山梨醇增加糖尿病患者腰椎管狭窄症炎性反应因子的表达

目的探讨糖尿病腰椎管狭窄患者黄韧带增生肥厚的发生机制。方法 24例糖尿病和20例非糖尿病的腰椎管狭窄患者列为研究对象,观测黄韧带标本结构,D-Sorbitol/Xylitol试剂盒检测山梨醇水平。体外实验中使用小鼠成纤维细胞(NIH3T3)细胞系,用Western blot及q PCR分别检测高糖培养条件及醛糖还原酶抑制剂(ARI):依帕司他(EP)作用对细胞炎性反应因子及TGF-β表达水平的影响。结果糖尿病组较非糖尿病组的山梨醇水平更高、黄韧带平均厚度更大、标本弹力纤维降解、胶原纤维增生更为显著、免疫组化CD68阳性染色率更高(P0.01);体外实验中,NIH3T3细胞系在高糖培养与正常糖浓度培养相比山梨醇、促炎性细胞因子和TGF-β表达水平更高,而山梨醇、促炎性细胞因子和TGF-β增高的表达水平可被醛糖还原酶抑制剂所抑制并且呈剂量依赖(P0.05)。结论糖尿病腰椎管狭窄患者黄韧带中山梨醇水平显著增高,进而促进炎性反应因子及纤维化相关因子TGF-β表达增加,使得黄韧带炎性增生。     

Frequency of the 677 C-->T mutation of the methylenetetrahydrofolate reductase gene among Kuwaiti sickle cell disease patients

Sickle cell disease (SCD) is relatively mild among Kuwaiti Arabs. However, an atypical subset of patients exists with frequent, severe vaso-occlusive crisis and osteonecrosis. The thermolabile variant of MTHFR, resulting from a C-->T mutation at nucleotide 677, has been shown to be associated with hyperhomocysteinemia, which is an important risk factor for premature vascular disease. We have screened an unselected group of 41 Kuwaiti SCD patients (33 SS and 8 Sbeta(0)-thal) attending the Hematology Clinic of Kuwait University Teaching Hospital for the MTHFR mutation, using a PCR-RFLP method. The patients were aged 2-41 years (mean of 12.8 +/- 8.6). One (2.4%) individual was homozygous for the mutation while 15 (36.6%) were heterozygous, giving an allele frequency of 20.7%. Twenty-one patients (14 SS and 7 Sbeta(0)-thal) were screened for osteonecrosis using MRI of the hip (spin-echo T1- and T2-weighted images). Seven (33.3%) had varying degrees of osteonecrosis, among whom the frequency of the 677 C-->T allele was 21.4%. The frequency was identical among those without osteonecrosis. Although the allele frequency is higher among our patients compared to American SS patients, our results do not suggest an association with osteonecrosis.     

同型半胱氨酸及其相关酶基因多态性与糖尿病周围神经病变的关系

研究对象为 2型糖尿病 (DM )有周围神经病变组 (60例 )、2型DM无周围神经病变组 (4 6例 )和正常对照组 (5 0例 )。分别测定 3组血浆同型半胱氨酸 (Hcy) ,血清叶酸、维生素B12 水平及Hcy代谢关键酶亚甲基四氢叶酸还原酶 (MTHFR)的基因型。结果显示 ,高Hcy及低叶酸、维生素B12 水平与 2型DM患者伴发周围神经病变相关 ,而MTHFR的基因多态性只与DM有关而与DM周围神经病变无相关性。     

Prognostic value of aldo-keto reductase family 1 member B10 (AKR1B10) in digestive system cancers: A meta-analysis

