Blunted Exercise Pressor Response to Isometric Knee Extension and Post Exercise Ischemia in Individuals with Down Syndrome.

Introduction: Individuals with Down syndrome (DS) exhibit autonomic dysfunction, which contributes to reduced work capacity. The metaboreflex produces exercise-induced sympathoexcitation and can be assessed via post-exercise muscle ischemia (PEMI). Blunted sympathoexcitation is common in individuals with DS and contributes to the physiological basis for reduced work capacity observed this population, but the influence of the metaboreflex is unknown.

Reduction in peripheral arterial stiffness after reactive hyperemia is dependent on increases in blood flow.

The acute reduction in peripheral arterial stiffness during reactive hyperemia is assumed to be flow-mediated; however, the mechanism remains unproven. We hypothesized that restricting the blood flow increase during reactive hyperemia would abolish the reduction in peripheral arterial stiffness. Fourteen healthy young adults (5 females, 25 ± 5 years, mean ± SD) underwent reactive hyperemia with a rapid-release cuff on the upper arm inflated to 220 mmHg for 5 min: once with unrestricted blood flow and once with restricted blood flow by manually applying pressure to the brachial artery.

Accumulated physical activity and the association with obesity, fitness, and cardiometabolic risk factors in healthy adults.

Objective: This study examined the prevalence of ≥150 min/wk of moderate-to-vigorous physical activity (MVPA) using different criteria for bout length and to examine associations with measures of obesity, cardiorespiratory fitness, and cardiometabolic risk factors in healthy adults with overweight or obesity.

Methods: Baseline data from healthy adults (N = 375; age [mean ± SD] = 45.2 ± 7.

Weight Management Strategies for the Patient with Diabetes.

Purpose Of Review: Obesity is associated with an increased risk for type 2 diabetes, and weight loss in adults with obesity and type 2 diabetes may be indicated to reduce health risk and improve diabetes control. It is important to understand the effectiveness of weight loss interventions for the prevention and treatment of type 2 diabetes.

Recent Findings: Lifestyle interventions for weight loss show effectiveness for prevention of type 2 diabetes.

Strategies for Physical Activity Interventions in the Treatment of Obesity.

Physical activity contributes to body weight regulation. At least 150 minutes per week of moderate-to-vigorous intensity physical activity may be needed. When not coupled with dietary restriction, physical activity contributes to an average weight loss of approximately 2 to 3 kg in interventions up to 6 months in duration; when added to modest dietary restriction it adds 20% additional weight loss compared with modest dietary restriction alone.

Mucosal and systemic SIV-specific cytotoxic CD4 T cell hierarchy in protection following intranasal/intramuscular recombinant pox-viral vaccination of pigtail macaques.

A HIV vaccine that provides mucosal immunity is urgently needed. We evaluated an intranasal recombinant Fowlpox virus (rFPV) priming vaccine followed by intramuscular Modified Vaccinia Ankara (rMVA) booster vaccine, both expressing SIV antigens. The vaccination generated mucosal and systemic SIV-specific CD4 T cell mediated immunity and was associated with partial protection against high-dose intrarectal SIV challenge in outbred pigtail macaques.

Unexpected involvement of IL-13 signalling via a STAT6 independent mechanism during murine IgG2a development following viral vaccination.

In this study, recombinant pox viral vaccination was shown to induce highly elevated IgG2a and low IgG1 antibody expression in mice lacking IL-4 or STAT6, whilst IL-13 mice exhibited elevated IgG1, but very low IgG2a. These findings revealed that IL-13 and IL-4 differentially regulated antibody development. To understand this further, when STAT6 mice were given a vaccine co-expressing IL-13Rα2 that temporarily sequestered IL-13, significantly reduced IgG2a expression, was detected.

Vaccination route can significantly alter the innate lymphoid cell subsets: a feedback between IL-13 and IFN-γ.

This study demonstrates that the fate of a vaccine is influenced by the cytokines produced by the innate lymphoid cells (ILC) recruited to the vaccination site, and it is vaccine route and adjuvant dependent. Intranasal virus vaccination induced ST2/IL-33R ILC2 in lung, while intramuscular vaccination induced exclusively IL-25R ILC2 in muscle. Interestingly, a larger proportion of IL-13 ILC2s were detected in muscle following i.

Heparan sulfate as a receptor for poxvirus infections and as a target for antiviral agents.

To establish the importance of virus-heparan sulfate (HS) interactions in virus infectivity, the poxvirus vaccinia virus (VACV) was used, as it binds HS and has both enveloped virus (EV) and non-enveloped mature virus (MV) forms. Initial studies showed that heparin inhibited plaque formation by both MV-rich WR and EV-rich IHD-J strains of VACV, with the EV-rich strain also losing trademark 'comet'-shaped plaques. However, using GFP-tagged EV and MV forms of VACV, based on IC values, heparin was 16-fold more effective at inhibiting the infectivity of the EV form compared to the MV form.

