Force-extension of the Amylose Polysaccharide

Atomic Force Microscopy (AFM) single-molecule stretching experiments have been used in a number of studies to characterise the elasticity of single polysaccharide molecules. Steered molecular dynamics (SMD) simulations can reproduce the force-extension behaviour of polysaccharides, while allowing for investigation of the molecular mechanisms behind the macroscopic behaviour. Various stretching experiments on single amylose molecules, using AFM combined with SMD simulations have shown that the molecular elasticity in saccharides is a function of both rotational motion about the glycosidic bonds and the flexibility of individual sugar rings. This study investigates the molecular mechanisms that determine the elastic properties exhibited by amylose when subjected to deformations with the use of constant force SMD simulations. Amylose is a linear polysaccharide of glucose linked mainly by (14) bonds. The elastic properties of amylose are explored by investigating the effect of both stretching speed and strand length on the force-extension profile. On the basis of this work, we confirm that the elastic behaviour of amylose is governed by the mechanics of the pyranose rings and their force-induced conformational transitions. The molecular mechanism can be explained by a combination of syn and anti-parallel conformations of the dihedral angles and chair-to-boat transitional changes. Almost half the chair-to-boat transitional changes of the pyranose rings occur in quick succession in the first part of the force-extension profile (cooperatively) and then the rest follow later (anti-cooperatively) at higher forces, with a much greater interval between them. At low forces, the stretching profile is characterised by the transition of the dihedral angles to the anti-conformation, with low elasticities measured for all the chain lengths. Chair-to-boat transitional changes of the pyranose rings of the shorter chains only occurred anti-cooperatively at high stretching forces, whereas much lower forces were recorded for the same conformational change in the longer chains. For the shorter chains most of these conversions produced the characteristic “shoulder" in the amylose stretching curve. Faster ramping rates were found to increase the force required to reach a particular extension of an amylose fragment. The transitions were similar in shape, but occur at lower forces, proving that decreasing the ramping rate lowers the expected force. The mechanism was also essentially the same, with very little change between the simulations. Simulations performed with slower ramping rates were found to be adequate for reproduction of the experimental curve

Genetics in heart failure:where are we headed?

Heart failure is a complex disease with many precipitating factors. Novel insights into the genetic background of heart failure have boosted new areas of research that gave rise to the concept of genetic predisposition for heart failure. Various genetic defects and variances have been identified and subsequently linked to the onset of or progression to heart failure. Nevertheless, our understanding of the genetic basis for heart failure is incomplete because we lack knowledge of the functionality of genetic variances. We also do not understand the impact of genetic variances in noncoding DNA because of logistic problems in performing whole-genome scans and difficulties in statistical evaluation of large amounts of data generated by the genetic boom. It is expected that in the future we will be able to overcome these problems and apply the knowledge gained by genetic analyses to target and optimize treatment.</p

Cost-effectiveness of counseling and pedometer use to increase physical activity in the Netherlands: a modeling study

Background: Counseling in combination with pedometer use has proven to be effective in increasing physical activity and improving health outcomes. We investigated the cost-effectiveness of this intervention targeted at one million insufficiently active adults who visit their general practitioner in the Netherlands.Methods: We used the RIVM chronic disease model to estimate the long-term effects of increased physical activity on the future health care costs and quality adjusted life years (QALY) gained, from a health care perspective.Results: The intervention resulted in almost 6000 people shifting to more favorable physical-activity levels, and in 5100 life years and 6100 QALYs gained, at an additional total cost of EUR 67.6 million. The incremental cost-effectiveness ratio (ICER) was EUR 13,200 per life year gained and EUR 11,100 per QALY gained. The intervention has a probability of 0.66 to be cost-effective if a QALY gained is valued at the Dutch informal threshold for cost-effectiveness of preventive intervention of EUR 20,000. A sensitivity analysis showed substantial uncertainty of ICER values.Conclusion: Counseling in combination with pedometer use aiming to increase physical activity may be a cost-effective intervention. However, the intervention only yields relatively small health benefits in the Netherlands

The value of genetic testing in the diagnosis and risk stratification of arrhythmogenic right ventricular cardiomyopathy

