Exercise-induced respiratory muscle work: Effects on blood flow, fatigue and performance

This is the post print version of this article. The official published version can be obtained from the link below.In healthy subjects, heavy intensity endurance exercise places substantial demands on the respiratory muscles as breathing frequency, ventilation and the work of breathing rise over time. In the highly trained subject working at high absolute work rates, the ventilatory demand often causes varying degrees of expiratory flow limitation, sometimes accompanied by lung hyperinflation and, therefore, increased elastic work of breathing. Time-dependant increases in effort perceptions for both dyspnea and limb discomfort accompany these increased ventilatory demands. Similar responses to endurance exercise but at much lower exercise intensities also occur in patients with COPD and CHF. Note that these responses significantly influence exercise performance times in both health and disease. This effect was demonstrated by the marked reductions in the rate of rise of effort perceptions and the enhanced exercise performance times elicited by unloading the respiratory muscles using pressure support ventilation or proportional assist mechanical ventilation. In healthy fit subjects, unloading the inspiratory work of breathing by about one half increased performance by an average of 14% (Harms et al. 2000), and in CHF and COPD patients performance time more than doubled with respiratory muscle unloading (O’Donnell et al. 2001). Why are effort perceptions of limb discomfort markedly reduced and exercise performance increased when the respiratory muscles are unloaded? Our hypothesis is shown in Fig. 1

At identical isowork rates, ageing influences cardiorespiratory adaptations in COPD out-patients

SummaryPurposeTo determine the extent to which younger COPD patients improve their cardiorespiratory function during exercise in comparison with older COPD patients, as a result of exercise training.MethodsThirty-nine COPD patients underwent an exercise program. They were divided into two groups: a younger group (57.2±1.0 years, n=18 patients) and an older group (68.8±0.6 years, n=21 patients). Forced expiratory volume in 1s was lower than 55% of the predicted value for all patients.ResultsAfter training, V˙O2 symptom-limited significantly improved by 10.3% and 8.4% for the younger and older COPD patients, respectively (P<0.05). Peak power significantly improved by 25.2% and 17.8% in the younger and older groups, respectively (P<0.05) with a greater improvement for the younger group (P<0.05). At submaximal exercise, ventilation and heart rate significantly decreased after training in the younger COPD patients (P<0.05) with no significant modification in the older COPD patients.ConclusionsThe results suggest that all patients with COPD benefit from exercise rehabilitation at maximal exercise workload, however, according to their age, submaximal cardiorespiratory adaptations were greater in younger patients

Model Independent Analysis of the Forward-Backward Asymmetry for the B→K1μ+μ−B\to K_{1}\mu^{+}\mu^{-} Decay

The sensitivity of the zero position of the forward backward asymmetry $\mathcal{A}_{FB}$ for the exclusive $B\rightarrow K_{1}(1270)\mu^{+}\mu^{-}$ decay is examined by using most general non-standard 4-fermion interactions. Our analysis shows that the zero position of the forward backward asymmetry is very sensitive to the sign and size of the Wilson coefficients corresponding to the new vector type interactions, which are the counter partners of the usual Standard Model operators but have opposite chirality. In addition to these, the other significant effect comes from the interference of Scalar-Pseudoscalar and Tensor type operators. These results will not only enhance our theoretical understanding about the axial vector mesons but will also serve as a good tool to look for physics beyond the SM.Comment: 14 pages, 8 figures, Published version that appears in EPJ

Rare Decays of \Lambda_b->\Lambda + \gamma and \Lambda_b ->\Lambda + l^{+} l^{-} in the Light-cone Sum Rules

Within the Standard Model, we investigate the weak decays of $\Lambda_b \to \Lambda + \gamma$ and $\Lambda_b \to \Lambda + l^{+} l^{-}$ with the light-cone sum rules approach. The higher twist distribution amplitudes of $\Lambda$ baryon to the leading conformal spin are included in the sum rules for transition form factors. Our results indicate that the higher twist distribution amplitudes almost have no influences on the transition form factors retaining the heavy quark spin symmetry, while such corrections can result in significant impacts on the form factors breaking the heavy quark spin symmetry. Two phenomenological models (COZ and FZOZ) for the wave function of $\Lambda$ baryon are also employed in the sum rules for a comparison, which can give rise to the form factors approximately 5 times larger than that in terms of conformal expansion. Utilizing the form factors calculated in LCSR, we then perform a careful study on the decay rate, polarization asymmetry and forward-backward asymmetry, with respect to the decays of $\Lambda_b \to \Lambda \gamma$, $\Lambda l^{+}l^{-}$.Comment: 38 pages, 15 figures, some typos are corrected and more references are adde

