Extracellular Water May Mask Actual Muscle Atrophy During Aging

Background.\nSkeletal muscle tissue holds a large volume of water partitioned into extracellular water (ECW) and intracellular water (ICW) fractions. As the ECW may not be related to muscle strength directly, we hypothesized that excluding ECW from muscle volume would strengthen the correlation with muscle strength.Methods.\nA total of 119 healthy men aged 20–88 years old participated in this study. Knee isometric extension strength, vertical jump, and standing from a chair were measured as indices of muscle strength and power in the lower extremities. The regional lean volume (LV), total water (TW), ICW, and ECW in the lower leg were estimated by anthropometry (skinfold and circumference measurements) and segmental multifrequency bioelectrical impedance spectroscopy (S-BIS). Then, we calculated the ECW/TW and ICW/TW ratios.Results.\nAlthough ICW and the LV index decreased significantly with age (p < .001), no significant changes in ECW were observed (p = .134). Consequently, the ECW/TW ratio increased significantly (p < .001) with age (young adult, 27.0 ± 2.9%; elderly, 34.3 ± 4.9%; advanced elderly, 37.2 ± 7.0%). Adjusting for this by including the ICW/TW ratio in our models significantly improved the correlation between the LV index and strength-related measurements and correlated with strength-related measurements independently of the LV index (p < .001).Conclusions.\nThe ECW/TW ratio increases in the lower leg with age. The results suggest that the expansion of ECW relative to ICW and the LV masked actual muscle cell atrophy with aging

Eosinophilic myocarditis without hypereosinophilia accompanied by giant cell infiltration

AbstractA 53-year-old woman with a history of allergic disease was admitted to our hospital because of syncope induced by sustained ventricular tachycardia. The clinical course and the laboratory data did not correspond to those of acute myocarditis. Although eosinophils in the peripheral blood count were not increased, the diagnosis of eosinophilic myocarditis was made following a right ventricular endomyocardial biopsy that showed a remarkable infiltration of eosinophils. While giant cells were another histopathological feature of this case, they were considered to be an expression of the disease severity. This is a rare case of eosinophilic myocarditis, without peripheral eosinophilia.<Learning objective: Eosinophils in the peripheral blood usually increase in eosinophilic myocarditis. We describe a case of eosinophilic myocarditis without hypereosinophilia. Even in the absence of hypereosinophilia, endomyocardial biopsy should be performed during the investigation of unexplained myocardial disease.

Regulation of the Human Taurine Transporter by Oxidative Stress in Retinal Pigment Epithelial Cells Stably Transformed to Overexpress Aldose Reductase

In diabetes, overexpression of aldose reductase (AR) and consequent glucose-induced impairment of antioxidant defense systems may predispose to oxidative stress and the development of diabetic complications, but the mechanisms are poorly understood. Taurine (2-aminoethanesulfonic acid) functions as an antioxidant, osmolyte, and calcium modulator such that its intracellular depletion could promote cytotoxicity in diabetes. The relationships of oxidative stress and basal AR gene expression to Na+-taurine cotransporter (TT) gene expression, protein abundance, and TT activity were therefore explored in low AR-expressing human retinal pigment epithelial (RPE) 47 cells and RPE 47 cells stably transformed to overexpress AR (RPE 75). Changes in TT gene expression were determined using a 4.6-kb TT promoter-luciferase fusion gene. Compared with RPE 47 cells, in high AR-expressing RPE 75 cells, TT promoter activity was decreased by 46%, which was prevented by an AR inhibitor. TT promoter activity increased up to 900% by prooxidant exposure, which was associated with increased TT peptide abundance and taurine transport. However, induction of TT promoter activity by oxidative stress was attenuated in high AR-expressing cells and partially corrected by AR inhibitor. Finally, exposure of RPE 75 cells to high glucose increased oxidative stress, but down-regulated TT expression. These studies demonstrate for the first time that the TT is regulated by oxidative stress and that overexpression of AR and high glucose impair this response. Abnormal expression of AR may therefore impair antioxidant defense, which may determine tissue susceptibility to chronic diabetic complications. Antioxid. Redox Signal. 7, 1530–1542.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/63284/1/ars.2005.7.1530.pd

