Plasma vitamin D-binding globulin in vitamin D deficiency, pregnancy and chronic liver disease.

Plasma concentrations of vitamin D-binding globulin were measured by radial immunodiffusion in healthy subjects, pregnancy, and during oestrogen therapy. Subjects with disorders of vitamin D metabolism (dietary deficiency, malabsorption, anticonvulsant therapy, chronic liver disease) were also studied. Neither sex nor age influenced the plasma vitamin D-binding globulin concentration in healthy subjects, but there was a significant increase in concentration during pregnancy and oestrogen therapy. Elevated levels were found in vitamin D deficient elderly but not younger subjects, while levels in subjects with chronic liver disease were significantly reduced. Normal levels of vitamin D-binding globulin were present in hypervitaminosis D and no vitamin D-binding globulin was detected in human milk. No correlation was observed between plasma 25-hydroxycholecalciferol levels and plasma vitamin D-binding globulin concentrations.     

Both Gimap5 and the diabetogenic BBDP allele of Gimap5 induce apoptosis in T cells

Gimap5, a member of the GTPase of the immunity-associated protein family (Gimap), regulates T cell survival. A strong indication of this is found in the diabetes-prone BioBreeding rat (BBDP), where a frameshift mutation in Gimap5 results in T-cell lymphopenia. We have investigated the function of human Gimap5 in T cells. We found that reduction of Gimap5 by RNA interference in Jurkat cells did not affect the number of apoptotic cells whereas transient over-expression of Gimap5 resulted in a major increase in the number of apoptotic cells. The same effect of over-expression was found in naive human T cells purified from blood but not in activated human T cells. This suggests that the apoptosis-inducing effect of Gimap5 over-expression is dependent on the activation status of the cells. Since the apoptosis-inducing effect of Gimap5 was contrary to the expected function of Gimap5 based on the phenotype of BBDP rats, we over-expressed rat wt Gimap5 and Gimap5 with the mutation found in BBDP (Gimap5-lyp). Both versions of rat Gimap5 induced apoptosis when expressed in the rat T-cell line C58(NT)D.1.G.OVAR.1, however, Gimap5-lyp greatly exacerbated cell death. Finally, we detected the subcellular localization of Gimap5 to be at the endoplasmic reticulum and by quantitative PCR, we found that endogenous Gimap5 mRNA is up-regulated in activated T cells.     

Bioactive GLP-1 in gut, receptor expression in pancreas, and insulin response to GLP-1 in diabetes-prone rats

Glucagon-like peptide-1 (GLP-1) is the most insulinogenic of the glucagon-like peptides secreted mainly by L cells in the small and large intestine in response to the ingestion of nutrients. It binds to a specific GLP-1 receptor (GLP-1R) on β-cells and can increase islet neogenesis and β-cell mass. It is not clear whether the transmission of information from the gut to islet β-cells by messengers such as GLP-1 is different in individuals who develop autoimmune diabetes. In the present study the expression of bioactive GLP-1 protein in the gut and its receptor in the pancreas was examined in diabetes-prone BioBreeding (BBdp) rats in the period before overt diabetes and in age-matched control, non-diabetes-prone BB (BBc) rats. An N-terminal directed antibody specific for the bioactive forms of GLP-1 (GLP-1^7-37 and GLP-1^7-36amide) was used to measure GLP-1 by radioimmunoassay in proximal, median, and distal gut. Pancreas GLP-1R area fraction, GLP-1R gene expression, and insulin content were analyzed, as were plasma GLP-1, glucose, and insulin. The concentration of GLP-1 protein in the jejunum and ileum of BBdp rats was lower than in BBc rats. Although these animals maintained normal blood glucose, there was impaired pancreatic endocrine function, characterized by low baseline insulin concentration in plasma and pancreas. GLP-1R mRNA expression was threefold less in islets isolated from BBdp rats, and GLP-1R⁺ islet area fraction in pancreas sections was decreased. When injected iv with GLP-1, BBdp rats displayed lower second-phase insulin response (and insulin/glucose ratios) compared with BBc rats. Thus, young BBdp rats displayed decreased concentrations of bioactive GLP-1 in jejunum and ileum, reduced GLP-1R in islets, and lower second-phase insulin response to iv GLP-1 than controls. The decrease in insulinogenic and islet β-cell mass-promoting signal from GLP-1 in BBdp rats may contribute to impaired glucoregulation and ineffective maintenance of normal islet mass that shifts islet homeostasis in favor of development of diabetes.     

