Atrial fibrillation (AF) is the most common clinical tachyarrhythmia associated with significant morbidity and mortality and is expected to affect approximately 30 million North Americans and Europeans by 2050. AF is a persistent disease, caused by progressive, often age-related, derailment of proteostasis resulting in structural remodeling of the atrial cardiomyocytes. It has been widely acknowledged that the progressive nature of the disease hampers the effective functional conversion to sinus rhythm in patients and explains the limited effect of current drug therapies. Therefore, research is directed at preventing new-onset AF by limiting the development of substrates underlying AF promotion. Upstream therapy refers to the use of drugs that modify the atrial substrate- or target-specific mechanisms of AF, with the ultimate aim to prevent the occurrence (primary prevention) and recurrence of the arrhythmia following (spontaneous) conversion and to prevent the progression of AF (secondary prevention). Recently, we observed that heat shock protein (HSP)-inducing drugs, such as geranylgeranylacetone, prevent derailment of proteostasis and remodeling of cardiomyocytes and thereby attenuate the AF substrate in cellular, Drosophila melanogaster, and animal experimental models. Also, correlative data from human studies were consistent with a protective role of HSPs in preventing the progression from paroxysmal AF to permanent AF and in the recurrence of AF. In this review, we discuss novel HSP-inducing compounds as emerging therapeutics for the primary and secondary prevention of AF. © 2012 Elsevier Inc.
DOCUMENT
Background: The heat shock protein (HSP) inducer, geranylgeranylacetone (GGA), was previously found to protect against atrial fibrillation (AF) remodeling in experimental model systems. Clinical application of GGA in AF is limited, due to low systemic concentrations owing to the hydrophobic character of GGA.Objectives: To identify novel HSP-inducing compounds, with improved physicochemical properties, that prevent contractile dysfunction in experimental model systems for AF.
DOCUMENT
BackgroundTo describe the prevalence of multimorbidity and to study the association between acute and chronic diseases in acutely hospitalized older patientsMethodsProspective cohort study conducted between 2006 and 2008 in three teaching hospitals in the Netherlands. 639 patients aged 65 years and older, hospitalized for > 48 h were included. Two physicians scored diseases, using ICD-9 codes. Chronic multimorbidity was defined as the presence of ≥ 2 chronic diseases, and acute multimorbidity as ≥ 1 acute diseases upon pre-existent chronic diseases. Logistic regression analyses were conducted to analyse cluster associations between a chronic index disease and the concurrent chronic or acute disease, corrected for age and sex.ResultsThe mean age of patients was 78 years, over 50% had ADL impairments. Prevalence of chronic multimorbidity was 69%, and acute multimorbidity was present in 88%. Hypertension (OR 1.16; 95% CI 1.08–1.24), diabetes (type I or type 2) (OR 1.12; 95% CI 1.04–1.21), heart failure (OR 1.25; 95% CI 1.14–1.38) and COPD (OR 1.19; 95% CI 1.05–1.34) were associated with acute renal failure. Hypertension (OR 1.10; 95% CI 1.04–1.17) and atrial fibrillation (OR 1.17; 95% CI 1.08–1.27) were associated with an adverse drug event. Gastro-intestinal bleeding was clustered with atrial fibrillation (OR 1.11; 95% CI 1.04–1.19) and gastric ulcer (OR 1.16; 95% CI 1.07–1.25).ConclusionBoth acute and chronic multimorbidity was frequently present in hospitalized older patients. We identified specific associations between acute and chronic diseases. There is a need for strategies addressing multimorbidity during the exacerbation of chronic diseases.
