Verges B deltasone 5 mg sale, Walter T generic 10 mg deltasone free shipping, Cariou B (2014) Endocrine side effects of anti-cancer drugs: effects of anti-cancer targeted therapies on lipid and glucose metabolism 10 mg deltasone. Rockwood K, Mitnitski A (2011) Frailty dened by decit accumulation and geriatric medi- cine dened by frailty. Cover illustration: Cassava green mite filled with resting spores of the fungus Neozygites tanajoae. When in March 1985 the rst issue of the journal was published, Leo already acted as associate editor, at the side of editor-in-chief prof. The formal difference between the two was cancelled in 1993, when both were mentioned on the journal s cover as plain editor. Throughout his research and teaching career Leo has always been involved with pathogens, rst of insects, later of mites. Therefore, it should not come as a surprise that I was struck by the idea to honour Leo s editorial retirement with a special journal issue dedicated to the subject that he nds most interesting: acarine pathogens and pathology. I discussed the idea with Leo, and was very pleased to learn that he not only appreciated the token, but also that he was willing to lend his expertise to the enterprise. Next, we asked about all relevant researchers we could think of to participate, and much to my surprise almost all accepted the invitation. The 24 contributions provide a wide variety of aspects of acaro- pathogens, just as we had hoped for. There are numerous highlights, but one particularly worthy of mention because it is the rst time in the journal s history, and because it is yet another token of appreciation is the formal description of an acaropathogenic fungus, new to science: Hirsutella vandergeesti. Diseases of mites and ticks: from basic pathology to microbial control an introduction Leo P. This effect was ascribed to the presence of an acaropathogenic fungus that was later described by Fisher (1950)asHirsutella thompsonii. It would still take several decades before any compre- hensive research would be conducted on pathogens of Acari. The current collection of 24 papers is a mixture of primary research articles and lit- erature reviews, presenting a broad overview of the developments in about all possible aspects of acarine diseases, stretching from basic pathology to microbial pest control. The pathogens include fungi, bacteria, and protozoa (as well as an occasional virus and unidentied organism), the hosts are mites and ticks from a variety of taxa (e. With such variety the contributions can be ordered in a near innite number of coherent ways, and we had to pick just one. Individual ticks are frequently infected by more than one (type of) pathogen, which may interact in various possible ways. Ginsberg presents a literature review of the possible effects of coinfection of ticks, and a simple model linking the implications of coinfection with pathogen trans- mission. Very different, yet equally basic, is the intriguing case study of the association L. The genus Neozygites has a worldwide distribution and it is well known for its entomo-/acaropath- ogenicity. Inventories in Poland and several other Central-European countries show the presence of Neozygites spp. Still mainly descriptive, but increasingly applied, is the extensive review of fungi found in association with a variety of tick species in South America (Fernandes and Bittencourt). An isolate of Beauveria bassiana has previ- ously been found to induce the falling of Varroa destructor Anderson and Trueman from bees. Commercial products based on entomopathogenic fungi are being applied in a growing number of control programmes against plant pests, but their application against animal ectoparasites lacks behind, as Polar et al. Still, laboratory studies as well as pasture applications of several fungal products have shown great promise. Instead of treating large areas of eld, it could be much more cost effective if cattle were treated topically, but so far topical application has shown variable results. One relevant feature of topical application of a myco-acaricide exposure to sunlight is explored in more detail in an experimental study by Hedimbi et al. Conidial suspensions of a variety of fungus species and strains were tested against the broad mite, Polyphagotarsonemus latus (Banks) on mulberry (Maketon et al. Acaropathogenic fungi may also help in the control of another mite also tiny, yet devastating, with a hidden lifestyle the coconut mite Aceria guerreronis Keifer. Kumar and Singh report the effect of a mycelial sus- pension of Hirsutella thompsonii against this eriophyid mite. Hirsutella thompsonii has been developed to a biological miticide by McCoy and co-workers in the 1970s for the control of the citrus rust mite in citrus orchards (cf. However, commercial develop- ment of mycelial preparations against the citrus rust mite failed because of lysis of hyphal material during storage and for that reason, the work was discontinued. Recently, the fungus has received renewed