Rationale and design of the PHOspholamban RElated CArdiomyopathy intervention STudy (i-PHORECAST)

Background: The p.Arg14del (c.40_42delAGA) phospholamban (PLN) pathogenic variant is a founder mutation that causes dilated cardiomyopathy (DCM) and arrhythmogenic cardiomyopathy (ACM). Carriers are at increased risk of malignant ventricular arrhythmias and heart failure, which has been ascribed to cardiac fibrosis. Importantly, cardiac fibrosis appears to be an early feature of the disease, occurring in many presymptomatic carriers before the onset of overt disease. As with most monogenic cardiomyopathies, no evidence-based treatment is available for presymptomatic carriers. Aims: The PHOspholamban RElated CArdiomyopathy intervention STudy (iPHORECAST) is designed to demonstrate that pre-emptive treatment of presymptomatic PLN p.Arg14del carriers using eplerenone, a mineralocorticoid receptor antagonist with established antifibrotic effects, can reduce disease progression and postpone the onset of overt disease. Methods: iPHORECAST has a multicentre, prospective, randomised, open-label, blinded endpoint (PROBE) design. Presymptomatic PLN p.Arg14del carriers are randomised to receive either 50 mg eplerenone once daily or no treatment. The primary endpoint of the study is a multiparametric assessment of disease progression including cardiac magnetic resonance parameters (left and right ventricular volumes, systolic function and fibrosis), electrocardiographic parameters (QRS voltage, ventricular ectopy), signs and/or symptoms related to DCM and ACM, and cardiovascular death. The follow-up duration is set at 3 years. Baseline results: A total of 84 presymptomatic PLN p.Arg14del carriers (n = 42 per group) were included. By design, at baseline, all participants were in New York Heart Association (NHYA) class I and had a left ventricular ejection fraction > 45% and < 2500 ventricular premature contractions during 24-hour Holter monitoring. There were no statistically significant differences between the two groups in any of the baseline characteristics. The study is currently well underway, with the last participants expected to finish in 2021. Conclusion: iPHORECAST is a multicentre, prospective randomised controlled trial designed to address whether pre-emptive treatment of PLN p.Arg14del carriers with eplerenone can prevent or delay the onset of cardiomyopathy. iPHORECAST has been registered in the clinicaltrials.gov-register (number: NCT01857856)

Effects of iron-ore mining and processing on metal bioavailability in a tropical coastal lagoon

In water systems, water quality and geochemical properties of sediments determine the speciation of trace metals, metal transport, and sediment-water exchange, influencing metal availability and its potential effects on biota. Studies from temperate climates have shown that iron-ore mining and tailing wastewaters, besides being a source of trace metals, usually show high levels of dissolved ions and particulate suspended matter, thus having the potential of indirectly changing metal bioavailability. For the first time in the tropics, we identified the effects of iron-ore mining and processing on metal bioavailability in a coastal lagoon. With an extensive sampling scheme, we investigated the potential sources of metals; the links among metal levels in water, sediments, and invertebrates; and the contrasting effects on metal speciation and bioavailability. The metals Fe, Mn, Al, Cr, Zn, Cu, Ni, Pb, Cd, Hg, and As were measured in water, sediments (surface and profiles), and invertebrates from Mãe-Bá Lagoon and in the sites directly influenced by the mining operations (tailing dams and nearby rivers). In addition, samples from two other lagoons, considered pristine, were analyzed. The study area is located in the southeast of Brazil (Iron Quadrangle Region and a coastal area of Espírito Santo State). General water characteristics included pH, dissolved organic carbon, alkalinity, and anion composition. Water metal speciation was assessed by a speciation model (Chemical Equilibria in Aquatic Systems). Grain-size distribution, organic carbon, carbonate, and acid volatile sulfide (AVS) were determined in sediments. Statistical methods included comparison of means by Mann-Whitney test, ordination and correlation analyses, and analysis of regression for geochemical normalization of metals with grain size. The dissolved metal concentrations, the total metal levels in sediments, and the normalization based on the fine sediment fraction showed that the mining operations constitute potential sources of Fe, Mn, Cr, Cu, Ni, Pb, As, and Hg to Mãe-Bá Lagoon. However, trace metal availability was reduced because of increased pH, hardness, and sulfide content (356 μmol/g) in the sites influenced by the mining. The lagoon showed similar water chemistry as in the mining sites, with metal bioavailability further decreased by the presence of dissolved organic carbon and chloride. Although AVS levels in the lagoon were low (0.48-56 μmol/g), metal bioavailability was reduced because of the presence of organic matter. Metal levels in invertebrates confirmed the predicted low metal bioavailability in Mãe-Bá Lagoon. The lagoon was considered moderately contaminated only by Hg and As. The iron-ore mining and processing studied here constitute potential sources of metal pollution into the tropical lagoon. Contrary to expectations, however, it also contributes to reducing the overall metal bioavailability in the lagoon. These findings are believed to be useful for evaluating metal exposure in a more integrated way, identifying not only the sources of pollution but also how they can affect the components involved in metal speciation and bioavailability in water systems, leading to new insights

