We previously reported that in mesenteric arteries from aged Otsuka Long-Evans Tokushima fatty (OLETF) rats (a type 2 diabetes model) endothelium-derived hyperpolarizing factor (EDHF)-type relaxation is impaired while endothelium-derived contracting factor (EDCF)-mediated contraction is enhanced (Matsumoto T, Kakami M, Noguchi E, Kobayashi T, Kamata K. Am J Physiol Heart Circ Physiol 293: H1480-H1490, 2007). Here we investigated whether acute and/or chronic treatment with metformin might improve this imbalance between the effects of the above endothelium-derived factors in mesenteric arteries isolated from OLETF rats. In acute studies on OLETF mesenteric arteries, ACh-induced relaxation was impaired and the relaxation became weaker at high ACh concentrations. Both metformin and 5-aminoimidazole-4-carboxamide-1-beta-D-ribofuranoside [AICAR, an AMP-activated protein kinase (AMPK) activator that is also activated by metformin] 1) diminished the tendency for the relaxation to reverse at high ACh concentrations and 2) suppressed both ACh-induced EDCF-mediated contraction and ACh-stimulated production of prostanoids (thromboxane A2 and PGE2). In studies on OLETF arteries from chronically treated animals, metformin treatment (300 mg.kg(-1).day(-1) for 4 wk) 1) improved ACh-induced nitric oxide- or EDHF-mediated relaxation and cyclooxygenase (COX)-mediated contraction, 2) reduced EDCF-mediated contraction, 3) suppressed production of prostanoids, and 4) reduced superoxide generation. Metformin did not alter the protein expressions of endothelial nitric oxide synthase (eNOS), phospho-eNOS (Ser1177), or COX-1, but it increased COX-2 protein. These results suggest that metformin improves endothelial functions in OLETF mesenteric arteries by suppressing vasoconstrictor prostanoids and by reducing oxidative stress. Our data suggest that within the timescale studied here, metformin improves endothelial function through this direct mechanism, rather than by improving metabolic abnormalities.

We investigated whether the balance between endothelium-derived relaxing factors (EDRFs) and endothelium-derived contracting factors (EDCFs) might be altered in mesenteric arteries from aged Otsuka Long-Evans Tokushima Fatty (OLETF) rats (a Type 2 diabetic model) [vs. age-matched control Long-Evans Tokushima Otsuka (LETO) rats]. ACh-induced relaxation was impaired in the OLETF group, and a tendency for the relaxation to reverse at high ACh concentrations was observed in both groups. This tendency was abolished by indomethacin. Nitric oxide- and/or endothelium-derived hypolarizing factor-mediated relaxation and the protein expressions of phospho-endothelial nitric oxide synthase (Ser1177) and extracellular superoxide dismutase were also reduced in OLETF. An ACh-induced contraction was observed at higher ACh concentrations in the presence of N(G)-nitro-L-arginine (L-NNA) but was greater in OLETF rats. This contraction in OLETF rats was reduced by cyclooxygenase (COX) inhibitors and by prostanoid-receptor antagonists. The ACh-induced productions of thromboxane A(2) and PGE(2) were greater in OLETF than LETO rats, as were the mesenteric artery COX-1 and COX-2 protein expressions. Moreover, tert-butyl hydroperoxide (t-BOOH) (membrane-permeant oxidant) induced a concentration-dependent contraction that was greater in OLETF rats. The t-BOOH-mediated contraction was increased both by L-NNA and by endothelium removal in LETO but not OLETF rats, suggesting that a negative modulatory role of the endothelium was lost in OLETF rats. These results suggest that an imbalance between EDRFs and EDCFs may be implicated in the endothelial dysfunction seen in aged OLETF mesenteric arteries, and may be attributable to increased oxidative stress.

