Exercise intolerance and fatigue in chronic heart failure: is there a role for group III/IV afferent feedback?

Exercise intolerance and early fatiguability are hallmark symptoms of chronic heart failure. While the malfunction of the heart is certainly the leading cause of chronic heart failure, the patho-physiological mechanisms of exercise intolerance in these patients are more complex, multifactorial and only partially understood. Some evidence points towards a potential role of an exaggerated afferent feedback from group III/IV muscle afferents in the genesis of these symptoms. Overactivity of feedback from these muscle afferents may cause exercise intolerance with a double action: by inducing cardiovascular dysregulation, by reducing motor output and by facilitating the development of central and peripheral fatigue during exercise. Importantly, physical inactivity appears to affect the progression of the syndrome negatively, while physical training can partially counteract this condition. In the present review, the role played by group III/IV afferent feedback in cardiovascular regulation during exercise and exercise-induced muscle fatigue of healthy people and their potential role in inducing exercise intolerance in chronic heart failure patients will be summarised

WARP: A ICN architecture for social data

Social network companies maintain complete visibility and ownership of the data they store. However users should be able to maintain full control over their content. For this purpose, we propose WARP, an architecture based upon Information-Centric Networking (ICN) designs, which expands the scope of the ICN architecture beyond media distribution, to provide data control in social networks. The benefit of our solution lies in the lightweight nature of the protocol and in its layered design. With WARP, data distribution and access policies are enforced on the user side. Data can still be replicated in an ICN fashion but we introduce control channels, named \textit{thread updates}, which ensures that the access to the data is always updated to the latest control policy. WARP decentralizes the social network but still offers APIs so that social network providers can build products and business models on top of WARP. Social applications run directly on the user's device and store their data on the user's \textit{butler} that takes care of encryption and distribution. Moreover, users can still rely on third parties to have high-availability without renouncing their privacy

A Novel null homozygous mutation confirms <i>CACNA2D2</i> as a gene mutated in epileptic encephalopathy

Contribution to epileptic encephalopathy (EE) of mutations in CACNA2D2, encoding α2δ-2 subunit of Voltage Dependent Calcium Channels, is unclear. To date only one CACNA2D2 mutation altering channel functionality has been identified in a single family. In the same family, a rare CELSR3 polymorphism also segregated with disease. Involvement of CACNA2D2 in EE is therefore not confirmed, while that of CELSR3 is questionable. In a patient with epilepsy, dyskinesia, cerebellar atrophy, psychomotor delay and dysmorphic features, offspring to consanguineous parents, we performed whole exome sequencing (WES) for homozygosity mapping and mutation detection. WES identified extended autozygosity on chromosome 3, containing two novel homozygous candidate mutations: c.1295delA (p.Asn432fs) in CACNA2D2 and c.G6407A (p.Gly2136Asp) in CELSR3. Gene prioritization pointed to CACNA2D2 as the most prominent candidate gene. The WES finding in CACNA2D2 resulted to be statistically significant (p = 0.032), unlike that in CELSR3. CACNA2D2 homozygous c.1295delA essentially abolished α2δ-2 expression. In summary, we identified a novel null CACNA2D2 mutation associated to a clinical phenotype strikingly similar to the Cacna2d2 null mouse model. Molecular and statistical analyses together argued in favor of a causal contribution of CACNA2D2 mutations to EE, while suggested that finding in CELSR3, although potentially damaging, is likely incidental

Explaining Engineered Computing Systems’ Behaviour: the Role of Abstraction and Idealization

This paper addresses the methodological problem of analysing what it is to explain observed behaviours of engineered computing systems (BECS), focusing on the crucial role that abstraction and idealization play in explanations of both correct and incorrect BECS. First, it is argued that an understanding of explanatory requests about observed miscomputations crucially involves reference to the rich background afforded by hierarchies of functional specifications. Second, many explanations concerning incorrect BECS are found to abstract away (and profitably so on account of both relevance and intelligibility of the explanans) from descriptions of physical components and processes of computing systems that one finds below the logic circuit and gate layer of functional specification hierarchies. Third, model-based explanations of both correct and incorrect BECS that are provided in the framework of formal verification methods often involve idealizations. Moreover, a distinction between restrictive and permissive idealizations is introduced and their roles in BECS explanations are analysed

Chronic hyperplastic anemia as an independent risk factor for atherosclerotic lesions: a lesson from thalassemia intermedia

