Clinical,autoimmune, and genetic characteristics of adult-onset diabetic patients with GAD autoantibodies in Japan (Ehime Study)

OBJECTIVE: To characterize the clinical, autoimmune, and genetic features in Japanese adult-onset diabetic patients with GAD autoantibodies. RESEARCH DESIGN AND METHODS: GAD autoantibodies (GADab) were screened in 4,980 diabetic patients with age of onset >20 years in the hospital-based Ehime Study, and the GADab-positive (GADab(+)) patients were then divided into two groups according to their insulin secretion and compared with nondiabetic subjects. The insulin-deficient state was defined as <0.33 nmol/l serum C-peptide (CPR) at 2 h postprandial or 6 min after a 1-mg glucagon load. RESULTS: GADab was detected in 188 (3.8%) of the 4,980 diabetic patients tested. Of these patients, 72 (38.3%) were classified as insulin deficient, 97 (51.6%) were classified as non-insulin deficient, and 19 (10.1%) were unclassified. The GADab(+) insulin-deficient patients were characterized by young age at onset of diabetes, low BMI, low maximum BMI, and high levels of HbA(1c). The prevalence of IA-2 autoantibodies and thyrogastric autoantibodies in the GADab(+) insulin-deficient patients were significantly higher than those in the GADab(+) non-insulin-deficient patients (P < 0.05). GADab(+) patients with insulin deficiency had increased frequencies of HLA DRB1*0405-DQB1*0401, *0802-*0302, and *0901-*0303 haplotypes, whereas the frequency of only HLA DRB1*0405-DQB1*0401 was increased in the case of GADab(+) non-insulin-deficient patients. Of note is the fact that the GADab(+) non-insulin-deficient group did not differ from healthy control subjects with respect to type 1 diabetes protective haplotype HLA DRB1*1502-DQB1*0601. A total of 13% of the GADab(+) patients with diabetes had genotypes comprising the DRB1*1501-DQB1*0602 or *1502-*0601 and were characterized by old age at onset of diabetes, high BMI, resistance to the insulin-deficient state, low titer of GADab, and low frequency of other organ-specific autoantibodies. CONCLUSIONS: We conclude that GADab(+) non-insulin-deficient patients differ from GADab(+) patients with insulin deficiency with respect to clinical characteristics, humoral autoimmunity to other organ-specific autoantibodies, as well as HLA class II genes.     

Effects of prostaglandin E1 infusion in the pre-operative management of critical congenital heart disease

Prostaglandin E1 (PGE1) was administered to 27 infants in whom pulmonary or systemic blood flow was entirely or significantly dependent upon the patency of the ductus arteriosus. In 12 patients with pulmonary atresia or severe pulmonary stenosis, PGE1 infusion was followed by an improvement in hypoxemia and acidemia (group I). In 2 patients with left ventricular outflow-tract obstruction, PGE1 infusion was followed by an improvement in arterial blood pressure, peripheral perfusion and urine output (group II). In 5 patients with d-transposition of the great arteries and intact ventricular septum who had persistent severe hypoxemia after creation of an interatrial communication, PGE1 infusion improved the arterial oxygenation with dilatation of the ductus arteriosus (group III). Seven patients (3 of group I, 2 of group II and 2 of group III) failed to respond to PGE1. There were no fatal side effects. It is concluded that PGE1 therapy is highly effective in stabilizing pre-operative conditions of infants with ductus-dependent congenital heart disease.     

Peginterferon‐alpha‐2b plus ribavirin therapy in patients with chronic hepatitis C as assessed by a multi‐institutional questionnaire in Japan

Background and aim: There has so far been no questionnaire report on patients who were treated with peginterferon plus ribavirin (PEG IFN+RBV) therapy. The purpose of this study was to investigate the problems of this therapy by a questionnaire survey. Patients and methods: A survey of 681 patients with chronic hepatitis C who received treatment with PEG IFN+RBV was conducted in the Kyushu region of Japan. Using an original questionnaire, the survey was conducted prior to the treatment, during the third month of treatment, at the completion of treatment or the discontinuation of treatment, and at 6 months after the completion of treatment. Results: It was indicated that the patients had a high level of comprehension and understanding of chronic hepatitis C and PEG IFN+RBV treatment. However, the results also indicated that patients had a high level of anxiety. Side effects were adequately dealt with by physicians. However, dermatological symptoms were not adequately explained to the patients, although they were the second most severe side‐effect. It was also revealed that side‐effects were most distressing during the first and second months after the start of treatment. Conclusion: The questionnaire survey provided new information that has never been reported. It is believed that understanding this information is important for future treatment.     

