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Aim: Left ventricular (LV) diastolic dysfunction has been reported to be prevalent in diabetic subjects, but this recognition could often be missed. We evaluated prevalence of LV diastolic dysfunction and diagnostic utility of brain-natriuretic peptide (BNP) in asymptomatic patients with type 2 diabetes mellitus. Research design and methods: Plasma BNP levels and LV geometry and diastolic filling indices, including the ratio of peak early transmitral Doppler flow (E) over flow propagation velocity (Vp) measured by colour M-mode Doppler echocardiography, were analysed in 98 consecutive asymptomatic patients with type 2 diabetes mellitus and 51 age-matched controls. Results: The LV mass index and relative wall thickness were higher in diabetic groups than controls without any differences in LV systolic function. The frequency of diastolic dysfunction defined as E/Vp ≥ 1.5 were 31% in diabetic groups and 15% in controls (χ2 = 4.364, p = 0.037). By receiver-operating characteristic (ROC) curve analysis, a BNP cutoff value of 19.2 pg/ml in controls had a 53.1% positive predictive value (53.1%) and a high negative predictive value (94.4%) for E/Vp ≥ 1.5, whereas a BNP cutoff value of 18.1 pg/ml in diabetic groups had a 61.8% positive and 97.3% negative predictive values. Conclusions: The frequency of E/Vp ≥ 1.5 was higher in asymptomatic diabetic patients, suggesting that LV diastolic dysfunction was prevalent. The plasma concentration of BNP could be used to depict LV diastolic dysfunction in such population. [ABSTRACT FROM AUTHOR]

Aim: This study was conducted to clarify cell death and survival signals in pancreatic β-cell lipotoxicity. Methods: Rat insulinoma INS-1 cells, with or without expression of dominant-negative mutant of Akt (K179M), were cultured with palmitate (C16:0) or oleate (C18:1) and cell numbers were determined by 0.2% eosin dye exclusion assay. The Akt activity was determined by anti-3′-phospho-inositide-dependent protein kinase (Akt)/protein kinase B (PKB) or anti-phospho-Akt (Serine 473) immunoblotting, and nuclear protein nuclear factor-kB (NF-κB)-binding activity was by supershift analysis. Results: Twenty-four hours treatment with palmitate increased the INS-1 cell number at 0.1–0.2 mm but decreased the cell number at 0.5–1 mm. Oleate did not affect cell number at 0.1–1.0 mm. Palmitate dose-dependently increased phosphorylation of 473th serine in Akt/PKB. The K179M form of Akt/PKB abolished palmitate-induced cell proliferation at the low dose and death at the high dose. Nuclear protein NF-κB binding was enhanced at 0.2 and 0.5 mm of palmitate but decreased at 1.0 mm. Conclusion: Results suggest that Akt/PKB signalling is involved in palmitate-induced cell death and survival of pancreatic β cell. [ABSTRACT FROM AUTHOR]

Tumour necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL) induces apoptosis in many transformed cells, but not in normal cells, and hence TRAIL has recently emerged as a novel anti-cancer agent. Adult T-cell leukaemia lymphoma (ATLL) is a neoplasm of T-lymphocyte origin aetiologically associated with human T-lymphotropic virus type 1 (HTLV-I), and is resistant to standard anti-cancer therapy. We thus characterized the sensitivity of ATLL cells to TRAIL in this study. Although most primary ATLL cells and cell lines expressed TRAIL death receptors on their surface, they showed only restricted sensitivity to TRAIL. Among the 10 ATLL cell lines examined, one was sensitive, but two had insufficient death-receptor expression, two had an unknown resistant mechanism with abrogation of the death signal upstream of caspase-8, and the remaining five showed attenuation of the signal in both extrinsic and intrinsic pathways by X-linked inhibitor of apoptosis and Bcl-2/Bcl-xL respectively. Furthermore, the level of HTLV-I tax expression was significantly correlated to TRAIL resistance. Interestingly, ATLL cells themselves expressed TRAIL on the cell surface. Constitutive production of TRAIL may offer resistance, thus allowing the development of TRAIL-resistant ATLL cells. Consequently, the resistant mechanism in ATLL cells against TRAIL was assigned to multiple factors and was not explained by a definitive single agent. [ABSTRACT FROM AUTHOR]

