The CTLA-4 gene region of chromosome 2q33 is linked to, and associated with, type 1 diabetes. Belgian Diabetes Registry

Susceptibility to autoimmune insulin-dependent (type 1) diabetes mellitus is determined by a combination of environmental and genetic factors, which include variation in MHC genes on chromosome 6p21 (IDDM1) and the insulin gene on chromosome 11p15 (IDDM2). However, linkage to IDDM1 and IDDM2 cannot explain the clustering of type 1 diabetes in families, and a role for other genes is inferred. In the present report we describe linkage and association of type 1 diabetes to the CTLA-4 gene (cytotoxic T lymphocyte associated-4) on chromosome 2q33 (designated IDDM12). CTLA-4 is a strong candidate gene for T cell- mediated autoimmune disease because it encodes a T cell receptor that mediates T cell apoptosis and is a vital negative regulator of T cell activation. In addition, we provide supporting evidence that CTLA-4 is associated with susceptibility to Graves' disease, another organ- specific autoimmune disease.      

IL-10 has a protective role in experimental autoimmune uveoretinitis

The role of IL-10 in the regulation of ocular autoimmune disease was studied in experimental autoimmune uveoretinitis (EAU) elicited in mice by immunization with the retinal antigen interphotoreceptor retinoid binding protein. IL-10-deficient mice were susceptible to EAU, indicating that pathogenesis can occur without presence of IL-10. Treatment of normal mice with IL-10 for 5 days after uveitogenic immunization ameliorated subsequent EAU scores, and down-regulated antigen-specific production of tumor necrosis factor-alpha and IFN- gamma. A concomitant treatment with IL-4 further reduced disease, and resulted in emergence of antigen-specific IL-4 and IL-10 production, as well as in enhancement of the IgG1 antibody isotype. IL-4 by itself was not protective. Only IL-10, but not IL-4, was able to inhibit the function of differentiated uveitogenic T cells in culture. Expression of mRNA for Th1 and Th2 cytokines in the eye during the course of EAU showed that while a Th1 pattern predominated early, IL-10 mRNA expression coincided with down-regulation of the Th1 response and resolution of EAU. Systemic neutralization of IL-10 during the expression phase of EAU resulted in elevated disease scores. Our results suggest that endogenous IL-10 limits expression of EAU and may play a role in the natural resolution of disease. The data further suggest that exogenous IL-10 may be useful in therapeutic control of autoimmune uveitis. While IL-10 by itself is sufficient to suppress Th1 effector development and function, a concomitant administration of IL-4 is required to shift the autoimmune response towards a non-pathogenic Th2 pathway.      

Rising incidence of type 1 diabetes in Scottish children, 1984-93. The Scottish Study Group for the Care of Young Diabetics

OBJECTIVES: To calculate the incidence of type 1 diabetes in Scottish children aged less than 15 years between 1984 and 1993; to examine changes in incidence; and to calculate the prevalence of diabetes at the end of this period. DESIGN: Three data sources were used to construct the Scottish Study Group for the Care of Young Diabetics register: active reporting of all new cases; reports from the Scottish Morbidity Register 1; and local registers. SUBJECTS: All children resident in Scotland diagnosed with primary insulin dependent diabetes mellitus when less than 15 years of age between 1984 and 1993. MAIN OUTCOME MEASURES: Annual incidence and prevalence rate for Scotland; time trend in incidence over the 10 years; differences in incidence between the three different age groups; and completeness of the register. RESULTS: The average annual incidence for Scotland was 23.9/100,000 children. The prevalence rate was 1.5/1000 in 1993. A total of 2326 cases was identified from the three sources. Capture-recapture analysis suggests a case ascertainment of 98.6%. The annual incidence rates increased at a rate of 2% each year (rate ratio = 1.02, 95% confidence interval (CI) 1.01 to 1.03). The incidence was higher in boys than girls (rate ratio = 1.08, 95% CI 1.00 to 1.18), and the incidence rates increased with age: 15.3/100,000/year for age 0-4 years, 24.4/ 100,000/year for age 5-9 years, and 31.9/ 100,000/year for age 10-14 years. CONCLUSIONS: The incidence of type 1 diabetes in Scotland is increasing and the prevalence is relatively high. These findings have important implications for health service resource allocation. The Scottish Study Group for the Care of Young Diabetics' register provides a base for monitoring and research.     

