55 research outputs found
The role of urate and xanthine oxidase in vascular oxidative stress:Future directions
No full textVascular oxidative stress has been shown to be a potent factor in the pathophysiology of endothelial dysfunction. Despite current optimal evidence-based therapy, mortality from various cardiovascular disorders remains high. The search for newer, novel ways of attenuating endothelial dysfunction has yielded several new and exciting possibilities, one of which is the manipulation of urate levels using xanthine oxidase inhibitors. Agents such as allopurinol have shown marked improvements in vascular endothelial function in various cohorts at risk of cardiovascular events. Most of the evidence so far comes from smaller mechanistic studies. The few large randomized controlled trials have failed to show any significant mortality benefit using these agents. This article highlights the potential avenues of further research such as dose-response, and the potential for these agents to regress left ventricular hypertrophy. The role of newer agents such as febuxostat and oxypurinol are discussed as well as potential reasons why some of the current newer agents have failed to live up to the promising early-phase data. It is crucial that these remaining questions surrounding urate, xanthine oxidase and the role of various agents that affect this important oxidative stress-generating system are answered, and therefore these promising agents should not be discarded prematurely
The Sec1/Munc18 protein Vps45 regulates cellular levels of its SNARE binding partners Tlg2 and Snc2 in Saccharomyces cerevisiae
No full textIntracellular membrane trafficking pathways must be tightly regulated to ensure proper functioning of all eukaryotic cells. Central to membrane trafficking is the formation of specific SNARE (soluble N-ethylmeleimide-sensitive factor attachment protein receptor) complexes between proteins on opposing lipid bilayers. The Sec1/Munc18 (SM) family of proteins play an essential role in SNARE-mediated membrane fusion, and like the SNAREs are conserved through evolution from yeast to humans. The SM protein Vps45 is required for the formation of yeast endosomal SNARE complexes and is thus essential for traffic through the endosomal system. Here we report that, in addition to its role in regulating SNARE complex assembly, Vps45 regulates cellular levels of its SNARE binding partners: the syntaxin Tlg2 and the v-SNARE Snc2: Cells lacking Vps45 have reduced cellular levels of Tlg2 and Snc2; and elevation of Vps45 levels results in concomitant increases in the levels of both Tlg2 and Snc2. As well as regulating traffic through the endosomal system, the Snc v-SNAREs are also required for exocytosis. Unlike most vps mutants, cells lacking Vps45 display multiple growth phenotypes. Here we report that these can be reversed by selectively restoring Snc2 levels in vps45 mutant cells. Our data indicate that as well as functioning as part of the machinery that controls SNARE complex assembly, Vps45 also plays a key role in determining the levels of its cognate SNARE proteins; another key factor in regulation of membrane traffic
Sarcopenia:a potential target for Angiotensin-converting enzyme inhibition?
No full textSociety is ageing. There has been a steady increase in the number of people aged 65 years and over throughout the 20th century and this trend is predicted to continue worldwide. This has resulted in an increase in the incidence of sarcopenia, which is a loss of muscle mass and function with age. Maintenance of muscular function into old age is critical to sustaining normal daily activity and functional independence. Sarcopenia is associated with increased morbidity and mortality. Till now most efforts to counteract sarcopenia have met with limited success. We postulate that targeting the renin-angiotensin system through angiotensin-converting enzyme (ACE) inhibition could play a role in countering sarcopenia. ACE inhibitors could work by preventing mitochondrial decline and improving endothelial function and muscle metabolism. We describe the literature to support our hypothesis that sarcopenia may be a potential therapeutic target for ACE inhibitors
Social, environmental and psychological factors associated with objective physical activity levels in the over 65s
No full textObjective: To assess physical activity levels objectively using accelerometers in community dwelling over 65 s and to examine associations with health, social, environmental and psychological factors. Design: Cross sectional survey. Setting: 17 general practices in Scotland, United Kingdom. Participants: Random sampling of over 65 s registered with the practices in four strata young-old (65–80 years), old-old (over 80 years), more affluent and less affluent groups. Main Outcome Measures: Accelerometry counts of activity per day. Associations between activity and Theory of Planned Behaviour variables, the physical environment, health, wellbeing and demographic variables were examined with multiple regression analysis and multilevel modelling. Results: 547 older people (mean (SD) age 79(8) years, 54% female) were analysed representing 94% of those surveyed. Accelerometry counts were highest in the affluent younger group, followed by the deprived younger group, with lowest levels in the deprived over 80 s group. Multiple regression analysis showed that lower age, higher perceived behavioural control, the physical function subscale of SF-36, and having someone nearby to turn to were all independently associated with higher physical activity levels (R2 = 0.32). In addition, hours of sunshine were independently significantly associated with greater physical activity in a multilevel model. Conclusions: Other than age and hours of sunlight, the variables identified are modifiable, and provide a strong basis for the future development of novel multidimensional interventions aimed at increasing activity participation in later life.Peer reviewe
Incomprehension or resistance? : the Markan disciples and the narrative logic of Mark 4:1—8:30
No full textThe characterization of the Markan disciples has been and continues to be the object of much scholarly reflection and speculation. For many, the Markan author’s presentation of Jesus’ disciples holds a key, if not the key, to unlocking the purpose and function of the gospel as a whole. Commentators differ as to whether the Markan disciples ultimately serve a pedagogical or polemical function, yet they are generally agreed that the disciples in Mark come off rather badly, especially when compared to their literary counterparts in Matthew, Luke, and John.