BACKGROUND: Arrhythmogenic right ventricular cardiomyopathy (ARVC) is characterized by risk of malignant ventricular arrhythmias (VA). ARVC is diagnosed using an array of clinical tests in the consensus-based task force criteria (TFC), one of which is genetic testing. OBJECTIVE: To investigate the value of genetic testing in diagnosing ARVC and its relation to the occurrence of first malignant VA. METHODS: A multicenter cohort of ARVC patients was scored using the revised 2010 TFC with and without genetic criterion, analyzing any resulting loss or delay of diagnosis. Malignant VA was defined as sustained ventricular arrhythmia (≥30s duration at ≥100 bpm or requiring intervention). RESULTS: We included 402 subjects (55% male, 54% proband, 40 [27-51] years old at presentation) who were diagnosed with definite ARVC. A total of 232 (58%) subjects fulfilled genetic testing criteria. Removing the genetic criterion caused loss of diagnosis in 18 (4%) patients (11/216 [5%] probands, 7/186 [4%] relatives), and delay of diagnosis ≥30 days in 22 (5%) patients (21/216 [10%] probands, 1/186 [0.5%] relative). A first malignant VA occurred in no patients who lost diagnosis and in 3 patients (3/216 [1%] probands and no relatives) during their diagnosis delay, none fatal. Time to event analysis showed no significant difference in time from diagnosis to malignant VA between pathogenic variant carriers and non-carriers. CONCLUSION: Disregarding the genetic criterion of the TFC caused loss or delay of diagnosis in 10% (n=40/402) of ARVC patients. Malignant VA occurred in 1% (n=3/402) of cases with lost or delayed diagnosis, none fatal

Drafting a Surgical Procedure Using a Computational Anatomy Driven Approach for Precise, Robust, and Safe Vestibular Neuroprosthesis Placement-When One Size Does Not Fit All

OBJECTIVE: To design and evaluate a new vestibular implant and surgical procedure that should reach correct electrode placement in 95% of patients in silico. DESIGN: Computational anatomy driven implant and surgery design study. SETTING: Tertiary referral center. PARTICIPANTS: The population comprised 81 patients that had undergone a CT scan of the Mastoid region in the Maastricht University Medical Center. The population was subdivided in a vestibular implant eligible group (28) and a control group (53) without known vestibular loss. INTERVENTIONS: Canal lengths and relationships between landmarks were calculated for every patient. The relationships in group-anatomy were used to model a fenestration site on all three semicircular canals. Each patient's simulated individual distance from the fenestration site to the ampulla was calculated and compared with the populations average to determine if placement would be successful. MAIN OUTCOME MEASURES: Lengths of the semicircular canals, distances from fenestration site to ampulla (intralabyrinthine electrode length), and rate of successful electrode placement (robustness). RESULTS: The canal lengths for the lateral, posterior, and superior canal were respectively 12.1 mm ± 1.07, 18.8 mm ± 1.62, and 17.5 mm ± 1.23, the distances from electrode fenestration site to the ampulla were respectively 3.73 mm ± 0.53, 9.02 mm ± 0.90, and 5.31 mm ± 0.73 and electrode insertions were successful for each respective semicircular canal in 92.6%, 66.7%, and 86.4% of insertions in silico. The implant electrode was subsequently revised to include two more electrodes per lead, resulting in a robustness of 100%. CONCLUSIONS: The computational anatomy approach can be used to design and test surgical procedures. With small changes in electrode design, the proposed surgical procedure's target robustness was reached

Sex-specific aspects of phospholamban cardiomyopathy:The importance and prognostic value of low-voltage electrocardiograms

