IL-12p40 Homodimer Ameliorates Experimental Autoimmune Arthritis

IL-23 is the key cytokine that induces the expansion of Th17 cells. It is composed of p19 and p40 subunits of IL-12. The p40 subunit binds competitively to the receptor of IL-23 and blocks its activity. Our aim was to assess the preventive and therapeutic effect of the IL-12p40 homodimer (p40)(2) subunit in autoimmune arthritis animal models. In the current study, using IL-1R antagonist-knockout mice and a collagen-induced arthritis model, we investigated the suppressive effect of (p40)(2) on inflammatory arthritis. We demonstrated that the recombinant adenovirus-expressing mouse (p40)(2) model prevented the development of arthritis when given before the onset of arthritis. It also decreased the arthritis index and joint erosions in the mouse model if transferred after arthritis was established. (p40)(2) inhibited the production of inflammatory cytokines and Ag-specific T cell proliferation. It also induced CD4(+)CD25(+)Foxp3 regulatory T (Treg) cells in vitro and in vivo, whereas the generation of retinoic acid receptor-related organ receptor gamma t and Th17 cells was suppressed. The induction of Treg cells and the suppression of Th17 cells were mediated via activated STAT5 and suppressed STAT3. Our data suggest that (p40)(2) suppressed inflammatory arthritis successfully. This could be a useful therapeutic approach in autoimmune arthritis to regulate the Th17/Treg balance and IL-23 signaling.1156Ysciescopu

Clinical and laboratory findings associated with severe scrub typhus

<p>Abstract</p> <p>Background</p> <p>Scrub typhus is a mite-borne bacterial infection of humans caused by <it>Orientia tsutsugamushi </it>that causes a generalized vasculitis that may involve the tissues of any organ system. The aim of this study was to identify factors associated to severe complications from scrub typhus.</p> <p>Methods</p> <p>We conducted this prospective, case-control study on scrub typhus patients who presented to the Department of Internal Medicine at Chosun University Hospital between September, 2004 and December, 2006. Cases were 89 scrub typhus patients with severe complications and controls were 119 scrub typhus patients without severe complications.</p> <p>Results</p> <p>There were significant differences in the absence of eschar, white blood cell (WBC) counts, hemoglobin, albumin, serum creatinine, fibrinogen, C-reactive protein (CRP), and active partial thromboplastin time (aPTT) between the two groups. Multivariate analysis demonstrated that only the following four factors were significantly associated with the severe complications of scrub typhus: (1) age ≥ 60 years (odd ratio [OR] = 3.13, <it>P </it>= 0.002, confidence interval [CI] = 1.53-6.41), (2) the absence of eschar (OR = 6.62, <it>P </it>= 0.03, CI = 1.22-35.8, (3) WBC counts > 10, 000/mm3 (OR = 3.6, <it>P </it>= 0.001, CI = 1.65-7.89), and (4) albumin ≤ 3.0 g/dL (OR = 5.01, <it>P </it>= 0.004, CI = 1.69-14.86).</p> <p>Conclusions</p> <p>Our results suggest that clinicians should be aware of the potential for complications, when scrub typhus patients are older (≥ 60 years), presents without eschar, or laboratory findings such as WBC counts > 10, 000/mm3, and serum albumin level ≤ 3.0 g/dL. Close observation and intensive care for scrub typhus patients with the potential for complications may prevent serious complications with subsequent reduction in its mortality rate.</p

Health Centre Surveys as a Potential Tool for Monitoring Malaria Epidemiology by Area and over Time

BACKGROUND: Presently, many malaria control programmes use health facility data to evaluate the impact of their interventions. Facility-based malaria data, although useful, have problems with completeness, validity and representativeness and reliance on routinely collected health facility data might undermine demonstration of the magnitude of the impact of the recent scaleups of malaria interventions. To determine whether carefully conducted health centre surveys can be reliable means of monitoring area specific malaria epidemiology, we have compared malaria specific indices obtained from surveys in health centres with indices obtained from cross-sectional surveys conducted in their catchment communities. METHODS: A series of age stratified, seasonal, cross-sectional surveys were conducted during the peak malaria transmission season in 2008 and during the following dry season in 2009 in six ecologically diverse areas in The Gambia. Participants were patients who attended the health centres plus a representative sample from the catchment villages of these health facilities. Parasitaemia, anaemia, attributable proportion of fever and anti-MSP1-(19) antibody seroprevalence were compared in the health facility attendees and community participants. RESULTS: A total of 16,230 subjects completed the study; approximately half participated in the health centre surveys and half in the wet season surveys. Data from both the health centre and community surveys showed that malaria endemicity in The Gambia is now low, heterogeneous and seasonal. In the wet season, parasitaemia, seroprevalence and fever prevalence were higher in subjects seen in the health centres than in the community surveys. Age patterns of parasitaemia, attributable proportions of fever and seroprevalence rates were similar in subjects who participated in the community and health centre surveys. CONCLUSION: Health centre surveys have potential as a surveillance tool for evaluating area specific malaria control activities and for monitoring changes in local malaria epidemiology over time

