Protection from insulin-dependent diabetes mellitus is linked to a peptide transporter gene

HLA class II association with insulin-dependent diabetes mellitus (IDDM) is well established but is still difficult to map to a particular locus. Polymorphism of the genes coding for transporter associated with antigen processing (TAP1 and TAP2), and located in the HLA class II region, was studied in 167 IDDM patients (116 adult-onset and 51 childhood-onset patients) and 98 normal controls using oligotyping after genomic amplification. A dominant protective effect was observed for theTAP2*0201 allele [relative risk (RR)=0.3, corrected probability (pc) < 0.001]. Conversely, susceptibility to IDDM was associated with apparent homozygosity for the TAP2*0101 allele (RR=3.4, pc < 0.001). Protection was independent from but additive to the protection conferred by the DRB1*02 DQB1*0602 haplotype (RR=0.06, pc<0.05), and antagonistic to the DRB1*03 DQB1*0201 and DRB1*04 DQB 1*0302 haplotypes predisposing effect (RR=1.1, not significant), arguing in favor of an absence of linkage disequilibrium between TAP2 and HLA class II genes. This was assessed by x² analysis. TAP1 allelic distribution was not different among diabetics and controls. A significant association was observed between the presence of TAP2*0101 and that of islet cell antibodies (p < 0.05). These data suggest that the TAP2 gene, which encodes protein required for delivery of antigen peptides to class I molecules in the endoplasmic reticulum, could modulate the autoimmune response leading to β cell destruction. From a practical point of view, they make the combined screening of HLA class II and TAP2 loci a highly valuable tool in IDDM prediction.     

Psychological functioning of children with insulin-dependent diabetes mellitus: a longitudinal study

Assessed school-age youth repeatedly over the first 6 years of their insulin-dependent diabetes mellitus (IDDM) to determine self-perceived psychological adjustment. After the first year of IDDM, Ss exhibited a mild increase in depressive symptoms. Anxiety decreased for boys but increased for girls over the duration of IDDM. In contrast, self-esteem remained stable regardless of rehospitalizations or degree of metabolic control. Ss' adjustment shortly after IDDM onset, as reflected by levels of depression, anxiety, and self-esteem, were predictors of later adjustment. In general, Ss found the implications of IDDM more upsetting and the regimen more difficult with time, and girls were more upset by their illness than boys. The degree to which children were upset by the implications and management of IDDM varied as a function of their anxiety and depression.     

Subarachnoid hemorrhage in the African-American population: a cooperative study.

The clinical outcome of patients following subarachnoid hemorrhage is complicated by delayed cerebral ischemia and contributing factors such as hypertension. To observe the impact of hypertension and delayed cerebral ischemia on the outcome of a predominantly African-American cohort following subarachnoid hemorrhage, both retrospective (n = 42) and prospective (n = 21) studies were conducted. In the total pool (n = 63), the mean age was 49.7 years (range: 17 to 80) with a preponderance of female patients (70%). Aneurysm formation was significant in the region of the posterior communicating artery. Of the patients reviewed, 73.8% had preexisting hypertension and 45.9% developed delayed cerebral ischemia. Approximately 89% of the patients who suffered from delayed cerebral ischemia had hypertension. Results failed to display any significant beneficial association between the use of the calcium channel blocker nimodipine and delayed cerebral ischemia. Use of the antifibrinolytic drug aminocaproic acid demonstrated a worse patient outcome. It is not recommended that aminocaproic acid be used in this population. Subsequently, due to the proportional occurrence of delayed cerebral ischemia in hypertensive patients following subarachnoid hemorrhage, it is suggested that prophylactic surgical management of unruptured intracranial aneurysms be considered in hypertensive patients. Further study is needed to discern the association between hypertension, delayed cerebral ischemia, and stroke in patients following subarachnoid hemorrhage.     

Quality of life in adults with insulin-dependent diabetes mellitus

Conventional measures of psychiatric or medical morbidity do not adequately reflect the consequences of chronic illness. Quality of life refers to a more comprehensive assessment of the impact of illness. Uncomplicated insulin-dependent diabetes is usually associated with mild reported reduction in quality of life. Increased depressive and anxiety disorders have been reported in individuals with insulin-dependent diabetes mellitus, particularly in association with more severe medical complications and low social support. The potential benefits of intensive treatment approaches must be weighed against adverse effects on the quality of life.     