ADAMTS13 regulation of VWF multimer distribution in severe COVID‐19

Background Consistent with fulminant endothelial cell activation, elevated plasma von Willebrand factor (VWF) antigen levels have been reported in patients with COVID-19. The multimeric size and function of VWF are normally regulated through A Disintegrin And Metalloprotease with ThrombSpondin Motif type 1 motif, member 13 (ADAMTS-13)--mediated proteolysis. Objectives This study investigated the hypothesis that ADAMTS-13 regulation of VWF multimer distribution may be impaired in severe acute respiratory syndrome-coronavirus-2 (SARS-CoV-2) infection contributing to the observed microvascular thrombosis. Patients and Methods Patients with COVID-19 (n = 23) were recruited from the Beaumont Hospital Intensive Care Unit (ICU) in Dublin. Plasma VWF antigen, multimer distribution, ADAMTS-13 activity, and known inhibitors thereof were assessed. Results We observed markedly increased VWF collagen-binding activity in patients with severe COVID-19 compared to controls (median 509.1 versus 94.3 IU/dl). Conversely, plasma ADAMTS-13 activity was significantly reduced (median 68.2 IU/dl). In keeping with an increase in VWF:ADAMTS-13 ratio, abnormalities in VWF multimer distribution were common in patients with COVID-19, with reductions in high molecular weight VWF multimers. Terminal sialylation regulates VWF susceptibility to proteolysis by ADAMTS-13 and other proteases. We observed that both N- and O-linked sialylation were altered in severe COVID-19. Furthermore, plasma levels of the ADAMTS-13 inhibitors interleukin-6, thrombospondin-1, and platelet factor 4 were significantly elevated. Conclusions These findings support the hypothesis that SARS-CoV-2 is associated with profound quantitative and qualitative increases in plasma VWF levels, and a multifactorial down-regulation in ADAMTS-13 function. Further studies will be required to determine whether therapeutic interventions to correct ADAMTS-13-VWF multimer dysfunction may be useful in COVID-microvascular thrombosis and angiopathy

Phospholipid oxidation and carotenoid supplementation in Alzheimer’s disease patients

Alzheimer's disease (AD) is a progressive, neurodegenerative disease, characterised by decline of memory, cognitive function and changes in behaviour. Generic markers of lipid peroxidation are increased in AD, therefore reactive oxygen species have been suggested to be involved in the aetiology of cognitive decline. Carotenoids are depleted in AD serum, therefore we have compared serum lipid oxidation between AD and age-matched control subjects before and after carotenoid supplementation. The novel oxidised phospholipid biomarker 1-palmitoyl-2-(5'-oxo-valeroyl)-sn-glycero-3-phosphocholine (POVPC) was analysed using electrospray ionization tandem mass spectrometry (MS) with multiple reaction monitoring (MRM), 8-isoprostane (IsoP) was measured by ELISA and ferric reducing antioxidant potential (FRAP) was measured by a colorimetric assay. AD patients (n=21) and healthy age-matched control subjects (n=16) were supplemented with either Macushield™ (10 mg meso-zeaxanthin, 10 mg lutein, 2 mg zeaxanthin) or placebo (sunflower oil) for six months. The MRM-MS method determined serum POVPC sensitively (from 10 µl serum) and reproducibly (CV=7.9%). At baseline, AD subjects had higher serum POVPC compared to age-matched controls, (p=0.017) and cognitive function was correlated inversely with POVPC (r=−0.37; p=0.04). After six months of carotenoid intervention, serum POVPC was not different in AD patients compared to healthy controls. However, POVPC was significantly higher in control subjects after six months of carotenoid intervention compared to their baseline (p=0.03). Serum IsoP concentration was unrelated to disease or supplementation. Serum FRAP was significantly lower in AD than healthy controls but was unchanged by carotenoid intervention (p=0.003). In conclusion, serum POVPC is higher in AD patients compared to control subjects, is not reduced by carotenoid supplementation and correlates with cognitive function

