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Theparasites spread in the host order atorvastatin overnight cholesterol medication effects on liver, triggering immune attack against dominant antigens buy cheapest atorvastatin and atorvastatin cholesterol test when not fasting. The battle within the host develops through changes in population numbers—the num- bers of parasites with particular antigens and the numbers of immune cells that speciﬁcally bind to particular antigens order atorvastatin 20 mg on-line cholesterol ratio life insurance. Ithendiscusshow the successes and failures of diﬀerent parasite antigens within each host determine the rise and fall of parasite vari- ants over space and time purchase cheap atorvastatin on line cholesterol levels in fertilized eggs. The distribution of parasite variants sets the immune memory proﬁles of diﬀerenthosts,whichinturn shape the landscape in which parasite variants succeed or fail. These coevolution- ary processes determine the natural selection of antigenic variants and the course of evolution in the parasite population. Finally, I consider diﬀerent ways to study the evolution of antigenic variation. Experimental evolution of parasites under controlled condi- tions provides one way to study the relations between molecular rec- ognition, the dynamics of infections within hosts, and the evolution- ary changes in parasite antigens. Sampling of parasites from evolving populations provides another way to test ideas about what shapes the distribution of parasite variants. My primary goal is to synthesize across diﬀerent levels of analysis. How do the molecular details of recognition and speciﬁcity shape the changing patterns of variants in populations? How does the epidemio- logical spread of parasites between hosts shape the kinds and amounts of molecular variation in parasite antigens? Icompare diﬀerent types of parasites because comparative biology provides insight into evolutionary process. For example, parasites that spread rapidly and widely in host populations create a higher density of immune memory in their hosts than do parasites that spread slowly and sporadically. Host species that quickly replace their populations with oﬀspring decay their population-wide memory of antigens faster than do host species that reproduce more slowly. How do these epidemiological and demographic processes inﬂuence molecular variation of parasite antigens? These problems emphasize the great opportunities of modern biology. At the molecular level, new technologies provide structural data on the three- dimensional shape of host antibody molecules bound to parasite anti- gens. At the population level, genomic sequencing methods provide detailed data on the variations in parasite antigens. One can now map the nucleotide variations of antigens and their associated amino acid substitutions with regard to the three-dimensional location of antibody binding. Thus, the spread of nucleotide variations in populations can be directly associated with the changes in molecular binding that allow escape from antibody recognition. No other subject provides such opportunity for integrating the re- cent progress in structural and molecular analysis with the conceptual andmethodological advances in population dynamics and evolutionary biology. My problems for future research at the end of each chapter emphasize the new kinds of questions that one can ask by integrating diﬀerent levels of biological analysis. Chapter 2 summarizes the main features of vertebrate immunity. I present enough about the key cells and molecules so that one can understand how immune recog- nition shapes the diversity of parasites. Chapter 3 describesvariousbeneﬁts that antigenic variation provides to parasites. Thesebeneﬁts explain why parasites vary in certain ways. For example, antigenic variation can help to escape host immunity dur- ing a single infection, extending the time a parasite can live within a particular host. Or antigenic variation may avoid the immunological memory of hosts, allowing the variant to spread in a population that previously encountered a diﬀerent variant of that parasite. Diﬀerent beneﬁts favor diﬀerent patterns of antigenic variation. Chapter 4 describes the at- tributes of host and parasite molecules that contribute to immune rec- ognition. The nature of recognition depends on speciﬁcity, the degree to which the immune system distinguishes between diﬀerent antigens. Sometimes two diﬀerent antigens bind to the same immune receptors, perhaps with diﬀerent binding strength. This cross-reactivity protects INTRODUCTION 7 hosts against certain antigenic variants, and sets the molecular dis- tance by which antigenic types must vary to escape