Structural and functional characterization of a DARPin which inhibits Ras nucleotide exchange.

Ras mutations are the oncogenic drivers of many human cancers and yet there are still no approved Ras-targeted cancer therapies. Inhibition of Ras nucleotide exchange is a promising new approach but better understanding of this mechanism of action is needed. Here we describe an antibody mimetic, DARPin K27, which inhibits nucleotide exchange of Ras.

Recombinant fowlpox virus vector-based vaccines: expression kinetics, dissemination and safety profile following intranasal delivery.

We have previously established that mucosal uptake of recombinant fowlpox virus (rFPV) vaccines is far superior to other vector-based vaccines. Specifically, intranasal priming with rFPV vaccines can recruit unique antigen-presenting cells, which induce excellent mucosal and systemic HIV-specific CD8+ T-cell immunity. In this study, we have for the first time investigated the in vivo dissemination, safety and expression kinetics of rFPV post intranasal delivery using recombinant viruses expressing green fluorescent protein or mCherry.

Centers for Medicare & Medicaid Services Transition From Payments for Volume to Value: Implications for North Carolina Physicians, Providers, and Patients.

The US Department of Health and Human Services and the Centers for Medicare & Medicaid Services have announced goals and timelines to transition from payments based on volume to payments based on value, quality, and efficient delivery of care. These value-based payments and alternative payment models will impact all health care professionals and provider organizations by encouraging better care, healthier people, and spending health care dollars wisely and efficiently.

Intracranial venous injury, thrombosis and repair as hallmarks of mild blast traumatic brain injury in rats: Lessons from histological and immunohistochemical studies of decalcified sectioned heads and correlative microarray analysis.

Background: Many previous experimental studies of blast wave effects have reported vascular and parenchymal injury in brains extracted from the skulls prior to histopathological assessment. Brain removal disrupts vasculature and structural features of the meninges that may be sources of signs and symptoms of mild traumatic brain injury, particular at lower blast overpressures (<5psi peak).

New Method: Immunohistochemical and histopathological studies have been conducted in sections from decalcified, paraffin embedded, histologically sectioned whole rat heads.

Identification of biomarkers to measure HIV-specific mucosal and systemic CD8(+) T-cell immunity using single cell Fluidigm 48.48 Dynamic arrays.

Thirty genes composed of cytokines, chemokines, granzymes, perforin and integrins were evaluated in gut and splenic K(d)Gag197-205-specific single CD8(+) T cells using Fluidigm 48.48 Dynamic arrays, with the aim of identifying biomarkers to predict effective mucosal and systemic vaccine efficacy. The mRNA expression profiles were analyzed in three ways: (i) the "number" of K(d)Gag197-205-specific CD8(+) T cells expressing the biomarker, (ii) "level" of mRNA expression using principal component analysis (PCA) and (iii) poly-functionality in relation to RANTES expression.

Brucellosis and Coxiella burnetii Infection in Householders and Their Animals in Secure Villages in Herat Province, Afghanistan: A Cross-Sectional Study.

Background: Brucellosis and coxiellosis are known to be endemic in ruminant populations throughout Afghanistan, but information about their prevalence and factors that affect prevalence in householders and livestock under diverse husbandry systems and pastoral settings is sparse.

Methods/principal Findings: We conducted a cross-sectional survey to investigate the seroprevalence of brucellosis and Coxiella burnetii in humans and livestock in six secure districts in Herat from 26th December 2012-17th January 2013. A total of 204 households with livestock were surveyed in six Kuchi and five sedentary type villages.

Fibrinogen and prothrombin complex concentrate in trauma coagulopathy.

Background: Coagulopathy after injury contributes to hemorrhage and death. Treatment with specific coagulation factors could decrease hemorrhage and mortality. Our aim was to compare fibrinogen and prothrombin complex concentrate (PCC) in a rabbit model of hemorrhagic shock.

Efficacy and safety of N-acetylcysteine in prevention of noise induced hearing loss: a randomized clinical trial.

Despite a robust hearing conservation program, military personnel continue to be at high risk for noise induced hearing loss (NIHL). For more than a decade, a number of laboratories have investigated the use of antioxidants as a safe and effective adjunct to hearing conservation programs. Of the antioxidants that have been investigated, N-acetylcysteine (NAC) has consistently reduced permanent NIHL in the laboratory, but its clinical efficacy is still controversial.

Engineering therapeutic proteins for cell entry: the natural approach.

