Successful Amelioration of Mitochondrial Optic Neuropathy Using the Yeast NDI1 Gene in a Rat Animal Model

Background: Leber’s hereditary optic neuropathy (LHON) is a maternally inherited disorder with point mutations in mitochondrial DNA which result in loss of vision in young adults. The majority of mutations reported to date are within the genes encoding the subunits of the mitochondrial NADH-quinone oxidoreductase, complex I. Establishment of animal models of LHON should help elucidate mechanism of the disease and could be utilized for possible development of therapeutic strategies. Methodology/Principal Findings: We established a rat model which involves injection of rotenone-loaded microspheres into the optic layer of the rat superior colliculus. The animals exhibited the most common features of LHON. Visual loss was observed within 2 weeks of rotenone administration with no apparent effect on retinal ganglion cells. Death of retinal ganglion cells occurred at a later stage. Using our rat model, we investigated the effect of the yeast alternative NADH dehydrogenase, Ndi1. We were able to achieve efficient expression of the Ndi1 protein in the mitochondria of all regions of retinal ganglion cells and axons by delivering the NDI1 gene into the optical layer of the superior colliculus. Remarkably, even after the vision of the rats was severely impaired, treatment of the animals with the NDI1 gene led to a complete restoration of the vision to the normal level. Control groups that received either empty vector or the GFP gene had no effects

The elastic constants of MgSiO3 perovskite at pressures and temperatures of the Earth's mantle

The temperature anomalies in the Earth's mantle associated with thermal convection1 can be inferred from seismic tomography, provided that the elastic properties of mantle minerals are known as a function of temperature at mantle pressures. At present, however, such information is difficult to obtain directly through laboratory experiments. We have therefore taken advantage of recent advances in computer technology, and have performed finite-temperature ab initio molecular dynamics simulations of the elastic properties of MgSiO3 perovskite, the major mineral of the lower mantle, at relevant thermodynamic conditions. When combined with the results from tomographic images of the mantle, our results indicate that the lower mantle is either significantly anelastic or compositionally heterogeneous on large scales. We found the temperature contrast between the coldest and hottest regions of the mantle, at a given depth, to be about 800K at 1000 km, 1500K at 2000 km, and possibly over 2000K at the core-mantle boundary.Comment: Published in: Nature 411, 934-937 (2001

Not all coping strategies are created equal: a mixed methods study exploring physicians' self reported coping strategies

<p>Abstract</p> <p>Background</p> <p>Physicians experience workplace stress and draw on different coping strategies. The primary goal of this paper is to use interview data to explore physicians' self reported coping strategies. In addition, questionnaire data is utilized to explore the degree to which the coping strategies are used and are associated with feelings of emotional exhaustion, a key symptom of burnout.</p> <p>Methods</p> <p>This mixed methods study explores factors related to physician wellness within a large health region in Western Canada. This paper focuses on the coping strategies that physicians use in response to work-related stress. The qualitative component explores physicians' self reported coping strategies through open ended interviews of 42 physicians representing diverse medical specialties and settings (91% response rate). The major themes extracted from the qualitative interviews were used to construct 12 survey items that were included in the comprehensive quantitative questionnaire. Questionnaires were sent to all eligible physicians in the health region with 1178 completed surveys (40% response rate.) Questionnaire items were used to measure how often physicians draw on the various coping strategies. Feelings of burnout were also measured in the survey by 5 items from the Emotional Exhaustion subscale of the revised Maslach Burnout Inventory.</p> <p>Results</p> <p>Major themes identified from the interviews include coping strategies used at work (e.g., working through stress, talking with co-workers, taking a time out, using humor) and after work (e.g., exercise, quiet time, spending time with family). Analysis of the questionnaire data showed three often used workplace coping strategies were positively correlated with feeling emotionally exhausted (i.e., keeping stress to oneself (r = .23), concentrating on what to do next (r = .16), and going on as if nothing happened (r = .07)). Some less often used workplace coping strategies (e.g., taking a time out) and all those used after work were negatively correlated with frequency of emotional exhaustion.</p> <p>Conclusions</p> <p>Physicians' self reported coping strategies are not all created equal in terms of frequency of use and correlation with feeling emotionally exhausted from one's work. This knowledge may be integrated into practical physician stress reduction interventions.</p

