Does epigenetics play a role in the pathology of osteoarthritis?

Idiopathic osteoarthritis (OA) is a complex, late-onset disease whose causes are still unknown. In spite of tremendous efforts, the search for the genes pre-disposing towards osteoarthritis has so far met with little success. We hypothesize that epigenetic changes play a major role in the pathology of OA. Epigenetics refers to stable, heritable, but potentially reversible modifications of gene expression that do not involve mutations in the DNA sequence, for example DNA methylation or histone modification. Epigenetic changes are gene and cell-type specific, may arise sporadically with increasing age or be provoked by environmental factors. To investigate whether epigenetic changes are significant factors in OA, we examined the DNA methylation status of the promoter regions of three genes that are expressed by OA, but not by normal, articular chondrocytes, namely MMP-3 (stromelysin-1), MMP-9 (gelatinase B) and MMP-13 (collagenase3). We hypothesized that these genes are silenced in normal chondrocytes by methylation of the cytosines of CpG dinucleotides in the respective promoter regions, but that abnormal expression is associated with a de-methylation, leading to eunsilencing f of gene expression. Cartilage was obtained from the femoral heads of 16 OA and 10 femoral neck fracture (#NOF) patients, which served as controls due to the inverse relationship between osteoporosis and OA. The cartilage was milled in a freezer mill with liquid nitrogen, DNA was extracted with a Qiagen kit, digested with methylation sensitive restriction enzymes, followed by PCR amplification. These enzymes will cut at their specific cleavage sites only if the CpGs is not methylated and thus allow us to determine methylation status of specific CpG sites.Results. Less than 5% of the chondrocytes in superficial layer from #NOF cartilage expressed degradative enzymes, whereas all cloned chondrocytes from advanced-stage OA cartilage were immunopositive. The overall % of CpG demethylation in the promoters of control patients (whose chondrocytes did not express the enzymes) was 20.1%, whereas 48.6% of CpG sites were demethylated in degradative chondrocytes of OA patients (p<0.001). For MMP-13, the increase in demethylation between control and OA was from 4 ..20%; for MMP-9 from 47 ..81% and for MMP-3 from 30 ..57%. However, not all available CpG sites were equally demethylated. Some sites were uniformly methylated in both OA and controls, others were demethylated even in controls. However, there was at least one crucial site for each degradative enzyme, where the differences in the degree of methylation were greatest and statistically different. These sites were at –110 for MMP-13; –36 for MMP-9; –635 for MMP-3. There was no relation between the % demethylation and the patient fs age and no apparent difference between males and females.Conclusions: We have demonstrated an association between abnormal gene expression of MMP-3, MMP-9 and MMP-13 and promoter DNA demethylation. This epigenetic dysregulation of genes appeared to be clonally inherited by daughter cells and may be typical for osteoarthritis and other complex, late-onset diseases.Correspondence should be addressed to Mr Carlos Wigderowitz, Honorary Secretary BORS, University Dept of Orthopaedic & Trauma Surgery, Ninewells Hospital & Medical School, Dundee DD1 9SY.None of the authors have received anything of value from a commercial or other party related directly or indirectly to the subject of the presentatio

Atypical progressive multifocal leukoencephalopathy in HIV with a high CD4 count: the use of magnetic resonance imaging plus spectrometry studies

Progressive multifocal leukoencephalopathy (PML) is still a underinvestigated central nervous system infection, often linked to HIV-related immunodeficiency. We present an unusual case report characterized by motor involvement, which occurred as the first AIDS-defining event in the absence of appreciable immunodeficiency in a patient with previously undiagnosed HIV infection, who was also assessed by a functional-metabolic magnetic resonance imaging technique (MRI-spectrometry). A 45-year-old patient had HIV infection detected after the appearance of motor abnormalities, in the absence of other signs or symptoms. No significant immunodeficiency was found (initial CD4+ lymphocyte count of 566 cells/μL), and HIV viral load was 24,000 RNA copies/mL. Combination antiretroviral therapy was started with lamivudine, abacavir and lopinavir/ritonavir, with subsequent addition of efavirenz and enfuvirtide. Elevated cerebrospinal fluid levels of JC virus (JCV) (11,668 copies/μL) and consistent neuroradiological findings at contrast-enhanced computed tomography and MRI scans confirmed a diagnosis of PML. Despite the aggressive therapeutic approach, which achieved undetectable HIV viraemia, a CD4+ count above 700 cells/μL and disappearance of JCV after 20 days, the neurological motor involvement rapidly deteriorated, yet associated cognitive impairment never occurred. Clinical and neuroradiological deterioration occurred, and our patient died five months after the diagnosis due to respiratory failure. Combined MRI-spectrometry studies performed 10 days before death included proton ((1)H) spectrometry, and an MRI study-calculation of water diffusion and anisotropy: through this innovative technique combining morphological and metabolic findings, multiple abnormalities involving the subtentorial white matter were detected (with multiple encephalic trunk and ponto-bulbar lesions), which usually are not part of the PML course

Japanese intellectual responses to China's rise

One of Japan’s leading daily newspapers, the Asahi Shimbun, carried an interview on December 12, 2012 with Dean of Tsinghua University’s Institute of Modern International Relations Yan Xuetong. In the course of that interview, Yan made a number of interesting observations. First, he made clear that he regarded Sino–American ‘conflict and rivalry’ as ‘inevitable’. Second, he suggested that the United States and China should ‘drop’ the idea of ‘mutual trust’, and that they should instead seek ‘cooperation without mutual trust’. Yan also seemed certain that China need not lose out to the United States in a competition for the world’s hearts-and-minds. Arguing that China’s ‘political morality’ is at a higher level than that of the West, Yan argued that the ancient Chinese emphasis on ‘fairness’ trumps ‘equality’; similarly, ‘civility’ surpasses ‘freedom’; and also, ‘justice’ is better than ‘democracy’