DOCUMENT
Samenvatting Achtergrond: Een integrale behandeling inclusief zelfmanagement bij chronisch obstructieve longziekte (COPD) leidt tot betere klinische resultaten. eHealth kan zorgen voor meer betrokkenheid bij patiënten waardoor ze in staat zijn een gezondere levensstijl aan te nemen en vast te houden. Desondanks is er geen eenduidig bewijs van de impact van eHealth op de kwaliteit van leven (quality of life (QoL)). Doel: Het primaire doel van de e-Vita COPD-studie was om te onderzoeken wat de effecten zijn van het gebruik van eeneHealth-platform voor patiënten op de verschillende domeinen van ziektespecifieke kwaliteit van leven van COPD-patiënten (CCQ). Methoden: We hebben de impact beoordeeld van het gebruik van een eHealth-platform op de klinische COPD-vragenlijst (CCQ). Deze vragenlijst omvatte subschalen van symptomen, functionele en mentale toestand. Een design met onderbroken tijdreeksen (interrupted time series (ITS)) is gebruikt om CCQ-gegevens op verschillende tijdstippen te verzamelen. Er is gebruik gemaakt van multilevel lineaire regressieanalyse om de CCQ-trends vóór en na de interventie te vergelijken. Resultaten: Van de 742 uitgenodigde COPD-patiënten hebben er 244 het document voor ‘informed consent’ ondertekend. In de analyses hebben we uitsluitend patiënten opgenomen die daadwerkelijk gebruik hebben gemaakt van het eHealthplatform (n=123). De afname van CCQ-symptomen was 0,20% vóór de interventie en 0,27% na de interventie; dit was een statistisch significant verschil (P=0,027). De daling van CCQ-mentale toestand was 0,97% vóór de interventie en na de interventie was er sprake van een stijging van 0,017%; dit verschil was statistisch significant (P=0,01). Er werd geen significant verschil vastgesteld in het verloop van CCQ (P=0,12) en CCQ-functionele toestand (P=0,11) vóór en na de interventie. Conclusie: Het e-Vita eHealth-platform had een gunstig effect op de CCQ-symptomen van COPD-patiënten, maar niet op de functionele status. De CCQ-mentale toestand bleef stabiel na de interventie, maar dit was een verslechtering in vergelijking met de verbeterende situatie voorafgaand aan de start van het eHealth-platform. Deze studie laat dus zien dat patiënten na de introductie van het COPD-platform minder symptomen ervaarden, maar dat hun mentale toestand tegelijkertijd licht verslechterde. Zorgprofessionals moeten zich ervan bewust zijn dat, ondanks de verbetering van symptomen, er een lichte toename van angst en depressie kan optreden na invoering van een eHealth-interventie.
DOCUMENT
Circulating sex hormone levels have been linked to a wide range of cardiovascular risk factors in men, but studies on incident CVD have been inconclusive [1]. Recent data from meta-analyses show an increase in CVD risk with low testosterone in elderly men and no association with estradiol levels [2,3]. To clarify the role of sex hormones in male CVD risk, we examined the cross-sectional and longitudinal associations between endogenous sex hormones and subclinical atherosclerosis in a population-based cohort of middle-aged and older men.
DOCUMENT
According to the "membrane sensor" hypothesis, the membrane's physical properties and microdomain organization play an initiating role in the heat shock response. Clinical conditions such as cancer, diabetes and neurodegenerative diseases are all coupled with specific changes in the physical state and lipid composition of cellular membranes and characterized by altered heat shock protein levels in cells suggesting that these "membrane defects" can cause suboptimal hsp-gene expression. Such observations provide a new rationale for the introduction of novel, heat shock protein modulating drug candidates. Intercalating compounds can be used to alter membrane properties and by doing so normalize dysregulated expression of heat shock proteins, resulting in a beneficial therapeutic effect for reversing the pathological impact of disease. The membrane (and lipid) interacting hydroximic acid (HA) derivatives discussed in this review physiologically restore the heat shock protein stress response, creating a new class of "membrane-lipid therapy" pharmaceuticals. The diseases that HA derivatives potentially target are diverse and include, among others, insulin resistance and diabetes, neuropathy, atrial fibrillation, and amyotrophic lateral sclerosis. At a molecular level HA derivatives are broad spectrum, multi-target compounds as they fluidize yet stabilize membranes and remodel their lipid rafts while otherwise acting as PARP inhibitors. The HA derivatives have the potential to ameliorate disparate conditions, whether of acute or chronic nature. Many of these diseases presently are either untreatable or inadequately treated with currently available pharmaceuticals. Ultimately, the HA derivatives promise to play a major role in future pharmacotherapy.
LINK
Abstract Background: Integrated disease management with self-management for Chronic Obstructive Pulmonary Disease (COPD) is effective to improve clinical outcomes. eHealth can improve patients’ involvement to be able to accept and maintain a healthier lifestyle. Eventhough there is mixed evidence of the impact of eHealth on quality of life (QoL) in different settings. Aim: The primary aim of the e-Vita-COPD-study was to investigate the effect of use of eHealth patient platforms on disease specific QoL of COPD patients. Methods: We evaluated the impact of an eHealth platform on disease specific QoL measured with the clinical COPD questionnaire (CCQ), including subscales of symptoms, functional state and mental state. Interrupted time series (ITS) design was used to collect CCQ data at multiple time points. Multilevel linear regression modelling was used to compare trends in CCQ before and after the intervention. Results: Of 742 invited COPD patients, 244 signed informed consent. For the analyses, we only included patients who actually used the eHealth platform (n = 123). The decrease of CCQ-symptoms was 0.20% before the intervention and 0.27% after the intervention; this difference in slopes was statistically significant (P = 0.027). The decrease of CCQ-mental was 0.97% before the intervention and after the intervention there was an increase of 0.017%; this difference was statistically significant (P = 0.01). No significant difference was found in the slopes of CCQ (P = 0.12) and CCQ-function (P = 0.11) before and after the intervention. Conclusion: The e-Vita eHealth platform had a potential beneficial impact on the CCQ-symptoms of COPD patients, but not on functional state. The CCQ-mental state remained stable after the intervention, but this was a deterioration compared to the improving situation before the start of the eHealth platform. Therefore, health care providers should be aware that, although symptoms improve, there might be a slight increase in anxiety and depression after introducing an eHealth intervention to support self-management. Trial registration: Our study is registered in the Dutch Trial Register (national registration of clinical trails, mandatory for publication) with number NTR4098 and can be found at http://www.trialregister.nl/trial/3936.