Familial thrombocytopenia due to a complex structural variant resulting in a WAC-ANKRD26 fusion transcript

Advances in genome sequencing have resulted in the identification of the causes for numerous rare diseases. However, many cases remain unsolved with standard molecular analyses. We describe a family presenting with a phenotype resembling inherited thrombocytopenia 2 (THC2). THC2 is generally caused by single nucleotide variants that prevent silencing of ANKRD26 expression during hematopoietic differentiation. Short-read whole-exome and genome sequencing approaches were unable to identify a causal variant in this family. Using long-read whole-genome sequencing, a large complex structural variant involving a paired-duplication inversion was identified. Through functional studies, we show that this structural variant results in a pathogenic gain-of-function WAC-ANKRD26 fusion transcript. Our findings illustrate how complex structural variants that may be missed by conventional genome sequencing approaches can cause human disease

Recommendations for clinical interpretation of variants found in non-coding regions of the genome

Background The majority of clinical genetic testing focuses almost exclusively on regions of the genome that directly encode proteins. The important role of variants in non-coding regions in penetrant disease is, however, increasingly being demonstrated, and the use of whole genome sequencing in clinical diagnostic settings is rising across a large range of genetic disorders. Despite this, there is no existing guidance on how current guidelines designed primarily for variants in protein-coding regions should be adapted for variants identified in other genomic contexts. Methods We convened a panel of nine clinical and research scientists with wide-ranging expertise in clinical variant interpretation, with specific experience in variants within non-coding regions. This panel discussed and refined an initial draft of the guidelines which were then extensively tested and reviewed by external groups. Results We discuss considerations specifically for variants in non-coding regions of the genome. We outline how to define candidate regulatory elements, highlight examples of mechanisms through which non-coding region variants can lead to penetrant monogenic disease, and outline how existing guidelines can be adapted for the interpretation of these variants. Conclusions These recommendations aim to increase the number and range of non-coding region variants that can be clinically interpreted, which, together with a compatible phenotype, can lead to new diagnoses and catalyse the discovery of novel disease mechanisms

Nitric oxide and cyclic nucleotides: Their roles in junction dynamics and spermatogenesis

Spermatogenesis is a highly complicated process in which functional spermatozoa (haploid, 1n) are generated from primitive mitotic spermatogonia (diploid, 2n). This process involves the differentiation and transformation of several types of germ cells as spermatocytes and spermatids undergo meiosis and differentiation. Due to its sophistication and complexity, testis possesses intrinsic mechanisms to modulate and regulate different stages of germ cell development under the intimate and indirect cooperation with Sertoli and Leydig cells, respectively. Furthermore, developing germ cells must translocate from the basal to the apical (adluminal) compartment of the seminiferous epithelium. Thus, extensive junction restructuring must occur to assist germ cell movement. Within the seminiferous tubules, three principal types of junctions are found namely anchoring junctions, tight junctions, and gap junctions. Other less studied junctions are desmosome-like junctions and hemidesmosome junctions. With these varieties of junction types, testes are using different regulators to monitor junction turnover. Among the uncountable junction modulators, nitric oxide (NO) is a prominent candidate due to its versatility and extensive downstream network. NO is synthesized by nitric oxide synthase (NOS). Three traditional NOS, specified as endothelial NOS (eNOS), inducible NOS (iNOS), and neuronal NOS (nNOS), and one testis-specific nNOS (TnNOS) are found in the testis. For these, eNOS and iNOS were recently shown to have putative junction regulation properties. More important, these two NOSs likely rely on the downstream soluble guanylyl cyclase/cGMP/protein kinase G signaling pathway to regulate the structural components at the tight junctions and adherens junctions in the testes. Apart from the involvement in junction regulation, NOS/NO also participates in controlling the levels of cytokines and hormones in the testes. On the other hand, NO is playing a unique role in modulating germ cell viability and development, and indirectly acting on some aspects of male infertility and testicular pathological conditions. Thus, NOS/NO bears an irreplaceable role in maintaining the homeostasis of the microenvironment in the seminiferous epithelium via its different downstream signaling pathways