Comparison of pregnancy outcomes between women with gestational diabetes and overt diabetes first diagnosed in pregnancy: a retrospective multi-institutional study in Japan.

AIMS: To determine differences in pregnancy outcomes including diabetic complications, maternal and perinatal complications between gestational diabetes mellitus and overt diabetes in pregnancy in Japan. METHODS: A multi-institutional retrospective study compared pregnancy outcomes between gestational diabetes mellitus and overt diabetes in pregnancy. We examined pregnant women who met the former criteria for gestational diabetes mellitus and received dietary intervention with self-monitoring of blood glucose with or without insulin. Overt diabetes in pregnancy was defined as ≥2 abnormal values on 75-g oral glucose tolerance test, fasting glucose ≥126 mg/dl (7.0 mmol/l) and 2-h postprandial glucose ≥200 mg/dl (11.1 mmol/l), or glycated hemoglobin levels ≥6.5% (48 mmol/mol). RESULTS: Data were collected on 1267 women with gestational diabetes and 348 with overt diabetes in pregnancy. Pregestational body mass index was higher (26.2 ± 6.1 vs. 24.9 ± 5.7 kg, P<0.05) and gestational age at delivery was earlier (37.8 ± 2.5 weeks vs. 38.1 ± 2.1 weeks, P<0.05) in overt diabetes than in gestational diabetes. Glycated hemoglobin (6.8 ± 1.1% [51 mmol/mol] vs. 5.8 ± 0.5% [40 mmol/mol], P<0.05) and glucose on 75-g oral glucose tolerance test and prevalence of retinopathy (1.2% vs. 0%, P<0.05) and pregnancy-induced hypertension (10.1% vs. 6.1%, P<0.05) were higher in overt diabetes than in gestational diabetes. Pregnancy-induced hypertension was associated with pregestational body mass index, gestational weight gain, chronic hypertension, and nulliparity but not with 75-g oral glucose tolerance test. CONCLUSIONS: Overt diabetes in pregnancy is significantly associated with maternal complications such as retinopathy and pregnancy-induced hypertension.

Genetic deletion of granzyme B does not confer resistance to the development of spontaneous diabetes in non-obese diabetic mice.

Granzyme B (GzmB) and perforin are proteins, secreted mainly by natural killer cells and cytotoxic T lymphocytes that are largely responsible for the induction of apoptosis in target cells. Because type 1 diabetes results from the selective destruction of ß cells and perforin deficiency effectively reduces diabetes in non-obese diabetic (NOD) mice, it can be deduced that ß cell apoptosis involves the GzmB/perforin pathway. However, the relevance of GzmB remains totally unknown in non-obese diabetic (NOD) mice. In this study we have focused on GzmB and examined the consequence of GzmB deficiency in NOD mice. We found that NOD.GzmB(-/-) mice developed diabetes spontaneously with kinetics similar to those of wild-type NOD (wt-NOD) mice. Adoptive transfer study with regulatory T cell (Treg )-depleted splenocytes (SPCs) into NOD-SCID mice or in-vivo Treg depletion by anti-CD25 antibody at 4 weeks of age comparably induced the rapid progression of diabetes in the NOD.GzmB(-/-) mice and wt-NOD mice. Expression of GzmA and Fas was enhanced in the islets from pre-diabetic NOD.GzmB(-/-) mice. In contrast to spontaneous diabetes, GzmB deficiency suppressed the development of cyclophosphamide-promoted diabetes in male NOD mice. Cyclophosphamide treatment led to a significantly lower percentage of apoptotic CD4(+) , CD8(+) and CD4(+) CD25(+) T cells in SPCs from NOD.GzmB(-/-) mice than those from wt-NOD mice. In conclusion, GzmB, in contrast to perforin, is not essentially involved in the effector mechanisms for ß cell destruction in NOD mice.

Double deficiency in IL-17 and IFN-γ signalling significantly suppresses the development of diabetes in the NOD mouse.