This narrative-critical study considers the characterization of the Markan disciples within the Sea Crossing movement (Mark 4:1–8:30). While commentators have, on the whole, interpreted the disciples’ negative characterization in this movement in terms of lack of faith and/or incomprehension, neither of these, nor a combination of the two, fully accounts for the severity of language leveled against the disciples by the narrator (6:52) and Jesus (8:17–18). Taking as its starting point an argument by Jeffrey B. Gibson (1986) that the harshness of Jesus’ rebuke in Mark 8:14–21 is occasioned not by the disciples’ lack of faith or incomprehension but by their active resistance to his Gentile mission, this investigation uncovers additional examples of the disciples’ resistance to Gentile mission, offering a better account of their negative portrayal within the Sea Crossing movement and helping explain many of their other failures.
In short, this study argues that in Mark 4:1–8:26, the disciples are characterized as resistant to Jesus’ Gentile mission and to their participation in that mission, the chief consequence being that they are rendered incapable of recognizing Jesus’ vocational identity as Israel’s Messiah (Thesis A). This leads to a secondary thesis, namely, that in Mark 8:27–30, Peter’s recognition of Jesus’ messianic identity indicates that the disciples have finally come to accept Jesus’ Gentile mission and their participation in it (Thesis B).
“Chapter One: Introduction” offers a selective review of scholarly treatments of the Markan disciples, which shows that few scholars attribute resistance, let alone purposeful resistance, to the disciples.
“Chapter Two: The Rhetoric of Repetition” introduces the methodological tools, concepts, and perspectives employed in the study. It includes a section on narrative criticism, which focuses upon the story-as-discoursed and the implied author and reader, and a section on Construction Grammar, a branch of cognitive linguistics founded by Charles Fillmore and further developed by Paul Danove, which focuses upon semantic and narrative frames and case frame analysis.
“Chapter Three: The Sea Crossing Movement, Mark 4:1–8:30” addresses the question of Markan structure and argues that Mark 4:1–8:30 comprises a single, unified, narrative movement, whose action and plot is oriented to the Sea of Galilee and whose most distinctive feature is the network of sea crossings that transport Jesus and his disciples back and forth between Jewish and Gentile geopolitical spaces.
Following William Freedman, “Chapter Four: The Literary Motif” introduces two criteria (frequency and avoidability) for determining objectively what constitutes a literary motif and provides the methodological basis and starting point for the analyses performed in chapters five and six.
“Chapter Five: The Sea Crossing Motif” establishes and then carries out a lengthy narrative analysis of the Sea Crossing motif, which is oriented around Mark’s use of θάλασσα (thalassa) and πλοῖον (ploion), and “Chapter Six: The Loaves Motif” does the same for The Loaves motif, oriented around Mark’s use of ἄρτος (artos).
Finally, “Chapter Seven: The Narrative Logic of the Disciples (In)comprehension” draws together all narrative, linguistic, and exegetical insights of the previous chapters and offers a single coherent reading of the Sea Crossing movement that establishes Theses A and B.