Background: A pathogenic variant in the gene encoding phospholamban (PLN), a protein that regulates calcium homeostasis of cardiomyocytes, causes PLN cardiomyopathy. It is characterized by a high arrhythmic burden and can progress to severe cardiomyopathy. Risk assessment guides implantable cardioverter-defibrillator therapy and benefits from personalization. Whether sex-specific differences in PLN cardiomyopathy exist is unknown. Objective: The purpose of this study was to improve the accuracy of PLN cardiomyopathy diagnosis and risk assessment by investigating sex-specific aspects. Methods: We analyzed a multicenter cohort of 933 patients (412 male, 521 female) with the PLN p.(Arg14del) pathogenic variant following up on a recently developed PLN risk model. Sex-specific differences in the incidence of risk model components were investigated: low-voltage electrocardiogram (ECG), premature ventricular contractions, negative T waves, and left ventricular ejection fraction. Results: Sustained ventricular arrhythmias (VAs) occurred in 77 males (18.7%) and 61 females (11.7%) (P =.004). Of the 933 cohort members, 287 (31%) had ≥1 low-voltage ECG during follow-up (180 females [63%], 107 males [37%]; P =.006). Female sex, age, age at clinical presentation, and proband status predicted low-voltage ECG during follow-up (area under the curve: 0.78). Sustained VA-free survival was lowest in males with low-voltage ECG (P <.001). Conclusion: Low-voltage ECGs predict sustained VA and are a component of the PLN risk model. Low-voltage ECGs are more common in females, yet prognostic value is greater in males. Future studies should determine the impact of this difference on the risk prediction of PLN cardiomyopathy and possibly other cardiomyopathies

The phospholamban p.(Arg14del) pathogenic variant leads to cardiomyopathy with heart failure and is unreponsive to standard heart failure therapy

Phospholamban (PLN) plays a role in cardiomyocyte calcium handling as primary inhibitor of sarco/endoplasmic reticulum Ca2+-ATPase (SERCA). The p.(Arg14del) pathogenic variant in the PLN gene results in a high risk of developing dilated or arrhythmogenic cardiomyopathy with heart failure. There is no established treatment other than standard heart failure therapy or heart transplantation. In this study, we generated a novel mouse model with the PLN-R14del pathogenic variant, performed detailed phenotyping, and tested the efficacy of established heart failure therapies eplerenone or metoprolol. Heterozygous PLN-R14del mice demonstrated increased susceptibility to ex vivo induced arrhythmias, and cardiomyopathy at 18 months of age, which was not accelerated by isoproterenol infusion. Homozygous PLN-R14del mice exhibited an accelerated phenotype including cardiac dilatation, contractile dysfunction, decreased ECG potentials, high susceptibility to ex vivo induced arrhythmias, myocardial fibrosis, PLN protein aggregation, and early mortality. Neither eplerenone nor metoprolol administration improved cardiac function or survival. In conclusion, our novel PLN-R14del mouse model exhibits most features of human disease. Administration of standard heart failure therapy did not rescue the phenotype, underscoring the need for better understanding of the pathophysiology of PLN-R14del-associated cardiomyopathy. This model provides a great opportunity to study the pathophysiology, and to screen for potential therapeutic treatments

Fibrotic Marker Galectin-3 Identifies Males at Risk of Developing Cancer and Heart Failure

BACKGROUND: Cancer and heart failure (HF) are the leading causes of death in the Western world. Shared mechanisms such as fibrosis may underlie either disease entity, furthermore it is unknown whether this relationship is sex-specific.OBJECTIVES: We sought to investigate how fibrosis-related biomarker galectin-3 (gal-3) aids in identifying individuals at risk for new-onset cancer and HF, and how this differs between sexes.METHODS: Gal-3 was measured at baseline and at 4-year follow-up in 5,786 patients of the PREVEND (Prevention of Renal and Vascular Endstage Disease) study. The total follow-up period was 11.5 years. An increase of ≥50% in gal-3 levels between measurements was considered relevant. We performed sex-stratified log-rank tests and Cox regression analyses overall and by sex to evaluate the association of gal-3 over time with both new-onset cancer and new-onset HF.RESULTS: Of the 5,786 healthy participants (50% males), 399 (59% males) developed new-onset cancer, and 192 (65% males) developed new-onset HF. In males, an increase in gal-3 was significantly associated with new-onset cancer (both combined and certain cancer-specific subtypes), after adjusting for age, body mass index, hypertension, smoking status, estimated glomerular filtration rate, diabetes mellitus, triglycerides, coronary artery disease, and C-reactive protein (HR: 1.89; 95% CI: 1.32-2.71; P &lt; 0.001). Similar analyses demonstrated an association with new-onset HF in males (HR: 1.77; 95% CI: 1.07-2.95; P = 0.028). In females, changes in gal-3 over time were neither associated with new-onset cancer nor new-onset HF. CONCLUSIONS: Gal-3, a marker of fibrosis, is associated with new-onset cancer and new-onset HF in males, but not in females.</p