Transgenic mouse as a tool for the study of autoimmune disease: insulin-dependent diabetes mellitus.

Transgenic mice have been used for analyses of cis-acting elements which are involved in the tissue-specific and developmental-specific expression, for analyses of physiological function of genes, or for the production of a human disease model. This approach is especially successful in the fields of immunology and oncology. Several years ago it was shown that the major histocompatibility complex (MHC) class II gene is identical to the immune response gene by demonstrating that the immune response can be restored by the new expression of class II molecules on immunocompetent cells. Recent evidence suggests that the class II molecule is involved in the generation of autoimmune disease, such as insulin-dependent diabetes mellitus (IDDM). The NOD (non-obese diabetic) mouse is shown to be a mouse model for human IDDM. Concerning the class II genes, the NOD mouse has two characteristic features, the lack of I-E and the presence of unique I-A. It is discussed how the role of class II molecules in the development of IDDM in the NOD mouse can be analyzed. In addition, the transgenic technique can be applied to the study of differentiation and oncogenesis of lymphoid cells. Factors or molecules that affect these processes will also be discussed.     

Quantitative electron microscopic study of capillaries in diabetes mellitus.

A systematic microscopic examination of all elements of the capillary wall was performed on quadriceps muscle biopsies from 9 diabetic patients and 8 controls. The capillary basement membrane (CBM) was markedly thicker in diabetics; it consisted of several lamellae and contained large vacuoles which were never observed in non-diabetic subjects. Large magnifications revealed fibrils in greater number and markedly larger in diameter in diabetics, these accounting for a considerable volume of the CBM and the adventitia and increased diameter and thickness of the capillary wall, without encroaching on the lumen. The intracellular fibrils in pericytes and endothelial cells were also larger and thicker in diabetic subjects. The prevalence of fibrillar material in the vascular disease of diabetes mellitus suggests the importance of research into possible measures to arrest fibril formation.     

Haptoglobin genotype and endothelial function in diabetes mellitus: a pilot study

Endothelial function (EnF) is impaired in patients with diabetes mellitus (DM) due in large part to an increase in oxidative stress. Haptoglobin (Hp) is a potent antioxidant protein which is encoded by two different alleles (1 and 2) with the Hp 1 protein being a superior antioxidant to the Hp 2 protein. We hypothesized that DM individuals with the Hp 2-2 genotype would have greater endothelial dysfunction as compared to DM individuals with the Hp 1-1 genotype. We studied EnF in 16 Hp 2-2, 14 Hp 1-1 DM individuals and 14 healthy subjects. DM patients’ groups were matched in terms of age, cardiovascular risk factors and metabolic characteristics. EnF was assessed using post-ischemic reactive hyperemia and strain gauge plethysmography and expressed either as the maximal flow after the ischemic period or as the area under the flow–time curve (AUC). We showed that EnF indices, AUC and maximal flow, were also higher in the healthy and Hp 1-1 groups compared with Hp 2-2 genotype group (615 ± 60 and 600 ± 40 vs. 450 ± 50 ml dl⁻¹, 29 ± 2.6 and 25 ± 3 vs. 14 ± 1.8 ml min⁻¹ dl⁻¹, P < 0.003 and P < 0.05, for AUC and maximal flow, one-way ANOVA, respectively). We concluded that Hp 2-2 diabetic patients had a worse EnF than controls and Hp 1-1 diabetic subjects.     

Early parental separation experiences among patients with bipolar disorder and major depression: a case-control study.

BACKGROUND: Although the association between childhood parental loss and later development of mood disorder has received much research interest in the past, the results obtained and conclusions drawn have been various, and inconsistent with each other. The present study aims to examine this old, yet unresolved, question among the Japanese. METHODS: Patients with bipolar disorder (n = 73) and unipolar depression (n = 570) and community healthy controls (n = 122) were examined as to their psychopathology and childhood parental loss experiences with semi-structured interviews. RESULTS: Stratified for sex and age, no statistically significant difference was observed in the incidence of paternal or maternal death or separation before age 16 between bipolar patients and healthy controls. Female patients with unipolar depression under the age of 54 experienced significantly more maternal loss than the corresponding controls. This excess in loss appeared to be largely due to the patients experiencing separation from their mothers. CONCLUSION: Our findings concerning bipolar disorder have replicated the previous two studies reported in the literature. Those concerning unipolar depression appear to be in line with several recent studies on the subject but, as stated, many discrepant findings can also be found in the literature.     

