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Prophylaxis of cytotoxic chemotherapy induced emesis with the 5HT-3 receptor inhibitor ondansetron discount 40 mg betapace overnight delivery. Gratz I order betapace 40mg with mastercard, Allen E, Afshar M, Joslyn AF, Buxbaum J, Prilliman B. The effects of the menstrual cycle on the incidence of emesis and efficacy of ondansetron. Oral dolasetron mesylate in patients receiving moderately emetogenic platinum-containing chemotherapy. Antiemetics Page 129 of 136 Final Report Update 1 Drug Effectiveness Review Project Exclusion Excluded Studies code # Harvey VJ, Evans BD, Mitchell PLR, et al. Reduction of carboplatin induced 2 emesis by ondansetron. Henriksson R, Lomberg H, Israelsson G, Zackrisson B, Franzen L. The effect of ondansetron on radiation-induced emesis and diarrhoea. Dose-ranging evaluation of the antiemetic efficacy of intravenous dolasetron in patients receiving 2 chemotherapy with doxorubicin or cyclophosphamide. Effective emetic control during conditioning of children for bone marrow transplantation using ondansetron, 2 a 5-HT3 antagonist. Increased incidence of retching and vomiting during periovulatory phase after middle ear surgery. Granisetron, a selective 5-HT3 receptor antagonist, for the prevention of radiation induced emesis during 6 total body irradiation. The efficacy and safety of granisetron in pediatric cancer patients who had failed standard 2 antiemetic therapy during anticancer chemotherapy. Effects of granisetron with doxorubicin or epirubicin on ECG intervals. Phase III clinical studies with ondansetron (Qilu) in the prophylaxis of nausea and vomiting induced by non-cisplatin 1 chemotherapy. Ondansetron as prophylaxis for chemotherapy and 6 radiotherapy-induced emesis in children. Phase II trials of ondansetron with high-dose cisplatin. Kris MG, Clark RA, Tyson LB, Hahne WF, Pisters KMW, Gralla RJ. Phase II trial of a single intravenous dose of ondansetron in patients receiving 2 cisplatin (greater-than or equal to) 100 mg/m2. American Journal of Clinical Oncology: Cancer Clinical Trials. Dose-ranging evaluation of the serotonin antagonist dolasetron mesylate in patients receiving high-dose 2 cisplatin. Antiemetics Page 130 of 136 Final Report Update 1 Drug Effectiveness Review Project Exclusion Excluded Studies code # Lemerle J, Amaral D, Southall DP, Upward J, Murdoch RD. Efficacy and safety of granisetron in the prevention of chemotherapy-induced emesis in 2 paediatric patients. Ondansetron in radiation therapy of brain 2 tumor in children. Experience using the FLIE questionnaire in a randomised study of 2 the NK-1 antagonist aprepitant. Vascular complications in patients receiving chemotherapy: What role do third generation antiemetics play? Multicenter postmarketing surveillance of ondansetron therapy in pediatric patients. A phase I antiemetic study of MDL 73,147EF, a novel 5-hydroxytryptamine antagonist in cancer patients 2 receiving emetogenic chemotherapy. Preliminary experience with use of a selective 5HT3 receptor antagonist (ondansetron) to prevent high dose 2 chemotherapy induced emesis. Peters II MD, Long KS, Patel HS, Reitz JA, Jessen LM, Emhart GC. Multicenter evaluation of ondansetron use in hospitalized oncology patients. Ondansetron in the control of refractory emesis following 2 radiotherapy. Ondansetron (GR38032) in the prophylaxis of acute and delayed cisplatin-induced emesis.

