Τετάρτη 24 Ιανουαρίου 2018

Response to phenotypic hetergeneity of POMT2 variants



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Clinical and cytogenomic findings in OAV spectrum

The oculoauriculovertebral spectrum (OAVS) is characterized by anomalies involving the development of the first and second pharyngeal arches during the embryonic period. The phenotype is highly heterogeneous, involving ears, eyes, face, neck, and other systems and organs. There is no agreement in the literature for the minimum phenotypic inclusion criteria, but the primary phenotype involves hemifacial microsomia with facial asymmetry and microtia. Most cases are sporadic and the etiology of this syndrome is not well known. Environmental factors, family cases that demonstrate Mendelian inheritance, such as preauricular appendages, microtia, mandibular hypoplasia, and facial asymmetry; chromosomal abnormalities and some candidate genes suggest a multifactorial inheritance model. We evaluated clinical, cytogenomic and molecularly 72 patients with OAVS, and compared our findings with patients from the literature. We found 15 CNVs (copy number variations) considered pathogenic or possibly pathogenic in 13 out of 72 patients. Our results did not indicated a single candidate genomic region, but recurrent chromosomal imbalances were observed in chromosome 4 and 22, in regions containing genes relevant to the OAVS phenotype or related to known OMIM diseases suggesting different pathogenic mechanisms involved in this genetically and phenotypic heterogeneous spectrum.



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JNA Journal Club

No abstract available

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A calcium optimum for cytotoxic T lymphocyte and natural killer cell cytotoxicity

Abstract

Cytotoxic T lymphocytes (CTL) and natural killer (NK) cells are required to protect the human body against cancer. Ca2+ is a key metabolic factor for lymphocyte function and cancer homeostasis. We analysed the Ca2+ dependence of CTL and NK cell cytotoxicity against cancer cells and found that CTL have a bell-shaped Ca2+ dependence with an optimum for cancer cell elimination at rather low [Ca2+]ext (23–630 μm) and [Ca2+]int (122–334 nm). This finding predicts that a partial inhibition of Orai1 should increase (rather than decrease) cytotoxicity of CTL at [Ca2+]ext higher than 630 μm. We tested this hypothesis in CTL and indeed found that partial down-regulation of Orai1 by siRNA increases the efficiency of cancer cell killing. We found two mechanisms that may account for the Ca2+ optimum of cancer cell killing: 1) Migration velocity and persistence have a moderate optimum between 500 and 1000 μm [Ca2+]ext in CTL, and 2) lytic granule release at the immune synapse between CTL and cancer cells is increased at 146 μm comparted to 3 or 800 μm, compatible with the Ca2+ optimum for cancer cell killing. It has been demonstrated in many cancer cell types that Orai1-dependent Ca2+ signals enhance proliferation. We propose that a decrease of [Ca2+]ext or partial inhibition of Orai1 activity by selective blockers in the tumor microenvironment could efficiently reduce cancer growth by simultaneously increasing CTL and NK cell cytotoxicity and decreasing cancer cell proliferation.

This article is protected by copyright. All rights reserved



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Intellectual developmental disorder with cardiac arrhythmia syndrome in a child with compound heterozygous GNB5 variants

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Identification of a novel compound heterozygous of GNB5 in a patient with intellectual developmental disorder with cardiac arrhytmia (IDDCA), from non-consaguineous family. Three-dimensional modelling and in silico predictions suggest that GNB5 variants are causative of the phenotype, extending the number of IDDCA patients so far identified.



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{-}{-}{-}Pleiotropic Functions of the Chromodomain-Containing Protein Hat-trick During Oogenesis in Drosophila melanogaster

Chromatin-remodeling proteins play a profound role in the transcriptional regulation of gene expression during development. Here, we have shown that the chromodomain-containing protein Hat-trick is predominantly expressed within ­­­­the oocyte nucleus, specifically within the heterochromatinized karyosome and that a mild expression is observed in follicle cells. Co-localization of Hat-trick with Heterochromatin Protein 1 and a Synaptonemal Complex component- C(3)G along with the diffused karyosome after hat-trick down-regulation shows the role of this protein in heterochromatin clustering and karyosome maintenance. Germline mosaic analysis reveals that hat-trick is required for maintaining the dorso-ventral patterning of eggs by regulating the expression of Gurken. The increased incidence of Double strand breaks (DSBs), delayed DSB repair, defects in karyosome formation, altered Vasa mobility and consequently misexpression and altered localization of Gurken in hat-trick mutant egg chambers, clearly suggest a putative involvement of Hat-trick in the early stages of oogenesis. In addition, based on phenotypic observations in hat-trick mutant egg chambers, we speculate a substantial role of hat-trick in cystoblast proliferation, oocyte determination, nurse cell endoreplication, germ cell positioning, cyst encapsulation, and nurse cell migration. Our results demonstrate that hat-trick has profound pleiotropic functions during oogenesis in Drosophila melanogaster.