AIMS/HYPOTHESIS: T helper type (Th) 17 cells have been shown to play important roles in mouse models of several autoimmune diseases that have been classified as Th1 diseases. In the NOD mouse, the relevance of Th1 and Th17 is controversial, because single-cytokine-deficient NOD mice develop diabetes similarly to wild-type NOD mice. METHODS: We studied the impact of IL-17/IFN-γ receptor double deficiency in NOD mice on the development of insulitis/diabetes compared with IL-17 single-deficient mice and wild-type mice by monitoring diabetes-related phenotypes. The lymphocyte phenotypes were determined by flow cytometric analysis. RESULTS: IL-17 single-deficient NOD mice showed delayed onset of diabetes and reduced severity of insulitis, but the cumulative incidence of longstanding diabetes in the IL-17-deficient mice was similar to that in wild-type mice. The IL-17/IFN-γ receptor double-deficient NOD mice showed an apparent decline in longstanding diabetes onset, but not in insulitis compared with that in the IL-17 single-deficient mice. We also found that double-deficient NOD mice had a severe lymphopenic phenotype and preferential increase in regulatory T cells among CD4(+) T cells compared with the IL-17 single-deficient mice and wild-type NOD mice. An adoptive transfer study with CD4(+)CD25(-) T cells from young non-diabetic IL-17 single-deficient NOD mice, but not those from older mice, showed significantly delayed disease onset in immune-deficient hosts compared with the corresponding wild-type mice. CONCLUSIONS/INTERPRETATION: These results indicate that IL-17/Th17 participates in the development of insulitis and that both IL-17 and IFN-γ signalling may synergistically contribute to the development of diabetes in NOD mice.

[Perioperative management of three patients with streptococcal toxic shock syndrome].

We report the perioperative management of three patients with streptococcal toxic shock syndrome (STSS) caused by group A streptococcal infection. Three of two patients survived but one patient died from multiple organ dysfunction in spite of vigorous treatments. These patients required the treatments including administration of antibiotics, circulatory and respiratory care, surgical debridement, anticoagulant therapy for disseminated intravascular coagulation and hemofiltration. The early diagnosis and surgical intervention play a key role in the successful management of this syndrome because it has a rapid course and frequent fatal outcome. The anesthetic management of these patients should be targeted to maintain perfusion of the vital organs and to control the blood clotting disorders.

Biotransformation of (-)-dihydromyrcenyl acetate using the plant parasitic fungus Glomerella cingulata as a biocatalyst.

The microbial transformation of (-)-dihydromyrcenyl acetate was investigated using the plant parasitic fungus Glomerella cingulata. As a result, (-)-dihydromyrcenyl acetate was converted to dihydromyrcenol, 3,7-dihydroxy-3,7-dimethyl-1-octene-7-carboxylate, 3,7-dihydroxy-3,7-dimethyl-1-octene, 3,7-dimethyloctane-1,2, 7-triol-7-carboxylate, and 3,7-dimethyloctane-1,2,7-triol. In addition, microbial transformation of dihydromyrcenol by G. cingulata was carried out. The metabolic pathway of (-)-dihydromyrcenyl acetate is discussed.

Efficacy of troglitazone on body fat distribution in type 2 diabetes.