Combining beta interferon and atorvastatin may increase disease activity in multiple sclerosis purchase betapace 40 mg with mastercard. The effect of glatiramer acetate (Copaxone) on MRI-detected disease activity in patients with relapsing-remitting multiple sclerosis: a multi-center buy 40mg betapace, 5 randomized, double-blind, placebo-controlled study extened by open-label treatment. The effects of interferon beta 1a (Rebif) in patients with acute neurological syndromes suggestive of multiple sclerosis: a multi- 5 centre, randomised, double-blind, placebo-controlled study. The effect of glatiramer acetate (Copaxone) on disease activity as measured by cerebral MRI in patients with relapsing-remitting multiple sclerosis (RRMS): a multi-center, randomized, double- 5 blind, placebo-controlled study extended by open-label treatment. Quality of life in low-disability multiple sclerosis patients participating in a phase III trial of interferon beta-1a for relapsing 5 multiple sclerosis. Treatment of relapsing-remitting multiple sclerosis with natural interferon beta: a multicenter, randomized clinical trial. Effects of oral glatiramer acetate on clinical and MRI-monitored disease activity in patients with relapsing multiple sclerosis: a 3 multicentre, double-blind, randomised, placebo-controlled study. Application of beta interferon and copolymer-1 in relapsing-remitting multiple 1 sclerosis. GLANCE: results of a phase 2, randomized, double-blind, placebo-controlled study. Mitoxantrone in progressive multiple sclerosis (MS): a placebo-controlled, randomized, observer-blind European phase III multicenter study 5 - clinical results. Mitoxantrone in progressive multiple sclerosis (MS): 5 clinical results and three-year follow-up of the MIMS trial. Disease-modifying drugs for multiple sclerosis Page 112 of 120 Final Report Update 1 Drug Effectiveness Review Project Excluded trials Exclusion code Hughes RAC. Interferon-beta 1a (REBIF) in the treatment of relapsing-remitting multiple sclerosis: the clinical results of a large multicentre study. A Multicenter, Randomized, Double-Blind, Parallel-Group, Placebo- Controlled Study to Evaluate the Efficacy and Safety of PEGylated Interferon Beta- 6 1a (BIIB017) in Subjects With Relapsing Multiple Sclerosis. Results of a phase III trial of intramuscular recombinant beta interferon as treatment for multiple sclerosis. Extended observations on MS patients treated with IM interferon-beta1a (Avonex (TM)): implications for modern MS trials and therapeutics. Intrathecally administered natural human fibroblast interferon reduces exacerbations of multiple sclerosis. Experimental therapy of relapsing-remitting multiple sclerosis with 5 copolymer-1. Management of relapsing/remitting multiple sclerosis with copolymer 1 5 (Copaxone). Extended use of glatiramer acetate (Copaxone) is well tolerated and maintains its clinical effect on multiple sclerosis 6 relapse rate and degree of disability. Copolymer 1 reduces relapse rate and improves disability in relapsing-remitting multiple sclerosis: Results of a phase III 5 multicenter, double-blind, placebo-controlled trial. Extended use of glatiramer acetate (Copaxone) is well tolerated and maintains its clinical effect on multiple sclerosis 5 relapse rate and degree of disability. Profile of clinical responders to interferon-beta-1a treatment in relapsing-remitting multiple sclerosis. European 6 journal of neurology : the official journal of the European Federation of Neurological Societies. Efficacy of intramuscular interferon beta- 1a in patients with clinically isolated syndrome: analysis of subgroups based on new 6 risk criteria. Prospective assessment of changing from placebo to IFN beta-1a in relapsing MS: the PRISMS study. Oral interferon beta-1a in relapsing-remitting multiple sclerosis: a double-blind randomized study. Subgroups of the BENEFIT study: risk of developing MS and treatment effect of interferon beta-1b. Randomized, Placebo-Controlled Phase II Monocentric Trial for the Neuroprotective Effect of Lamotrigine Plus Interferon Beta 1a 30mcg Once Weekly 3 Intramuscular in Patients With Relapsing-Remitting Multiple Sclerosis. Impact of interferon beta-1a on neurologic disability in relapsing multiple sclerosis. The Multiple Sclerosis 6 Collaborative Research Group (MSCRG). Disease-modifying drugs for multiple sclerosis Page 113 of 120 Final Report Update 1 Drug Effectiveness Review Project Excluded trials Exclusion code Sandberg-Wollheim M, Hommes OR, Hughes RA, Paty DW, Abdul-Ahad AK. Recombinant human interferon beta in the treatment of relapsing-remitting and 5 secondary progressive multiple sclerosis. Clinical efficacy of interferon beta-1b in multiple sclerosis: The US /Canadian multicentre trial evidence. Other trials Cohen JA, Calabresi PA, Chakraborty S, et al. Avonex Combination Trial in relapsing--remitting MS: rationale, design and baseline data.