recognition. Cross- reactivity may also interfere with immune recognition when immune receptors bind a variant suﬃcientlytopreventanewresponse but not strongly enough to clear the variant. Chapter 5 summarizes the diﬀerent ways in which parasites gener- ate antigenic variants. Many parasites generate variants by the stan- dard process of rare mutations during replication. Baseline mutation rates vary greatly, from about 10−5 per nucleotide per generation for the small genomes of some RNA viruses to about 10−11 for larger ge- nomes. Although mutations occur rarely at any particular site during replication, large populations generatesigniﬁcant numbers of mutations in each generation. Some parasites focus hypermutation directly on antigenic loci. Other parasites store within each genome many genetic variants for an antigenic molecule. These parasites express only one genetic variant at a time and use specialized molecular mechanisms to switch gene expression between the variants. Part III focuses on the dynamics of a single infection within a par- ticular host. Chapter 6 emphasizes the host side, describing how the immune response develops strongly against only a fewofthemany dif- ferent antigens that occur in each parasite. This immunodominance arises from interactions between the populations of immune cells with diﬀerent recognition speciﬁcities and the population of parasites within the host. Immunodominance determines which parasite antigens face strong pressure from natural selection and therefore which antigens are likely to vary over space and time. To understand immunodominance, I step through the dynamic processes that regulate an immune response and determine which recognition speciﬁcities become ampliﬁed. Chapter 7 considers the ways in whichparasites escape recognition during an infection and the consequences for antigenic diversity within hosts. The chapter begins with the role of escape by mutation in persis- tent infections by HIV and hepatitis C virus. I then discuss how other parasites extend infection by switching gene expression between vari- ants stored within each genome. This switching leads to interesting population dynamics within the host. The diﬀerent variants rise and fall in abundance according to the rate of switching between variants, the time lag in the expansion of parasite lineages expressing a particular variant, and the time laginthehost immune response to each variant. Chapter 8 considers genetic diﬀerences among hosts in im- mune response.
Prospective study: A study in which participants are identified according to current risk status or exposure and followed forward through time to observe outcome discount atorvastatin 20mg online cholesterol ratio is 3.4. Overactive bladder Page 59 of 73 Final Report Update 4 Drug Effectiveness Review Project Prevalence: How often or how frequently a disease or condition occurs in a group of people discount atorvastatin cholesterol phospholipid ratio. Prevalence is calculated by dividing the number of people who have the disease or condition by the total number of people in the group buy discount atorvastatin on line cholesterol lowering foods list mayo clinic. Probability: The likelihood (or chance) that an event will occur generic atorvastatin 20mg on line average cholesterol during pregnancy. In a clinical research study, it is the number of times a condition or event occurs in a study group divided by the number of people being studied. Publication bias: A bias caused by only a subset of the relevant data being available. The publication of research can depend on the nature and direction of the study results. Studies in which an intervention is not found to be effective are sometimes not published. Because of this, systematic reviews that fail to include unpublished studies may overestimate the true effect of an intervention. In addition, a published report might present a biased set of results (for example, only outcomes or subgroups for which a statistically significant difference was found). P value: The probability (ranging from zero to one) that the results observed in a study could have occurred by chance if the null hypothesis was true. Q-statistic: A measure of statistical heterogeneity of the estimates of effect from studies. It is calculated as the weighted sum of the squared difference of each estimate from the mean estimate. Random-effects model: A statistical model in which both within-study sampling error (variance) and between-studies variation are included in the assessment of the uncertainty (confidence interval) of the results of a meta-analysis. When there is heterogeneity among the results of the included studies beyond chance, random-effects models will give wider confidence intervals than