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Systematic Functional Characterization of Human 21st Chromosome Orthologs in Caenorhabditis elegans

Individuals with Down syndrome have neurological and muscle impairments due to an additional copy of the human 21st chromosome (HSA21). Only a few of ~200 HSA21 genes encoding protein have been linked to specific Down syndrome phenotypes, while the remainder are understudied. To identify poorly characterized HSA21 genes required for nervous system function, we studied behavioral phenotypes caused by loss-of-function mutations in conserved HSA21 orthologs in the nematode Caenorhabditis elegans. We identified ten HSA21 orthologs that are required for neuromuscular behaviors: cle-1 (COL18A1), cysl-2 (CBS), dnsn-1 (DONSON), eva-1 (EVA1C), mtq-2 (N6ATM1), ncam-1 (NCAM2), pad-2 (POFUT2), pdxk-1 (PDXK), rnt-1 (RUNX1), and unc-26 (SYNJ1).  We also found that three of these genes are required for normal release of the neurotransmitter acetylcholine. This includes a known synaptic gene unc-26 (SYNJ1), as well as uncharacterized genes pdxk-1 (PDXK) and mtq-2 (N6ATM1). As the first systematic functional analysis of HSA21 orthologs, this study may serve as a platform to understand genes that underlie phenotypes associated with Down syndrome.



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Cortical contributions to anticipatory postural adjustments in the trunk

Abstract

Voluntary limb movements are associated with increases in trunk muscle activity, some of which occur within a time window considered too fast to be induced by sensory feedback; these increases are termed anticipatory postural adjustments (APAs). Although it is known that the function of APAs is to maintain postural stability in response to perturbations, excitability of the corticospinal projections to the trunk muscles during the APAs remain unclear. Thirty-four healthy subjects performed rapid shoulder flexion in response to a visual cue in standing and lying positions. Transcranial magnetic stimulation (TMS) was delivered over the trunk motor cortex to examine motor evoked potentials (MEPs) in erector spinae (ES) and in rectus abdominis (RA) at several time points prior to the rise in electromyographic activity (EMG) of anterior deltoid (AD). TMS was also used to assess short-interval intracortical inhibition (SICI) and cervicomedullary MEPs (CMEPs) in ES in the standing position. MEPs in ES were larger at time points closer to the rise in AD EMG in both standing and lying positions, whereas MEPs in RA did not differ over the time course examined. Notably, SICI was reduced at time points closer to the rise in AD EMG with no change in CMEPs. Our results demonstrate that increasing excitability of corticospinal projections to the trunk muscles prior to a voluntary limb movement is likely cortical in origin and is muscle specific.

This article is protected by copyright. All rights reserved



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Emergency Reporting offers enhanced, highly customizable Length of Service Awards Program (LOSAP) tracking tools

Emergency Reporting's LOSAP tracking tools and reports have been enhanced to create a highly customized and user-friendly experience. Easily track and organize yearly activity such as incident and non-incident, event and committee attendance.

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New product announcement: Public Access Quiklitter

SALIDA, Colo. — The new Rescue Essentials Public Access QuikLitter™ was designed specifically to be a more visible and easily accessible casualty extraction litter placed in public places, such as commercial buildings, entertainment venues, or transportation hubs. The Public Access Quiklitter, is intended to complement existing public access to AED and bleeding control stations and can be ...

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NH EMS agency honors volunteer for 45 years of service

By Deborah McDermott Portsmouth Herald YORK, N.H. — Forty-five years ago, Mary Andrews was chief of a three-person crew on the very first ambulance owned by the fledgling York Volunteer Ambulance Association. It was stored in her garage, with a heater inside to keep the oxygen warm powered by a yellow electrical cord that snaked inside her house - and that sometimes inadvertently went on rides ...