The dilute Russell viper venous thrombosis buy discount betapace 40mg online, although the evidence for this is not strong 40 mg betapace for sale. In contrast, the activated partial treatment with either an antiplatelet agent such as aspirin or an thromboplastin time (aPTT), the kaolin clotting time (KCT), and the anticoagulant such as a vitamin K antagonist (VKA; i. They involve coating of an ELISA plate with either 2GPI or the anionic phospholipid cardiolipin, adding the patient’s serum at a prespecified dilution (1:50), followed by the application of a secondary labeled antibody that allows quantitation of the bound IgG or IgM isotypes. It also detects aAbs that bind to 2GPI that has been coated onto the anionic phospholipid surface. Schematic representation of the classification criteria for diagnosing APS. ELISA is theoretically less specific than the anti- 2GPI ELISA in diagnosing APS because the former also detects nonspecific antibod- ies that are present in an individual’s plasma as a result of diverse common coagulation pathways. Although aAbs detected currently exist, so in their respective guidelines, they recommend by the anti- 2GPI ELISA and the LAC assays theoretically are less that 2 different assays with distinct performance principles be likely to detect non-APS-related aAbs than the aCL ELISA, it is still undertaken to detect LAC. It has 5 domains, ELISA assays used for diagnosing APS. Domain V also contains a positively charged specific aAbs responsible for LAC activity are anti- 2GPI and lysine-rich region, in close proximity to a hydrophobic loop region, anti-PT. The 2GPI molecule, screening assay be performed, with silica as the activator, and low when in the closed circular conformation, hides a cryptic epitope on phospholipid content to increase the sensitivity of the assay. In contrast, Ellagic acid as an activator is not advised due to its insensitivity for when 2GPI is immobilized on a negatively charged phospholipid LAC. SCT has the above a certain antigen density threshold, emphasizing the critical 322 American Society of Hematology APS patients who are negative on the anti- 2GPI and aCL ELISAs. Shown is the autoantibody (Y) binding negatively charged ( ) (or one fetal death after 10 weeks gestation) and negative for aPL phospholipid. Shown is the Abs and 279 women carrying a genetic thrombophilia polymor- phism. Being LAC cant interlaboratory variability with the performance of the anti- positive was the main predictor for unprovoked proximal or distal 2GPI ELISA may reside in the inconsistent exposure of residues 40 DVT and superficial vein thrombosis. The pretest probability of the diagno- other placenta-mediated complications. A significant increased percentage (obstetric and/or thrombotic) and/or systemic lupus erythematosus of LAC or anti- 2GPI ELISA positivity in premenopausal women at the time of entry into the study and healthy controls. Patients with a history of individuals have higher titers of anti- 2GPI aAbs compared with thrombosis or pregnancy complications consistent with APS were individuals who are only positive on the anti- GPI and/or aCL excluded from the study. There was no control arm in this LAC positive have anti- 2GPI aAbs that specifically bind to the 19, prospective study. Summary of commonalities and contrasts between recent ISTH, BCSH, and CLSI guidelines for LAC detection Area of recommendation ISTH 2009 BCSH 2012 CLSI 2014 Sample preparation Double centrifugation Double centrifugation Double centrifugation Assays to use dRVVT and aPTT dRVVT and aPTT and/or others dRVVT and aPTT and/or others Testing order Screen-mix-confirm Screen-mix-confirm Screen-confirm-mix Ratio derivation NPP denominator NPP denominator RI mean denominator RI/cutoffs 99th percentile 97. CLSI that discuss preanalytical, analytical, and postanalytical vari- (2014) recommends deriving the reference