Mark Corson

P. Milten. University of Texas of the Permian Basin.

Several parasites such as Trypano- soma brucei and Borrelia hermsii store archival libraries of antigenic variants discount cardura 4mg free shipping. Strong positive selec- tion probably favored diversicationofthearchival variants during the initial evolution of antigenic switching cheap cardura 2 mg with amex. However cheap cardura 4 mg with visa, once a genome con- tains a large library of diverged variants, negative selection may act pri- marily to retain the existing antigenic dierences between the variants. Their sampling did not provide multiple alleles at individual loci, so they did not report on the selective pressures re- cently acting on each individual locus. An extended study that analyzed variation within and between loci would be interesting. Rare antigenic variants often have an advantage because they encounter specic immune memory less often thancommon antigens. Conway (1997) suggested that this rare-type advantage promotes a bal- anced distribution of allele frequencies among antigenic variants. By this theory, such balancing selection reduces the uctuations in allele frequencies when compared with loci experiencing little or no selection. The neutral loci would have allele frequencies drifting over time and space, whereas the balanced antigenic loci would face a continual pres- sure to raise any allele frequency that temporarily dropped to a low level. Conway (1997) suggested that one could infer which loci experienced strong immune selection by examining the spatial distribution of al- lele frequencies. Balancing selection may cause immune-selected loci to have a more even, less variable distribution of allele frequencies across space than other loci. Theydivided the long (5 kb) msp1 gene into domains and measured the allele frequencies for each domain over six African and two Southeast Asian populations. Recombination occurs frequently within the gene, causing low linkage disequilibrium between domains. One domain, block 2,hadveryeven distributions of its three allelic types over the dierent populations within each continent. The other domains all had signicant variations in allele frequency over the populations. However, the theoretical prediction of relatively stable allele frequencies over space requires further study. In the typical model, frequency dependence causes strong uctuations in allele frequencies rather than stable allele frequencies. A rare parasite type, x,increasesbecause most hosts do not recognize the rare type. As x increases in frequency, thisfavorsanincrease in the frequency of the hosts that recognize x,causinginturnadeclinein the frequency of x. Conway (1997) suggested that frequency dependence stabilizes allele frequencies rather than causes enhanced uctuations. This may be true for the particular dynamics that follow from Plasmodium demography and the time course of host immune memory. However, this should be studied with theoretical models that analyze uctuations over space in antigenic allele frequencies and host memory proles. Recap of Some Interesting Problems 16 My Problems for Future Research span many dierent technical and con- ceptual challenges for understanding antigenic variation. These fty-six problems arise from my synthesis of the molecular processes of recog- nition, the dynamics of infections within hosts, the variability of popu- lations, and the methods for studying evolution. In- stead, I have chosen to recap four examples, to highlight the kinds of problems that integrate dierent levels of analysis. Measles can vary its dominant surface antigen, hemagglutinin, and limited variation does occur (Grin 2001). So it is an interesting puzzle why antigenic variants do not spread as in many other viruses. Perhaps the very high infectiousness of measles causes the common strain to spread so widely in the host population that little heterogeneity occurs among hosts in immune memory proles. If memory responds against a few dierent epitopes, then no single-step mutational change allows a measles variant to spread between previously infected hosts. The only nearby susceptible class of hosts arises from the inux of naive newborns, which depends on thebirthrate of the host population. This explanation for the lack of antigenic variation suggests that the epidemiological properties of the parasite and the demographic struc- ture of the hosts aect the patterns of molecular variation in antigens. These population processes do not control the possible types of varia- tion or the molecular recognition between host and parasite, but instead shape the actual distribution of variants. The lack of variation may simply reect conservation of some essential viral function in a domi- nant antigen, such as binding to host receptors. My point here is that the lack of molecular variation does not necessarily mean that the expla- nation resides at the molecular level. Population processes can strongly inuence the distribution of molecular variants. For example, ve or so amino acids determine most of the binding energy between an antibody and an antigen. Often a single amino acid substi- tution in the antigen can abolish the defensive capability of a particular antibody specicity for a matching epitope. This type of recognition is qualitative, in which a single change determines whether or not recog- nition occurs. But the dynamics of an infection within a host depend on all of the parasite s epitopesandallofthe specic B and T cell lineages that recognize dierent epitopes.

