Evidence that orexins A and B stimulate insulin secretion from rat pancreatic islets via both receptor subtypes

Orexins are recently identified neuropeptides that appear to play a role in the regulation of energy homeostasis and arousal. They bind to and activate two closely related G protein-coupled receptors (OXR1 and OXR2), previously described as orphans. In this study we examined involvement of orexins in regulation of insulin secretion from rat pancreatic islets utilizing an in situ perfused pancreas and isolated pancreatic islet models. By means of RT-PCR we found that both OXR1 and OXR2 are expressed in rat pancreatic islets. Furthermore, the expression levels of OXR1 were higher than OXR2. In both experimental models applied, orexins A and B (1, 10 and 100 nmol/l) concentration dependently stimulated insulin secretion at two different glucose concentrations (6.66 or 26.4 mmol/l), with orexin A being more potent than orexin B. This study demonstrates that orexins A and B modulate insulin secretion in vitro.     

Curcumin and Its Potential Impact on Microbiota

Curcumin is one of the most frequently researched herbal substances; however, it has been reported to have a poor bioavailability and fast metabolism, which has led to doubts about its effectiveness. Curcumin has antioxidant and anti-inflammatory effects, and has demonstrated favorable health effects. Nevertheless, well-reported in vivo pharmacological activities of curcumin are limited by its poor solubility, bioavailability, and pharmacokinetic profile. The bidirectional interactions between curcumin and gut microbiota play key roles in understanding the ambiguity between the bioavailability and biological activity of curcumin, including its wider health impact.     

Involvement of adenosine A1 and A2A receptors in the motor effects of caffeine after its acute and chronic administration.

The involvement of adenosine A(1) and A(2A) receptors in the motor effects of caffeine is still a matter of debate. In the present study, counteraction of the motor-depressant effects of the selective A(1) receptor agonist CPA and the A(2A) receptor agonist CGS 21680 by caffeine, the selective A(1) receptor antagonist CPT, and the A(2A) receptor antagonist MSX-3 was compared. CPT and MSX-3 produced motor activation at the same doses that selectively counteracted motor depression induced by CPA and CGS 21680, respectively. Caffeine also counteracted motor depression induced by CPA and CGS 21680 at doses that produced motor activation. However, caffeine was less effective than CPT at counteracting CPA and even less effective than MSX-3 at counteracting CGS 21680. On the other hand, when administered alone in habituated animals, caffeine produced stronger motor activation than CPT or MSX-3. An additive effect on motor activation was obtained when CPT and MSX-3 were coadministered. Altogether, these results suggest that the motor-activating effects of acutely administered caffeine in rats involve the central blockade of both A(1) and A(2A) receptors. Chronic exposure to caffeine in the drinking water (1.0 mg/ml) resulted in tolerance to the motor effects of an acute administration of caffeine, lack of tolerance to amphetamine, apparent tolerance to MSX-3 (shift to the left of its 'bell-shaped' dose-response curve), and true cross-tolerance to CPT. The present results suggest that development of tolerance to the effects of A(1) receptor blockade might be mostly responsible for the tolerance to the motor-activating effects of caffeine and that the residual motor-activating effects of caffeine in tolerant individuals might be mostly because of A(2A) receptor blockade.     

Health-related quality of life parameters as prognostic factors in a nonmetastatic breast cancer population: an international multicenter study.

PURPOSE: The purpose of this research was to evaluate whether baseline health-related quality of life (HRQOL) parameters are prognostic factors for survival in locally advanced breast cancer patients. Although the literature highlights the important role of HRQOL parameters in predicting survival in advanced metastatic disease, little evidence exists for earlier stages. PATIENTS AND METHODS: The overall sample consisted of 448 patients randomly assigned to receive cyclophosphamide, epirubicin, and fluorouracil versus epirubicin, cyclophosphamide, and granulocyte colony-stimulating factor. Patients were enrolled in 12 countries. HRQOL baseline scores were assessed using the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire C30. The Cox proportional hazards regression model was used for both univariate and multivariate analyses of survival. In addition, a bootstrap resampling technique was used to assess the stability of the outcomes. Bootstrap results were then applied for model averaging purposes as a means to account for the observed model selection uncertainty. RESULTS: The final multivariate model retained inflammatory breast cancer (T4d) as the only factor predicting overall survival (OS) with a hazard ratio of 1.375 (95% CI, 1.027 to 1.840; P =.03). The presence of inflammatory breast cancer lowers the median survival time from 6.6 to 4.2 years (36% reduction). None of the preselected HRQOL variables were prognostic for OS or disease-free survival, in either the univariate or multivariate analysis. CONCLUSION: Our findings suggest that baseline HRQOL parameters have no prognostic value in a nonmetastatic breast cancer population.     