AIMS: This randomized crossover placebo-controlled study aimed to assess the efficacy of nateglinide, a phenylalanine-derived insulin secretagogue, on forearm endothelial function in diabetic subjects before and after an oral glucose load. METHODS: Forearm blood flow (FBF) was measured using strain-gauge plethysmography during reactive hyperaemia before and after an oral glucose load (75 g) with a prior use of placebo or nateglinide (90 mg) in 15 diet-treated Type 2 diabetic patients or age-matched controls with normal glucose tolerance. RESULTS: The peak FBF response and total reactive hyperaemic flow (flow debt repayment: FDR), indices of resistance artery endothelial function, were decreased after an oral glucose load in diabetic patients, but unchanged in controls. Nateglinide administered to diabetic patients accelerated insulin secretion and reduced post-challenge plasma glucose, and also abolished the post-challenge impairment of endothelial function. The peak FBF and FDR were well correlated with 120-min glucose levels and 30-min insulinogenic index. CONCLUSIONS: A single challenge of glucose was shown to impair endothelial function in diabetic patients, and the post-challenge endothelial dysfunction was improved by a prior use of nateglinide. Long-term effects of nateglinide on endothelial function in Type 2 diabetic patients need to be clarified in future studies. [ABSTRACT FROM AUTHOR]

Group IB secretory phospholipase A[sub 2] (sPLA[sub 2]-IB) mediates cell proliferation, cell migration, hormone release and eicosanoid production via its receptor in peripheral tissues. In the CNS, high-affinity binding sites of sPLA[sub 2]-IB have been documented. However, it remains obscure whether sPLA[sub 2]-IB causes biologic or pathologic response in the CNS. To this end, we examined effects of sPLA[sub 2]-IB on neuronal survival in primary cultures of rat cortical neurons. sPLA[sub 2]-IB induced neuronal cell death in a concentration-dependent manner. This death was a delayed response requiring a latent time for 6 h; sPLA[sub 2]-IB-induced neuronal cell death was accompanied with apoptotic blebbing, condensed chromatin, and fragmented DNA, exhibiting apoptotic features. Before cell death, sPLA[sub 2]-IB liberated arachidonic acid (AA) and generated prostaglandin D[sub 2] (PGD[sub 2]) from neurons. PGD[sub 2] and its metabolite, Δ12-PGJ[sub 2], exhibited neurotoxicity. Inhibitors of sPLA[sub 2] and cyclooxygenase-2 (COX-2) significantly suppressed not only AA release, but also PGD[sub 2] generation. These inhibitors significantly prevented neurons from sPLA[sub 2]-IB-induced neuronal cell death. In conclusion, we demonstrate a novel biological response, apoptosis, of sPLA[sub 2]-IB in the CNS. Furthermore, the present study suggests that PGD[sub 2] metabolites, especially Δ12-PGJ[sub 2], might mediate sPLA[sub 2]-IB-induced apoptosis. [ABSTRACT FROM AUTHOR]

Calcinosis universalis associated with dermatomyositis occurred in a 58-year-old woman. Tissues removed from the sublingual region in the patient were studied by ordinary microscopy, electron microscopy, and an electron-microanalytic method. The calcified materials were distributed on collagen fibers and seemed to have a relationship with foci of fibrinoid degeneration. Moreover, globular and/or membranous structures, considered to originate from the degenerate cells of the stroma, were observed in these calcified zones. Some of them contained electron-dense materials. Therefore, the globular and/or membranous structures were thought to be concerned with initial calcification in this case. Furthermore, irregular bone tissue was formed adjacent to the calcified masses. In addition, the calcified materials were identified by X-ray diffraction examination and electron microscopy as hydro- xyapatite. [ABSTRACT FROM AUTHOR]

Presents a response by Y. Ohshiro and N. Takasu to a letter to the editor about their article on the role of sustained hypoglycemia in causing brain injury.

