Maternal environment affects endogenous virus induction in the offspring of type 1 diabetes model non-obese diabetic mice

Type 1 diabetes results from the destruction of pancreatic b-cells (insulitis). It is a multifactorial disease involving genetic and environmental factors, including the maternal environment. Viruses have also been implicated in the pathogenesis of human type 1 diabetes as well as in its model non-obese diabetic (NOD) mice during the perinatal period, as endogenous viruses and/or as infectious agents vertically transmitted from mothers. However, the role of virus as genetic or environmental factor and its interaction with other maternal factors remain unclear. In a series of experiments, we transplanted preimplantation-stage NOD embryos into the uterus of recipient Institute of Cancer Research (ICR) mice, which are without diabetic genetic predisposition, and NOD mice, which did not exhibit overt diabetes during the experiment, and designated offspring as NOD/ICR and NOD/NOD, respectively. We previously observed that NOD/ICR offspring developed insulitis significantly earlier than NOD/NOD offspring. To assess the role of viruses in the development of insulitis, we examined the appearance of viral particles and expression of retroviruses between NOD/ICR and NOD/NOD. NOD/ICR showed earlier expression of env region of the xenotropic type C retrovirus by polymerase chain reaction analysis than NOD/NOD, while the retrovirus-like particles were observed in the islet b-cells similarly in both groups by electron microscopy. Serum corticosterone level, which is suggested to enhance retroviral induction, was significantly higher in the ICR than in the NOD surrogate mothers. These findings suggest that the observed virus is endogenous and that maternal environmental factors, including hormone levels, affect the induction of endogenous viruses and cause the earlier onset of insulitis.     

Maternal dietary n‐6/n‐3 fatty acid ratio affects type 1 diabetes development in the offspring of non‐obese diabetic mice

Environment factors, including maternal or infant dietary nutrition have been reported to have an influence on the pathogenesis of type 1 diabetes. In the present study, to investigate the effect of maternal or post‐weaning offspring's nutrition, in particular the essential fatty acid ratio (n‐6/n‐3) on the development of type 1 diabetes, we prepared two kinds of chows with n‐6/n‐3 ratios of 3.0 (L) and 14.5 (H), and provided them to mothers of non‐obese diabetic (NOD) mice during gestation and lactation and to the offspring after weaning. The n‐6/n‐3 ratios in breast milk and erythrocyte membrane of NOD offspring became nearly the same with that of the maternal diet at 2 weeks after birth. In the L chow‐fed offspring from L chow‐fed mother (LLL), levels of insulitis were higher than those in the H chow‐fed offspring from H chow‐fed mother (HHH) at 4 weeks of age, while the levels in the LLL offspring became lower than those in the HHH after 6 weeks. Early insulin autoantibody expressions were found from 2 to 6 weeks in the HHH offspring, but not in the LLL. The LLL offspring exhibited strong suppression of overt diabetes development in regard to the onset and accumulated incidence of diabetes compared to the HHH. The study with combined L and H chows during gestation, lactation in mother and in post‐weaning offspring revealed that only the LLH chow significantly suppressed the development of diabetes with similar kinetics to LLL chow, although the other combinations may delay the onset of diabetes. The present findings suggest that n‐6/n‐3 ratio of the maternal diet during gestation and lactation rather than that of offspring after weaning strongly affects the development of overt diabetes in NOD mice.     

腺病毒介导的白介素10基因转导对鼠胰岛β细胞的保护作用

目的观察腺病毒介导的白介素10(IL-10)基因转导对体外及体内胰岛β细胞的保护作用。方法用携带有IL-10基因的重组腺病毒载体感染RINm5F细胞、昆明小鼠及链脲佐菌素(STZ)诱导的1型糖尿病小鼠,ELISA检测IL-10基因表达、胰岛素水平,病理切片及免疫组化观察胰岛炎积分。结果 RINm5F细胞中检测到IL-10基因及蛋白的有效表达,含IL-10的重组腺病毒(Ad-IL-10)可抑制STZ致细胞凋亡作用。昆明小鼠腹腔注射Ad-IL-10后,再经STZ诱发为1型糖尿病,Ad-IL-10组胰岛炎积分明显降低。经STZ诱导的早期1型糖尿病小鼠,Ad-IL-10组与其他组相比平均血糖水平差别无统计学意义,小鼠胰岛炎症浸润程度与糖尿病对照组差别无统计学意义。结论腺病毒介导的IL-10可在胰岛RINm5F细胞有效表达,并且具有抗凋亡的能力。IL-10基因能够保护胰岛β细胞功能,促进胰岛素分泌,减少小鼠的胰岛炎和糖尿病的发生。IL-10基因对于已发生1型糖尿病早期的昆明小鼠无显著的治疗作用。     

