Hypoglycaemia causes degeneration of large myelinated nerve fibres in the vagus nerve of insulin-treated diabetic BB/Wor rats

The aim of this study was to find out whether dysglycaemia causes neuropathy in the vagus nerve of insulin-treated diabetic BB/Wor rats. Specimens were collected from the left vagus nerve proximal and distal to the level of recurrent laryngeal branch and from the recurrent branch itself in control rats and diabetic BB/Wor rats subjected to hyper- or hypoglycaemia. Myelinated and unmyelinated axons were counted and myelinated axon diameters were measured by electron microscopy. In controls, the vagus nerve proximal to the recurrent branch exhibited three regions in terms of fibre composition: part A was mainly composed of large myelinated axons, part B contained small myelinated and unmyelinated axons, and part C contained mainly unmyelinated axons. The distal level resembled part C at the proximal level and the recurrent branch resembled parts A and B. In hyperglycaemic rats, a normal picture was found at the proximal and distal levels of the vagus nerve and in the recurrent branch. In hypoglycaemic rats, signs of past and ongoing degeneration and regeneration of large myelinated axons were found at the proximal and distal levels and in the recurrent branch. We conclude that hypoglycaemia elicits degenerative alterations in large myelinated axons in the vagus and recurrent laryngeal nerves in diabetic BB/Wor rats. The absence of signs of neuropathy in unmyelinated and small myelinated axons suggests that the sensory and autonomic components of the nerve are less affected. In contrast, the hyperglycaemic rats examined here did not show obvious degenerative alterations.     

Gut Permeability and Intestinal Mucins,Invertase, and Peroxidase in Control and Diabetes-Prone BB Rats Fed Either a Protective or a Diabetogenic Diet

This study deals with the enteropathy recently identified in diabetes-prone BB rats (BBdp). Diabetes-resistant BB rats (BBc) and BBdp rats were fed from days 32–39 onward either a protective diabetes-retardant hydrolyzed casein diet (HC) or a plant-based diabetogenic (NTP) diet. The NTP diet decreased body weight and plasma insulin in BBc and BBdp rats. The BBdp rats displayed low intestinal invertase and increased intestinal peroxidase activity. In the BBdp rats fed the HC diet, the mucin content 30–35 cm below the pylorus was higher and the gut permeability lower than in the other three rat groups. There was a significant inverse correlation between gut permeability and the insulinogenic index in the BBdp rats fed the HC or NTP diet. Thus, in BBdp rats, the HC diet somehow prevents the increase in gut permeability and the decrease in the insulinogenic index otherwise found in some of these diabetes-prone animals.     

2,3,7,8-tetrachlorodibenzo-p-dioxin augments the modulation of gene expression mediated by the thyroid hormone receptor

Previously, we reported on genes whose expression was highly modulated by T3 in the HeLaTR cells that stably expressed the thyroid hormone receptor (TR). In this study, we examined the effects of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) on TR-mediated gene expression. In the HeLaTR cells, T3 induced the expression of the reporter gene in a thyroid hormone responsible element (TRE)-dependent manner. When the cells were cultured in the presence of T3, the addition of TCDD but not 4-hydroxy-2',3,4',5,6'-pentachlorobiphenyl (PCB-OH), bisphenol A (BPA), or di(2-ethylhexyl)phthalate (DEHP) to the culture media further enhanced the T3-induced expression of the reporter gene. RT-PCR revealed that mRNA levels of 4-1BB, fmfc, PSCA, PSG7, RANTES, and TRAF1, which were highly increased by T3, were further elevated in cells exposed to T3 and TCDD. Also, the mRNA level of BMP6, which was decreased by T3, further declined in the cells exposed to both T3 and TCDD. In contrast to the effect of TCDD, PCB-OH suppressed the modulation of these gene expressions by T3. Neither TCDD nor PCB-OH alone affected the expression of 4-1BB, fmfc, PSCA, PSG7, RANTES, TRAF1, or BMP6. These results indicate that TCDD augments the cellular responses to T3 by hyperactivating TR-mediated gene expression, whereas PCB-OH suppresses cellular responses to T3 by negatively regulating it. Based on these findings, enzyme-linked immunosorbent assay (ELISA) for the PSCA protein in the HeLaTR cells was established. Such assays will be useful to monitor the effects of endocrine disrupting chemicals (EDCs) on TR-mediated gene expression.     