Background:Numbers of studies have reported that the expression of aldo-keto reductase family 1 member B10 (AKR1B10) is abnormal in digestive system cancers, and could be used as a prognostic biomarker. However, the results are argued. Therefore, we conduct a meta-analysis to comprehensively evaluate the prognostic value of high AKR1B10 expression for overall survival (OS), disease specific survival (DSS), and disease-free survival/recurrence-free survival (DFS/PFS) in digestive system cancers.Methods:Hazard ratios (HRs) with its 95% confidence intervals (CIs) were calculated to assess the prognostic value of AKR1B10 by using the random effects model. The STATA version 12.0 software were used to perform all the analyses.Results:Eleven articles including 1428 patients involved in this meta-analysis. The pooled analysis suggested that high AKR1B10 expression was not associated with OS (HR: 1.18; 95% CI: 0.69–2.00) and DFS/PFS (HR: 1.08, 95% CI: 0.67–1.76) in digestive system cancers. However, Further analysis revealed that high AKR1B10 expression indicated poor OS in oral squamous cell carcinomas (OSCC) (HR: 2.92, 95% CI: 1.86–4.58) and favorable DSS in hepatocellular carcinoma (HCC) (HR: 0.71, 95% CI: 0.52–0.97).Conclusions:The prognostic value of high AKR1B10 expression varied in different types of digestive system cancers. Further studies exploring the prognostic role of AKR1B10 in digestive system cancers are needed.     

Comparison of the effects of inhibitors of aldose reductase and sorbitol dehydrogenase on neurovascular function, nerve conduction and tissue polyol pathway metabolites in streptozotocin-diabetic rats

Summary Aldose reductase inhibitors (ARIs) attenuate diabetic complications in several tissues, including lens, retina, kidney, blood vessels, striated muscle and peripheral nerve. However, it is unclear whether their action in diabetes mellitus depends directly on inhibiting the conversion of glucose to sorbitol by aldose reductase or indirectly by reducing the sorbitol available for subsequent metabolism to fructose by sorbitol dehydrogenase. To identify the polyol pathway step most relevant to complications, particularly neuropathy, we compared the biochemical effects of a sorbitol dehydrogenase inhibitor, WAY-135 706, (250 mg · kg⁻¹· day⁻¹) and an ARI, WAY-121 509, (10 mg · kg⁻¹· day⁻¹) on a variety of tissues, and their effects on nerve perfusion and conduction velocity. After 6 weeks of untreated streptozotocin diabetes, rats were treated for 2 weeks. Sorbitol was elevated 2.1–32.6-fold by diabetes in lens, retina, kidney, aorta, diaphragm, erythrocytes and sciatic nerve; this was further increased (1.6–8.2-fold) by WAY-135 706 whereas WAY-121 509 caused a marked reduction. Fructose 1.6–8.0-fold elevated by diabetes in tissues other than diaphragm, was reduced by WAY-135 706 and WAY-121 509, except in the kidney. Motor and sensory nerve conduction velocities were decreased by 20.2 and 13.9 %, respectively with diabetes. These deficits were corrected by WAY-121 509, but WAY-135 706 was completely ineffective. A 48.6 % diabetes-induced deficit in sciatic nutritive endoneurial blood flow was corrected by WAY-121 509, but was unaltered by WAY-135 706. Thus, despite profound sorbitol dehydrogenase inhibition, WAY-135 706 had no beneficial effect on nerve function. The data demonstrate that aldose reductase activity, the first step in the polyol pathway, makes a markedly greater contribution to the aetiology of diabetic neurovascular and neurological dysfunction than does the second step involving sorbitol dehydrogenase. [Diabetologia (1997) 40: 271–281] Received: 13 August 1996 and in final revised form: 6 December 1996     

Hepatic cholesterol and bile acid synthesis in Japanese patients with cholesterol gallstones