interval using the ables. Likewise, guidelines for laboratories to follow have been published ing validating cutoffs that have been previously established either by for the performance of the APS ELISAs that are part of the the reagent manufacturer or from a different analyzer using just 20-60 24,45 healthy donors regardless of whether the 97. The corollary of this is that anionic phospholipid expressed on the platelet surface. It is using the 99th percentile may lead to more false negatives and a failure recommended that plasma be rendered platelet poor via a process of to detect clinically meaningful LAC-positive patients. Previously, filtration of the plasma The sequence of tests performed by laboratories to determine LAC sample through 0. This procedure may cause loss of VWF and ing test, then the mixing studies, and, if the mixing studies consequently factor VIII, leading to artificial prolongation of demonstrate lack of correction, to then proceed to a confirmatory coagulation tests responsive to factor VIII, namely aPTT. Concerns have been raised at having the mixing reason, plasma filtration is no longer recommended. The reasoning is that mixing Testing for LAC during an acute illness is discouraged because studies may dilute out the in vitro effect of clinically relevant aPL factor VIII or C-reactive protein levels may be elevated; the former aAbs and thus may systematically bias results toward false-negative can mask the LAC-screening test, leading to a false-negative result, readings for LAC if a decision to proceed to the confirmatory test is and the latter may lead to a false-positive screening test result. It has been reasoned that, in the context that other types of coagulation disturbances have been excluded by Reference intervals and cutoffs undertaking routine coagulation screening, including PT time, The ISTH 2009 guidelines recommend that the cutoff for consider- thrombin time, and aPTT using a LAC-unresponsive aPTT reagent, ing a LAC screening assay to be positive be based on determining that testing positive at the screening and confirmatory test stages, locally the reference intervals specific to the reagent–analyzer even if the mixing studies are negative, is adequate to consider the pairings in use and using the 99th percentile. As discussed by Moore,15 this is a to screening, confirmatory testing, and then mixing studies. Summary of recommendations for aCL and anti- 2GPI testing Assay characteristic Recommendations Specimen requirements Serum: heat inactivation at 56°C for 30 minutes should be avoided. Use of nonhemolyzed, nonlipemic samples is recommended. Plasma: manufacturers must specify the specimen type, including the anticoagulant used.

Interestingly generic betapace 40mg with visa, the use of DNA-based BCR- ABL1 PCR cheap 40mg betapace overnight delivery, which is 1 to 2 logs more sensitive that RT-PCR, showed detectable BCR-ABL1 fusion genes in most patients who JAK-STAT pathway sustained CMR off of TKI therapy. Despite this effort, the role of JAK kinases in CML able BCR-ABL1 transcripts on at least one occasion. Several JAK kinase family long-term outcome for patients with detectable BCR-ABL1 cells members, including JAK2, are activated in BCR-ABL1–expressing who do not resume TKI treatment is unknown, but the situation cells. JAK2 kinase inhibitors decrease the proliferation and Collectively, what do these translational and clinical studies tell us? However, these disease, because some patients have now been off therapy for more studies do not exclude a role for JAK2 in the maintenance of CML than 4 years. Although late relapses ( 5 years after transplantation) LSCs. A recent study demonstrated that the adapter protein AHI-1 can occur in allografted CML patients who achieve stable CMR,37 mediates physical interaction between BCR-ABL1 and JAK2 in these are rare and long-term treatment-free