Kawasaki disease: a prospective population survey in the UK and Ireland from 2013 to 2015

OBJECTIVES: Kawasaki disease (KD) is an increasingly common vasculitis with risk of coronary artery aneurysms (CAAs). The last UK survey was in 1990, whereas current epidemiology, treatment patterns and complication rates are unknown. The aim of this study was to address this knowledge gap. METHODS: A British Paediatric Surveillance Unit survey in the UK and Ireland from 1 January 2013 to 28 February 2015 ascertained demographics, ethnicity, seasonal incidence, treatment and complication rates. RESULTS: 553 cases were notified: 389 had complete KD, 46 had atypical KD and 116 had incomplete KD; 2 were diagnosed at postmortem with an incidence of 4.55/100 000 children under 5 years, with a male to female ratio of 1.5:1 and a median age of 2.7 years (2.5 months–15 years). Presentation was highest in January and in rural areas. Most were white (64%), and Chinese and Japanese Asians were over-represented as were black African or African mixed-race children. 94% received intravenous immunoglobulin (IVIG). The overall CAA rate was 19%, and all-cardiac complications affected 28%. Those with CAA received IVIG later than in those without (median 10 days vs 7 days). Those under 1 year had fewer symptoms, but the highest CAA rate (39%). Overall 8 of 512 cases (1.6%) had giant CAA, and 4 of 86 cases (5%) under 1 year of age developed giant CAA. Mortality from KD was 0.36%. CONCLUSIONS: The UK and Ireland incidence of KD has increased and is more frequently seen in winter and rural areas. Delayed IVIG treatment is associated with CAA, suggesting earlier and adjunctive primary treatment might reduce complications to prevent CAA, particularly in the very young

Spatiotemporal patterns and environmental drivers of human echinococcoses over a twenty-year period in Ningxia Hui Autonomous Region, China

Background Human cystic (CE) and alveolar (AE) echinococcoses are zoonotic parasitic diseases that can be influenced by environmental variability and change through effects on the parasites, animal intermediate and definitive hosts, and human populations. We aimed to assess and quantify the spatiotemporal patterns of human echinococcoses in Ningxia Hui Autonomous Region (NHAR), China between January 1994 and December 2013, and examine associations between these infections and indicators of environmental variability and change, including large-scale landscape regeneration undertaken by the Chinese authorities. Methods Data on the number of human echinococcosis cases were obtained from a hospital-based retrospective survey conducted in NHAR for the period 1 January 1994 through 31 December 2013. High-resolution imagery from Landsat 4/5-TM and 8-OLI was used to create single date land cover maps. Meteorological data were also collected for the period January 1980 to December 2013 to derive time series of bioclimatic variables. A Bayesian spatio-temporal conditional autoregressive model was used to quantify the relationship between annual cases of CE and AE and environmental variables. Results Annual CE incidence demonstrated a negative temporal trend and was positively associated with winter mean temperature at a 10-year lag. There was also a significant, nonlinear effect of annual mean temperature at 13-year lag. The findings also revealed a negative association between AE incidence with temporal moving averages of bareland/artificial surface coverage and annual mean temperature calculated for the period 11–15 years before diagnosis and winter mean temperature for the period 0–4 years. Unlike CE risk, the selected environmental covariates accounted for some of the spatial variation in the risk of AE. Conclusions The present study contributes towards efforts to understand the role of environmental factors in determining the spatial heterogeneity of human echinococcoses. The identification of areas with high incidence of CE and AE may assist in the development and refinement of interventions for these diseases, and enhanced environmental change risk assessment

