Leigh syndrome: One disorder, more than 75 monogenic causes.

Leigh syndrome is the most common pediatric presentation of mitochondrial disease. This neurodegenerative disorder is genetically heterogeneous, and to date pathogenic mutations in >75 genes have been identified, encoded by 2 genomes (mitochondrial and nuclear). More than one-third of these disease genes have been characterized in the past 5 years alone, reflecting the significant advances made in understanding its etiological basis. We review the diverse biochemical and genetic etiology of Leigh syndrome and associated clinical, neuroradiological, and metabolic features that can provide clues for diagnosis. We discuss the emergence of genotype-phenotype correlations, insights gleaned into the molecular basis of disease, and available therapeutic options. Ann Neurol 2016;79:190-203

Hidden Magnetism and Quantum Criticality in the Heavy Fermion Superconductor CeRhIn5

With understood exceptions, conventional superconductivity does not coexist with long-range magnetic order[1]. In contrast, unconventional superconductivity develops near a boundary separating magnetically ordered and magnetically disordered phases[2,3]. A maximum in the superconducting transition temperature Tc develops where this boundary extrapolates to T=0 K, suggesting that fluctuations associated with this magnetic quantum-critical point are essential for unconventional superconductivity[4,5]. Invariably though, unconventional superconductivity hides the magnetic boundary when T < Tc, preventing proof of a magnetic quantum-critical point[5]. Here we report specific heat measurements of the pressure-tuned unconventional superconductor CeRhIn5 in which we find a line of quantum-phase transitions induced inside the superconducting state by an applied magnetic field. This quantum-critical line separates a phase of coexisting antiferromagnetism and superconductivity from a purely unconventional superconducting phase and terminates at a quantum tetracritical point where the magnetic field completely suppresses superconductivity. The T->0 K magnetic field-pressure phase diagram of CeRhIn5 is well described with a theoretical model[6,7] developed to explain field-induced magnetism in the high-Tc cuprates but in which a clear delineation of quantum-phase boundaries has not been possible. These experiments establish a common relationship among hidden magnetism, quantum criticality and unconventional superconductivity in cuprate and heavy-electron systems, such as CeRhIn5.Comment: journal reference adde

The pseudogap: friend or foe of high Tc?

Although nineteen years have passed since the discovery of high temperature superconductivity, there is still no consensus on its physical origin. This is in large part because of a lack of understanding of the state of matter out of which the superconductivity arises. In optimally and underdoped materials, this state exhibits a pseudogap at temperatures large compared to the superconducting transition temperature. Although discovered only three years after the pioneering work of Bednorz and Muller, the physical origin of this pseudogap behavior and whether it constitutes a distinct phase of matter is still shrouded in mystery. In the summer of 2004, a band of physicists gathered for five weeks at the Aspen Center for Physics to discuss the pseudogap. In this perspective, we would like to summarize some of the results presented there and discuss its importance in the context of strongly correlated electron systems.Comment: expanded version, 20 pages, 11 figures, to be published, Advances in Physic

Current opportunities to catalyze research in nutrition and cancer prevention – an interdisciplinary perspective

Cancer Research UK and Ludwig Cancer Research convened an inaugural international Cancer Prevention and Nutrition Conference in London on December 3–4, 2018. Much of the discussion focused on the need for systematic, interdisciplinary approaches to better understand the relationships of nutrition, exercise, obesity and metabolic dysfunction with cancer development. Scientists at the meeting underscored the importance of studying the temporal natural history of exposures that may cumulatively impact cancer risk later in life. A robust dialogue identified obesity as a major risk for cancer, and the food environment, especially high energy and low nutrient processed foods, as strong and prevalent risk factors for obesity. Further engagement highlighted challenges in the post-diagnostic setting, where similar opportunities to understand the complex interplay of nutrition, physical activity, and weight will inform better health outcomes. Going forward, holistic research approaches, encompassing insights from multiple disciplines and perspectives, will catalyze progress urgently needed to prevent cancer and improve public health

Large Fragment Pre-S Deletion and High Viral Load Independently Predict Hepatitis B Relapse after Liver Transplantation

Hepatitis B virus (HBV) associated end-stage liver diseases are the leading causes of liver transplantation (LT) in Taiwan. Relapse of hepatitis B occurs after LT, raising the risk of graft failure and reducing patient survival. Although several oral antiviral agents have been approved for anti-HBV treatment, lamivudine (LAM) remained to be the most widely used preventive regimen in Taiwan. While several clinical predictors have been identified for hepatitis B relapse, the predictive roles of the histopathological characteristics in liver explants as well as the genotypic features of the viruses in pre-LT serum samples have not been assessed. Between September 2002 and August 2009, 150 consecutive hepatitis B surface antigen (HBsAg) positive patients undergoing LT were included for outcome analysis following assessment of the clinicopathological and virological factors prior to LT. Kaplan-Meier analyses discovered that pre-operative LAM treatment ≤3 months; membranous distribution and higher expression of tissue HBsAg in liver explants; preoperative viral load ≧106 copies/ml; and presence of large fragment (>100 base pairs) pre-S deletion (LFpreSDel) correlated significantly with hepatitis B relapse. Multivariate Cox regression analysis showed that the presence of LFpreSDel (P = 0.001) and viral load ≧106 copies/mL (P = 0.023) were independent predictors for hepatitis B relapse. In conclusion, besides high viral load, LFpreSDel mutation is an important independent predictor for hepatitis B relapse after LT. More aggressive preventive strategies should be applied for patients carrying these risk factors

