[P2–575]: Apoe Epsilon 4 Status Modifies The Effects Of Aerobic, Resistance, Or Combined Training On Cognitive Function In Older Adults

Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/152588/1/alzjjalz2017061234.pd

Falls in community‐dwelling prefrail older adults

Frailty has been established as a risk factor for falls, and prefrailty also seems a risk; however, few studies have focused on the association between falls and each of the five components of frailty proposed by Fried. In the present study, we sought to elucidate the association between prefrailty and falls, and moreover, the association of frailty component with falls. Participants were community‐dwelling older people who had cognitive complaints but not dementia (N = 447, male 54.6%). Prefrailty was defined as exhibiting one or two of the five Fried criteria. Frail individuals were excluded. Background characteristics were compared between the prefrail and robust groups, and multiple regression analysis was performed to investigate the associations between fall history within the past year and factors that were significantly different between the groups. We also performed logistic regression analysis with adjustment for age, education and gender to assess associations with frailty components. We found that prefrailty was associated with fall history. Depressed mood was also significantly associated with fall history. Among the five frailty criteria, exhaustion was significantly associated with falls. Prefrailty, especially the criteria of exhaustion, and depressed mood were associated with fall history.Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/153214/1/hsc12845_am.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/153214/2/hsc12845.pd

P3‐005: Effects of Aerobic, Resistance, or Combined Training on Cognitive Function in Older Adults: A Randomized Controlled Trial

Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/152606/1/alzjjalz2016061662.pd

Pravastatin restored the infarct size-limiting effect of ischemic preconditioning blunted by hypercholesterolemia in the rabbit model of myocardial infarction

AbstractOBJECTIVESWe tested to find out whether pravastatin restores the infarct size (IS)-limiting effect of ischemic preconditioning (IP) and if it has any effect on the IP-induced activation of adenosine producing enzyme ecto-5′-nucleotidase which plays a key role in the IP-induced cardioprotection.BACKGROUNDThe IS-limiting effect of IP is blunted by hypercholesterolemia. Recently, HMG-CoA reductase inhibitors are shown to have direct cytoprotective effects.METHODSRabbits were fed with a normal or cholesterol (1%) added diet with or without pravastatin (5 mg/kg/day) treatment. Infarct size was measured after 30 min occlusion and 3 h reperfusion of circumflex coronary artery with or without the IP procedure (5 min occlusion and 10 min reperfusion). Additionally, ecto-5′-nucleotidase activities of ischemic and nonischemic myocardium were measured immediately after IP procedure.RESULTSThis dose of pravastatin did not normalize the increased level of serum cholesterol. The IS-limiting effect of preceding IP (IS reduced from 36.7% to 9.6%, p < 0.001) was abolished by hypercholesterolemia (from 46.1% to 31.3%, p = NS) and restored by pravastatin treatment (from 35.2% to 9.4%, p < 0.001). Pravastatin treatment did not affect IS or the effect of IP under normocholesterolemia. The activation of ecto-5′-nucleotidase presented as the activity ratio of ischemic to nonischemic myocardium (3.1-fold in normocholesterolemia) was blunted by hypercholesterolemia (1.8-fold, p < 0.05) and restored by pravastatin treatment (2.9-fold).CONCLUSIONSPravastatin, at the dose serum cholesterol was not normalized, restored the IS-limiting effect of IP and IP-induced ecto-5′-nucleotidase activation, which were both blunted by hypercholesterolemia. The activation of ecto-5′-nucleotidase may be worth further investigation as a possible mechanism for the hypercholesterolemia-induced retardation and pravastatin-mediated restoration of the cardioprotective effect of IP

Postprandial Hyperglycemia Is Associated With White Matter Hyperintensity and Brain Atrophy in Older Patients With Type 2 Diabetes Mellitus

Type 2 diabetes mellitus is associated with neurodegeneration and cerebrovascular disease. However, the precise mechanism underlying the effects of glucose management on brain abnormalities is not fully understood. The differential impacts of glucose alteration on brain changes in patients with and without cognitive impairment are also unclear. This cross-sectional study included 57 older type 2 diabetes patients with a diagnosis of Alzheimer’s disease (AD) or normal cognition (NC). We examined the effects of hypoglycemia, postprandial hyperglycemia and glucose fluctuations on regional white matter hyperintensity (WMH) and brain atrophy among these patients. In a multiple regression analysis, postprandial hyperglycemia was independently associated with frontal WMH in the AD patients. In addition, postprandial hyperglycemia was significantly associated with brain atrophy, regardless of the presence of cognitive decline. Altogether, our findings indicate that postprandial hyperglycemia is associated with WMH in AD patients but not NC patients, which suggests that AD patients are more susceptible to postprandial hyperglycemia associated with WMH

Mechanisms With Clinical Implications for Atrial Fibrillation–Associated Remodeling: Cathepsin K Expression, Regulation, and Therapeutic Target and Biomarker

