Urinary C-peptide creatinine ratio to detect absolute insulin deficiency in type 2 diabetes

BackgroundNational Institute for Health and Clinical Excellence guidelines (CG87) recommend neutral protamine hagedorn (NPH) insulin for the provision of basal insulin in type 2 diabetes, but use of analogue insulin is as much as 40%. Where residual endogenous insulin secretory capacity is present there is no evidence that analogue insulins provide any additional benefit over human insulins, and they come at an expensive premium. Anecdotally, however, there is a reluctance to switch people back to NPH insulin, partly because of a perceived risk of pancreatic failure and potential ketosis. Urinary C-peptide creatinine ratio (UCPCR) has been validated as a method for evaluating residual endogenous insulin secretion in type 1 and type 2 diabetes, with a UCPCR of no more than 0·2 nmol/mmol suggestive of absolute insulin deficiency. We aimed to evaluate the prevalence of true insulin deficiency among patients with type 2 diabetes with UCPCR, and confirm findings with the gold standard mixed meal tolerance test (MMTT).Methods191 insulin-treated patients with a clinical diagnosis of type 2 diabetes (diagnosed at or after age 45 years and who did not start insulin within the first year of diagnosis) collected a 2-h post-prandial urine sample for UCPCR measurement. Nine patients from two subgroups (UCPCR ≤0·2 nmol/mmol and UCPCR >0·2) completed a standard MMTT.Findings11 (5·8%) of 191 patients had two consistent UCPCRs of less than or equal to 0·2 nmol/mmol. Nine were able to do the MMTT, of whom five were confirmed to have absolute insulin deficiency (stimulated serum c-peptide <0·2 nmol/L). Three of these five patients were glutamic acid decarboxylase antibody-negative. Nine of nine patients with UCPCR of more than 0·2 nmol/L had confirmed endogenous insulin secretion in their MMTT. Those with insulin deficiency had a shorter time to starting insulin (median 2·5 years [IQR 1·5–3·0] vs 6·0 [3·0–10·75], p=0·005) and lower body-mass index (25 kg/m² vs 29, p=0·04) but no other significant differences in clinical characteristics.InterpretationWe have demonstrated a very low prevalence of true pancreatic failure in this population of insulin-treated patients with type 2 diabetes. This requires further exploration by comparison of a population being treated with NPH insulin with one on analogue insulin, and then determining whether UCPCR could act as a clinical decision support tool to safely switch from analogue insulin to NPH insulin.FundingNational Institute for Health Research.     

肺源性心脏病急性发作期免疫功能的改变

目的:观察肺源性心脏病(简称肺心病)急性发作期患者免疫功能的变化。方法:选择南华大学附属第一医院2004-11/2006-01收治慢性肺心病急性发作期患者60例为肺心病组,于急性加重期入院第2天7:00,空腹抽取静脉血,采用流式细胞仪检测T细胞亚群CD3 、CD4 、CD8 及自然杀伤细胞活性,免疫浊度法检测体液免疫指标(IgG,IgM,IgA及补体C3)。以同期60例健康体检者为对照。结果:120例是否受试者均进入结果分析。①T细胞亚群:肺心病组CD3 ,CD4 水平低于对照组(0.52±0.06,0.62±0.04;0.32±0.06,0.41±0.06;P均<0.05),CD4 /CD8 高于对照组(1.96±0.26,1.84±0.78,P<0.05)。②免疫血清指标:肺心病组IgA、补体C3及自然杀伤细胞活性低于对照组[(1.26±0.74),(2.45±0.85)g/L;(6200±217),(9960±302)mg/L;0.34±0.08,0.57±0.07;P均<0.05]。结论:肺源性心脏病急性发作期患者的细胞免疫和体液免疫功能均受损,尤以细胞免疫功能受损更突出,且与病情呈平行关系。     

Histamine levels in stored platelet concentrates. Relationship to white cell content

The histamine levels in samples from platelet concentrates (PC) were measured at various storage times by a radioenzymatic assay. Elevated histamine levels were detected in 5 of 14 PC after 3 days of storage (range, less than 1 to 13.3 ng/ml) and in 9 of 14 PC after 5 days (range, less than 1 to 22.2 ng/ml). A very good linear correlation (r = 0.913) was found between the initial white cell content of the PC and the histamine level at 5 days of storage. The rise in histamine content was not influenced by the type of plastic container. The results indicate a process of histamine release by the white cells during storage. Although histamine is metabolized rapidly in vivo, a critical histamine threshold could be reached in man by the rapid infusion of stored PC containing high levels of histamine. This could explain some unexpected transfusion reactions in patients receiving PC.     