One of the clinical features of myotonic dystrophy is insulin resistance with non-obese diabetes mellitus (DM). Recently, the mechanism of insulin resistance in patients with myotonic dystrophy was revealed. The optimal treatment of DM with myotonic dystrophy has not been established. We report the effect of metformin in a patient with myotonic dystrophy without obesity.A 58-year-old woman (BMI= 22.1 kg/m2) with myotonic dystrophy and DM was followed at our clinic. She had been treated with glimepiride for DM for the last 6 months, without achieving good control (HbA1c 9.3%). She was admitted with congestive heart failure and cholecystitis. She was treated with diuretics, antibiotics and insulin. As her blood glucose fell, we discontinued insulin and started glimepiride, but her glycaemic control had worsened. We started metformin instead of glimepiride. After 4 weeks of metformin, HbA1c was decreased to 7.4%, while HOMA-IR during glimepiride treatment was 4.9, and 3.7 with metformin. Three months later, HbA1c was maintained (7.5%).It is important to choose the optimal treatment for DM in myotonic dystrophy, because the patients have hyperinsulinemia caused by specific mechanism and could not reduce the insulin resistance. Metformin improved hyperglycemia through increased insulin-independent glucose uptake in peripheral muscle. We believe metformin is the optimal agent for these patients.Diabet. Med. 22, 346–347 (2005) [ABSTRACT FROM AUTHOR]

Presents a letter to the editor, on the role of nitroglycerin spray to reduce pain in a patient with chronic painful diabetic neuropathy.

The development of hemiplegia as a result of hypoglycaemia was first described in 1928. However, the mechanism remains unclear. We report a case of a 58-year-old male with diabetes, who developed left hemiplegia during a severe hypoglycaemic event. Diffusion-weighted magnetic resonance imaging detected an increased signal intensity in the pons, indicating that the patient's hemiplegia resulted from acute brain injury. This report provides evidence that acute brain injury may be a cause of the neurological deficit. Diabet. Med. 21, 623–624 (2004) [ABSTRACT FROM AUTHOR]

Primary adrenal lymphoma (PAL) is very rare; the majority of cases reported previously were of B-cell origin. We report a rare case of primary adrenal adult T-cell leukemia/lymphoma (primary adrenal ATLL). ATLL is a highly aggressive T-cell type non-Hodgkin's lymphoma and etiologically associated with human T-cell lymphotropic virus 1 (HTLV-1). Most ATLL patients present with leukemia and widespread lymphadenopathy. A 37-year-old Japanese woman presented with back pain in January 2004. Examination showed no peripheral lymphadenopathy, circulating lymphoma cells, hepatosplenomegaly, and skin lesions. Imaging studies demonstrated large adrenal masses bilaterally. Subsequently, she underwent open adrenal biopsy and pathological diagnosis was confirmed as T-cell lymphoma. The serum antibody to HTLV-1 was positive. Southern blot analysis detected monoclonal integration of proviral DNA of HTLV-1 into host genome in the biopsy specimen. The diagnosis of ATLL arising in adrenal glands was established. Despite repeated systemic chemotherapy, the patient died of progressive disease in December 2004. ATLL could primarily involve the adrenal gland and this disease entity should be included in the differential diagnosis of adrenal mass lesions.

Aim: This study was conducted to clarify cell death and survival signals in pancreatic beta-cell lipotoxicity., Methods: Rat insulinoma INS-1 cells, with or without expression of dominant-negative mutant of Akt (K179M), were cultured with palmitate (C16:0) or oleate (C18:1) and cell numbers were determined by 0.2% eosin dye exclusion assay. The Akt activity was determined by anti-3'-phospho-inositide-dependent protein kinase (Akt)/protein kinase B (PKB) or anti-phospho-Akt (Serine 473) immunoblotting, and nuclear protein nuclear factor-kB (NF-kappaB)-binding activity was by supershift analysis., Results: Twenty-four hours treatment with palmitate increased the INS-1 cell number at 0.1-0.2 mM but decreased the cell number at 0.5-1 mM. Oleate did not affect cell number at 0.1-1.0 mM. Palmitate dose-dependently increased phosphorylation of 473th serine in Akt/PKB. The K179M form of Akt/PKB abolished palmitate-induced cell proliferation at the low dose and death at the high dose. Nuclear protein NF-kappaB binding was enhanced at 0.2 and 0.5 mM of palmitate but decreased at 1.0 mM., Conclusion: Results suggest that Akt/PKB signalling is involved in palmitate-induced cell death and survival of pancreatic beta cell.