remissions have also primitive CML progenitors, whereas combined treatment with been described in CML patients treated only with IFN-. Strategies, pathways, and targets for eradicating CML stem cells Mechanism of action or Pathway/target Drug or agent strategy Clinical trials Reference(s) Signaling pathways JAK2 Ruxolitinib JAK2 inhibitor NCT01702064, NCT01751425 49 PI3K/AKT/mTOR Everolimus, temsirolimus mTOR inhibitors NCT01188889, NCT00093639, 60,61,64 NCT00101088 WNT/ -catenin Indomethacin COX inhibitor 69 SB216763 GSK-3 inhibitor 74 CGP57380 MNK inhibitor 140 Hh pathway* LDE225, PF-04449913, Smo antagonists NCT01456676, NCT00953758, 77-79 BMS-833923 NCT01218477 ALOX5 pathway Zileuton 5-LO inhibitor NCT01130688 81 BCR-ABL1 stability Retaspimycin, HSP90 inhibitors NCT00066326, NCT00100997 87 tanespimycin Arsenic trioxide PML degradation NCT00250042, NCT01397734 89 Autophagy pathway Chloroquine Autophagy inhibitor NCT01227135 93,95 Epigenetic regulators Panobinostat Pan-HDAC inhibitor NCT00451035, NCT00686218 100 Resveratrol, SRT501 SIRT1 inhibitors 102 BCL2 family Sabutoclax Pan-BCL2 inhibitor 104 Omacetaxine Protein synthesis inhibitor NCT00375219 108-110 Immunological approaches IFN- * IFN- Immunomodulatory agent NCT00219739, NCT01657604, 111,112,115 NCT01392170, NCT00573378 Vaccination BCR-ABL1 peptides Vaccine NCT00267085, NCT00466726 117-119 WT1 Vaccine NCT00923910 122 PR1 Vaccine NCT00499772, NCT00004918 124,125 GVAX Vaccine 126 Cell surface antigens IL-1RAP Monoclonal antibody 127,128 mAb CSL362, SL-401 CD123/IL-3R antagonists (DT-IL3) Leukemic stem cell niche Myeloid cytokines G-CSF Cell cycle stimulation 132 Stromal cytokines*: G/GM-CSF; IL-6 JAK2 inhibitor, Inhibition of cytokine signaling; 135,134 placental GF VEGFR1 inhibitor inhibition of PlGF signaling Stroma adhesion: CXCL12 pathway Plerixafor CXCR4 inhibitor 136,137 N-cadherin/ -catenin Osteoblastic LSC niche PTH PTH-TGF signaling 139 *Intheauthors’opinion,thesearepotentiallythemostpromisingnear-termclinicalapproachestobeprioritized. Given that the safety and efficacy of a potent JAK2 could soon be tested directly in the clinical setting. Phase 1 studies of ruxolitinib in combination with ABL1 through the GAB2 adapter protein,55 and many downstream targets TKIs in CML with residual disease (www. However, relatively little is known about the role of this complex pathway in the regulation of CML stem cells. In Ph The transcription factor STAT5 is a major substrate of JAK2, but myeloid progenitors, activated AKT phosphorylates the FOXO3a whether inhibiting STAT5 would effectively target CML stem cells transcription factor, causing its retention in the cytoplasm. Constitutively active mutants of STAT5a induce contrast, the most primitive CML stem cells display inactive AKT, CML-like leukemia in primary mouse hematopoietic cells,50 whereas nuclear FOXO3a, and nuclear phospho-SMAD2/3, the latter a deletion of STAT5 abolishes fatal CML-like leukemia induced by hallmark of TGF- signaling. In contrast, studies in primary human data suggest that autocrine TGF- signaling, through an unknown CD34 cells demonstrated that knock-down of STAT5B inhibits mechanism, may suppress AKT inhibition of FOXO3a in CML clonogenicity and LTCIC function of both normal and CML LSCs. This raises the question of whether TGF- antagonists, such progenitors. Signaling pathways and potential targets for elimination of the malignant clone in CML. Shown is schematic representation of the signaling pathways discussed that may contribute to the proliferation and survival of CML stem cells. Arrowheads indicate activation of a downstream molecule. A bar at the end of a line indicates inhibition of a downstream molecule. Several phase 1 trials of rapalogs in novel peptidomimetic inhibitor of BCL6 corepressor binding, combination with ABL1 TKIs in CML are in progress (www. RI-BPI,58 inhibited BCR-ABL1 leukemogenesis