<Emphasis Type="Italic">TCF7L2</Emphasis>variant genotypes and type 2 diabetes risk in Brazil: significant association,but not a significant tool for risk stratification in the general population

Background  

Genetic polymorphisms of the TCF7L2 gene are strongly associated with large increments in type 2 diabetes risk in different populations worldwide. In this study, we aimed to confirm the effect of the TCF7L2 polymorphism rs7903146 on diabetes risk in a Brazilian population and to assess the use of this genetic marker in improving diabetes risk prediction in the general population.     

Stimulation of β-adrenoceptors inhibits store-operated channel currents via a cAMP-dependent protein kinase mechanism in rabbit portal vein myocytes

Previously we have described the properties of store-operated channel currents (SOCs) in freshly dispersed rabbit portal vein smooth muscle cells. In addition to Ca²⁺ store depletion these SOCs could also be activated by α-adrenoceptor stimulation and diacylglycerol (DAG) via a protein kinase C (PKC)-dependent mechanism. In the present study we have investigated the effect of β-adrenoceptor stimulation on SOCs in rabbit portal vein myocytes. With whole-cell recording the selective β-adrenoceptor agonist isoprenaline reduced the current evoked by cyclopiazonic acid (CPA, sarcoplasmic/endoplasmic reticulum ATPase inhibitor) by over 85%. With cell-attached patch recording, bath application of isoprenaline produced a pronounced inhibition of SOC activity evoked by either CPA or the acetoxymethyl ester form of BAPTA (BAPTA-AM). SOC activity evoked by CPA, the DAG analogue, 1-oleoyl-acetyl- sn -glycerol (OAG) or the phorbol ester, phorbol-12,13-dibutyrate (PDBu) was also markedly inhibited by the adenylate cyclase activator, forskolin, and the cell-permeable non-hydrolysable analogue of cyclic adenosine monophosphate (cAMP), 8-Br-cAMP. With inside-out patches, bath application of PDBu evoked channel currents with similar properties to SOCs which were inhibited by over 90% by a catalytic subunit of protein kinase A (PKA) and by 8-Br-cAMP. Moreover bath application of PKA inhibitors, H-89, KT5720 and an inhibitory peptide to quiescent cell-attached or inside-out patches, activated channel currents with similar properties to SOCs. These data suggest that in rabbit portal vein myocytes, stimulation of β-adrenoceptors inhibits SOC activity via a cAMP-dependent protein kinase signal transduction cascade. In addition it is concluded that constitutive PKA activity has a profound inhibitory effect on SOC activity in this vascular preparation.     

Healthy subjects express differences in clinical responses to inhaled lipopolysaccharide that are related with inflammation and with atopy

BACKGROUND: Endotoxin and its purified derivative LPS are important contaminants of both domestic and occupational environments that have been related to airway diseases. A body of data suggests that there is considerable interindividual variability in LPS sensitivity. OBJECTIVE: The aim of the study was to relate the individual clinical responses to inhaled LPS with the inflammatory process and the atopic status. METHODS: Fifteen healthy subjects were challenged each week by inhalation with saline solution or LPS (0.5, 5, or 50 microg). The systemic response was defined by the increase in body temperature, blood neutrophilia, acute-phase proteins (C-reactive protein and LPS-binding protein [LBP]), and E-selectin. The LPS-induced airway response was defined as the increase in airway responsiveness and related to the cell count and concentration of TNF-alpha, myeloperoxidase, and eosinophil cationic protein in induced sputum. The atopic status was defined as an increase in IgE or a positive skin prick test result. RESULTS: Subjects (n = 7) with a significant increase in body temperature had a larger increase in the systemic inflammatory response (blood neutrophilia; P <.01) and in blood concentrations of C-reactive protein (P <.02) and LBP (P <.01). Subjects with a significant increase in airway responsiveness (n = 8) had an increase in the sputum concentration of eosinophil cationic protein (P <.01). The amplitude of the systemic response (increase in body temperature [P <.001], blood neutrophilia [P <.02], and rise in LBP [P <.05] and decrease in FEV(1) [P <.01]) were inversely associated with the atopic status, suggesting a link between atopy and LPS responsiveness. CONCLUSIONS: The clinical response to LPS occurs systemically or locally and is associated with inflammation. The atopic status was inversely related to the systemic inflammation.     

Functional polymorphism of IgG FcRII (CD32) on human neutrophils.

In this study we demonstrate that Fc gamma RII on polymorphonuclear cells (PMN) (i) mediates binding of immune complexes, and (ii) is polymorphic, similar to the polymorphism described for monocytes and platelets. This was demonstrated in an adherence assay of PMN to activated human umbilical vein endothelial cells (HUVEC). Precoating of activated HUVEC with a mouse IgG1 monoclonal antibody (mAb) ENA1, which is highly reactive with activated HUVEC, caused an enhanced adhesion in 11 of 15 experiments using PMN from different donors. Enhanced adhesion of the PMN corresponded with expression of a high-responder (HR) Fc gamma RII on monocytes isolated from the same donor, as identified by anti-CD3-induced T-cell proliferation. These data led to the conclusion that Fc gamma RII on PMN is polymorphic. This conclusion was, furthermore, supported by immunofluorescence (IF) studies using a new mAb 41H16, which selectively reacts with the HR allotype of Fc gamma RII.     