Owing to the challenges of cell entry, protein-based therapies have so far been restricted to extracellular targets, whereas intracellular targets have been almost exclusively addressed by small molecules. The specificity and potency of proteins would enable them to be effective intracellular drugs, provided that the proteins are delivered efficiently to appropriate intracellular compartments within specific cell types. By mimicking the natural mechanisms of toxins and other natural proteins, new intracellular delivery systems are being developed, the first of which are showing clinical efficacy.

IL-17A expression in HIV-specific CD8 T cells is regulated by IL-4/IL-13 following HIV-1 prime-boost immunization.

Although Th1 and Th2 cytokines can inhibit interleukin (IL)-17-secreting T cells, how these cells are regulated under different infectious conditions is still debated. Our previous studies have shown that vaccination of IL-4 and IL-13 gene knockout (KO) mice can induce high-avidity HIV K(d)Gag197-205-specific CD8 T cells with better protective efficacy. In this study, when IL-13, IL-4, STAT6 KO, and wild-type BALB/c mice were prime-boost immunized with an HIV poxviral modality, elevated numbers of IL-17A(+) splenic K(d)Gag197-205-specific CD8 T cells were observed in all the KO mice compared with the wt BALB/c control.

Different HIV pox viral vector-based vaccines and adjuvants can induce unique antigen presenting cells that modulate CD8 T cell avidity.

The lung-derived dendritic cell (LDC) recruitment following intranasal (i.n.) vaccination of different poxviral vector-based vaccines/adjuvants were evaluated to decipher how these factors influenced CD8(+) T cell avidity.

Use of an in vivo FTA assay to assess the magnitude, functional avidity and epitope variant cross-reactivity of T cell responses following HIV-1 recombinant poxvirus vaccination.

Qualitative characteristics of cytotoxic CD8+ T cells (CTLs) are important in measuring the effectiveness of CTLs in controlling HIV-1 infections. Indeed, in recent studies patients who are naturally resistant to HIV-1 infections have been shown to possess CTLs that are of high functional avidity and have a high capacity to recognize HIV epitope variants, when compared to HIV-1 infection progressors. When developing efficacious vaccines, assays that can effectively measure CTL quality specifically in vivo are becoming increasingly important.

IL-4 and IL-13 receptors: Roles in immunity and powerful vaccine adjuvants.

The roles of interleukin (IL)-4 and IL-13 during both innate and adaptive Th2 mediated immunity have received considerable scrutiny, however, mechanisms by which these cytokines influence the cellular interactions involved in negatively modulating the development of effective Th1 immunity are poorly characterized. In this article we discuss the recent advances in IL-4/IL-13 biology, mainly (i) role of these cytokines in allergic inflammation, atopic dermatitis, cancer, transplant rejection, bacterial/viral infections, and specifically the therapeutic potential of IL-13Rα2, (ii) insights into how "alarmin" stimulation activate IL-4/IL-13 at the lung mucosae, (iii) how these two cytokines modulate antigen-specific CD8(+) T cell quality/avidity in a vaccine route dependent manner and (iv) finally discuss the potential of using transient inhibition of IL-4 and/or IL-13 at the vaccination site as a platform vaccine technology to induce strong sustained high quality CD8(+) T cell immunity for protection against many chronic mucosal pathogens such as HIV-1.

Novel HIV IL-4R antagonist vaccine strategy can induce both high avidity CD8 T and B cell immunity with greater protective efficacy.

We have established that the efficacy of a heterologous poxvirus vectored HIV vaccine, fowlpox virus (FPV)-HIV gag/pol prime followed by attenuated vaccinia virus (VV)-HIV gag/pol booster immunisation, is strongly influenced by the cytokine milieu at the priming vaccination site, with endogenous IL-13 detrimental to the quality of the HIV specific CD8+ T cell response induced. We have now developed a novel HIV vaccine that co-expresses a C-terminal deletion mutant of the mouse IL-4, deleted for the essential tyrosine (Y119) required for signalling. In our vaccine system, the mutant IL-4C118 can bind to IL-4 type I and II receptors with high affinity, and transiently prevent the signalling of both IL-4 and IL-13 at the vaccination site.

Progresses in DNA-based heterologous prime-boost immunization strategies.

Although recombinant DNA and recombinant viral vectors expressing HIV antigens have yielded positive outcomes in animal models, these vaccines have not been effectively translated to humans. Despite this, there is still a high level of optimism that poxviral-based vaccine strategies could offer the best hope for developing an effective vaccine against not only HIV-1 but also other chronic diseases where good-quality T and B cell immunity is needed for protection. In this chapter we discuss step by step (1) how recombinant poxviral vectors co-expressing HIV antigens and promising mucosal/systemic adjuvants (e.