NK and CD8+ T cell-mediated eradication of poorly immunogenic B16-F10 melanoma by the combined action of IL-12 gene therapy and 4-1BB costimulation

In previous reports, systemic administration of a stimulatory monoclonal antibody directed against the 4-1BB receptor had no effect on survival or tumor burden in mice inoculated with the poorly immunogenic B16-F10 melanoma. We combined IL-12 gene transfer with 4-1BB costimulation to explore a previously noted cooperative anti-tumor effect against this model tumor. We hypothesize that the innate immune response mediated by IL-12-activated natural killer (NK) cells initiates the activation of the immune system, leading to the priming of T cells, whereas 4-1BB costimulation enhances the function of primed tumor-specific T cells. The effect of the combination therapy on the growth of subcutaneous (s.c.) tumors and pulmonary metastasis was examined. The combination therapy significantly retarded the growth of subcutaneously-inoculated tumors, and 50% of tumor-bearing mice survived with complete tumor regression. In contrast, neither IL-12 gene transfer nor anti-4-1BB antibody administration alone was as effective. Enhanced CTL activity against both B16-F10 tumor cells and TRP-2-pulsed EL4 syngeneic tumor cells was observed in tumor-bearing animals treated with the combination therapy 2 weeks after treatment and, in long-term survivors from this combination therapy, at >120 days. In a pulmonary metastatic model, only the combination therapy generated significant protection against metastasis. In vivo depletion of NK or CD8(+) but not CD4(+) subsets eliminated the protective immunity. Furthermore, NK cell depletion significantly reduced both tumor-specific CTL activity and the number of tumor-specific IFN-gamma-producing cells, suggesting that this synergistic effect requires the participation of both NK and CD8(+) T cells.     

Aminoguanidine downregulates expression of cytokine-induced Fas and inducible nitric oxide synthase but not cytokine-enhanced surface antigens of rat islet cells

Autoimmune beta-cell destruction occurs directly by cell-mediated cytotoxicity or indirectly by cytokines released from infiltrating lymphocytes. Cytokines (IL-1beta/IFN-gamma) modify or induce expression of MHC antigens and ICAM-1 on beta-cells which can lead to an improved binding of T-lymphocytes to beta-cells and finally to an enhanced cell-mediated cytotoxicity. Cytokines also induce Fas-expression and inducible nitric oxide synthase (iNOS) causing generation of nitric oxide (NO) which is toxic for beta-cells. The iNOS inhibitor aminoguanidine (AG) delays diabetes onset, but does not reduce diabetes incidence. We wanted to know whether AG inhibits cytokine-induced expression of Fas, MHC antigens and ICAM-1 on beta-cells of LEW.1W and BB/OK rat islets after culture with IL-1beta/IFN-gamma. NO was completely inhibited by 5.0 mmol/L AG while 0.5 mmol/L had no inhibitory effect. AG downregulated Fas-expression on the surface of beta-cells. Cytokine-induced/enhanced expression of MHC class-II and ICAM-1 was not affected by any AG concentration. AG syngergistically increased cytokine-induced enhancement of MHC class-I antigen density. AG possibly blocks the indirect pathway of beta-cell damage in vivo due to inhibition of Fas and iNOS and improves direct cell-mediated cytotoxicity due to drastic increased MHC class-I expression. Inhibition of only one pathway of beta-cell destruction is not sufficient to prevent diabetes.     

