Blood-based biomarkers for detecting mild osteoarthritis in the human knee

SummaryObjectiveThis study was designed to test the utility of a blood-based approach to identify mild osteoarthritis (OA) of the knee.MethodsBlood samples were drawn from 161 subjects, including 85 subjects with arthroscopically diagnosed mild OA of the knee and 76 controls. Following RNA isolation, an in-house custom cDNA microarray was used to screen for differentially expressed genes. A subset of selected genes was then tested using real-time RT-PCR. Logistic regression analysis was used to evaluate linear combinations of the biomarkers and receiver operating characteristic curve analysis was used to assess the discriminatory power of the combinations.ResultsGenes differentially expressed (3543 genes) between mild knee OA and control samples were identified through microarray analysis. Subsequent real-time RT-PCR verification identified six genes significantly down-regulated in mild OA: heat shock 90kDa protein 1, alpha; inhibitor of kappa light polypeptide gene enhancer in B-cells, kinase complex-associated protein; interleukin 13 receptor, alpha 1; laminin, gamma 1; platelet factor 4 (also known as chemokine (C-X-C motif) ligand 4) and tumor necrosis factor, alpha-induced protein 6. Logistic regression analysis identified linear combinations of nine genes – the above six genes, early growth response 1; alpha glucosidase II alpha subunit; and v-maf musculoaponeurotic fibrosarcoma oncogene homolog B (avian) – as discriminatory between subjects with mild OA and controls, with a sensitivity of 86% and specificity of 83% in a training set of 78 samples. The optimal biomarker combinations were then evaluated using a blind test set (67 subjects) which showed 72% sensitivity and 66% specificity.ConclusionsLinear combinations of blood RNA biomarkers offer a substantial improvement over currently available diagnostic tools for mild OA. Blood-derived RNA biomarkers may be of significant clinical value for the diagnosis of early, asymptomatic OA of the knee

Essays in International Mergers and Acqusition Research

成功的企業購併需仰賴正確的投資評估以及有效的購併過程管理,本文包含兩個部分,第一部分主要探討購併利益評估的問題,使用的方法為real-option approach簡化了購併效益之評估,且可獲得較正確的結果;第二部分為兩家國際出版業合併之個案研究,就此成功的例子而言,管理者可以獲得較有利且完善的合併經營方法。Successful mergers depend on proper valuation of this special type of investment and effective management of this process. First essay devoted to the problem of merger profitability valuation. Using real-option approach, a simple model is developed to expand accuracy in decision making process about merger possibility. This model considers uncertainty of situation and provides flexibility in company’s strategy. According to this approach profitability of merger may be calculated by using value of premium paid for acquiring company and value of synergy that expected from merge of two companies. Main problem of merger’s valuation in this approach is correct definition of synergy. In second essay, merger of two publishing companies Addison Wesley Longman and Simon & Schuster is analyzed. Positive experience in choosing candidates for merge, pre- and post-acquisition decision making process can serve as a good example of effective merger’s management

Mitochondrial dysfunction and Purkinje cell loss in autosomal recessive spastic ataxia of Charlevoix-Saguenay (ARSACS)

Autosomal recessive spastic ataxia of Charlevoix-Saguenay (ARSACS) is a childhood-onset neurological disease resulting from mutations in the SACS gene encoding sacsin, a 4,579-aa protein of unknown function. Originally identified as a founder disease in Québec, ARSACS is now recognized worldwide. Prominent features include pyramidal spasticity and cerebellar ataxia, but the underlying pathology and pathophysiological mechanisms are unknown. We have generated an animal model for ARSACS, sacsin knockout mice, that display age-dependent neurodegeneration of cerebellar Purkinje cells. To explore the pathophysiological basis for this observation, we examined the cell biological properties of sacsin. We show that sacsin localizes to mitochondria in non-neuronal cells and primary neurons and that it interacts with dynamin-related protein 1, which participates in mitochondrial fission. Fibroblasts from ARSACS patients show a hyperfused mitochondrial network, consistent with defects in mitochondrial fission. Sacsin knockdown leads to an overly interconnected and functionally impaired mitochondrial network, and mitochondria accumulate in the soma and proximal dendrites of sacsin knockdown neurons. Disruption of mitochondrial transport into dendrites has been shown to lead to abnormal dendritic morphology, and we observe striking alterations in the organization of dendritic fields in the cerebellum of knockout mice that precedes Purkinje cell death. Our data identifies mitochondrial dysfunction/mislocalization as the likely cellular basis for ARSACS and indicates a role for sacsin in regulation of mitochondrial dynamics