attention for the control of other eriophyids, e. Successful attempts have been made in India to develop a biological acaricide with the fungus as active ingredient (Kumar and Singh). Hirsutella thompsonii and several other fungi are also studied in Israel by Gerson and co-workers, especially for their effect on citrus rust mite, but also some others. They report some very promising results of a couple of recently described fungi (two Meira species and Diseases of Mites and Ticks 5 an Acaromyces), including their probable compatibility with currently used chemical pesticides. Entomophthoralean infections are well-known in insect and mites, particularly in spider mites. The best-studied species is probably Neozygites tanajoae, a fungus that is specic for the cassava green mite, Mononychellus tanajoa (Bondar). In the 1980s, the fungus was considered to be a possible classical biological control agent that could be the solution for the enormous infestations in cassava by M. In this issue, Hountondji reviews the current status of microbial control of the cassava green mite in Africa. A second paper on much the same players, but now on the Brazilian site of the system, explores the possible causes of failing control of M. A series of contributions deals with the control of Tetranychus species, most noticeably the two-spotted spider mite, T. Pseudomonas putida, a saprotrophic bacterium isolated from the soil in a Turkish greenhouse, appears to have T. Klingen and colleagues investigated the overwintering capa- bility of Neozygites oridana in hibernating T. It turns out that the insulation experienced within the mites bodies allows the fungus to survive the winter and to sporulate and infect new spider mites in early spring. The inuence of temperature and humidity regimes on the efcacy of conidial suspensions of Beauveria bassiana against especially the egg stage of T. Like the cassava green mite, also the tomato red spider mite, Tetranychus evansi Baker and Pritchard, is suspected to originate from South America. Tetranychus evansi specializes on solanaceous horticultural crops, especially tomato. Under the hot and dry conditions of eastern and southern Africa it can wipe out whole tomato plants within a month. Biological pest (mite) control by means of benecial insects and/or mites has seen a rapid development since the 1960s. A well-known example is the phytoseiid mite Phy- toseiulus persimilis Athias-Henriot. However, in a number of instances, control was unsatisfactory due to suboptimal performance of the 6 J. It turned out that pathogens could negatively affect predator populations, thus hampering the success of pest control. Bjrnson gives a crisp and concise overview of the various types of pathogens (viruses, bacteria, microsporidia) that can pop up in mass-rearings of com- mercial phytoseiid biocontrol agents. Schutte and Dicke treat partly the same subject, but it a much wider context they systematically, consistently and carefully review all (possible) microorganisms known to have some negative effect on phytoseiid mites. In passing, they provide much inside information on their own 10-year quest for the agent, causing the strange behavior and poor performance of P. Finally, Hoy and Jeyaprakash extend the subject of pathogens from predatory mites to endosymbionts, focussing on their pet phytoseiid biocontrol agent, Metaseiulus occidentalis. Although the study of these endosymbiotic bacteria, such as Wolbachia and Cardinium, is still relatively new, they have already been found to be virtually omnipresent they have been found in many groups of invertebrates and they may have a great impact on the population dynamics of a species. Although we feel this collection of papers offers a rich variety of sides to the subject of diseases in mites and ticks, complete coverage of mite pathology is not possible in a single volume of Experimental and Applied Acarology. We cordially thank all contributing authors, as well as the more than 50 peer reviewers, who helped us to prepare this end result.
Because of its direct impact on responsiveness to treatment buy deltasone 5 mg free shipping, a signi- cant concern was a potential imbalance in disease severity between treatment groups purchase deltasone 5 mg online. It was hoped that this would improve the eciency of the comparisons for a small study generic 10mg deltasone fast delivery. These sites also administered study drug, but because of the burden of administering weekly infusions of study drug to 90 patients, other centres were recruited to perform study drug infusions but not clinical testing. The primary end point showed the greatest statistically signif- icant dierence between the weekly Elaprase-treated group and the placebo group (p 0. It was also evident that the weekly dosing regimen was superior to the every other week dosing regimen of Elaprase. In contrast, the every other week dosing regimen did not reach statistical signicance for any of these outcomes. In terms of joint range of motion, only an