Astrocytes modulate microglial phenotype and dendritic cell-like properties

Microglia are the resident immune cells of the CNS. In the healthy CNS, they express negligible levels of MHC II molecules as well as co-stimulatory molecules CD40, CD80 and CD86 necessary for antigen presentation to and activation of T cells. Co-stimulatory molecule expression can be induced in isolated microglia in vitro by sequential treatment with granulocyte monocyte colony-stimulating factor (GM-CSF) followed by lipopolysaccharide (LPS). Upon such treatment, they become mature dendritic cells (DCs), capable of activating T cells. However, microglia are not isolated in life, but rather exist in an environment enriched by other cells, notably astrocytes. Therefore, to determine the effect of astrocytes on the assumption by microglia of the DC phenotype, microglia were treated with GM-CSF and LPS either in the presence or absence of astrocytes and assayed for the DC phenotypic marker CD11c and the co-stimulatory CD40, CD80, CD86 and MHC II by flow cytometry. When compared to isolated microglia, a significantly lower percentage of microglia co-cultured with astrocytes expressed these markers. Astrocytes also prevent the expression of these molecules in bone marrow-derived DCs. Neither interleukin-10, transforming growth factor-beta, nor prostaglandin E2 are responsible for the inhibition. Rather, contact with the astrocytic environment is responsible for the suppressive qualities. Microglia cultured in the presence of astrocytes are also functionally distinct from those cultured in isolation. Microglia in association with astrocytes promote T cell proliferation more robustly than do microglia in isolation. By contrast, a significantly higher percentage of CD4+ T cells stimulated with αCD3 in the presence of isolated microglia acquire an anti-inflammatory Foxp3+ T regulatory phenotype when compared to T cells cultured with microglia in the presence of astrocytes. This is not due to interactions between CD80/CD86 and CTLA4. The elevated presence of Foxp3+ T cells appears to be responsible for the lower level of T cell proliferation in the presence of isolated microglia. Finally, analysis of the supernatants from the T cell co-culture experiments reveal that astrocytic interaction(s) with microglia suppress T cell production of pro-inflammatory cytoki nes i nterferon-γ and interleukin-17. These data taken together suggest that astrocytes play a crucial role in modulating the microgl i al immune response in the CNS

High-Resolution Mapping and Successful Ablation of Purkinje Ectopy–Triggered Ventricular Fibrillation Storm

Catheter ablation is recognized as a central therapeutic option in treating patients with drug-refractory, scar-related monomorphic ventricular tachycardia (VT). Catheter ablation also has a role in selected cases of polymorphic VT (PMVT) and/or ventricular fibrillation (VF). Rarely, premature ventricular contractions (PVCs) originating from the Purkinje network can induce PMVT/VF. Although not completely elucidated, the electrophysiologic mechanisms behind this lethal arrhythmia have generally been thought to be related to abnormal automaticity and triggered activity. Ablation of the triggering PVCs can prevent VF recurrence and is potentially lifesavin

Immune Function and Muscle Adaptations to Resistance exercise in Older Adults: Study Protocol for a Randomized Controlled Trial of a Nutritional Supplement

