Interaction Mechanism Between the HSV-1 Glycoprotein B and the Antimicrobial Peptide Amyloid-ß.

Background: Unravelling the mystery of Alzheimer's disease (AD) requires urgent resolution given the worldwide increase of the aging population. There is a growing concern that the current leading AD hypothesis, the amyloid cascade hypothesis, does not stand up to validation with respect to emerging new data. Indeed, several paradoxes are being discussed in the literature, for instance, both the deposition of the amyloid-ß peptide (Aß) and the intracellular neurofibrillary tangles could occur within the brain without any cognitive pathology. Thus, these paradoxes suggest that something more fundamental is at play in the onset of the disease and other key and related pathomechanisms must be investigated. Objective: The present study follows our previous investigations on the infectious hypothesis, which posits that some pathogens are linked to late onset AD. Our studies also build upon the finding that Aß is a powerful antimicrobial agent, produced by neurons in response to viral infection, capable of inhibiting pathogens as observed in in vitro experiments. Herein, we ask what are the molecular mechanisms in play when Aß neutralizes infectious pathogens? Methods: To answer this question, we probed at nanoscale lengths with FRET (Förster Resonance Energy Transfer), the interaction between Aß peptides and glycoprotein B (responsible of virus-cell binding) within the HSV-1 virion. Results: The experiments show an energy transfer between Aß peptides and glycoprotein B when membrane is intact. No energy transfer occurs after membrane disruption or treatment with blocking antibody. Conclusion: We concluded that Aß insert into viral membrane, close to glycoprotein B, and participate in virus neutralization.

Mindfulness-Based Stress Reduction in Older Adults at Risk for Coronary Artery Disease: A Pilot Randomized Trial.

OBJECTIVES: Stress influences metabolic activity and increases risk for cardiovascular disease (CVD). We sought to a) examine feasibility and acceptability of mindfulness-based stress reduction (MBSR) in older adults at risk for CVD, and b) obtain preliminary data on its metabolic impact. METHODS: A pilot RCT was conducted using a pre-post, 2-month follow-up design. Eighty-one individuals with metabolic syndrome and non-normative responses to stress in a previous investigation were invited. Participants were randomized (by sex and stress response) to a 9-week MBSR or a wait-list control group. Feasibility and acceptability were assessed and blood assayed. Between-subjects (MBSR vs waitlist control) ANOVAs on metabolic parameter change scores, and one-way repeated measures ANOVAs (pre-, post-, follow-up) were performed. RESULTS: Thirty-three individuals (41%) responded to invitations, 26 were interested, of whom 19 were randomized (Mage = 67 years, SD = 7.70). Completion rate of MBSR was 72% and overall attendance was 96%. Reported benefits included increased relaxation, greater interpersonal connection, and increased body awareness. MBSR led to a decrease of 15% in LDL cholesterol and 10% in total cholesterol versus 4.5% and 1%, respectively, in the waitlist. Within group analyses showed notable decreases in LDL, triglycerides, and waist circumference post-MBSR and 2 months later. CONCLUSIONS: A RCT was largely feasible and MBSR acceptable to participants. MBSR may lead to sustained decreases in cholesterol levels, warranting development of large-scale research on this topic. CLINICAL IMPLICATIONS: Given the role of stress in CVD, addition of stress management interventions may serve as a useful complement to risk management among older individuals.

The associations of hostility and defensiveness with telomere length are influenced by sex and health status.

BACKGROUND: Shorter telomere length (TL) may indicate premature cellular aging and increased risk for disease. While there is substantial evidence for shorter TL in individuals suffering from psychiatric disorders, data is scarce on maladaptive personality traits related to coronary artery disease (CAD). The purpose of this study was to evaluate the association of TL with hostility and defensiveness in individuals with CAD or other non-cardiovascular illnesses and whether associations were moderated by CAD status and sex. METHODS: One thousand thirty-six individuals (Mage = 65.40 ± 6.73 years) with and without CAD completed the Marlowe-Crowne Social Desirability Scale and the Cook-Medley Hostility Scale. Relative TL was measured via quantitative polymerase chain reaction of total genomic DNA samples. Analyses involved hierarchical regressions on TL, performed separately for hostility and defensiveness, controlling for pertinent sociodemographic, behavioural, and medical risk factors. Separate analyses were performed on 25 healthy participants. RESULTS: A hostility by sex interaction emerged (ß = - .08, p = .006) in the patient groups, where greater hostility was associated with shorter TL in women only (p < .01). A Defensiveness by CAD status interaction (ß = - .06, p = .049) revealed longer TL in more defensive CAD patients only (p = .06). In healthy men, shorter TL was observed in those with greater defensiveness (ß = .52, p = .006) but lower hostility (ß = - .43, p = .049). CONCLUSION: Hostility and defensiveness are differentially associated with TL as a function of sex and health status. The implication of these results for health remains to be determined, but propose an additional pathway through which the effect of maladaptive personality traits may contribute to CV and other disease.