improvement in elbow mobility was detected between the weekly Elaprase and placebo groups. Infusions of Elaprase were generally well tolerated, with no patients withdrawing from the 1 year study due to an infusion-related reaction. Although certain patients in the Elaprase-treated groups developed IgG antibodies to Elaprase during the course of the study, there was no mean- ingful correlation of these antibodies with adverse events or clinical assessments. View Online Discovery and Clinical Development of Idursulfase 179 The percentage of patients developing antibodies to idursulfase has ranged from 51% to 68%, with a proportion having antibodies that neutralise either the uptake of idursulfase into cells or enzymatic activity. Antibody-positive patients appear to have a higher incidence of hypersensitivity reactions and a reduced systemic exposure to idursulfase. Not surprisingly, an association between the patient s genotype and immunogenicity has been observed, indicating that the patient s endogenous expression of iduronate-2-sulfatase (lack of expression or expression of an altered protein) is an important factor in idursulfase immunogenicity. Regardless of antibody status, however, Elaprase treatment has continued to result in pharmacodynamic and clinical eects. It was clear that the weekly dosing regimen, which allowed Elaprase to be continuously present in the tissues, was critical for demonstrating ecacy and clinical benet. In addition, the composite scoring approach resulted in a powerful and sensitive analysis for the primary ecacy end point. This process resulted in Elaprase having a human glycosylation prole, analogous to the naturally occurring enzyme. The clinical development of rare disease therapies must be thoughtfully optimised to be able to successfully demonstrate clinical benet in small heterogeneous patient populations with therapeutics that are unique and complex. Committee on Strategies for Small-Number-Participant Clinical Trials, Institute of Medicine, Small Clinical Trials: Issues and Challenges, ed. In the mid-1990s the ability to produce human antibodies with high anity for the target molecule by immunisation of mice carrying the human antibody repertoire was developed to maturity. HuMab mice carry part of the human antibody repertoire of the IgG1 heavy and light chain, giving rise to a human antibody response to administered antigens. Several dierent antibodies emerged from this endeavour, and two of them were progressed into pre-clinical development. This exquisitely high species selectivity posed a problem for the pre-clinical development of canakinumab, as the commonly used macaque non-human Table 8. Marmoset monkeys belong to the group of non-human primates, and breeding colonies for pharmacological testing exist for this species. Therefore, marmoset monkeys fullled the criteria of a relevant species for toxicological examination of canakinumab. However, toxicological studies required for the clinical development of antibodies in marmoset monkeys were never reported before, and reagents for immunophenotyping in this species were largely lacking. Standard 4, 13 and 26 week toxicology for canakinumab and part of the embryo-foetal development programme was conducted in marmosets without revealing pre-clinical safety signals (Table 8. The most straightforward understanding of the aetiology of a disease comes from studies on monogenetic diseases in which the physiology of the aected gene product is linked to known pathophysiological pathways. Complete clinical responses were subsequently observed in the same patients 1 upon i. Canakinumab exhibits dose-proportional 1 pharmacokinetics, both when given as an i. Maximum serum concentrations (Cmax) reached by the marketed strength of 150 mg is 1 40 about 16 mgmL aer s. Based on the data obtained from seven patients, Monte Carlo simulations were run, and the derived are-probability model predicted that a dose regimen of 150 mg s. Those patients with a complete response to treatment in part 1 entered part 2 and were randomly assigned to either 150 mg of canakinumab or placebo every 8 weeks for up to 24 weeks. Previous medication with canakinumab or anakinra was permitted, but enrolment in the open-label part 1 required a discontinuation of previous treatment and recurrence of disease. Thirty-four out of 35 patients who entered part 1 of the study had a complete response to a single dose of canakinumab. Thirty-one patients who maintained complete response during the 8 week period of part 1 were randomised to either placebo or a 150 mg s. All 15 patients in the canakinumab group remained in remission during the 24 week time period of part 2. Flares occurred in this group starting at 12 weeks aer the rst dose and throughout the 24 weeks of part 2. Disease activity was judged absent or minimal in >85% of patients by day 8 and at the end of part 1, and clinical response was maintained until the end of study. The median duration of treatment was 414 days (range 29 687 days) in the entire