Interleukin-33 expression is specifically enhanced in inflamed mucosa of ulcerative colitis

Background   

Interleukin (IL)-33 is a cytokine belonging to the IL-1 family. IL-33 has been shown to elicit a Th2-like cytokine response in immune cells. In this study, we investigated IL-33 expression in the inflamed mucosa of patients with inflammatory bowel disease (IBD), and characterized the molecular mechanisms responsible for IL-33 expression in human colonic subepithelial myofibroblasts (SEMFs).     

CXCL12 and CCL20 play a significant role in mucosal T-lymphocyte adherence to intestinal microvessels in mice

OBJECTIVE: Although it is known that the chemokines CXCL12 and CCL20 are expressed in the intestine, their contribution to lymphocyte homing has not been investigated in detail. The authors investigated whether the CXCL12-CXCR4 and CCL20-CCR6 systems are involved in T lymphocyte-endothelial interaction in microvessels of the small and large intestines. METHODS: Labeled lamina proprial lymphocytes (LPLs) were administered to mice, and their adhesion to microvessels of normal and TNF-alpha -induced inflamed intestinal mucosa was observed under an intravital microscope. Antibodies against CXCL12, CCL-20, or CCL-25 were administered prior to lymphocyte administration, and in some experiments CXCR4 or CCR6 on LPLs was desensitized with an excess amount of chemokine. RESULTS: LPLs adhered to microvessels of the ileum and colon, and TNF-alpha induced a significant accumulation at both sites. Blocking of the CXCL12-CXCR4 system significantly inhibited the LPL adhesion in the ileum and colon under both normal and TNF-alpha -treated conditions. However, blocking of the CCL20-CCR6 system significantly attenuated LPL adhesion only under a TNF-alpha -treated condition. There was an additive inhibitory effect on LPL adherence by CXCL12 and CCL20 blocking in TNF-alpha -induced inflamed intestines. There was also an additive function of the CCL25-CCR9 system in LPL accumulation in the small intestine. CONCLUSION: Several chemokine systems may play significant roles cooperatively in vivo in LPL adherence to microvessels of intestinal mucosa.     

Agitated depression successfully treated with electroconvulsive therapy combined with steroid cover in a patient with Addison's disease

We report the case of a 70-year-old man with Addison's disease who developed severe agitated depression resulting in life-threatening medical conditions. The depression was treated safely with electroconvulsive therapy (ECT) combined with steroid cover. Administration of steroid cover just before each ECT session may increase safety of the ECT procedure in psychiatric patients with Addison's disease.     

Wnt-5a signaling is correlated with infiltrative activity in human glioma by inducing cellular migration and MMP-2

Wnts are secreted ligands that consist of 19 members in humans, regulate cell proliferation, differentiation, motility and fate in many stages including the embryonic stage and tumorigenesis. Wnts bind to cell surface receptors named Frizzleds and LRPs, and transduce their signals through β-catenin-dependent and -independent intracellular pathways. Gliomas are one of the most common intracranial tumors. Gliomas exhibit a progression associated with widespread infiltration into surrounding neuronal tissues. However, the molecular mechanisms that stimulate the invasion of glioma cells are not fully understood. We established two cell lines from human glioma cases and analyzed the expression of all Wnt and Frizzled members in these cell lines and other well-known glioma cell lines by real-time PCR study. The mRNA of Wnt-5a and -7b and Frizzled-2, -6 and -7 were overexpressed in glioma cells. The elevation of Wnt-5a expression was most remarkable. Although Wnt-5a is reported to have oncogenic and antioncogenic activity in several cancers, the role of Wnt-5a signaling in human glioma cells remains unclear. Immunohistochemical study also revealed high expression of Wnt-5a in 26 (79%) of 33 human glioma cases. The positivity of Wnt-5a expression was correlated with the clinical grade. Knockdown of Wnt-5a expression suppressed migration, invasion and expression of matrix metalloproteinase-2 of glioma cells. Reciprocally, treatment with purified Wnt-5a ligand resulted in stimulation of cell migration and invasion. MMP-2 inhibitor suppressed the Wnt-5a-dependent invasion of U251 cells. These results suggested that Wnt-5a is not only a prognostic factor but also a therapeutic target molecule in gliomas for preventing tumor cell infiltration.     

A case of antiphospholipid syndrome with cutaneous ulcer and intrauterine fetal growth retardation

A 28-year-old patient presented with severe intrauterine fetal growth retardation (IUGR) at 34 weeks' gestation. There was a prior history of a recurrent cutaneous ulcer on the left thigh. Serological tests for IgG anticardiolipin antibody were positive. A live premature male infant was delivered by an urgent cesarean section because of fetal distress. Histopathological examination revealed that the causes of the cutaneous ulcer and IUGR were thrombosis of the small blood vessels and placental infarction, respectively. Early diagnosis and proper treatment are important in the management of the antiphospholipid syndrome.