Elucidating the Role of Ezh2 in Tolerogenic Function of NOD Bone Marrow-Derived Dendritic Cells Expressing Constitutively Active Stat5b.

Tolerogenic dendritic cells (toDCs) are crucial to controlling the development of autoreactive T cell responses and the prevention of autoimmunity. We have reported that NOD.CD11cStat5b-CA transgenic mice expressing a constitutively active (CA) form of Stat5b under the control of a CD11c promoter are protected from diabetes and that Stat5b-CA-expressing DCs are tolerogenic and halt ongoing diabetes in NOD mice. However, the molecular mechanisms by which Stat5b-CA modulates DC tolerogenic function are not fully understood. Here, we used bone marrow-derived DCs (BMDCs) from NOD.CD11cStat5b-CA transgenic mice (Stat5b-CA.BMDCs) and found that Stat5b-CA.BMDCs displayed high levels of MHC class II, CD80, CD86, PD-L1, and PD-L2 and produced elevated amounts of TGFß but low amounts of TNFα and IL-23. Stat5b-CA.BMDCs upregulated Irf4 and downregulated Irf8 genes and protein expression and promoted CD11c+CD11b+ DC2 subset differentiation. Interestingly, we found that the histone methyltransferase Ezh2 and Stat5b-CA bound gamma-interferon activated site (GAS) sequences in the Irf8 enhancer IRF8 transcription, whereas Stat5b but not Ezh2 bound GAS sequences in the Irf4 promoter to enhance IRF4 transcription. Injection of Stat5b-CA.BMDCs into prediabetic NOD mice halted progression of islet inflammation and protected against diabetes. Importantly, inhibition of Ezh2 in tolerogenic Stat5b-CA.BMDCs reduced their ability to prevent diabetes development in NOD recipient mice. Taken together, our data suggest that the active form of Stat5b induces tolerogenic DC function by modulating IRF4 and IRF8 expression through recruitment of Ezh2 and highlight the fundamental role of Ezh2 in Stat5b-mediated induction of tolerogenic DC function.

Improving delivery of care in rural emergency departments: a qualitative pilot study mobilizing health professionals, decision-makers and citizens in Baie-Saint-Paul and the Magdalen Islands, Québec, Canada.

BACKGROUND: Emergency departments (EDs) in rural and remote areas face challenges in delivering accessible, high quality and efficient services. The objective of this pilot study was to test the feasibility and relevance of the selected approach and to explore challenges and solutions to improve delivery of care in selected EDs. METHODS: We conducted an exploratory multiple case study in two rural EDs in Québec, Canada. A survey filled out by the head nurse for each ED provided a descriptive statistical portrait. Semi-structured interviews were conducted with ED health professionals, decision-makers and citizens (n = 68) and analyzed inductively and thematically. RESULTS: The two EDs differed with regards to number of annual visits, inter-facility transfers and wait time. Stakeholders stressed the influence of context on ED challenges and solutions, related to: 1) governance and management (e.g. lack of representation, poor efficiency, ill-adapted standards); 2) health services organization (e.g. limited access to primary healthcare and long-term care, challenges with transfers); 3) resources (e.g. lack of infrastructure, limited access to specialists, difficult staff recruitment/retention); 4) and professional practice (e.g. isolation, large scope, maintaining competencies with low case volumes, need for continuing education, teamwork and protocols). There was a general agreement between stakeholder groups. CONCLUSIONS: Our findings show the feasibility and relevance of mobilizing stakeholders to identify context-specific challenges and solutions. It confirms the importance of undertaking a larger study to improve the delivery of care in rural EDs.

Profile of trauma mortality and trauma care resources at rural emergency departments and urban trauma centres in Quebec: a population-based, retrospective cohort study.