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Cherenkov-excited Multi-Fluorophore Sensing in Tissue-Simulating Phantoms and In Vivo from External Beam Radiotherapy

Radiation Research, Volume 189, Issue 2, Page 197-204, February 2018.


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Why Genetic Effects of Radiation are Observed in Mice but not in Humans

Radiation Research, Volume 189, Issue 2, Page 117-127, February 2018.


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MRI Study on the Changes of Bone Marrow Microvascular Permeability and Fat Content after Total-Body X-Ray Irradiation

Radiation Research, Volume 189, Issue 2, Page 205-212, February 2018.


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Rapid Decrease in KRT14 and TP53 mRNA Expression in the Buccal Mucosa of Patients Receiving Total-Body Irradiation for Allogeneic Stem Cell Transplantation

Radiation Research, Volume 189, Issue 2, Page 213-218, February 2018.


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Chronic Exposure to External Low-Dose Gamma Radiation Induces an Increase in Anti-inflammatory and Anti-oxidative Parameters Resulting in Atherosclerotic Plaque Size Reduction in ApoE–/– Mice

Radiation Research, Volume 189, Issue 2, Page 187-196, February 2018.


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Factors Modifying the Radon-Related Lung Cancer Risk at Low Exposures and Exposure Rates among German Uranium Miners

Radiation Research, Volume 189, Issue 2, Page 165-176, February 2018.


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The Role of FABP5 in Radiation-Induced Human Skin Fibrosis

Radiation Research, Volume 189, Issue 2, Page 177-186, February 2018.


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Is there Unmeasured Indication Bias in Radiation-Related Cancer Risk Estimates from Studies of Computed Tomography?

Radiation Research, Volume 189, Issue 2, Page 128-135, February 2018.


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FTIR Microspectroscopy Probes Particle-Radiation Effect on HCT116 cells (p53+/+, p53–/–)

Radiation Research, Volume 189, Issue 2, Page 156-164, February 2018.


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Quantitative Proteomic Analysis of the Hippocampus of Rats with GCR-Induced Spatial Memory Impairment

Radiation Research, Volume 189, Issue 2, Page 136-145, February 2018.


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Characterization of Diffuse Intrinsic Pontine Glioma Radiosensitivity using Synchrotron Microbeam Radiotherapy and Conventional Radiation Therapy In Vitro

Radiation Research, Volume 189, Issue 2, Page 146-155, February 2018.


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WNT10B mutations associated with isolated dental anomalies

ABSTRACT

Isolated hypodontia is the most common human malformation. It is caused by heterozygous variants in various genes, with heterozygous WNT10A variants being the most common cause. WNT10A and WNT10B are paralogs that likely evolved from a common ancestral gene after its duplication. Recently an association of WNT10B variants with oligodontia (severe tooth agenesis) has been reported. We performed mutational analysis in our cohort of 256 unrelated Thai families with various kinds of isolated dental anomalies. In seven families afflicted with dental anomalies we detected four heterozygous missense variants in WNT10B. We performed whole exome sequencing in the patients who had WNT10B mutations and found no mutations in other known hypodontia-associated genes, including WNT10A, MSX1, PAX9, EDA, AXIN2, EDAR, EDARADD, LPR6, TFAP2B, LPR6, NEMO, KRT17, and GREM2. Our findings indicate that the variants c.475G>C [p.( Ala159Pro)], found in four families, and c.1052G>A [p.(Arg351His)], found in one family, are most probably causative. They also show that WNT10B variants are associated not only with oligodontia and isolated tooth agenesis, but also with microdontia, short tooth roots, dental pulp stones, and taurodontism.

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Autosomal dominant myopia associated to a novel P4HA2 missense variant and defective collagen hydroxylation

ABSTRACT

We recently described a complex multisystem syndrome in which mild-moderate myopia segregated as an independent trait. A plethora of genes has been related to sporadic and familial myopia. More recently, in Chinese patients severe myopia (MYP25, OMIM:617238) has been linked to mutations in P4HA2 gene.

Seven family members complaining of reduced distance vision especially at dusk underwent complete ophthalmological examination. Whole exome sequencing was performed to identify the gene responsible for myopia in the pedigree.

