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Immunostimulatory cytidyl guanosyl (CpG) motifs are of great interest as cancer vaccine adjuvants. They act as potent inducers of Th1 responses, including the activation of cytotoxic CD8+ T lymphocytes (CTL). Whereas animal models have provided clear evidence that CpG enhances antitumor immunity, clinical trials in humans have thus far been less successful. Applying cryosurgery as an instant in situ tumor destruction technique, we now show that timing of CpG administration crucially affects colocalization of antigen and CpG within EEA-1+ and LAMP-1+ compartments within dendritic cells in vivo. Moreover, antigen/CpG colocalization is directly correlated with antigen cross-presentation, the presence of CTL, and protective antitumor immunity. Thus, failure or success of CpG as a vaccine adjuvant may depend on colocalization of antigen/CpG inside DCs and hence on the timing of CpG administration. These data might aid in the design of future immunotherapeutic strategies for cancer patients. [Cancer Res 2008;68(13):5390–6]

Supplementary Figure 1 from In vivo Colocalization of Antigen and CpG within Dendritic Cells Is Associated with the Efficacy of Cancer Immunotherapy

Background: The spectrum of illness and long-term outcome of critically ill patients admitted to intensive care units (ICUs) in South Africa remains largely unknown.Objectives: This study was designed to provide data on ICU outcomes and disease burden in public sector ICUs in KwaZulu- Natal. The primary objective was to describe 30-day mortality of all patients admitted to participating sites. Secondary objectives included clinical demographics and spectrum of illness amongst these patients, and testing a template to demonstrate feasibilityof such data collection.Methods: 30DOS was a multicentre, prospective, observational cohort study conducted over 30 days. An a priori decision was made to report study results separately for adults and paediatric patients. This article reports the results for adult patients. The complete 30-DOS study included 11 ICUs in six hospitals. All adult patients admitted to study ICUs were included. Patients were followed up telephonically by a research assistant. Data on patient demographics, preadmission functional scoring, injury severity scoring, co-morbidities, admission diagnosis/es, organ support, and outcome were collected.Results: A total of 228 adults were included. The majority of admissions (73.7%) occurred on an emergency basis, with 68.4% occurring in the postoperative period. Approximately half were for non-communicable disease (49.6%), followed by trauma (29.0%) and infectious disease (21.5%). There were a total of 59 (25.9%) deaths within the first 30 days after admission. In-ICU mortality was 19.7%. There were 12 (5.3%) in-hospital deaths following discharge and two (0.9%) out-of-hospital deaths. Thirty-day survival was known for 174 (76.3%) admissions with a 33.9% mortality rate.Conclusion: Overall in-ICU mortality was 19.7% with a large trauma burden in a young population. Thirty-day mortality was 33.9%. Information pertaining to patient demographics and spectrum of illness provided novel information to further the understanding of the demand placed on critical care resources within South Africa.Keywords: critical care, 30-day mortality, Outcome, South Africa

Over the last decade, there has been a growing interest in the use of interventions that target the intestinal microbiota as a treatment approach for asthma. This study is aimed at exploring the therapeutic effects of long-term treatment with a combination of Bifidobacterium breve with non-digestible oligosaccharides on airway inflammation and remodeling. A murine ovalbumin-induced chronic asthma model was used. Pulmonary airway inflammation; mRNA expression of pattern recognition receptors, Th-specific cytokines and transcription factors in lung tissue; expression of Foxp3 in blood Th cells; in vitro T cell activation; mast cell degranulation; and airway remodeling were examined. The combination of B. breve with non-digestible oligosaccharides suppressed pulmonary airway inflammation; reduced T cell activation and mast cell degranulation; modulated expression of pattern recognition receptors, cytokines and transcription factors; and reduced airway remodeling. The treatment induced regulatory T cell responses, as shown by increased Il10 and Foxp3 transcription in lung tissue, and augmented Foxp3 protein expression in blood CD4+CD25+Foxp3+ T cells. This specific combination of beneficial bacteria with non-digestible oligosaccharides has strong anti-inflammatory properties, possibly via the induction of a regulatory T cell response, resulting in reduced airway remodeling and, therefore, may be beneficial in the treatment of chronic inflammation in allergic asthma.

