Cardiovascular risk profile and frailty in a population-based study of older British men.

BACKGROUND: Frailty in older age is known to be associated with cardiovascular disease (CVD) risk. However, the extent to which frailty is associated with the CVD risk profile has been little studied. Our aim was to examine the associations of a range of cardiovascular risk factors with frailty and to assess whether these are independent of established CVD. METHODS: Cross-sectional study of a socially representative sample of 1622 surviving men aged 71-92 examined in 2010-2012 across 24 British towns, from a prospective study initiated in 1978-1980. Frailty was defined using the Fried phenotype, including weight loss, grip strength, exhaustion, slowness and low physical activity. RESULTS: Among 1622 men, 303 (19%) were frail and 876 (54%) were pre-frail. Compared with non-frail, those with frailty had a higher odds of obesity (OR 2.03, 95% CI 1.38 to 2.99), high waist circumference (OR 2.30, 95% CI 1.67 to 3.17), low high-density lipoprotein-cholesterol (HDL-C) (OR 2.28, 95% CI 1.47 to 3.54) and hypertension (OR 1.79, 95% CI 1.27 to 2.54). Prevalence of these factors was also higher in those with frailty (prevalence in frail vs non-frail groups was 46% vs 31% for high waist circumference, 20% vs 11% for low HDL and 78% vs 65% for hypertension). Frail individuals had a worse cardiovascular risk profile with an increased risk of high heart rate, poor lung function (forced expiratory volume in 1 s (FEV1)), raised white cell count (WCC), poor renal function (low estimated glomerular filtration rate), low alanine transaminase and low serum sodium. Some risk factors (HDL-C, hypertension, WCC, FEV1, renal function and albumin) were also associated with being pre-frail. These associations remained when men with prevalent CVD were excluded. CONCLUSIONS: Frailty was associated with increased risk of a range of cardiovascular factors (including obesity, HDL-C, hypertension, heart rate, lung function, renal function) in older people; these associations were independent of established CVD

FK 506 ameliorates the hepatic injury associated with ischemia and reperfusion in rats

The effect of FK 506 on regeneration of the liver was studied in rats after a two‐thirds partial hepatectomy after 60 min of ischemia of the unresected liver. The animals were divided into three distinct groups of 10 rats each. Group 1 (controls) received 0.5 ml saline solution intravenously 30 min after the induction of ischemia. Groups 2 and 3 were injected with FK 506 (0.3 mg/kg) intravenously 30 min after and 24 min before the induction of hepatic ischemia, respectively. The hepatic content of ATP and serum levels of ALT and lactate dehydrogenase were determined on each animal. In addition, the histological appearance and mitotic activity of the remnant liver was determined at regular 24‐hr intervals after hepatic ischemia. All 10 control animals died within 72 hr. Treatment with FK 506 resulted in improved survival in groups 2 and 3 (30% and 80%, respectively). The improved survival seen in the FK 506–treated animals was reflected by a restoration of hepatic ATP content, a reduction in the serum levels of ALT and lactate dehydrogenase, an amelioration of hepatic necrosis and neutrophilic infiltration and an increase in the mitotic activity of the liver. These results suggest that FK 506 ameliorates the hepatic injury associated with ischemia/reperfusion and has a potent stimulatory effect on liver cell regeneration that may make it valuable as a hepatoprotective agent when administered to organ donors before graft harvesting. (HEPATOLOGY 1991;13:947–951.) Copyright © 1991 American Association for the Study of Liver Disease

Latent acetylcholinesterase in secretory vesicles isolated from adrenal medulla

A new procedure is described for the preparation of highly purified and stable secretory vesicles from adrenal medulla. Two forms of acetylcholinesterase, a membrane bound form as well as a soluble form, were found within these vesicles. The secretory vesicles, isolated by differential centrifugation, were further purified on a continuous isotonic Percoll™ gradient. In this way, secretory vesicles were separated from mitochondrial, microsomal and cell membrane contamination. The secretory vesicles recovered from the gradient contained an average of 2.26 μmol adrenalin/mg protein. On incubation for 30 min at 37°C in media differing in ionic strength, pH, Mg2+ and Ca2+ concentration, the vesicles released less than 20% of total adrenalin. Acetylcholinesterase could hardly be detected in the secretory vesicle fraction when assayed in isotonic media. However, in hypotonic media (<400 mosmol/kg) or in Triton X-100 (0.2% final concentration) acetylcholinesterase activity was markedly higher. During hypotonic treatment or when secretory vesicles were specifically lyzed with 2 mM Mg2+ and 2 mM ATP, adrenalin as well as part of acetylcholinesterase was released from the vesicular content. On polyacrylamide gel electrophoresis this soluble enzyme exhibited the same electrophoretic mobility as the enzyme released into the perfusate from adrenal glands upon stimulation. In addition to the soluble enzyme a membrane bound form of acetylcholinesterase exists within secretory vesicles, which sediments with the secretory vesicle membranes and exhibits a different electrophoretic mobility compared to the soluble enzyme. It is concluded, that the soluble enzyme found within isolated secretory vesicles is secreted via exocytosis, whilst the membrane-bound form is transported to the cell membrane during this process, contributing to the biogenesis of the cell membrane

