Observation of Multi-TeV Gamma Rays from the Crab Nebula using the Tibet Air Shower Array.

The Tibet experiment, operating at Yangbajing (4300 m above sea level), is the lowest energy air shower array, and the new high-density array constructed in 1996 is sensitive to gamma-ray air showers at energies as low as 3 TeV. With this new array, the Crab Nebula was observed in multi-TeV gamma-rays and a signal was detected at the 5.5 sigma level.

A protein kinase C-beta-selective inhibitor ameliorates neural dysfunction in streptozotocin-induced diabetic rats.

Increased protein kinase C (PKC) activity has been implicated in the pathogenesis of diabetic retinopathy and nephropathy. However, the role of PKC in diabetic neuropathy remains unclear. The present study was conducted to compare the effect of PKC inhibition by a PKC-beta-selective inhibitor, LY333531 (LY), on diabetic nerve dysfunction with that of an aldose reductase inhibitor, NZ-314 (NZ).

An aldose reductase inhibitor prevents the glucose-induced increase in PDGF-beta receptor in cultured rat aortic smooth muscle cells.

To examine the role of platelet-derived growth factor (PDGF) and the polyol pathway in the growth activity of smooth muscle cells (SMCs), [(3)H]-thymidine incorporation, [(125)I]-PDGF-BB binding and expression of PDGF-beta receptor protein were measured in rat aortic SMCs cultured with 5.5 or 20 mM glucose with or without anti-PDGF antibody or an aldose reductase inhibitor, epalrestat. SMCs cultured with 20 mM glucose demonstrated an accelerated thymidine incorporation compared with SMCs cultured with 5.

Effect of vitamin E and allylamine on the proliferation of cultured aortic smooth muscle cells from streptozotocin-induced diabetic rats.

To investigate the effect of vitamin E on the proliferation activity of vascular smooth muscle cells (SMCs) in diabetes mellitus, [3H]-thymidine incorporation was measured in cultured SMCs isolated from normal and streptozotocin-induced diabetic rats treated with or without vitamin E and/or allylamine. Untreated diabetic rats demonstrated significantly elevated concentrations of serum total cholesterol, triglycerides and malondialdehyde (MDA). Allylamine caused a further increase in serum MDA.

Characterization of a newly found stretch-activated KCa,ATP channel in cultured chick ventricular myocytes.

With the use of the patch-clamp technique, five kinds of stretch-activated (SA) ion channels were identified on the basis of their single-channel conductances and ion selectivities in cultured chick ventricular myocytes. Because a high-conductance K+-selective channel predominated among these channels, we concentrated on characterizing its properties mostly using excised inside-out patches. With 145 mM KCl solution in the pipette and the bath, the channel had a conductance of 199.

Effect of aldose reductase inhibitors on glucose-induced changes in sorbitol and myo-inositol metabolism in human neutrophils.

Aim: To investigate the influence of glucose and the efficacy of two different aldose reductase (AR) inhibitors, epalrestat and SNK-860, on the polyol pathway and myo-inositol metabolism in human neutrophils.

Methods: We incubated neutrophils with various concentrations of glucose and AR inhibitors. The neutrophils from healthy volunteers were incubated in the media containing 5-40 mmol/l glucose with or without an AR inhibitor.

Risk factors for IgA nephropathy: a case-control study in Japan.

To disclose the risk factors for immunoglobulin A nephropathy (IgAN), we conducted a case-control study in the Tokai area of central Japan. The subjects were 94 patients, aged 20 years or older at diagnosis, who had histologically confirmed IgAN. Two sex-, age-, and residence-matched controls were randomly selected for each case from the general population.

Hyaluronan activates mitogen-activated protein kinase via Ras-signaling pathway.