Moderate myopia was diagnosed in the family which was associated to the novel missense variant c.1147A>G p.(Lys383Glu) in the prolyl 4-hydroxylase,alpha-polypeptide 2 (P4HA2) gene, which catalyzes the formation of 4-hydroxyproline residues in the collagen strands. In vitro studies demonstrated P4HA2 mRNA and protein reduced expression level as well as decreased collagen hydroxylation and deposition in mutated fibroblast primary cultures compared to healthy cell lines.

This study suggests that P4HA2 mutations may lead to myopic axial elongation of eyeball as a consequence of quantitative and structural alterations of collagen. This is the first confirmatory study which associates a novel dominant missense variant in P4HA2 with myopia in Caucasian patients. Further studies in larger cohorts are advisable to fully clarify genotype-phenotype correlations.

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Slow viscoelastic response of resilin

Abstract

The high importance of resilin in invertebrate biomechanics is widely known. It is generally assumed to be an almost perfect elastomer in different tissues. Whereas mechanical properties of resilin were previously determined mainly in tension, here we aimed at studying its mechanical properties in compression. Microindentation of resilin from the wing hinge of Locusta migratoria revealed the clear viscoelastic response of resilin: about a quarter of the mechanical response was assigned to a viscous component in our experiments. Mechanical properties were characterized using a generalized Maxwell model with two characteristic time constants, poroelasticity theory, and alternatively using a 1D model with just one characteristic time constant. Slow viscous responses with 1.7 and 16 s characteristic times were observed during indentation. These results demonstrate that the locust flight system is adapted to both fast and slow mechanical processes. The fast highly elastic process is related to the flight function and the slow viscoelastic process may be related to the wing folding.



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Whole genome variant analysis in three ethnically diverse Indians

Abstract

India represents an amazing confluence of geographically, linguistically and socially disparate ethnic populations (Indian Genome Variation Consortium, J Genet 87:3–20, 2008). Understanding the genetic diversity of Indian population remains a daunting task. In this paper we present detailed analysis of genomic variations (high-depth coverage (~ 30×) using Illumina Hiseq 2000 platform) from three healthy Indian male individuals each belonging to three geographically delineated regions and linguistic phylum viz. high altitude region of Ladakh (Tibeto-Burman linguistic phylum), sub mountainous region of Kumaun (Indo-European linguistic phylum) and sea level region of Telangana (Dravidian linguistic phylum) for probing the extent of genetic diversity in our population. The sequencing analysis provided high quality data (~ 95% of the total reads aligned to the human reference genome for each sample) and very good alignment quality (> 80% of the filtered mapped reads had a quality score of 60). A total of 4.3, 3.7 and 4.3 million single nucleotide variations were identified in the genome of high altitude, sub mountainous and sea level respectively by comparing with human reference genome. Approximately 17.3, 18.2, 17.4% of the variants were unique in the three genomes. The study identified many novel variations in the three diverse genomes (132,970 in Ladakh, 112,317 in Kumaun and 128,881 in Telangana individual) and is an important resource for creating a baseline and a comprehensive catalogue of human genomic variation across the Indian as well as the Asian continent.



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Origins of Portal Hypertension in Nonalcoholic Fatty Liver Disease

Abstract

Nonalcoholic fatty liver disease (NAFLD) advanced to cirrhosis is often complicated by clinically significant portal hypertension, which is primarily caused by increased intrahepatic vascular resistance. Liver fibrosis has been identified as a critical determinant of this process. However, there is evidence that portal venous pressure may begin to rise in the earliest stages of NAFLD when fibrosis is far less advanced or absent. The biological and clinical significance of these early changes in sinusoidal homeostasis remains unclear. Experimental and human observations indicate that sinusoidal space restriction due to hepatocellular lipid accumulation and ballooning may impair sinusoidal flow and generate shear stress, increasingly disrupting sinusoidal microcirculation. Sinusoidal endothelial cells, hepatic stellate cells, and Kupffer cells are key partners of hepatocytes affected by NAFLD in promoting endothelial dysfunction through enhanced contractility, capillarization, adhesion and entrapment of blood cells, extracellular matrix deposition, and neovascularization. These biomechanical and rheological changes are aggravated by a dysfunctional gut–liver axis and splanchnic vasoregulation, culminating in fibrosis and clinically significant portal hypertension. We may speculate that increased portal venous pressure is an essential element of the pathogenesis across the entire spectrum of NAFLD. Improved methods of noninvasive portal venous pressure monitoring will hopefully give new insights into the pathobiology of NAFLD and help efforts to identify patients at increased risk for adverse outcomes. In addition, novel drug candidates targeting reversible components of aberrant sinusoidal circulation may prevent progression in NAFLD.