cohort. Another 23 patients showed a partial clinical response with the rst 3 weeks of treatment. Available data from 141 patients showed that 90% of the patients had no relapse with the chosen 8 weekly dosing interval and the established dose. Improvement in neurological manifestation was observed in 9 out of 20 patients with observed neurological abnormalities. Hearing normalised or improved in a fraction of patients during the 2 year study period. In general, canakinumab was well tolerated and most adverse events were transient and mild in nature. Reported adverse events did not cluster around a specic phenotype or age group, other than more infections reported in children. In the 2 year study the most common infection-related adverse events were bronchitis (event rate per patient-year 0. The most common observed adverse eects are a mildly increased rate of infec- tions, which is compatible with its mode of action. Although these infections are mostly upper respiratory tract or urinary infections, some cases of severe bacterial infections have been observed in the overall development pro- gramme for canakinumab. Mild, transient and asymptomatic cases of elevations of serum transaminases, bilirubin or triglycerides have been re- ported in clinical trials. Transient episodes of neutropenia have been observed under treatment with canakinumab. Deciency in this enzyme leads to accumulation of mevalonate, and further downstream in the pathway to a shortage of iso- prenoids, like farnesyl- and geranylgeranylpyrophosphate. The aetiology of Schnitzler s syndrome, another extremely rare auto-inammatory disorder, is unknown, but excellent clinical responses to treatment with canakinumab or anakinra have been reported. The eld of rare monogenic diseases constitutes a unique opportunity to develop drugs on genetically validated targets. Positive target engagement with the appropriate safety prole should guarantee a successful clinical development and translate into patients with the desired disease-modifying therapeutic eect. Nevertheless, the eld of rare genetic diseases is still largely an uncharted territory for drug development. Most of the genetically validated targets are non-druggable targets or pathways, not always easily amenable to high- throughput discovery technologies and without a track record for lead generation. Natural history studies for these diseases are scarce and vali- dated clinical end points are lacking for most of them. Among the rare genetic diseases, the eld of protein misfolding diseases witnessed several successful drug development stories in the past two decades (Table 9. Since 1994 and the approval of Ceredase and Cerezyme for the treatment of Gaucher disease, treatments have been identied in several rare genetic diseases caused by protein misfolding.
The sequence data were unique cheap 40 mg deltasone, but most closely related to sequences obtained from GenBank from Nosema apis (U26534) generic deltasone 5mg on line, N deltasone 20 mg visa. There are other recent examples where mor- phological and molecular data conXict and future molecular data on microsporidia from other mites and arachnids, as well as members of the Unikaryonidae, may establish better relationships. Infection status appeared to have no eVect on male longevity or progeny survival to larval and adult stages. Three diVerent heat treatments were tested to determine if it was possible to heat-cure the colonies (Olson and Hoy 2002). By contrast, Diseases of Mites and Ticks 333 when Go eggs were deposited within the growth chamber and they and their progeny (G1) were reared to adulthood at 33 C, all the G1 mites were disease free. We had no evidence that the microsporidia are transmitted in feces of infected mites. The crowding and stress associated with mass rearing would facilitate the spread of the disease, especially if prey densities were inadequate. Other species of microsporidia have been found infecting other species of predatory mites, including Phytoseiulus persimilis Athias-Henriot (Bjornson et al. These colonies were examined because they were producing few eggs and several colonies died out. The sick mites had two diVerent pathologies: some adult females were plump and had a cream to pink plug that extruded from the rectum. The second pathology aVected females and immatures; in this case the mites became very pale and thin. These females failed to oviposit and the immatures often died, especially during their molts. The two forms were described based on cell wall structure and cytoplasmic inclusions, although the forms were also described as pleomorphic (Hess and Hoy 1982). Type A was observed in all mites examined, while type B was observed in approximately two-thirds of the sick and healthy mites examined. Type B microorganisms occurred in all ovaries and eggs, indicating transovarial transmission may take place. In some mites, large numbers of type B bacteria were observed in all the internal organs, within the hemocoel, and within Malpighian tubule lumens