in mice and eradi- clinicaltrials. WNT/ -catenin pathway Abnormal WNT/ -catenin signaling was first linked to CML by the The serine/threonine kinase mammalian target of rapamycin (mTOR) discovery of aberrant constitutive nuclear -catenin in granulocyte- is a downstream target of PI3K/AKT that regulates mRNA transla- macrophage progenitors in patients with CML myeloid blast crisis tion in mammalian cells, controlling cell growth and proliferation. Consistent with this, gene expression analysis showed imatinib prolonged survival in the retroviral CML model and was increased expression of several WNT target genes in accelerated effective against disease induced by imatinib-resistant mutants of phase and mBC CML. As yet, there are no agents in clinical trials that BCR-ABL1 failed to induce CML-like leukemia. A small-molecule directly antagonize WNT signaling, but some small-molecule WNT 5-LO inhibitor, zileuton, was more effective than imatinib in pathway inhibitors have been shown to reduce -catenin and induce prolonging survival of mice with BCR-ABL1–induced CML-like apoptosis in primary CML cells. Although the Hedgehog (Hh) signaling controls the response to stress, injury, gene expression screen was based on a signature of NF- B healing, and regeneration and plays a critical role in the self-renewal inhibition and induction of oxidative stress, the mechanism of of somatic stem cells. Binding of Hh ligands to their receptor, 12 BCR-ABL1 stem cell killing by -PGJ3 did not appear to involve Patched (PTCH), results in the activation of Smoothened (SMO), induction of reactive oxygen species, but rather activation of ATM which promotes the nuclear translocation of the GLI family of 83 and p53. Moving this exciting treatment strategy into the clinical transcription factors (GLI1-3). The GLI family modulates the 12 setting might be complicated; although -PGJ3 can be produced expression of genes such as Cyclin D, c-MYC, and BCL2 and thus endogenously from the dietary fish-oil component eicosapentaneoic controls cell proliferation and survival. Several lines of evidence 75 acid, it is not clear that adequate tissue concentrations can be implicate the Hh pathway in CML (for review, see Jagani et al ). GLI1 and PTCH1, was noted in the human CML stem cell compartment as well as in BCR-ABL1 cells in both chronic phase 76 Modulating BCR-ABL1 stability and blast crisis. Subsequent studies in the retroviral mouse model The chaperone HSP90 plays a role in regulating survival, prolifera- showed that Smo deficiency attenuated BCR-ABL1–induced CML- tion, and apoptosis of cancer cells by acting as a chaperone for like leukemia and decreased the efficiency of secondary transplanta- 84 several client oncoproteins such as BCR-ABL1 and HER2. Treatment with the SMO inhibitor cyclopamine 17-Allylamino-17-demethoxygeldanamycin (17-AAG; tanespimy- caused significant prolongation of survival, a reduction in CML cin) inhibits the binding of HSP90 to BCR-ABL1, resulting in stem cells, and a reduction of disease onset in secondary transplanta- 85 down-regulation of BCR-ABL1 and apoptosis of CML cell lines. Complementary to these results, the small-molecule Interestingly, imatinib-resistant mutants of BCR-ABL1 are more SMO antagonist LDE225 (Novartis) caused a significant reduction sensitive to inhibition of HSP90 by 17-AAG than native BCR- in secondary colony formation and replating efficacy in primary 86 ABL1. Two phase 1 trials of tanespimycin in refractory CML have CML cells in vitro, as well as improved survival in mouse models of 77,78 been completed (www. LDE-225 is in a phase 1b trial in combination with and NCT00100997), but further clinical development of the drug nilotinib for relapsed/refractory CML (www. Preliminary clinical results with another 17-AAG analog with better solubility, induces dissociation of SMO antagonist, PF-04449913 (Pfizer; www.