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NRP1 haploinsufficiency predisposes to the development of Tetralogy of Fallot

Tetralogy of Fallot (TOF) is the most common cyanotic congenital heart defect. It involves anatomical abnormalities that change the normal flow of blood through the heart resulting in low oxygenation. Although not all of the underlying causes of TOF are completely understood, the disease has been associated with varying genetic etiologies including chromosomal abnormalities and Mendelian disorders, but can also occur as an isolated defect. In this report, we describe a familial case of TOF associated with a 1.8 Mb deletion of chromosome 10p11. Among the three genes in the region one is Neuropilin1 (NRP1), a membrane co-receptor of VEGF that modulates vasculogenesis. Hemizygous levels of NRP1 resulted in a reduced expression at the transcriptional and protein levels in patient-derived cells. Reduction of NRP1 also lead to decreased function of its activity as a co-receptor in intermolecular VEGF signaling. These findings support that diminished levels of NRP1 contribute to the development of TOF, likely through its function in mediating VEGF signal and vasculogenesis.



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Non-pharmacological treatment of psychiatric disorders in individuals with 22q11.2 deletion syndrome; a systematic review

22q11.2 deletion syndrome (22q11.2DS) is associated with high rates of anxiety disorders, psychotic disorders, and other psychiatric conditions. In the general population, psychiatric disorders are treated with proven pharmacological and non-pharmacological therapies, such as cognitive behavioral therapy (CBT). To begin to assess the feasibility and efficacy of non-pharmacological therapies in 22q11.2DS, we performed a systematic search to identify literature on non-pharmacological interventions for psychiatric disorders in individuals with 22q11.2DS. Of 1,240 individual publications up to mid-2016 initially identified, 11 met inclusion criteria. There were five literature reviews, five publications reporting original research (two originating from a single study), and one publication not fitting either category that suggested adaptations to an intervention without providing scientific evidence. None of the original research involved direct study of the evidence-based non-pharmacological therapies available for psychiatric disorders. Rather, these four studies involved computer-based or group interventions aimed at improving neuropsychological deficits that may be associated with psychiatric disorders. Although the sample sizes were relatively small (maximum 28 participants in the intervention group), these reports documented the promising feasibility of these interventions, and improvements in domains of neuropsychological functioning, including working memory, attention, and social cognition. The results of this review underline the need for research into the feasibility and efficacy of non-pharmacological treatments of psychiatric disorders in individuals with 22q11.2DS to inform clinical care, using larger samples, and optimally, standard randomized, placebo-controlled, clinical trials methodology.



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Genetics of the human face: Identification of large-effect single gene variants [Genetics]

To discover specific variants with relatively large effects on the human face, we have devised an approach to identifying facial features with high heritability. This is based on using twin data to estimate the additive genetic value of each point on a face, as provided by a 3D camera system....

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DNA double-strand break response factors influence end-joining features of IgH class switch and general translocation junctions [Genetics]

Ig heavy chain (IgH) class switch recombination (CSR) in B lymphocytes switches IgH constant regions to change antibody functions. CSR is initiated by DNA double-strand breaks (DSBs) within a donor IgH switch (S) region and a downstream acceptor S region. CSR is completed by fusing donor and acceptor S region...

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A mixed modality approach towards Xi reactivation for Rett syndrome and other X-linked disorders [Genetics]

The X-chromosome harbors hundreds of disease genes whose associated diseases predominantly affect males. However, a subset, including neurodevelopmental disorders, Rett syndrome (RTT), fragile X syndrome, and CDKL5 syndrome, also affects females. These disorders lack disease-specific treatment. Because female cells carry two X chromosomes, an emerging treatment strategy has been to...