In Australia cardura 4mg amex, the main focus is North Queensland purchase cardura 4 mg otc, with 92 cases reported over the past 44 years [10] cardura 2 mg with mastercard. The exact mode(s) of transmission from the environment and the ultimate natural source(s) of infection remain obscure. One plausible mode of transmission is local, minor, often unnoticed skin trauma that permits inoculation of M. Clinical picture Infection versus disease Somewhat similar to tuberculosis, exposure of cutaneous tissues to M. Delayed onset of disease, that is, 3 months after leaving an endemic area, may represent activation of latent infection. In contrast, the incuba- tion period may occasionally be short (15 days), with lesions developing in proximity to a bruise or sprain, without clinically detectable damage to the skin. Nonulcerative forms often occur in early stages, sometimes ignored by patients, and occasionally heal spontaneously. Disseminated disease involves lesions present at dif- ferent sites, sometimes in different morphologies. As such, it is important to examine patients thoroughly, looking for new and old lesions. In Africa, osteomyeli- tis, either contiguous or metastatic, is observed in approximately 10% of patients. Contiguous osteomyelitis involves reactive osteitis beneath destroyed overlying skin and soft tissue. Bone disease should be referred for specialty care to reduce the risk of serious consequences, such as limb amputation. Adhesion and contracture of periarticular scars reduce joint range of motion, which may then ankylose and become largely immobile. Squamous cell carcinoma (Marjolin s ulcer) may develop in unhealed lesions or scars, the latter espe- cially in hypopigmented areas. Clinical differential and diagnosis Differential diagnoses include bacterial, deep fungal and parasitic infec- tions, inammatory lesions, and tumors. If surgery is conducted, specimens should be collected from excised tissues for bacte- riological and histopathological analyses. Sampling at least two sites of each lesion is suggested, which may increase sensitivity over a single sample 102 Imported Skin Diseases by up to 25%. Direct smear and culture provide about 60% sensitivity for nodules, versus up to 80% for edematous forms. At the community level, direct smears are useful, but rapid diagnostic tests are needed. Antibiotics were generally considered ineffective, even though by the 1970s encouraging reports of rifampicin (R) antibiotic therapy for early lesions appeared [25]. However, the timing of surgery in relation to antibiotic adminis- tration is unclear. All-oral regimens are less toxic, convenient alterna- tives to R + S that may improve compliance, and are especially relevant in pregnancy, in which streptomycin is contraindicated [35]. Lesions developing after treatment completion may represent anamnestic-like immune responses to clear subclinical foci of M. Proceed- ings of the National Academy of Sciences of the United States, 101, 1345 1349. Guidance on sampling techniques for laboratory- conrmation of Mycobacterium ulcerans infection (Buruli ulcer disease). The term pyoderma covers several clinically distinct skin lesions that are mainly caused by Staphylococcus aureus or group A -hemolytic streptococcus. Generally, there seems to be no difference in the colonization of chronic wounds in the tropics as compared with those in the temperate developed regions of the world. However, the prevalence of antimicrobial resistance, which is high in some locations in the tropics, may complicate treatment. Microcirculatory disturbances leading to sub- clinical edema, especially in the lower legs, have been noted in travelers. Leishmaniasis should always be considered in returning travelers, but diphtheria is probably often overlooked [4,5]. However, there are only few published studies available on the prevalence or the incidence of pyoderma under tropical conditions [6]. A study performed in Blantyre, Malawi did not show a high incidence of ulcerating pyoderma at the in- and the out- patient population at a hospital [7]. Skin lesions and the upper respiratory tract are the primary focal sites of infection. It seems that at least a minor trauma is necessary for the devel- opment of streptococcal pyoderma. Since protecting clothing is used less under tropical conditions, minor trauma of the skin is more likely to occur providing a port of entry for an infection. Carrier sites are the anterior nares, the perineum, the axillae, and the toe webs. Infec- tion may be initiated after colonization of skin lesions, especially moist Ulcerating Pyodermas 109 lesions. Whether an infection is contained or spreads depends on sev- eral complex factors such as the host defense mechanisms and the viru- lence of the S.

