Thrombomodulin Ala455Val Polymorphism and the risk of cerebral infarction in a biracial population: the Stroke Prevention in Young Women Study

BACKGROUND: The genes encoding proteins in the thrombomodulin-protein C pathway are promising candidate genes for stroke susceptibility because of their importance in thrombosis regulation and inflammatory response. Several published studies have shown that the Ala455Val thrombomodulin polymorphism is associated with ischemic heart disease, but none has examined the association with stroke. Using data from the Stroke Prevention in Young Women Study, we sought to determine the association between the Ala455Val thrombomodulin polymorphism and the occurrence of ischemic stroke in young women. METHODS: All 59 hospitals in the greater Baltimore-Washington area participated in a population-based case-control study of stroke in young women. We compared 141 cases of first ischemic stroke (44% black) among women 15 to 44 years of age with 210 control subjects (35% black) who were identified by random digit dialing and frequency matched to the cases by age and geographical region of residence. Data on historical risk factors were collected by standardized interview. Genotyping of the thrombomodulin Ala455Val polymorphism was performed by pyrosequencing. RESULTS: The A allele (frequency = 0.85) was associated with stroke under the recessive model. After adjustment for age, race, cigarette smoking, hypertension, and diabetes, the AA genotype, compared with the AV and VV genotypes combined, was significantly associated with stroke (odds ratio 1.9, 95% CI 1.1–3.3). The AA genotype was more common among black than white control subjects (81% versus 68%) but there was no significant interaction between the risk genotype and race (adjusted odds ratio 2.7 for blacks and 1.6 for whites). A secondary analysis removing all probable (n = 16) and possible (n = 15) cardioembolic strokes demonstrated an increased association (odds ratio 2.2, 95% CI 1.2–4.2). CONCLUSIONS: Among women aged 15 to 44 years, the AA genotype is more prevalent among blacks than whites and is associated with increased risk of early onset ischemic stroke. Removing strokes potentially related to cardioembolic phenomena increased this association. Further studies are needed to determine whether this polymorphism is functionally related to thrombomodulin expression or whether the association is due to population stratification or linkage to a nearby functional polymorphism

Cardiac myosin binding protein C phosphorylation in cardiac disease

Perturbations in sarcomeric function may in part underlie systolic and diastolic dysfunction of the failing heart. Sarcomeric dysfunction has been ascribed to changes in phosphorylation status of sarcomeric proteins caused by an altered balance between intracellular kinases and phosphatases during the development of cardiac disease. In the present review we discuss changes in phosphorylation of the thick filament protein myosin binding protein C (cMyBP-C) reported in failing myocardium, with emphasis on phosphorylation changes observed in familial hypertrophic cardiomyopathy caused by mutations in MYBPC3. Moreover, we will discuss assays which allow to distinguish between functional consequences of mutant sarcomeric proteins and (mal)adaptive changes in sarcomeric protein phosphorylation

Simian virus 40 inhibits differentiation and maturation of rhesus macaque DC-SIGN+-dendritic cells

Dendritic cells (DC) are the initiators and modulators of the immune responses. Some species of pathogenic microorganisms have developed immune evasion strategies by controlling antigen presentation function of DC. Simian virus 40 (SV40) is a DNA tumor virus of rhesus monkey origin. It can induce cell transformation and tumorigenesis in many vertebrate species, but often causes no visible effects and persists as a latent infection in rhesus monkeys under natural conditions. To investigate the interaction between SV40 and rhesus monkey DC, rhesus monkey peripheral blood monocyte-derived DC were induced using recombinant human Interleukin-4 (rhIL-4) and infective SV40, the phenotype and function of DC-specific intracellular adhesion molecule-3 grabbing nonintegrin (DC-SIGN)+ DC were analyzed by flow cytometry (FCM) and mixed lymphocyte reaction (MLR). Results showed that SV40 can down-regulate the expression of CD83 and CD86 on DC and impair DC-induced activation of T cell proliferation. These findings suggest that SV40 might also cause immune suppression by influencing differentiation and maturation of DC

A pilot study on peritraumatic dissociation and coping styles as risk factors for posttraumatic stress, anxiety and depression in parents after their child's unexpected admission to a Pediatric Intensive Care Unit

Aim: To study the prevalence of posttraumatic stress disorder (PTSD), anxiety and depression in parents three months after pediatric intensive care treatment of their child and examine if peritraumatic dissocation and coping styles are related to these mental health problems. Methods: This is a prospective cohort study and included parents of children unexpectedly admitted to the Pediatric Intensive Care Unit (PICU) from January 2006 to March 2007. At three months follow-up parents completed PTSD (n = 115), anxiety and depression (n = 128) questionnaires. Immediately after discharge, parents completed peritraumatic dissocation and coping questionnaires. Linear regression models with generalized estimating equations examined risk factors for mental health problems. Results: Over 10% of the parents were likely to meet criteria for PTSD and almost one quarter for subclinical PTSD. Respectively 15% to 23% of the parents reported clinically significant levels of depression and anxiety. Peritraumatic dissocation was most strongly associated with PTSD, anxiety as well as depression. Avoidance coping was primarily associated with PTSD. Conclusion: A significant number of parents have mental health problems three months after unexpected PICU treatment of their child. Improving detection and raise awareness of mental health problems is important to minimize the negative effect of these problems on parents' well-being. © 2009 Bronner et al; licensee BioMed Central Ltd

Role of MC1R variants in uveal melanoma

Variants of the melanocortin-1 receptor (MC1R) gene have been linked to sun-sensitive skin types and hair colour, and may independently play a role in susceptibility to cutaneous melanoma. To assess the role of MC1R variants in uveal melanoma, we have analysed a cohort of 350 patients for the changes within the major region of the gene displaying sequence variation. Eight variants were detected – V60L, D84E, V92M, R151C, I155T, R160W, R163Q and D294H – 63% of these patients being hetero- or homozygous for at least one variant. Standard melanoma risk factor data were available on 119 of the patients. MC1R variants were significantly associated with hair colour (P¼0.03) but not skin or eye colour. The frequency of the variants detected in the 350 patients was comparable with those in the general population, and comparison of the cumulative tumour distribution by age at diagnosis in carriers and noncarriers provided no evidence that MC1R variants confer an increased risk of uveal melanoma. We interpret the data as indicating that MC1R variants do not appear to be major determinants of susceptibility to uveal melanoma. © 2003 Cancer Research U

Disease proteomics

Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/62680/1/nature01514.pd