Regulation of CD8+ T cell responses to Toxoplasma gondii

Protective immunity to Toxoplasma gondii, an intracellular protozoan parasite, is characterized by a strongly polarized Th1-mediated immune response that is dependent on CD4+ and CD8+ T cells. In order to study the factors that influence development of CD8+ T cell responses to this parasite, a system was developed using a replication-deficient parasite that expressed the model antigen ovalbumin (OVA). These initial studies revealed that an OVA-specific CD8+ T cell response was induced and peaked at day 10 post-immunization, that the primary response was CD4+ T cell-dependent, and that the cells induced by immunization primarily resembled effector cells. Protective immunity to rechallenge using this model was mediated by CD8+ T cells. Long-term study of the CD8+ T cell response was undertaken, in WT mice as well as in c-Rel-/- mice, which are susceptible to T. gondii infection. In these studies, c-Rel was required for optimal primary expansion of CD8+ T cells in response to T. gondii. Surprisingly, while T cells express c-Rel, it was not intrinsically required by the T cells themselves, since adoptive transfer of c-Rel-/- CD8+ T cells to WT mice restored their expansion. Further examination revealed that the inflammatory environment but not the T cells themselves required expression of c-Rel, because exogenous IL-12 rescues the CD8+ T cell responses in c-Rel-/- mice. Maintenance of memory CD8+ T cells as well as secondary expansion of these cells following challenge was independent of c-Rel. This work provided the first characterization of an antigen-specific memory CD8+ T cell response to non-replicating strain of T. gondii as well as showing that c-Rel is not intrinsically required by CD8+ T cells for expansion or effector function following infection, and provides new insights into the requirements for memory cell formation

Contributions of Ca^(2+)-Independent Thin Filament Activation to Cardiac Muscle Function

Although Ca^(2+) is the principal regulator of contraction in striated muscle, in vitro evidence suggests that some actin-myosin interaction is still possible even in its absence. Whether this Ca^(2+)-independent activation (CIA) occurs under physiological conditions remains unclear, as does its potential impact on the function of intact cardiac muscle. The purpose of this study was to investigate CIA using computational analysis. We added a structurally motivated representation of this phenomenon to an existing myofilament model, which allowed predictions of CIA-dependent muscle behavior. We found that a certain amount of CIA was essential for the model to reproduce reported effects of nonfunctional troponin C on myofilament force generation. Consequently, those data enabled estimation of ΔG_(CIA), the energy barrier for activating a thin filament regulatory unit in the absence of Ca^(2+). Using this estimate of ΔG_(CIA) as a point of reference (∼7 kJ mol^(−1)), we examined its impact on various aspects of muscle function through additional simulations. CIA decreased the Hill coefficient of steady-state force while increasing myofilament Ca^(2+) sensitivity. At the same time, CIA had minimal effect on the rate of force redevelopment after slack/restretch. Simulations of twitch tension show that the presence of CIA increases peak tension while profoundly delaying relaxation. We tested the model’s ability to represent perturbations to the Ca^(2+) regulatory mechanism by analyzing twitch records measured in transgenic mice expressing a cardiac troponin I mutation (R145G). The effects of the mutation on twitch dynamics were fully reproduced by a single parameter change, namely lowering ΔG_(CIA) by 2.3 kJ mol^(−1) relative to its wild-type value. Our analyses suggest that CIA is present in cardiac muscle under normal conditions and that its modulation by gene mutations or other factors can alter both systolic and diastolic function

Factors Related to the Likelihood of Hiring a Health Advocate

This study was designed to explore factors related to the likelihood of hiring a health advocate. Independent variables were selected from the health service use model to capture predisposing, enabling, and illness-level factors. Participants were 889 adults (M age = 50.9 years, SD = 17.9 years, 52% female) recruited from a large cultural park in San Diego, California during the spring and summer of 2008. Participants read a description of a health advocate and completed a brief set of questions on age, gender, confidence in health care, effort maintaining health, self-rated health, and the likelihood of hiring a health advocate. Hierarchical regression analysis revealed that participants age 40-64 , non-Caucasians , participants who exerted more effort maintaining their health , and participants 65 and older who were less satisfied with their social support reported greater likelihood of hiring a health advocate. Findings were similar to those of studies that applied the health service use model to predict use of other health services, such as medical visits. These findings suggest factors that health care organizations offering health advocacy services could consider when targeting potential clients

Kinetics and Phenotype of Vaccine-Induced CD8+ T-Cell Responses to Toxoplasma gondii

Multiple studies have established that the ability of CD8+ T cells to act as cytolytic effectors and produce gamma interferon is important in mediating resistance to the intracellular parasite Toxoplasma gondii. To better understand the generation of the antigen-specific CD8+ T-cell responses induced by T. gondii, mice were immunized with replication-deficient parasites that express the model antigen ovalbumin (OVA). Class I tetramers specific for SIINFEKL were used to track the OVA-specific endogenous CD8+ T cells. The peak CD8+ T-cell response was found at day 10 postimmunization, after which the frequency and numbers of antigen-specific cells declined. Unexpectedly, replication-deficient parasites were found to induce antigen-specific cells with faster kinetics than replicating parasites. The generation of optimal numbers of antigen-specific CD8+ effector T cells was found to require CD4+ T-cell help. At 7 days following immunization, antigen-specific cells were found to be CD62Llow, KLRG1+, and CD127low, and they maintained this phenotype for more than 70 days. Antigen-specific CD8+ effector T cells in immunized mice exhibited potent perforin-dependent OVA-specific cytolytic activity in vivo. Perforin-dependent cytolysis appeared to be the major cytolytic mechanism; however, a perforin-independent pathway that was not mediated via Fas-FasL was also detected. This study provides further insight into vaccine-induced cytotoxic T-lymphocyte responses that correlate with protective immunity to T. gondii and identifies a critical role for CD4+ T cells in the generation of protective CD8+ T-cell responses