and in the rectal plug. Because Rickettsia are intracellular microorganisms, their presence outside of tissues suggests they were pathogenic to their host cells. Exterior to the plasma membrane was a clear zone of variable width (12 15 nm) inside of which an intermediate electron-dense layer was often seen. Another diagnostic of this organism was an internal fascicle of parallel-arranged tubular structures approximately 11 nm in diameter extending trans- versely through the organism. These tubular structures were associated with an electron- dense plate through which they extended to connect to the plasma membrane. These were most numerous in the midgut, Malpighian tubules, and epider- mis; their numbers increased to the point of Wlling the cytoplasm of a cell when type B microorganisms were also present. Type B microorganisms were both intra- and extra-cellular, were rod-shaped, measuring 0. They often had an indistinct internal unit membrane 7 m wide and were bounded by an outer trilaminar mem- brane of about 9 nm. Type B organisms varied considerably in substructure, but all possessed the same bounding membranes. Group B organisms were also found within membrane-bound vacuoles of cells similar in structure to the mycetomes of insects (Hess and Hoy 1982). To our knowledge, mycet- omes have not been identiWed in the Phytoseiidae, but should be looked for because their presence suggests a very longterm relationship between the mite and the microbial inhabit- ants of the mycetomes. The substructure of the microorganisms within the membrane- bound vacuoles diVered from that of the microorganisms found free in the hemocoel and within the ovary, suggesting there might have been a third type of microorganism pres- ent. Because Hoy and Jeyaprakash (2005) found two bacterial species (Bacteroidetes and Enterobacter) typically associated with the gut of arthropods within M. These data suggest, but do not prove, that titers of one or more endosymbiont could increase in stressed mites, leading to disease. Infection by a particular bacterium may be beneWcial to a host under some circumstances but harmful in other hosts or environments. Hoy and Jeyaprakash (2005) subse- quently found a Rickettsia-like organism in some populations of T. Without molecular data to identify the bacteria it is diYcult to compare past and current observations. Recent surveys, however, have shown that Rickettsia are found fairly often in arthropods and other invertebrates, even though the arthropod hosts are not associated with vertebrates. These results suggest that poor mass-rearing conditions could facilitate the infection of M. Symbionts of Metaseiulus occidentalis The mitochondrion: the ultimate microbial endosymbiont Mitochondria are descended from microbial endosymbionts and are now essential cellular organelles. The gene order is completely diVerent from the pattern in mitochondria from all other known Chelicerata. Because Enterobacter strains are usually found associated with the digestive tract in arthropods, we concluded that it is likely that the two unidentiWed strains of Entero- bacter in M. As noted by McCutcheon and Moran (2007), Bacteroidetes species are widely distributed in the environment and can be found in coastal marine waters, the human gut and dental plaques, and in insects. McCutcheon and Moran (2007) sequenced the genome of a Bacteroidetes species (Sulcia) that was isolated from the bacteriome of the sharp- shooter Homalodisca vitripennis (German) and found that its genome was extremely reduced (to only 245 kb, encoding 228 protein genes), which is approximately one-tenth the size of the smallest known Bacteroidetes genome. It appears that the metabolic capabilities of Sulcia and Baumannia (the other symbiont of the sharpshooter) are broadly complementary in that Sulcia is primarily devoted to amino acid biosynthesis whereas Baumannia is primarily devoted to cofactor and vitamin synthesis (McCutcheon and Moran 2007). It is interesting to note that all Cardinium sequences cluster together, as expected. It also clusters with the endosymbiotic bacteria associated with bacteriomes from armored scale insects (Gruwell et al. The main anomaly in this clade is the endosymbiont from the ladybeetle Coleomegilla maculata (Mulsant), which Hurst et al. Alternatively, other Bacteroidetes species (especially Cardinium) have been implicated as causing reproductive incompatibility, parthenogenesis, or feminization in some arthro- pods (Hunter et al. Clearly, much more needs to be learned about the role of Bacteroidetes species in arthropod biology. As expected, both the Wolbachia and bacteria related to Candidatus Cardinium hertigii are transovarially transmitted (Jeyaprakash and Hoy 2004). The role(s) that the Enterobacter, Wolbachia, Cardinium or unnamed species of Bacter- oidetes symbionts play remains unclear due to several methodological diYculties (and due to a lack of resources to conduct the experiments). Without conducting in situ hybrid- ization on diVerent tissues