IL-12对支气管哮喘小鼠Th2免疫应答的影响

目的　哮喘是Th2细胞介导的气道慢性非特异性炎症。IL 12在抗原致敏阶段可有效抑制Th2免 疫应答形成,而对已产生的Th2免疫应答是否同样具有抑制作用尚有争议。本研究探讨IL 12对哮喘时已产生的 Th2免疫应答的影响,为临床应用提供可靠的理论依据。方法　实验一:取25只6～8周雌性BALB/c小鼠,腹腔 注射鸡卵清蛋白(OVA)和氢氧化铝致敏。于致敏前、致敏后第7,14,21,28天,各取处死5只检测脾脏单个核细胞 培养上清液中的Th2类细胞因子IL 4和IL 5水平,观察Th2免疫反应形成情况。实验二:另取40只相同小鼠随机 分为哮喘组(n=20)和IL 12治疗组(n=20),均腹腔注射鸡卵清蛋白(OVA)和氢氧化铝致敏后雾化吸入OVA诱 发哮喘。IL 12治疗组在致敏后25d开始连续5d腹腔内注射0.5μg(1mL)重组IL 12,哮喘组仅注射PBS。两组 均在最后1次诱发后(致敏后30d)处死,取支气管肺泡灌洗液(BALF)和脾脏单个核细胞培养上清液检测Th2类 细胞因子IL 4、IL 5和Th1类细胞因子IFN γ水平(ELISA法)。结果　实验一:小鼠在致敏后14d脾脏单个核细 胞分泌IL 4和IL 5明显增高,说明小鼠致敏后第14天已形成Th2免疫应答。实验二:与哮喘组比较,IL 12治疗组 BALF中IL 4(192±19pg/mLvs19±5pg/mL)和IL 5浓度(328±71pg/mLvs141±15pg/mL     

Umbilical cord levels of interleukin-1 receptor antagonist and neonatal outcome

BACKGROUND: Previous studies indicate that there may be infant gender differences in cytokine expression associated with differences in neonatal morbidity. OBJECTIVE: We tested the hypothesis that umbilical cord interleukin-1 receptor antagonist (IL-1ra) correlates with infant gender and neonatal outcome in preterm infants. STUDY DESIGN: IL-1ra was measured in cord blood taken from 58 preterm infants (33 males, 25 females) with gestational age less than 32 weeks. Receiver operating characteristics (ROC) curve were used for identifying IL-1ra values with high sensitivity and specificity for neonatal morbidity and adverse outcome, i.e., death or survival with severe intraventricular hemorrhage or periventricular leukomalacia. RESULTS: In the female infants, but not the male infants, cord IL-1ra values correlated with postnatal depression, expressed as Apgar scores at 1 min (correlation coefficient, r(s); p value: -0.542; 0.005), 5 min (-0.571; 0.018), and 10 min (-0.442; 0.035); and postnatal age at intubation (-0.799; 0.001). The ROC area under the curve (AUC) was 0.735 for adverse outcome (p=0.013), and 0.683 for bronchopulmonary dysplasia (p=0.021) when all infants were included. However, there was a significant gender difference in the ROC curve for adverse outcome (p=0.026), with AUC 0.640 (p=0.240) in males and AUC 0.929 (p=0.008) in females. Above a chosen cutoff at 13,500 ng/l for IL-1ra cord the sensitivity and specificity for predicting adverse outcome was 100 and 81%, respectively in females versus 50 and 84% in males. CONCLUSION: Increased levels of cord IL-1ra levels are associated with neonatal morbidity and adverse outcome in preterm infants. Comparable levels of IL-1ra have different predictive value depending on infant gender.     