Clinical significance of hypoalbuminemia in outcome of patients with scrub typhus

<p>Abstract</p> <p>Background</p> <p>This study was designed to investigate the clinical significance of hypoalbuminemia as a marker of severity and mortality in patients with Scrub typhus.</p> <p>Methods</p> <p>The patients with scrub typhus were divided into two groups based on the serum albumin levels; Group I (serum albumin <3.0 g/dL) and Group II (serum albumin ≥3.0 g/dL). The outcome of patients with hypoalbuminemia was compared with that of normoalbuminemia.</p> <p>Results</p> <p>Of the total 246 patients who underwent the study, 84 patients (34.1%) were categorized as Group I and 162 patients were (65.9%) as Group II. Group I showed significantly higher incidence of confusion (24.6% vs. 5.3%, <it>p </it>< 0.001), pulmonary edema (15.8% vs. 3.2%, <it>p </it>= 0.002), pleural effusion (22.8% vs. 11.1%, <it>p </it>= 0.03), arrhythmia (12.3% vs. 2.6%, <it>p </it>= 0.008) and non-oliguric acute renal failure (40.4% vs. 11.1%, <it>p </it>< 0.001) compared to group II. Hypoalbuminemic group had a higher APACHE II score (11.37 ± 5.0 vs. 6.94 ± 4.2, <it>p </it>< 0.001), longer hospital stay (19.9 ± 42.1 days vs 7.5 ± 13.8 days, <it>p </it>= 0.012), and higher hospital cost compared to Group II.</p> <p>Conclusions</p> <p>This study showed hypoalbuminemia in scrub typhus was closely related to the frequency of various complication, longer hospital stay, consequently the higher medical cost, necessitating more efficient management of patients, including medical resources.</p

Determinants of GBP Recruitment to Toxoplasma gondii Vacuoles and the Parasitic Factors That Control It

IFN-γ is a major cytokine that mediates resistance against the intracellular parasite Toxoplasma gondii. The p65 guanylate-binding proteins (GBPs) are strongly induced by IFN-γ. We studied the behavior of murine GBP1 (mGBP1) upon infection with T. gondii in vitro and confirmed that IFN-γ-dependent re-localization of mGBP1 to the parasitophorous vacuole (PV) correlates with the virulence type of the parasite. We identified three parasitic factors, ROP16, ROP18, and GRA15 that determine strain-specific accumulation of mGBP1 on the PV. These highly polymorphic proteins are held responsible for a large part of the strain-specific differences in virulence. Therefore, our data suggest that virulence of T. gondii in animals may rely in part on recognition by GBPs. However, phagosomes or vacuoles containing Trypanosoma cruzi did not recruit mGBP1. Co-immunoprecipitation revealed mGBP2, mGBP4, and mGBP5 as binding partners of mGBP1. Indeed, mGBP2 and mGBP5 co-localize with mGBP1 in T. gondii-infected cells. T. gondii thus elicits a cell-autonomous immune response in mice with GBPs involved. Three parasitic virulence factors and unknown IFN-γ-dependent host factors regulate this complex process. Depending on the virulence of the strains involved, numerous GBPs are brought to the PV as part of a large, multimeric structure to combat T. gondii.National Institutes of Health (U.S.)Massachusetts Life Sciences Center (New Investigator Award)National Institute of General Medical Sciences (U.S.) (Pre-Doctoral Grant in the Biological Sciences (5-T32-GM007287-33))Studienstiftung des deutschen VolkesCancer Research Institute (New York, N.Y.)Cleo and Paul Schimmel FoundationBayer HealthcareHuman Frontier Science Program (Strasbourg, France

Compressed representation of a partially defined integer function over multiple arguments

In OLAP (OnLine Analitical Processing) data are analysed in an n-dimensional cube. The cube may be represented as a partially defined function over n arguments. Considering that often the function is not defined everywhere, we ask: is there a known way of representing the function or the points in which it is defined, in a more compact manner than the trivial one

Cellular responses to modified Plasmodium falciparum MSP119 antigens in individuals previously exposed to natural malaria infection