Pattern recognition receptors (PRRs), such as Toll-like receptors (TLRs), contribute to the development of intestinal inflammatory diseases, like inflammatory bowel disease (IBD). Supporting investigations of the underlying mechanisms of IBD, this study provides an extensive PRR expression survey together with T-cell associated factors along the murine colon during experimental colitis. 8–12 week-old C57BL/6 mice were treated with dextran sodium sulfate (DSS) to induce colitis. The mRNA expression levels of Tlr1–9, Nod1, Nod2, T cell subset-associated master transcription factors and cytokines were determined using qPCR. The expression of TLR2, 4, 5 and 6 was determined with immunohistochemistry. Th1 and Th17 associated responses were quantified in the mesenteric lymph nodes (mLNs) using flow cytometry. In DSS treated mice, the mRNA expression of the majority of PRRs was increased relative to healthy controls and correlated with the degree of inflammation. The exceptions were Tlr1 and Tlr5, which displayed unchanged and down-regulated transcription, respectively. Furthermore, in healthy animals, there was increased transcription of Tlr2, 3 and 5 near the caecum as opposed the region near the rectum. Within the inflamed regions, the mRNA expression of Th1-, Th17- and regulatory T-cell associated cytokines was enhanced, while there was no change for Th2-associated cytokines. In agreement with the mRNA expression, enhanced IFNγ and IL-17 producing cells were observed in stimulated mLNs. This study provides an extensive expression survey of PRRs along the colon during the acute colitis and shows that the induced inflammation is characterized by a Th1- and IL-17 mediated cytokine response.

Background. Antibiotics are among the most commonly used drugs in a paediatric intensive care unit (PICU). Despite guidelines and protocols for the use of antibiotics, inappropriate use may contribute to an increase in antibiotic resistance. The factors behind changes in antibiotic prescriptions in the PICU at Grey’s Hospital are unknown. Objective. To establish the frequency, process and rationale behind antibiotic prescription changes in the PICU. Methods. A retrospective descriptive study of all eligible patients admitted to the PICU during a 6-month period. Results. Three-quarters of patients admitted to the PICU received antibiotics during their stay. The antibiotic prescription was changed in 80 (58%) of the138 patients, with most changes (63.4%) occurring within 3 days of admission. Patients younger than 1 year and those who were malnourished accounted for 57% of the changes. The majority (65%) of the changes entailed the escalation of antibiotics and 89% of these were empiric therapy. De-escalation accounted for 35% of the changes. The rationale for a prescription change was not documented in 80% of cases. Conclusion. Antibiotic use in this PICU and changes to prescriptions were common. Changes were generally made on an empirical basis soon after admission and were more likely to occur in young malnourished children and patients admitted for a medical reason or surgical emergency.

Dietary intervention with short-chain galacto-oligosaccharides (scGOS), long-chain fructo-oligosaccharides (lcFOS) and

In Nepal, antenatal iron-folic acid supplementation improved aspects of intellectual, executive, and fine motor function among school-age children. We examined the impact of added zinc to the maternal antenatal supplement (M-IFAZn) and preschool supplementation from 12 to 36 mo with iron-folic acid (C-IFA) ± zinc (C-IFAZn) on cognitive outcomes compared to maternal iron-folic acid (M-IFA) alone. Children 7-9 y old (n = 780) who participated in early childhood micronutrient supplementation trial during 2001-2004 and whose mothers participated in an antenatal micronutrient supplementation between 1999 and 2001 were followed for cognitive assessments in 2007-2009. Using multivariate analysis of variance and adjusting for confounders, M-IFA with child supplementation (either C-IFA or C-IFAZn) did not impact scores on the tests of general intelligence (Universal Nonverbal Intelligence Test), and executive function (Stroop and go/no go tests) relative to the M-IFA alone. However, children in the C-IFAZn group had slightly lower scores on the backward digit span (-0.29, 95% CI: -0.55, -0.04) and Movement Assessment Battery for Children (1.33, 95% CI: 0.26, 2.40) relative to the referent group, whereas both C-IFA (-1.92, 95% CI: -3.12, -0.71) and C-IFAZn (-1.78, 95% CI: -2.63, -0.92) produced somewhat lower finger tapping test scores (fine motor skills). The combination of M-IFAZn and C-IFA or C-IFAZn did not lead to any outcome differences relative to M-IFA alone. Preschool iron-folic acid ± zinc to children exposed to iron-folic acid in utero or addition of zinc to maternal iron-folic acid conferred no additional benefit to cognitive outcomes assessed in early school age. The late timing of supplementation during preschool may explain the lack of impact of iron and/or zinc.