Estrogen receptor-alpha, sexual dimorphism and reduced-size liver ischemia and reperfusion injury in mice

Estrogen (E(2)) exerts its effect on target organs principally by interacting with specific estrogen receptors (ER) such as ER-alpha or ER-beta. The role that these E(2) receptors play in mediating the protective effects observed in RSL+I/R induced injury remains to be defined. To study the role of ER-alpha, we anesthetized female and male wild type (wt; C57Bl/6) and ER-alpha-deficient (alphaERKO) mice and subjected them to 70% liver ischemia for 45 min followed by resection of the remaining 30% nonischemic lobes and reperfusion of the ischemic tissue. For some experiments, wt and alphaERKO male mice were injected with E(2). Survival was monitored on a daily basis while liver injury was assessed by quantifying serum alanine aminotransferase (ALT) levels and histopathology. Hepatic eNOS mRNA levels were evaluated using semi-quantitative RT-PCR. Our data showed that untreated females or males treated with E(2) survived RSL+I/R surgery indefinitely whereas all male mice given vehicle died within 3-5 days following surgery. This protective effect was diminished in alphaERKO female mice such that only 40% of alphaERKO females survived 7 d following RSL+I/R. Furthermore, liver injury was significantly higher in alphaERKO females compared with their wt counterparts and similar to those seen in wild type males and alphaERKO males. The protective effect observed in wild type females or E(2) treated males correlated well with increases in hepatic eNOS message whereas both male and female alphaERKO mice exhibited significantly lower levels of eNOS mRNA. We conclude that this protection may in part be due to the E(2)/ER-alpha-mediated activation of eNOS.     

The epidemiology of lost residual beta-cell function in short term diabetic children

Using the country-wide Swedish childhood diabetes register 526 children, who had had diabetes for 6-30 months were traced for measurements of 24-hour urinary C-peptide. Lost beta-cell function was defined as a 24-hour urinary C-peptide excretion per kg body weight less than 10% of the mean for healthy children (less than 0.025 nmol/kg). The estimated cumulative incidence of lost beta-cell function was 0.64 at 30 months. The incidence of lost beta-cell function did not differ by sex. Neither was there any significant variation in season at onset for cases with lost beta-cell function. A significant age dependency was shown for the cumulative incidence of lost beta-cell function with the highest incidence in the young age groups, i.e. a reversed age dependency compared to that of clinical onset. In contrast to the clinical onset of diabetes no significant geographical variation was found for lost beta-cell function when comparing standardized morbidity ratios. The urinary C-peptide excretion was significantly correlated to age at onset but not to degree or duration of ketonuria at onset. It is concluded that there are striking differences when comparing the epidemiology of lost beta-cell function to that of clinical onset in terms of age, sex, seasonal and geographical variations. The timing of clinical onset may thus partly be determined by factors different from those determining the rate of fall in beta-cell function.     

金银花水提物对卵清蛋白致敏小鼠的免疫调控作用

目的研究中药金银花水提物（以下简称金银花）对卵清蛋白（OVA）致敏小鼠的免疫调控作用,探索中药治疗食物过敏的可行性。方法取BALB／c小鼠40只,均分为5组,每组8只,按照肠道激发后灌服不同浓度的金银花水提物分为100mg／100ml（H）、50mg／100ml（M）、25mg／100ml（L）浓度组,激发后不给药组（Ch）,以及正常生理盐水（NS）对照组。取空肠行HE及甲苯胺蓝染色;组织荧光法测定小肠组胺含量;ELISA法测定外周淋巴组织单个核细胞（PLNMC）培养上清液中白细胞介素4（IL-4）、γ干扰素（IFN-γ）及血清OVA特异性IgE（OVA-sIgE）水平;RT-PCR测定PLNMC中IL-12p40 mRNA表达;足垫肿胀实验检测迟发型超敏反应。结果H、M组浓度的金银花水提物可缓解过敏小鼠小肠绒毛炎症,减轻肥大细胞聚集和脱颗粒,提高固有层完整肥大细胞比率,减轻过敏小鼠肠道组胺释放,降低过敏小鼠体内IL-4、OVA-sIgE水平及IL-4／IFN-γ比值,抑制PLNMC中IL-12 mRNA表达;三种浓度金银花可缓解OVA介导的小鼠足垫迟发性超敏反应（DTH）。结论证实金银花水提物可参与OVA致敏小鼠的免疫调控,对缓解OVA介导的小鼠IgE及细胞介导的变态反应有利,用于食物过敏治疗具有潜在研究价值。     