BACKGROUND: Immune function may influence the ability of older adults to maintain or improve muscle mass, strength, and function during aging. Thus, nutritional supplementation that supports the immune system could complement resistance exercise as an intervention for age-associated muscle loss. The current study will determine the relationship between immune function and exercise training outcomes for older adults who consume a nutritional supplement or placebo during resistance training and post-training follow-up. The supplement was chosen due to evidence suggesting its ingredients [arginine (Arg), glutamine (Gln), and β-hydroxy β-methylbutyrate (HMB)] can improve immune function, promote muscle growth, and counteract muscle loss. METHODS/DESIGN: Veterans (age 60 to 80 yrs, N = 50) of the United States military will participate in a randomized double-blind placebo-controlled trial of consumption of a nutritional supplement or placebo during completion of three study objectives: 1) determine if 2 weeks of supplementation improve immune function measured as the response to vaccination and systemic and cellular responses to acute resistance exercise; 2) determine if supplementation during 36 sessions of resistance training boosts gains in muscle size, strength, and function; and 3) determine if continued supplementation for 26 weeks post-training promotes retention of training-induced gains in muscle size, strength, and function. Analyses of the results for these objectives will determine the relationship between immune function and the training outcomes. Participants will undergo nine blood draws and five muscle (vastus lateralis) biopsies so that the effects of the supplement on immune function and the systemic and cellular responses to exercise can be measured. DISCUSSION: Exercise has known effects on immune function. However, the study will attempt to modulate immune function using a nutritional supplement and determine the effects on training outcomes. The study will also examine post-training benefit retention, an important issue for older adults, usually omitted from exercise studies. The study will potentially advance our understanding of the mechanisms of muscle gain and loss in older adults, but more importantly, a nutritional intervention will be evaluated as a complement to exercise for supporting muscle health during aging. TRIAL REGISTRATION: Clinicaltrials.gov identifier: NCT02261961, registration date 10 June 2014, recruitment active

Wii-Fit for Improving Gait and Balance in an Assisted Living Facility: A Pilot Study

Objectives. To determine the effects on balance and gait of a Wii-Fit program compared to a walking program in subjects with mild Alzheimer's dementia (AD). Methods. A prospective randomized (1 : 1) pilot study with two intervention arms was conducted in an assisted living facility with twenty-two mild AD subjects. In both groups the intervention occurred under supervision for 30 minutes daily, five times a week for eight weeks. Repeated measures ANOVA and paired t-tests were used to analyze changes. Results. Both groups showed improvement in Berg Balance Scale (BBS), Tinetti Test (TT) and Timed Up and Go (TUG) over 8 weeks. However, there was no statistically significant difference between the groups over time. Intragroup analysis in the Wii-Fit group showed significant improvement on BBS (P = 0.003), and TT (P = 0.013). The walking group showed a trend towards improvement on BBS (P = 0.06) and TUG (P = 0.07) and significant improvement in TT (P = 0.06). Conclusion. This pilot study demonstrates the safety and efficacy of Wii-Fit in an assisted living facility in subjects with mild AD. Use of Wii-Fit resulted in significant improvements in balance and gait comparable to those in the robust monitored walking program. These results need to be confirmed in a larger, methodologically sound study

WII-FIT FOR BALANCE AND GAIT IN SKILLED NURSING FACILITY: A RETROSPECTIVE STUDY

Background: Falls in elderly are a major public health problem. Poor balance and gait abnormalities are risk factors for falls. Exercise improves gait and balance in elderly. However, it is difficult to engage patients in exercise programs. Wii-Fit might bridge this gap by providing high level of engagement at an affordable price. Wii-Fit is a Nintendo game used for balance, yoga, aerobics, and strength training. It is a TV based self-directed activity. Virtual trainers talk the user through the activity and track progress while visual and auditory feedback improve engagement. Anecdotal reports suggest improvement in balance and social benefits with Wii-Fit, but no systematic studies are available. Objective: To compare the effect of Wii-Fit augmentation to physical therapy alone in subjects undergoing rehabilitation in skilled nursing facility (SNF) using a retrospective chart review. Methods: 100 charts were reviewed of which seventeen patients were noted to have used Wii-Fit during their rehabilitation. These subjects were matched with seventeen controls who did physical therapy alone. Results: There were no baseline differences between the groups. The mean age was 77.7 years, with 11 females in each group. All the subjects were Caucasians. The average length of stay was 30 days in each group. Mean duration of the Wii-Fit use was 4-weeks. Wii-Fit augmentation group improved significantly in Activities of Daily Living (p=0.008), balance (p=0.0001), and assistance with gait (p=0.05) when compared to the control group. Conclusion: Wii-Fit can be used safely in a SNF, and it may improve balance, gait, and functional status

The N-Terminal Domain of Y-Box Binding Protein-1 Induces Cell Cycle Arrest in G2/M Phase by Binding to Cyclin D1