The impact of transrectal ultrasound on stage migration in a predominantly African-American population.

An important question left unanswered is whether transrectal ultrasound will result in earlier diagnosis in African Americans. Tumor registry data for 1985 and 1990 for a predominantly African-American population were reviewed to determine whether transrectal ultrasound influenced the stage at diagnosis of prostate cancer. Diagnosis by ultrasound increased from 0% to 60% of cases in those 5 years. Curable diseases (stages A and B) increased from 38% to 57% of cases. It is concluded that transrectal ultrasound can increase the diagnostic yield of potentially curable disease in a predominantly African-American population.     

A project to reduce the burden of diabetes in the African-American Community: Project DIRECT.

Project DIRECT (Diabetes Interventions Reaching and Educating Communities Together) is the first comprehensive community diabetes demonstration project in the United States in an African-American community. This article describes its intervention components and evaluation design. The development and implementation of Project DIRECT has included the community since the project''s beginning. Interventions are targeted in three areas: health promotion (improving diet and physical activity levels), outreach (improving diabetes awareness, detection of undiagnosed diabetes, and ensuring that persons with diabetes who are not receiving continuing diabetes care are integrated into the health-care system), and diabetes care (improving self-care, increasing access, and improving the quality of diabetes preventive care received within the health-care system). Evaluation will be internal (conducted by Project DIRECT staff to assess process outcomes in persons directly exposed to each specific intervention) and external (review of outcomes to assess the impact of the multi-intervention program at the level of the entire community). Because diabetes exacts a disproportionate toll among African Americans, the findings from this project should aid in developing strategies to lessen the burden of this disorder, particularly among minority populations.     

Immunology of diabetes mellitus.

Insulin-dependent diabetes is an autoimmune disease that may be becoming more prevalent. It has a polygenic mode of inheritance with a major gene being present in the HLA DQ locus on chromosome 6. Inferential data suggest that environmental factors may be important to genetic penetrance albeit we still lack proof for involvement of often maligned viruses. Patients with IDD and their families are predisposed to organ-specific autoimmunities which should be routinely screened for. Autoantibodies to insulin, to a beta cell cytoplasmic lipid containing moiety and to a beta cell protein of 64KDa, which is believed to be the GABA forming enzyme GAD, can be used to predict IDD among relatives and probably the general population as well. Immunosuppressive therapy can modify the course of IDD after diagnosis and should be able to delay the clinical onset if given before diagnosis. Rigorous insulin therapy should also be given as needed to control hyperglycemia and avoid glucose toxicity to the islets. Such trials are now underway.     

Diabetes mellitus and its complications in an African-American community: project DIRECT.

Project DIRECT (Diabetes Intervention Reaching and Educating Communities Together) is a multilevel community-based intervention project designed to address diabetes and its complications in an African-American community. This article presents results of the Project DIRECT pilot study and describes risk factors for diabetes, diabetes prevalence, complications, and care practices. During 1993, a pilot study was conducted among persons 20 to 74 years of age in Wake County, North Carolina. The study involved household interviews and examinations, and more extensive health center interviews and examinations based on the race of the head of the household, previous diagnosis of diabetes, and results of capillary glucose tests done in the household. Of the black population aged 20 to 74 years, 52 +/- 3% reported being inactive and 51 +/- 3% were overweight; the prevalence of diagnosed diabetes was 5.2 +/- 0.9%; the prevalence of undiagnosed diabetes was 5.7 +/- 2.7%; and the prevalence of impaired glucose tolerance was 11.4 +/- 7.5%. Blacks with diabetes were significantly more likely than nonblacks with diabetes to have uncontrolled hypertension and to smoke cigarettes. Blacks with diabetes were significantly less likely to report having health insurance or to have a private health-care provider. Diabetes mellitus is a major public health problem in the African-American community of Wake County. Modifiable risk factors for diabetes and undiagnosed diabetes are common. Project DIRECT is attempting to improve the health-related quality of life of this population by reducing the burden of diabetes and its complications through a multilevel, community-based intervention.