Head Lowery (beerpalm58)

Mitochondrial dysfunction is implicated in the pathogenesis of multiple neurological diseases, but elucidation of underlying mechanisms is limited experimentally by the inability to damage specific mitochondria in defined neuronal groups. We developed a precision chemoptogenetic approach to target neuronal mitochondria in the intact nervous system in vivo. MG2I, a chemical fluorogen, produces singlet oxygen when bound to the fluorogen-activating protein dL5** and exposed to far-red light. Transgenic zebrafish expressing dL5** within neuronal mitochondria showed dramatic MG2I- and light-dependent neurobehavioral deficits, caused by neuronal bioenergetic crisis and acute neuronal depolarization. These abnormalities resulted from loss of neuronal respiration, associated with mitochondrial fragmentation, swelling and elimination of cristae. Remaining cellular ultrastructure was preserved initially, but cellular pathology downstream of mitochondrial damage eventually culminated in neuronal death. Our work providesn the future, the method could be adapted to work in any type of cell and deactivate other cell compartments, so that it can be used to study many types of diseases.Epidemiological studies show mixed findings for serum vitamin B12 and both cognitive and regional volume outcomes. No studies to date have comprehensively examined, in non-supplemented individuals, serum B12 level associations with neurodegeneration, hypometabolism, and cognition across the Alzheimer's disease (AD) spectrum. Serum vitamin B12 was assayed from the Alzheimer's Disease Neuroimaging Initiative (ADNI) and the Australian Imaging, Biomarker & Lifestyle Flagship Study of Ageing (AIBL). Voxel-wise analyses regressed B12 levels against regional gray matter (GM) volume and glucose metabolism (p less then .05, family-wise corrected). For ADNI GM, there were 39 cognitively normal (CN), 73 mild cognitive impairment (MCI), and 31 AD participants. For AIBL GM, there were 311 CN, 59 MCI, and 31 AD participants. Covariates were age, sex, baseline diagnosis, APOE4 status, and Body Mass Index (BMI). In ADNI, higher B12 was negatively associated with GM in the right precuneus and bilateral frontal gyri. When diagnostic groups were examined separately, only participants with MCI or above an established cutoff for CSF total tau showed such associations. In AIBL, higher B12 was associated with more grey matter in the right amygdala and right superior temporal pole, which largely seemed to be driven by CN participants that constituted most of the sample. Our results suggest that B12 may show different patterns of association based on clinical status and, for ADNI, AD CSF biomarkers. Accounting for these factors may clarify the relationship between B12 with neural outcomes in late-life.In a recent issue of BJPsych Open, McPherson & Hengartner (see https//doi.org/10.1192/bjo.2019.65) reviewed 11 trials examining psychological and pharmacological treatment outcomes for chronic or treatment-resistant depression. They concluded that when assessed in the long term, antidepressants become less effective whereas psychological therapies become more effective. We argue that the evidence does not support this; indeed, most of the studies reviewed do not directly compare antidepressant with psychological therapy treatments and there is little consistency between them in terms of populations and interventions examined. The issue of long-term outcomes is key for optimising clinical guidelines and deserves more intensive research and scrutiny to improve patient response in routine practice.BACKGROUND The Pediatric Heart Network Normal Echocardiogram Database Study had unanticipated challenges. We sought to describe these challenges and lessons learned to improve the design of future studies. METHODS Challenges were divided into three categories enrolment, echocardiographic imaging, and protocol violations. Memoranda, Core Lab reports, and adjudication logs were reviewed. A