MetroWest Medical Center

About: MetroWest Medical Center is a healthcare organization based out in Framingham, Massachusetts, United States. It is known for research contribution in the topics: Health care & Odds ratio. The organization has 171 authors who have published 202 publications receiving 6242 citations.

Hypomethylation of MB-COMT promoter is a major risk factor for schizophrenia and bipolar disorder

Abstract: The variability in phenotypic presentations and the lack of consistency of genetic associations in mental illnesses remain a major challenge in molecular psychiatry. Recently, it has become increasingly clear that altered promoter DNA methylation could play a critical role in mediating differential regulation of genes and in facilitating short-term adaptation in response to the environment. Here, we report the investigation of the differential activity of membrane-bound catechol-O-methyltransferase (MB-COMT) due to altered promoter methylation and the nature of the contribution of COMT Val158Met polymorphism as risk factors for schizophrenia and bipolar disorder by analyzing 115 post-mortem brain samples from the frontal lobe. These studies are the first to reveal that the MB-COMT promoter DNA is frequently hypomethylated in schizophrenia and bipolar disorder patients, compared with the controls (methylation rate: 26 and 29 versus 60%; P = 0.004 and 0.008, respectively), particularly in the left frontal lobes (methylation rate: 29 and 30 versus 81%; P = 0.003 and 0.002, respectively). Quantitative gene-expression analyses showed a corresponding increase in transcript levels of MB-COMT in schizophrenia and bipolar disorder patients compared with the controls (P = 0.02) with an accompanying inverse correlation between MB-COMT and DRD1 expression. Furthermore, there was a tendency for the enrichment of the Val allele of the COMT Val158Met polymorphism with MB-COMT hypomethylation in the patients. These findings suggest that MB-COMT over-expression due to promoter hypomethylation and/or hyperactive allele of COMT may increase dopamine degradation in the frontal lobe providing a molecular basis for the shared symptoms of schizophrenia and bipolar disorder.

Hypermethylation of the reelin (RELN) promoter in the brain of schizophrenic patients: a preliminary report.

Abstract: DNA methylation changes could provide a mechanism for DNA plasticity and dynamism for short-term adaptation, enabling a type of cell memory to register cellular history under different environmental conditions. Some environmental insults may also result in pathological methylation with corresponding alteration of gene expression patterns. Evidence from several studies has suggested that in schizophrenia and bipolar disorder, mRNA of the reelin gene (RELN), which encodes a protein necessary for neuronal migration, axonal branching, synaptogenesis, and cell signaling, is severely reduced in post-mortem brains. Therefore, we investigated the methylation status of the RELN promoter region in schizophrenic patients and normal controls as a potential mechanism for down regulation of its expression. Ten post-mortem frontal lobe brain samples from male schizophrenic patients and normal controls were obtained from the Harvard Brain Tissue Resources Center. DNA was extracted using a standard phenol–chloroform DNA extraction protocol. To evaluate differences between patients and controls, we applied methylation specific PCR (MSP) using primers localized to CpG islands flanking a potential cyclic AMP response element (CRE) and a stimulating protein-1 (SP1) binding site located in the promoter region. For each sample, DNA extraction, bisulfite treatment, and MSP were independently repeated at least four times to accurately determine the methylation status of the target region. Forty-three PCR trials were performed on the test and control samples. MSP analysis of the RELN promoter revealed an unmethylated signal in all reactions (43 of 43) using DNA from the frontal brain tissue, derived from either the schizophrenic patients or normal controls indicating that this region of the RELN promoter is predominantly unmethylated. However, we observed a distinct methylated signal in 73% of the trials (16 of 22) in schizophrenic patients compared with 24% (5 of 21) of controls. Thus, the hypermethylation of the CpG islands flanking a CRE and SP1 binding site observed at a significantly higher level (t = −5.07, P = 0.001) may provide a mechanism for the decreased RELN expression, frequently observed in post-mortem brains of schizophrenic patients. We also found an inverse relationship between the level of DNA methylation using MSP analysis and the expression of the RELN gene using semi-quantitative RT-PCR. Despite the small sample size, these studies indicate that promoter hypermethylation of the RELN gene could be a significant contributor in effecting epigenetic alterations and provides a molecular basis for the RELN gene hypoactivity in schizophrenia. Further studies with a larger sample set would be required to validate these preliminary observations. © 2005 Wiley-Liss, Inc.

Childhood Injury Prevention Counseling in Primary Care Settings: A Critical Review of the Literature

Abstract: OBJECTIVES. The American Academy of Pediatrics (AAP) believes that health education, through office-based counseling, can contribute to childhood injury prevention. This report presents the results of a critical review of the scientific literature on the effectiveness of primary care-based counseling to prevent childhood unintentional injury. METHODS. A panel selected from the AAP Committee and the AAP Section on Injury and Poison Prevention searched the English-language scientific literature for all articles about childhood unintentional injury prevention counseling. A standardized format was developed to record data on each study. Two members of the panel independently reviewed each article. Articles that were original reports and in which unintentional injury prevention counseling took place in a primary care setting were included. Articles were encoded and analyzed by computer and then grouped by quality of evidence using the US Preventive Services Task Force (USPSTF) method of categorizing results of medical care evaluation. Articles were rated by strength of study design in order to compare studies within each USPSTF group. RESULTS. Twenty articles met the criteria for inclusion. Of these, 18 showed positive effects of injury prevention counseling including five randomized/controlled, 10 non-randomized/controlled, two multiple time series, and one descriptive study. In 15 of the positive studies, physicians performed the counseling. Positive outcomes as measured by increased knowledge, improved behavior, or decreased injury occurrence were reported for both motor vehicle and non-motor vehicle injuries. CONCLUSIONS. The literature review supports the recommendation of the AAP to include injury prevention counseling as part of routine health supervision. This recommendation has implications for health care reimbursement and care content.