CCL20 is expected to play a crucial role in the initiation of immune responses and tumour growth. However, expression of CCL20 in Epstein-Barr virus (EBV)-associated diseases has not been studied. We examined the contribution of EBV infection and EBV-encoded latent membrane protein (LMP)-1 to CCL20 expression. EBV infection and LMP-1 induced CCL20 mRNA expression in the EBV-negative Burkitt lymphoma (BL) cell lines and the embryonic kidney cell line. Histone deacetylase inhibitor-stimulated endogenous LMP-1 also induced CCL20 expression in an EBV-positive BL cell line. Analysis of the CCL20 promoter showed that it was activated by LMP-1 C-terminal activation region (CTAR)-1 and CTAR-2. Co-expression of IkappaB alpha, IkappaB beta, IkappaB kinase (IKK)alpha, IKKbeta, IKKgamma, nuclear factor (NF)-kappaB-inducing kinase and tumour necrosis factor receptor-associated factor 2 dominant-negative constructs with LMP-1 inhibited the activation of the CCL20 promoter by LMP-1, suggesting that LMP-1 induces CCL20 via NF-kappaB signalling. The requirement for the NF-kappaB-binding site in the CCL20 promoter in LMP-1 responsiveness was established. Our results indicate that activation of the NF-kappaB pathway by LMP-1 is required for the activation of CCL20 expression.

The aim of the present study was to determine the usefulness of a newly developed thyroid-stimulating antibody (TSAb) assay. We developed a highly sensitive TSAb (sTSAb) assay with 22.5% polyethylene glycol-precipitated crude IgG. The thyroid-stimulating hormone (TSH) receptor antibody (TRAb) causes Graves' disease and TRAb has been measured as TSH-binding inhibitor immunoglobulin (TBII) and thyroid-stimulating antibody (TSAb). The TSAb stimulates the thyroid glands and causes hyperthyroidism. In addition to investigating the usefulness of the newly developed sTSAb assay, we also investigated the frequencies of positive TRAb in thyrotoxic patients with subacute thyroiditis, painless thyroiditis or a solitary toxic nodule. We studied 700 untreated Graves' patients with hyperthyroidism and 923 normal controls. We also studied thyrotoxic patients with subacute thyroiditis, painless thyroiditis or a solitary toxic nodule. Conventional TSAb (cTSAb) and sTSAb were measured as TSAb, whereas porcine TBII (pTBII) and human recombinant TBII (hTBII) were measured as TBII. Levels of cTSAb and sTSAb were determined in 923 normal controls and 629 untreated Graves' patients and cTSAb and sTSAb were found to be normally distributed in normal controls, but not in untreated Graves' patients. Receiver operating characteristic (ROC) curve analysis demonstrated that cTSAb and sTSAb had high sensitivity and specificity for Graves' disease. Of the patients investigated, 96.5% of untreated Graves' patients were positive for sTSAb and/or pTBII. Some untreated Graves' patients who were negative for cTSAb were positive for sTSAb. Paired determinations of cTSAb and sTSAb were performed in 146 untreated Graves' patients. A positive correlation was found between cTSAb and sTSAb. Titres of sTSAb were higher than those of cTSAb and sTSAb had high sensitivity. Of the 35 untreated Graves' hyperthyroid patients who were negative for cTSAb, 18 (51%) were positive for sTSAb. Of the 36 untreated Graves' patients who were negative for hTBII, nine (25%) were positive for sTSAb. Some untreated Graves' patients who were negative for cTSAb were positive for sTSAb and some who were negative for hTBII and pTBII were positive for sTSAb. 5. Some thyrotoxic patients with subacute thyroiditis or painless thyroiditis were positive for TRAb. However, the frequency of TRAb-positive patients was low in this group. None of the patients with a solitary toxic nodule was positive for TRAb. In conclusion, sTSAb had higher sensitivity than cTSAb. Graves' patients who were cTSAb negative and hTBII negative could be sTSAb positive. The sTSAb indicates TSAb activity, but pTBII and hTBII do not necessarily do so. We recommended that the sTSAb is used in Graves' patients.