Environmental mercury exposure,semen quality and reproductive hormones in Greenlandic Inuit and European men: a cross-sectional study

Several animal studies indicate that mercury is a male reproductive toxicant, but human studies are few and contradictory. We examined semen characteristics and serum levels of reproductive hormones in relation to environmental exposure to mercury. Blood and semen samples were collected from 529 male partners of pregnant women living in Greenland, Poland and Ukraine between May 2002 and February 2004. The median concentration of the total content of mercury in whole blood was 9.2 ng ml⁻¹ in Greenland (0.2–385.8 ng ml⁻¹), 1.0 ng ml⁻¹ in Poland (0.2–6.4 ng ml⁻¹) and 1.0 ng ml⁻¹ in Ukraine (0.2–4.9 ng ml⁻¹). We found a significantly positive association between the blood levels of mercury and serum concentration of inhibin B in men from Greenland (β=0.074, 95% confidence interval (CI)=0.021 to 0.126) and in an analysis including men from all three regions (β=0.067, 95% CI=0.024 to 0.110). The association may be due to beneficial effects of polyunsaturated fatty acids (PUFAs), which are contained in seafood and fish. No significant association (P>0.05) was found between blood concentrations of mercury and any of the other measured semen characteristics (semen volume, total sperm count, sperm concentration, morphology and motility) and reproductive hormones (free androgen index (FAI), follicle-stimulating hormone (FSH), luteinizing hormone (LH), testosterone and LH×testosterone) in any region. In conclusion, the findings do not provide evidence that environmental mercury exposure in Greenlandic and European men with median whole blood concentration up to 10 ng ml⁻¹ has adverse effects on biomarkers of male reproductive health.     

Reduced adipsin expression in murine obesity: effect of age and treatment with the sympathomimetic-thermogenic drug mixture ephedrine and caffeine

Adipsin gene expression is greatly diminished in certain forms of genetic and acquired obesity. In the present study we evaluate the time course for the development of adipsin deficiency in obesity and its regulation by the sympathomimetic-thermogenic drug mixture ephedrine and caffeine. Previously, it was unknown whether adipsin deficiency occurred before or after the development of massive obesity. In the first series of experiments in which mice were treated with monosodium glutamate (MSG) for the first week of life, we demonstrate that adipsin deficiency occurs early in the development of MSG-induced obesity as evidenced by decreased circulating adipsin concentrations by 1 week of age and deficient adipsin mRNA levels in white adipose tissue (WAT) by 2 weeks. In db/db mice, diminished circulating adipsin was noted at 2 weeks of age. In both models, decreased adipsin gene expression precedes the development of marked obesity. Little is known about the factors which regulate adipsin gene expression in obesity. Common to the ob/ob, db/db and MSG models is diminished thermogenesis and sympathetic nervous system activity. In a second series of experiments we sought to determine whether adipsin deficiency in obesity could be corrected by treatment with ephedrine and caffeine (E+C), a sympathomimetic-thermogenic mixture previously shown to increase thermogenesis and reverse obesity in some models. In the present study, E+C treatment of MSG obese mice reversed obesity and markedly increased serum adipsin and adipsin mRNA levels in WAT and brown adipose tissue (BAT). In ob/ob mice, however, E+C treatment produced a negligible increase in adipsin mRNA levels in WAT and BAT as well as serum adipsin concentrations and this correlated with only a very small decrease in obesity. Thus, the ability of E+C to increase adipsin gene expression correlated with its ability to reverse obesity in these two models. Finally, the effect of E+C on adipsin gene expression may not be exerted directly on the fat cell since treatment of cultured 3T3-F442A adipocytes and isolated rat adipocytes in primary culture produced no effect on adipsin mRNA or secreted protein despite a lipolytic effect as measured by increased glycerol release. In summary, decreased adipsin gene expression occurs early in the development of MSG and db/db obesity and is markedly increased in the MSG model by the sympathomimetic-thermogenic drug mixture, E+C, which also reverses obesity. Elucidation of the factors responsible for these effects may enhance our understanding of fat cell gene regulation and obesity.     