OBJECTIVE: The insulin-sensitizing action of troglitazone may be mediated through the activation of peroxisome proliferator-activated receptor-gamma (PPAR-gamma) and the promotion of preadipocyte differentiation in adipose tissue on which troglitazone has depot-specific effects. We investigated the relationship between efficacy of the drug and body fat distribution. Changes in body fat distribution were also investigated by long-term administration of the drug. RESEARCH DESIGN AND METHODS: Troglitazone was given at a dose of 400 mg/day to 20 patients with type 2 diabetes whose diet and sulfonylurea therapy produced unsatisfactory glycemic control (HbA(1c) >7.8%) and whose insulin secretory capacity was found to be preserved (postprandial C-peptide >3 ng/ml). HbA(1c) values, serum lipid levels, and body weight were measured monthly Body fat distribution was evaluated in subcutaneous (SC) and visceral fat using a computed tomography scan at umbilical levels before and after troglitazone therapy RESULTS: During the 1-year troglitazone treatment, HbA(1c) was significantly decreased (from 9.2 +/- 0.2 to 7.1 +/- 0.2%, P < 0.01), showing lowest values at 4-6 months, whereas body weight was significantly increased (BMI 24.6 +/- 0.6 to 25.7 +/- 0.6 kg/m2, P < 0.01). Reduction of HbA(1c) (deltaHbA(1c)) from the baseline value during treatment was significantly greater in obese patients (BMI >26 kg/m2) than in nonobese patients (-3.2 +/- 0.4 vs. -2.1 +/- 0.3%, P < 0.05) and was more significant in women than in men (-3.2 +/- 0.2 vs. - 1.4 +/- 0.2%, P < 0.01). The level of deltaHbA(1c) during treatment showed a significant negative correlation with SC fat area (r = -0.742, P < 0.01) but not with visceral fat area. Weight gain during troglitazone treatment resulted in increased accumulation of SC fat without a change in visceral fat area and, consequently. in a significant decrease in the visceral-to-SC fat ratio. CONCLUSIONS: Predominant accumulation of SC fat for the visceral fat tissue was an important predictor of the efficacy of troglitazone therapy in patients with type 2 diabetes. Greater efficacy of troglitazone was observed in women who were characterized by more accumulation of SC adipose tissue than men. Long-term administration of the drug resulted in weight gain with increased accumulation of SC adipose tissue, probably because of the activation of PPAR-gamma in the region.

[Metachronous bilateral primary malignant lymphoma of the testis: a case report].

A 72-year-old man was referred to our department with the chief complaint of painless swelling of the left scrotum in May 1997. Left high orchiectomy was performed under the diagnosis of primary testicular tumor. Histological findings revealed non-Hodgkin's lymphoma (NHL) of diffuse, mixed type, B cells. No evidence of tumors in any other site was detected by further examinations. About 3 years and a month earlier, he had undergone right high orchiectomy and postoperative radiotherapy (inverted Y irradiation) and chemotherapy (CHOP 5 cycles) for a right testicular tumor whose histological findings were NHL of diffuse, large cell type, B cells. Metachronous bilateral primary malignant lymphoma of the testis is very rare and we discussed each tumor origin by using IgH gene (IgJHDNA) rearrangement as a tumor specific marker of B cell lineage malignant lymphoma. We discussed the clonality of IgJHDNA rearrangement using polymerase chain reaction (PCR) in each paraffin fragment diagnosed pathologically as NHL of B cell origin.

Autoantibodies to multiple islet autoantigens in patients with abrupt onset type 1 diabetes and diabetes diagnosed with urinary glucose screening.

It has been reported that there is a heterogeneity in the clinical course of Japanese patients with type 1 diabetes. To elucidate the associations of expression of autoantibodies to multiple islet antigens with age of onset and mode of diagnosis of diabetes in Japanese patients with type 1 diabetes, autoantibodies against the protein tyrosine phosphatase-like molecules ICA512 (IA-2) and phogrin (IA-2beta) (ICA512/phogrin-A), GAD (GADA), insulin (IAA), and islet cell cytoplasm (ICA) were determined in sera from 73 Japanese patients with type 1 diabetes obtained within 14 days of diagnosis. Patients were divided into groups based on the age of onset (10 years, n=49) or the mode of onset (abrupt onset, n=59 and urinary screening identified, n=14). Of 73 new-onset patients with type 1 diabetes, 43 (59%) and 32 (44%) had ICA512A and phogrin-A levels exceeding the 99th percentile of 184 normal control subjects, respectively. Forty-five patients (62%) were positive for either ICA512A or phogrin-A. The frequencies for other autoantibodies were 71% for GADA, 48% for IAA, and 62% for ICA. The frequency of ICA512/phogrin-A was significantly higher in patients with an age of onset less than 10 years (83%) than in patients aged >10 years (51%, P<0.01). The positivity of ICA512/phogrin-A was less in patients whose diabetes was diagnosed by the urine glucose screening test (21%, P<0.001) than in abrupt onset patients (71%). Combined analysis (>/=1 antibody) of GADA, IAA, and ICA512/phogrin-A detected 88% of abrupt onset and 93% of screening-positive patients vs. 70% and 29%, respectively, for ICA (P<0.0005). These results indicate that the expression of ICA512/phogrin-A and cytoplasmic ICA is less in patients identified by urinary glucose testing but indicate that with combined autoantibody testing 90% of patients can be identified independent of the mode of diagnosis.