Item does not contain fulltext OBJECTIVE: Regulatory T cells play an important role in the prevention of autoimmunity and have been shown to be effective in the treatment of experimental colitis, a T cell-mediated and organ-specific disease. We previously demonstrated that intrinsic CD25+ regulatory T cells modulate the severity of collagen-induced arthritis (CIA), which, in contrast to colitis, is a systemic antibody-mediated disease and an accepted model of rheumatoid arthritis. We undertook this study to determine whether regulatory T cells have the potential to be used therapeutically in arthritis. METHODS: We transferred CD4+,CD25+ T cells into mice exhibiting arthritis symptoms, both immunocompetent mice and mice subjected to lethal irradiation and rescued with syngeneic bone marrow transplantation. RESULTS: A single transfer of regulatory T cells markedly slowed disease progression, which could not be attributed to losses of systemic type II collagen-specific T and B cell responses, since these remained unchanged after adoptive transfer. However, regulatory T cells could be found in the inflamed synovium soon after transfer, indicating that regulation may occur locally in the joint. CONCLUSION: Our data indicate that CD25+ regulatory T cells can be used for the treatment of systemic, antibody-mediated autoimmune diseases, such as CIA.

Objective Proline–glycine–proline (PGP) has been shown to have chemotactic effects on neutrophils via CXCR2 in several lung diseases. PGP is derived from collagen by the combined action of matrix metalloproteinase (MMP) 8 and/or MMP9 and prolyl endopeptidase (PE). We investigated the role of PGP in inflammatory bowel disease (IBD). Design In intestinal tissue from patients with IBD and mice with dextran sodium sulfate (DSS)-induced colitis, MMP8, MMP9 and PE were evaluated by ELISA, immunoblot and immunohistochemistry. Peripheral blood polymorphonuclear cell (PMN) supernatants were also analysed accordingly and incubated with collagen to assess PGP generation ex vivo. PGP levels were measured by mass spectrometry, and PGP neutralisation was achieved with a PGP antagonist and PGP antibodies. Results In the intestine of patients with IBD, MMP8 and MMP9 levels were elevated, while PE was expressed at similar levels to control tissue. PGP levels were increased in intestinal tissue of patients with IBD. Similar results were obtained in intestine from DSS-treated mice. PMN supernatants from patients with IBD were far more capable of generating PGP from collagen ex vivo than healthy controls. Furthermore, PGP neutralisation during DSS-induced colitis led to a significant reduction in neutrophil infiltration in the intestine. Conclusions The proteolytic cascade that generates PGP from collagen, as well as the tripeptide itself, is present in the intestine of patients with IBD and mice with DSS-induced colitis. PGP neutralisation in DSS-treated mice showed the importance of PGP-guided neutrophilic infiltration in the intestine and indicates a vicious circle in neutrophilic inflammation in IBD.

We describe a modification of two-dimensional (2-D) polyacrylamide gel electrophoresis that requires only a single gel to reproducibly detect differences between two protein samples. This was accomplished by fluorescently tagging the two samples with two different dyes, running them on the same 2-D gel, post-run fluorescence imaging of the gel into two images, and superimposing the images. The amine reactive dyes were designed to insure that proteins common to both samples have the same relative mobility regardless of the dye used to tag them. Thus, this technique, called difference gel electrophoresis (DIGE), circumvents the need to compare several 2-D gels. DIGE is reproducible, sensitive, and can detect an exogenous difference between two Drosophila embryo extracts at nanogram levels. Moreover, an inducible protein from E. coli was detected after 15 min of induction and identified using DIGE preparatively.

