ATG5 is essential for ATG8-dependent autophagy and mitochondrial homeostasis in Leishmania major

Macroautophagy has been shown to be important for the cellular remodelling required for Leishmania differentiation. We now demonstrate that L. major contains a functional ATG12-ATG5 conjugation system, which is required for ATG8-dependent autophagosome formation. Nascent autophagosomes were found commonly associated with the mitochondrion. L. major mutants lacking ATG5 (Δatg5) were viable as promastigotes but were unable to form autophagosomes, had morphological abnormalities including a much reduced flagellum, were less able to differentiate and had greatly reduced virulence to macrophages and mice. Analyses of the lipid metabolome of Δatg5 revealed marked elevation of phosphatidylethanolamines (PE) in comparison to wild type parasites. The Δatg5 mutants also had increased mitochondrial mass but reduced mitochondrial membrane potential and higher levels of reactive oxygen species. These findings indicate that the lack of ATG5 and autophagy leads to perturbation of the phospholipid balance in the mitochondrion, possibly through ablation of membrane use and conjugation of mitochondrial PE to ATG8 for autophagosome biogenesis, resulting in a dysfunctional mitochondrion with impaired oxidative ability and energy generation. The overall result of this is reduced virulence

Brain Changes in Long-Term Zen Meditators Using Proton Magnetic Resonance Spectroscopy and Diffusion Tensor Imaging: A Controlled Study

Introduction: This work aimed to determine whether 1H magnetic resonance imaging (MRI), magnetic resonance spectroscopy (MRS), diffusion-weighted imaging (DWI) and diffusion tensor imaging (DTI) are correlated with years of meditation and psychological variables in long-term Zen meditators compared to healthy non-meditator controls. Materials and Methods: Design. Controlled, cross-sectional study. Sample. Meditators were recruited from a Zen Buddhist monastery. The control group was recruited from hospital staff. Meditators were administered questionnaires on anxiety, depression, cognitive impairment and mindfulness. 1H-MRS (1.5 T) of the brain was carried out by exploring four areas: both thalami, both hippocampi, the posterior superior parietal lobule (PSPL) and posterior cingulate gyrus. Predefined areas of the brain were measured for diffusivity (ADC) and fractional anisotropy (FA) by MR-DTI. Results: Myo-inositol (mI) was increased in the posterior cingulate gyrus and Glutamate (Glu), N-acetyl-aspartate (NAA) and N-acetyl-aspartate/Creatine (NAA/Cr) was reduced in the left thalamus in meditators. We found a significant positive correlation between mI in the posterior cingulate and years of meditation (r = 0.518; p = .019). We also found significant negative correlations between Glu (r =20.452; p = .045), NAA (r =20.617; p = .003) and NAA/Cr (r =20.448; P = .047) in the left thalamus and years of meditation. Meditators showed a lower Apparent Diffusion Coefficient (ADC) in the left posterior parietal white matter than did controls, and the ADC was negatively correlated with years of meditation (r =20.4850, p = .0066). Conclusions: The results are consistent with the view that mI, Glu and NAA are the most important altered metabolites. This study provides evidence of subtle abnormalities in neuronal function in regions of the white matter in meditators

Social problems in oncology

A study was undertaken to describe, evaluate and categorise the social problems experienced by cancer patients. Ninety-six adult cancer patients at all stages of disease participated in either a telephone focus group discussion, a face to face focus group or an individual interview which were tape recorded and transcribed. Six experts analysed the transcripts. A total of 32 social problems were identified categorized under eight headings plus four single items. The categories were: problems with (1) managing in the home, (2) health and welfare services, (3) finances, (4) employment, (5) legal matters, (6) relationships, (7) sexuality and body image and (8) recreation. Problems with relationships and communication were the most frequently reported with financial, employment, body image and domestic problems also being widely endorsed. Female groups, younger patient groups and groups where the aim of treatment was palliative reported more social problems than other groups. Social problems are common and important to cancer patients. The social problems identified in this study will contribute to an item pool generated for developing a Social Problems Inventory that may be included in patient centred assessment as part of routine oncology practice

Communication in cancer genetic counselling: does it reflect counselees' previsit needs and preferences?