Impacts of multiple pollutants on pollinator activity in road verges

Funder: Cornwall Area of Outstanding Natural Beauty unitTo tackle pollinator declines, there is a major need to increase the quantity of flower‐rich habitats. Road verges offer one such opportunity but are exposed to diverse forms of pollution from roads and road traffic. We carried out a broad initial assessment to establish if and how pollution affects the quality of road verges as pollinator foraging environments. We assessed the spatial distribution of pollution, flowers and pollinators in road verges, then used field experiments to simulate and measure the impacts of four ubiquitous and little studied forms of road pollution (noise, turbulence, dust and metals) on pollinator densities and foraging behaviour. We found that pollinators in road verges were exposed to noise, turbulence, dust and metal pollution, which decreased with distance from the road edge but, with the exception of turbulence, extended more than 8 m into road verges. Pollinator densities were lower closer to the road edge—particularly within first 2 m (55% lower than at 7–9 m)—where pollution is greatest. This was despite a similar density and species richness of flowers. Simulated turbulence deterred pollinators by causing intermittent disturbance (reducing visit duration by up to 54%), and some pollinator taxa preferentially avoided concentrations of metals that were more frequently found in flowers within 2 m of roads (resulting in up to 75% fewer visits), while noise and dust had no apparent effect. Synthesis and applications. Pollinators in road verges are exposed to many forms of pollution, and we found impacts of roadside‐realistic levels of turbulence and metals on pollinator densities and foraging behaviour. Although the findings suggest that road verges are largely suitable for pollinator conservation, management enhancements should prioritise areas more than 2 m from the road edge, and verges along roads with relatively lower traffic densities

Mapping gene associations in human mitochondria using clinical disease phenotypes

Nuclear genes encode most mitochondrial proteins, and their mutations cause diverse and debilitating clinical disorders. To date, 1,200 of these mitochondrial genes have been recorded, while no standardized catalog exists of the associated clinical phenotypes. Such a catalog would be useful to develop methods to analyze human phenotypic data, to determine genotype-phenotype relations among many genes and diseases, and to support the clinical diagnosis of mitochondrial disorders. Here we establish a clinical phenotype catalog of 174 mitochondrial disease genes and study associations of diseases and genes. Phenotypic features such as clinical signs and symptoms were manually annotated from full-text medical articles and classified based on the hierarchical MeSH ontology. This classification of phenotypic features of each gene allowed for the comparison of diseases between different genes. In turn, we were then able to measure the phenotypic associations of disease genes for which we calculated a quantitative value that is based on their shared phenotypic features. The results showed that genes sharing more similar phenotypes have a stronger tendency for functional interactions, proving the usefulness of phenotype similarity values in disease gene network analysis. We then constructed a functional network of mitochondrial genes and discovered a higher connectivity for non-disease than for disease genes, and a tendency of disease genes to interact with each other. Utilizing these differences, we propose 168 candidate genes that resemble the characteristic interaction patterns of mitochondrial disease genes. Through their network associations, the candidates are further prioritized for the study of specific disorders such as optic neuropathies and Parkinson disease. Most mitochondrial disease phenotypes involve several clinical categories including neurologic, metabolic, and gastrointestinal disorders, which might indicate the effects of gene defects within the mitochondrial system. The accompanying knowledgebase (http://www.mitophenome.org/) supports the study of clinical diseases and associated genes

Evaluating the organisational climate in Italian public healthcare institutions by means of a questionnaire

<p>Abstract</p> <p>Background</p> <p>By means of the ICONAS project, the Healthcare Agency of an Italian Region developed, and used a standardised questionnaire to quantify the organisational climate. The aims of the project were (a) to investigate whether the healthcare institutions were interested in measuring climate, (b) to estimate the range of applicability and reliability of the instrument, (c) to analyse the dimensions of climate among healthcare personnel, (d) to assess the differences among employees with different contractual positions.</p> <p>Methods</p> <p>The anonymous questionnaire containing 50 items, each with a scale from 1 to 10, was offered to the healthcare organisations, to be compiled during ad hoc meetings. The data were sent to the central project coordinator. The differences between highly specialised staff (mostly physicians) and other employees were assessed after descriptive statistical analysis of the single items. Both Principal Component Analysis and Factor Analysis were used.</p> <p>Results</p> <p>Ten healthcare organisations agreed to partecipate. The questionnaire was completed by 8691 employees out of 13202. The mean value of organisational climate was 4.79 (range 1–10). There were significant differences among single items and between the 2 groups of employees. Multivariate methods showed: (a) one principal component explained > 40% of the variance, (b) 7 factors summarised the data.</p> <p>Conclusion</p> <p>Italian healthcare institutions are interested in assessing organisational phenomena, especially after the reforms of the nineties. The instrument was found to be applicable and suitable for measuring organisational climate. Administration of the questionnaire leads to an acceptable response rate. Climate can be discribed by means of 7 underlying dimensions.</p