More data of this sort might show different genomic components changing their population struc- tures relative to each other over different temporal and spatial scales buy cheap betapace 40mg on-line. Such data could provide insight into the scale-dependent effects of de- mographic cheap 40 mg betapace with visa, genetic, and selective processes. Variant alleles at antigenic loci ap- pear to trace their phylogenetic history back to common ancestors more recent than the putative bottleneck event. This pattern suggests intense natural selection favoring novel diversity at antigenic sites against a background of low genome-wide diversity caused by a recent bottleneck. Alternatively, the antigenic variants could trace their history back to ancestors that predated the bottleneck (Hughes 1992; Hughes and Hughes 1995; Hughes and Verra 2001). This pattern arises when natural selection strongly favors rare variant antigens, holding diverse antigens in the population through the bottleneck that reduced variation in the rest of the genome. Ancient polymorphisms of this sort suggest that natural selection preserves existing variants rather than favors de novo generation of new variants (Ayala 1995; O’hUigin et al. If this estimate applies to the var genes aswellas thelocistudied by Volkman et al. Further studies of different genomic regions will contribute to understanding the speed of diversification in the var archival library. Many classical genetic models develop the island structure for populations(Wright 1978). However, those general studies of migration, selection, and stochastic perturbation provide little guid- ance for the genetic structure of parasites. Studies for parasites must account for the density and variability of host immune memory, the longevity of infections, the genetic diversity of inocula, and the patterns of genetic mixing between parasites. STRUCTURE OF PARASITE POPULATIONS 171 Much insight can be gained by island models focused specifically on the special biology of parasites (Hastings and Wedgwood-Oppenheim 1997). Rouzine and Coffin’s (1999) study shows how a clear model of population genetic process can lead to predictions about the expected patterns in the data. This suggestshowone could couple process- oriented theory with the problem of statistical inference. PART V STUDYING EVOLUTION Classifications by Antigenicity and 11 Phylogeny In this chapter, I compare immunological and phylogenetic classifica- tions of antigenic variation. Contrasts between these classifications pro- vide insight into how natural selection shapes observed patterns of di- versity. Following chapters take up other methods to infer processes of selection. The first section describes immunological measures of antigenicity. These measures summarize the ability of specific antibodies to recog- nize different antigenic variants. The reactivities for various antibodies tested against different antigenic isolates form a matrix of antigenic or immunological distances between parasite variants. These distances can be used to classify antigenic variants into related clusters. The second section notesthatantigenic variants can also be classified by phylogeny. This classification scheme measures relatedness between variants by distance back in time to a common ancestor. Such distances arise from the patterns of nucleotide or amino acid differences in ge- nomic sequences. The third section defines possiblerelationsbetween antigenic and phylogenetic classifications. Concordance commonly occurs because antigenic distance often increases with time since a common ancestor, reflecting the natural tendency for similarity by common descent. A particular pattern of discord between antigenic and phylogenetic clas- sifications suggests hypotheses about evolutionary process. Suppose, for example, that phylogenetically divergent parasites are antigenically close at certain epitopes. This suggests asahypothesis that selective pressure by antibodies has favored recurrent evolution of a particular antigenic variant. The fourth section presents flaviviruses as an example of concor- dant antigenic and phylogenetic classifications. This example compares strains that differ by relatively long phylogenetic distances with anti- genicity measured by averaging reactivity over many different epitopes. Aggregate antigenicity tends to diverge steadily over time as amino acid 176 CHAPTER 11 differences accumulate (Benjamin et al. Particular details of nat- ural selectionwithregardtoeachaminoacid substitution disappear in the averaging over many independent events. The fifth section shows a mixture of discordance and concordance between antigenic and phylogenetic classifications for influenza A. The classifications cover a history of transfers between different host spe- cies. Antigenicity and phylogeny bothseparate isolates from pigs into two groups, the classical swine types and avian-like swine types more recently transferred from birds to pigs.