Intravenous Infusion of the β(3)-Adrenergic Receptor Antagonist APD418 Improves Left Ventricular Systolic Function in Dogs with Systolic Heart Failure: β(3)-Adrenergic Receptor Antagonist in Heart Failure

BACKGROUND: Unlike β(1)- and β(2)-adrenergic receptors (ARs), β(3)-AR stimulation inhibits cardiac contractility and relaxation. In the failing left ventricular (LV) myocardium, β(3)-ARs are upregulated, and can be maladaptive in the setting of decompensation by contributing to LV dysfunction. This study examined the effects of intravenous (i.v.) infusions of the β(3)-AR antagonist APD418 on cardiovascular function and safety in dogs with systolic heart failure (HF). METHODS AND RESULTS: Three separate studies were performed in 21 dogs with coronary microembolization-induced HF (LV ejection fraction [LVEF] of approximately 35%). Studies 1 and 2 (n = 7 dogs each) were APD418 dose escalation studies (dosing range, 0.35-15.00 mg/kg/h) designed to identify an effective dose of APD418 to be used in study 3. Study 3, the sustained efficacy study, (n = 7 dogs) was a 6-hour constant intravenous infusion of APD418 at a dose of 4.224 mg/kg (0.70 mg/kg/h) measuring key hemodynamic endpoints (e.g., EF, cardiac output, the time velocity integral of the mitral inflow velocity waveform representing early filling to time-velocity integral representing left atrial contraction [Ei/Ai]). Studies 1 and 2 showed a dose-dependent increase of LVEF and Ei/Ai, the latter being an index of LV diastolic function. In study 3, infusion of APD418 over 6 hours increased LVEF from 31 ± 1% to 38 ± 1% (P \u3c .05) and increased Ei/Ai from 3.4 ± 0.4 to 4.9 ± 0.5 (P \u3c .05). Vehicle had no effect on the LVEF or Ei/Ai. In study 3, APD418 had no significant effects on the HR or the systemic blood pressure. CONCLUSIONS: Intravenous infusions of APD418 in dogs with systolic HF elicit significant positive inotropic and lusitropic effects. These findings support the development of APD418 for the in-hospital treatment of patients with an acute exacerbation of chronic HF

Evaluation of the psychometric properties of the SF-36 health survey for use among Turkish and Moroccan ethnic minority populations in the Netherlands

Purpose: To evaluate the psychometrics of the SF-36 Health Survey among Turkish and Moroccan ethnic minority populations in the Netherlands and to compare the results to those based on the indigenous Dutch population. Methods: Data were derived from the Second Dutch National Survey of General Practice. In total, SF-36 data were available for 409 Turkish, 377 Moroccan, and 9,628 Dutch respondents. Language subgroup analyses were performed for the Turkish (n = 162) and Moroccan-Arabic (n = 52) versions of the SF-36. Psychometric properties were evaluated by descriptive statistics, factor analysis, internal consistency estimates, known-group comparisons, and differential item function (DIF) analysis. Results Low levels of missing SF-36 data were observed across all groups. Confirmatory factor analysis supported the hypothesized SF-36 scale structure for the Dutch and Turkish group, but high correlations between the MH and VT factors were observed in the Moroccan group. All Cronbach’s alpha coefficients were above 0.70, except for the Vitality scale in the Moroccan group and the Vitality and Social Functioning scales in the Moroccan-Arabic language subgroup. Known-groups validity was found across samples using age, sex, education, and comorbidity as grouping variables, but not marital status. Some evidence for DIF was found in both ethnic group samples. Conclusions: The results generally support the use of the SF-36 for general population research among Turkish and Moroccan ethnic minorities in the Netherlands. Additional studies are needed to confirm the psychometrics of the questionnaire when used among these populations in other Western European countries. (aut. ref.

Impact of Rheumatic Musculoskeletal Disease on Psychological Development in Adolescents and Young Adults

Adolescents and young adults (AYAs) undergo significant physiological and psychological transformations. When developmental milestones are combined with additional challenges of growing up with a chronic rheumatic musculoskeletal disease (RMD), it can increase AYA's susceptibility to psychological problems. Emotional issues in adolescence can often persist into adulthood and negatively impact future health, social, and work outcomes. This chapter summarises psychological challenges for AYAs and recommends ways for healthcare professionals (HCPs) to promote mental wellbeing in AYAs with RMD