This study sought to describe counsellor–counselee interaction during initial cancer genetic counselling consultations and to examine whether the communication reflects counselees' previsit needs. A total of 130 consecutive counselees, referred mainly for breast or colon cancer, completed a questionnaire before their first appointment at a genetic clinic. Their visit was videotaped. Counselee and counsellor verbal communications were analysed and initiative to discuss 11 genetics-specific conversational topics was assessed. The content of the visit appeared relatively standard. Overall, counselees had a stronger psychosocial focus than counsellors. Counsellors directed the communication more and initiated the discussion of most of the topics assessed. Counselees did not appear to communicate readily in a manner that reflected their previsit needs. Counsellors provided more psychosocial information to counselees in higher need for emotional support, yet did not enquire more about counselees' specific concerns. New counselees may be helped by receiving more information on the counselling procedure prior to their visit, and may be advised to prepare the visit more thoroughly so as to help them verbalise more their queries during the visit

A Population Genetic Approach to Mapping Neurological Disorder Genes Using Deep Resequencing

Deep resequencing of functional regions in human genomes is key to identifying potentially causal rare variants for complex disorders. Here, we present the results from a large-sample resequencing (n = 285 patients) study of candidate genes coupled with population genetics and statistical methods to identify rare variants associated with Autism Spectrum Disorder and Schizophrenia. Three genes, MAP1A, GRIN2B, and CACNA1F, were consistently identified by different methods as having significant excess of rare missense mutations in either one or both disease cohorts. In a broader context, we also found that the overall site frequency spectrum of variation in these cases is best explained by population models of both selection and complex demography rather than neutral models or models accounting for complex demography alone. Mutations in the three disease-associated genes explained much of the difference in the overall site frequency spectrum among the cases versus controls. This study demonstrates that genes associated with complex disorders can be mapped using resequencing and analytical methods with sample sizes far smaller than those required by genome-wide association studies. Additionally, our findings support the hypothesis that rare mutations account for a proportion of the phenotypic variance of these complex disorders

Assessment of the feasibility of a rehabilitation intervention program for breast cancer survivors with cognitive complaints

To assess the feasibility of a cognitive rehabilitation program in breast cancer survivors (BCS) with persistent post-treatment cognitive complaints. BCS with cognitive complaints, 18-months to 5-years post-treatment, were recruited for a once-weekly, five-week, group cognitive training intervention. Outcome measures included self-reported mood and cognitive function, and neurocognitive tests administered at pre-intervention, immediate-, two-month and four-month post-intervention. A sub-study in eight participants evaluated resting state quantitative electroencephalography (qEEG) changes from pre- to immediate post-intervention in relationship to post-intervention changes in cognitive complaints. Twenty-seven BCS completed the protocol and tolerated the intervention well. We observed significant reductions in total and memory-specific cognitive complaints from pre-intervention to immediate post-intervention (p = 0.031 and p = 0.009, respectively) and at four-months post-intervention (p < 0.0001 and p < 0.001, respectively). Significant improvement in neurocognitive tests were found for Symbol Digit, Stroop, and Trails A tests (df = 26, all p's <0.05). Effect sizes for changes from pre-intervention to immediate and to four-month post intervention ranged from 0.429 to 0.607, and from 0.439 to 0.741, respectively. Increase in qEEG absolute alpha power over the course of the intervention was associated with reduced complaints at immediate post-intervention (r = -0.78, p = 0.021), two-months (r range = -0.76 to -0.82, p-value range 0.004 to 0.03), and four-months (r = -0.71, p = 0.048). A five-week group cognitive training intervention is feasible and well tolerated. Cognitive complaints and neurocognitive test performances showed positive changes. qEEG may serve as a potential biomarker for improvement in self-reported complaints. A randomized clinical trial is underway to test the efficacy of the intervention