IMPORTANCE Antisynthetase syndrome, characterized by myositis, interstitial lung disease, skin rash, arthropathy, and Raynaud phenomenon, is a clinical entity based on the presence of aminoacyl transfer RNA synthetase (ARS) antibodies in patients' serum. However, antisynthetase syndrome is not included in the histological subsets of idiopathic inflammatory myopathies.OBJECTIVE To elucidate the clinical features of myositis in patients with antisynthetase syndrome. DESIGN, SETTING, AND PARTICIPANTSIn this cohort study, muscle biopsy and blood samples were collected from 460 patients with idiopathic inflammatory myositis from various regional referral centers throughout Japan between October 2010 and December 2014. Data were analyzed in March 2016.EXPOSURES Six different anti-ARS antibodies were detected in serum by RNA immunoprecipitation. Line blot assay and protein immunoprecipitation were also performed. HLA-DRB1 alleles were genotyped. MAIN OUTCOMES AND MEASURESThe main outcomes were muscle manifestations and histological findings. Predisposing factors, extramuscular symptoms, and follow-up information were also studied. RESULTSOf 460 patients with idiopathic inflammatory myopathies, 51 (11.1%) had anti-ARS antibodies. Of this subset, 31 (61%) were women, with a mean (SD) age at disease onset of 60.2 (16.1) years. Among 6 different anti-ARS antibodies, only 1-the anti-OJ antibody-was not detected by line blot assay but by RNA immunoprecipitation. There were no significant HLA-DRB1 alleles associated with anti-ARS antibodies. All 51 patients presented with muscle limb weakness; 14 (27%) had severe limb weakness, 17 (33%) had neck muscle weakness, 15 (29%) had dysphagia, and 15 (29%) had muscle atrophy. Although patients with anti-OJ antibodies showed severe muscle weakness, the clinical presentations of antisynthetase syndrome were relatively homogeneous. In histology, perifascicular necrosis, the characteristic finding of antisynthetase syndrome, was found in 24 patients (47%). Myositis with anti-ARS antibodies responded to the combination of immunosuppressive therapy with favorable outcomes. Interstitial lung disease, found in 41 patients (80%), was more closely associated with mortality than myositis. CONCLUSIONS AND RELEVANCEAlthough clinical presentations of antisynthetase syndrome were relatively homogeneous, anti-OJ antibodies were associated with severe muscle involvement. Antisynthetase syndrome is a clinical and histological subset among idiopathic inflammatory myopathies.

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Background: Most cases of dementia with Lewy bodies (DLB) show Alzheimer's disease pathology-like senile plaques and neurofibrillary tangles. Several studies have also revealed a high prevalence of positive amyloid imaging with positron emission tomography (PET) in DLB and moderate prevalence in Parkinson's disease (PD) with dementia. However, it remains unclear in PD without dementia as to when the brain β amyloid (Aβ) burden begins and progresses. Our study aimed to determine the prevalence of Aβ deposition in PD without dementia using amyloid PET. Methods: This was a cross-sectional study on 33 patients with PD without dementia, of whom 21 had normal cognition and 12 met the criteria for PD-mild cognitive impairment. All subjects underwent neuropsychological assessment and [¹⁸F] florbetaben (FBB) PET. Results: All subjects had Lewy body-related disorders, displaying a significantly reduced myocardial [¹²³I] metaiodobenzylguanidine uptake. The cortical FBB-binding pattern in all subjects, including APOE e4 carriers, suggested negative Aβ deposition. Conclusion: Patients with PD without dementia exhibit an extremely low prevalence of Aβ positivity compared with those reported in cognitively normal elderly controls. Further longitudinal imaging studies and long-term follow-up are needed; however, our findings provide novel insights for understanding Aβ metabolism in PD.

These results suggest that impairments of beta-adrenergic and Ca(2+)-handling mechanisms occur early in the development of cardiomyopathy in STZ-induced diabetic rats, and that this is followed by augmentation of alpha(1A) adrenoceptor-mediated inotropy due to alpha(1A) adrenoceptor upregulation.

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