OBJECTIVES: As Canada's second largest province, the geography of Quebec poses unique challenges for trauma management. Our primary objective was to compare mortality rates between trauma patients treated at rural emergency departments (EDs) and urban trauma centres in Quebec. As a secondary objective, we compared the availability of trauma care resources and services between these two settings. DESIGN: Retrospective cohort study. SETTING: 26 rural EDs and 33 level 1 and 2 urban trauma centres in Quebec, Canada. PARTICIPANTS: 79 957 trauma cases collected from Quebec's trauma registry. PRIMARY AND SECONDARY OUTCOME MEASURES: Our primary outcome measure was mortality (prehospital, ED, in-hospital). Secondary outcome measures were the availability of trauma-related services and staff specialties at rural and urban facilities. Multivariable generalised linear mixed models were used to determine the relationship between the primary facility and mortality. RESULTS: Overall, 7215 (9.0%) trauma patients were treated in a rural ED and 72 742 (91.0%) received treatment at an urban centre. Mortality rates were higher in rural EDs compared with urban trauma centres (13.3% vs 7.9%, p<0.001). After controlling for available potential confounders, the odds of prehospital or ED mortality were over three times greater for patients treated in a rural ED (OR 3.44, 95% CI 1.88 to 6.28). Trauma care setting (rural vs urban) was not associated with in-hospital mortality. Nearly all of the specialised services evaluated were more present at urban trauma centres. CONCLUSIONS: Trauma patients treated in rural EDs had a higher mortality rate and were more likely to die prehospital or in the ED compared with patients treated at an urban trauma centre. Our results were limited by a lack of accurate prehospital times in the trauma registry.

The Quebec emergency department guide: A cross-sectional study to evaluate its use, perceived usefulness, and implementation in rural emergency departments.

OBJECTIVES: The Quebec Emergency Department Management Guide (QEDMG) is a unique document with 78 recommendations designed to improve the organization of emergency departments (EDs) in the province of Quebec. However, no study has examined how this guide is perceived or used by rural health care management. METHODS: We invited all directors of professional services (DPS), directors of nursing services (DNS), head nurses (HN), and emergency department directors (EDD) working in Quebec's rural hospitals to complete an online survey (144 questions). Simple frequency analyses (percentage [%] and 95% confidence interval) were conducted to establish general familiarity and use of the QEDMG, as well as perceived usefulness and implementation of its recommendations. RESULTS: Seventy-three percent (19/26) of Quebec's rural EDs participated in the study. A total of 82% (62/76) of the targeted stakeholders participated. Sixty-one percent of respondents reported being "moderately or a lot" familiar with the QEDMG, whereas 77% reported "almost never or sometimes" refer to this guide. Physician management (DPS, EDD) were more likely than nursing management (DNS and especially HN) to report "not at all" or "little" familiarity on use of the guide. Finally, 98% of the QEDMG recommendations were considered useful. CONCLUSIONS: Although the QEDMG is considered a useful guide for rural EDs, it is not optimally known or used in rural EDs, especially by physician management. Stakeholders should consider these findings before implementing the revised versions of the QEDMG.

Role of the p38 MAPK/C/EBPß Pathway in the Regulation of Phenotype and IL-10 and IL-12 Production by Tolerogenic Bone Marrow-Derived Dendritic Cells.

Dendritic cells (DCs) play a major role in innate and adaptive immunity and self-immune tolerance. Immunogenic versus tolerogenic DC functions are dictated by their levels of costimulatory molecules and their cytokine expression profile. The transcription factor C/EBPß regulates the expression of several inflammatory genes in many cell types including macrophages. However, little is known regarding the role of C/EBPß in tolerogenic versus immunogenic DCs functions. We have previously reported that bone marrow-derived DCs generated with GM-CSF (GM/DCs) acquire the signature of semi-mature tolerogenic IL-10-producing DCs as opposed to immunogenic DCs generated with GM-CSF and IL-4 (IL-4/DCs). Here, we show that tolerogenic GM/DCs exhibit higher levels of phosphorylation and enhanced DNA binding activity of C/EBPß and CREB than immunogenic IL-4/DCs. We also show that the p38 MAPK/CREB axis and GSK3 play an important role in regulating C/EBPß phosphorylation and DNA binding activity. Inhibition of p38 MAPK in GM/DCs resulted in a drastic decrease of C/EBPß and CREB DNA binding activities, a reduction of their IL-10 production and an increase of their IL-12p70 production, a characteristic of immunogenic IL-4/DCs. We also present evidence that GSK3 inhibition in GM/DCs reduced C/EBPß DNA binding activity and increased expression of costimulatory molecules in GM/DCs and their production of IL-10. Analysis of GM/DCs of C/EBPß-/- mice showed that C/EBPß was essential to maintain the semimature phenotype and the production of IL-10 as well as low CD4⁺ T cell proliferation. Our results highlight the importance of the p38MAPK-C/EBPß pathway in regulating phenotype and function of tolerogenic GM/DCs.