using probes speciWc for these microorganisms, we can only speculate that they are restricted to speciWc tissues. Some Wolbachia, for example, can be found in tissues other than the reproductive tract in other arthropods. Other potential endosymbionts, including pathogens Enigl and Schausberger (2007) conducted a survey of seven species of phytoseiids using Wolbachia, Cardinium, and Spiroplasma primers. Spiroplasma was detected in the phytoseiid Neoseiulus (Amblyseius) californicus (McGregor), but none of the other phytoseiid species tested. This bacterium reduced longevity and fecundity and altered behavior, reducing attraction to herbivore-induced plant volatiles, which could reduce eYcacy of these important natural enemies in augmen- tative biological control programs. Wolbachia infection dynamics in experimental laboratory populations of Metaseiulus occidentalis Wolbachia has been shown to increase the prevalence of Wolbachia-infected hosts in a population (reviewed by Johanowicz and Hoy 1999). Models using three parameters (the proportional failure of a mother to transmit Wolbachia to her oVspring, the proportion of progeny produced by incompatible crosses relative to compatible crosses, and the relative Wtness of infected matings relative to uninfected matings) have been used to predict whether Wolbachia would sweep through a population, which could be useful in driving useful genes into target populations in genetic manipulation projects. Unfortunately, at the time of this experiment, we were not aware that this population was also infected with Cardinium, Enterobacter or the unnamed species of Bacteroidetes. Alterna- tively, the failure to eliminate both bacteria could be because the Wolbachia or Cardinium genomes have been incorporated into the nuclear genome of M. Diseases of Mites and Ticks 341 In any case, Johanowicz and Hoy (1999) found that the proportion of compatible crosses did not change over time in the mixed populations containing individuals putatively with and without Wolbachia. Furthermore, unexpected compatibility occurred, which could be explained most easily by imperfect maternal transmission of Wolbachia, at a rate of 0. Fewer daughters were produced in the incompatible crosses, which could be due to the eVects of Wolbachia (or Cardinium) on the parahaploid genetic system of M. Thus, the initial infection frequency of 10% was apparently below an unstable equilibrium frequency (HoVman et al.
The typical approach to syn- thesis uses an academic discipline to focus a biological subject order deltasone 5mg with mastercard. I use the biological problem of parasite variation to tie togethermanydierent approaches and levels of analysis buy discount deltasone 10 mg on line. Why should parasitevariationbethe touchstone for the integration of disciplines in modern biology? On the practical side purchase 10mg deltasone visa, infectious dis- ease remains a major cause of morbidity and mortality. Consequently, great research eort has been devoted to parasites and to host immune responses that ght parasites. This has led to rapid progress in under- standing the biology of parasites, including the molecular details about how parasites invade hosts and escape host immune defenses. But many parasites escape host defense by varying their antigenic molecules recognized by host immunity. The challenge has been to link molecular understanding of parasite molecules to their evolutionary change and to the antigenic variation in populations of parasites. On the academic side, the growth of information about antigenic vari- ation provides a special opportunity. For example, one can nd in the literature details about how single amino acid changes in parasite mol- ecules allow escape from antibody binding, and how that escape pro- motes the spread of variant parasites. Evolutionary studies no longer depend on abstractions one can pinpoint the physical basis for success or failure and the consequences for change in populations. Molecular understanding of host-parasite recognition leads to a com- parative question about the forces that shape variability. Why do some viruses escape host immunity by varying so rapidly over a few years, whereas other viruses hardly changetheirantigens? The answer leads to the processes that shape genetic variability and evolutionary change. The causes of variability and change provide the basis for understanding why simple vaccines work well against some viruses, whereas complex vaccine strategies achieve only limited success against other viruses. Rather, I have long been interested in how the molecular basis of rec- ognition between attackers and defenders sets the temporal and spatial scale of the battle. The battle often comes down to the rates at which attacker and defender molecules bind or evade each other. The bio- chemical details of binding and recognition set the rules of engagement that shape the pacing, scale, and pattern of diversity and the nature of evolutionary change. Of the many cases of attack and defense across all of biology, the major parasites of humans and their domestic animals provide the most information ranging from the molecular to the population levels. New advances in the conceptual understanding of attack and defense will likely rise from the facts and the puzzles of this subject. From that foundation, I describe new puzzles and dene the key problems for the future study of parasite variation and escape from host recognition. I summarize the many dierent ways in which parasites generate new variants in order to escape molec- ular recognition. Next, I build up the individual molecular interactions into the dynam- ics of a single infection within a host. Theparasites spread in the host, triggering immune attack against dominant antigens. 