Longitudinal Changes in Muscle Mass,Muscle Strength,and Physical Performance in Acutely Hospitalized Older Adults

ObjectivesAcute hospitalization may lead to a decrease in muscle measures, but limited studies are reporting on the changes after discharge. The aim of this study was to determine longitudinal changes in muscle mass, muscle strength, and physical performance in acutely hospitalized older adults from admission up to 3 months post-discharge.DesignA prospective observational cohort study was conducted.Setting and ParticipantsThis study included 401 participants aged ≥70 years who were acutely hospitalized in 6 hospitals. All variables were assessed at hospital admission, discharge, and 1 and 3 months post-discharge.MethodsMuscle mass in kilograms was assessed by multifrequency Bio-electrical Impedance Analysis (MF-BIA) (Bodystat; Quadscan 4000) and muscle strength by handgrip strength (JAMAR). Chair stand and gait speed test were assessed as part of the Short Physical Performance Battery (SPPB). Norm values were based on the consensus statement of the European Working Group on Sarcopenia in Older People.ResultsA total of 343 acute hospitalized older adults were included in the analyses with a mean (SD) age of 79.3 (6.6) years, 49.3% were women. From admission up to 3 months post-discharge, muscle mass (?0.1 kg/m²; P = .03) decreased significantly and muscle strength (?0.5 kg; P = .08) decreased nonsignificantly. The chair stand (+0.7 points; P < .001) and gait speed test (+0.9 points; P < .001) improved significantly up to 3 months post-discharge. At 3 months post-discharge, 80%, 18%, and 43% of the older adults scored below the cutoff points for muscle mass, muscle strength, and physical performance, respectively.Conclusions and ImplicationsPhysical performance improved during and after acute hospitalization, although muscle mass decreased, and muscle strength did not change. At 3 months post-discharge, muscle mass, muscle strength, and physical performance did not reach normative levels on a population level. Further research is needed to examine the role of exercise interventions for improving muscle measures and physical performance after hospitalization.     

侧脑室注射血管紧张素Ⅱ促进内源性洋地黄样因子释放

目的 探讨侧脑室注射血管紧张素Ⅱ对内源性洋地黄样因子（EDLF）释放的影响。方法 大鼠侧脑室注射血管紧张素Ⅱ及侧脑室注射Saralasin或损毁第三脑室前腹区（AV3V）预处理,放射免疫方法测定血清EDLF浓度的变化。结果 侧脑室注射AngⅡ可引起血清EDLF浓度升高;Saralasin预处理或海人酸损毁AV3V区可阻断侧脑室注射AngⅡ引起的血清EDLF升高效应。结论 侧脑室注射血管紧张素Ⅱ促进EDLF释放。     

13Carbon mixed triglyceride breath test and pancreatic enzyme supplementation in cystic fibrosis

Children with cystic fibrosis have variable degrees of exocrine pancreatic insufficiency which, if untreated, is the main cause of fat malabsorption. The impact of pancreatic enzyme supplementation on fat digestion was measured in 41 children with cystic fibrosis, 11 healthy controls, and five children with mucosal diseases by a non-invasive test of intraluminal lipolysis using 13carbon (13C) labelled mixed triglyceride (1,3-distearyl, 2[13C] octanoyl glycerol). The children with cystic fibrosis without pancreatic supplements had a median (range) 13C cumulative percentage dose recovered over six hours (cPDR) of 3.1% (0-31.7), the controls 31.0% (21.8-41.1), and the subjects with mucosal disease 27.8% (19.7-32.5). In 23 subjects with cystic fibrosis the usual dose of pancreatic enzyme supplements increased the cPDR to a median of 23.9% (0-45.6), and twice the usual dose of enteric coated microspheres increased the cPDR to 31.1% (11.1-47.8). There was no significant difference between the median cPDR of normal controls and children with mucosal disease, but there was a highly significant difference between these groups and children with untreated cystic fibrosis. Thirteen children with cystic fibrosis had no 13C recovery in their breath without enzymes and 10 showed marked increases with regular enzymes. In eight children doubling the dose of enzymes caused no or minimal improvement. The mixed triglyceride breath test offers a simple, non-invasive way of assessing the need for pancreatic enzyme supplementation in children with cystic fibrosis and could be used to optimise treatment.     

慢性肾小球肾炎伴肾衰患者血清α1肾上腺素受体和抗血管紧张素Ⅱ受体1型自身抗体检测结果分析

目的 探讨抗血管紧张素Ⅱ受体1型（AT1-受体）、α1-肾上腺素受体（α1-受体）、自身抗体是否与慢性肾小球肾炎（CaN）发病有关。方法 以合成的AT1受体和α1受体多肽片段为抗原，应用酶联免疫吸附测定（ELISA）技术，检测66例CGN患者、58例高血压病患者及柏例正常人血清中抗AT1和α1受体自身抗体。结果 CGN肾功能不全组抗AT1和α1受体抗体阳性率分别为56．1％（37／66）和53．0%（36／66），高于高血压无肾损害组（分别为15．5％和12．1％）及正常对照组（分别为10％和12．5％），P〈0．01。结论 抗G蛋白偶联型受体自身抗体可能与慢性肾小球肾炎发病有关。