Long-Term Use of Aldosterone-Receptor Antagonists in Uncontrolled Hypertension: A Retrospective Analysis

Background. The long-term efficacy of aldosterone-receptor antagonists (ARAs) as add-on treatment in uncontrolled hypertension has not yet been reported. Methods. Data from 123 patients (21 with primary aldosteronism, 102 with essential hypertension) with difficult-to-treat hypertension who received an ARA between May 2005 and September 2009 were analyzed retrospectively for their blood pressure (BP) and biochemical response at first followup after start with ARA and the last follow-up available. Results. Systolic BP decreased by 22 ± 20 and diastolic BP by 9.4 ± 12 mmHg after a median treatment duration of 25 months. In patients that received treatment >5 years, SBP was 33 ± 20 and DBP was 16 ± 13 mmHg lower than at baseline. Multivariate analysis revealed that baseline BP and follow-up duration were positively correlated with BP response. Conclusion. Add-on ARA treatment in difficult-to-treat hypertension results in a profound and sustained BP reduction

Increased Excretion of C4-Carnitine Species after a Therapeutic Acetylsalicylic Acid Dose: Evidence for an Inhibitory Effect on Short-Chain Fatty Acid Metabolism

Acetylsalicylic acid and/or its metabolites are implicated to have various effects on metabolism and, especially, on mitochondrial function. These effects include both inhibitory and stimulatory effects. We investigated the effect of both combined and separate oral acetylsalicylic acid and acetaminophen administration at therapeutic doses on the urinary metabolite profile of human subjects. In this paper, we provided in vivo evidence, in human subjects, of a statistically significant increase in isobutyrylcarnitine after the administration of a therapeutic dose of acetylsalicylic acid. We, therefore, propose an inhibitory effect of acetylsalicylic acid on the short-chain fatty acid metabolism, possibly at the level of isobutyryl-CoA dehydrogenase

Ventilator-induced endothelial activation and inflammation in the lung and distal organs

Introduction Results from clinical studies have provided evidence for the importance of leukocyte-endothelial interactions in the pathogenesis of pulmonary diseases such as acute lung injury (ALI) and acute respiratory distress syndrome (ARDS), as well as in systemic events like sepsis and multiple organ failure (MOF). The present study was designed to investigate whether alveolar stretch due to mechanical ventilation (MV) may evoke endothelial activation and inflammation in healthy mice, not only in the lung but also in organs distal to the lung. Methods Healthy male C3H/HeN mice were anesthetized, tracheotomized and mechanically ventilated for either 1, 2 or 4 hours. To study the effects of alveolar stretch in vivo, we applied a MV strategy that causes overstretch of pulmonary tissue i.e. 20 cmH(2)O peak inspiratory pressure (PIP) and 0 cmH(2)O positive end expiratory pressure (PEEP). Non-ventilated, shamoperated animals served as a reference group (non-ventilated controls, NVC). Results Alveolar stretch imposed by MV did not only induce de novo synthesis of adhesion molecules in the lung but also in organs distal to the lung, like liver and kidney. No activation was observed in the brain. In addition, we demonstrated elevated cytokine and chemokine expression in pulmonary, hepatic and renal tissue after MV which was accompanied by enhanced recruitment of granulocytes to these organs. Conclusions Our data implicate that MV causes endothelial activation and inflammation in mice without pre-existing pulmonary injury, both in the lung and distal organs

Monitoring storage induced changes in the platelet proteome employing label free quantitative mass spectrometry

Shelf life of platelet concentrates is limited to 5-7 days due to loss of platelet function during storage, commonly referred to as the platelet storage lesion (PSL). To get more insight into the development of the PSL, we used label free quantitative mass spectrometry to identify changes in the platelet proteome during storage. In total 2501 proteins were accurately quantified in 3 biological replicates on at least 1 of the 7 different time-points analyzed. Significant changes in levels of 21 proteins were observed over time. Gene ontology enrichment analysis of these proteins revealed that the majority of this set was involved in platelet degranulation, secretion and regulated exocytosis. Twelve of these proteins have been shown to reside in α-granules. Upon prolonged storage (13-16 days) elevated levels of α-2-macroglobulin, glycogenin and Ig μ chain C region were identified. Taken together this study identifies novel markers for monitoring of the PSL that may potentially also be used for the detection of "young" and "old" platelets in the circulation

Probabilistic Model-Based Safety Analysis

Model-based safety analysis approaches aim at finding critical failure combinations by analysis of models of the whole system (i.e. software, hardware, failure modes and environment). The advantage of these methods compared to traditional approaches is that the analysis of the whole system gives more precise results. Only few model-based approaches have been applied to answer quantitative questions in safety analysis, often limited to analysis of specific failure propagation models, limited types of failure modes or without system dynamics and behavior, as direct quantitative analysis is uses large amounts of computing resources. New achievements in the domain of (probabilistic) model-checking now allow for overcoming this problem. This paper shows how functional models based on synchronous parallel semantics, which can be used for system design, implementation and qualitative safety analysis, can be directly re-used for (model-based) quantitative safety analysis. Accurate modeling of different types of probabilistic failure occurrence is shown as well as accurate interpretation of the results of the analysis. This allows for reliable and expressive assessment of the safety of a system in early design stages