Comprehensive analysis of common mitochondrial DNA variants and colorectal cancer risk.

Several lines of evidence implicate mitochondrial dysfunction in the development of cancer. To test the hypothesis that common mtDNA variation influences the risk of colorectal cancer (CRC), we genotyped 132 tagging mtDNA variants in a sample of 2854 CRC cases and 2822 controls. The variants examined capture approximately 80% of mtDNA common variation (excluding the hypervariable D-loop). We first tested for single marker associations; the strongest association detected was with A5657G (P=0.06). Overall the distribution of association P-values was consistent with a null distribution. Next, we classified individuals into the nine common European haplogroups and compared their distribution in cases and controls. This analysis also provided no evidence of an association between mitochondrial variation and CRC risk. In conclusion, our results provide little evidence that mitochondrial genetic background plays a role in modifying an individual's risk of developing CRC

Readability estimates for commonly used health-related quality of life surveys

To estimate readability of seven commonly used health-related quality of life instruments: SF-36, HUI, EQ-5D, QWB-SA, HALex, Minnesota Living with Heart Failure Questionnaire (MLHFQ), and the NEI-VFQ-25. The Flesch–Kincaid (F–K) and Flesch Reading Ease (FRE) formulae were used to estimate readability for every item in each measure. The percentage of items that require more than 5 years of formal schooling according to F–K was 50 for the EQ-5D, 53 for the SF-36, 80 for the VFQ-25, 85 for the QWB-SA, 100 for the HUI, HALex, and the MLHFQ. The percentage of items deemed harder than “easy” according to FRE was 50 for the SF-36, 67 for the EQ-5D, 79 for the QWB-SA, 80 for the VFQ-25, 100 for the HUI, HALex, and the MLHFQ. All seven surveys have a substantial number of items with high readability levels that may not be appropriate for the general population

Outbreak of acute gastroenteritis in an air force base in Western Greece

BACKGROUND: On the 20(th )September 2005, soldiers and staff at the Air Force base in Western Greece experienced an outbreak of acute gastroenteritis. The purpose of this study was to identify the agent and the source of the outbreak in order to develop control measures and to avoid similar outbreaks in the future. METHODS: A case-control analytical approach was employed with 100 randomly selected cases and 66 controls. Patients completed standardized questionnaires, odds ratios were calculated and statistical significance was determined using χ(2 )test. In addition, to identify the source of the infection, we performed bacteriological examination of food samples (included raw beef, cooked minced meat, grated cheese and grated cheese in sealed package) collected from the cuisine of the military unit. RESULTS: More than 600 out of the 1,050 individuals who ate lunch that day, became ill. The overall attack rate, as the military doctor of the unit estimated it, was at least 60%. The overall odds ratio of gastroenteritis among those who had lunch was 370 (95% CI: 48–7700) as compared to those who didn't eat lunch. Among the symptoms the most prominent were watery diarrhoea (96%) and abdominal pain (73%). The mean incubation period was 9 h and the median duration of the symptoms was 21 h. In the bacteriological examination, Staphylococcus aureus was detected in a sample of raw beef (2,000 cfu per g) and in two samples of grated cheese; leftover cheese from lunch (7,800 cfu per g) and an unopened package purchased from the market (3,000 cfu per g). CONCLUSION: The findings of this study suggest that the aetiological agent of this outbreak was S. aureus. The food vehicle was the grated cheese, which was mixed with the beef and served for lunch in the military unit. This outbreak highlights the capacity of enterotoxin-producing bacteria to cause short term, moderately-severe illness in a young and healthy population. It underscores the need for proper food handling practices and reinforces the public health importance of timely notification of such outbreaks