Impact of individual metabolic risk components or its clustering on endothelial and smooth muscle cell function in men

Background: Impaired vasoreactivity is often observed in subjects with metabolic syndrome, a condition that includes the presence of a specific cluster of risk factors for obesity and cardiovascular disease. However, hierarchical causes in the impaired vasoreactivity have not been clarified. We evaluated the impact of individual metabolic risk components or its clustering under the condition of insulin resistance on endothelial and smooth muscle cell function. Methods: Vascular reactivity to acetylcholine (Ach), with or without nitric oxide synthase (NOS) inhibitor NG-monomethyl-l-arginine (L-NMMA), or sodium nitroprusside (SNP) by forearm venous occlusion plethysmography and insulin sensitivity index (M mg/kg/min) in euglycemic clamp were measured in men without (n = 18, control group) or with (n = 19, metabolic syndrome group) metabolic syndrome. Results: (1) Ach-induced maximal forearm blood flow (maxFBF) was impaired in subjects with metabolic syndrome. In particular, the NOS-dependent component of Ach-induced maxFBF was selectively decreased, while the NOS-independent component remained relatively unchanged. (2) Ach-induced maxFBF and ΔAch-induced maxFBF with L-NMMA were correlated with waist circumference, glucose, and triglycerides, and most strongly correlated with visceral fat area, adiponectin, and M. (3) Multivariate regression analysis indicated that individual metabolic risk components explained Ach-induced maxFBF by 4–21 %. Clustering of all metabolic risk components increased this to 35 %, and the presence of metabolic syndrome explained 30 %, indicating that defining metabolic syndrome can effectively predict impairment of endothelial dysfunction. Conclusions: Endothelial dysfunction was correlated with individual metabolic risk components, but more strongly with clustering of the components under a condition with low insulin sensitivity. We suggest that in subjects with metabolic syndrome, endothelial function is impaired by multiple cardiovascular risk factors exclusively when under the condition of insulin insensitivity and also that defining metabolic syndrome can effectively predict impairment of endothelial dysfunction

Evidence for receptor-mediated inhibition of intrinsic activity of GTP-binding protein, Gi1 and Gi2, but not G0 in reconstitution experiments

AbstractThe receptor-mediated inhibition of intrinsic activities of GTP-binding proteins (G-proteins) was studied. Pertussis toxin (IAP)-substrate G-protein, Gi1, Gi2 or G0, was prelabeled with [α-32P]GDP and reconstituted with synaptic membranes of the guinea pig cerebellum in the presence of 0.02% of Chaps. Intrinsic activities of G-proteins were evaluated by the release of [α-32P]GDP in exchange for added GppNHp or GDP in reconstituted preparations. U-50,488H (1 nM-10 μM), a specific ϰ-subtype of opioid receptor agonist, inhibited the [α-32P]GDP release in exchange for added 1 μM GppNHp in Gi1-reconstituted preparations in a concentration-dependent manner. On the other hand, the ϰ-opioid agonist at 10 μM increases the Km values of GppNHp, but not GDP in exchange for [α-32P]GDP release in preparations reconstituted with Gi1 or Gi2, but not with G0. These findings indicate that ϰ-opioid receptor is coupled to inhibition of intrinsic activities of Gi1 and Gi2, but not G0, in guinea pig cerebellar membranes. In addition, it was revealed that the mode of action is mediated by a decrease in affinity of GTP (or its analog) for G-proteins, but not by a change in affinity of GDP

Open monitoring meditation reduces the involvement of brain regions related to memory function

洞察瞑想時に自伝的記憶関連脳領域間の結合性が低下することを発見 --今この瞬間に生じている経験にありのままに気づくことの神経基盤--. 京都大学プレスリリース. 2018-07-05.Mindfulness meditation consists of focused attention meditation (FAM) and open monitoring meditation (OMM), both of which reduce activation of the default mode network (DMN) and mind-wandering. Although it is known that FAM requires intentional focused attention, the mechanisms of OMM remain largely unknown. To investigate this, we examined striatal functional connectivity in 17 experienced meditators (mean total practice hours = 920.6) during pre-resting, meditation, and post-resting states comparing OMM with FAM, using functional magnetic resonance imaging. Both FAM and OMM reduced functional connectivity between the striatum and posterior cingulate cortex, which is a core hub region of the DMN. Furthermore, OMM reduced functional connectivity of the ventral striatum with both the visual cortex related to intentional focused attention in the attentional network and retrosplenial cortex related to memory function in the DMN. In contrast, FAM increased functional connectivity in these regions. Our findings suggest that OMM reduces intentional focused attention and increases detachment from autobiographical memory. This detachment may play an important role in non-judgmental and non-reactive attitude during OMM. These findings provide new insights into the mechanisms underlying the contribution of OMM to well-being and happiness