Effects of Meal Frequency on Metabolic Profiles and Substrate Partitioning in Lean Healthy Males

The daily number of meals has an effect on postprandial glucose and insulin responses, which may affect substrate partitioning and thus weight control. This study investigated the effects of meal frequency on 24 h profiles of metabolic markers and substrate partitioning.Twelve (BMI:21.6 ± 0.6 kg/m(2)) healthy male subjects stayed after 3 days of food intake and physical activity standardization 2 × 36 hours in a respiration chamber to measure substrate partitioning. All subjects randomly received two isoenergetic diets with a Low meal Frequency (3 ×; LFr) or a High meal Frequency (14 ×; HFr) consisting of 15 En% protein, 30 En% fat, and 55 En% carbohydrates. Blood was sampled at fixed time points during the day to measure metabolic markers and satiety hormones.Glucose and insulin profiles showed greater fluctuations, but a lower AUC of glucose in the LFr diet compared with the HFr diet. No differences between the frequency diets were observed on fat and carbohydrate oxidation. Though, protein oxidation and RMR (in this case SMR + DIT) were significantly increased in the LFr diet compared with the HFr diet. The LFr diet increased satiety and reduced hunger ratings compared with the HFr diet during the day.The higher rise and subsequently fall of insulin in the LFr diet did not lead to a higher fat oxidation as hypothesized. The LFr diet decreased glucose levels throughout the day (AUC) indicating glycemic improvements. RMR and appetite control increased in the LFr diet, which can be relevant for body weight control on the long term.ClinicalTrials.gov NCT01034293

Does osteoporosis predispose falls? a study on obstacle avoidance and balance confidence

Contains fulltext : 96832.pdf (publisher's version ) (Open Access)BACKGROUND: Osteoporosis is associated with changes in balance and physical performance and has psychosocial consequences which increase the risk of falling. Most falls occur during walking; therefore an efficient obstacle avoidance performance might contribute to a reduction in fall risk. Since it was shown that persons with osteoporosis are unstable during obstacle crossing it was hypothesized that they more frequently hit obstacles, specifically under challenging conditions. METHODS: Obstacle avoidance performance was measured on a treadmill and compared between persons with osteoporosis (n = 85) and the comparison group (n = 99). The obstacle was released at different available response times (ART) to create different levels of difficulty by increasing time pressure. Furthermore, balance confidence, measured with the short ABC-questionnaire, was compared between the groups. RESULTS: No differences were found between the groups in success rates on the obstacle avoidance task (p = 0.173). Furthermore, the persons with osteoporosis had similar levels of balance confidence as the comparison group (p = 0.091). The level of balance confidence was not associated with the performance on the obstacle avoidance task (p = 0.145). CONCLUSION: Obstacle avoidance abilities were not impaired in persons with osteoporosis and they did not experience less balance confidence than the comparison group. These findings imply that persons with osteoporosis do not have an additional risk of falling because of poorer obstacle avoidance abilities

Prevalence of myocardial crypts in a large retrospective cohort study by cardiovascular magnetic resonance

BACKGROUND: Myocardial crypts are discrete clefts or fissures in otherwise compacted myocardium of the left ventricle (LV). Recent reports suggest a higher prevalence of crypts in patients with hypertrophic cardiomyopathy (HCM) and also within small samples of genotype positive but phenotype negative relatives. The presence of a crypt has been suggested to be a predictor of gene carrier status. However, the prevalence and clinical significance of crypts in the general population is unclear. We aimed to determine the prevalence of myocardial crypts in a large cohort of subjects using clinical cardiovascular magnetic resonance (CMR). METHODS: Consecutive subjects referred for clinical CMR during a 12-month period (n = 1020, age 52.6 ± 17, males: 61%) were included. Crypts were defined as >50% invagination into normal myocardium and their overall prevalence, location and shape was investigated and compared between different patient groups. RESULTS: The overall prevalence of crypts was 64/1020 (6.3%). In a predefined ‘normal’ control group the prevalence was lower (11/306, 3.6%, p = 0.031), but were equally prevalent in ischemic heart disease (12/236, 5.1%, p = n/s) and the combined non-ischemic cardiomyopathy (NICM) groups (24/373; 6.4%, p = n/s). Within the NICM group, crypts were significantly more common in HCM (9/76, 11.7%, p = 0.04) and hypertensive CM subjects (3/11, 27%, p = 0.03). In patients referred for CMR for family screening of inherited forms of CM, crypts were significantly more prevalent (10/41, 23%, p < 0.001), including a smaller group with a first degree relative with HCM (3/9, 33%, p = 0.01). CONCLUSION: Myocardial crypts are relatively common in the normal population, and increasingly common in HCM and hypertensive cardiomyopathy. Crypts are also more frequently seen in normal phenotype subjects referred because of a family history of an inherited cardiomyopathy and HCM specifically. It is uncertain what the significance of crypts are in this group, and because of variability in the imaging protocols used and their relative frequency within the normal population, should not be used to clinically stratify these patients. Prospective studies are required to confirm the clinical significance of myocardial crypts, as their significance remains unclear. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (doi:10.1186/s12968-014-0066-0) contains supplementary material, which is available to authorized users