<p>Abstract</p> <p>Background</p> <p>MSP1 processing-inhibitory antibodies bind to epitopes on the 19 kDa C-terminal region of the <it>Plasmodium falciparum </it>merozoite surface protein 1 (MSP1₁₉), inhibiting erythrocyte invasion. Blocking antibodies also bind to this antigen but prevent inhibitory antibodies binding, allowing invasion to proceed. Recombinant MSP1₁₉had been modified previously to allow inhibitory but not blocking antibodies to continue to bind. Immunization with these modified proteins, therefore, has the potential to induce more effective protective antibodies. However, it was unclear whether the modification of MSP1₁₉would affect critical T-cell responses to epitopes in this antigen.</p> <p>Methods</p> <p>The cellular responses to wild-type MSP1₁₉and a panel of modified MSP1₁₉antigens were measured using an <it>in-vitro </it>assay for two groups of individuals: the first were malaria-naïve and the second had been naturally exposed to <it>Plasmodium falciparum </it>infection. The cellular responses to the modified proteins were examined using cells from malaria-exposed infants and adults.</p> <p>Results</p> <p>Interestingly, stimulation indices (SI) for responses induced by some of the modified proteins were at least two-fold higher than those elicited by the wild-type MSP1₁₉. A protein with four amino acid substitutions (Glu27→Tyr, Leu31→Arg, Tyr34→Ser and Glu43→Leu) had the highest stimulation index (SI up to 360) and induced large responses in 64% of the samples that had significant cellular responses to the modified proteins.</p> <p>Conclusion</p> <p>This study suggests that specific MSP1₁₉variants that have been engineered to improve their antigenicity for inhibitory antibodies, retain T-cell epitopes and the ability to induce cellular responses. These proteins are candidates for the development of MSP1-based malaria vaccines.</p

Current anti-doping policy: a critical appraisal

BACKGROUND: Current anti-doping in competitive sports is advocated for reasons of fair-play and concern for the athlete's health. With the inception of the World Anti Doping Agency (WADA), anti-doping effort has been considerably intensified. Resources invested in anti-doping are rising steeply and increasingly involve public funding. Most of the effort concerns elite athletes with much less impact on amateur sports and the general public. DISCUSSION: We review this recent development of increasingly severe anti-doping control measures and find them based on questionable ethical grounds. The ethical foundation of the war on doping consists of largely unsubstantiated assumptions about fairness in sports and the concept of a "level playing field". Moreover, it relies on dubious claims about the protection of an athlete's health and the value of the essentialist view that sports achievements reflect natural capacities. In addition, costly antidoping efforts in elite competitive sports concern only a small fraction of the population. From a public health perspective this is problematic since the high prevalence of uncontrolled, medically unsupervised doping practiced in amateur sports and doping-like behaviour in the general population (substance use for performance enhancement outside sport) exposes greater numbers of people to potential harm. In addition, anti-doping has pushed doping and doping-like behaviour underground, thus fostering dangerous practices such as sharing needles for injection. Finally, we argue that the involvement of the medical profession in doping and anti-doping challenges the principles of non-maleficience and of privacy protection. As such, current anti-doping measures potentially introduce problems of greater impact than are solved, and place physicians working with athletes or in anti-doping settings in an ethically difficult position. In response, we argue on behalf of enhancement practices in sports within a framework of medical supervision. SUMMARY: Current anti-doping strategy is aimed at eradication of doping in elite sports by means of all-out repression, buttressed by a war-like ideology similar to the public discourse sustaining international efforts against illicit drugs. Rather than striving for eradication of doping in sports, which appears to be an unattainable goal, a more pragmatic approach aimed at controlled use and harm reduction may be a viable alternative to cope with doping and doping-like behaviour

Subcellular Antigen Location Influences T-Cell Activation during Acute Infection with Toxoplasma gondii

Effective control of the intracellular protozoan parasite Toxoplasma gondii depends on the activation of antigen-specific CD8+ T-cells that manage acute disease and prevent recrudescence during chronic infection. T-cell activation in turn, requires presentation of parasite antigens by MHC-I molecules on the surface of antigen presenting cells. CD8+ T-cell epitopes have been defined for several T. gondii proteins, but it is unclear how these antigens enter into the presentation pathway. We have exploited the well-characterized model antigen ovalbumin (OVA) to investigate the ability of parasite proteins to enter the MHC-I presentation pathway, by engineering recombinant expression in various organelles. CD8+ T-cell activation was assayed using ‘B3Z’ reporter cells in vitro, or adoptively-transferred OVA-specific ‘OT-I’ CD8+ T-cells in vivo. As expected, OVA secreted into the parasitophorous vacuole strongly stimulated antigen-presenting cells. Lower levels of activation were observed using glycophosphatidyl inositol (GPI) anchored OVA associated with (or shed from) the parasite surface. Little CD8+ T-cell activation was detected using parasites expressing intracellular OVA in the cytosol, mitochondrion, or inner membrane complex (IMC). These results indicate that effective presentation of parasite proteins to CD8+ T-cells is a consequence of active protein secretion by T. gondii and escape from the parasitophorous vacuole, rather than degradation of phagocytosed parasites or parasite products