Sustained proliferation in cancer: mechanisms and novel therapeutic targets

Proliferation is an important part of cancer development and progression. This is manifest by altered expression and/or activity of cell cycle related proteins. Constitutive activation of many signal transduction pathways also stimulates cell growth. Early steps in tumor development are associated with a fibrogenic response and the development of a hypoxic environment which favors the survival and proliferation of cancer stem cells. Part of the survival strategy of cancer stem cells may manifested by alterations in cell metabolism. Once tumors appear, growth and metastasis may be supported by overproduction of appropriate hormones (in hormonally dependent cancers), by promoting angiogenesis, by undergoing epithelial to mesenchymal transition, by triggering autophagy, and by taking cues from surrounding stromal cells. A number of natural compounds (e.g., curcumin, resveratrol, indole-3-carbinol, brassinin, sulforaphane, epigallocatechin-3-gallate, genistein, ellagitannins, lycopene and quercetin) have been found to inhibit one or more pathways that contribute to proliferation (e.g., hypoxia inducible factor 1, nuclear factor kappa B, phosphoinositide 3 kinase/Akt, insulin-like growth factor receptor 1, Wnt, cell cycle associated proteins, as well as androgen and estrogen receptor signaling). These data, in combination with bioinformatics analyses, will be very important for identifying signaling pathways and molecular targets that may provide early diagnostic markers and/or critical targets for the development of new drugs or drug combinations that block tumor formation and progression

Surface Plasmon Resonance Reveals a Different Pattern of Proinsulin Autoantibodies Concentration and Affinity in Diabetic Patients

Type 1 diabetes mellitus (DM) is characterized by autoimmune aggression against pancreatic beta cells resulting in absolute deficiency of insulin secretion. The first detectable sign of emerging autoimmunity during the preclinical asymptomatic period is the appearance of diabetes-related autoantibodies. In children at risk for type 1 DM, high-affinity Insulin autoantibodies reactive to proinsulin, are associated with diabetes risk. Autoantibodies are usually measured by radioligand binding assay (RBA) that provides quasi-quantitative values reflecting potency (product between concentration and affinity) of specific autoantibodies. Aiming to improve the characterization of the specific humoral immune response, we selected surface plasmon resonance (SPR) as an alternative method to measure proinsulin autoantibodies (PAA). This novel technology has allowed real time detection of antibodies interaction and kinetic analysis. Herein, we have employed SPR to characterize the PAA present in sera from 28 childhood-onset (mean age 8.31±4.20) and 23 adult-onset diabetic patients (≥65 years old, BMI<30) in terms of concentration and affinity. When evaluating comparatively samples from both groups, childhood-onset diabetic patients presented lower PAA concentrations and higher affinities (median 67.12×10−9 M and 3.50×107 M−1, respectively) than the adults (median 167.4×10−9 M and 0.84×107 M−1, respectively). These results are consistent with those from the reference method RBA (Standard Deviation score median 9.49 for childhood-onset group and 5.04 for adult-onset group) where the binding can be directly related to the intrinsic affinity of the antibody, suggesting that there is a different etiopathogenic pathway between both types of clinical presentation of the disease. This technology has shown to be a useful tool for the characterization of PAAs parameters as an alternative to radioimmunoassay, with high versatility and reproducibility associated to low occupational and environmental risk. However, this technology is not eligible for routine marker screening, but this is a powerful technique for a fine description of the thermodynamic parameters of antigen-antibody interaction

Strategy for enhancing reliability and lifetime of DC-AC inverters used for wind turbines

Lifetime of wind turbine inverters is below expectations therefore, novel design and drive strategies are timely required to achieve optimum life span. In this work, a novel driving strategy to mitigate stresses on inverters is proposed. First, an electro thermal analysis was carried out using finite element modelling methods. Subsequently, the outcomes of the models were validated using DC/AC IGBT based power inverter module interfaced to 1.1 kW electrical outputs of a horizontal wind turbine operated under different wind speeds. Real time data was collected using both dSPACE system and high speed thermal imaging camera. The proposed driving method is based on adjusting the switching frequency according to wind speed. Edge detection scheme was embedded in Simulink to determine temperature fluctuations caused by variations in wind speed profile. Effects of these fluctuations are mitigated by regulating the switching frequency and power losses based on a look up table and interpolation method. The proposed strategy of operation reduces cyclic temperature depended lifetime span (total lifetime consumption) to 1.45×10−5 cycles compared to 1.88×10−5 when operated under conventional fixed frequency. Wire-bond thermal stress was also reduced from 54.5 MPa, for the fixed switching frequency, to 45.5 MPa. This represents about 21% reduction in total lifetime consumption of inverter's wire-bond which, brings huge benefits to wind energy industry

Tissue Transglutaminase Promotes Drug Resistance and Invasion by Inducing Mesenchymal Transition in Mammary Epithelial Cells