Protein utilisation and intermediary metabolism of Senegalese sole (Solea senegalensis) as a function of protein:lipid ratio

Previous experiments with Senegalese sole (Solea senegalensis) have demonstrated that dietary lipid levels above 8% impaired growth and did not promote protein retention. We hypothesised that this low ability to use high-lipid diets may depend on the dietary protein level. In the present study, a 2 x 2 factorial design was applied where two dietary lipid (4-17% DM) and two dietary protein (below and above the requirement levels, 48 and 54% DM) levels were tested in juveniles for 114 d. Growth performance was not improved by the increase in dietary fat, irrespectively of the dietary protein levels. Protein retention was similar among the diets, although fish fed the diets with high lipid content resulted in significantly lower protein gain. Among the enzymes involved in amino acid catabolism, only aspartate aminotransferase activity in the liver was affected by the dietary lipid levels, being stimulated in fish fed high-lipid diets. Moreover, phosphofructokinase 1 activity was significantly elevated in the muscle of Senegalese sole fed 4% lipid diets, suggesting enhanced glycolysis in the muscle when the dietary lipid supply was limited and dietary starch increased. The results confirmed that high-lipid diets do not enhance growth, and data from the selected enzymes support the assumption that lipids are not efficiently used for energy production and protein sparing, even when dietary protein is below the protein requirement of the species. Furthermore, data suggest a significant role of glucose as the energy source in Senegalese sole.Fundacao para a Ciencia e Tecnologia of Portugal [SFRH/BD/47,780/2008]info:eu-repo/semantics/publishedVersio

Non-invasive assessment of liver disease in rats using multiparametric magnetic resonance imaging: a feasibility study

Non-invasive quantitation of liver disease using multiparametric magnetic resonance imaging (MRI) could refine clinical care pathways, trial design and preclinical drug development. The aim of this study was to evaluate the use of multiparametric MRI in experimental models of liver disease. Liver injury was induced in rats using 4 or 12 weeks of carbon tetrachloride (CCl4) intoxication and 4 or 8 weeks on a methionine and choline deficient (MCD) diet. Liver MRI was performed using a 7.0 Tesla small animal scanner at baseline and specified timepoints after liver injury. Multiparametric liver MRI parameters [T1 mapping, T2* mapping and proton density fat fraction (PDFF)] were correlated with gold standard histopathological measures. Mean hepatic T1 increased significantly in rats treated with CCl4 for 12 weeks compared to controls [1122±78 ms versus 959±114 ms; d=162.7, 95% CI (11.92, 313.4), P=0.038] and correlated strongly with histological collagen content (rs=0.717, P=0.037). In MCD diet-treated rats, hepatic PDFF correlated strongly with histological fat content (rs=0.819, P<0.0001), steatosis grade (rs=0.850, P<0.0001) and steatohepatitis score (rs=0.818, P<0.0001). Although there was minimal histological iron, progressive fat accumulation in MCD diet-treated livers significantly shortened T2*. In preclinical models, quantitative MRI markers correlated with histopathological assessments, especially for fatty liver disease. Validation in longitudinal studies is required. This article has an associated First Person interview with the first author of the paper

Glycoprotein Ib activation by thrombin stimulates the energy metabolism in human platelets

<div><p>Thrombin-induced platelet activation requires substantial amounts of ATP. However, the specific contribution of each ATP-generating pathway <i>i</i>.<i>e</i>., oxidative phosphorylation (OxPhos) versus glycolysis and the biochemical mechanisms involved in the thrombin-induced activation of energy metabolism remain unclear. Here we report an integral analysis on the role of both energy pathways in human platelets activated by several agonists, and the signal transducing mechanisms associated with such activation. We found that thrombin, Trap-6, arachidonic acid, collagen, A23187, epinephrine and ADP significantly increased glycolytic flux (3–38 times <i>vs</i>. non-activated platelets) whereas ristocetin was ineffective. OxPhos (33 times) and mitochondrial transmembrane potential (88%) were increased only by thrombin. OxPhos was the main source of ATP in thrombin-activated platelets, whereas in platelets activated by any of the other agonists, glycolysis was the principal ATP supplier. In order to establish the biochemical mechanisms involved in the thrombin-induced OxPhos activation in platelets, several signaling pathways associated with mitochondrial activation were analyzed. Wortmannin and LY294002 (PI3K/Akt pathway inhibitors), ristocetin and heparin (GPIb inhibitors) as well as resveratrol, ATP (calcium-release inhibitors) and PP1 (Tyr-phosphorylation inhibitor) prevented the thrombin-induced platelet activation. These results suggest that thrombin activates OxPhos and glycolysis through GPIb-dependent signaling involving PI3K and Akt activation, calcium mobilization and protein phosphorylation.</p></div