Methotrexate Is a JAK/STAT Pathway Inhibitor

Background: The JAK/STAT pathway transduces signals from multiple cytokines and controls haematopoiesis, immunity and inflammation. In addition, pathological activation is seen in multiple malignancies including the myeloproliferative neoplasms (MPNs). Given this, drug development efforts have targeted the pathway with JAK inhibitors such as ruxolitinib. Although effective, high costs and side effects have limited its adoption. Thus, a need for effective low cost treatments remains. Methods & Findings: We used the low-complexity Drosophila melanogaster pathway to screen for small molecules that modulate JAK/STAT signalling. This screen identified methotrexate and the closely related aminopterin as potent suppressors of STAT activation. We show that methotrexate suppresses human JAK/STAT signalling without affecting other phosphorylation-dependent pathways. Furthermore, methotrexate significantly reduces STAT5 phosphorylation in cells expressing JAK2 V617F, a mutation associated with most human MPNs. Methotrexate acts independently of dihydrofolate reductase (DHFR) and is comparable to the JAK1/2 inhibitor ruxolitinib. However, cells treated with methotrexate still retain their ability to respond to physiological levels of the ligand erythropoietin. Conclusions: Aminopterin and methotrexate represent the first chemotherapy agents developed and act as competitive inhibitors of DHFR. Methotrexate is also widely used at low doses to treat inflammatory and immune-mediated conditions including rheumatoid arthritis. In this low-dose regime, folate supplements are given to mitigate side effects by bypassing the biochemical requirement for DHFR. Although independent of DHFR, the mechanism-of-action underlying the low-dose effects of methotrexate is unknown. Given that multiple pro-inflammatory cytokines signal through the pathway, we suggest that suppression of the JAK/STAT pathway is likely to be the principal anti-inflammatory and immunosuppressive mechanism-of-action of low-dose methotrexate. In addition, we suggest that patients with JAK/STAT-associated haematological malignancies may benefit from low-dose methotrexate treatments. While the JAK1/2 inhibitor ruxolitinib is effective, a £43,200 annual cost precludes widespread adoption. With an annual methotrexate cost of around £32, our findings represent an important development with significant future potential

FDI and regional development policy

The transformations in the worldwide division of labour brought about by globalisation and technological change have shown an unintended negative effect, particularly evident in advanced economic systems: uneven spatial distribution of wealth and rising within-country inequality. Although the latter has featured prominently in recent academic and policy debates, in this paper we argue that the relevance of connectivity (here proxied by foreign capital investments, FDI) for regional economic development is still underestimated and suffers from a nation-biased perspective. As a consequence, the relationship between the spatial inequality spurred by the global division of labour and the changes in the structural advantages of regions remains to be fully understood in its implications for economic growth, territorial resilience and industrial policy. Furthermore, even though connectivity entails bi-directional links – i.e. with regions being simultaneously receivers and senders – attractiveness to foreign capital has long been at the centre of policy attention whilst internationalisation through investment abroad has been disregarded, and sometimes purposely ignored, in regional development policy agendas. We use three broad-brushed European case-studies to discuss some guiding principles for a place-sensitive regional policy eager to integrate the connectivity dimension in pursuing local economic development and territorial equity

Cardiac nitric oxide: emerging role for nNOS in regulating physiological function.

Emerging evidence shows that neuronal nitric oxide synthase (nNOS) plays several diverging roles in modulating cardiac function. This review examines the nitric oxide (NO) pathway and the regulatory mechanisms to which nNOS signalling is sensitive. These mechanisms are diverse and include regulation of gene expression, posttranscriptional regulation, protein trafficking, allosteric modulation of nNOS and redox modification to alter NO bioavailability once synthesised. Functionally, alteration in nNOS-NO signalling in the heart may correlate with different cardiac regulatory states. The idea of this being associated with exercise-trained states and myocardial disease is discussed

Cholinergic control of heart rate by nitric oxide is site specific.

Parasympathetic control of heart rate involves the exocytotic release of acetylcholine and muscarinic receptor regulation of pacemaking currents. Endogenous nitric oxide can potentially regulate all of these processes; however, recent work suggests that the main functional role of nitric oxide lies in the modulation of acetylcholine release

Targeting neuronal nitric oxide synthase with gene transfer to modulate cardiac autonomic function.