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 specically bind to particular antigens. Ithendiscusshow the successes and failures of dierent parasite antigens within each host determine the rise and fall of parasite vari- ants over space and time. The distribution of parasite variants sets the immune memory proles of dierenthosts,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. 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. How do the molecular details of recognition and specicity 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 dierent 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 ospring decay their population-wide memory of antigens faster than do host species that reproduce more slowly. How do these epidemiological and demographic processes inuence molecular variation of parasite antigens? 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 dierent levels of biological analysis. I present enough about the key cells and molecules so that one can understand how immune recog- nition shapes the diversity of parasites. 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 dierent variant of that parasite. The nature of recognition depends on specicity, the degree to which the immune system distinguishes between dierent antigens. Sometimes two dierent antigens bind to the same immune receptors, perhaps with dierent binding strength. Cross- reactivity may also interfere with immune recognition when immune receptors bind a variant sucientlytopreventanewresponse but not strongly enough to clear the variant. Many parasites generate variants by the stan- dard process of rare mutations during replication. Although mutations occur rarely at any particular site during replication, large populations generatesignicant numbers of mutations in each generation. 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. This immunodominance arises from interactions between the populations of immune cells with dierent recognition specicities 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 specicities become amplied. I then discuss how other parasites extend infection by switching gene expression between vari- ants stored within each genome. The dierent 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. This host variability can strongly aect the relative success of antigenic variants as they attempt to spread from host to host. Hosts also dier in mi- nor ways in other genetic components of specic recognition. These quantitative dierences in the timing and intensity of immune reactions provide an interesting modelsystemforstudying the genetics of regulatory control. Each host typically retains the ability to respond quickly to antigens that it encountered in prior infections. This memory pro- tects the host against reinfection by the same antigens, but not against antigenic variants that escape recognition.
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Exercise and dietary weight loss in overweight and obese older adults with knee osteoarthritis: the Arthritis, Diet, and Activity Promotion Trial. Change in body fat, but not body weight or metabolic correlates of obesity, is related to symptomatic relief of obese patients with knee osteoarthritis after a weight control program. Musculoskeletal findings in obese subjects before and after weight loss following bariatric surgery. Sule and Michelle Petri Summary There are interesting data on nutritional supplementation in the treatment of systemic lupus erythematous. However, at this time, there is little convincing human data to support dietary modifications or nutritional supplementation. The course can be quite variable, ranging from intermittent exacerbations to severe, life-threatening disease. Females are affected nine times more frequently than men, and disease preva- lence is higher in African Americans, Asians, and Hispanics. However, studies examining the role of dietary modification have shown some promise. These autoantibodies are deposited in the kidneys by 4 to 5 months of age, leading to nephritis and renal disease by 9 to10 months of age (1). Caloric restriction in this murine model has a profound effect on the onset and progression of nephritis and has been shown to improve survival (2). In B/W mice, the life span is