An Essential Role for the Proximal but Not the Distal Cytoplasmic Tail of Glycoprotein M in Murid Herpesvirus 4 Infection

Murid herpesvirus-4 (MuHV-4) provides a tractable model with which to define common, conserved features of gamma-herpesvirus biology. The multi-membrane spanning glycoprotein M (gM) is one of only 4 glycoproteins that are essential for MuHV-4 lytic replication. gM binds to gN and is thought to function mainly secondary envelopment and virion egress, for which several predicted trafficking motifs in its C-terminal cytoplasmic tail could be important. We tested the contribution of the gM cytoplasmic tail to MuHV-4 lytic replication by making recombinant viruses with varying C-terminal deletions. Removing an acidic cluster and a distal YXXΦ motif altered the capsid distribution somewhat in infected cells but had little effect on virus replication, either in vitro or in vivo. In contrast, removing a proximal YXXΦ motif as well completely prevented productive replication. gM was still expressed, but unlike its longer forms showed only limited colocalization with co-transfected gN, and in the context of whole virus appeared to support gN expression less well. We conclude that some elements of the gM cytoplasmic tail are dispensible for MuHV-4 replication, but the tail as a whole is not

The economic costs of alcohol consumption in Thailand, 2006

<p>Abstract</p> <p>Background</p> <p>There is evidence that the adverse consequences of alcohol impose a substantial economic burden on societies worldwide. Given the lack of generalizability of study results across different settings, many attempts have been made to estimate the economic costs of alcohol for various settings; however, these have mostly been confined to industrialized countries. To our knowledge, there are a very limited number of well-designed studies which estimate the economic costs of alcohol consumption in developing countries, including Thailand. Therefore, this study aims to estimate these economic costs, in Thailand, 2006.</p> <p>Methods</p> <p>This is a prevalence-based, cost-of-illness study. The estimated costs in this study included both direct and indirect costs. Direct costs included health care costs, costs of law enforcement, and costs of property damage due to road-traffic accidents. Indirect costs included costs of productivity loss due to premature mortality, and costs of reduced productivity due to absenteeism and presenteeism (reduced on-the-job productivity).</p> <p>Results</p> <p>The total economic cost of alcohol consumption in Thailand in 2006 was estimated at 156,105.4 million baht (9,627 million US$PPP) or about 1.99$ PPP), followed by cost of productivity loss due to reduced productivity (45,464.6 million baht/2,804 million US$PPP), health care cost (5,491.2 million baht/339 million US$ PPP), cost of property damage as a result of road traffic accidents (779.4 million baht/48 million US$PPP), and cost of law enforcement (242.4 million baht/15 million US$ PPP), respectively. The results from the sensitivity analysis revealed that the cost ranges from 115,160.4 million baht to 214,053.0 million baht (7,102.1 - 13,201 million US$ PPP) depending on the methods and assumptions employed.</p> <p>Conclusions</p> <p>Alcohol imposes a substantial economic burden on Thai society, and according to these findings, the Thai government needs to pay significantly more attention to implementing more effective alcohol policies/interventions in order to reduce the negative consequences associated with alcohol.</p

Therapeutic effects of the mitochondrial ROS-redox modulator KH176 in a mammalian model of Leigh Disease

Leigh Disease is a progressive neurometabolic disorder for which a clinical effective treatment is currently still lacking. Here, we report on the therapeutic efficacy of KH176, a new chemical entity derivative of Trolox, in Ndufs4 (-/-) mice, a mammalian model for Leigh Disease. Using in vivo brain diffusion tensor imaging, we show a loss of brain microstructural coherence in Ndufs4 (-/-) mice in the cerebral cortex, external capsule and cerebral peduncle. These findings are in line with the white matter diffusivity changes described in mitochondrial disease patients. Long-term KH176 treatment retained brain microstructural coherence in the external capsule in Ndufs4 (-/-) mice and normalized the increased lipid peroxidation in this area and the cerebral cortex. Furthermore, KH176 treatment was able to significantly improve rotarod and gait performance and reduced the degeneration of retinal ganglion cells in Ndufs4 (-/-) mice. These in vivo findings show that further development of KH176 as a potential treatment for mitochondrial disorders is worthwhile to pursue. Clinical trial studies to explore the potency, safety and efficacy of KH176 are ongoing

Effect of Propranolol on Functional Connectivity in Autism Spectrum Disorder—A Pilot Study

A decrease in interaction between brain regions is observed in individuals with autism spectrum disorder (ASD), which is believed to be related to restricted neural network access in ASD. Propranolol, a beta-adrenergic antagonist, has revealed benefit during performance of tasks involving flexibility of access to networks, a benefit also seen in ASD. Our goal was to determine the effect of propranolol on functional connectivity in ASD during a verbal decision making task as compared to nadolol, thereby accounting for the potential spurious fMRI effects due to peripheral hemodynamic effects of propranolol. Ten ASD subjects underwent fMRI scans after administration of placebo, propranolol or nadolol, while performing a phonological decision making task. Comparison of functional connectivity between pre-defined ROI-pairs revealed a significant increase with propranolol compared to nadolol, suggesting a potential imaging marker for the cognitive effects of propranolol in ASD