社区2型糖尿病患者血糖自我管理水平调查及并发糖尿病周围神经病变的影响因素分析

摘要 目的：调查社区2型糖尿病（T2DM）患者血糖自我管理水平及分析T2DM并发糖尿病周围神经病变（DPN）的影响因素。方法：于2016年6月~2017年6月期间采用整群随机抽样法随机抽取苏州市6个社区符合纳排标准的539例T2DM患者进行问卷调查,了解社区T2DM患者血糖自我管理水平情况,对患者进行体格检查并检测血生化指标,统计社区T2DM患者的DPN发生情况,采用多因素logistic回归分析T2DM患者并发DPN的影响因素。结果：本次研究共发放调查问卷539份,实际回收531份,其中T2DM并发DPN者86例,根据是否并发DPN将所有入选患者分为DPN组（n=86）和无DPN组（n=445）。社区T2DM患者的糖尿病自我管理行为量表（SDSCA）平均得分率为（49.38±5.23）%,DPN组和无DPN组在病程、体质量指数（BMI）、腰围、糖化血红蛋白（HbAlc）、空腹胰岛素（FINS）、低 密 度 脂 蛋 白（LDL-C）、血 尿 素 氮（BUN）、血肌酐（Cr）、合并外周动脉疾病（PAD）、合并糖尿病视网膜病变（DR）中比较差异有统计学意义（P<0.05）。多因素logistic回归分析结果显示：病程≥7年、HbAlc≥8 mmol/L、合并PAD、合并DR、BMI≥25 kg/m²是社区 T2DM患者并发DPN的危险因素（P<0.05）。结论：苏州市6个社区的T2DM患者血糖自我管理水平较低,且T2DM并发DPN的概率较高,病程≥7年、HbAlc≥8 mmol/L、合并PAD、合并DR、BMI≥25 kg/m²均是社区 T2DM患者并发DPN的危险因素,临床可对上述危险因素采取积极有效的措施,以有效降低T2DM并发DPN的发生率。     

The investigation of therapeutic potential of oxytocin and liraglutide on vincristine‐induced neuropathy in rats

The aim of this study was to assess the therapeutic potential of oxytocin and liraglutide (LIR), a GLP‐1 analogue, in a rat model of vincristine‐induced neuropathy. Rats were injected with vincristine (VCR) at a dose of 4 mg/kg twice a week for 5 weeks. The VCR‐administered rats were divided into three groups and received saline, oxytocin, or liraglutide simultaneously with VCR. After the treatment period, electrophysiological, biochemical, histological, and immunohistochemical investigations were performed. Electromyography (EMG) recordings demonstrated significant alterations in the VCR + saline group (p < .001). Also, motor performance was decreased in the VCR + saline group (p < .05). Histologically, the axonal diameter was decreased in all groups. VCR + saline group showed significantly increased lipid peroxidation and decreased nerve growth factor (NGF) expression. However, the administration of oxytocin and liraglutide significantly prevented the EMG alterations, lipid peroxidation, and reduction in neuronal NGF expression. On the basis of these findings, oxytocin and liraglutide may be considered as potential agents for the prevention of VCR‐induced neuropathy.     

Identification of novel inhibitors for the tyrosyl-DNA-phosphodiesterase 1 (Tdp1) mutant SCAN1 using virtual screening

Spinocerebellar ataxia syndrome with axonal neuropathy (SCAN1) is a debilitating neurological disease that is caused by the mutation the Tyrosyl-DNA phosphodiesterase 1 (TDP1) DNA repair enzyme. The crucial His493 in TDP1′s binding site is replaced with an arginine amino acid residue rendering the enzyme dysfunctional. A virtual screen was performed against the homology model of SCAN1 and seventeen compounds were identified and tested in a novel SCAN1 specific biochemical assay. Six compounds showed activity with IC₅₀ values between 3.5 and 25.1 µM. The most active ligand 5 (3.5 µM) is a dicoumarin followed by a close structural analogue 6 at 6.0 µM. A less potent series of β-carbolines (14 and 15) was found with potency in the mid-teens. According to molecular modelling an excellent fit for the active ligands into the binding pocket is predicted. To the best of our knowledge, data on inhibitors of the mutant form of TDP1 has not been reported previously. The virtual hits were also tested for wild type TDP1 activity and all six SCAN1 inhibitors are potent for the former, e.g., ligand 5 has a measured IC₅₀ at 99 nM.In the last decade, TDP1 is considered as a promising target for adjuvant therapy against cancer in combination with Topoisomerase 1 poisons. The active ligands are mostly non-toxic to cancer cell lines A-549, T98G and MCF-7 as well as the immortalized WI-38 human fetal lung cells. Furthermore, ligands 5 and 7, show promising synergy in conjunction with topotecan, a clinically used topoisomerase 1 anticancer drug. The active ligands 5, 7, 14 and 15 have a good balance of the physicochemical properties required for oral bioavailability making the excellent candidates for further development.     