Recent observations that aberrant expression of tissue transglutaminase (TG2) promotes growth, survival, and metastasis of multiple tumor types is of great significance and could yield novel therapeutic targets for improved patient outcomes. To accomplish this, a clear understanding of how TG2 contributes to these phenotypes is essential. Using mammary epithelial cell lines (MCF10A, MCF12A, MCF7 and MCF7/RT) as a model system, we determined the impact of TG2 expression on cell growth, cell survival, invasion, and differentiation. Our results show that TG2 expression promotes drug resistance and invasive functions by inducing epithelial-mesenchymal transition (EMT). Thus, TG2 expression supported anchorage-independent growth of mammary epithelial cells in soft-agar, disrupted the apical-basal polarity, and resulted in disorganized acini structures when grown in 3D-culture. At molecular level, TG2 expression resulted in loss of E-cadherin and increased the expression of various transcriptional repressors (Snail1, Zeb1, Zeb2 and Twist1). Tumor growth factor-beta (TGF-β) failed to induce EMT in cells lacking TG2 expression, suggesting that TG2 is a downstream effector of TGF-β-induced EMT. Moreover, TG2 expression induced stem cell-like phenotype in mammary epithelial cells as revealed by enrichment of CD44+/CD24-/low cell populations. Overall, our studies show that aberrant expression of TG2 is sufficient for inducing EMT in epithelial cells and establish a strong link between TG2 expression and progression of metastatic breast disease

Muramyl Dipeptide Induces NOD2-Dependent Ly6Chigh Monocyte Recruitment to the Lungs and Protects Against Influenza Virus Infection

Bacterial peptidoglycan-derived muramyl dipeptide (MDP) and derivatives have long-recognized antiviral properties but their mechanism of action remains unclear. In recent years, the pattern-recognition receptor NOD2 has been shown to mediate innate responses to MDP. Here, we show that MDP treatment of mice infected with Influenza A virus (IAV) significantly reduces mortality, viral load and pulmonary inflammation in a NOD2-dependent manner. Importantly, the induction of type I interferon (IFN) and CCL2 chemokine was markedly increased in the lungs following MDP treatment and correlated with a NOD2-dependent enhancement in circulating monocytes. Mechanistically, the protective effect of MDP could be explained by the NOD2-dependent transient increase in recruitment of Ly6Chigh “inflammatory” monocytes and, to a lesser extent, neutrophils to the lungs. Indeed, impairment in both Ly6Chigh monocyte recruitment and survival observed in infected Nod2-/- mice treated with MDP was recapitulated in mice deficient for the chemokine receptor CCR2 required for CCL2-mediated Ly6Chigh monocyte migration from the bone marrow into the lungs. MDP-induced pulmonary monocyte recruitment occurred normally in IAV-infected and MDP-treated Ips-1-/- mice. However, IPS-1 was required for improved survival upon MDP treatment. Finally, mycobacterial N-glycolyl MDP was more potent than N-acetyl MDP expressed by most bacteria at reducing viral burden while both forms of MDP restored pulmonary function following IAV challenge. Overall, our work sheds light on the antiviral mechanism of a clinically relevant bacterial-derived compound and identifies the NOD2 pathway as a potential therapeutic target against IAV

Contextual and individual factors associated with dental services utilisation by Brazilian adults: A multilevel analysis

BACKGROUND: Inequalities in the utilisation of dental services in Brazil are remarkable. The aim of this study was to evaluate the association of contextual and individual factors with the utilisation of dental services by Brazilian adults using the Andersen's behavioural model. METHODS: Individual-level data from 27,017 adults residents in the State capitals who were interviewed in the 2013 Brazilian National Health Survey were pooled with contextual city-level data. The outcomes were non-utilisation of dental services and last dental visit over 12 months ago. Individual predisposing variables were age, sex, race/skin colour, schooling and social network. Individual enabling variables included income, health insurance and registration in primary health care. Individual need variables were self-perceived dental health and self-reported missing teeth. Multilevel logistic regression models were performed to estimate odds ratio (OR) and 95% confidence intervals (95% CIs) of the association of contextual and individual predisposing, enabling and need-related variables with dental services outcomes. RESULTS: Predisposing (OR = 0.89; 95% CI 0.81-0.97) and enabling (OR = 0.90; 95% CI 0.85-0.96) contextual factors were associated with non-utilisation of dental services. Individual predisposing (sex, race/skin colour, schooling), enabling (income, health insurance) and need (self-perceived oral health, missing teeth) were associated with non-utilisation of dental services and last dental visit over 12 months ago. The latter was also associated with other individual predisposing (age, social network) and need (eating difficulties due to oral problems) characteristics. CONCLUSIONS: Individual and contextual determinants influenced dental services utilisation in Brazilian adults. These factors should be on the policy agenda and considered in the organisation of health services aiming to reduce oral health inequalities related to access and utilisation of dental services