increased from 345 days in controls to 494 days in caloric-restricted mice. The calorie restriction (40% less food) also significantly delays the onset of nephritis. By 14 months of age, 0% of the calorie-restricted mice develop nephritis, compared with 100% of the controls (3). However, in order to implement this calorie restriction in humans, 25 to 35% or more of total intake would have to be cut, beginning before adolescence and continuing for life. Low-Protein Diets High protein intakes have been associated with acceleration of kidney damage in both humans and experimental animals (7). In humans, protein restriction has long been a recommended treatment modality in patients with renal failure. Dietary Fat Intake Over the last 20 years, there have been numerous studies of fatty acids and their role in inflammation. Omega-3 (n-3) and omega-6 (n-6) fatty acids are considered essential fatty acids, which means that they are essential to human health but cannot be made in the body and must be obtained from food. Both types of fatty acids play a crucial role in brain function as well as normal growth and development (12,13). The n-3 fatty acids have anti- inflammatory, anti-arrhythmic, and anti-thrombotic properties (14). The n-3 polyunsaturated fatty acids are found in oily fish and vegetable sources such as the seeds of chia, perilla, flax, and walnuts. Fish-oil supplementation also improves survival in female mice and decreases proteinuria. The anti-inflammatory effects of fish oil seem to depend on the synergistic effects of at least two n-3 fatty acids. The 18 g of fish-oil supplement reduced triglycerides by 38%, very low-density lipoprotein cholesterol by 39% and increased high-density lipoprotein cholesterol by 28%. Twenty-six patients with lupus nephritis were given fish oil in a double-blind cross-over trial. Vitamin E Vitamin E, a fat-soluble vitamin, is an antioxidant vitamin involved in the metabolism of all cells. It protects essential fatty acids from oxidation and prevents breakdown of body tissues. A meta-analysis of 135,967 participants in 19 clinical trials identified a dose-dependent relationship between vitamin E and all-cause mortality. Selenium Selenium is a natural antioxidant associated with anti-inflammatory properties. Levels of blood glutathione-peroxidase increase after selenium and vitamin E supplementation. Signs of selenium toxicity include diarrhea, vomiting, hair and nail loss, and lesions of the central nervous system. It acts as a catalytic regulatory ion for enzymes, proteins, and transcription factors. As opposed to other dietary manipulations, zinc restriction was found to be beneficial both early (after weaning) and later in life (at 6 months of age). However, if the zinc deficiency was introduced later in life (at 10 weeks of age), it had little beneficial effect on disease progression (31). These data suggest that there is a critical period in which manipulation of dietary zinc can alter the course of autoimmune disease. In those who were compliant, serum creatinine during flaxseed administration declined from a mean of 0. Reported complications include diarrhea, infertility, and one reported case of death resulting from cardiac shock (35). Dehydroepiandrosterone Autoimmune diseases are more prevalent in women and immune responses may be influenced by sex hormones. Renal histopathology was more severe in iron-supplemented mice than in pair-fed control mice. Immunostaining with anti-IgG and anti-C3 in severely iron-deficient mice (fed 3 mg iron/kg, normal: 35 mg/kg) was more intense. Additionally, the concentration of circulating immune complexes in serum was significantly higher in severely iron- deficient mice, compared with controls (41). This suggests that alterations in serum iron concentration can worsen disease in lupus-prone mice. It has been used by the Chinese since the 6th century to treat kidney stones and edema. Autoimmune mice fed l-canavanine had increased autoantibody production and higher renal histology scores compared to normal controls. In vitro experiments suggest that l-canavanine, an amino acid in alfalfa sprouts, suppressed T-cell regulation of antibody synthesis and lymphocyte proliferation (44). In an analysis of the Baltimore Lupus Environment Study, ingestion of alfalfa sprouts was significantly associated with the development of lupus (45). Conflicting data exist regarding efficacy in shortening the duration of cold symptoms (47 50). Echinacea is known to have immunostimulatory effects on natural killer cells, neutrophils, and monocytes (51 53). These cells have been shown to be increased in both the bone marrow and spleen as soon as 1 week after starting therapy. Noni Juice (Morinda citrifolia) Noni juice is prepared from the fruit of Morinda citrifolia, a Polynesian plant. Reported manufacturer health claims include improvement in arthralgias, fibromyalgia, and cancer; however, there is very little scientific data regarding noni juice.
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