In Japan the composition of gallstones is changing rapidly from the once-predominant brownpigment stones to cholesterol ones. The present work was undertaken to clarify the mechanism of cholesterol supersaturated bile production in Japanese patients with cholesterol gallstones. In 26 non-obese and normolipidemic patients (11 with cholesterol gallstones, 8 with black- or brown-pigment gallstones, 7 without gallstones) a liver biopsy and hepatic bile were surgically obtained under standardized conditions. The cholesterol saturation of hepatic bile was significantly higher in cholesterol gallstone patients than in gallstone-free controls (195 ±10 vs. 146 ±8%, respectively; P < 0.01). The microsomal activities of 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase, the rate-limiting enzyme for cholesterol synthesis, cholesterol 7 α-hydroxylase, the rate-limiting enzyme for bile acid synthesis, and 7 α-hydroxy-4-cholesten-3-one 12 α-hydroxylase (12 α-hydroxylase), the rate-limiting enzyme for cholic acid synthesis, were assayed simultaneously in the same subjects. There were positive correlations between HMG-CoA reductase and cholesterol 7 α-hydroxylase activities (Rs = 0.62, P < 0.005), and between cholesterol 7 α-hydroxylase and 12 α-hydroxylase activities (Rs = 0.44, P < 0.05) in all subjects, irrespective of the existence of gallstones. The activities of the three rate-limiting enzymes did not differ significantly among the three groups (cholesterol stone, pigment stone and stone-free). In conclusion, the cholesterol supersaturation of hepatic bile in nonobese and normolipidemic Japanese patients with cholesterol gallstones does not result from an increased hepatic cholesterol synthesis or a decreased bile acid synthesis. This study was supported in part by a Grant-in-Aid for Scientific Research (No. 02454226) from the Ministry of Education, Science and Culture of Japan, and a grant from University of Tsukuba Project Research.     

A 12-month randomized controlled study of the aldose reductase inhibitor ponalrestat in patients with chronic symptomatic diabetic neuropathy.

The effects of the aldose reductase inhibitor ponalrestat (600 mg day-1) on sensory, electrophysiological, and autonomic function were examined in 50 patients with chronic symptomatic, distal symmetrical diabetic neuropathy in a 52-week randomized, double-blind, parallel-group, placebo-controlled, single-centre study. In an endeavour to identify patients with a degree of neuropathy potentially amenable to pharmacological intervention, a minimum conduction velocity of 30 m s-1 was set for the peroneal motor nerve. At 52 weeks, no significant differences were observed between the ponalrestat and placebo groups in motor (ulnar, median, and peroneal) or sensory (ulnar and radial) nerve conduction velocities, vibration perception thresholds, adjectival symptom scores or tests of autonomic function (mean electrocardiographic R-R interval variability on deep breathing and orthostatic blood pressure response). Ponalrestat was clinically well tolerated and had no significant effect on glycaemic control. The lack of beneficial effects of ponalrestat may in part reflect the advanced stage of the neuropathic process in patients with established symptomatic disease, and the poor reproducibility of current neurophysiological techniques. Firmer knowledge of clinico-pathological correlates allied to improved non-invasive neurophysiological measurement techniques should facilitate the selection of patients for future therapeutic trials in diabetic neuropathy.     

Clinical effects of antiplatelet drugs and statins on D‐dimer levels

Background

Acute pulmonary embolism may be ruled out by combining nonhigh clinical probability and a normal D‐dimer level. Both antiplatelet drugs and HMG‐CoA reductase inhibitors (statins) have been associated with effects on thrombus formation, potentially influencing D‐dimer levels in this setting, leading to a higher rate of false‐negative tests. Therefore, we determined whether D‐dimer levels in patients with suspected pulmonary embolism are affected by concomitant use of antiplatelet drugs and/or statins and evaluated whether the effect of antiplatelet drugs or statins might affect diagnostic accuracy.

Materials and methods

We performed a posthoc analysis in the YEARS diagnostic study, comparing age‐ and sex‐adjusted D‐dimer levels among users of antiplatelet drugs, statins and nonusers. We then reclassified patients within the YEARS algorithm by developing a model in which we adjusted D‐dimer cut‐offs for statin use and evaluated diagnostic accuracy.

Results

We included 156 statins users, 147 antiplatelet drugs users and 726 nonusers of either drugs, all with suspected pulmonary embolism . Use of antiplatelet drugs did not have a significant effect, whereas statin use was associated with 15% decrease in D‐dimer levels (95% CI, ?28% to ?0.6%). An algorithm with lower D‐dimer thresholds in statin users yielded lower specificity (0.42 compared to 0.33) with no difference in false‐negative tests.

Conclusions

We conclude that use of statins but not of antiplatelet agents is associated with a modest decrease in D‐dimer levels. Adjusting D‐dimer cut‐offs for statin use did, however, not result in a safer diagnostic strategy in our cohort.