Rising neurodegenerative and depressive disease prevalence combined with the lack of effective pharmaceutical treatments and dangerous side effects, has created an urgent need for the development of effective therapies. Considering that these disorders are multifactorial in origin, treatments designed to interfere at different mechanistic levels may be more effective than the traditional single-targeted pharmacological concepts. To that end, an experimental diet composed of zinc, melatonin, curcumin, piperine, eicosapentaenoic acid (EPA, 20:5, n-3), docosahexaenoic acid (DHA, 22:6, n-3), uridine, and choline was formulated. This diet was tested on the olfactory bulbectomized rat (OBX), an established animal model of depression and cognitive decline. The ingredients of the diet have been individually shown to attenuate glutamate excitoxicity, exert potent anti-oxidant/anti-inflammatory properties, and improve synaptogenesis; processes that all have been implicated in neurodegenerative diseases and in the cognitive deficits following OBX in rodents. Dietary treatment started 2 weeks before OBX surgery, continuing for 6 weeks in total. The diet attenuated OBX-induced cognitive and behavioral deficits, except long-term spatial memory. Ameliorating effects of the diet extended to the control animals. Furthermore, the experimental diet reduced hippocampal atrophy and decreased the peripheral immune activation in the OBX rats. The ameliorating effects of the diet on the OBX-induced changes were comparable to those of the NMDA receptor antagonist, memantine, a drug used for the management of Alzheimer's disease. This proof-of-concept study suggests that a diet, which simultaneously targets multiple disease etiologies, can prevent/impede the development of a neurodegenerative and depressive disorders and the concomitant cognitive deficits.

CD4+ T cell responses against oral antigens can develop in inflammatory bowel disease (IBD) patients, which may modulate disease. Dextran sodium sulfate (DSS) colitis is commonly used to study IBD, however, it is not considered the best model in which to study T cell involvement in intestinal disease. Our aim was to determine if antigen-specific T cells could be induced during DSS colitis and if they could be detected after disease resolution. To induce antigen-specific T cells, the tracking antigen, ovalbumin (OVA), was administered orally during colitis initiation. Disease severity was monitored, and the antigen-reactivity of CD4+ T cells examined using CD69 expression. While OVA-directed, CD4+ Foxp3+ regulatory T cells could be detected in the spleens of both OVA-treated control and DSS mice, OVA-reactive, CD4+ Foxp3-T cells were only found in the OVA and DSS-treated mice. These results indicate that during DSS colitis T cells develop that are specific against oral antigens, and they are found systemically after colitis resolution. This gives added depth and utility to the DSS model as well as a way to track T cells that are primed against luminal antigens.

The 6th Child Health Priorities Conference was convened by the South African Child Health Priorities Association at the University of KwaZulu-Natal in Pietermaritzburg from 3 to 5 December 2015. The theme of the conference, 'Walk the Talk', tackled the challenges of implementing the recommendations from the reports of two child health-related ministerial committees.

Objective To examine intellectual and motor functioning of children who received micronutrient supplementation from 12 to 35 months of age. Design Cohort follow-up of children 7 to 9 years of age who participated in a 2 × 2 factorial, placebo-controlled, randomized trial from October 2001 through January 2006. Setting Rural Nepal. Participants A total of 734 children 12 to 35 months of age at supplementation and 7 to 9 years of age at testing. Interventions Children received iron plus folic acid (12.5 mg of iron and 50 μg of folic acid); zinc (10 mg); iron plus folic acid and zinc; or placebo. Main Outcome Measures Intellectual, motor, and executive function. Results In both the unadjusted and adjusted analyses, iron plus folic acid supplementation had no effect overall or on any individual outcome measures being tested. In the unadjusted analysis, zinc supplementation had an overall effect, although none of the individual test score differences were significant. In the adjusted analysis, the overall difference was not significant. Conclusion In rural Nepal, we found that iron plus folic acid or zinc supplementation during the preschool years had no effect on aspects of intellectual, executive, and motor function at 7 to 9 years of age, suggesting no long-term developmental benefit of iron or zinc supplementation during 12 to 35 months of age.

Cyclooxygenase-2 (COX-2) is thought to play a role in the pathogenesis of various neurodegenerative disorders. However, clinical trials with COX-2 inhibitors have yielded contradictory results. In the present study we investigated whether COX-2 plays a role in the behavioral and cognitive impairments seen in olfactory bulbectomized rats. These impairments arise from neurodegenerative processes. First, we determined the time course of the OBX-induced behavioral (hyperactivity) and cognitive changes (fear memory) and how these correlate with changes in COX-2 mRNA expression in hippocampus. This experiment showed that the major impairments in behavior and cognition developed between Days 3 and 14 after OBX surgery, which correlated with changes in mRNA levels of COX-2, which increased at Days 7 and 14 after surgery but not anymore at day 28. In a subsequent experiment, rats were treated, starting two days before surgery, with the COX-2 inhibitor celecoxib (10 mg/kg, dissolved in drinking water) for 4 weeks. OBX-induced hyperactivity in the open field was normalized after 2 weeks of celecoxib treatment, but not longer after 4 weeks. Celecoxib partly rescued fear learning and memory deficits without affecting spatial memory. The effects of celecoxib on fear memory lasted up to 1 week posttreatment, but disappeared thereafter. Our results show that COX-2 plays a limited role (both in magnitude and time) in the development of the OBX syndrome.