Assessing quality of life in psychosocial and mental health disorders in children:a comprehensive overview and appraisal of generic health related quality of life measures

Background: Mental health problems often arise in childhood and adolescence and can have detrimental effects on people's quality of life (QoL). Therefore, it is of great importance for clinicians, policymakers and researchers to adequately measure QoL in children. With this review, we aim to provide an overview of existing generic measures of QoL suitable for economic evaluations in children with mental health problems. Methods: First, we undertook a meta-review of QoL instruments in which we identified all relevant instruments. Next, we performed a systematic review of the psychometric properties of the identified instruments. Lastly, the results were summarized in a decision tree. Results: This review provides an overview of these 22 generic instruments available to measure QoL in children with psychosocial and or mental health problems and their psychometric properties. A systematic search into the psychometric quality of these instruments found 195 suitable papers, of which 30 assessed psychometric quality in child and adolescent mental health. Conclusions: We found that none of the instruments was perfect for use in economic evaluation of child and adolescent mental health care as all instruments had disadvantages, ranging from lack of psychometric research, no proxy version, not being suitable for young children, no age-specific value set for children under 18, to insufficient focus on relevant domains (e.g. social and emotional domains)

White Matter Connectivity Abnormalities in Prediabetes and Type 2 Diabetes:The Maastricht Study

OBJECTIVE: Prediabetes and type 2 diabetes are associated with structural brain abnormalities, often observed in cognitive disorders. Besides visible lesions, (pre)diabetes might also be associated with alterations of the intrinsic organization of the white matter. In this population-based cohort study, the association of prediabetes and type 2 diabetes with white matter network organization was assessed. RESEARCH DESIGN AND METHODS: In the Maastricht Study, a type 2 diabetes-enriched population-based cohort study (1,361 normal glucose metabolism, 348 prediabetes, and 510 type 2 diabetes assessed by oral glucose tolerance test; 52% men; aged 59 ± 8 years), 3 Tesla structural and diffusion MRI was performed. Whole-brain white matter tractography was used to assess the number of connections (node degree) between 94 brain regions and the topology (graph measures). Multivariable linear regression analyses were used to investigate the associations of glucose metabolism status with network measures. Associations were adjusted for age, sex, education, and cardiovascular risk factors. RESULTS: Prediabetes and type 2 diabetes were associated with lower node degree after full adjustment (standardized [st]βPrediabetes = -0.055 [95% CI -0.172, -0.062], stβType2diabetes = -0.256 [-0.379, -0.133], Ptrend < 0.001). Prediabetes was associated with lower local efficiency (stβ = -0.084 [95% CI -0.159, -0.008], P = 0.033) and lower clustering coefficient (stβ = -0.097 [95% CI -0.189, -0.005], P = 0.049), whereas type 2 diabetes was not. Type 2 diabetes was associated with higher communicability (stβ = 0.148 [95% CI 0.042, 0.253], P = 0.008). CONCLUSIONS: These findings indicate that prediabetes and type 2 diabetes are associated with fewer white matter connections and weaker organization of white matter networks. Type 2 diabetes was associated with higher communicability, which was not yet observed in prediabetes and may reflect the use of alternative white matter connections

Prediabetes Is Associated With Structural Brain Abnormalities:The Maastricht Study

OBJECTIVE Structural brain abnormalities are key risk factors for brain diseases, such as dementia, stroke, and depression, in type 2 diabetes. It is unknown whether structural brain abnormalities already occur in prediabetes. Therefore, we investigated whether both prediabetes and type 2 diabetes are associated with lacunar infarcts (LIs), white matter hyperintensities (WMHs), cerebral microbleeds (CMBs), and brain atrophy. RESEARCH DESIGN and METHODS We used data from 2,228 participants (1,373 with normal glucose metabolism [NGM], 347 with prediabetes, and 508 with type 2 diabetes (oversampled); mean age 59.2 6 8.2 years; 48.3% women) of the Maastricht Study, a population-based cohort study. Diabetes status was determined with an oral glucose tolerance test. Brain imaging was performed with 3 Tesla MRI. Results were analyzed with multivariable logistic and linear regression analyses. RESULTS Prediabetes and type 2 diabetes were associated with the presence of LIs (odds ratio 1.61 [95% CI 0.98-2.63] and 1.67 [1.04-2.68], respectively; P trend = 0.027), larger WMH (b 0.07 log10-transformed mL [log-mL] [95% CI 0.00-0.15] and 0.21 log-mL [0.14-0.28], respectively; P trend <0.001), and smaller white matter volumes (b 24.0 mL [27.3 to 20.6] and 27.2 mL [210.4 to 24.0], respectively; P trend <0.001) compared with NGM. Prediabetes was not associated with gray matter volumes or the presence of CMBs. CONCLUSIONS Prediabetes is associated with structural brain abnormalities, with further deterioration in type 2 diabetes. These results indicate that, in middle-aged populations, structural brain abnormalities already occur in prediabetes, which may suggest that the treatment of early dysglycemia may contribute to the prevention of brain diseases