Association of lower limb muscle mass and energy expenditure with visceral fat mass in healthy men

BACKGROUND: A high-calorie diet and physical inactivity, an imbalance between caloric intake and energy consumption, are major causes of metabolic syndrome (MetS), which manifests as accumulation of visceral fat and insulin resistance. However, the lifestyle-related factors associated with visceral fat mass in healthy men are not fully understood. METHODS: We evaluated visceral fat area (VFA), skeletal muscle mass, caloric intake, and energy expenditure in 67 healthy male participants (mean age, 36.9 ± 8.8 years; body mass index 23.4 ± 2.5 kg/m(2)). RESULTS: Multiple regression analysis showed that the total skeletal muscle mass (P < 0.001) were negatively and age (P < 0.001) were positively associated with VFA. Lower limb muscle mass (P < 0.001) was strongly associated with VFA. However, total caloric intake, total energy expenditure, and energy expenditure during exercise were not associated with VFA. CONCLUSIONS: Skeletal muscle mass especially lower limb muscle mass negatively contributes to visceral fat mass in healthy men. Therefore, maintaining lower limb muscular fitness through daily activity may be a useful strategy for controlling visceral obesity and metabolic syndrome

Truncated KCNQ1 mutant, A178fs/105, forms hetero-multimer channel with wild-type causing a dominant-negative suppression due to trafficking defect

AbstractWe identified a novel mutation Ala178fs/105 missing S3–S6 and C-terminus portions of KCNQ1 channel. Ala178fs/105-KCNQ1 expressed in COS-7 cells demonstrated no current expression. Co-expression with wild-type (WT) revealed a dominant-negative effect, which suggests the formation of hetero-multimer by mutant and WT. Confocal laser microscopy displayed intracellular retention of Ala178fs/105-KCNQ1 protein. Co-expression of the mutant and WT also increased intracellular retention of channel protein compared to WT alone. Our findings suggest a novel mechanism for LQT1 that the truncated S1–S2 KCNQ1 mutant forms hetero-multimer and cause a dominant-negative effect due to trafficking defect

Effect of ipragliflozin on carotid intima-media thickness in type 2 diabetes patients

Aims To examine the effects of a 24-month treatment with ipragliflozin on carotid intima-media thickness (IMT) in type 2 diabetes patients. Methods and results In this multicenter, prospective, randomized, open-label, and blinded-endpoint investigator-initiated clinical trial, adults with type 2 diabetes and haemoglobin A1C (HbA1c) of 6.0–10.0% (42–86 mmol/mol) were randomized equally to ipragliflozin (50 mg daily) and non-sodium-glucose cotransporter-2 (SGLT2) inhibitor use of standard-care (control group) for type 2 diabetes and were followed-up to 24 months. The primary endpoint was the change in mean common carotid artery IMT (CCA-IMT) from baseline to 24 months. A total of 482 patients were equally allocated to the ipragliflozin (N = 241) and control (N = 241) groups, and 464 patients (median age 68 years, female 31.7%, median type 2 diabetes duration 8 years, median HbA1c 7.3%) were included in the analyses. For the primary endpoint, the changes in the mean CCA-IMT from baseline to 24 months were 0.0013 [95% confidence interval (CI), −0.0155–0.0182] mm and 0.0015 (95% CI, −0.0155–0.0184) mm in the ipragliflozin and control groups, respectively, with an estimated group difference (ipragliflozin-control) of −0.0001 mm (95% CI, −0.0191–0.0189; P = 0.989). A group difference in HbA1c change at 24 months was also non-significant between the treatment groups [−0.1% (95% CI, −0.2–0.1); P = 0.359]. Conclusion Twenty-four months of ipragliflozin treatment did not affect carotid IMT status in patients with type 2 diabetes recruited in the PROTECT study, relative to the non-SGLT2 inhibitor-use standard care for type 2 diabetes

