Neuromapping: Inflight Evaluation of Cognition and Adaptability

In consideration of the health and performance of crewmembers during flight and postflight, we are conducting a controlled prospective longitudinal study to investigate the effects of spaceflight on the extent, longevity and neural bases of sensorimotor, cognitive, and neural changes. Previous studies investigating sensorimotor adaptation to the microgravity environment longitudinally inflight have shown reduction in the ability to perform complex dual tasks. In this study we perform a series of tests investigating the longitudinal effects of adaptation to the microgravity environment and how it affects spatial cognition, manual visuo-motor adaption and dual tasking

Bulk Damage Effects in Irradiated Silicon Detectors due to Clustered Divacancies

High resistivity silicon particle detectors will be used extensively in experiments at the future CERN Large Hadron Collider where the enormous particle fluences give rise to significant atomic displacement damage. A model has been developed to estimate the evolution of defect concentrations during irradiation and their electrical behaviour according to Shockley-Read-Hall (SRH) semiconductor statistics. The observed increases in leakage current and doping concentration changes can be described well after gamma irradiation but less well after fast neutron irradiation. A possible non-SRH mechanism is considered, based on the hypothesis of charge transfer between clustered divacancy defects in neutron damaged silicon detectors. This leads to a large enhancement over the SRH prediction for V2 acceptor state occupancy and carrier generation rate which may resolve the discrepancy

Lessons from Toxicology: Developing a 21st‑Century Paradigm for Medical Research

Biomedical developments in the 21st century provide an unprecedented opportunity to gain a dynamic systems-level and human-specific understanding of the causes and pathophysiologies of disease. This understanding is a vital need, in view of continuing failures in health research, drug discovery, and clinical translation. The full potential of advanced approaches may not be achieved within a 20th-century conceptual framework dominated by animal models. Novel technologies are being integrated into environmental health research and are also applicable to disease research, but these advances need a new medical research and drug discovery paradigm to gain maximal benefits. We suggest a new conceptual framework that repurposes the 21st-century transition underway in toxicology. Human disease should be conceived as resulting from integrated extrinsic and intrinsic causes, with research focused on modern human-specific models to understand disease pathways at multiple biological levels that are analogous to adverse outcome pathways in toxicology. Systems biology tools should be used to integrate and interpret data about disease causation and pathophysiology. Such an approach promises progress in overcoming the current roadblocks to understanding human disease and successful drug discovery and translation. A discourse should begin now to identify and consider the many challenges and questions that need to be solved

Clinical and Molecular Characterization of Ataxia with Oculomotor Apraxia Patients In Saudi Arabia

<p>Abstract</p> <p>Background</p> <p>Autosomal recessive ataxias represent a group of clinically overlapping disorders. These include ataxia with oculomotor apraxia type1 (AOA1), ataxia with oculomotor apraxia type 2 (AOA2) and ataxia-telangiectasia-like disease (ATLD). Patients are mainly characterized by cerebellar ataxia and oculomotor apraxia. Although these forms are not quite distinctive phenotypically, different genes have been linked to these disorders. Mutations in the <it>APTX </it>gene were reported in AOA1 patients, mutations in <it>SETX </it>gene were reported in patients with AOA2 and mutations in <it>MRE11 </it>were identified in ATLD patients. In the present study we describe in detail the clinical features and results of genetic analysis of 9 patients from 4 Saudi families with ataxia and oculomotor apraxia.</p> <p>Methods</p> <p>This study was conducted in the period between 2005-2010 to clinically and molecularly characterize patients with AOA phenotype. Comprehensive sequencing of all coding exons of previously reported genes related to this disorder (<it>APTX</it>, <it>SETX </it>and <it>MRE11</it>).</p> <p>Results</p> <p>A novel nonsense truncating mutation c.6859 C > T, R2287X in <it>SETX </it>gene was identified in patients from one family with AOA2. The previously reported missense mutation W210C in <it>MRE11 </it>gene was identified in two families with autosomal recessive ataxia and oculomotor apraxia.</p> <p>Conclusion</p> <p>Mutations in <it>APTX </it>, <it>SETX </it>and <it>MRE11 </it>are common in patients with autosomal recessive ataxia and oculomotor apraxia. The results of the comprehensive screening of these genes in 4 Saudi families identified mutations in <it>SETX </it>and <it>MRE11 </it>genes but failed to identify mutations in <it>APTX </it>gene.</p

Can Acute Dermal Systemic Toxicity Tests Be Replaced With Oral Tests? A Comparison of Route-Specific Systemic Toxicity and Hazard Classifications Under the Globally Harmonized System of Classification and Labelling of Chemicals (GHS)

Acute systemic toxicity data (LD50 values) and hazard classifications derived in the rat following oral administration and dermal application have been analysed to examine whether or not orally-derived hazard classification or LD50 values can be used to determine dermal hazard classification. Comparing the oral and dermal classifications for 335 substances derived from oral and dermal LD50 values respectively revealed 17% concordance, and indicated that 7% of substances would be classified less severely while 76% would be classified more severely if oral classifications were applied directly to the dermal route. In contrast, applying the oral LD50 values within the dermal classification criteria to determine the dermal classification reduced the concordance to 15% and the relative ‘under-classification’ to 1%, but increased the relative ‘over-classification’ to 84%. Both under- and over-classification are undesirable, and mitigation strategies are discussed. Finally, no substance with an oral LD50 of \u3e2000 mg/kg was classified for acute systemic toxicity by the dermal route, suggesting that dermal testing for acute systemic toxicity of such substances adds nothing to the hazard characterisation and should be removed from routine regulatory data requirements

Can Acute Dermal Systemic Toxicity Tests Be Replaced With Oral Tests? A Comparison of Route-Specific Systemic Toxicity and Hazard Classifications Under the Globally Harmonized System of Classification and Labelling of Chemicals (GHS)

Acute systemic toxicity data (LD50 values) and hazard classifications derived in the rat following oral administration and dermal application have been analysed to examine whether or not orally-derived hazard classification or LD50 values can be used to determine dermal hazard classification. Comparing the oral and dermal classifications for 335 substances derived from oral and dermal LD50 values respectively revealed 17% concordance, and indicated that 7% of substances would be classified less severely while 76% would be classified more severely if oral classifications were applied directly to the dermal route. In contrast, applying the oral LD50 values within the dermal classification criteria to determine the dermal classification reduced the concordance to 15% and the relative ‘under-classification’ to 1%, but increased the relative ‘over-classification’ to 84%. Both under- and over-classification are undesirable, and mitigation strategies are discussed. Finally, no substance with an oral LD50 of \u3e2000 mg/kg was classified for acute systemic toxicity by the dermal route, suggesting that dermal testing for acute systemic toxicity of such substances adds nothing to the hazard characterisation and should be removed from routine regulatory data requirements