In summary cheap 4 mg cardura free shipping, there are a number of potential benefits of n-3 fatty acid supple- ments cardura 4 mg without prescription. Furthermore generic cardura 1 mg without a prescription, n-3 fatty acids have favorable cardiovascular benefits through anti-thrombotic properties. As discussed in the fish-oil section, n-3 fatty acids are anti-inflammatory and n-6 fatty acids are for the most part pro-inflammatory. However, certain n-6 fatty acids derived from plant seed oils have predominantly anti- inflammatory effects. In reports that showed benefit, the results became apparent after 3 to 4 months of supplementation. The study size was small with 19 subjects in the treatment group and 18 subjects in the placebo control group. Although no patients withdrew from the study because of adverse effects, a 28% withdrawal rate was observed in each group, perhaps because of the large number of capsules administered. There was no statistically significant improvement in the primary end point of fatigue. Consumption of borage seeds is not recom- mended during pregnancy and lactation due to potential contamination with liver-toxic pyrrolizidine alkaloids (45). Vitamins Vitamins are organic compounds that are required in small amounts for normal metabolism. The human body does not synthesize vitamins, except for vitamin D; therefore, vitamins must be ingested in the diet. Therefore, vitamin supplementation has been promoted for good health and as a preventive measure against certain ailments. The evidence for vitamin supplemen- tation in rheumatic conditions is reviewed in the following section. Vitamin C is important for the growth, development, and enzymatic reactions of bone and cartilage. Vitamin C acts as an antioxidant in facili- tating the hydroxylation of proline and lysine to hydroxyproline and hydroxylysine in procollagen. These products are essential to the maturation of collagen molecules and, thus, to the construction of the extracellular matrix of cartilage. This may be related to alterations in enzymatic activity or reduc- tions in proline hydroxylation or both (52). It was hypothesized, because animals receiving higher doses had higher cartilages weights, that vitamin C protected against cartilage loss by stimulating collagen synthesis (53). However, more recent work has suggested that long-term exposure to vitamin C supplementation might have deleterious effects (54). Guinea pigs were supplemented with low, medium, and high doses of vitamin C for 8 months. On subsequent histological evaluation, the animals that had received the medium and high doses had more severe histological changes, including the formation of osteo- phytes. The investigators hypothesized that the process of chondrophyte formation, with evolution into osteophytes, may have been facilitated by the enhanced collagen synthesis afforded by higher doses of ascorbic acid. On the basis of the most recent guinea pig data, it has been suggested that vitamin C supplementation above the currently recommended daily doses of 75 to 90 mg not be advised (54). The only human data comes from an epidemiological investigation using the Framingham population (55). This relationship was statistically significant in men and African Americans, but not for women or other ethnic groups among 400 participants studied. There was no difference in medial or lateral tibial cartilage volume loss between the vitamin E-supplemented group and those who got placebo at the end of the trial. Furthermore, there was no relationship between dietary levels of antioxidants and cartilage volume loss. It is an essential cofactor in the formation of skeletal matrix proteins containing the -carboxyglutamic acid residue. These proteins have high affinity for calcium and phosphate allowing for mineralization of skeletal tissue. Insufficient vitamin K can lead to abnormal chondrocyte differentiation and endochondral bone formation (58,59). The vitamin-K dependent bone and cartilage proteins can inhibit excessive extracellular matrix calcifications believed to be responsible for abnormal osteophyte formation in osteoarthritis. This statistically significant effect was seen in the radiographs of the hands and knees of a cohort of 672 subjects (59). Glucosamine is an aminomonosac- charide that is a component of glycoproteins, proteoglycans, and glycosaminoglycans. Glucosamine and chondroitin levels are reduced or altered in osteoarthritic cartilage and synovial fluid (61,62). Therefore, the notion of replenishing these agents through dietary intake in order to reduce joint symptoms has been proposed. Orally administered glucosamine is detectable at low levels in the sera of human subjects, but there has been no direct demonstration that glucosamine is incorporated into cartilage (63). In the subjects who took 1,500 mg of glucosamine sulfate mixed with water, the serum glucosamine levels reached a maximum of 4. Based on the low serum levels achieved, the investigators concluded that it was unlikely that glucosamine contributed to proteoglycan synthesis in vivo. In addition to simply serving as building blocks of cartilage, glucosamine and chondrointin might affect the metabolism of cartilage constituents. It was shown in in vitro studies that glucosamine could stimulate proteoglycan synthesis by human chondrocytes and become incorporated into glycosaminoglycans (62,64).