Drug-induced kidney disease: a study of the Japan Renal Biopsy Registry from 2007 to 2015

IntroductionThe Japan Renal Biopsy Registry (J-RBR) was started in 2007 by the Committee for the Standardization of Renal Pathological Diagnosis and the Committee for the Kidney Disease Registry of the Japanese Society of Nephrology. The purpose of this report is to clarify drug-induced kidney disease (DIKD) of renal biopsied cases in Japan.Subjects and methodsWe analyzed the data of 26,535 cases that were registered in the J-RBR from 2007 to 2015.ResultsBased on clinical and pathological diagnoses, 328 cases (176 males and 152 females) of renal biopsy-proven DIKD were registered in the J-RBR from 2007 to 2015 (1.24 % of all cases). The frequency of DIKD increased with age. The number of cases peaked in the 6th–8th decade in all pathological categories, except for the number of chronic tubulointerstitial lesions (CTIL), which peaked in the 4th–5th decade. Overall, the frequency of DIKD was 3 times higher in the 7th decade than in the 2nd decade (1.86 vs. 0.62 %). The main clinical diagnoses were DIKD in 150 cases (45.7 %), nephrotic syndrome in 66 cases (20.1 %), chronic nephritic syndrome in 55 cases (16.8 %), and rapidly progressive glomerulonephritis in 30 cases (9.1 %). DIKD was registered as a secondary diagnosis in 136 cases (41.5 %). The pathological findings of these cases were glomerular lesions in 105 cases (32.0 %), acute tubulointerstitial lesions (ATIL) in 87 cases (26.5 %), CTIL in 72 cases (22.0 %), and sclerotic glomerular lesions and/or nephrosclerosis in 18 cases (5.5 %). ATIL and CTIL were mainly found in cases in which DIKD was diagnosed on the basis of the patient’s clinical findings. In addition, nephrotic syndrome-related membranous nephropathy (MN) was the major cause of renal damage in 59.4 % of the cases involving glomerular injuries. According to the CGA risk classification, high-risk (red zone) cases accounted for 56.1 % of all cases of DIKD and 75.9, 64.9, and 33.3 % of the cases involving ATIL, CTIL, and glomerular injuries, respectively. The causative drugs were identified in 102 cases, including bucillamine in 38 cases of MN, gemcitabine in 3 cases of thrombotic microangiopathy, and other anticancer drugs in 14 cases (anti-vascular endothelial growth factor drugs in 3 cases and propyl thiouracil in 3 cases of anti-neutrophil cytoplasmic antibody-related nephritis).ConclusionOur analysis of the J-RBR revealed that DIKD mainly affects elderly people in Japan. ATIL or CTIL were found in approximately half of the biopsied cases of DIKD, and one-third involved glomerular lesions, mainly MN or clinical nephrotic syndrome

Health Checkup and Telemedical Intervention Program for Preventive Medicine in Developing Countries: Verification Study

Background: The prevalence of non-communicable diseases is increasing throughout the world, including developing countries. / Objective: The intent was to conduct a study of a preventive medical service in a developing country, combining eHealth checkups and teleconsultation as well as assess stratification rules and the short-term effects of intervention. / Methods: We developed an eHealth system that comprises a set of sensor devices in an attaché case, a data transmission system linked to a mobile network, and a data management application. We provided eHealth checkups for the populations of five villages and the employees of five factories/offices in Bangladesh. Individual health condition was automatically categorized into four grades based on international diagnostic standards: green (healthy), yellow (caution), orange (affected), and red (emergent). We provided teleconsultation for orange- and red-grade subjects and we provided teleprescription for these subjects as required. / Results: The first checkup was provided to 16,741 subjects. After one year, 2361 subjects participated in the second checkup and the systolic blood pressure of these subjects was significantly decreased from an average of 121 mmHg to an average of 116 mmHg (P<.001). Based on these results, we propose a cost-effective method using a machine learning technique (random forest method) using the medical interview, subject profiles, and checkup results as predictor to avoid costly measurements of blood sugar, to ensure sustainability of the program in developing countries. / Conclusions: The results of this study demonstrate the benefits of an eHealth checkup and teleconsultation program as an effective health care system in developing countries

Review Article : Feudalism or Absolute Monarchism?

Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/68809/2/10.1177_009770049001600304.pd