头孢呋辛对哮喘儿童外周血单个核细胞Th1/Th2平衡的影响

目的研究头孢呋辛对哮喘儿童外周血单个核细胞Th1/Th2平衡的影响。方法采用流式细胞术检测哮喘和健康儿童外周血单个核细胞IFN-γ和IL-4水平,以及哮喘儿童外周血单个核细胞经头孢呋辛体外干预后的IFN-γ和IL-4水平。结果与健康儿童相比,哮喘患儿外周血单个核细胞的IFN-γ和IFN-γ/IL-4比值降低,差异有统计学意义(P<0.05);哮喘患儿外周血单个核细胞在体外与头孢呋辛(100 mg/L)孵育48 h后,IL-4水平升高,差异有统计学意义(P<0.05),而IFN-γ的变化无统计学意义(P>0.05);IFN-γ/IL-4比值则降低,差异有统计学意义(P<0.01)。结论哮喘患儿外周血单个核细胞以Th2(IL-4)占优势,Th1/Th2比值平衡失调;而头孢呋辛更加剧这一倾斜,不利于哮喘治疗。     

Diet with a low n‐6/n‐3 essential fatty acid ratio when started immediately after the onset of overt diabetes prolongs survival of type 1 diabetes model NOD mice

Type 1 diabetes is a multifactorial disease involving genetic and environmental factors and results from the destruction of pancreatic islet β cells, virtually the only source of insulin. When the majority of β cells are lost, a ‘honeymoon’ period of variable length follows: namely, a fleeting phase of residual endogenous insulin production, during which glycemic control is achieved with modest or no doses of insulin. However, the remaining β cells are eventually lost, causing the individual to become insulin‐dependent and to require long‐term insulin therapy or islet transplantation. Here we show that NOD mice, a type 1 diabetes model, survived significantly longer when their diet was changed from one chow with a high essential fatty acid (EFA) ratio (n‐6/n‐3, 14.5) to another with a low n‐6/n‐3 ratio (3.0) within 6 days after the onset of overt diabetes (i.e. the ‘honeymoon’ period), than mice that were continuously fed with the chow with the high n‐6/n‐3 ratio. This effect was not observed when the chow was changed later than 9 days after the onset. Significantly larger number of islets remained with suggestive islet neogenesis from the pancreatic duct and pathological changes in renal glomeruli were significantly milder in NOD mice fed the chow with the low n‐6/n‐3 ratio within 6 days after the onset of overt diabetes than those continuously fed with the high‐n‐6/n‐3‐ratio chow. These findings indicate that a diet with a low n‐6/n‐3 ratio prolongs the ‘honeymoon’ period by retaining the β cell mass, suggesting its potential therapeutic merit.     

Autoimmunity and insulin-dependent diabetes mellitus. Experimental data and therapeutic prospects