Item does not contain fulltext The induction of tumor-specific immune responses is largely dependent on the ability of dendritic cells (DCs) to present tumor-associated antigens to T lymphocytes. Therefore, we investigated the use of DC-associated promoter-driven genetic vaccines to specifically target DC in vivo. Restricted expression of vaccine-encoding genes in DC should enhance specificity and improves their safety for clinical applications. Hereto, 3-5 kb upstream sequences of the murine genes encoding CD11c, DC-SIGN, DC-STAMP and Langerin were isolated, characterized and subcloned into enhanced green fluorescent protein (EGFP) reporter constructs. Upon electroporation, EGFP was expressed in DC cell lines, but not in other cell lines, confirming DC-restricted promoter activity. When these promoters were cloned into a construct upstream of the gene for ovalbumin (OVA), it appeared that DC-STAMP promoter-driven expression of OVA (pDCSTAMP/OVA) in DC yielded the most efficient OVA-specific CD4+ and CD8+ T-cell responses in vitro. Administration of pDC-STAMP/OVA in vivo, using the tattoo gun vaccination system, evoked specific immune responses as evidenced in a mouse tumor model. Adoptively transferred pDC-STAMP/OVA-transfected DCs induced strong CD8+ T-cell proliferation in vivo. These experiments demonstrate that our DC-directed promoter constructs are potential tools to restrict antigen expression in DC and could be implemented to modulate DC function by the introduction of relevant proteins. 01 mei 2012

In Nepal, antenatal iron-folic acid supplementation improved aspects of intellectual, executive, and fine motor function among school-age children. We examined the impact of added zinc to the maternal antenatal supplement (M-IFAZn) and preschool supplementation from 12 to 36 mo with iron-folic acid (C-IFA) ± zinc (C-IFAZn) on cognitive outcomes compared to maternal iron-folic acid (M-IFA) alone. Children 7-9 y old (n = 780) who participated in early childhood micronutrient supplementation trial during 2001-2004 and whose mothers participated in an antenatal micronutrient supplementation between 1999 and 2001 were followed for cognitive assessments in 2007-2009. Using multivariate analysis of variance and adjusting for confounders, M-IFA with child supplementation (either C-IFA or C-IFAZn) did not impact scores on the tests of general intelligence (Universal Nonverbal Intelligence Test), and executive function (Stroop and go/no go tests) relative to the M-IFA alone. However, children in the C-IFAZn group had slightly lower scores on the backward digit span (-0.29, 95% CI: -0.55, -0.04) and Movement Assessment Battery for Children (1.33, 95% CI: 0.26, 2.40) relative to the referent group, whereas both C-IFA (-1.92, 95% CI: -3.12, -0.71) and C-IFAZn (-1.78, 95% CI: -2.63, -0.92) produced somewhat lower finger tapping test scores (fine motor skills). The combination of M-IFAZn and C-IFA or C-IFAZn did not lead to any outcome differences relative to M-IFA alone. Preschool iron-folic acid ± zinc to children exposed to iron-folic acid in utero or addition of zinc to maternal iron-folic acid conferred no additional benefit to cognitive outcomes assessed in early school age. The late timing of supplementation during preschool may explain the lack of impact of iron and/or zinc.

The psychoanalytic literature on the meaning of therapist gender for individual patients is reviewed and considered in relation to the practice of marital psychotherapy. Clinical examples are considered and it is concluded that the gender of the therapist(s) in psychoanalytical work with couples is significant. It is likely that couple psychotherapy with a male/female therapist pair can be quicker than individual therapy because there is the opportunity for several issues to be worked through in parallel in the former; where the co-therapists are of the same gender, the therapeutic relationship may seem less accessible to the opposite sex patient; the gender of the therapist affects the way in which transference develops. It seems that providing a male/female therapist pair maximizes the opportunity to work through therapeutic issues.