Y-box binding protein YB-1 is a multifunctional protein involved in cell proliferation, regulation of transcription and translation. Our previous study indicated that disruption of one allele of Chk-YB-1b gene in DT-40 cells resulted in major defects in the cell cycle. The abnormalities seen in heterozygous mutants could be attributed to a dominant negative effect exerted by the disrupted YB-1 allele product. To test this hypothesis the N-terminal sequence of the YB-1 was fused with the third helix of antennapedia and the green fluorescent protein. These purified fusion proteins were introduced into rat hepatoma cells and their effect on cell proliferation was studied. Results indicate that the N-terminal 77 amino acid domain of the YB-1 protein induced the cells to arrest in G2/M phase of the cell cycle and undergo apoptosis. Additional deletion analysis indicated that as few as 26 amino acids of the N-terminus of YB-1 can cause these phenotypic changes. We further demonstrated that this N-terminal 77 amino acid domain of YB-1 sequesters cyclin D1 in the cytoplasm of cells at G2/M phase of cell cycle. We conclude that the N-terminal domain of YB-1 plays a major role in cell cycle progression through G2/M phase of cell cycle

Neural Adaptive Admission Control Framework: SLA-driven action termination for real-time application service management

Although most modern cloud-based enterprise systems, or operating systems, do not commonly allow configurable/automatic termination of processes, tasks or actions, it is common practice for systems administrators to manually terminate, or stop, tasks or actions at any level of the system. The paper investigates the potential of automatic adaptive control with action termination as a method for adapting the system to more appropriate conditions in environments with established goals for both system’s performance and economics. A machine-learning driven control mechanism, employing neural networks, is derived and applied within data-intensive systems. Control policies that have been designed following this approach are evaluated under different load patterns and service level requirements. The experimental results demonstrate performance characteristics and benefits as well as implications of termination control when applied to different action types with distinct run-time characteristics. An automatic termination approach may be eminently suitable for systems with harsh execution time Service Level Agreements, or systems running under conditions of hard pressure on power supply or other constraints. The proposed control mechanisms can be combined with other available toolkits to support deployment of autonomous controllers in high-dimensional enterprise information systems

Association of CYBA gene (-930 A/G and 242 C/T) polymorphisms with oxidative stress in breast cancer: a case-control study

Background Oxidative stress (OS) is a key characteristic feature in cancer initiation and progression. Among multiple cancers, NADPH oxidase (NOX) dependent free radical production is implicated in oxidative stress. P22phox, a subunit of NADPH oxidase encoded by the CYBA gene has functional polymorphisms associated with various complex diseases. The present study was aimed to examine the importance and association of the functional polymorphisms of CYBA gene (-930 A/G and 242 C/T) with the oxidative stress in breast cancer (BC) development and progression. Materials and Methods We have performed a case-control study on 300 breast cancer patients and 300 healthy individuals as controls to examine the role of CYBA gene -930 A/G and 242 C/T single nucleotide polymorphisms (SNPs) using As-PCR and PCR-RFLP assays and its association with OS as measured by plasma MDA levels. Linkage disequilibrium (LD) plots were generated using Haploviewtool and Multifactor dimensionality reduction (MDR) analysis was applied to assess high-order interactions between the SNPs. The Insilco analysis has been performed to predict the effect of SNPs on the gene regulation using online tools. Results We have found that genotype frequencies of CYBA gene -930 A/G and 242C/T polymorphism were significantly different between controls and BC patients (p < 0.05). The haplotype combination -930G/242C and -930G/242T were associated with 1.44 & 1.56 folds increased risk for breast cancer respectively. Further, the MDA levels were higher in the patients carrying -930G/242C and -930G/242T haplotype (p < 0.001). Our results have been substantiated by Insilco analysis. Conclusion Results of the present study suggest that GG genotype of -930 A/G polymorphism, -930G/242C and -930G/242T haplotypes of CYBA gene polymorphisms have shown association with higher MDA levels in breast cancer patients, signify that elevated oxidative stress might aid in increased risk for breast cancer initiation and progression