Experimental results and therapeutic strategies. Insulin-dependent diabetes mellitus (IDDM) results from an autoimmune aggression toward beta cells in genetically predisposed individuals. Examination of the frequency of the different antigens coded by the major histocompatibility complex reveals an increased proportion of DR3-DQ2 and DR4-DQ8 haplotypes in IDDM subjects. Sequencing DQ-beta chains in such patients indicates the absence of aspartate in position 57 when compared to control individuals. Islet cell cytoplasmic autoantibodies are early markers of ongoing autoimmunity in addition to insulin autoantibodies before administration of exogenous insulin. Experimental models of autoimmune diabetes like the NOD (NonObese Diabetes) mouse underline the predominant role of T lymphocytes in the constitution of both insulitis and beta cell destruction. In humans, an increased proportion of activated T lymphocytes can be observed but is not specific of the disease. This underlines the need for new cellular markers of the autoimmune process. Transgenic mice allow studies on the consequences of abnormal expression of new molecules on beta cell surface like cytokines or MHC class II molecules which represent a new field of investigation on the pathogenesis of IDDM. Prospective studies in first degree relatives of type I diabetic patients indicate the existence of an asymptomatic phase of beta cell destruction where specific autoimmune markers can be individualized. In some individuals abnormal insulin response to glucose--loss of first phase insulin release during intravenous glucose tolerance test--precedes insulin deficiency. The identification of an autoimmune process leading to beta cell destruction allows new therapeutic approaches with immunointervention at early stages of the disease.     

Galectin-9及其受体Tim-3 在哮喘小鼠肺组织中的表达

目的：探讨半乳糖凝集素-9（Galectin-9）及其受体T 细胞免疫球蛋白粘蛋白分子-3（Tim-3）在哮喘小鼠肺组织中的表达及 PPAR-γ激动剂罗格列酮（ROS）对其表达的影响。方法45 只清洁级雌性 BALB/c 小鼠随机分为对照组、哮喘组、ROS干预组。观察卵清蛋白激发及ROS干预治疗后哮喘小鼠肺组织的病理变化;应用 RT-PCR 方法检测肺组织 Galectin-9 和 Tim-3 mRNA 的表达;采用酶联免疫吸附测定法检测外周血 IL-4 及 IFN-γ的表达水平。结果哮喘组肺组织 Galectin-9 和 Tim-3 mRNA 表达显著高于对照组及 ROS 干预组（P<0.05）。哮喘组外周血 IL-4 的表达量较对照组及 ROS 组明显升高,而 IFN-γ表达量较对照组及 ROS 组明显降低（P<0.05）。Galectin-9 和 Tim-3 mRNA 表达量与 IL-4 呈正相关（r=0.792,0.794,P<0.05）,与 IFN-γ呈负相关（r=-0.692,-0.757,P<0.05）。结论 哮喘小鼠气道肺组织中 Galectin-9 和 Tim-3 mRNA 表达有明显升高,并且其改变与 Th1/Th2 细胞因子表达量具有相关性,ROS干预治疗后 Galectin-9 和 Tim-3 mRNA 表达下调。     

Immunological aspects on IDDM in children

Diabetes mellitus in childhood is connected to several immunological phenomena which per se do not prove that immunological mechanisms do cause the beta cell destruction, as such mechanisms could be just secondary. However, there is now evidence which strongly supports the autoimmune hypothesis, like the beta-cell destruction in the transplant given from a healthy twin to the diabetic monozygotic co-twin, the effect in newly-diagnosed diabetes of immunosuppression, the passive transfer in experimental animals of an immune process creating diabetes etc. Several facts such as presence of activated T-cells in the insulitis indicate that the cell-mediated immunity is important, while it is still debatable whether humoral factors, and if so which, alone could be responsible for the beta cell destruction. Recently interleukins and other lymphokines have shown to be of great interest as well as the release of free radicals. This knowledge opens new views on the possibility to put an end to or even prevent the beta cell destruction. Rough immunosuppression with cytostatics or cyclosporin has such severe side-effects that such therapy is contra-indicated at least in children. Until more specific therapies are discovered e.g. vaccination with lymphoblasts or blocking the autoantigens with monoclonal antibodies, supportive measures to protect the beta cells may be one practical way.     