The limited repertoire of eleven genes and the crude on-o switching suggest that variable expression hasmore to do with altering cell tropism than with escape from host immunity (Fussenegger 1997) purchase cardura 1mg with amex. On-o switches can also be created by short repeats in transcriptional control regions buy 4mg cardura with amex. Bordetella pertussis controls expression of two distinct mbriae by transcriptional switching (Willems et al purchase 2mg cardura with amex. Sequencesofabout 15 C nucleotides in the transcriptional promoters of each of the two genes inuence expression. The actual length of the poly-C sequence varies, probably by slipped-strand mispairing during replication. Thus, by the stochas- tic process of replication errors, the individual loci are turned on and o. Again, this sort of switching may have more to do with tissue tropism than with escape from immune recognition. For example, there may be a single active expression site at which transcription occurs. Occa- sionally, one of the variant loci copies itself to the expression site by gene conversion a type of intragenomic recombination that converts the target without altering the donor sequence. The genome preserves the archival library without change, but alters the expressed allele. The spirochete Borrelia hermsii has approximately thirty alternative loci that encode an abundant surface lipoprotein (Barbour 1993). The expression site is changed by gene con- version to one of the variant archival copies at a rate of about 104 103 percell division (Stoenner et al. A small number of antigenic variants dominate the initial parasitemia of this blood-borne pathogen. Those switches provide new variants that cause a second parasitemia, which is eventually recognized by the host and cleared. The protozoan Trypanosoma brucei has hundreds of alternative loci that encode the dominant surface glycoprotein (Barry 1997; Pays and Nolan 1998). Switches in expression occur at a rate of up to 102 per cell divi- sion (Turner 1997). The switch mechanism is similar to that in Borrelia hermsii gene conversion of archival copies into a transcriptionally ac- tive expression site. Thus, this parasite can also change expression by switchingbetween transcription sites. Thepromoter triggers transcrip- tion in only one direction, thus expressing only one of the two variants. The ends of the promoter have inverted repeats, which play a role in the recombination event that mediates the sequence inversion. Salmonella uses a similar mechanism to control agellum expression (Silverman et al. The variable part of the pilin gene has alternate cassettes stored in adjacent locations. Inverted repeats ank the pair of alternate cassettes, causing the whole complex occasionally to ip orientation. Several bacteriophage use a similar inversion system to switch genes encoding their tail bers, which determine host range (Kamp et al. These low-diversity switches provideonlyalimitedadvantage against immunity because, even if the switch rates were low, an infection would soon contain all variants at appreciable abundance. Thus, these switch mechanisms may serve mainly to generate alternative attachment vari- ants. Antigenic vari- ation appears to be common and to be caused by diverse mechanisms. Infection and reproduction in host erythrocytes determine the build- up of parasite numbers within the host (Mims et al. Each parasite exports only one var type to the erythrocyte surface, but a clone of par- asites switches between var types(Smith et al. Switching between var loci does not depend on the mechanism of gene conversion found in Borrelia hermsii and Trypanosoma brucei. There are at least eleven and perhaps as many as fty discrete genes that encode variants of p235 (Borre et al. Within an erythrocyte, the parasite develops a multinucleate stage and then divides into new merozoites that burst the host cell. They suggest that upon division into separate merozoites, each merozoite presents a dierent p235 protein on its surface. The various p235 mole- cules may facilitate invasion of dierent classes of erythrocytes. Other Plasmodium species express surface proteins that are distantly relatedtop235, but in those cases the surface molecules do not arise from an antigenically diverse, multicopy gene family (Barnwell 1999). Some of the Plasmodium species have diverged tens of millions of years ago, so it is not surprising that they have dierent strategies for attach- ment, immune evasion, and antigenic variation. The parasite expresses only a small subset of these genes in an infected erythrocyte. Sera from twenty-ve previously infected hosts provided a panel of antibodies to test for prior exposure to the vir gene products.