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Genome-Wide Screen for New Components of the Drosophila melanogaster Torso Receptor Tyrosine Kinase Pathway

Patterning of the Drosophila embryonic termini by the Torso (Tor) receptor pathway has long served as a valuable paradigm for understanding how Receptor Tyrosine Kinase (RTK) signalling is controlled. However, the mechanisms that underpin the control of Tor signalling remain to be fully understood. In particular, it is unclear how the Perforin-like protein Torso-like (Tsl) localises Tor activity to the embryonic termini. To shed light on this, together with other aspects of Tor pathway function, we conducted a genome-wide screen to identify new pathway components that operate downstream of Tsl. Using a set of molecularly-defined chromosomal deficiencies, we screened for suppressors of ligand-dependent Tor signalling induced by unrestricted Tsl expression. This approach yielded 59 genomic suppressor regions, 11 of which we mapped to the causative gene, and a further 29 that were mapped to less than 15 genes. Of the identified genes, six represent previously unknown regulators of embryonic Tor signalling. These include twins, which encodes an integral subunit of the protein phosphatase 2A complex, and α-tubulin at 84B, a major constituent of the microtubule network, suggesting that these may play an important role in terminal patterning. Together these data comprise a valuable resource for the discovery of new Tor pathway components. Many of these may also be required for other roles of Tor in development, such as in the larval prothoracic gland where Tor signalling controls the initiation of metamorphosis.



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Pulmonary arterial hypertension reduces energy efficiency of right, but not left, rat ventricular trabeculae

Abstract

Pulmonary arterial hypertension (PAH) greatly increases the afterload on the right ventricle (RV), triggering RV hypertrophy, which progressively leads to RV failure. In contrast, the disease reduces the passive filling pressure of the left ventricle (LV), resulting in LV atrophy. We investigated whether these distinct structural and functional consequences to the ventricles affect their respective energy efficiencies. We studied trabeculae isolated from both ventricles of Wistar rats with monocrotaline-induced PAH and their respective Control groups. Trabeculae were mounted in a calorimeter at 37°C. While contracting at 5 Hz, they were subjected to stress-length work-loops over a wide range of afterloads. They were subsequently required to undergo a series of isometric contractions at various muscle lengths. In both protocols, stress production, length change, and suprabasal heat output were simultaneously measured. We found that RV trabeculae from PAH rats generated higher activation heat, but developed normal active stress. Their peak external work output was lower due to reduced extent and velocity of shortening. Despite lower peak work output, suprabasal enthalpy was unaffected, thereby rendering suprabasal efficiency lower. Crossbridge efficiency, however, was unaffected. In contrast, LV trabeculae from PAH rats maintained normal mechano-energetic performance. Pulmonary arterial hypertension reduces the suprabasal energy efficiency of hypertrophied right-ventricular tissues, as a consequence of the increased energy cost for Ca2+ cycling.

This article is protected by copyright. All rights reserved



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Drinking Strategies: Planned Drinking Versus Drinking to Thirst

Abstract

In humans, thirst tends to be alleviated before complete rehydration is achieved. When sweating rates are high and ad libitum fluid consumption is not sufficient to replace sweat losses, a cumulative loss in body water results. Body mass losses of 2% or greater take time to accumulate. Dehydration of ≥  2% body mass is associated with impaired thermoregulatory function, elevated cardiovascular strain and, in many conditions (e.g., warmer, longer, more intense), impaired aerobic exercise performance. Circumstances where planned drinking is optimal include longer duration activities of >  90 min, particularly in the heat; higher-intensity exercise with high sweat rates; exercise where performance is a concern; and when carbohydrate intake of 1 g/min is desired. Individuals with high sweat rates and/or those concerned with exercise performance should determine sweat rates under conditions (exercise intensity, pace) and environments similar to that anticipated when competing and tailor drinking to prevent body mass losses >  2%. Circumstances where drinking to thirst may be sufficient include short duration exercise of <  1 h to 90 min; exercise in cooler conditions; and lower-intensity exercise. It is recommended to never drink so much that weight is gained.



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Does Cold Water or Ice Slurry Ingestion During Exercise Elicit a Net Body Cooling Effect in the Heat?

