes that escape recognition. Escape substitutionsmayavoid peptide processing and transport, reduce binding to MHC molecules, or lower affinity for theTcell receptor (Borrow and Shaw 1998). In this chapter, I discuss ex- perimental evolution studies of CTL escape. I also discuss nonevolution- ary studies that provide background or suggest promising experimental systems. The first section reviews mechanisms of escape during peptide cleav- age and transport. Two studies of murine leukemia virus describe single amino acid substitutions that changed patterns of peptide cleavage in cellular proteasomes. One substitution added a cleavage site within an epitope. Before the substitution, a significant amount of that epitope wastransported to the endoplasmic reticulum, bound to MHC mole- cules, and presented to CTLs at the cell surface. The new cleavage site greatly reduced the abundance of the epitope available for MHC binding. Adifferent substitution abrogated cleavage at the carboxyl terminus of an epitope, preventing transport of the peptide from the proteasome to the endoplasmic reticulum. The second section describes escape from binding to MHC molecules during experimental evolution. Studies of influenza and lymphocytic choriomeningitis virus used a transgenic mouse with almost all of its CTLs specific for a single epitope, creating intense selective pressure for escape. Structural analyses of the peptide-MHC complex illuminate the biochemical mechanisms by which escape variants reduce binding to MHC. Experiments with simian immunodeficiency virus compared the spread of amino acid substitutions in several epitopes when in differ- ent host MHC genotypes. If the host had an MHC molecule that could present a particular epitope, that epitope was much more likely to evolve escape substitutions during infection. The third section summarizes escape from binding to the T cell re- ceptor (TCR). The experimental evolution studies of influenza and lym- phocytic choriomeningitis with transgenic, monoclonal T cells yielded some TCR escape substitutions. Structural studies of peptide-MHC com- EXPERIMENTAL EVOLUTION: CTL ESCAPE 231 plexes and binding affinity studies of the complexes with TCRs clarified the biochemical mechanisms by which escape occurs. The fourth section considers how the function of pathogen proteins may be altered by CTL escape substitutions. The Tax protein of human T cell leukemia virus type 1 provides a major target for CTL attack. Intense immune pressure selects for escape substitutions in naturally occurring infections. Tax plays a key role in many viral and cellular processes that affect viral fitness. Functional studies of Tax mutants suggest that substitutions reduce Tax performance. In HIV, amino acid substitutions in response to drugs sometimes increase binding to MHC molecules. It may be that the wild-type sequence reflects a balance between protein function and avoidance of MHC binding. Drugs or other experimental perturbations may upset that balance, exposing the mechanisms that mediate balancing selection. The fifth section lists kinetic processes that determine the success or failure of escape variants. Kinetic processes connect the biochem- ical mechanisms of molecular interaction to the ultimate fitness conse- quences that shape observed patterns of antigenic variation. No exper- imental evolutionary studies have focused on these kinetic processes. The final section highlights some topics for future research. Proteasomal cleavage patterns of proteins determine which pep- tides will be transported into the endoplasmic reticulum by transporter (TAP) molecules and made available for binding and presentation by the MHC system.

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