Introduction. Cardiovascular involvement represents a well-known complication and the primary cause of mortality, both in transfusion-dependent beta thalassemia major (&#x3b2;-TM) and in transfusion-independent beta thalassemia intermedia (&#x3b2;-TI). In &#x3b2;-TM, heart iron overload is considered the main cause of this complication. This is likely due to poor adherence to iron-chelating therapy, resulting in the inability of the body to efficiently remove iron excess derived from transfused red blood cell breakdown. Different clinical pictures may instead be evoked in cardiovascular involvement occurring in &#x3b2;-TI; however, until now, no factor has emerged as the major one responsible for these complications. &#xd;&#xa;Design and Methods. In the present study, iron status, and lipid profiles in serum, as well as lipid content in peripheral blood mononuclear cells (PBMCs) were evaluated in 70 adult &#x3b2;-TM and in 22 adult &#x3b2;-TI patients. Ninety-two age-matched blood donors, free from any form of thalassemia, were utilized as controls. The mRNA levels of genes involved in the regulation of iron metabolism, such as interleukine 1 alfa (IL1&#x3b1;), tumor necrosis factor alfa (TNF&#x3b1;), as well as those involved in cholesterol homeostasis, such as acetyl-coenzymeA: cholesterol acyltransferase (ACAT-1), neutral cholesterol ester hydrolase (nCEH), and ATP binding cassette-A (ABCA1), were also evaluated in PBMCs from the above subjects.&#xd;&#xa;Results. In &#x3b2;-TI patients, serum iron, transferrin saturation and erythropoietin levels were higher, while transferrin and hepcidin were lower, compared to both &#x3b2;-TM and controls. Hepcidin and IL&#x3b1; mRNA levels were found to be reduced in &#x3b2;-TI-PBMCs, while those of TNF&#x3b1; were increased. A reduction in total and high density lipoprotein cholesterol (TC and HDL-C) in serum, and an accumulation of neutral lipids (NL), coupled with increased mRNA levels of ACAT-1 and decreased nCEH in PBMCs were also observed in &#x3b2;-TI. &#xd;&#xa;Conclusions. Since most of the parameters found to be altered in &#x3b2;-TI patients have a key role in the initiation and progression of atherosclerosis, we suggest that cardiovascular complications in these patients may be, at least partially, dependent on the occurrence of premature atherosclerotic lesions. &#xd;&#xa

High-Throughput Computing on High-Performance Platforms: A Case Study

The computing systems used by LHC experiments has historically consisted of the federation of hundreds to thousands of distributed resources, ranging from small to mid-size resource. In spite of the impressive scale of the existing distributed computing solutions, the federation of small to mid-size resources will be insufficient to meet projected future demands. This paper is a case study of how the ATLAS experiment has embraced Titan---a DOE leadership facility in conjunction with traditional distributed high- throughput computing to reach sustained production scales of approximately 52M core-hours a years. The three main contributions of this paper are: (i) a critical evaluation of design and operational considerations to support the sustained, scalable and production usage of Titan; (ii) a preliminary characterization of a next generation executor for PanDA to support new workloads and advanced execution modes; and (iii) early lessons for how current and future experimental and observational systems can be integrated with production supercomputers and other platforms in a general and extensible manner

Task‐specific strength increases after lower‐limb compound resistance training occurred in the absence of corticospinal changes in vastus lateralis

Neural adaptations subserving strength increases have been shown to be task‐specific, but responses and adaptation to lower‐limb compound exercises such as the squat are commonly assessed in a single‐limb isometric task. This two‐part study assessed neuromuscular responses to an acute bout (Study A) and 4 weeks (Study B) of squat resistance training at 80% of one‐repetition‐maximum, with measures taken during a task‐specific isometric squat (IS) and non‐specific isometric knee extension (KE). Eighteen healthy volunteers (25 ± 5 years) were randomised into either a training (n = 10) or a control (n = 8) group. Neural responses were evoked at the intracortical, corticospinal and spinal levels, and muscle thickness was assessed using ultrasound. The results of Study A showed that the acute bout of squat resistance training decreased maximum voluntary contraction (MVC) for up to 45 min post‐exercise (−23%, P < 0.001). From 15–45 min post‐exercise, spinally evoked responses were increased in both tasks (P = 0.008); however, no other evoked responses were affected (P ≥ 0.240). Study B demonstrated that following short‐term resistance training, participants improved their one repetition maximum squat (+35%, P < 0.001), which was reflected by a task‐specific increase in IS MVC (+49%, P = 0.001), but not KE (+1%, P = 0.882). However, no training‐induced changes were observed in muscle thickness (P = 0.468) or any evoked responses (P = 0.141). Adjustments in spinal motoneuronal excitability are evident after acute resistance training. After a period of short‐term training, there were no changes in the responses to central nervous system stimulation, which suggests that alterations in corticospinal properties of the vastus lateralis might not contribute to increases in strength

Glucose-6-phosphate-dehydrogenase deficiency as a risk factor in proliferative disorder development