The puzzle of TRPV4 channelopathies

Hereditary channelopathies, that is, mutations in channel genes that alter channel function and are causal for the pathogenesis of the disease, have been described for several members of the transient receptor potential channel family. Mutations in the TRPV4 gene, encoding a polymodal Ca²⁺ permeable channel, are causative for several human diseases, which affect the skeletal system and the peripheral nervous system, with highly variable phenotypes. In this review, we describe the phenotypes of TRPV4 channelopathies and overlapping symptoms. Putative mechanisms to explain the puzzle, and how mutations in the same region of the channel cause different diseases, are discussed and experimental approaches to tackle this surprising problem are suggested.     

Update on the pathobiology of neuropathic pain

Nerve injury or dysfunction in the peripheral and central nervous systems are the leading causes for the development of neuropathies, which are frequently associated with allodynia and hyperalgesia. Treatment of these disorders is often unsatisfactory due to side effects or insufficient analgesia of the currently available drugs. Therefore, elucidating the molecular mechanisms of neuropathic pain is an important prerequisite for the rational development of novel analgesic drugs for the therapy of neuropathic pain. Several proteomic approaches have been performed to explore protein modifications in the nervous system associated with neuropathies in different animal models, which might contribute to the detection of new drug targets. Furthermore, there are proteomic studies investigating human cerebrospinal fluid from patients suffering from neuropathies. The results of these studies and the potential clinical value of the proteomic data are summarized and discussed in this review.     

TMEM126A is a mitochondrial located mRNA (MLR) protein of the mitochondrial inner membrane

Background

Hereditary optic neuropathies (HONs) are a heterogeneous group of disorders that affect retinal ganglion cells (RGCs) and axons that form the optic nerve. Leber's Hereditary Optic Neuropathy and the autosomal dominant optic atrophy related to OPA1 mutations are the most common forms. Nonsyndromic autosomal recessive optic neuropathies are rare and their existence has been long debated. We recently identified the first gene responsible for these conditions, TMEM126A. This gene is highly expressed in retinal cellular compartments enriched in mitochondria and supposed to encode a mitochondrial transmembrane protein of unknown function.

Methods

A specific polyclonal antibody targeting the TMEM126A protein has been generated. Quantitative fluorescent in situ hybridization, cellular fractionation, mitochondrial membrane association study, mitochondrial sub compartmentalization analysis by both proteolysis assays and transmission electron microscopy, and expression analysis of truncated TMEM126A constructs by immunofluorescence confocal microscopy were carried out.

Results

TMEM126A mRNAs are strongly enriched in the vicinity of mitochondria and encode an inner mitochondrial membrane associated cristae protein. Moreover, the second transmembrane domain of TMEM126A is required for its mitochondrial localization.

Conclusions

TMEM126A is a mitochondrial located mRNA (MLR) that may be translated in the mitochondrial surface and the protein is subsequently imported to the inner membrane. These data constitute the first step toward a better understanding of the mechanism of action of TMEM126A in RGCs and support the importance of mitochondrial dysfunction in the pathogenesis of HON.

General significance

Local translation of nuclearly encoded mitochondrial mRNAs might be a mechanism for rapid onsite supply of mitochondrial membrane proteins.     

