A practical approach to refractory Kawasaki disease

Kawasaki disease (KD) is a medium vessel vasculitis and is the most common cause of acquired heart disease in childhood. If left untreated, KD leads to coronary artery aneurysms in 15–25% of patients and the mortality rate in the UK is currently 0.4%. As such, KD is an important preventable cause of heart disease in the young. The aetiology of KD remains unknown, but most likely it represents an aberrant inflammatory host response to one or more as yet unidentified immunological trigger(s) in genetically predisposed individuals. The purpose of this article is not to provide an exhaustive review of KD. Rather we provide practical guidance to the clinical approach to refractory KD. Only brief background on the pathogenesis and epidemiology of KD, and emerging newer clinical trials is provided, to place our clinical approach in context

Bereavement reduces neutrophil oxidative burst only in older adults: role of the HPA axis and immunesenescence

Background The effect of the chronic stress of bereavement on immunity is poorly understood. Previous studies have demonstrated negative effects on immunity in older adults, and those who report higher depressive symptoms. The aim of the present study was to compare the effect of bereavement on neutrophil function in healthy young and old adults, also assessing serum levels of the stress hormones, cortisol and dehydroepiandrosterone sulphate (DHEAS). 41 young (mean age 32 years) and 52 older adults (mean age 72 years), bereaved and non-bereaved, took part in the study. They completed questionnaires on socio-demographic and health behaviour characteristics, as well as psychosocial variables, and provided a blood sample for analysis of neutrophil function (phagocytosis and reactive oxygen species (ROS) production) and stress hormone analysis. Results Bereaved participants in both age groups reported more symptoms of depression and anxiety than controls and scored moderately highly on bereavement-specific questionnaires for these symptoms. Despite this, young bereaved participants showed robust neutrophil function when compared to age-matched non-bereaved controls, and comparable stress hormone levels, while reduced neutrophil ROS production and raised stress hormone levels (cortisol:DHEAS ratio) were seen in the older bereaved group compared to their age-matched controls. Conclusions Reduced neutrophil function among older bereaved participants may be the result of the inability to maintain stress hormone balance, specifically the cortisol:DHEAS ratio

PGC-1α is Dispensable for Exercise-Induced Mitochondrial Biogenesis in Skeletal Muscle

Exercise confers numerous health benefits, many of which are thought to stem from exercise-induced mitochondrial biogenesis (EIMB) in skeletal muscle. The transcriptional coactivator PGC-1α, a potent regulator of metabolism in numerous tissues, is widely believed to be required for EIMB. We show here that this is not the case. Mice engineered to lack PGC-1α specifically in skeletal muscle (Myo-PGC-1αKO mice) retained intact EIMB. The exercise capacity of these mice was comparable to littermate controls. Induction of metabolic genes after 2 weeks of in-cage voluntary wheel running was intact. Electron microscopy revealed no gross abnormalities in mitochondria, and the mitochondrial biogenic response to endurance exercise was as robust in Myo-PGC-1αKO mice as in wildtype mice. The induction of enzymatic activity of the electron transport chain by exercise was likewise unperturbed in Myo-PGC-1αKO mice. These data demonstrate that PGC-1α is dispensable for exercise-induced mitochondrial biogenesis in skeletal muscle, in sharp contrast to the prevalent assumption in the field

Expression of the alternative oxidase mitigates beta-amyloid production and toxicity in model systems

Mitochondrial dysfunction has been widely associated with the pathology of Alzheimer's disease, but there is no consensus on whether it is a cause or consequence of disease, nor on the precise mechanism(s). We addressed these issues by testing the effects of expressing the alternative oxidase AOX from Ciona intestinalis, in different models of AD pathology. AOX can restore respiratory electron flow when the cytochrome segment of the mitochondrial respiratory chain is inhibited, supporting ATP synthesis, maintaining cellular redox homeostasis and mitigating excess superoxide production at respiratory complexes I and III. In human HEK293-derived cells, AOX expression decreased the production of beta-amyloid peptide resulting from antimycin inhibition of respiratory complex III. Because hydrogen peroxide was neither a direct product nor substrate of AOX, the ability of AOX to mimic antioxidants in this assay must be indirect. In addition, AOX expression was able to partially alleviate the short lifespan of Drosophila models neuronally expressing human beta-amyloid peptides, whilst abrogating the induction of markers of oxidative stress. Our findings support the idea of respiratory chain dysfunction and excess ROS production as both an early step and as a pathologically meaningful target in Alzheimer's disease pathogenesis, supporting the concept of a mitochondrial vicious cycle underlying the disease. (C) 2016 The Authors. Published by Elsevier Inc.Peer reviewe

