The use of modern neuroimaging approaches has demonstrated resting-state regional cerebral blood flow (rCBF) to be tightly coupled to resting cerebral glucose metabolism (rCMRglu) in healthy brains. In schizophrenia, several lines of evidence point toward aberrant neurovascular coupling, especially in the prefrontal regions. To investigate this, we used Signed Differential Mapping to undertake a voxel-based bimodal meta-analysis examining the relationship between rCBF and rCMRglu in schizophrenia, as measured by arterial spin labeling (ASL) and 18 Flurodeoxyglucose positron emission tomography (FDG-PET) respectively. We used 19 studies comprised of data from 557 patients and 584 controls. Our results suggest that several key regions implicated in the pathophysiology of schizophrenia such as the frontoinsular cortex, dorsal ACC, putamen, and temporal pole show conjoint metabolic and perfusion abnormalities in patients. In contrast, discordance between metabolism and perfusion were seen in superior frontal gyrus and cerebellum, indicating that factors contributing to neurovascular uncoupling (e.g. inflammation, mitochondrial dysfunction, oxidative stress) are likely operates at these loci. Studies enrolling patients on high doses of antipsychotics had showed larger rCBF/rCMRglu effects in patients in the left dorsal striatum. Hybrid ASL-PET studies focusing on these regions could confirm our proposition regarding neurovascular uncoupling at superior frontal gyrus in schizophrenia.
Kallikreins (KLKs) are a group of 15 serine proteases encoded by the KLK locus on chromosome 19. Certain single nucleotide variants (SNVs) within the KLK locus have been linked to human disease. Next-generation sequencing of large human cohorts enables reexamination of genomic variation at the KLK locus. We aimed to identify all KLK-related SNVs and examine their impact on gene regulation and function. To this end, we mined KLK SNVs across Ensembl and Exome Variant Server, with exome-sequencing data from 6503 individuals. PolyPhen-2-based prediction of damaging SNVs and population frequencies of these SNVs were examined. Damaging SNVs were plotted on protein sequence and structure. We identified 4866 SNVs, the largest number of KLK-related SNVs reported. Fourteen percent of noncoding SNVs overlapped with transcription factor binding sites. We identified 602 missense coding SNVs, among which 148 were predicted to be damaging. Nine missense SNVs were common (>1% frequency) and displayed significantly different frequencies between European-American and African-American populations. SNVs predicted to be damaging appeared to alter tertiary structure of KLK1 and KLK6. Similarly, these missense SNVs may affect KLK function, resulting in disease phenotypes. Our study represents a mine of information for those studying KLK-related SNVs and their associations with diseases.
SUKUMAR, N., S. Priyadharshini, U. Anazodo, L. Palaniyappan. Neurovascular uncoupling in schizophrenia: A bimodal meta-analysis of brain perfusion and glucose metabolism. NEUROSCI BIOBEHAV REV X(X) XXX-XXX, XXXX. -The use of modern neuroimaging approaches has demonstrated resting-state regional cerebral blood flow (rCBF) to be tightly coupled to resting cerebral glucose metabolism (rCMRglu) in healthy brains. In schizophrenia, several lines of evidence point towards aberrant neurovascular coupling, especially in the prefrontal regions. To investigate this, we used Signed Differential Mapping to undertake a voxel-based bimodal metaanalysis examining the relationship between rCBF and rCMRglu in schizophrenia, as measured by Arterial Spin Labeling (ASL) and 18 Flurodeoxyglucose Positron Emission Tomography (FDG-PET) respectively. We used 19 studies comprised of data from 557 patients and 584 controls. Our results suggest that several key regions implicated in the pathophysiology of schizophrenia such as the frontoinsular cortex, dorsal ACC, putamen, and temporal pole show conjoint metabolic and perfusion abnormalities in patients. In contrast, discordance between metabolism and perfusion were seen in superior frontal gyrus and cerebellum, indicating that factors contributing to neurovascular uncoupling (e.g. inflammation, mitochondrial dysfunction, oxidative stress) are likely operates at these loci. Hybrid ASL-PET studies focusing on these regions could confirm our proposition.
Ontario, like many other countries around the world, follows a voluntary organ donor system. Citizens are given the option of becoming donors at the age of 16 and are scarcely reminded of the option ever after. As such, less than a quarter of Ontarians are registered organ donors. Not only is this an unnecessary waste of precious organs, it is also an extremely unfair system, as both donors and non-donors are considered of equal priority to receive organ transplants. We thus call for a compulsory incentivized organ donationsystem in Ontario, as a fairer and more efficient organ donor policy. This policy automatically considers all citizens as organ donors after a certain age, where unwilling citizens can opt out if they wish to do so. However, individuals that choose to opt out are given less priority for organ transplants as compared to those who remain as organ donors. By automating organ donor registration and providing disincentive to opt out of organ donation, such a policy ensures a greater availability of organs for all Ontarians.
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