Abstract

Cold water or ice slurry ingestion during exercise seems to be an effective and practical means to improve endurance exercise performance in the heat. However, transient reductions in sweating appear to decrease the potential for evaporative heat loss from the skin by a magnitude that at least negates the additional internal heat loss as a cold ingested fluid warms up to equilibrate with body temperature; thus explaining equivalent core temperatures during exercise at a fixed heat production irrespective of the ingested fluid temperature. Internal heat transfer with cold fluid/ice is always 100% efficient; therefore, when a decrement occurs in the efficiency that sweat evaporates from the skin surface (i.e. sweating efficiency), a net cooling effect should begin to develop. Using established relationships between activity, climate and sweating efficiency, the boundary conditions beyond which cold ingested fluids are beneficial in terms of increasing net heat loss can be calculated. These conditions are warmer and more humid for cycling relative to running by virtue of the greater skin surface airflow, which promotes evaporation, for a given metabolic heat production and thus sweat rate. Within these boundary conditions, athletes should ingest fluids at the temperature they find most palatable, which likely varies from athlete to athlete, and therefore best maintain hydration status. The cooling benefits of cold fluid/ice ingestion during exercise are likely disproportionately greater for athletes with physiological disruptions to sweating, such as those with a spinal cord injury or burn injuries, as their capacity for skin surface evaporative heat loss is much lower; however, more research examining these groups is needed.



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Cell shortening and calcium dynamics in epicardial and endocardial myocytes from the left ventricle of the Goto-Kakizaki type 2 diabetic rats

Abstract

Diabetic cardiomyopathy is considered as one of the major diabetes-associated complications and the pathogenesis of cardiac dysfunction is not well understood. The electromechanical properties of cardiac myocytes vary across the walls of the chambers The aim of this study was to investigate shortening and Ca2+ transport in epicardial (EPI) and endocardial (ENDO) left ventricular myocytes in the Goto-Kakizaki (GK) type 2 diabetic rat heart. Shortening and intracellular Ca2+ transients were measured by video edge detection and fluorescence photometry. Myocyte surface area was increased in EPI-GK and ENDO-GK compared to EPI-CON and ENDO-CON myocytes. Time to peak (TPK) shortening was prolonged in EPI-GK compared to EPI-CON and in ENDO-CON compared to EPI-CON myocytes. Time to half (THALF) relaxation of shortening was prolonged in EPI-GK compared to EPI-CON myocytes. TPK Ca2+ transient was prolonged in EPI-GK compared to EPI-CON myocytes. THALF decay of the Ca2+ transient was prolonged in EPI-CON compared to EPI-GK and in EPI-CON compared to ENDO-CON myocytes. Amplitude of shortening and the Ca2+ transient were unaltered in EPI-GK and ENDO-GK compared to their respective controls. Sarcoplasmic reticulum Ca2+ and myofilament sensitivity to Ca2+ were unaltered in EPI-GK and ENDO-GK compared to their respective controls. Regional differences in Ca2+ signaling in healthy and diabetic myocytes may account for variation in the dynamics of myocyte shortening. Further studies will be required to clarify the mechanisms underlying regional differences in the time course of shortening and the Ca2+ transient in EPI and ENDO myocytes from diabetic and control hearts.

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Acute-phase predictors of 6-month functional outcome in Italian stroke patients eligible for In-Hospital Rehabilitation