Demonstration of reversible priming of human neutrophils using platelet- activating factor

Exposure of neutrophils to agents such as lipopolysaccharide, tumor necrosis factor-alpha (TNF-alpha), and the granulocyte-macrophage colony-stimulating factor causes a major upregulation of subsequent agonist-induced NADPH oxidase activation. This priming effect is a prerequisite for neutrophil-mediated tissue damage and has been widely considered to be an irreversible process. We have investigated the potential for neutrophils to recover from a priming stimulus by studying the effects of platelet-activating factor (PAF). PAF did not stimulate respiratory burst activity directly, but caused a rapid (maximal at 10 minutes) and concentration-dependent (EC50 50.2 nmol/L) increase in N-formyl-methionyl-leucyl-phenylalanine (fMLP)-stimulated superoxide anion release. At time-points > 10 minutes, this priming effect spontaneously declined, with return to basal levels of fMLP- stimulated superoxide anion generation by 120 minutes. An identical priming time-course was observed with N-methyl carbamyl PAF, a nonmetabolizable analogue of PAF, indicating that the transient nature of PAF-induced priming was not secondary to PAF metabolism. Two structurally diverse PAF receptor antagonists (UK-74,505 and WEB 2086), added 10 minutes after PAF addition, increased the rate of decay of the priming effect. In contrast, TNF-alpha-induced priming, which was of a similar magnitude to that observed for PAF, was slower to evolve (maximal at 30 minutes) and remained constant for at least 120 minutes. The reversible nature of PAF-induced priming was confirmed by demonstrating that PAF-, but not TNF-alpha-, induced cell polarization (shape change) and CD11b-dependent neutrophil binding of albumin-coated latex beads was also transient, with return to basal, unstimulated levels by 120 minutes. Furthermore, cells that had spontaneously deprimed following PAF exposure retained their capacity to be fully reprimed by a subsequent addition of either PAF or TNF-alpha. These data imply that neutrophil priming is not an irreversible event: the demonstration of a cycle of complete priming, depriming, and repriming offers the potential for functional recycling of neutrophils at sites of inflammation.     

Contribution of VANGL2 mutations to isolated neural tube defects

Kibar Z, Salem S, Bosoi CM, Pauwels E, De Marco P, Merello E, Bassuk AG, Capra V, Gros P. Contribution of VANGL2 mutations to isolated neural tube defects. Vangl2 was identified as the gene defective in the Looptail (Lp) mouse model for neural tube defects (NTDs). This gene forms part of the planar cell polarity (PCP) pathway, also called the non‐canonical Frizzled/Dishevelled pathway, which mediates the morphogenetic process of convergent extension essential for proper gastrulation and neural tube formation in vertebrates. Genetic defects in PCP signaling have strongly been associated with NTDs in mouse models. To assess the role of VANGL2 in the complex etiology of NTDs in humans, we resequenced this gene in a large multi‐ethnic cohort of 673 familial and sporadic NTD patients, including 453 open spina bifida and 202 closed spinal NTD cases. Six novel rare missense mutations were identified in seven patients, five of which were affected with closed spinal NTDs. This suggests that VANGL2 mutations may predispose to NTDs in approximately 2.5% of closed spinal NTDs (5 in 202), at a frequency that is significantly different from that of 0.4% (2 in 453) detected in open spina bifida patients (p = 0.027). Our findings strongly implicate VANGL2 in the genetic causation of spinal NTDs in a subset of patients and provide additional evidence for a pathogenic role of PCP signaling in these malformations.