Association between drinking-related antisocial behavior and a polymorphism in the serotonin transporter gene in a Japanese population.

BACKGROUND: Involvement of the serotoninergic system (S/S) in alcoholism has been suggested in both mice and humans. Previous studies have suggested the S/S genotype of the serotonin transporter gene promoter polymorphism to be associated with severe alcohol dependence marked by severe withdrawal symptoms. It has also been associated with alcoholics who exhibit a dissocial personality disorder. METHODS: We examined the polymorphism in 166 Japanese alcoholics who experienced withdrawal seizure or delirium and 290 Japanese controls. RESULTS: The S/S genotype was not increased in the patients. Exploratory analyses showed significantly less frequent S allele and S/S genotype frequencies in the alcoholics with a history of drinking-related arrests than in the controls (p = 0.009 and p = 0.03, respectively), perhaps reflecting previously reported harm avoidance personality traits associated with S/S. Alcoholics with the L allele had a significantly earlier onset of alcohol dependence than those with the S/S genotype (p = 0.01). CONCLUSIONS: The present study failed to provide supportive evidence for an association of the S/S genotype with severe alcoholism marked by physical withdrawal symptoms or with antisocial behaviors among the Japanese. Although our data support involvement of the central serotoninergic system in some types of alcoholism, the potential association findings of this study emerged as only exploratory and, therefore, should be understood as tentative until replicated in other studies.

[Primary treatment for stage D2 prostate cancer: a randomized study of combined androgen blockade alone versus combined with UFT].

To evaluate the efficacy of chemoendocrine therapy for the initial treatment of stage D2 prostate cancer, we conducted a prospective randomized study which compared combined androgen blockade alone to that combined with UFT. Twenty-one patients received LH-RH agonist and flutamide (Group-A), and 23 patients received LH-RH agonist, flutamide and UFT (Group-B). The overall response rate and the PSA response rate of Group-A was 71.4% and 100% respectively, against 65.2% and 90%, respectively in Group-B. The median follow-up period was 24 months. The 2-year progression-free survival rate of Group-A was 7.4% and that of Group-B was 15.9%. The response rate and progression-free survival rate did not differ significantly between the 2 groups. Liver dysfunction due to flutamide was common in both groups, and a total of 4 patients did not continue the treatment because of this adverse effect. We conclude that in patients with stage D2 prostate cancer, treatment with combined androgen blockade and UFT is not superior to treatment with combined androgen blockade alone.

[Comparison of five patient-controlled analgesia drug delivery devices].

We report the performance and our impression of five patient-controlled analgesia (PCA) drug delivery devices commercially available; Atom PCA Pump 500, AP-II, Deltec CADD-PCA 5800, Sabratek 6060 and Verifuse. Each of these devices has unique features for PCA. However, these devices still leave some room for improvement. Especially, we hope that future devices will be lighter to carry and use dry batteries more economically. In order to use these devices effectively for the management of pain, it is important to understand their characteristics.

Significance of glutathione-dependent antioxidant system in diabetes-induced embryonic malformations.