fixed-effect models. Randomization: The process by which study participants are allocated to treatment groups in a trial. Adequate (that is, unbiased) methods of randomization include computer generated schedules and random-numbers tables. Randomized controlled trial: A trial in which two or more interventions are compared through random allocation of participants. Regression analysis: A statistical modeling technique used to estimate or predict the influence of one or more independent variables on a dependent variable, for example, the effect of age, sex, or confounding disease on the effectiveness of an intervention. Relative risk: The ratio of risks in two groups; same as a risk ratio. Retrospective study: A study in which the outcomes have occurred prior to study entry. Risk: A way of expressing the chance that something will happen. It is a measure of the association between exposure to something and what happens (the outcome). Risk is the same as probability, but it usually is used to describe the probability of an adverse event. It is the rate of events (such as breast cancer) in the total population of people who could have the event (such as women of a certain age). Risk difference: The difference in size of risk between two groups. Overactive bladder Page 60 of 73 Final Report Update 4 Drug Effectiveness Review Project Risk ratio: The ratio of risks in two groups. In intervention studies, it is the ratio of the risk in the intervention group to the risk in the control group. A risk ratio of 1 indicates no difference between comparison groups. For undesirable outcomes, a risk ratio that is <1 indicates that the intervention was effective in reducing the risk of that outcome. Run-in period: Run in period: A period before randomization when participants are monitored but receive no treatment (or they sometimes all receive one of the study treatments, possibly in a blind fashion). The data from this stage of a trial are only occasionally of value but can serve a valuable role in screening out ineligible or non-compliant participants, in ensuring that participants are in a stable condition, and in providing baseline observations. A run-in period is sometimes called a washout period if treatments that participants were using before entering the trial are discontinued. This term (or the term ‘‘safe’’) should not be used when evidence on harms is simply absent or is insufficient. Sample size: The number of people included in a study. In research reports, sample size is usually expressed as "n. Larger sample sizes also increase the chance that rare events (such as adverse effects of drugs) will be detected. Sensitivity analysis: An analysis used to determine how sensitive the results of a study or systematic review are to changes in how it was done. Sensitivity analyses are used to assess how robust the results are to uncertain decisions or assumptions about the data and the methods that were used. Side effect: Any unintended effect of an intervention. Side effects are most commonly associated with pharmaceutical products, in which case they are related to the pharmacological properties of the drug at doses normally used for therapeutic purposes in humans. Standard deviation (SD): A measure of the spread or dispersion of a set of observations, calculated as the average difference from the mean value in the sample. Standard error (SE): A measure of the variation in the sample statistic over all possible samples of the same size. The standard error decreases as the sample size increases. Standard treatment: The treatment or procedure that is most commonly used to treat a disease or condition. In clinical trials, new or experimental treatments sometimes are compared to standard treatments to measure whether the new treatment is better. Statistically significant: A result that is unlikely to have happened by chance. Study: A research process in which information is recorded for a group of people. The data are used to answer questions about a health care problem. Study population: The group of people participating in a clinical research study. The study population often includes people with a particular problem or disease.