DOCUMENT
Purpose Pre-stroke frailty in older adults is associated with adverse outcomes after stroke in community-based and hospitalbased populations. The aim of our study was to investigate the prevalence of pre-stroke frailty among older stroke survivors receiving medical specialistic rehabilitation and its association with outcomes and recovery. Methods Pre-stroke frailty was measured by the Groningen Frailty Indicator (GFI, score ≥ 4 indicates frailty) in patients≥65 years receiving stroke medical specialistic rehabilitation. Baseline, follow-up and change (i.e. recovery) scores of the Barthel index (BI), Stroke Impact Scale (SIS) ‘mobility’, ‘communication’, and ‘memory and thinking’, Hospital Anxiety and Depression Scale (HADS) and the EuroQoL-5 dimensions (EQ-5D) were compared between frail and non-frail patients with a multivariable regression model adjusting for confounders. Results Of 322 included patients (34.2% females, median age 70 years), 43 (13.4%) patients reported pre-stroke frailty. There were no diferences in BI or in destination of discharge between pre-stroke frail and non-frail stroke survivors receiving inpatient rehabilitation. However, pre-stroke frailty was associated with worse follow-up scores for all other measures. Recovery in pre-stroke frail patients was less favorable compared to non-frail patients for SIS mobility, HADS subscales and EQ-5D index and visual analogue scale. Conclusion Pre-stroke frailty was present in a minority of older stroke survivors receiving medical specialistic rehabilitation. BI and destination of discharge did not difer. Nevertheless, pre-stroke frailty was associated with worse functioning at follow-up for most measures of health status and with smaller improvements in mobility, mood and quality of life.
DOCUMENT
PURPOSE: Clinical examination is often the first step to diagnose shock and estimate cardiac index. In the Simple Intensive Care Studies-I, we assessed the association and diagnostic performance of clinical signs for estimation of cardiac index in critically ill patients.METHODS: In this prospective, single-centre cohort study, we included all acutely ill patients admitted to the ICU and expected to stay > 24 h. We conducted a protocolised clinical examination of 19 clinical signs followed by critical care ultrasonography for cardiac index measurement. Clinical signs were associated with cardiac index and a low cardiac index (< 2.2 L min-1 m2) in multivariable analyses. Diagnostic test accuracies were also assessed.RESULTS: We included 1075 patients, of whom 783 (73%) had a validated cardiac index measurement. In multivariable regression, respiratory rate, heart rate and rhythm, systolic and diastolic blood pressure, central-to-peripheral temperature difference, and capillary refill time were statistically independently associated with cardiac index, with an overall R2 of 0.30 (98.5% CI 0.25-0.35). A low cardiac index was observed in 280 (36%) patients. Sensitivities and positive and negative predictive values were below 90% for all signs. Specificities above 90% were observed only for 110/280 patients, who had atrial fibrillation, systolic blood pressures < 90 mmHg, altered consciousness, capillary refill times > 4.5 s, or skin mottling over the knee.CONCLUSIONS: Seven out of 19 clinical examination findings were independently associated with cardiac index. For estimation of cardiac index, clinical examination was found to be insufficient in multivariable analyses and in diagnostic accuracy tests. Additional measurements such as critical care ultrasonography remain necessary.
DOCUMENT
Author supplied Business rules play a critical role in an organization’s daily activities. With the increased use of business rules (solutions) the interest in modelling guidelines that address the manageability of business rules has increased as well. However, current research on modelling guidelines is mainly based on a theoretical view of modifications that can occur to a business rule set. Research on actual modifications that occur in practice is limited. The goal of this study is to identify modifications that can occur to a business rule set and underlying business rules. To accomplish this goal we conducted a grounded theory study on 229 rules set, as applied from March 2006 till June 2014, by the National Health Service. In total 3495 modifications have been analysed from which we defined eleven modification categories that can occur to a business rule set. The classification provides a framework for the analysis and design of business rules management architectures.
DOCUMENT