Hyaluronan (HA) triggers a wide variety of cellular functions, yet its signaling pathway remains largely unclear. We found that HA-treatment of 3Y1 cells activated tyrosine phosphorylation of cellular proteins and mitogen-activated protein (MAP) kinase in a time- and dose-dependent manner, and, subsequently, stimulated cell growth. This HA-activity was resistant to boiling at 100 degrees C but completely abolished by treatment with hyaluronidase, suggesting that HA itself, but not any HA-associated proteins, has the activity.

Central nervous system-mediated hyperglycemic effects of NIK-247, a cholinesterase inhibitor, and MKC-231, a choline uptake enhancer, in rats.

We investigated the effects of intracerebroventricular administration of NIK-247 (9-amino-2,3,5,6,7,8-hexahydro-1H-cyclo-penta(b)-quinoline monohydrate hydrochloride; a cholinesterase inhibitor) or MKC-231 (2-(2-oxypyrrolidin-1-yl)-N-(2,3-dimethyl-5,6,7,8-tetrahydrofur o[2,3-b]quinolin-4-yl) acetoamide; a choline uptake enhancer) on plasma glucose level in comparison with that of neostigmine administration in rats. The extents of NIK-247- and MKC-231-induced hyperglycemia were considerably less than that by neostigmine, suggesting that the potencies of the drugs to produce the peripheral hyperglycemia may be pharmacologically negligible.

Regulation of intracellular free Mg2+ concentration in isolated rat hearts via beta-adrenergic and muscarinic receptors.

Regulation of the intracellular free magnesium concentration ([Mg2+]i) was investigated in isolated rat hearts, using 31P-nuclear magnetic resonance (31P-NMR). [Mg2+]i was found to be slowly and significantly decreased during prolonged application of isoproterenol (ISO) through beta-adrenergic receptor stimulation, and restored by subsequent washouts. The ISO-induced decrease in [Mg2+]i was antagonized by addition of a muscarinic receptor agonist, carbachol (CCh).

Polyol pathway hyperactivity is closely related to carnitine deficiency in the pathogenesis of diabetic neuropathy of streptozotocin-diabetic rats.

To investigate the relationship between polyol pathway hyperactivity and altered carnitine metabolism in the pathogenesis of diabetic neuropathy, the effects of an aldose reductase inhibitor, [5-(3-thienyl) tetrazol-1-yl]acetic acid (TAT), and a carnitine analog, acetyl-L-carnitine (ALC), on neural functions and biochemistry and hemodynamic factors were compared in streptozotocin-diabetic rats. Significantly delayed motor nerve conduction velocity, decreased R-R interval variation, reduced sciatic nerve blood flow and decreased erythrocyte 2, 3-diphosphoglycerate concentrations in diabetic rats were all ameliorated by treatment with TAT (administered with rat chow containing 0.05% TAT, approximately 50 mg/kg/day) or ALC (by gavage, 300 mg/kg/day) for 4 weeks.

Effects of propionyl-L-carnitine on cardiac dysfunction in streptozotocin-diabetic rats.

The effects of orally administered propionyl-L-carnitine on cardiac dysfunction in rats with streptozotocin-induced diabetes were investigated. Wistar male rats were divided into four groups: untreated normal, propionyl-L-carnitine (daily for 4 weeks with 3 g/kg orally) -treated normal, untreated diabetic, propionyl-L-carnitine-treated diabetic. Four weeks after streptozotocin administration, plasma lipid levels were increased and myocardial carnitine content was decreased in untreated diabetic rats.

The incidence and characteristics of silent cerebral infarction in elderly diabetic patients: association with serum-soluble adhesion molecules.

The purpose of this study was to investigate the relationship between complications arising from silent cerebral infarction (SCI) and changes in the levels of serum-soluble adhesion molecules in 82 elderly diabetic patients aged 60 years and older. SCI was found in 43 % of the 82 patients, with incidence increasing in relation to age. The prevalence of SCI was higher in subjects with hypertension, poor metabolic control and increased fibrinolysis.

Centrally administered TRH-induced insulin secretion is impaired in the Otsuka-Long-Evans-Tokushima Fatty rats, a model of spontaneous non-insulin-dependent diabetes mellitus.

