Significant morphological change in osteoarthritic hips identified over 6-12 months using Statistical Shape Modelling

Acknowledgements We are grateful to all the study participants. We thank Lana Gibson and Jennifer Scott for their expertise with the iDXA scanner as well as iDXA precision data. Funding source This study was supported by an award (Ref: WHMSB_AU068/071) from the Translational Medicine Research Collaboration – a consortium made up of the Universities of Aberdeen, Dundee, Edinburgh and Glasgow, the four associated NHS Health Boards (Grampian, Tayside, Lothian and Greater Glasgow & Clyde), Scottish Enterprise and initially Wyeth, now Pfizer. The funder had no involvement in the collection, analysis and interpretation of data; in the writing of the manuscript; or in the decision to submit the manuscript for publication. Dr J.S. Gregory was the holder of an MRC New Investigator award (Ref: G0901242).Peer reviewedPostprin

Statistical shape modelling provides a responsive measure of morphological change in knee osteoarthritis over 12 months

Funding: This study was supported by an award (Ref: WHMSB_AU068/071) from the Translational Medicine Research Collaboration (TMRC) – a consortium made up of the Universities of Aberdeen, Dundee, Edinburgh and Glasgow, the four associated NHS Health Boards (Grampian, Tayside, Lothian and Greater Glasgow & Clyde), Scottish Enterprise and initially Wyeth, now Pfizer. The funder had no involvement in the collection, analysis and interpretation of data; in the writing of the manuscript; or in the decision to submit the manuscript for publication. Dr J.S. Gregory was the holder of an MRC New Investigator award (Ref: G0901242). Acknowledgements We are grateful to all the study participants. We thank Lana Gibson and Jennifer Scott for their expertise with the iDXA scanner as well as iDXA precision data and Dr Sandro Galea-Solar for assistance with KL grading.Peer reviewedPostprin

Common effects of lithium and valproate on mitochondrial functions: protection against methamphetamine-induced mitochondrial damage

Accumulating evidence suggests that mitochondrial dysfunction plays a critical role in the progression of a variety of neurodegenerative and psychiatric disorders. Thus, enhancing mitochondrial function could potentially help ameliorate the impairments of neural plasticity and cellular resilience associated with a variety of neuropsychiatric disorders. A series of studies was undertaken to investigate the effects of mood stabilizers on mitochondrial function, and against mitochondrially mediated neurotoxicity. We found that long-term treatment with lithium and valproate (VPA) enhanced cell respiration rate. Furthermore, chronic treatment with lithium or VPA enhanced mitochondrial function as determined by mitochondrial membrane potential, and mitochondrial oxidation in SH-SY5Y cells. In-vivo studies showed that long-term treatment with lithium or VPA protected against methamphetamine (Meth)-induced toxicity at the mitochondrial level. Furthermore, these agents prevented the Meth-induced reduction of mitochondrial cytochrome c, the mitochondrial anti-apoptotic Bcl-2/Bax ratio, and mitochondrial cytochrome oxidase (COX) activity. Oligoarray analysis demonstrated that the gene expression of several proteins related to the apoptotic pathway and mitochondrial functions were altered by Meth, and these changes were attenuated by treatment with lithium or VPA. One of the genes, Bcl-2, is a common target for lithium and VPA. Knock-down of Bcl-2 with specific Bcl-2 siRNA reduced the lithium- and VPA-induced increases in mitochondrial oxidation. These findings illustrate that lithium and VPA enhance mitochondrial function and protect against mitochondrially mediated toxicity. These agents may have potential clinical utility in the treatment of other diseases associated with impaired mitochondrial function, such as neurodegenerative diseases and schizophrenia

Biomarkers in the Age of Omics: Time for a Systems Biology Approach

Limitations to biomarker discovery are not only technical or bioinformatic but conceptual as well. In our attempt to offer a solution, we are highlighting three issues that we think are limiting progress in biomarkers discovery. First, the confusion stemming from the imposition of a pathology-type immunohistochemical marker (IHCM) concept on omics data without fully understanding the characteristics and limitations of IHCMs as applied in clinical pathology. Second, the lack of serious consideration for the scope of disease heterogeneity. Third, the refusal of the biomedical community to borrow from other biological disciplines their well established methods for dealing with heterogeneity. Therefore, real progress in biomarker discovery will be attained when we recognize that an omics biomarker cannot be assigned and validated without a priori data modeling and subtyping of the disease itself to reveal the extent of its heterogeneity, and its omics' clonal aberrations (drivers) underlying its subtypes and pathways' diversity. To further support our viewpoints, we are contributing a novel a systems biology method such as parsimony phylogenetic approach for disease modeling prior to biomarker circumscription. As an analytical approach that has been successfully used for a half of a century in other biological disciplines, parsimony phylogenetics simultaneously achieves several objectives: it provides disease modeling in a hierarchical phylogenetic classification, identifies biomarkers as the shared derived expressions or mutations—synapomorphies, constructs the omics profiles of specimens based on the most parsimonious arrangement of their heterogeneous data, and permits network profiling of affected signaling pathways as the biosignature of disease classes