Contains fulltext : 69140.pdf (Publisher’s version ) (Closed access) CD4+CD25+ regulatory T (Treg) cells play an essential role in maintaining tolerance to self and nonself. In several models of T cell-mediated (auto) immunity, Treg cells exert protective effects by the inhibition of pathogenic T cell responses. In addition, Treg cells can modulate T cell-independent inflammation. We now show that CD4+CD25+ Treg cells are able to shed large amounts of TNFRII. This is paralleled by their ability to inhibit the action of TNF-alpha both in vitro and in vivo. In vivo, Treg cells suppressed IL-6 production in response to LPS injection in mice. In contrast, Treg cells from TNFRII-deficient mice were unable to do so despite their unhampered capacity to suppress T cell proliferation in a conventional in vitro suppression assay. Thus, shedding of TNFRII represents a novel mechanism by which Treg cells can inhibit the action of TNF, a pivotal cytokine driving inflammation.

Contains fulltext : 51074.pdf (Publisher’s version ) (Closed access) Regulatory T (Treg) cells maintain peripheral tolerance and limit effector responses to prevent excessive immune-mediated tissue damage. However, recent research reveals that Treg cells also dampen the induction of immune responses and, thus, must be controlled to enable the effective protection against infections and cancer. Until now, this control of Treg-cell function has been believed to be by communication through cytokines or by stimulation through co-stimulatory molecules on antigen-presenting cells. However, new evidence has demonstrated that Treg cells can also sense pathogens directly through Toll-like receptors (TLRs) and, consequently, modify their behaviour. This review examines the ramifications of TLR engagement on Treg cells and conventional T cells, and discusses the potential role of TLRs on Treg cells and the consequences for disease therapy.

Contains fulltext : 48463.pdf (Publisher’s version ) (Closed access) Expression of the transcription factor Foxp3 (forkhead box P3) has been implicated as a key element for CD25(+) T regulatory cell function in mice. However, literature over similar involvement of FOXP3 expression in human T regulatory cells is limited. We found that, unlike murine cells, FOXP3 mRNA expression could be induced in human CD25(-) and CD8(+) peripheral blood mononuclear cells, which were both negative for FOXP3 mRNA expression after isolation. Expression of FOXP3 mRNA began as soon as 24-40 hours after stimulation, demonstrating a correlation between activation and FOXP3 mRNA expression in human cells. In order to determine whether FOXP3 expression is confined to CD4(+)CD25(+) T cells with a regulatory phenotype, we analyzed several well-defined T-cell clones and lines with various specificities. Surprisingly, expression of FOXP3 mRNA was detected in all clones and limited to the CD25(hi) populations. Nonetheless, the CD25(hi) fraction did not display regulatory properties because both the CD25(hi) and CD25(low) populations exhibited a similar proliferative- and interferon-gamma-secreting potential after antigenic stimulation. These results indicate that FOXP3 expression in humans, unlike mice, may not be specific for cells with a regulatory phenotype and may be only a consequence of activation status.

Item does not contain fulltext In the last decade, CD4+CD25+ T regulatory cells have been implicated in the protection against autoimmune diseases. The human DQ8 major histocompatibility complex (MHC) class II molecule is associated with rheumatoid arthritis (RA) and various other autoimmune diseases in humans. The human leukocyte antigen (HLA)-DQ8 transgenic mouse, containing the human DQ8 MHC class II molecule, is predisposed toward collagen-induced arthritis. However, the biologic pathways responsible for DQ8-associated autoimmunity have yet to be defined, including possible defects in the CD4+CD25+ T regulatory cell compartment. To explore this concept, we examined the suppressive capacity of CD4+CD25+ T regulatory cells from DQ8 transgenic mice in vitro and, using CD25-specific depleting antibodies, investigated their influence on collagen-induced arthritis in vivo. CD4+CD25+ T regulatory cells isolated from DQ8 transgenic mice were found to be sufficient suppressors of splenocyte proliferation and interferon (INF)-gamma production. Furthermore, depletion of these cells before immunization led to significant increases in arthritis severity, collagen-specific antibodies, and INF-gamma production. These results indicate that HLA-DQ8 mice contain naturally occurring CD25+ regulatory cells that modulate collagen-induced arthritis and imply that DQ8 expression does not hinder the development of CD25+ T regulatory cells.