Zika Virus Infection during Pregnancy and Effects on Early Childhood Development, French Polynesia, 2013-2016.

Congenital Zika virus syndrome consists of a large spectrum of neurologic abnormalities seen in infants infected with Zika virus in utero. However, little is known about the effects of Zika virus intrauterine infection on the neurocognitive development of children born without birth defects. Using a case-control study design, we investigated the temporal association of a cluster of congenital defects with Zika virus infection. In a nested study, we also assessed the early childhood development of children recruited in the initial study as controls who were born without known birth defects,. We found evidence for an association of congenital defects with both maternal Zika virus seropositivity (time of infection unknown) and symptomatic Zika virus infection during pregnancy. Although the early childhood development assessment found no excess burden of developmental delay associated with maternal Zika virus infection, larger, longer-term studies are needed.

Can an Infection Hypothesis Explain the Beta Amyloid Hypothesis of Alzheimer's Disease?

Alzheimer's disease (AD) is the most frequent type of dementia. The pathological hallmarks of the disease are extracellular senile plaques composed of beta-amyloid peptide (Aß) and intracellular neurofibrillary tangles composed of pTau. These findings led to the "beta-amyloid hypothesis" that proposes that Aß is the major cause of AD. Clinical trials targeting Aß in the brain have mostly failed, whether they attempted to decrease Aß production by BACE inhibitors or by antibodies. These failures suggest a need to find new hypotheses to explain AD pathogenesis and generate new targets for intervention to prevent and treat the disease. Many years ago, the "infection hypothesis" was proposed, but received little attention. However, the recent discovery that Aß is an antimicrobial peptide (AMP) acting against bacteria, fungi, and viruses gives increased credence to an infection hypothesis in the etiology of AD. We and others have shown that microbial infection increases the synthesis of this AMP. Here, we propose that the production of Aß as an AMP will be beneficial on first microbial challenge but will become progressively detrimental as the infection becomes chronic and reactivates from time to time. Furthermore, we propose that host measures to remove excess Aß decrease over time due to microglial senescence and microbial biofilm formation. We propose that this biofilm aggregates with Aß to form the plaques in the brain of AD patients. In this review, we will develop this connection between Infection - Aß - AD and discuss future possible treatments based on this paradigm.

Rural versus urban academic hospital mortality following stroke in Canada.

INTRODUCTION: Stroke is one of the leading causes of death in Canada. While stroke care has improved dramatically over the last decade, outcomes following stroke among patients treated in rural hospitals have not yet been reported in Canada. OBJECTIVES: To describe variation in 30-day post-stroke in-hospital mortality rates between rural and urban academic hospitals in Canada. We also examined 24/7 in-hospital access to CT scanners and selected services in rural hospitals. MATERIALS AND METHODS: We included Canadian Institute for Health Information (CIHI) data on adjusted 30-day in-hospital mortality following stroke from 2007 to 2011 for all acute care hospitals in Canada excluding Quebec and the Territories. We categorized rural hospitals as those located in rural small towns providing 24/7 emergency physician coverage with inpatient beds. Urban hospitals were academic centres designated as Level 1 or 2 trauma centres. We computed descriptive data on local access to a CT scanner and other services and compared mean 30-day adjusted post-stroke mortality rates for rural and urban hospitals to the overall Canadian rate. RESULTS: A total of 286 rural hospitals (3.4 million emergency department (ED) visits/year) and 24 urban hospitals (1.5 million ED visits/year) met inclusion criteria. From 2007 to 2011, 30-day in-hospital mortality rates following stroke were significantly higher in rural than in urban hospitals and higher than the Canadian average for every year except 2008 (rural average range = 18.26 to 21.04 and urban average range = 14.11 to 16.78). Only 11% of rural hospitals had a CT-scanner, 1% had MRI, 21% had in-hospital ICU, 94% had laboratory and 92% had basic x-ray facilities. CONCLUSION: Rural hospitals in Canada had higher 30-day in-hospital mortality rates following stroke than urban academic hospitals and the Canadian average. Rural hospitals also have very limited local access to CT scanners and ICUs. These rural/urban discrepancies are cause for concern in the context of Canada's universal health care system.