Selection of the T-cell repertoire: receptor-controlled phisms in immunoregulatory genes buy cheap atorvastatin cholesterol medication pros and cons, and FVIII/FIX mutations were checkpoints in T-cell development discount atorvastatin 20 mg mastercard cholesterol ratio or total. However generic atorvastatin 20 mg without prescription cholesterol levels chart singapore, the immunoregulatory pathways that give rise peptides bound to class II MHC molecules buy 40 mg atorvastatin amex cholesterol levels guide uk. Dangerous liaisons: how the immune system deals with factor VIII. Conﬂict-of-interest disclosure: The author is employed by Baxter 22. HLA class II molecules inﬂuence Correspondence susceptibility versus protection in inﬂammatory diseases by determining Birgit M. Reipert, Baxter Innovation GmbH, Industriestrasse 72, the cytokine proﬁle. A-1220 Vienna, Austria; Phone: 43-1-20100-2471285; Fax: 43-1- 24. HLA class II proﬁle: a weak 20100-5049; e-mail: birgit_reipert@baxter. Oldenburg J, Picard JK, Schwaab R, Brackmann HH, Tuddenham EG, 1. HLA genotype of patients with severe haemophilia A due to inhibitor development in severe hemophilia A. Factor VIII inhibitors in mild and moderate-severity haemo- 26. Factor VIII gene (F8) tumor necrosis factor-alpha and cytotoxic T-lymphocyte antigen-4 mutation and risk of inhibitor development in nonsevere hemophilia A. Inhibitor development in haemophilia B: an orphan ously applied human FVIII in humanized hemophilic E17 HLA- disease in need of attention. Factor IX: molecular structure, epitopes, and mutations 28. HLA-DR-presented peptide repertoires derived from human 7. Genetic risk factors for inhibitors to factors monocyte-derived dendritic cells pulsed with blood coagulation factor VIII and IX. Basic aspects of inhibitors to factors VIII and IX and the 29. Observations regarding the inﬂuence of non-genetic risk factors. How tolerogenic dendritic cells inhibitor development in severe hemophilia A. In: Lee C, Berntorp E, oxygenase-1 in factor VIII-deﬁcient mice reduces the immune response Hoots KW, eds. Oxford: Blackwell; 2005:235- to therapeutic factor VIII. Improve- antibodies to therapeutic factor VIII in severe hemophilia A is associ- ments in factor VIII inhibitor detection: from Bethesda to Nijmegen. Astermark J, Oldenburg J, Pavlova A, Berntorp E, Lefvert AK; MIBS antibody responses against factor VIII in healthy individuals and in Study Group. Polymorphisms in the IL10 but not in the IL1beta and IL4 Hematology 2014 377 genes are associated with inhibitor development in patients with possible role for pharmacogenetics in FVIII inhibitor development? Inhibitors of factor VIII in gene and the risk of inhibitor development in patients with hemophilia black patients with hemophilia. Astermark J, Wang X, Oldenburg J, Berntorp E, Lefvert AK; MIBS 39. Polymorphisms in the CTLA-4 gene and inhibitor risk: results from the Hemophilia Inhibitor Genetics Study (HIGS) development in patients with severe hemophilia A. Preventing restimulation of of inhibitors in hemophilia A: results from the Hemophilia Inhibitor memory B cells in hemophilia A: a potential new strategy for the Genetics Study (HIGS) Combined Cohort. African-Americans express limitations of mouse models humanized for HLA class II antigens. J multiple haplotypic forms of the wildtype factor VIII (FVIII) protein: a Thromb Haemost. It is clear that the antepartum and postpartum periods have different magnitudes of risk and distinct risk factors for VTE and therefore must be considered separately. Absolute daily risks of VTE must be understood and explored when deciding to prescribe antepartum or postpartum thromboprophylaxis and must also be balanced against the downsides of prophylaxis. When the risks for VTE and bleeding are both low, other burdens of thromboprophylaxis must be weighed in and a decision made after an individualized patient values- and patient preferences–based discussion. Risk stratiﬁcation is essential to ensure that the practicing clinician strikes the right balance. The in pregnancy and the postpartum period hypercoagulability of pregnancy, although maximally present in the early postpartum period, gradually returns to the nonpregnant state, as evidenced by progressive normalization of markers of coagula- Introduction 9,10 tion activation to prepregnancy levels. Symptomatic pregnancy associated venous thromboembolism (VTE), comprising deep vein thrombosis (DVT) and pulmonary embolism (PE), is estimated to occur antepartum (from conception to delivery, Striking the right balance: aiming to prevent enough ie, 40 weeks) in 5-12 per 10 000 pregnancies and to occur VTE to warrant the downsides of prophylaxis postpartum (6 weeks) in 3-7 per 10 000 deliveries. Therefore, we must focus on known high-risk groups in the United States (http://www. A recently updated Cochrane Review addressed the effectiveness and safety of prophy- We recently completed the Thrombophilia in Pregnancy Prophy- laxis for VTE in pregnancy and the early postpartum period. The laxis Study (“TIPPS”), which offered some new insights on reviewers conclude that: “There is insufﬁcient evidence available preventing VTE in pregnancy. In the absence of clear randomized VTE in pregnancy. First, venous stasis caused by progesterone-induced antepartum or