The molecular genetic basis for hypertrophic cardiomyopathy

Hypertrophic cardiomyopathy (HCM), a relatively common disease, is diagnosed clinically by unexplained cardiac hypertrophy and pathologically by myocyte hypertrophy, disarray, and interstitial fibrosis. HCM is the most common cause of sudden cardiac death (SCD) in the young and a major cause of morbidity and mortality in elderly. Hypertrophy and fibrosis are the major determinants of morbidity and SCD. More than 100 mutations in nine genes, all encoding sarcomeric proteins have been identified in patients with HCM, which had led to the notion that HCM is a disease of contractile sarcomeric proteins. The beta -myosin heavy chain (MyHC), cardiac troponin T (cTnT) and myosin binding protein-C (MyBP-C) are the most common genes accounting for approximately 2/3 of all HCM cases. Genotype-phenotype correlation studies suggest that mutations in the beta -MyHC gene are associated with more extensive hypertrophy and a higher risk of SCD as compared to mutations in genes coding for other sarcomeric proteins, such as MyBP-C and cTnT. The prognostic significance of mutations is related to their hypertrophic expressivity and penetrance, with the exception of those in the cTnT, which are associated with mild hypertrophic response and a high incidence of SCD. However, there is a significant variability and factors, such as modifier genes and probably the environmental factors affect the phenotypic expression of HCM. The molecular pathogenesis of HCM is not completely understood. In vitro and in vivo studies suggest that mutations impart a diverse array of functional defects including reduced ATPase activity of myosin, acto-myosin interaction, cross-bridging kinetics, myocyte contractility, and altered Ca2+ sensitivity. Hypertrophy and other clinical and pathological phenotypes are considered compensatory phenotypes secondary to functional defects. In summary, the molecular genetic basis of HCM has been identified, which affords the opportunity to delineate its pathogenesis. Understanding the pathogenesis of HCM could provide for genetic based diagnosis, risk stratification, treatment and prevention of cardiac phenotypes.     

An overview of robotic/mechanical devices for post-stroke thumb rehabilitation

Purpose: This article aims to clarify the current state-of-the-art of robotic/mechanical devices for post-stroke thumb rehabilitation as well as the anatomical characteristics and motions of the thumb that are crucial for the development of any device that aims to support its motion.

Methods: A systematic literature search was conducted to identify robotic/mechanical devices for post-stroke thumb rehabilitation. Specific electronic databases and well-defined search terms and inclusion/exclusion criteria were used for such purpose. A reasoning model was devised to support the structured abstraction of relevant data from the literature of interest.

Results: Following the main search and after removing duplicated and other non-relevant studies, 68 articles (corresponding to 32 devices) were left for further examination. These articles were analyzed to extract data relative to (i) the motions assisted/permitted – either actively or passively – by the device per anatomical joint of the thumb and (ii) mechanical-related aspects (i.e., architecture, connections to thumb, other fingers supported, adjustability to different hand sizes, actuators – type, quantity, location, power transmission and motion trajectory).

Conclusions: Most articles describe preliminary design and testing of prototypes, rather than the thorough evaluation of commercially ready devices. Defining appropriate kinematic models of the thumb upon which to design such devices still remains a challenging and unresolved task. Further research is needed before these devices can actually be implemented in clinical environments to serve their intended purpose of complementing the labour of therapists by facilitating intensive treatment with precise and repeatable exercises.

• Implications for Rehabilitation

• Post-stroke functional disability of the hand, and particularly of the thumb, significantly affects the capability to perform activities of daily living, threatening the independence and quality of life of the stroke survivors. The latest studies show that a high-dose intensive therapy (in terms of frequency, duration and intensity/effort) is the key to effectively modify neural organization and recover the motor skills that were lost after a stroke. Conventional therapy based on manual interaction with physical therapists makes the procedure labour intensive and increases the costs.

• Robotic/mechanical devices hold promise for complementing conventional post-stroke therapy. Specifically, these devices can provide reliable and accurate therapy for long periods of time without the associated fatigue. Also, they can be used as a means to assess patients? performance and progress in an objective and consistent manner.

• The full potential of robot-assisted therapy is still to be unveiled. Further exploration will surely lead to devices that can be well accepted equally by therapists and patients and that can be useful both in clinical and home-based rehabilitation practice such that motor recovery of the hand becomes a common outcome in stroke survivors.

• This overview provides the reader, possibly a designer of such a device, with a complete overview of the state-of-the-art of robotic/mechanical devices consisting of or including features for the rehabilitation of the thumb. Also, we clarify the anatomical characteristics and motions of the thumb that are crucial for the development of any device that aims to support its motion.

• Hopefully, this?combined with the outlined opportunities for further research?leads to the improvement of current devices and the development of new technology and knowledge in the field.

     

Optimized Cholesterol-siRNA Chemistry Improves Productive Loading onto Extracellular Vesicles

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Interactions between angiotensin-I converting enzyme insertion/deletion polymorphism and response of plasma lipids and coronary atherosclerosis to treatment with fluvastatin: the lipoprotein and coronary atherosclerosis study

OBJECTIVES: Our objectives were to determine whether angiotensin-1 converting enzyme (ACE) insertion/deletion (I/D) polymorphism was associated with the severity of coronary artery disease (CAD) and its progression/regression in response to fluvastatin therapy in the Lipoprotein and Coronary Atherosclerosis Study (LCAS) population. BACKGROUND: Genetic factors are involved in susceptibility to CAD. Angiotensin-1 converting enzyme I/D polymorphism, which accounts for half of the variance of plasma and tissue levels of ACE, has been implicated in susceptibility to CAD and myocardial infarction (MI). METHODS: Angiotensin-1 converting enzyme genotypes were determined by polymerase chain reaction (PCR). Fasting plasma lipids were measured and quantitative coronary angiograms were obtained at baseline and 2.5 years following randomization to fluvastatin or placebo. RESULTS: Ninety-one subjects had DD, 198 ID and 75 II genotypes. The mean blood pressure, minimum lumen diameter (MLD), number of coronary lesions and total occlusions were not significantly different at baseline or follow-up among the genotypes. There was a significant genotype-by-treatment interaction for total cholesterol (p = 0.018), low-density lipoprotein cholesterol (LDL-C) (p = 0.005) and apolipoprotein (apo) B (p = 0.045). In response to fluvastatin therapy, subjects with DD, compared with those with ID and II genotypes, had a greater reduction in total cholesterol (19% vs. 15% vs. 13%), LDL-C (31% vs. 25% vs. 21%) and apo B (23% vs. 15% vs. 12%). Definite progression was less (14%) and regression was more common (24%) in DD as compared with those with ID (32% and 17%) and II (33% and 3%) genotypes (p = 0.023). Changes in the mean MLD and lesion-specific MLD also followed the same trend. CONCLUSIONS: Angiotensin-1 converting enzyme I/D polymorphism is associated with the response of plasma lipids and coronary atherosclerosis to treatment with fluvastatin. Subjects with DD genotype had a greater reduction in LDL-C, a higher rate of regression and a lower rate of progression of CAD.