Impaired inhibitory G-protein function contributes to increased calcium currents in rats with diabetic neuropathy

There is a growing body of evidence that sensory neuropathy in diabetes is associated with abnormal calcium signaling in dorsal root ganglion (DRG) neurons. Enhanced influx of calcium via multiple high‐threshold calcium currents is present in sensory neurons of several models of diabetes mellitus, including the spontaneously diabetic BioBred/Worchester (BB/W) rat and the chemical streptozotocin (STZ)‐induced rat. We believe that abnormal calcium signaling in diabetes has pathologic significance as elevation of calcium influx and cytosolic calcium release has been implicated in other neurodegenerative conditions characterized by neuronal dysfunction and death. Using electrophysiologic and pharmacologic techniques, the present study provides evidence that significant impairment of G‐protein‐coupled modulation of calcium channel function may underlie the enhanced calcium entry in diabetes. N‐ and P‐type voltage‐activated, high‐threshold calcium channels in DRGs are coupled to mu opiate receptors via inhibitory G(o)‐type G proteins. The responsiveness of this receptor coupled model was tested in dorsal root ganglion (DRG) neurons from spontaneously‐diabetic BB/W rats, and streptozotocin‐induced (STZ) diabetic rats. Intracellular dialysis with GTPgammaS decreased calcium current amplitude in diabetic BB/W DRG neurons compared with those of age‐matched, nondiabetic controls, suggesting that inhibitory G‐protein activity was diminished in diabetes, resulting in larger calcium currents. Facilitation of calcium current density (I(DCa)) by large‐amplitude depolarizing prepulses (proposed to transiently inactivate G proteins), was significantly less effective in neurons from BB/W and STZ‐induced diabetic DRGs. Facilitation was enhanced by intracellular dialysis with GTPgammaS, decreased by pertussis toxin, and abolished by GDPbetaS within 5 min. Direct measurement of GTPase activity using opiate‐mediated GTPgamma[(35)S] binding, confirmed that G‐protein activity was significantly diminished in STZ‐induced diabetic neurons compared with age‐matched nondiabetic controls. Diabetes did not alter the level of expression of mu opiate receptors and G‐protein alpha subunits. These studies indicate that impaired regulation of calcium channels by G proteins is an important mechanism contributing to enhanced calcium influx in diabetes.     

营养药理学--谷氨酰胺、n-3脂肪酸和精氨酸等简介

引言营养不良总是影响外科患者的预后,20世纪初就有人注意到伴有营养不良(以体重降低20%为依据)的消化性溃疡患者术后恢复较慢。后来几十年的研究证明,特殊营养素(如某些维生素和矿物质)缺乏能导致疾病,给予补充则可恢复健康。近年来研究发现,低蛋白血症等营养不良指标与并发症的发生率和死亡率相关。20世纪60年代至70年代的研究表明,对于严重烧伤儿童,只增加营养素(蛋白)的相对浓度而不增加总热卡摄入,可纠正免疫功能低下,提高生存率,改善患儿预后。谷氨酰胺、n-3脂肪酸和精氨酸对疾病的影响引起人们的特别关注,许多学者致力于研究这些营养…     

An empirical evaluation of the performance of antibody identification tasks

Four empirical studies were conducted for better understanding of the nature of problem-solving activities by medical technologists and medical technology students when performing antibody identification tasks. The results indicated the importance of strategies that ensure the collection of converging evidence, as these strategies protect against the fallibility of commonly used heuristics and against errors due to simple slips. The results also indicate that not only do students make significant numbers of errors, but so do practicing technologists. In one of the studies covering a 1-year period, for instance, a group of 16 technologists made a total of 41 errors in 1057 cases. On the basis of these findings, several alternatives are proposed to reduce errors.     

Withdrawing versus not offering cardiopulmonary resuscitation: Is there a difference?

Conflict between substitute decision makers (SDMs) and health care providers in the intensive care unit is commonly related to goals of treatment at the end of life. Based on recent court decisions, even medical consensus that ongoing treatment is not clinically indicated cannot justify withdrawal of mechanical ventilation without consent from the SDM. Cardiopulmonary resuscitation (CPR), similar to mechanical ventilation, is a life-sustaining therapy that can result in disagreement between SDMs and clinicians. In contrast to mechanical ventilation, in cases for which CPR is judged by the medical team to not be clinically indicated, there is no explicit or case law in Canada that dictates that withholding/not offering of CPR requires the consent of SDMs. In such cases, physicians can ethically and legally not offer CPR, even against SDM or patient wishes. To ensure that nonclinically indicated CPR is not inappropriately performed, hospitals should consider developing ‘scope of treatment’ forms that make it clear that even if CPR is desired, the individual components of resuscitation to be offered, if any, will be dictated by the medical team’s clinical assessment.