Item does not contain fulltext OBJECTIVE: CD4+,CD25+ T regulatory cells may offer opportunities to intervene in the course of autoimmune disease. We wished to evaluate their potential for influencing systemic and chronic joint inflammation by investigating their involvement in collagen-induced arthritis (CIA). METHODS: We depleted DBA/1 mice of CD25+ regulatory cells by injection of a depleting monoclonal antibody specific for CD25 14 days before a single immunization with type II collagen (CII) in Freund's complete adjuvant. CD4+,CD25+ T cells were adoptively transferred to some groups of mice during immunization. Mice were then scored for signs of arthritis, and blood was taken periodically to measure the amounts of CII-specific antibodies. Splenocytes of treated mice were examined in vitro to determine the effects of depletion on proliferation to CII and control antigens. RESULTS: CD25+ cell-depleted DBA/1 mice had significantly more severe disease than control mice following collagen immunization. The magnified severity was also accompanied by higher antibody titers against collagen, and in vitro tests showed increased proliferation of collagen-specific T cells. Adoptively transferring CD4+,CD25+ T cells into depleted mice was shown to reverse the heightened severity. Control mice, which were depleted and immunized with the neoantigen keyhole limpet hemocyanin (KLH), had neither an increased antibody response toward KLH nor an augmented proliferative response, indicating that CD25+ cell depletion preferentially affects immunity against self antigen. CONCLUSION: These results establish a link between CD4+,CD25+ regulatory cells and CIA and provide a rationale for investigating CD4+,CD25+ T regulatory cells in the treatment and prevention of arthritis.

While some probiotics have shown beneficial effects on preventing or treating colitis development, others have shown no effects. In this study, we have assessed the immunomodulating effects of two probiotic strains, Lactobacillus rhamnosus (L. rhamnosus) and Bifidobacterium breve (B. breve) on T cell polarization in vitro, using human peripheral blood mononuclear cells (PBMC), and in vivo, using murine dextran sodium sulfate (DSS) colitis model. With respect to the latter, the mRNA expression of T cell subset-associated transcription factors and cytokines in the colon was measured and the T helper type (Th) 17 and regulatory T cell (Treg) subsets were determined in the Peyer's patches. Both L. rhamnosus and B. breve incubations in vitro reduced Th17 and increased Th2 cell subsets in human PBMCs. In addition, B. breve incubation was also able to reduce Th1 and increase Treg cell subsets in contrast to L. rhamnosus. In vivo intervention with B. breve, but not L. rhamnosus, significantly attenuated the severity of DSS-induced colitis. In DSS-treated C57BL/6 mice, intervention with B. breve increased the expression of mRNA encoding for Th2- and Treg-associated cytokines in the distal colon. In addition, intervention with B. breve led to increases of Treg and decreases of Th17 cell subsets in Peyer's patches of DSS-treated mice. B. breve modulates T cell polarization towards Th2 and Treg cell-associated responses in vitro and in vivo. In vivo B. breve intervention ameliorates DSS-induced colitis symptoms and this protective effect may mediated by its effects on the T-cell composition.

Background Asthma is estimated to affect as many as 300 million people worldwide and its incidence and prevalence are rapidly increasing throughout the world, especially in children and within developing countries. Recently, there has been a growing interest in the use of potentially beneficial bacteria for allergic diseases. This study is aimed at exploring the therapeutic effects of long-term treatment with two different beneficial bacterial strains (Bifidobacterium breve M-16 V and Lactobacillus rhamnosus NutRes1) and a glucocorticoid (budesonide), as a reference treatment, on inflammatory response in a murine model for chronic allergic asthma. Methods To mimic the chronic disease in asthmatic patients, we used the murine ovalbumin-induced asthma model combined with prolonged allergen exposure. Airway function; pulmonary airway inflammation; airway remodelling, mRNA expression of pattern recognition receptors, Th-specific cytokines and transcription factors in lung tissue; mast cell degranulation; in vitro T cell activation; and expression of Foxp3 in blood Th cells were examined. Results Lactobacillus rhamnosus reduced lung resistance to a similar extent as budesonide treatment in chronically asthmatic mice. Pulmonary airway inflammation, mast cell degranulation, T cell activation and airway remodelling were suppressed by all treatments. Beneficial bacteria and budesonide differentially modulated the expression of toll-like receptors (TLRs), nod-like receptors (NLRs), cytokines and T cell transcription factors. Bifidobacterium breve induced regulatory T cell responses in the airways by increasing Il10 and Foxp3 transcription in lung tissue as well as systemic by augmenting the mean fluorescence intensity of Foxp3 in blood CD4+ T cells. Conclusion These findings show that Bifidobacterium breve M-16 V and Lactobacillus rhamnosus NutRes1 have strong anti-inflammatory properties that are comparable to budesonide and therefore may be beneficial in the treatment of chronic asthma.