Signal transduction changes in CD4+ and CD8+ T cell subpopulations with aging.

The innate and adaptive branches of the immune system display changes with aging, a fact referred to as immunosenescence. Furthermore, it has been established that adaptive immunity is more susceptible to age-related changes than innate immunity. The most prominent phenotypic changes that reflect the specific differentiation and role of each T cell subpopulation are two-fold. They are a decreased number of naïve T cells that parallels an increase in memory T cells, mainly in the cytotoxic CD8+ T cell population, which can be subdivided into naïve, central, effector memory and TEMRA cells. The two main T cell properties that are the most affected with aging are the altered clonal expansion and decreased cytokine production, especially IL-2. These T cell functions have been shown to be affected in the early events of signaling. The aim of the present study was to investigate the influence of age on TCR- and CD28-dependent activation of the downstream signaling effectors Lck, SHP-1, Akt, PI3K p85α and mTOR in differentiated subpopulations of CD4+ and CD8+ T cells. Results showed that lymphocytes of elderly subjects were already in an activated state that could not be upregulated by external stimulation. Results also showed that the age-related signal transduction changes were more important than phenotype in the CD4+ and CD8+ T subpopulations. These observations suggested that age-related molecular and biochemical changes have a more significant influence on T cell functions than T cell phenotype.

Role of the peripheral innate immune system in the development of Alzheimer's disease.

Alzheimer's disease is one of the most devastating neurodegenerative diseases. The exact cause of the disease is still not known although many scientists believe in the beta amyloid hypothesis which states that the accumulation of the amyloid peptide beta (Aß) in brain is the initial cause which consequently leads to pathological neuroinflammation. However, it was recently shown that Aß may have an important role in defending the brain against infections. Thus, the balance between positive and negative impact of Aß may determine disease progression. Microglia in the brain are innate immune cells, and brain-initiated inflammatory responses reflected in the periphery suggests that Alzheimer's disease is to some extent also a systemic inflammatory disease. Greater permeability of the blood brain barrier facilitates the transport of peripheral immune cells to the brain and vice versa so that a vicious circle originating on the periphery may contribute to the development of overt clinical AD. Persistent inflammatory challenges by pathogens in the periphery, increasing with age, may also contribute to the central propagation of the pathological changes seen clinically. Therefore, the activation status of peripheral innate immune cells may represent an early biomarker of the upcoming impact on the brain. The modulation of these cells may thus become a useful mechanism for modifying disease progression.

Group interventions to reduce emotional distress and fatigue in breast cancer patients: a 9-month follow-up pragmatic trial.

BACKGROUND: Long-term effects of psychosocial interventions to reduce emotional distress, sleep difficulties, and fatigue of breast cancer patients are rarely examined. We aim to assess the effectiveness of three group interventions, based on cognitive behavioural therapy (CBT), yoga, and self-hypnosis, in comparison to a control group at a 9-month follow-up. METHODS: A total of 123 patients chose to participate in one of the interventions. A control group was set up for those who agreed not to participate. Emotional distress, fatigue, and sleep quality were assessed before (T0) and after interventions (T1), and at 3-month (T2) and 9-month follow-ups (T3). RESULTS: Nine months after interventions, there was a decrease of anxiety (P=0.000), depression (P=0.000), and fatigue (P=0.002) in the hypnosis group, and a decrease of anxiety (P=0.024) in the yoga group. There were no significant improvements for all the investigated variables in the CBT and control groups. CONCLUSIONS: Our results showed that mind-body interventions seem to be an interesting psychological approach to improve the well-being of breast cancer patients. Further research is needed to improve the understanding of the mechanisms of action of such interventions and their long-term effects on quality of life.

Polymorphonuclear Neutrophil Functions are Differentially Altered in Amnestic Mild Cognitive Impairment and Mild Alzheimer's Disease Patients.