Analyses of mutation and loss of heterozygosity of coding sequences of the entire transforming growth factor beta type II receptor gene in sporadic human gastric cancer

Mutations in the transforming growth factor beta type II receptor (TGFbetaRII) gene have been detected in several human cancer types exhibiting microsatellite instability. Using intron primers previously reported for examination of the entire coding region of the TGFbetaRII gene, 29 sporadic gastric cancers were screened with non-radioactive single strand conformation polymorphism and subsequent DNA sequencing analysis. Mutations of the TGFbetaRII gene were detected in three out of 29 tumors (10%). Two cases showed deletions in a polyadenine tract in both alleles and was positively associated with replication error. One case had an insertion of GA dinucleotide sequence in one allele. Mutations of the TGFbetaRII gene were restricted to exon 3 and other coding regions were not affected. Loss of heterozygosity was detected by analyzing a polymorphic site in intron 2. Three out of nine (33%) informative cases, which were all of intestinal type and advanced cases, showed loss of heterozygosity but neither TGFbetaRII mutation nor replication error was found in these cases. Immunoreactivity of TGFbetaRII in tumor tissues was reduced to a different extent in the gastric cancer with genetically abnormal transforming growth factor. Although the numbers studied are small, homozygous (A)10 deletion or loss of heterozygosity of TGFbetaRII is involved in tumorigenesis and progression of at least some part of sporadic gastric cancer.      

Toxic cardiogenic shock in a patient receiving weekly 24-h infusion of high-dose 5-fluorouracil and leucovorin

A 54-year-old man was treated with weekly 24-h infusion of high-dose 5-fluorouracil (2600 mg/m2) and leucovorin (100 mg/m2) for metastatic colon cancer. At first, he tolerated the treatment well and no significant toxicity was identified. After a total of eight courses of treatment, a stable disease was observed, but mild shortness of breath was found on occasion. The patient had no previous history of cardiac disease and the heart performance assessed by left ventricular ejection fraction before treatment was normal. Unfortunately, acute pulmonary edema with lethal cardiogenic shock occurred during the ninth course of treatment, in spite of intensive medical treatment. The chest X-ray showed extreme cardiomegaly. Repeated assessment of his heart function by echocardiogram and ventricular ejection fraction revealed a very poor cardiac performance. Toxic cardiogenic shock during weekly 24-h infusion of high-dose 5-fluorouracil and leucovorin is extremely rare. To the best of our knowledge, no case has been reported in the English literature. We report a case and the relevant literature about the incidence, clinical picture and possible pathophysiology on 5-fluorouracil-related cardioxicity is reviewed.      

术前口服依他昔布对妇科手术后病人自控镇痛的影响

目的:观察妇科开腹手术患者术前给予依他昔布120mg对术后自控镇痛(PCA)吗啡用量的影响及其副作用。方法:随机选取全麻下接受妇科开腹全子宫(双附件)切除患者40例,术前分别给予安慰剂或依他昔布120mg口服。在手术后观察24h患者PCA吗啡用量,同时记录患者的疼痛评分和满意度评分,并观察不良反应。结果:术后PCA吗啡24h消耗量在依他昔布组为9.4±7.6mg,显著低于安慰剂组15.7±8.9mg。两组患者24h内对PCA的按压次数依他昔布组也低于安慰剂组(P<0.05)。其中术后3、6、8和12hPCA吗啡消耗量在两组间无显著差异。两组患者术后24h疼痛评分和对镇痛治疗的满意度也无差异。两组患者不良反应的发生率亦无差别。结论:在妇科开腹手术患者术前应用依他昔布120mg可使患者术后PCA吗啡消耗量降低,且在术后12h后下降明显。未发现与依他昔布应用相关的副作用。