Relocation has received increasing attention from the Army Leadership since 1983. This interest has been in response to the Army's acknowledgment that both soldiers and families have an impact on readiness and retention and that the demographics of the Total Army Family has changed over a period of years. Permanent Change of Station is an inevitable aspect of military life and a source of many stressors for military members, spouses and children. This study explores how stressful Senior Army Officers and spouses feel certain aspects of a mobile lifestyle are for themselves their spouses and their children. In addition, the study explores how helpful they feel certain Army programs and services are in alleviating the stress associated with PCS moves. Finally, their coping methods and recommendations as to what the Army can do to assist them in lessening stressors are addressed. The study shows that despite the seniority and experience of the respondents PCS moves were stressful events for individuals and the family as a unit and although the Army has improved relocation support programs, they still need command emphasis, funding and improvement.

CD4+ regulatory T cells expressing the activation marker CD25 have been strongly implicated in the control of autoimmune diseases. For example, immune compromised mice that receive splenocytes depleted of CD25+cells develop a variety of organ-specific autoimmune diseases such as colitis, gastritis, oophoritis, orchitis, and thyroiditis. Nonetheless, the role of regulatory T cells in many other autoimmune diseases, particularly systemic autoimmune diseases, has not been explored. We have now analyzed the role of CD25+CD4+ T cells in the control of collagen-induced arthritis (CIA), a commonly accepted model of rheumatoid arthritis. Depletion of CD25+ T cells in CIA susceptible DBA/1 mice leads to an earlier and more aggressive disease as evidenced by the development of severely swollen limbs following collagen injection. These mice also showed an increase in collagen specific antibodies. In addition, B6 mice, which are normally not susceptible to CIA, rapidly develop arthritis when vaccination is performed after depletion of CD25+ cells. Together, these findings indicate the importance of CD25+ cells in modulating CIA, establishing them as significant contributors in the control of chronic and systemic joint-related inflammation like that found in rheumatoid arthritis.

L'A., soeur de Kamau Brathwaite, propose un court recit biographique des premieres experiences et influences qui ont faconne les visions et points de vue de Brathwaite : la presence continue de l'ocean au debut de sa vie, etablissant le lien entre l'Afrique et les Caraibes, l'insistance de sa mere sur les liens et relations avec l'Afrique, les recits familiaux nombreux, qui ont mis en eveil son esprit, et qui l'ont sensibilise a des questions qui n'etaient pas abordees dans le systeme educatif colonial auquel il etait soumis.

✓ Age-related norms for the regional cerebral blood flow (rCBF) response to Diamox (acetazolamide) were based on studies of 55 normal subjects at rest and on studies of 33 of these 55 normal subjects following an intravenous injection of Diamox (22 mg/kg). After the Diamox injection, rCBF increased at all locations measured in all subjects. On average, rCBF increased 1.7 times. The following were found for rCBF in both resting and Diamox-treated subjects: 1) rCBF decreased significantly with increasing age; 2) slope and intercept for the regression of rCBF on age were largest for frontal detectors, intermediate for parietal detectors, and smallest for occipital detectors; 3) rCBF hyperfrontality was most noticeable in younger subjects; 4) in subjects of any age, 95% confidence intervals for rCBF were relatively large (expected value ± 30%) and lower 95% confidence intervals for Diamox rCBF tended to overlap the upper 95% confidence intervals for resting rCBF; and 5) side-to-side percentage difference in rCBF did not have a significant regression on age and tended to be less than 10% to 20%. Diamox did not have an important effect on blood pressure, pulse rate, or respiratory rate. The normative data for the rCBF response to Diamox was used in evaluating 20 patients with cerebrovascular disease. Forty percent of these patients, all of whom exhibited angiographic evidence of potentially hemodynamically significant lesions, had normal rCBF at rest and after Diamox injection. Twenty percent had normal resting flows with abnormal Diamox-activated flows. Asymmetry in rCBF was the most sensitive indicator of a potential abnormality in cerebral perfusion. Thirty percent of the abnormal studies showed only significant asymmetry. It is suggested that rCBF studies at rest and after Diamox treatment, with age-related norms, may be useful in the management of patients with cerebrovascular disease.