Hyperglycemia-induced embryonic malformations may be due to an increase in radical formation and depletion of intracellular glutathione (GSH) in embryonic tissues. In the past, we have investigated the role of the glutathione-dependent antioxidant system and GSH on diabetes-related embryonic malformations. Embryos from streptozotocin-induced diabetic rats on gestational day 11 showed a significantly higher frequency of embryonic malformations (neural lesions 21.5 vs. 2.8%, P<0.001; nonneural lesions 47.4 vs. 6.4%, P<0.001) and growth retardation than those of normal mothers. The formation of intracellular reactive oxygen species (ROS), estimated by flow cytometry, was increased in isolated embryonic cells of diabetic rats on gestational day 11. The concentration of intracellular GSH in embryonic tissues of diabetic pregnant rats on day 11 was significantly lower than that of normal rats. The activity of y-glutamylcysteine synthetase (gamma-GCS), the rate-limiting GSH synthesizing enzyme, in embryos of diabetic rats was significantly low, associated with reduced expression of gamma-GCS mRNA. Administration of buthionine sulfoxamine (BSO), a specific inhibitor of gamma-GCS, to diabetic rats during the period of maximal teratogenic susceptibility (days 6-11 of gestation) reduced GSH by 46.7% and increased the frequency of neural lesions (62.1 vs. 21.5%, P<0.01) and nonneural lesions (79.3 vs. 47.4%, P<0.01). Administration of GSH ester to diabetic rats restored GSH concentration in the embryos and reduced the formation of ROS, leading to normalization of neural lesions (1.9 vs. 21.5%) and improvement in nonneural lesions (26.7 vs. 47.4%) and growth retardation. Administration of insulin in another group of pregnant rats during the same period resulted in complete normalization of neural lesions (4.3 vs. 21.5%), nonneural lesions (4.3 vs. 47.4%), and growth retardation with the restoration of GSH contents. Our results indicate that GSH depletion and impaired responsiveness of GSH-synthesizing enzyme to oxidative stress during organogenesis may have important roles in the development of embryonic malformations in diabetes.

[Postoperative prophylactic intravesical instillation of tetrahydropyranyl-adriamycin (THP) for superficial bladder cancer].

Intravesical instillation of tetrahydropyranyl-adriamycin (THP) was performed on 51 patients with superficial bladder cancer after transurethral resection (TUR) for prophylaxis of recurrence. The instillation was carried out with 20 mg of THP dissolved in 40 ml of distilled normal saline. Instillation was performed once 24 hours postoperatively, 9 times every 2 weeks, and 8 times every 4 weeks. These drugs were instilled for 30 to 60 minutes. The recurrence-free survival at 1, 2 and 3 years was 74.5%, 64.6% and 58.0%, respectively. Side effects of THP instillation were observed in only 4 cases (7.8%) as slight urinary frequency or micturition pain. Cases involving 5 or more tumors, or tumors measuring 3 cm or larger, more frequently demonstrated recurrence. The cases that did not respond to preoperative intravesical instillation of THP demonstrated a high frequency of recurrence. Intravesical instillation of THP as a prophylaxis against recurrence of superficial bladder cancer was effective in selected patients.

Immunohistochemical detection of thymidylate synthase in advanced gastric cancer: a prognostic indicator in patients undergoing gastrectomy followed by adjuvant chemotherapy with 5-fluoropyrimidines.

To investigate prognostic indicators for gastric adenocarcinomas in advanced stage, we have carried out immunohistochemical determination of thymidylate synthase (TS) in carcinoma tissues. Sixty seven cases of curatively resected gastric carcinoma, under 70 years old at the time of surgery, who had been in the same grade of invasion and lymph nodal involvements (pT3/pN2, Stage IIIB), and had underwent postoperative 5FU-related chemotherapy for a long period were extracted from the files of our hospital. Formalin-fixed and paraffin-embedded specimens were stained with an antibody for human TS (polyclonal). A positive signal was always compared with some types of inflammatory cells in the same slide because of their constantly strong signal. Normal control tissue used was human bone marrow containing blastic cells. Both staining intensity and the fraction of positively stained carcinoma cells were examined in each case, and then the results were summarized with respect to fraction of positively stained carcinoma cells. The present study indicates that the TS-negative group had better survival than the positive group (p < 0.05), the 5 year survival rates being 42.3% and 25.1%, respectively, which suggests that the frequency of TS-positive carcinoma cells could also be a prognostic indicator.