AbstractPurposeto assess early post-stroke prognostic factors in patients admitted for post-acute phase rehabilitation.Methodsa one-year multicenter prospective project was conducted in four Italian regions on 352 patients who were hospitalized after a first stroke and were eligible for post-acute rehabilitation. Clinical data were collected in the Stroke or Acute Care Units (acute phase), then in Rehabilitation Units (post-acute phase) and, subsequently, after a 6-month post-stroke period (follow-up). Clinical outcome measures were represented using the Barthel Index (BI) and the modified Rankin Scale (mRS). Univariate and multivariate analyses were performed to identify the most important prognostic index.ResultsmRS score, minor neurologic impairment and early out-of-bed mobilization (within 2 days after the stroke) proved to be important factors related to a better recovery according to BI (power of prediction = 37%). Similarly, age, pre-morbid mRS score and early out-of-bed mobilization were seen to be significant factors in achieving better overall participation and activity according to the mRS (power of prediction = 48%). BI at admission and certain comorbidities were also significant prognostic factors correlated with a better outcome.Conclusionsaccording to the BI and mRS, early mobilization is an early predictor of favorable outcome. Purpose to assess early post-stroke prognostic factors in patients admitted for post-acute phase rehabilitation. Methods a one-year multicenter prospective project was conducted in four Italian regions on 352 patients who were hospitalized after a first stroke and were eligible for post-acute rehabilitation. Clinical data were collected in the Stroke or Acute Care Units (acute phase), then in Rehabilitation Units (post-acute phase) and, subsequently, after a 6-month post-stroke period (follow-up). Clinical outcome measures were represented using the Barthel Index (BI) and the modified Rankin Scale (mRS). Univariate and multivariate analyses were performed to identify the most important prognostic index. Results mRS score, minor neurologic impairment and early out-of-bed mobilization (within 2 days after the stroke) proved to be important factors related to a better recovery according to BI (power of prediction = 37%). Similarly, age, pre-morbid mRS score and early out-of-bed mobilization were seen to be significant factors in achieving better overall participation and activity according to the mRS (power of prediction = 48%). BI at admission and certain comorbidities were also significant prognostic factors correlated with a better outcome. Conclusions according to the BI and mRS, early mobilization is an early predictor of favorable outcome. Corresponding author: Marco Franceschini, Department of Neurorehabilitation, IRCCS San Raffaele Pisana, Rome, Italy, Via della Pisana 235, 00163, Rome - Italy. Tel + 39 06 52252402 - fax +39 06 52255683. e-mail: marco.franceschini@sanraffaele.it Sources of Funding The project received financial support from Italian Ministry of Health for the Implementation of Stroke Care (ISC Study) within the CCM 2010 program. Subject Terms: Prognosis, Rehabilitation, Cerebrovascular Disease/Stroke Copyright © 2018 Wolters Kluwer Health, Inc. All rights reserved.

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Does goal-directed haemodynamic and fluid therapy improve peri-operative outcomes?: A systematic review and meta-analysis

BACKGROUND Much uncertainty exists as to whether peri-operative goal-directed therapy is of benefit. OBJECTIVES To discover if peri-operative goal-directed therapy decreases mortality and morbidity in adult surgical patients. DESIGN An updated systematic review and random effects meta-analysis of randomised controlled trials. DATA SOURCES Medline, Embase and the Cochrane Library were searched up to 31 December 2016. ELIGIBILITY CRITERIA Randomised controlled trials enrolling adult surgical patients allocated to receive goal-directed therapy or standard care were eligible for inclusion. Trauma patients and parturients were excluded. Goal-directed therapy was defined as fluid and/or vasopressor therapy titrated to haemodynamic goals [e.g. cardiac output (CO)]. Outcomes included mortality, morbidity and hospital length of stay. Risk of bias was assessed using Cochrane methodology. RESULTS Ninety-five randomised trials (11 659 patients) were included. Only four studies were at low risk of bias. Modern goal-directed therapy reduced mortality compared with standard care [odds ratio (OR) 0.66; 95% confidence interval (CI) 0.50 to 0.87; number needed to treat = 59; N = 52; I2 = 0.0%]. In subgroup analysis, there was no mortality benefit for fluid-only goal-directed therapy, cardiac surgery patients or nonelective surgery. Contemporary goal-directed therapy also reduced pneumonia (OR 0.69; 95% CI, 0.51 to 0. 92; number needed to treat = 38), acute kidney injury (OR 0. 73; 95% CI, 0.58 to 0.92; number needed to treat = 29), wound infection (OR 0.48; 95% CI, 0.37 to 0.63; number needed to treat = 19) and hospital length of stay (days) (−0.90; 95% CI, −1.32 to −0.48; I2 = 81. 2%). No important differences in outcomes were found for the pulmonary artery catheter studies, after accounting for advances in the standard of care. CONCLUSION Peri-operative modern goal-directed therapy reduces morbidity and mortality. Importantly, the quality of evidence was low to very low (e.g. Grading of Recommendations, Assessment, Development and Evaluation scoring), and there was much clinical heterogeneity among the goal-directed therapy devices and protocols. Additional well designed and adequately powered trials on peri-operative goal-directed therapy are necessary. Correspondence to Dr Matthew A. Chong, MD, Department of Anesthesia and Perioperative Medicine, University Hospital – London Health Sciences Centre, 339 Windermere Road, C3-108, London, ON, Canada N6A 5A5 E-mail: matthew.a.chong@gmail.com Supplemental digital content is available for this article. Direct URL citations appear in the printed text and are provided in the HTML and PDF versions of this article on the journal's Website (http://ift.tt/2ylyqmW). © 2018 European Society of Anaesthesiology

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