In Search of the Optimal Surgical Treatment for Velopharyngeal Dysfunction in 22q11.2 Deletion Syndrome: A Systematic Review

<div><h3>Background</h3><p>Patients with the 22q11.2 deletion syndrome (22qDS) and velopharyngeal dysfunction (VPD) tend to have residual VPD following surgery. This systematic review seeks to determine whether a particular surgical procedure results in superior speech outcome or less morbidity.</p> <h3>Methodology/ Principal Findings</h3><p>A combined computerized and hand-search yielded 70 studies, of which 27 were deemed relevant for this review, reporting on a total of 525 patients with 22qDS and VPD undergoing surgery for VPD. All studies were levels 2c or 4 evidence. The methodological quality of these studies was assessed using criteria based on the Cochrane Collaboration's tool for assessing risk of bias. Heterogeneous groups of patients were reported on in the studies. The surgical procedure was often tailored to findings on preoperative imaging. Overall, 50% of patients attained normal resonance, 48% attained normal nasal emissions scores, and 83% had understandable speech postoperatively. However, 5% became hyponasal, 1% had obstructive sleep apnea (OSA), and 17% required further surgery. There were no significant differences in speech outcome between patients who underwent a fat injection, Furlow or intravelar veloplasty, pharyngeal flap pharyngoplasty, Honig pharyngoplasty, or sphincter pharyngoplasty or Hynes procedures. There was a trend that a lower percentage of patients attained normal resonance after a fat injection or palatoplasty than after the more obstructive pharyngoplasties (11–18% versus 44–62%, p = 0.08). Only patients who underwent pharyngeal flaps or sphincter pharyngoplasties incurred OSA, yet this was not statistically significantly more often than after other procedures (p = 0.25). More patients who underwent a palatoplasty needed further surgery than those who underwent a pharyngoplasty (50% versus 7–13%, p = 0.03).</p> <h3>Conclusions/ Significance</h3><p>In the heterogeneous group of patients with 22qDS and VPD, a grade C recommendation can be made to minimize the morbidity of further surgery by choosing to perform a pharyngoplasty directly instead of only a palatoplasty.</p> </div

Joint sequencing of human and pathogen genomes reveals the genetics of pneumococcal meningitis.

Streptococcus pneumoniae is a common nasopharyngeal colonizer, but can also cause life-threatening invasive diseases such as empyema, bacteremia and meningitis. Genetic variation of host and pathogen is known to play a role in invasive pneumococcal disease, though to what extent is unknown. In a genome-wide association study of human and pathogen we show that human variation explains almost half of variation in susceptibility to pneumococcal meningitis and one-third of variation in severity, identifying variants in CCDC33 associated with susceptibility. Pneumococcal genetic variation explains a large amount of invasive potential (70%), but has no effect on severity. Serotype alone is insufficient to explain invasiveness, suggesting other pneumococcal factors are involved in progression to invasive disease. We identify pneumococcal genes involved in invasiveness including pspC and zmpD, and perform a human-bacteria interaction analysis. These genes are potential candidates for the development of more broadly-acting pneumococcal vaccines

Molecular mechanisms of cell death: recommendations of the Nomenclature Committee on Cell Death 2018.

Over the past decade, the Nomenclature Committee on Cell Death (NCCD) has formulated guidelines for the definition and interpretation of cell death from morphological, biochemical, and functional perspectives. Since the field continues to expand and novel mechanisms that orchestrate multiple cell death pathways are unveiled, we propose an updated classification of cell death subroutines focusing on mechanistic and essential (as opposed to correlative and dispensable) aspects of the process. As we provide molecularly oriented definitions of terms including intrinsic apoptosis, extrinsic apoptosis, mitochondrial permeability transition (MPT)-driven necrosis, necroptosis, ferroptosis, pyroptosis, parthanatos, entotic cell death, NETotic cell death, lysosome-dependent cell death, autophagy-dependent cell death, immunogenic cell death, cellular senescence, and mitotic catastrophe, we discuss the utility of neologisms that refer to highly specialized instances of these processes. The mission of the NCCD is to provide a widely accepted nomenclature on cell death in support of the continued development of the field