肺炎支原体肺炎患儿心肌损伤标志物的变化及结果分析

目的观察肺炎支原体肺炎(MPP)患儿心肌酶谱、肌红蛋白(Mb)、肌钙蛋白I(cTnI)、糖原磷酸化酶同工酶BB(GPBB)的变化,以探讨其在肺炎支原体肺炎诊治中的意义。方法对56例支原体肺炎急性期患儿和50例正常对照组儿童,采用全自动生化分析仪检测血清心肌酶谱变化,选用电化学发光方法检测血清Mb和cTnI含量,采用ELISA方法检测血清GPBB的变化。结果MPP患儿组血清AST、LDH、α-HBDH、CK与正常对照组比较,增高极为显著(p<0.01),CK-MB增高显著(p<0.05);MPP患儿组血清Mb含量比正常对照组显著增高,二者相差极为显著(p<0.01),而cTnI、GPBB与正常对照组比较,增高没有Mb程度大(p<0.05)。结论观察MPP急性期患儿心肌损伤标志物的变化情况对于疾病的诊治非常重要,而且对于研究MPP的发病机理也有帮助。     

自发性糖尿病大鼠生长发育与繁殖研究

本试验应用从加拿大引种自发性糖尿病大鼠(简称BB Wistar大鼠)进行一年半的饲养繁殖试验。通过对该动物的生长发育、代谢观察及脏器重量等项指标的检测以及对影响其子代发病率的因素进行了讨论。结果证明:自发性糖尿病大鼠后代发病率较高(10％～39％),不同家系内和亲代不同交配方式影响子代发病率。此外,发病鼠的生长发育、机体代谢与人类青年型糖尿病十分相似。BB Wistar大鼠可作为一种自发性动物模型用于人类青年型糖尿病及其并发症的研究。     

Brain evoked potentials are functional correlates of induced pain in man.

Electrical potentials evoked by 5 intensities of painful dental stimulation were recorded at the scalp. During testing, volunteers indicated subjective painfulness by verbal pain ratings and visual analogue scales. Evoked potentials (EPs) to each intensity, observed between 50 and 400 msec, were characterized by 4 waveform components. The peak-to-peak amplitudes, but not the peak latencies, of all 4 EP components systematically increased with increased stimulation. The amplitudes of the two earlier components correlated with stimulus intensity when the effect of subjective painfulness was controlled, but this was not the case for the later components. In contrast, the amplitudes of the two later components were associated with subjective painfulness but not with stimulus intensity. A strong linear relationship was observed between subjective painfulness and peak-to-peak amplitude for the EP component observed between 175 and 260 msec. The data suggest that the earlier EP components may reflect sensory transmission processes while the later components indicate brain activity when pain is perceived.     

急性颅脑损伤患者血清CK—BB监测的临床意义

目的；探讨急性颅脑损伤患者血清ＣＫ－ＢＢ活性及动态变化的临床意义。方法：逐日监测５０例急性脑伤患者血清ＣＫ－ＢＢ活性，与临床指标对比评价其临床价值，并分析其变化规律与治疗转归，预后的关系，结果：血清ＣＫ－ＢＢ在伤后早期升高，且与伤情成正比相关，ＣＫ－ＢＢ较快恢复正常是治疗有效、无并发症和预后良好的标志。结论；血清ＣＫ－ＢＢ是急性脑损伤的可靠，特异性、量化指标，其动态变化规律对判断疗效，迟发病症，并     

4-1BB配体在肿瘤细胞株上的表达及其与肿瘤细胞增殖的关系

目的检测4-1BBL在肿瘤细胞株上的表达及其功能。方法半定量RT-PCR检测几种肿瘤细胞株内4-1BBL mRNA表达;流式细胞术检测肿瘤细胞表面4-1BBL蛋白的表达;MTT法检测4-1BBLmAb对肿瘤细胞增殖的影响。结果4- 1BBL在Raji和THP-1细胞株表面表达率分别为26.8%和15.3%,而在T1301和Jurkat细胞株中,4-1BBL mRNA水平虽有一定表达,但蛋白水平却几乎不表达;4-1BBLmAb可以促进肿瘤细胞的增殖。结论4-1BBL在不同肿瘤细胞株上的表达有差异;4-1BBL在肿瘤细胞的增殖和长期存活中发挥重要作用。