postpartum) is a key fact that should underpin venodilation, pelvic venous compression by the gravid uterus, and decisions about choice, cost, intensity, and duration of VTE pulsatile compression of the left iliac vein by the right iliac artery,5 prevention. At the extremes, the risk of postpartum VTE in women leading to the marked propensity for left leg DVT in pregnancy with prior unprovoked VTE and thrombophilia without thrombopro- ( 80%). Conversely, we would need to treat 1000 activator inhibitor type 1 and 2 (PAI-1 and 2) activity and decreased average-risk women for the entire antepartum period to prevent one tissue plasminogen activator (t-PA) activity. Clearly, patients, clinicians, and policy makers would ﬁnd an Hematology 2014 387 Table 1. Pooled proportions of major bleeding in antepartum and postpartum periods in RCTs exploring prophylactic LMWH versus control RCT Antepartum LMWH No antepartum LMWH Postpartum LMWH No postpartum LMWH Rodger et al24 0/143 0/141 1/284 0/0 de Vries et al49 0/70 0/69 1/139 - Gris et al50 0/112 0/112 0/224 0/0 Gris et al51 0/80 0/80 - - Martinelli et al52 0/63 0/65 - - Rey et al53 0/57 0/57 - - Kaandorp et al25 0/103 0/207 - - Gates et al54 0/8 0/8 - - - - 0/70 0/71 Burrows et al55 - - 0/39 0/37 Gibson et al61 - - 0/11 0/0 Total 0/636; 0% (95% CI: 0%–0. Data clariﬁcations obtained from corresponding authors. NNT of 20 for the short postpartum period reasonable, but none associated with LMWH use is major bleeding. In Table 1, I have would consider an NNT of 1000 reasonable for the 40 week summarized and provide a pooled proportion of major bleeds in antenatal period.
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The CR Advantages Disadvantages rates in the 2 arms were comparable (65% and 66% buy cheap atorvastatin 20 mg online cholesterol natural remedies, respectively) but not signiﬁcantly higher than historical controls cheap atorvastatin 5 mg online cholesterol medication debate. However order atorvastatin with amex cholesterol ratio heart disease risk, the Naked antibodies Decreased toxicity Limited single-agent activity rate of CMR was higher (42%) than with the backbone chemotherapy BiTE antibodies Increased efﬁcacy; Blinatumomab needs to be 19 well tolerated administered as a regimen (25%; P purchase atorvastatin visa cholesterol test finger prick. This latter point is important because early continuous IV infusion MRD response was a strong predictor for event-free survival in the Immunoconjugates Increased efﬁcacy Potential toxicity due to the previous COG relapsed ALL trial and the kinetic pattern of MRD may conjugate: hematologic/ also be predictive of longer-term outcomes in relapsed ALL. Therefore, liver/VOD (calicheamicin) longer follow-up of these patients will be important. Thirty-two evaluable and cytoreduction prior to eligible patients were treated (median age of 41 years, range 20-68). CD19 is a type I transmem- refractory, and 4 patients (13%) had undergone a prior AHCT. The brane protein of the immunoglobulin superfamily and regulates response rate was 45%, including 8 CRs and 5 CRs with incomplete B-cell fate and differentiation through modulation of the B-cell count recovery (CRi). MRD information was present in only 5 of 13 receptor (Table 3). No additional class of BiTE antibodies and combines a CD3-binding site for T toxicities attributed to antibody were noted. However, the ﬁrst dose cells and a CD19-binding site for B cells. The agent engages T cells of epratuzumab was given on day 7 to decrease the tumor burden for directed lysis of CD19 target cells. This CR/CRi rate was induce perforin-mediated death of the target cell. In patients with MRD-positive ALL, the median latter group of patients was more heavily pretreated, the signiﬁ- time to relapse was 4-5 months. IntReALL, an lineage ALL in complete hematologic remission were eligible if ongoing randomized study of epratuzumab in combination with they expressed the pre-B phenotype and were either molecularly chemotherapy in relapsed pediatric ALL, will hopefully better refractory (ie, had never achieved MRD-negative status) or had a deﬁne the role of this antibody for this disease. Alemtuzumab, a humanized anti-CD52 monoclonal antibody, Blinatumomab was administered to 21 patients as a 4-week has demonstrated signiﬁcant activity in chronic lymphocytic leuke- continuous IV infusion at a dose of 15 g/m2/d. As a single agent, alemtuzumab has demonstrated limited 47 years and 7 patients had poor-risk cytogenetics (5 were Ph and 2 activity in patients with acute myeloid leukemia and ALL (CR rate were mixed-lineage leukemia positive). The most common adverse events (AEs) therapy (CALGB 19802) in adult patients with newly diagnosed were pyrexia, chills, and