Impaired Recovery of Left Ventricular Function in Patients With Cardiomyopathy and Left Bundle Branch Block

Background

Patients with left bundle branch block (LBBB) often respond to cardiac resynchronization therapy (CRT) with left ventricular ejection fraction (LVEF) improvement. Guideline-directed medical therapy (GDMT), not CRT, is first-line therapy for patients with reduced LVEF with LBBB. However, there are little data on how patients with reduced LVEF and LBBB respond to GDMT.

Tissue ascorbic acid and polyol pathway metabolism in experimental diabetes

Summary Previous studies demonstrating reduced plasma concentrations of ascorbic acid (AA) in diabetes and interactions between this vitamin and biochemical mechanisms such as synthesis of structural proteins, oxidative stress, polyol pathway and non-enzymatic glycation of proteins suggest that disturbed AA metabolism may be important in the pathogenesis of diabetic microangiopathy. However, limited information is available on the concentration of AA in tissues which develop diabetic complications. This study demonstrates reduced renal but not sciatic nerve or plasma AA concentration in two animal models of insulin-dependent diabetes mellitus, namely the STZ-diabetic rat and the spontaneously diabetic BB rat. Decreased lens AA concentration was also observed in STZ-diabetic rats. Improvement of glycaemic control by insulin treatment (albeit insufficient to achieve normoglycaemia) partially corrected lens and renal AA concentration in STZ-diabetic rats. AA treatment increased kidney and lens AA concentrations of STZ-diabetic and non-diabetic rats and corrected the abnormalities observed for untreated diabetic rats. Sciatic nerve AA concentration was not increased by AA treatment in any group. Tissue ratios of dehydroascorbic acid (DHAA)/AA, one index of oxidative stress, were not different between the diabetic and non-diabetic groups and were unaltered by AA supplementation. AA treatment of STZ-diabetic rats had no effect on elevated tissue concentrations of glucose, sorbitol and fructose or reduced myo-inositol concentration. The effect of reduced tissue AA levels in diabetes on either collagen synthesis or ability to combat increased free radical production is not known. However, correction of abnormal kidney and lens AA concentrations in experimental diabetes by AA supplementation suggests that if AA does have a role in the development or progression of the renal and ocular complications of diabetes, this treatment could be beneficial. [Diabetologia (1998) 41: 516–523] Received: 6 October 1997 and in final revised form: 15 January 1998     

Masked uncontrolled hypertension: Prevalence and predictors

Background

There are limited data on ‘masked uncontrolled hypertension’ (MUCH) in patients with treated and apparently well-controlled BP is unknown.

Peroxidase activity in the intestinal tract of Wistar-Furth, BBc and BBdp rats

BACKGROUND: The development of immune-mediated diabetes in BB rats may involve an inflammatory lesion of the intestinal tract. METHODS: In order to further explore this issue, the activity of peroxidase was measured, in the absence and presence of either bromide or dapsone, at day 10, 30, 45, 70, 95 and 120 in three segments (top, mid and bottom) of the intestinal tract from Wistar-Furth rats and both diabetes-resistant and diabetes-prone BB rats fed after weaning either diabetes-promoting diets or a protective diet, which decreases the incidence of diabetes in the BB rats. RESULTS: In the present study, from day 30 onwards, an age-related increase in peroxidase activity was found in the intestine of diabetes-prone BB rats (BBdp rats) fed diabetogenic diets, when compared with either Wistar-Furth or diabetes-resistant BB rats (BBc rats). This increase was most pronounced in the distal segments of the intestinal tract. Even when fed a protective diet, higher peroxidase activity was found in BBdp than BBc rats. Yet, in BBc rats, and to a lesser extent in BBdp rats, the diabetogenic diets lowered peroxidase activity below the value found in rats of the same strain fed the protective diet. There was a tight correlation between the activity of peroxidase and its susceptibility to be increased by bromide. CONCLUSION: It is proposed that diabetogenic diets may decrease peroxidase activity in intestinal cells, this effect becoming masked in BBdp rats by an age-related increase in the contribution of inflammatory cells. The latter phenomenon affects preferentially the distal segments of the intestinal tract.     