Constructing an index of physical fitness age for Japanese elderly based on 7-year longitudinal data: sex differences in estimated physical fitness age

A standardized method for assessing the physical fitness of elderly adults has not yet been established. In this study, we developed an index of physical fitness age (fitness age score, FAS) for older Japanese adults and investigated sex differences based on the estimated FAS. Healthy elderly adults (52 men, 70 women) who underwent physical fitness tests once yearly for 7 years between 2002 and 2008 were included in this study. The age of the participants at the beginning of this study ranged from 60.0 to 83.0 years. The physical fitness tests consisted of 13 items to measure balance, agility, flexibility, muscle strength, and endurance. Three criteria were used to evaluate fitness markers of aging: (1) significant cross-sectional correlation with age; (2) significant longitudinal change with age consistent with the cross-sectional correlation; and (3) significant stability of individual differences. We developed an equation to assess individual FAS values using the first principal component derived from principal component analysis. Five candidate fitness markers of aging (10-m walking time, functional reach, one leg stand with eyes open, vertical jump and grip strength) were selected from the 13 physical fitness tests. Individual FAS was predicted from these five fitness markers using a principal component model. Individual FAS showed high longitudinal stability for age-related changes. This investigation of the longitudinal changes of individual FAS revealed that women had relatively lower physical fitness compared with men, but their rate of physical fitness aging was slower than that of men

Effects of Physical Exercise and of Dietary Protein Levels on Nitrogen Retention in Energy-Restricted Adult Rats

たんぱく質および脂肪含量が異なる種々の実験食を自由摂取時の50〜60%量与え, 同時に1日30分のトレッドミル歩行(20m/分)または50分の遊泳を課して10〜35日間減量させた成熟ラット(約100日齢)について, 窒素出納, 体組成, 血液性状, 筋グリコーゲン量などを測定し, 以下の成績が得られた.1.食餌制限した運動負荷ラットは, たんぱく質摂取水準が等しい非運動ラットに比べて窒素保留量の増加がみられ, 体構成的にも水分とたんぱく質が多くなり脂肪が著るしく減少した.2.運動・非運動群ともに, 25%カゼイン食給与ラットは10%および40%カゼイン食ラットと比較すると, 窒素出納が正に傾き, 減食に伴う体たんぱく質の損失も著るしく軽減された.3.食餌制限下においても, 運動群ラットの血清コレステロール値は同一食の非運動群ラットよりも低下する傾向が認められた.また, 自由摂取時に血清コレステロール上昇作用をもつラードとカゼインは食餌中の添加量が増すにつれ, 減食中のラットに対しても血清コレステロール値を高めるように作用した.4.10%カゼイン食給与ラットを食餌制限と運動負荷を併用して減量させると貧血傾向が出現したが, 25%および40%カゼイン食ラットではこの傾向は認められなかった.運動群ラットの筋グリコーゲン量は非運動群ラットに比べて著明に増加した.以上の結果から, 減食時の運動は体たんぱく質さらには活性組織の損失を抑制し体脂肪の減少を促進するほかに, 血清コレステロール値を低下させ筋グリコーゲン量を高めるなど, 体力・保健上有利な作用を示すことが明らかになった.また, 減食時の体構成の変化に食餌たんぱく質量, 血清コレステロール値には食餌脂肪がそれぞれ強く影響する

Meta-analysis of genome-wide association studies identifies eight new loci for type 2 diabetes in east Asians

We conducted a three-stage genetic study to identify susceptibility loci for type 2 diabetes (T2D) in East Asian populations. The first stage meta-analysis of eight T2D genome-wide association studies (6,952 cases and 11,865 controls) was followed by a second stage in silico replication analysis (5,843 cases and 4,574 controls) and a stage 3 de novo replication analysis (12,284 cases and 13,172 controls). The combined analysis identified eight new T2D loci reaching genome-wide significance, which were mapped in or near GLIS3, PEPD, FITM2-R3HDML-HNF4A, KCNK16, MAEA, GCC1-PAX4, PSMD6 and ZFAND3. GLIS3, involved in pancreatic beta cell development and insulin gene expression1,2, is known for its association with fasting glucose levels3,4. The evidence of T2D association for PEPD5 and HNF4A6,7 has been detected in previous studies. KCNK16 may regulate glucose-dependent insulin secretion in the pancreas. These findings derived from East Asians provide new perspectives on the etiology of T2D