low immunoglobulin levels. Two CNS events duration, overall survival, and clearance of MRD. Alemtuzumab occurred: 1 seizure and 1 episode of syncope. In follow-up, there was dose escalated to a maximum of 30 mg subcutaneously 3 times was continued ampliﬁcation of the T-cell effector memory subset. Longer follow-up of this four patients were enrolled in the phase 1 trial; their median age was trial is now available and has demonstrated impressive results. Seventeen patients With a median follow-up of 33 months, the relapse-free survival had evaluable cytogenetics: 5 favorable, 8 intermediate, and 2 poor rate is 61%. The nonhematologic toxicities were mild; hematologic remission. However, even more exciting, 6 of 11 however, 4 patients developed grade 3-4 myelosuppression and 4 patients not proceeding to transplantation remain in remission. Serial MRD measure- A subsequent trial has evaluated blinatumomab in morphologically ments were performed by quantitative clone-speciﬁc PCR in 11 27 relapsed/refractory ALL. In this trial, blinatumomab was adminis- cases and demonstrated a median 1 log decrease in MRD in the 20 22 tered as a continuous infusion for 28 days, which was followed by a and 30 mg dosing cohorts. The dosing for the ﬁrst week was 5 g/m /d because weeks after the last dose was administered. With a median 27 of concern for infusion reactions with active disease. The majority follow-up of 51 months at last presentation, the median disease-free of AEs were grade 1-2 (pyrexia: 67%; headaches 33%), with 7 grade survival was 53 months and the median overall survival was 55 22 3 or higher AEs occurring in 5 patients (infection, seizures, months, which is impressive. A phase 2 trial studying 70 27 decreased platelets). Responders were allowed to receive 3 additional patients has completed accrual and the results are awaited additional cycles of therapy. As of the last report, 36 patients had to determine the efﬁcacy and toxicity of this approach. Seventeen patients had of strategies such as CMV prophylaxis to decrease toxicities will be achieved CR or CR with partial hematologic recovery and MRD important if this approach demonstrates promising results. BiTE antibodies are a novel class of bispeciﬁc single-chain antibod- This latter mechanism of resistance is a concern with the develop- ies that retarget cytotoxic T lymphocytes at preselected surface ment of antibody-targeted therapies and approaching this mecha- antigens on tumor cells. Blinatumomab Of the various novel therapeutics, blinatumomab is one of the most CD19 is the most commonly expressed antigen in pre-B-ALL and promising. Ultimately, moving blinatumomab to the upfront setting has the highest density of expression. The US Intergroup Hematology 2013 133 (E1910) is planning a trial of chemotherapy with and without blinatu- activity in cell line and patient samples. In a pediatric study, 3 of 17 momab in adults with newly diagnosed ALL to help address this ALL patients achieved a CR. The initiation and outcome of this trial are eagerly awaited. This appears to be due to a unique amino acid motif in the ricin toxin Immunotoxins/immunoconjugates A chain that damages vascular endothelial cells. Ongoing ap- proaches include mutating the recombinant ricin toxin A to disable Immunotoxins/immunoconjugates are composed of a monoclonal this site. Another approach is to shorten the half-life of the immuno- antibody or a cell-antigen-binding fragment and a toxin moiety that toxin in vivo, and studies with this latter approach are ongoing. Serum levels of the agent correlated with dose level and fragment of an antibody linked to a 38 kDa truncated derivative of the percentage of circulating blasts. The often rapid rebound in Pseudomonas exotoxin A (PE38) as the toxin moiety for their 29 peripheral blasts after the last dose of combotox suggests that immunotoxins. These agents bind to CD22, after which they are continued dosing with a reduced dose might lead to more durable internalized via receptor-mediated endocytosis and processed by remissions. BL22 and CAT-8015 CD22 represents an attractive therapeutic target for this approach because the CD22 antigen-immunotoxin is rapidly internalized. In a phase 1 trial including ALL patients, no allergic/infusion reactions, vascular leak, or hemolytic uremic is extremely potent, with an EC50 in the subnanomolar range. Three of 23 patients did develop neutraliz- SAR3419 binds to CD19 and is subsequently internalized via ing antibodies. Only modest activity was noted in ALL and there were no CRs. Sixteen of 23 patients did have a other grade 3 or 4 toxicities exceeded 10% and there were no reduction in blast count. SAR3419 seems to have a large therapeutic window with minimal toxicity.