Association of day length and weather conditions with physical activity levels in older community dwelling people
No full textBackground: Weather is a potentially important determinant of physical activity. Little work has been done examining the relationship between weather and physical activity, and potential modifiers of any relationship in older people. Wetherefore examined the relationship between weather and physical activity in a cohort of older community-dwelling people.Methods: We analysed prospectively collected cross-sectional activity data from community-dwelling people aged 65 and over in the Physical Activity Cohort Scotland. We correlated seven day triaxial accelerometry data with daily weather data (temperature, day length, sunshine, snow, rain), and a series of potential effect modifiers were tested in mixed models: environmental variables (urban vs rural dwelling, percentage of green space), psychological variables (anxiety, depression, perceived behavioural control), social variables (number of close contacts) and health status measured using the SF-36questionnaire.Results: 547 participants, mean age 78.5 years, were included in this analysis. Higher minimum daily temperature and longer day length were associated with higher activity levels; these associations remained robust to adjustment for othersignificant associates of activity: age, perceived behavioural control, number of social contacts and physical function. Of the potential effect modifier variables, only urban vs rural dwelling and the SF-36 measure of social functioning enhanced the association between day length and activity; no variable modified the association between minimum temperature and activity.Conclusions: In older community dwelling people, minimum temperature and day length were associated with objectively measured activity. There was little evidence for moderation of these associations through potentially modifiable health, environmental, social or psychological variables<br/
Predictors of exercise capacity and everyday activity in older heart failure patients
No full textBackground: Exercise capacity and daily activity are key outcomes for older, frail heart failure patients. Little is known about the determinants of these outcomes in this patient group. Aims: To explore predictors of exercise capacity and daily activity in older, frail heart failure patients. Methods: Analysis of prospectively collected data from a cohort of 82 patients aged 70 years and over, enrolled in a randomised controlled trial of exercise in heart failure patients. Pathophysiological, demographic, psychological and social factors were analysed by multivariate regression to determine predictors of exercise capacity (6-min walk distance) and daily activity (daily accelerometer counts). Results: Between 49% and 55% of the variance in 6-min walk distance was explained by variables including New York Heart Association class, depression score, attitude to ageing and use of walking aids. Only 11% to 26% of the variance in accelerometer scores was explained by the model; 6-min walk distance was the only consistent predictor of daily activity. Conclusions: Physical, psychological and attitudinal variables contribute to variance of the 6-min walk. Six-minute walk distance predicts a small amount of the variance in daily activity, but the majority of variance in daily activity remains unexplained and requires further investigation
Long-term follow-up of very old heart failure patients enrolled in a trial of exercise training
No full textLittle is known about how physical and psychological status changes with time in older heart failure patients. The authors followed up a cohort of 82 patients (mean age, 80.5 years) enrolled in a randomized controlled trial of exercise training in heart failure. Six-minute walk test, accelerometry, functional status, quality of life, anxiety, and depression were measured at baseline, 3 months, 6 months, and a mean of 19 months post-enrollment. There were no significant differences between the exercise and control groups at long-term follow-up. Six-minute walk distance declined by only 0.2 m/month in those attending final follow-up (vs 4.6 m/month in nonattenders; P=.03). Similar results were seen for other outcomes. Only a small proportion of the variance in change of any of the outcomes was explained by differences in baseline variables
Long-term follow-up for mortality and cancer in a randomized placebo-controlled trial of vitamin D3 and/or calcium (RECORD Trial)
No full textContext: Vitamin D or calcium supplementation may have effects on vascular disease and cancer. Objective: Our objective was to investigate whether vitamin D or calcium supplementation affects mortality, vascular disease, and cancer in older people. Design and Setting: The study included long-term follow-up of participants in a two by two factorial, randomized controlled trial from 21 orthopedic centers in the United Kingdom. Participants: Participants were 5292 people (85% women) aged at least 70 yr with previous low-trauma fracture. Interventions: Participants were randomly allocated to daily vitamin D3 (800 IU), calcium (1000 mg), both, or placebo for 24–62 months, with a follow-up of 3 yr after intervention. Main Outcome Measures: All-cause mortality, vascular disease mortality, cancer mortality, and cancer incidence were evaluated. Results: In intention-to-treat analyses, mortality [hazard ratio (HR) = 0.93; 95% confidence interval (CI) = 0.85–1.02], vascular disease mortality (HR = 0.91; 95% CI = 0.79–1.05), cancer mortality (HR = 0.85; 95% CI = 0.68–1.06), and cancer incidence (HR = 1.07; 95% CI = 0.92–1.25) did not differ significantly between participants allocated vitamin D and those not. All-cause mortality (HR = 1.03; 95% CI = 0.94–1.13), vascular disease mortality (HR = 1.07; 95% CI = 0.92–1.24), cancer mortality (HR = 1.13; 95% CI = 0.91–1.40), and cancer incidence (HR = 1.06; 95% CI = 0.91–1.23) also did not differ significantly between participants allocated calcium and those not. In a post hoc statistical analysis adjusting for compliance, thus with fewer participants, trends for reduced mortality with vitamin D and increased mortality with calcium were accentuated, although all results remain nonsignificant. Conclusions: Daily vitamin D or calcium supplementation did not affect mortality, vascular disease, cancer mortality, or cancer incidence
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