Chimeric antigen receptors: a costimulatory boost promotes immunological memory to B-cell malignancies

Evaluation of: Porter DL, Levine BL, Kalos M et al. Chimeric antigen receptor-modified T cells in chronic lymphoid leukemia. N. Engl. J. Med. 365(8), 725–733 (2011).

Cellular immunotherapies offer perhaps the best proof of concept of the ability of immune cells to eradicate malignancy. However, the majority of these data derive from either the use of expanded tumor-infiltrating lymphocytes to treat metastatic melanoma or the use of donor lymphocytes in relapsed hematological malignancies following allogeneic hematopoietic stem cell transplantation. Genetic engineering of T cells to redirect specificity against tumor-associated antigens potentially overcomes one of the major hurdles to more widespread application. Despite early evidence of possible activity, limited in vivo expansion and persistence of adoptively transferred cells has been associated with disappointing clinical efficacy. A report from Porter and colleagues now demonstrates more fully the potential of such genetic modification in a patient with chronic lymphocytic leukemia, illustrating that when delivered in the right setting with appropriate costimulatory signaling, these cells can expand and persist, and in doing so effect quite remarkable anti-tumor activity.     

Prevention of autoimmune but not allogeneic destruction of grafted islets by different therapeutic strategies

Grafting autoimmune-diabetic recipients with allogeneic islets, graft rejection and disease recurrence as major problems of reaching indefinite survival and tolerance induction have to be solved. Anti-CD25 and anti-CD4 monoclonal antibodies were successfully used after allogeneic islet transplantation in experimentally diabetic rats. A temporary anti-CD25 therapy also prevented disease recurrence in autoimmune-diabetic BB rats, while this was not yet reported for an anti-CD4 treatment. In autoimmune-diabetic NOD mice disease recurrence can be successfully treated using an anti-CD4 monoclonal antibody. We, therefore, compared the efficacy of a short-term anti-CD25 and anti-CD4 treatment regarding the prevention of allograft rejection and disease recurrence in autoimmune-diabetic BB/OK rats. Both monoclonal antibodies were combined with low doses of Cyclosporin A. Untreated BB/OK rats relapsed into hyperglycaemia within 3 weeks independent of the islet donor, LEW.1A, LEW.1BB/OK or BB/OK rats. However, after grafting MHC-identical allogeneic (LEW.1BB/OK) or syngeneic (BB/OK) islets we observed about 30% spontaneous acceptance. Both the anti-CD25 and anti-CD4 therapy significantly prolonged the survival of allogeneic grafted islets. After MHC-identical allogeneic and syngeneic islet transplantation the temporary immunotherapy increased the proportion of permanent acceptors to 63% and 75%, respectively. The efficacy of both treatment strategies in prolonging allograft survival and prevention of disease recurrence was identical. In summary, anti-CD25 as well as anti-CD4 therapy prevented autoimmune but not allogeneic islet destruction in autoimmune-diabetic BB/OK rats. In conclusion, targeting different immune cells by monoclonal antibodies with different specificities can lead to very similar results with respect to an interruption of allograft rejection and autoimmune reaction.     

基于BB平台的中药学教学方法改革思路探讨

中药学课程是中医药教学体系中从专业基础课程过渡到专业课程的重要桥梁。随着信息与网络时代的到来,学生们对信息的需求日益多元化,获取信息的渠道更加多样化。中药学传统的课堂式教学模式已不能完全适应时代的要求。充分利用BB平台等网络多媒体教学技术,可使中药学教学内容形象地呈现在学生面前,使原本枯燥乏味的教学过程变得生动、活泼,并可促进师生互动,延伸课堂教学,从而达到提高教学质量的目的。