短发夹RNA沉默Tim3分子表达对哮喘小鼠外周血Th1和Th17细胞的影响

目的：建立小鼠支气管哮喘模型,采用T 细胞免疫球蛋白黏蛋白分子-3（Tim-3）特异短发夹RNA（shRNA）沉默外周血单个核细胞（PBMCs）中Tim-3的表达,探讨Tim-3对辅助性T细胞1 (Th1)和Th17细胞分化的影响。方法：用卵白蛋白(OVA)致敏并激发建立哮喘小鼠模型,分离哮喘小鼠PBMCs,用 Tim-3特异的shRNA 片段沉默哮喘小鼠PBMCs中高表达的Tim-3 基因。Real-time PCR 和 Western blot 检测 Tim-3 的表达,流式细胞分析技术（FACS）检测Th1和Th17的比例;ELISA 检测细胞培养上清液中干扰素 γ（IFN-γ）,白介素-4（IL-4）,和 白介素-17（IL-17）的水平。结果：哮喘组小鼠PBMCs中Tim-3 mRNA表达明显升高; 使用特异Tim-3 shRNA沉默哮喘小鼠PBMCs后,沉默组PBMCs中Th1细胞比例显著升高,Th17细胞比例显著下降,与阴性对照组相比差异有统计学意义（P<0.01）;沉默组PBMCs培养上清液中IFN-γ明显升高,IL-17明显降低,与阴性对照组相比差异有统计学意义（P<0.05）, IL- 4水平无明显变化。结论：特异Tim-3 shRNA有效地沉默了Tim-3的表达,Tim-3表达的改变影响了T 细胞的分化。     

Pancreatic islets in older patients with cystic fibrosis with and without diabetes mellitus: morphometric and immunocytologic studies

Forty patients with cystic fibrosis (CF), including 34 who died above age 10 years without having developed clinical diabetes mellitus and 6 who died with both cystic fibrosis and diabetes mellitus, were studied. The mean age of the female patients with CF but not diabetes was 15.8 +/- 5.6 years; of males without diabetes, 17.2 +/- 6.4 years; of female patients with CF and diabetes mellitus, 20.2 +/- 6.9 years; and of males with CF and diabetes, 21.3 +/- 6.6 years. The mean number of pancreatic islets in microscopic sections for patients with cystic fibrosis but not diabetes was 4.18 +/- 2.76/mm2, and the value for patients with both cystic fibrosis and diabetes mellitus was 2.61 +/- 2.07/mm2. The lowest density of pancreatic islets (1.69 +/- 0.48/mm2) for cystic fibrosis was found in patients with the latest-stage pathologic lesion. Nesidioblastosis (presence of ductuloinsular complexes) was identified in 14 of 38 cystic fibrosis patients, both with and without diabetes mellitus. The pancreatic islets of both diabetic and nondiabetic patients with CF showed hypertrophy; the mean volume of the three largest pancreatic islets for CF only was 0.0117 +/- 0.00657 mm3 and that for cystic fibrosis and diabetes was 0.00795 +/- 0.00599 mm3, both values being larger than normal. Ratios of the amounts of islet endocrine cells, A cells, B cells, and D cells, were determined by peroxidase--anti-peroxidase labeled antibody staining. The B cells composed 43.0% of endocrine cell mass in cystic fibrosis alone and 30.1% in cystic fibrosis with diabetes mellitus, which were lower than normal proportions. The D cell values, 11.9% in cystic fibrosis and 15.1% in cystic fibrosis with diabetes mellitus, on the other hand, were greater than normal ratios.     

The role of the gut in beta-cell autoimmunity and type 1 diabetes: a hypothesis

The origin of autoimmunity leading to the destruction of insulin-producing beta-cells is not known. Several studies suggest that a link exists between the gut immune system and the islets infiltrating lymphocytes. Inflamed pancreatic islets express the same adhesion molecules involved with the homing of gut-associated lymphocytes. The manifestation of autoimmune diabetes in the animal models can be modified by dietary factors, which cause changes in the cytokine production by islet-infiltrating lymphocytes. Increased risk of type 1 diabetes has been associated with an early introduction of cows' milk formula in infancy, indicating that triggering of the gut immune system in early infancy may contribute to the later development of beta-cell autoimmunity. Enhanced immune reactivity to cow milk (CM) proteins in the patients with type 1 diabetes suggests aberrant regulation of the gut immune system in this disease. In the patients with newly diagnosed type 1 diabetes, anti-glutamate decarboxylase (GAD)-reactivity was found in the subpopulation of lymphocytes expressing gut-associated homing receptor alpha 4 beta 7. Based on these findings, the hypothesis that aberrant function of the gut immune system would lead to the development of beta-cell autoimmunity and type 1 diabetes has recently received a lot of attention. The possibility that regulation of the gut immune system is not normal in subjects at risk of autoimmune diabetes should be considered when treatments interfering with mucosal immunity for the prevention of type 1 diabetes are planned.     