Background: The cysteine protease cathepsin K (CatK) has been implicated in the pathogenesis of cardiovascular disease. We sought to determine the link between atrial fibrillation (AF) and plasma CatK levels and to investigate the expression of and therapeutic target for CatK in vivo and in vitro. Methods and Results: Plasma CatK and extracellular matrix protein peptides (intact procollagen type I of N‐terminal propeptide; carboxyl‐terminal telopeptide of type I collagen [ICTP]) were measured in 209 consecutive patients with AF (paroxysmal AF, 146; persistent AF, 63) and 112 control subjects. In addition, the regulation of CatK expression was investigated in vivo and vitro. Patients with AF had higher plasma CatK and ICTP levels than did control subjects. Patients with persistent AF had higher levels of plasma CatK and ICTP than did patients with paroxysmal AF. CatK was correlated with ICTP concentration and left atrial diameter in all subjects. In rabbits, superoxide production, CatK activity, fibrosis, and the levels of atrial tissue angiotensin II, angiotensin type 1 receptor, gp91phox, phospho‐p38 mitogen‐activated protein kinase, and CatK were greater in those with tachypacing‐induced AF than in controls, and these changes were reversed with angiotensin type 1 receptor antagonist. Olmesartan and mitogen‐activated protein kinase inhibitor decreased the CatK expression induced by angiotensin II in rat neonatal myocytes. Conclusions: These data indicated that increased plasma CatK levels are linked with the presence of AF. Angiotensin type 1 receptor antagonist appears to be effective in alleviating atrial fibrosis in a rabbit AF model, partly reducing angiotensin type 1 receptor‐p38mitogen‐activated protein kinase‐dependent and ‐independent CatK activation, thus preventing AF

Randomised, multicentre prospective trial of transarterial chemoembolisation (TACE) plus sorafenib as compared with TACE alone in patients with hepatocellular carcinoma: TACTICS trial.

OBJECTIVE:This trial compared the efficacy and safety of transarterial chemoembolisation (TACE) plus sorafenib with TACE alone using a newly established TACE-specific endpoint and pre-treatment of sorafenib before initial TACE. DESIGN:Patients with unresectable hepatocellular carcinoma (HCC) were randomised to TACE plus sorafenib (n=80) or TACE alone (n=76). Patients in the combination group received sorafenib 400 mg once daily for 2-3 weeks before TACE, followed by 800 mg once daily during on-demand conventional TACE sessions until time to untreatable (unTACEable) progression (TTUP), defined as untreatable tumour progression, transient deterioration to Child-Pugh C or appearance of vascular invasion/extrahepatic spread. Co-primary endpoints were progression-free survival (PFS), which is not a conventional one but defined as TTUP, or time to any cause of death plus overall survival (OS). Multiplicity was adjusted by gatekeeping hierarchical testing. RESULTS:Median PFS was significantly longer in the TACE plus sorafenib than in the TACE alone group (25.2 vs 13.5 months; p=0.006). OS was not analysed because only 73.6% of OS events were reached. Median TTUP (26.7 vs 20.6 months; p=0.02) was also significantly longer in the TACE plus sorafenib group. OS at 1 year and 2 years in TACE plus sorafenib group and TACE alone group were 96.2% and 82.7% and 77.2% and 64.6%, respectively. There were no unexpected toxicities. CONCLUSION:TACE plus sorafenib significantly improved PFS over TACE alone in patients with unresectable HCC. Adverse events were consistent with those of previous TACE combination trials. TRIAL REGISTRATION NUMBER:NCT01217034

Cathepsin K activity controls cardiotoxin‐induced skeletal muscle repair in mice

Abstract Background: Cathepsin K (CatK) is a widely expressed cysteine protease that has gained attention because of its enzymatic and non‐enzymatic functions in signalling. Here, we examined whether CatK‐deficiency (CatK−/−) would mitigate injury‐related skeletal muscle remodelling and fibrosis in mice, with a special focus on inflammation and muscle cell apoptosis. Methods: Cardiotoxin (CTX, 20 μM/200 μL) was injected into the left gastrocnemius muscle of male wild‐type (CatK+/+) and CatK−/− mice, and the mice were processed for morphological and biochemical studies. Results: On post‐injection Day 14, CatK deletion ameliorated muscle interstitial fibrosis and remodelling and performance. At an early time point (Day 3), CatK−/− reduced the lesion macrophage and leucocyte contents and cell apoptosis, the mRNA levels of monocyte chemoattractant protein‐1, toll‐like receptor‐2 and toll‐like receptor‐4, and the gelatinolytic activity related to matrix metalloproteinase‐2/‐9. CatK deletion also restored the protein levels of caspase‐3 and cleaved caspase‐8 and the ratio of the BAX to the Bcl‐2. Moreover, CatK deficiency protected muscle fibre laminin and desmin disorder in response to CTX injury. These beneficial muscle effects were mimicked by CatK‐specific inhibitor treatment. In vitro experiments demonstrated that pharmacological CatK inhibition reduced the apoptosis of C2C12 mouse myoblasts and the levels of BAX and caspase‐3 proteins induced by CTX. Conclusions: These results demonstrate that CatK plays an essential role in skeletal muscle loss and fibrosis in response to CTX injury, possibly via a reduction of inflammation and cell apoptosis, suggesting a novel therapeutic strategy for the control of skeletal muscle diseases by regulating CatK activity