Two novel methods to assess ulnar nerve conduction across the elbow

PurposeNerve conduction studies (NCS) are used as an electrodiagnostic method for diagnosing ulnar neuropathy of the elbow (UNE). The purpose of this study was to determine normal and reliability values of across elbow ulnar nerve conduction velocity using two novel methods.MethodsUlnar nerve conduction studies were performed on both upper extremities of 104 healthy subjects. Two different techniques were used to evaluate ulnar nerve function at the elbow: Technique 1 (W-BE-AE) determined mixed NCV across the elbow indirectly while Technique 2 (BE-AE) measured conduction time directly. Twenty subjects returned within one week for re-testing to generate reliability data.ResultsThe mean NCV for the BE-AE segment using Technique 1 was 59.68 m/s (±8.91 m/s). The mean peak latency for the BE-AE segment using Technique 2 was 2.03 ms (±0.24 ms). The interrater and intrarater reliability intraclass correlation coefficient (ICC) for Technique 1 was 0.454 and 0.756, respectively. For Technique 2, the interrater and intrarater reliability ICC was 0.76 and 0.814, respectively.ConclusionThis study identified normal values for ulnar nerve conduction across the elbow with reliability ranging from poor to good, depending on the technique. These two novel techniques provide alternative methods to traditional techniques to measure ulnar nerve conduction across the elbow.     

Discovery and evaluation of novel FAAH inhibitors in neuropathic pain model

Conceptual design and modification of urea moiety in chemotype PF-3845/04457845, the bench marking irreversible inhibitor of fatty acid amide hydrolase (FAAH), led to discovery of a novel nicotinamide-based lead 12a having reversible mechanism of action. Focused SAR around the pyridine heterocycle (Ar) in 12a (Tables 1 and 2) resulted into four shortlisted compounds, (?)-12a, (?)-12i, (?)-12l–m. The required (?)-enantiomers were obtained via diastereomeric resolution of a novel chiral dissymmetric intermediate 15. Based on comparative profile of FAAH potency, metabolic stability in liver microsome, liability of inhibiting major hCYP450 isoforms, rat PK, and brain penetration ability, two SAR optimized compounds, (?)-12l and (?)-12m, were selected for efficacy study in rat model of chemotherapy-induced peripheral neuropathy (CIPN). Both the compounds exhibited dose related antihyperalgesic effects, when treated with 3–30?mg/kg po for 7?days. The effects at 30?mg/kg are comparable to that of PF-04457845 (10?mg/kg) and Tramadol (40?mg/kg).     

Emerging roles of long non‐coding RNAs in neuropathic pain

Neuropathic pain, a type of chronic and potentially disabling pain resulting from primary injury/dysfunction of the somatosensory nervous system and spinal cord injury, is one of the most intense types of chronic pain, which incurs a significant economic and public health burden. However, our understanding of its cellular and molecular pathogenesis is still far from complete. Long non‐coding RNAs (lncRNAs) are important regulators of gene expression and have recently been characterized as key modulators of neuronal functions. Emerging evidence suggested that lncRNAs are deregulated and play pivotal roles in the development of neuropathic pain. This review summarizes the current knowledge about the roles of deregulated lncRNAs (eg, KCNA2‐AS, uc.48+, NONRATT021972, MRAK009713, XIST, CCAT1) in the development of neuropathic pain. These studies suggested that specific regulation of lncRNAs or their downstream targets might provide novel therapeutic avenues for this refractory disease.     

Mouse models of the laminopathies

The A and B type lamins are nuclear intermediate filament proteins that comprise the bulk of the nuclear lamina, a thin proteinaceous structure underlying the inner nuclear membrane. The A type lamins are encoded by the lamin A gene (LMNA). Mutations in this gene have been linked to at least nine diseases, including the progeroid diseases Hutchinson-Gilford progeria and atypical Werner's syndromes, striated muscle diseases including muscular dystrophies and dilated cardiomyopathies, lipodystrophies affecting adipose tissue deposition, diseases affecting skeletal development, and a peripheral neuropathy. To understand how different diseases arise from different mutations in the same gene, mouse lines carrying some of the same mutations found in the human diseases have been established. We, and others have generated mice with different mutations that result in progeria, muscular dystrophy, and dilated cardiomyopathy. To further our understanding of the functions of the lamins, we also created mice lacking lamin B1, as well as mice expressing only one of the A type lamins. These mouse lines are providing insights into the functions of the lamina and how changes to the lamina affect the mechanical integrity of the nucleus as well as signaling pathways that, when disrupted, may contribute to the disease.