Antigen‐specific B lymphocytes acquire proteoglycan aggrecan from cartilage extracellular matrix resulting in antigen presentation and CD4+ T‐cell activation

The majority of studies examining antigen‐presenting cell (APC) function have focused on the capture and presentation of antigens released from pathogens or damaged cells. However, antigen‐specific B cells are also capable of efficiently extracting antigens that are either tethered to, or integrally part of the plasma membrane of various target cells. In this study we show that B cells are also highly efficient at extracting integral components of the extracellular matrix (ECM) for subsequent presentation. In particular we demonstrate that B cells specific for aggrecan, an integral component of cartilage ECM, acquire this rheumatoid arthritis candidate autoantigen in both a B‐cell‐receptor‐dependent and a contact‐dependent manner. We also demonstrate that the subsequent presentation of aggregan from ECM leads to CD4⁺ T‐cell activation and effector cell formation. Recent studies have identified B‐cell‐mediated antigen presentation as essential for the development of autoimmunity, but a unique role for B cells compared with other APC has yet to be defined. Our findings lead us to propose that the acquisition of ECM‐derived autoantigens represents a mechanism that defines the APC requirement for B cells in the development of autoimmunity.     

20-MHz Ultrasound for Measurements of Flow-Mediated Dilation and Shear Rate in the Radial Artery

A high-frequency scanning system consisting of a 20-MHz linear array transducer combined with a 20-MHz pulsed Doppler probe was introduced to evaluate the degree of radial artery flow-mediated dilation (FMD [%]) in two groups of patients after 5?min of controlled forearm ischemia followed by reactive hyperemia. In group I, comprising 27 healthy volunteers, FMD (mean?±?standard deviation) was 15.26?±?4.90% (95% confidence interval [CI]: 13.32%–17.20%); in group II, comprising 17 patients with chronic coronary artery disease, FMD was significantly less at 4.53?±?4.11% (95% CI: 2.42%–6.64%). Specifically, the ratio FMD/SR (mean?±?standard deviation), was equal to 5.36?×?10^?4?±?4.64?×?10^?4 (95% CI: 3.54?×?10^?4 to 7.18?×?10^?4) in group I and 1.38?×?10^?4?±?0.89?×?10^?4 (95% CI: 0.70?×?10^?4 to 2.06?×?10^?4) in group II. Statistically significant differences between the two groups were confirmed by a Wilcoxon–Mann–Whitney test for both FMD and FMD/SR (p?<0.01). Areas under receiver operating characteristic curves for FMD and FMD/SR were greater than 0.9. The results confirm the usefulness of the proposed measurements of radial artery FMD and SR in differentiation of normal patients from those with chronic coronary artery disease.     

Immune reconstitution after haematopoietic cell transplantation in children: immunophenotype analysis with regard to factors affecting the speed of recovery

Immune reconstitution was studied prospectively in 66 children who underwent 77 haematopoietic cell transplantations (HCT): 46 autologous HCTs in 39 patients and 31 allogeneic HCTs in 27 patients. We studied the dynamic analysis of immune recovery with regard to potential factors affecting its speed, including age, type of HCT, diagnosis, graft-versus-host disease (GvHD) and cytomegalovirus (CMV) infection reactivation. Absolute counts of different lymphocyte subsets and immunoglobulin serum levels were determined in peripheral blood of patients on d -7 and +16, and then at various intervals up to 24 months post transplant. Common patterns of immune recovery after both allogeneic and autologous HCT were identified: (i) CD4+CD45RO+ peripheral T-cell expansion on d +16; (ii) inverted CD4+:CD8+ ratio from d +30 onwards; (iii) rapid natural killer (NK) cell (CD16+/-CD56+) count normalization. We observed prolonged T-cell lymphopenia (CD3+, CD3+CD4+, CD4+CD45RA+) until 24 months after autologous HCT, whereas in the allogeneic setting CD3+CD4+ cells, including naive CD45RA+ cells, returned to normal values at 9 months post transplant. Age > 10 years and coexistence of GvHD and CMV reactivation were associated with a substantial delay in T- (CD4+, including CD45RA+) and B-cell recovery after allogeneic HCT. Multidrug GvHD prophylaxis resulted in impaired T- (CD4+, CD4+CD45RA+) and B-cell reconstitution only in the early phase after allogeneic HCT (up to 4 months). Our results demonstrated that T-cell recovery was severely impaired in children after autologous HCT. It should be emphasized that specific approaches to enhance immune reconstitution are necessary to control minimal residual disease and avoid the risk of infectious complications in the autologous setting. Thymic involution after allogeneic HCT seems to be associated with age and coexistence of GvHD and CMV reactivation.