Atrasentan and renal events in patients with type 2 diabetes and chronic kidney disease (SONAR): a double-blind, randomised, placebo-controlled trial

Background: Short-term treatment for people with type 2 diabetes using a low dose of the selective endothelin A receptor antagonist atrasentan reduces albuminuria without causing significant sodium retention. We report the long-term effects of treatment with atrasentan on major renal outcomes. Methods: We did this double-blind, randomised, placebo-controlled trial at 689 sites in 41 countries. We enrolled adults aged 18–85 years with type 2 diabetes, estimated glomerular filtration rate (eGFR)25–75 mL/min per 1·73 m 2 of body surface area, and a urine albumin-to-creatinine ratio (UACR)of 300–5000 mg/g who had received maximum labelled or tolerated renin–angiotensin system inhibition for at least 4 weeks. Participants were given atrasentan 0·75 mg orally daily during an enrichment period before random group assignment. Those with a UACR decrease of at least 30% with no substantial fluid retention during the enrichment period (responders)were included in the double-blind treatment period. Responders were randomly assigned to receive either atrasentan 0·75 mg orally daily or placebo. All patients and investigators were masked to treatment assignment. The primary endpoint was a composite of doubling of serum creatinine (sustained for ≥30 days)or end-stage kidney disease (eGFR <15 mL/min per 1·73 m 2 sustained for ≥90 days, chronic dialysis for ≥90 days, kidney transplantation, or death from kidney failure)in the intention-to-treat population of all responders. Safety was assessed in all patients who received at least one dose of their assigned study treatment. The study is registered with ClinicalTrials.gov, number NCT01858532. Findings: Between May 17, 2013, and July 13, 2017, 11 087 patients were screened; 5117 entered the enrichment period, and 4711 completed the enrichment period. Of these, 2648 patients were responders and were randomly assigned to the atrasentan group (n=1325)or placebo group (n=1323). Median follow-up was 2·2 years (IQR 1·4–2·9). 79 (6·0%)of 1325 patients in the atrasentan group and 105 (7·9%)of 1323 in the placebo group had a primary composite renal endpoint event (hazard ratio [HR]0·65 [95% CI 0·49–0·88]; p=0·0047). Fluid retention and anaemia adverse events, which have been previously attributed to endothelin receptor antagonists, were more frequent in the atrasentan group than in the placebo group. Hospital admission for heart failure occurred in 47 (3·5%)of 1325 patients in the atrasentan group and 34 (2·6%)of 1323 patients in the placebo group (HR 1·33 [95% CI 0·85–2·07]; p=0·208). 58 (4·4%)patients in the atrasentan group and 52 (3·9%)in the placebo group died (HR 1·09 [95% CI 0·75–1·59]; p=0·65). Interpretation: Atrasentan reduced the risk of renal events in patients with diabetes and chronic kidney disease who were selected to optimise efficacy and safety. These data support a potential role for selective endothelin receptor antagonists in protecting renal function in patients with type 2 diabetes at high risk of developing end-stage kidney disease. Funding: AbbVie

Meta-analysis of genome-wide association studies identifies eight new loci for type 2 diabetes in east Asians

We conducted a three-stage genetic study to identify susceptibility loci for type 2 diabetes (T2D) in east Asian populations. We followed our stage 1 meta-analysis of eight T2D genome-wide association studies (6,952 cases with T2D and 11,865 controls) with a stage 2 in silico replication analysis (5,843 cases and 4,574 controls) and a stage 3 de novo replication analysis (12,284 cases and 13,172 controls). The combined analysis identified eight new T2D loci reaching genome-wide significance, which mapped in or near GLIS3, PEPD, FITM2-R3HDML-HNF4A, KCNK16, MAEA, GCC1-PAX4, PSMD6 and ZFAND3. GLIS3, which is involved in pancreatic beta cell development and insulin gene expression1,2, is known for its association with fasting glucose levels3,4. The evidence of an association with T2D for PEPD5 and HNF4A6,7 has been shown in previous studies. KCNK16 may regulate glucose-dependent insulin secretion in the pancreas. These findings, derived from an east Asian population, provide new perspectives on the etiology of T2D