The physiological roles of carnosine and β-alanine in exercising human skeletal muscle

Carnosine (β-alanyl-L-histidine) plays an important role in exercise performance and skeletal muscle homeostasis. Dietary supplementation with the rate-limiting precursor β-alanine leads to an increase in skeletal muscle carnosine content, which further potentiates its effects. There is significant interest in carnosine and β-alanine across athletic and clinical populations. Traditionally, attention has been given to performance outcomes with less focus on the underlying mechanism(s). Putative physiological roles in human skeletal muscle include acting as an intracellular pH buffer, modulating energy metabolism, regulating Ca2+ handling and myofilament sensitivity, and scavenging of reactive species. Emerging evidence shows that carnosine could also act as a cytoplasmic Ca2+–H+ exchanger and form stable conjugates with exercise-induced reactive aldehydes. The enigmatic nature of carnosine means there is still much to learn regarding its actions and applications in exercise, health and disease. In this review, we examine the research relating to each physiological role attributed to carnosine, and its precursor β-alanine, in exercising human skeletal muscle

Development and inter-rater reliability of the Liverpool adverse drug reaction causality assessment tool.

To develop and test a new adverse drug reaction (ADR) causality assessment tool (CAT)

Understanding the Relationship Between Biotherapeutic Protein Stability and Solid-Liquid Interfacial Shear in Constant Region Mutants of IgG1 and IgG4.

Relative stability of therapeutic antibody candidates is currently evaluated primarily through their response to thermal degradation, yet this technique is not always predictive of stability in manufacture, shipping, and storage. A rotating disk shear device is proposed that produces defined shear conditions at a known solid-liquid interface to measure stability in this environment. Five variants of IgG1 and IgG4 antibodies were created using combinations of two discrete triple amino acid sequence mutations denoted TM and YTE. Antibodies were ranked for stability based on shear device output (protein decay coefficient, PDC), and compared with accelerated thermal stability data and the melting temperature of the CH2 domain (Tm 1) from differential scanning calorimetry to investigate technique complimentarity. Results suggest that the techniques are orthogonal, with thermal methods based on intramolecular interaction and shear device stability based on localized unfolding revealing less stable regions that drive aggregation. Molecular modeling shows the modifications' effects on the antibody structures and indicates a possible role for Fc conformation and Fab-Fc docking in determining suspended protein stability. The data introduce the PDC value as an orthogonal stability indicator, complementary to traditional thermal methods, allowing lead antibody selection based on a more full understanding of process stability. © 2013 The Authors. Journal of Pharmaceutical Sciences published by Wiley Periodicals, Inc. and the American Pharmacists Association J Pharm Sci

Skyrmion fluctuations at a first-order phase transition boundary

Magnetic skyrmions are topologically protected spin textures with promising prospects for applications in data storage. They can form a lattice state due to competing magnetic interactions and are commonly found in a small region of the temperature - magnetic field phase diagram. Recent work has demonstrated that these magnetic quasi-particles fluctuate at the μeV energy scale. Here, we use a coherent x-ray correlation method at an x-ray free-electron laser to investigate these fluctuations in a magnetic phase coexistence region near a first-order transition boundary where fluctuations are not expected to play a major role. Surprisingly, we find that the relaxation of the intermediate scattering function at this transition differs significantly compared to that deep in the skyrmion lattice phase. The observation of a compressed exponential behavior suggests solid-like dynamics, often associated with jamming. We assign this behavior to disorder and the phase coexistence observed in a narrow field-window near the transition, which can cause fluctuations that lead to glassy behavior

A breakup model for transient Diesel fuel sprays

In this paper a breakup model for analysing the evolution of transient fuel sprays characterised by a coherent liquid core emerging from the injection nozzle, throughout the injection process, is proposed. The coherent liquid core is modelled as a liquid jet and a breakup model is formulated. The spray breakup is described using a composite model that separately addresses the disintegration of the liquid core into droplets and their further aerodynamic breakup. The jet breakup model uses the results of hydrodynamic stability theory to define the breakup length of the jet, and downstream of this point, the spray breakup process is modelled for droplets only. The composite breakup model is incorporated into the KIVA II Computational Fluid Dynamics (CFD) code and its results are compared with existing breakup models, including the classic WAVE model and a previously developed composite WAVE model (modified WAVE model) and in-house experimental observations of transient Diesel fuel sprays. The hydrodynamic stability results used in both the jet breakup model and the WAVE droplet breakup model are also investigated. A new velocity profile is considered for these models which consists of a jet with a linear shear layer in the gas phase surrounding the liquid core to model the effect of a viscous gas on the breakup process. This velocity profile changes the driving instability mechanism of the jet from a surface tension driven instability for the currently used plug flow jet with no shear layers, to an instability driven by the thickness of the shear layer. In particular, it is shown that appreciation of the shear layer instability mechanism in the composite model allows larger droplets to be predicted at jet breakup, and gives droplet sizes which are more consistent with the experimental observations. The inclusion of the shear layer into the jet velocity profile is supported by previous experimental studies, and further extends the inviscid flow theory used in the formulation of the classic WAVE breakup model

Adverse drug reactions and off-label and unlicensed medicines in children: a nested case control study of inpatients in a pediatric hospital

Off-label and unlicensed (OLUL) prescribing has been prevalent in pediatric practice. Using data from a prospective cohort study of adverse drug reactions (ADRs) among pediatric inpatients, we aimed to test the hypothesis that OLUL status is a risk factor for ADRs

Incidence, characteristics and risk factors of adverse drug reactions in hospitalized children - a prospective observational cohort study of 6,601 admissions

Adverse drug reactions (ADRs) are an important cause of harm in children. Current data are incomplete due to methodological differences between studies: only half of all studies provide drug data, incidence rates vary (0.6% to 16.8%) and very few studies provide data on causality, severity and risk factors of pediatric ADRs. We aimed to determine the incidence of ADRs in hospitalized children, to characterize these ADRs in terms of type, drug etiology, causality and severity and to identify risk factors