The mechanisms of neurodegeneration in Alzheimer's disease (AD) remain under investigation. Alterations in the blood-brain barrier facilitate exchange of inflammatory mediators and immune cells between the brain and the periphery in AD. Here, we report analysis of phenotype and functions of polymorphonuclear neutrophils (PMN) in peripheral blood from patients with amnestic mild cognitive impairment (aMCI, n = 13), patients with mild AD (mAD, n = 15), and healthy elderly controls (n = 13). Results showed an increased expression of CD177 in mAD but not in healthy or aMCI patients. IL-8 stimulated increased expression of the CD11b integrin in PMN of healthy subjects in vitro but PMN of aMCI and mAD patients failed to respond. CD14 and CD16 expression was lower in PMN of mAD but not in aMCI individuals relative to controls. Only PMN of aMCI subjects expressed lower levels of CD88. Phagocytosis toward opsonized E. coli was differentially impaired in PMN of aMCI and mAD subjects whereas the capacity to ingest Dextran particles was absent only in mAD subjects. Killing activity was severely impaired in aMCI and mAD subjects whereas free radical production was only impaired in mAD patients. Inflammatory cytokine (TNFα, IL-6, IL-1ß, IL-12p70) and chemokine (MIP-1α, MIP-1ß, IL-8) production in response to LPS stimulation was very low in aMCI and nearly absent in mAD subjects. TLR2 expression was low only in aMCI. Our data showed a differentially altered capacity of PMN of aMCI and mAD subjects to respond to pathological aggression that may impact impaired responses associated with AD development.

Rural emergency care 360°: mobilising healthcare professionals, decision-makers, patients and citizens to improve rural emergency care in the province of Quebec, Canada: a qualitative study protocol.

INTRODUCTION: Emergency departments (EDs) are an important safety net for rural populations. Results of our earlier studies suggest that rural Canadian hospitals have limited access to advanced imaging services and intensive care units and that patients are transferred over large distances. They also revealed significant geographical variations in rural services. In the absence of national standards, our studies raise questions about inequities in rural access to emergency services and the risks for citizens. Our goal is to build recommendations for improving services by mobilising stakeholders interested in rural emergency care. With help and full engagement of stakeholders, we will (1) identify solutions for improving quality and performance in rural EDs; (2) formulate and prioritise recommendations; (3) transfer knowledge of the recommendations to rural EDs and support operationalisation and (4) assess knowledge transfer and explore further impacts of this participatory action research project. METHODOLOGY: We will use a participatory action research approach. We will plan for a governance structure that includes all stakeholders’ representatives, so throughout this project, stakeholders are fully engaged at every step. Our sample will be 26 EDs in rural Quebec. We will conduct semistructured individual and focus group interviews with relevant and representative participants, including patients and citizens (estimated n=200). Interviews will be thematically analysed to extract potential solutions and other qualitative information.An expert panel (±15) will use an analysis grid to develop consensus recommendations from solutions suggested and will evaluate feasibility, impacts, costs, conditions for implementation and establish monitoring indicators. Recommendations will be transferred to stakeholders using tailored knowledge translation strategies (web platform, meetings and so on). DISCUSSION AND EXPECTED RESULTS: This study will result in a comprehensive consensus list of feasible and high-priority recommendations enabling decision-makers in emergency care to implement improvements in rural emergency care in Quebec. ETHICS AND DISSEMINATION: This protocol has been approved by the CSSS Alphonse-Desjardins research ethics committee (Project number: MP 2017-009). The qualitative material will be kept confidential and the data will be presented in a way that respects confidentiality. The dissemination plan for the study includes publications in scientific and professional journals. We will also use social media to disseminate our findings and activities such as communications in public conferences.

Differential Phenotypes of Myeloid-Derived Suppressor and T Regulatory Cells and Cytokine Levels in Amnestic Mild Cognitive Impairment Subjects Compared to Mild Alzheimer Diseased Patients.

