7 research outputs found
Levosimendan: Molecular mechanisms and clinical implications: consensus of experts on the mechanisms of action of levosimendan.
The molecular background of the Ca(2+)-sensitizing effect of levosimendan relates to its specific interaction with the Ca(2+)-sensor troponin C molecule in the cardiac myofilaments. Over the years, significant preclinical and clinical evidence has accumulated and revealed a variety of beneficial pleiotropic effects of levosimendan and of its long-lived metabolite, OR-1896. First of all, activation of ATP-sensitive sarcolemmal K(+) channels of smooth muscle cells appears as a powerful vasodilator mechanism. Additionally, activation of ATP-sensitive K(+) channels in the mitochondria potentially extends the range of cellular actions towards the modulation of mitochondrial ATP production and implicates a pharmacological mechanism for cardioprotection. Finally, it has become evident, that levosimendan possesses an isoform-selective phosphodiesterase-inhibitory effect. Interpretation of the complex mechanism of levosimendan action requires that all potential pharmacological interactions are analyzed carefully in the framework of the currently available evidence. These data indicate that the cardiovascular effects of levosimendan are exerted via more than an isolated drug-receptor interaction, and involve favorable energetic and neurohormonal changes that are unique in comparison to other types of inodilators
Placebo effect characteristics observed in a single, international, longitudinal study in Huntington's disease.
Item does not contain fulltextBACKGROUND: Classically, clinical trials are based on the placebo-control design. Our aim was to analyze the placebo effect in Huntington's disease. METHODS: Placebo data were obtained from an international, longitudinal, placebo-controlled trial for Huntington's disease (European Huntington's Disease Initiative Study Group). One-hundred and eighty patients were evaluated using the Unified Huntington Disease Rating Scale over 36 months. A placebo effect was defined as an improvement of at least 50% over baseline scores in the Unified Huntington Disease Rating Scale, and clinically relevant when at least 10% of the population met it. RESULTS: Only behavior showed a significant placebo effect, and the proportion of the patients with placebo effect ranged from 16% (first visit) to 41% (last visit). Nondepressed patients with better functional status were most likely to be placebo-responders over time. CONCLUSIONS: In Huntington's disease, behavior seems to be more vulnerable to placebo than overall motor function, cognition, and function1 maart 201
Guidelines for the use and interpretation of assays for monitoring autophagy in higher eukaryotes
Research in autophagy continues to accelerate,(1) and as a result many new scientists are entering the field. Accordingly, it is important to establish a standard set of criteria for monitoring macroautophagy in different organisms. Recent reviews have described the range of assays that have been used for this purpose.(2,3) There are many useful and convenient methods that can be used to monitor macroautophagy in yeast, but relatively few in other model systems, and there is much confusion regarding acceptable methods to measure macroautophagy in higher eukaryotes. A key point that needs to be emphasized is that there is a difference between measurements that monitor the numbers of autophagosomes versus those that measure flux through the autophagy pathway; thus, a block in macroautophagy that results in autophagosome accumulation needs to be differentiated from fully functional autophagy that includes delivery to, and degradation within, lysosomes (in most higher eukaryotes) or the vacuole (in plants and fungi). Here, we present a set of guidelines for the selection and interpretation of the methods that can be used by investigators who are attempting to examine macroautophagy and related processes, as well as by reviewers who need to provide realistic and reasonable critiques of papers that investigate these processes. This set of guidelines is not meant to be a formulaic set of rules, because the appropriate assays depend in part on the question being asked and the system being used. In addition, we emphasize that no individual assay is guaranteed to be the most appropriate one in every situation, and we strongly recommend the use of multiple assays to verify an autophagic response
Suicidal ideation in a European Huntington's disease population
Previous studies indicate increased prevalences of suicidal ideation,
suicide attempts, and completed suicide in Huntington's disease (HD) compared
with the general population. This study investigates correlates and predictors of
suicidal ideation in HD.
METHODS: The study cohort consisted of 2106 HD mutation carriers, all
participating in the REGISTRY study of the European Huntington's Disease Network.
Of the 1937 participants without suicidal ideation at baseline, 945 had one or
more follow-up measurements. Participants were assessed for suicidal ideation by
the behavioural subscale of the Unified Huntington's Disease Rating Scale
(UHDRS). Correlates of suicidal ideation were analyzed using logistic regression
analysis and predictors were analyzed using Cox regression analysis.
RESULTS: At baseline, 169 (8.0%) mutation carriers endorsed suicidal ideation.
Disease duration (odds ratio [OR]=0.96; 95% confidence interval [CI]: 0.9-1.0),
anxiety (OR=2.14; 95%CI: 1.4-3.3), aggression (OR=2.41; 95%CI: 1.5-3.8), a
previous suicide attempt (OR=3.95; 95%CI: 2.4-6.6), and a depressed mood
(OR=13.71; 95%CI: 6.7-28.0) were independently correlated to suicidal ideation at
baseline. The 4-year cumulative incidence of suicidal ideation was 9.9%.
Longitudinally, the presence of a depressed mood (hazard ratio [HR]=2.05; 95%CI:
1.1-4.0) and use of benzodiazepines (HR=2.44; 95%CI: 1.2-5.0) at baseline were
independent predictors of incident suicidal ideation, whereas a previous suicide
attempt was not predictive.
LIMITATIONS: As suicidal ideation was assessed by only one item, and participants
were a selection of all HD mutation carriers, the prevalence of suicidal ideation
was likely underestimated.
CONCLUSIONS: Suicidal ideation in HD frequently occurs. Assessment of suicidal
ideation is a priority in mutation carriers with a depressed mood and in those
using benzodiazepines
Outcomes from elective colorectal cancer surgery during the SARSâCoVâ2 pandemic
Aim
This study aimed to describe the change in surgical practice and the impact of SARS-CoV-2 on mortality after surgical resection of colorectal cancer during the initial phases of the SARS-CoV-2 pandemic.
Method
This was an international cohort study of patients undergoing elective resection of colon or rectal cancer without preoperative suspicion of SARS-CoV-2. Centres entered data from their first recorded case of COVID-19 until 19 April 2020. The primary outcome was 30-day mortality. Secondary outcomes included anastomotic leak, postoperative SARS-CoV-2 and a comparison with prepandemic European Society of Coloproctology cohort data.
Results
From 2073 patients in 40 countries, 1.3% (27/2073) had a defunctioning stoma and 3.0% (63/2073) had an end stoma instead of an anastomosis only. Thirty-day mortality was 1.8% (38/2073), the incidence of postoperative SARS-CoV-2 was 3.8% (78/2073) and the anastomotic leak rate was 4.9% (86/1738). Mortality was lowest in patients without a leak or SARS-CoV-2 (14/1601, 0.9%) and highest in patients with both a leak and SARS-CoV-2 (5/13, 38.5%). Mortality was independently associated with anastomotic leak (adjusted odds ratio 6.01, 95% confidence interval 2.58â14.06), postoperative SARS-CoV-2 (16.90, 7.86â36.38), male sex (2.46, 1.01â5.93), age >70 years (2.87, 1.32â6.20) and advanced cancer stage (3.43, 1.16â10.21). Compared with prepandemic data, there were fewer anastomotic leaks (4.9% versus 7.7%) and an overall shorter length of stay (6 versus 7 days) but higher mortality (1.7% versus 1.1%).
Conclusion
Surgeons need to further mitigate against both SARS-CoV-2 and anastomotic leak when offering surgery during current and future COVID-19 waves based on patient, operative and organizational risks