Identification of Genes and Pathways Regulated by Lamin A in Heart

Background Mutations in the LMNA gene, encoding LMNA (lamin A/C), causes distinct disorders, including dilated cardiomyopathies, collectively referred to as laminopathies. The genes (coding and noncoding) and regulatory pathways controlled by LMNA in the heart are not completely defined. Methods and Results We analyzed cardiac transcriptome from wild-type, loss-of-function (Lmna-/-), and gain-of-function (Lmna-/- injected with adeno-associated virus serotype 9 expressing LMNA) mice with normal cardiac function. Deletion of Lmna (Lmna-/-) led to differential expression of 2193 coding and 629 long noncoding RNA genes in the heart (q<0.05). Re-expression of LMNA in the Lmna-/- mouse heart, completely rescued 501 coding and 208 non-coding and partially rescued 1862 coding and 607 lncRNA genes. Pathway analysis of differentially expressed genes predicted activation of transcriptional regulators lysine-specific demethylase 5A, lysine-specific demethylase 5B, tumor protein 53, and suppression of retinoblastoma 1, paired-like homeodomain 2, and melanocyte-inducing transcription factor, which were completely or partially rescued upon reexpression of LMNA. Furthermore, lysine-specific demethylase 5A and 5B protein levels were increased in the Lmna-/- hearts and were partially rescued upon LMNA reexpression. Analysis of biological function for rescued genes identified activation of tumor necrosis factor-α, epithelial to mesenchymal transition, and suppression of the oxidative phosphorylation pathway upon Lmna deletion and their restoration upon LMNA reintroduction in the heart. Restoration of the gene expression and transcriptional regulators in the heart was associated with improved cardiac function and increased survival of the Lmna-/- mice. Conclusions The findings identify LMNA-regulated cardiac genes and their upstream transcriptional regulators in the heart and implicate lysine-specific demethylase 5A and B as epigenetic regulators of a subset of the dysregulated genes in laminopathies

Antioxidant properties of MitoTEMPOL and its hydroxylamine

Piperidine nitroxides such as TEMPOL have been widely used as antioxidants in vitro and in vivo. MitoTEMPOL is a mitochondria-targeted derivative of TEMPOL designed to protect mitochondria from the oxidative damage that they accumulate, but once there is rapidly reduced to its hydroxylamine, MitoTEMPOL-H. As little is known about the antioxidant efficacy of hydroxylamines, this study has assessed the antioxidant activity of both MitoTEMPOL and MitoTEMPOL-H. The hydroxylamine was more effective at preventing lipid-peroxidation than MitoTEMPOL and decreased oxidative damage to mitochondrial DNA caused by menadione. In contrast to MitoTEMPOL, MitoTEMPOL-H has no superoxide dismutase activity and its antioxidant actions are likely to be mediated by hydrogen atom donation. Therefore, even though MitoTEMPOL is rapidly reduced to MitoTEMPOL-H in cells, it remains an effective antioxidant. Furthermore, as TEMPOL is also reduced to a hydroxylamine in vivo, many of its antioxidant effects may also be mediated by its hydroxylamine

Integrating destination attributes, political (in)stability, destination image, tourist satisfaction, and intention to recommend: a study of UAE

Very limited attention has hitherto been paid to political-specific issues that may significantly guide the successful formation of destination image. Therefore, the purpose of this article is to examine the interrelationships between destination attributes, political (in)stability, destination image, tourist satisfaction, and intention to recommend, to build a conceptual framework of the drivers and outcomes of destination image. Twelve hypotheses (null and alternative) were developed and examined, using a sample of 829 tourists visiting the UAE. Results show that tourists' evaluation of the destination attributes and political (in)stability act as antecedents of perceived destination image. Furthermore, political (in)stability and destination image have a strong effect on tourist satisfaction and intention to recommend. The current study enhances current theorizations by examining the merits of political (in)stability in models of tourists' intention to recommend. From a practical perspective, the study presents significant implications for destination marketers

Effectiveness of initiating biologics in severe asthma patients with high steroid exposure

Peer reviewedPostprin

Generating a Generation of Proteasome Inhibitors: From Microbial Fermentation to Total Synthesis of Salinosporamide A (Marizomib) and Other Salinosporamides

The salinosporamides are potent proteasome inhibitors among which the parent marine-derived natural product salinosporamide A (marizomib; NPI-0052; 1) is currently in clinical trials for the treatment of various cancers. Methods to generate this class of compounds include fermentation and natural products chemistry, precursor-directed biosynthesis, mutasynthesis, semi-synthesis, and total synthesis. The end products range from biochemical tools for probing mechanism of action to clinical trials materials; in turn, the considerable efforts to produce the target molecules have expanded the technologies used to generate them. Here, the full complement of methods is reviewed, reflecting remarkable contributions from scientists of various disciplines over a period of 7 years since the first publication of the structure of 1