Alzheimer disease (AD) is the most prevalent form of dementia although the underlying cause(s) remains unknown at this time. However, neuroinflammation is believed to play an important role and suspected contributing immune parameters can be revealed in studies comparing patients at the stage of amnestic mild cognitive impairment (aMCI) to healthy age-matched individuals. A network of immune regulatory cells including regulatory T cells (Tregs) and myeloid-derived suppressor cells (MDSCs) maintains immune homeostasis but there are very few data on the role of these cells in AD. Here, we investigated the presence of these cells in the blood of subjects with aMCI and mild AD (mAD) in comparison with healthy age-matched controls. We also quantitated several pro- and anti-inflammatory cytokines in sera which can influence the development and activation of these cells. We found significantly higher levels of MDSCs and Tregs in aMCI but not in mAD patients, as well as higher serum IL-1ß levels. Stratifying the subjects based on CMV serostatus that is known to influence multiple immune parameters showed an absence of differences between aMCI subjects compared to mAD patients and healthy controls. We suggest that the increase in MDSCs and Tregs number in aMCI subjects may have a beneficial role in modulating inflammatory processes. However, this protective mechanism may have failed in mAD patients, allowing progression of the disease. This working hypothesis obviously requires testing in future studies.

The Effects of the Bali Yoga Program for Breast Cancer Patients on Chemotherapy-Induced Nausea and Vomiting: Results of a Partially Randomized and Blinded Controlled Trial.

Complementary and alternative medicine has been shown to be beneficial in reducing chemotherapy-induced nausea and vomiting. However, conclusive results are lacking in order to confirm its usefulness. The purpose of this study was to determine whether a standardized yoga intervention could reduce these adverse symptoms. This was a partially randomized and blinded controlled trial comparing a standardized yoga intervention with standard care. Eligible patients were adults diagnosed with stages I to III breast cancer receiving chemotherapy. Patients randomized to the experimental group participated in an 8-week yoga program. There was no significant difference between the experimental and control groups on chemotherapy-induced nausea and vomiting after 8 weeks. Results suggest the yoga program is not beneficial in managing these adverse symptoms. However, considering preliminary evidence suggesting yoga's beneficial impact in cancer symptom management, methodological limitations should be explored and additional studies should be conducted.

A Nonrandomized Comparison Study of Self-Hypnosis, Yoga, and Cognitive-Behavioral Therapy to Reduce Emotional Distress in Breast Cancer Patients.

The authors asked breast cancer (BC) patients to participate in 1 of 3 mind-body interventions (cognitive-behavioral therapy (CBT), yoga, or self-hypnosis) to explore their feasibility, ease of compliance, and impact on the participants' distress, quality of life (QoL), sleep, and mental adjustment. Ninety-nine patients completed an intervention (CBT: n = 10; yoga: n = 21; and self-hypnosis: n = 68). Results showed high feasibility and high compliance. After the interventions, there was no significant effect in the CBT group but significant positive effects on distress in the yoga and self-hypnosis groups, and, also, on QoL, sleep, and mental adjustment in the self-hypnosis group. In conclusion, mind-body interventions can decrease distress in BC patients, but RCTs are needed to confirm these findings.

Constitutively active Stat5b signaling confers tolerogenic functions to dendritic cells of NOD mice and halts diabetes progression.

Defects in dendritic cells (DCs) development and function lead to autoimmune disorders. Autoimmune diabetes in humans and NOD mice results from a breakdown of self-tolerance, ending in T cell-mediated ß-cell destruction. DCs dysfunction in NOD mice results in part from a defect in the JAK-STAT5 signaling pathway associated with the idd4 susceptibility locus. The involvement of Stat5b in DCs tolerogenic functions remains unknown. We have generated transgenic mice (NOD.CD11cStat5b-CA) expressing a constitutively active form of the Stat5b gene (Stat5b-CA) under control of CD11c promoter. All NOD.CD11cStat5b-CA mice were protected against diabetes. Protection was associated with an increased in the pool and suppressive function of Tregs, a promotion of Th2 and Tc2 immune response and a decreased percentage of CD8+ T cells. Splenic DCs of NOD.CD11cStat5b-CA mice acquired a mature phenotype, promoted and induced better conversion of CD4+CD25-Foxp3- T cells into Tregs (CD4+CD25+Foxp3+ T cells) than DCs of NOD mice. Stat5b-CA.DC-educated CD4+CD25- T cells delayed diabetes onset whereas Stat5b-CA.DC-educated Tregs blocked ongoing diabetes in 8-10 weeks old NOD recipient mice. Importantly, injection of Stat5b.CA.DC to 8-10-week old NOD mice halted diabetes progression and educated their splenocytes to loose their diabetogenic potential when transferred to NOD.SCID mice. Our work is the first to report that an active form of Stat5b restored DCs tolerogenic functions that re-educated Tregs to re-establish and to sustain long-term protective immune response against diabetes in NOD mice.