Glucose-6-phosphate dehydrogenase (G6PD) is an important site of metabolic control in the pentose phosphate pathway (PPP) which provides reducing power (NADPH) and pentose phosphates. The former is mainly involved in the detoxification of chemical reactive species; the latter in the regulation of cell proliferation. G6PD deficiency is the most common enzymopathy in the human population, characterized by decreased G6PD activity, mainly in red blood cells, but actually also in nucleated cells. This decreased activity is not due to enzyme synthesis impairment, but rather to reduced enzyme stability, which leads to a shortening of its half-life. Therefore, a major problem is to understand the underlying mechanisms linking G6PD deficiency to oxidative stress and cell proliferation. In order to address this issue, in the present study we utilized, as an experimental model, fibroblasts isolated from pterygium, an ocular proliferative lesion, from G6PD normal and deficient (PFs+ and PFs-, respectively) patients. Our choice was determined by the fact that pterygium is believed to be caused by chronic oxidative stress induced by UV exposure, and that pterygium fibroblasts resemble a tumorigenic phenotype. As controls we utilized fibroblasts isolated from conjunctiva from G6PD normal and deficient patients (NCFs+ and NCFs-, respectively) who had undergone cataract surgery. &#xd;&#xa;Growth rate analysis revealed that PFs grow faster than NCFs, but while NCFs- grow more slowly than NCFs+, PFs- and PFs+ grow at the same rate. This was associated with significantly lower G6PD activity in NCFs+ compared to NCFs-, while no significant differences in the G6PD activity of PFs+ and PFs- were noted. This result was supported by the finding that in PFs-, G6PD mRNA levels were significantly higher than in PFs+. Another interesting finding of this study was increased green autofluorescence in both NCFs- and PFs- compared to corresponding positive cells, indicative of pronounced oxidative stress in deficient cells. Finally, abnormal accumulation of neutral lipids, mainly cholesterol esters was observed both in PFs- and PFs+ compared to NCFs- and NCFs+. Though further studies are necessary for better understanding the exact mechanism which links G6PD to oxidative stress and cell proliferation, our data allow to speculate on the role of G6PD on tumorigenesis, and to consider G6PD-deficient subjects at major risk to develop common and dreaded proliferative disorders, such as atherosclerosis and cancer. &#xd;&#xa

Innovations in the treatment of ovarian cancer. Analysis of the therapeutic development: from platinum to immunotherapy

Ovarian cancer is the seventh most common cancer in women. The therapeutic approach provides for an appropriate integration between surgery and chemotherapy. Surgery is an important step for diagnosis, staging and therapy, aiming at the complete cytoreduction of all macroscopic visible disease. At the moment, adjuvant and first-line chemotherapy has as a standard the carboplatin-paclitaxel combination. Further, the addition of bevacizumab in the advanced stage (IIIB-IV) is strongly recommended. Despite the initial effectiveness, however, 70-80% of patients develop relapsed disease within the first two years and require subsequent treatment lines that have palliative, rather than curative purposes and that seek to reach a chronic state for the disease. Among the causes of recurrences, one of the most studied is related to the stem cells that, due to a quiescent state, are resistant to chemotherapy. The choice of these treatments must consider several factors, including the probability of extending the PFS and OS, the residual toxicity, symptoms control, and the improvement of quality of life, and always remains subject to platinum free interval (PFI). There are not standard therapy. Pegylated liposomal doxorubicin (PLD) as a single agent or in combination with other drugs is one of several treatment modalities that may be considered for relapsed ovaria cancer. In addition, in about 15% to 20% of epithelial tumors, there is a mutation of the BRCA1 and 2 genes. This is fundamental to identify immediately a therapeutic opportunity represented by PARP inhibitors. These drugs, such as olaparib and niraparib, used in maintenance after a previous platinum-response, even partial, have also shown in upfront an activity in BRCA wild type, homologous recombination deficent (HRD) and homologous recombination proficient (HRP). Therefore, after 20 years of chemotherapy alone, new targeted therapies are emerging that will help changing the therapeutic approach, making treatments increasingly personalized

The ergogenic effects of transcranial direct current stimulation on exercise performance

The physical limits of the human performance have been the object of study for a considerable time. Most of the research has focused on the locomotor muscles, lungs and heart. As a consequence, much of the contemporary literature has ignored the importance of the brain in the regulation of exercise performance. With the introduction and development of new non-invasive devices, the knowledge regarding the behaviour of the central nervous system during exercise has advanced. A first step has been provided from studies involving neuroimaging techniques where the role of specific brain areas have been identified during isolated muscle or whole-body exercise. Furthermore, a new interesting approach has been provided by studies involving non-invasive techniques to manipulate specific brain areas. These techniques most commonly involve the use of an electrical or magnetic field crossing the brain. In this regard, there has been emerging literature demonstrating the possibility to influence exercise outcomes in healthy people following stimulation of specific brain areas. Specifically, transcranial direct current stimulation (tDCS) has been recently used prior to exercise in order to improve exercise performance under a wide range of exercise types. In this review article, we discuss the evidence provided from experimental studies involving tDCS. The aim of this review is to provide a critical analysis of the experimental studies investigating the application of tDCS prior to exercise and how it influences brain function and performance. Finally, we provide a critical opinion of the usage of tDCS for exercise enhancement. This will consequently progress the current knowledge base regarding the effect of tDCS on exercise and provides both a methodological and theoretical foundation on which future research can be based