Microdomains of neuronal nitric oxide synthase (nNOS) are spatially localised within both autonomic neurons innervating the heart and post-junctional myocytes. This review examines the use of gene transfer to investigate the role of nNOS in cardiac autonomic control. Furthermore, it explores techniques that may be used to improve upon gene delivery to the cardiac autonomic nervous system, potentially allowing more specific delivery of genes to the target neurons/myocytes. This may involve modification of the tropism of the adenoviral vector, or the use of alternative viral and non-viral gene delivery mechanisms to minimise potential immune responses in the host. Here we show that adenoviral vectors provide an efficient method of gene delivery to cardiac-neural tissue. Functionally, adenovirus-nNOS can increase cardiac vagal responsiveness by facilitating cholinergic neurotransmission and decrease beta-adrenergic excitability. Whether gene transfer remains the preferred strategy for targeting cardiac autonomic impairment will depend on site-specific promoters eliciting sustained gene expression that results in restoration of physiological function

Neuropeptide Y reduces acetylcholine release and vagal bradycardia via a Y2 receptor-mediated, protein kinase C-dependent pathway.

The co-transmitter neuropeptide Y (NPY), released during prolonged cardiac sympathetic nerve stimulation, can attenuate vagal-induced bradycardia. We tested the hypothesis that NPY reduces acetylcholine release, at similar concentrations to which it attenuates vagal bradycardia, via pre-synaptic Y2 receptors modulating a pathway that is dependent on protein kinase A (PKA) or protein kinase C (PKC). The Y2 receptor was immunofluorescently colocalized with choline acetyl-transferase containing neurons at the guinea pig sinoatrial node. The effect of NPY in the presence of various enzyme inhibitors was then tested on the heart rate response to vagal nerve stimulation in isolated guinea pig sinoatrial node/right vagal nerve preparations and also on (3)H-acetylcholine release from right atria during field stimulation. NPY reduced the heart rate response to vagal stimulation at 1, 3 and 5 Hz (significant at 100 nM and reaching a plateau at 250 nM NPY, p<0.05, n=6) but not to the stable analogue of acetylcholine, carbamylcholine (30, 60 or 90 nM, n=6) which produced similar degrees of bradycardia. The reduced vagal response was abolished by the Y2 receptor antagonist BIIE 0246 (1 microM, n=4). NPY also significantly attenuated the release of (3)H-acetylcholine during field stimulation (250 nM, n=6). The effect of NPY (250 nM) on vagal bradycardia was abolished by the PKC inhibitors calphostin C (0.1 microM, n=5) and chelerythrine chloride (25 microM, n=6) but not the PKA inhibitor H89 (0.5 microM, n=6). Conversely, the PKC activator Phorbol-12-myristate-13-acetate (0.5 microM, n=7) mimicked the effect of NPY and significantly reduced (3)H-acetylcholine release during field stimulation. These results show that NPY attenuates vagal bradycardia via a pre-synaptic decrease in acetylcholine release that appears to be mediated by a Y2 receptor pathway involving modulation of PKC

Targeting cardiac sympatho-vagal imbalance using gene transfer of nitric oxide synthase.

Heightened sympathetic excitation and diminished parasympathetic suppression of heart rate, cardiac contractility and vascular tone are all associated with cardiovascular diseases such as hypertension and ischemic heart disease. This phenotype often exists before these disease states have been established and is a strong correlate of mortality in the population. However, the causal role of the autonomic phenotype in the development and maintenance of hypertension and myocardial ischemia remains a subject of debate, as are the mechanisms responsible for regulating sympathovagal balance. Emerging evidence suggests oxidative stress and reactive oxygen species (such as nitric oxide (NO) and superoxide) play important roles in the modulation of autonomic balance, but so far the most important sites of action of these ubiquitous signaling molecules are unclear. In many cases, these mediators have opposing effects in separate tissues rendering conventional pharmacological approaches non-efficacious. Novel techniques have recently been used to augment these signaling pathways experimentally in a targeted fashion to central autonomic nuclei, cardiac neurons, and myocytes using gene transfer of NO synthase. This review article discusses these recent advances in the understanding of the roles of NO and its oxidative metabolites on autonomic imbalance in models of cardiovascular disease