New‐onset diabetes mellitus after heart transplantation in children – Incidence and risk factors

Diabetes mellitus is a recognized complication of SOT in adults and is associated with decreased graft and patient survival. Little is known about NOD in pediatric HT recipients. We aimed to characterize the incidence and describe risk factors for development of NOD after HT in children. Children who developed diabetes after HT were identified from the OPTN database. Demographic and clinical data before and after transplant were compared between patients with and without NOD. A total of 2056 children were included, 56% were male, 54% were Caucasian, and 62% had cardiomyopathy prior to HT. NOD developed in 219 children (11%) after HT. The incidence of NOD was 2.4, 9.0, and 10.4% at one, five, and 10 yr after HT, respectively. Obesity (HR: 4.32), dialysis prior to transplant (HR: 2.38), African American race (HR: 1.86), transplant before year 2000 (HR: 1.82), female gender (HR: 1.68), and older age at transplant (HR: 1.28) were independent predictors of NOD. The major modifiable risk factor for NOD is obesity, imparting the maximum hazard. Improved surveillance for diabetes in high‐risk patients and specific prevention and intervention strategies are imperative in this population.     

Pancreatic Islets in Older Patients with Cystic Fibrosis with and without Diabetes Mellitus: Morphometric and Immunocytologic Studies

Forty patients with cystic fibrosis (CF), including 34 who died above age 10 years without having developed clinical diabetes mellitus and 6 who died with both cystic fibrosis and diabetes mellitus, were studied. The mean age of the female patients with CF but not diabetes was 15.8± 5.6 years; of males without diabetes, 17.2± 6.4 years; of female patients with CF and diabetes mellitus, 20.2± 6.9 years; and of males with CF and diabetes, 21.3± 6.6 years. The mean number of pancreatic islets in microscopic sections for patients with cystic fibrosis but not diabetes was 4.18± 2.76/mm², and the value for patients with both cystic fibrosis and diabetes mellitus was 2.61± 2.07/mm². The lowest density of pancreatic islets (1.69± 0.48/mm²) for cystic fibrosis was found in patients with the latest-stage pathologic lesion. Nesidioblastosis (presence of ductuloinsular complexes) was identified in 14 of 38 cystic fibrosis patients, both with and without diabetes mellitus. The pancreatic islets of both diabetic and nondiabetic patients with CF showed hypertrophy; the mean volume of the three largest pancreatic islets for CF only was 0.0117± 0.00657³ mm and that for cystic fibrosis and diabetes was 0.00795± 0.00599 mm³, both values being larger than normal. Ratios of the amounts of islet endocrine cells, A cells, B cells, and D cells, were determined by peroxidase-anti-peroxidase labeled antibody staining. The B cells composed 43.0% of endocrine cell mass in cystic fibrosis alone and 30.1% in cystic fibrosis with diabetes mellitus, which were lower than normal proportions. The D cell values, 11.9% in cystic fibrosis and 15.1% in cystic fibrosis with diabetes mellitus, on the other hand, were greater than normal ratios.     

Update on the genetics and pathophysiology of type I diabetes mellitus.

Type I diabetes mellitus results from the genetically predetermined autoimmune destruction of pancreatic beta-cells, resulting in gradual, but complete, loss of insulin secretion. There are strong associations with specific HLA haplotypes, but environmental triggers are also required to initiate beta-cell autoimmunity. These could possibly include enteroviral infection, early weaning from breastfeeding, early exposure to cow's milk antigens, and free radical damage. Once initiated, beta-cell autoimmunity does not always lead to clinical diabetes, suggesting that immunomodulators may be important in the control of beta-cell destruction. Current interventions designed to prevent type I diabetes mellitus are based on attempts to alter this immune response and to preserve beta-cell function. It is important for the pediatrician to understand the background of these trials and to be able to answer parents' questions regarding study participation.