To investigate whether insulin secretion induced by stimulation of the vagus nerve is preserved or impaired in Otsuka-Long-Evans-Tokushima Fatty (OLETF) rats, we injected 10(-8) mol of thyrotropin-releasing hormone (TRH) into the third cerebral ventricle and determined the serum level of insulin in the unanesthetized, unrestrained rats. Intracerebroventricular (i.c.

Demonstration of a Ca2+/calmodulin dependent protein kinase cascade in the hog heart.

Members of the Ca2+/calmodulin dependent protein kinase (CaMK) family and a CaMK cascade have been identified and well characterized in the brain, but little is known about their equivalents in the heart. Thus only CaMKII and its function have been reported so far. Therefore, we purified and characterized CaMKI and CaMK kinase (CaMKK) as an associated activator from the hog heart for the first time.

Influence of interindividual variability of aldose reductase protein content on polyol-pathway metabolites and redox state in erythrocytes in diabetic patients.

Objective: To clarify the influence of interindividual difference in the level of aldose reductase on the polyol pathway-related metabolism in diabetic patients.

Research Design And Methods: The enzyme protein content was determined by a two-site enzyme-linked immunosorbent assay using monoclonal and polyclonal antibodies to recombinant human aldose reductase in erythrocytes from 35 diabetic patients and 11 healthy volunteers. Patients were stratified into two groups by the median of aldose reductase content, and the erythrocyte sorbitol level, the fructose level, and the lactate-to-pyruvate ratio were compared between the two groups.

A case report of myolysis during high-dose amiodarone therapy for uncontrolled ventricular tachycardia.

We report a rare case of a 41-year-old male patient, a professional musician, with dilated cardiomyopathy and sustained ventricular tachycardia (VT) that was refractory to class I antiarrhythmic drugs. Severe myolysis developed after 10 months' administration of amiodarone (400 mg/day) in combination with mexiletine (300 mg/day) and disopyramide (400 mg/day). He had been suffering from severe moving muscle pain and an extremely high (16,830) IU/ml) serum level of creatine kinase (CK).

A new spontaneous animal model of NIDDM without obesity in the musk shrew.

The EDS (early-onset diabetes in suncus) colony has been developed as a new closed breeding colony of the musk shrew (Suncus murinus, Insectivora) exhibiting a high incidence of spontaneous diabetes mellitus. We investigated the characteristic features of diabetic shrews in this colony. All diabetic shrews are characterized by glycosuria (Tes-tape value > or = 3+), hyperglycemia (23.

New concepts and insights on pathogenesis and treatment of diabetic complications: polyol pathway and its inhibition.

The polyol pathway is one of the possible biochemical mechanisms by which hyperglycemia could impair the function and structure of the cells affected by diabetic complications. As possible hypothesis for the pathogenesis of diabetic complications, the polyol osmotic theory, alterations in myo-inositol and sodium metabolism, intermediary metabolites, abnormal changes of the redox state (NADH/NAD+ ratio) and an abnormality of kinase C dependent protein phosphorylation have been proposed. Recently, increasing evidence suggests that glycation and oxidative stress may have a cross-link with polyol pathway, contributing to the development of diabetic complications.

Electroretinogram in sucrose-fed diabetic rats treated with an aldose reductase inhibitor or an anticoagulant.

To investigate the role of increased polyol pathway activity and hemodynamic deficits in the pathogenesis of diabetic retinopathy in non-insulin-dependent diabetes mellitus (NIDDM), Otsuka Long-Evans Tokushima fatty (OLETF) rats, an animal model of human NIDDM, were given water with or without 30% sucrose and some of them were fed laboratory chow containing 0.03% cilostazol, an anticoagulant, or 0.05% [5-(3-thienyl)tetrazol-1-yl] acetic acid monohydrate (TAT), an aldose reductase inhibitor, for 8 wk.