Policy Recommendations for Meeting the Grand Challenge to Ensure Healthy Development for All Youth

This brief was created forSocial Innovation for America’s Renewal, a policy conference organized by the Center for Social Development in collaboration with the American Academy of Social Work & Social Welfare, which is leading theGrand Challenges for Social Work initiative to champion social progress. The conference site includes links to speeches, presentations, and a full list of the policy briefs

Implementation of the Tobacco Tactics intervention versus usual care in Trinity Health community hospitals

Abstract Background Guided by the Reach, Effectiveness, Adoption, Implementation, and Maintenance (RE-AIM) implementation framework, a National Institutes of Health-sponsored study compared the nurse-administered Tobacco Tactics intervention to usual care. A prior paper describes the effectiveness of the Tobacco Tactics intervention. This subsequent paper provides data describing the remaining constructs of the RE-AIM framework. Methods This pragmatic study used a mixed methods, quasi-experimental design in five Michigan community hospitals of which three received the nurse-administered Tobacco Tactics intervention and two received usual care. Nurses and patients were surveyed pre- and post-intervention. Measures included reach (patient participation rates, characteristics, and receipt of services), adoption (nurse participation rates and characteristics), implementation (pre-to post-training changes in nurses' attitudes, delivery of services, barriers to implementation, opinions about training, documentation of services, and numbers of volunteer follow-up phone calls), and maintenance (continuation of the intervention once the study ended). Results Reach: Patient participation rates were 71.5 %. Compared to no change in the control sites, there were significant pre- to post-intervention increases in self-reported receipt of print materials in the intervention hospitals (n = 1370, p < 0.001). Adoption: In the intervention hospitals, all targeted units and several non-targeted units participated; 76.0 % (n = 1028) of targeted nurses and 317 additional staff participated in the training, and 92.4 % were extremely or somewhat satisfied with the training. Implementation: Nurses in the intervention hospitals reported increases in providing advice to quit, counseling, medications, handouts, and DVD (all p < 0.05) and reported decreased barriers to implementing smoking cessation services (p < 0.001). Qualitative comments were very positive (“user friendly,” “streamlined,” or “saves time”), although problems with showing patients the DVD and charting in the electronic medical record were noted. Maintenance: Nurses continued to provide the intervention after the study ended. Conclusions Given that nurses represent the largest group of front-line providers, this intervention, which meets Joint Commission guidelines for treating inpatient smokers, has the potential to have a wide reach and to decrease smoking, morbidity, and mortality among inpatient smokers. As we move toward more population-based interventions, the RE-AIM framework is a valuable guide for implementation. Trial registration ClinicalTrials.gov, NCT0130921

CD8 T cell effector maturation in HIV-1-infected children

AbstractHIV-1 infection generates maturational responses in overall CD4 and CD8 T cell populations in adults, with elevated expression of lytic effector molecules perforin and granzyme B, and reduced expression of CCR7 and CD45RA. Here, we have found that these marked effects were significantly less pronounced in children, both in terms of the skewed CCR7/CD45RA expression profile as well as the increased perforin expression. Similar to adults, HIV-specific CD8 cells in children were largely CD27+ CD45RA− and lacked perforin. However, one pediatric subject with late-stage infection displayed robust expansion of Gag 77–85-specific CD8 T cells which were perforin+ and lytic, but lacked expression of CD27 and IFNγ. Our data indicate that the T cell effector maturation induced by HIV-1 infection is markedly weaker in children as compared to adults. The data also suggest, however, that the perforin-deficient state of HIV-specific CD8 T cells in children may be reversible

Emotional Support and Mental Health Among Somali Men in a Rural Midwestern Town

Perceived social support has been correlated with refugees’ positive mental health outcomes; yet, little is known about the perceived sources of support after secondary migration to new-destination rural towns. Somali refugee men (n _ 49) residing in a rural Midwest United States community were recruited using respondent-driven sampling to complete a self-administered structured survey in English or Somali using audio computer-assisted self-interview software. Questions assessed perceived sources of support, psychological distress, and happiness. Somali participants reported low utilization of both informal (30.4%) and formal (24.4%) supports when sad, stressed, or worried. Two thirds of participants reported low levels of distress and 98% reported being happy or very happy. This exploratory research contributes to understandings of Somali men’s perceived support in a postsecondary migration setting. We discuss implications for social support interventions and culturally tailored assessment, diagnoses, and treatment to enhance Somalis’ support and psychological well-being

Hypohidrotic Ectodermal Dysplasia and Immunodeficiency with Coincident NEMO and EDA Mutations

Ectodermal dysplasias (ED) are uncommon genetic disorders resulting in abnormalities in ectodermally derived structures. Many ED-associated genes have been described, of which ectodysplasin-A (EDA) is one of the more common. The NF-κB essential modulator (NEMO encoded by the IKBKG gene) is unique in that mutations result in severe humoral and cellular immunologic defects in addition to ED. We describe three unrelated kindreds with defects in both EDA and IKBKG resulting from X-chromosome crossover. This demonstrates the importance of thorough immunologic consideration of patients with ED even when an EDA etiology is confirmed, and raises the possibility of a specific phenotype arising from coincident mutations in EDA and IKBKG