Subclinical calcified atherosclerosis in men and its association with a family history of premature coronary heart disease in first- and second-degree relatives

The authors examined the associations between coronary artery calcification and a family history of premature coronary heart disease in either first-degree (immediate family) or second-degree (grandparents, aunts, uncles) relatives in 1619 asymptomatic healthy men ages 40-50 years. The prevalence of any coronary artery calcification was 19.3% in participants (n=1102) with no family history, 26.6% in those with a first-degree family history (n=203; 12.5%), 26.5% in those with a second-degree family history (n=215, 13.3%), and 30.3% with both (n=99, 6.1%, p=0.003). After controlling for the Framingham risk score, body mass index, and ethnicity, all categories of family history were significant predictors of coronary artery calcification. The odds ratios for coronary artery calcification associated with a first- (1.49; p=0.026) and second-degree (1.41; p=0.049) family history of coronary heart disease were similar. Clinical coronary risk assessments should broadly include an assessment of premature coronary heart disease in both first- and second-degree relatives.     

Opiate receptors and cardiovascular control in conscious SHR and WKY rats

This study examined the cardiovascular, respiratory, and sympathetic effects of selective mu and delta opioid agonists microinjected into the hypothalamic nucleus preopticus medialis (POM) of conscious SHR and WKY rats. The mu receptor agonist D-Ala2-MePhe4-Gly5-ol-enkephalin (DAGO) at a dose of 0.6 or 6.0 nanomoles (Nmol) increased the blood pressure and heart rate in WKY rats. In SHR rats, the lower dose of DAGO similarly had a pressor effect whereas the higher dose was depressor; heart rat was increased only by the 6.0 nmol dose in these animals. In both SHR and WKY rats, this opioid caused respiratory acidosis and elevation of plasma norepinephrine (NE) and epinephrine (E); plasma vasopressin was reduced by the higher dose of DAGO. All of these effects of the mu agonist were reversed by the opiate receptor antagonist naloxone (0.5 mg/kg, i.a.). The delta opiate-receptor agonist D-Ala2-D-leu5-eukephalin at a dose of 6.0 or 20.0 nmol increased blood pressure and heart rate in both SHR and WKY rats without affecting respiratory variables. Plasma NE and EPI were elevated at the peak of the pressor period. These studies suggest that the anteroventral hypothalamic region may be an important site in central autonomic regulation by opioid peptides. The mu-receptor agonist was more potent than the delta agonist in eliciting cardiovascular and respiratory effects and associated sympatho-adrenomedullary activation.(ABSTRACT TRUNCATED AT 250 WORDS)     

The LIM/double zinc-finger motif functions as a protein dimerization domain.

Protein-protein interactions resulting in dimerization and heterodimerization are of central importance in the control of gene expression and cell function. Proteins that share the 52-residue LIM/double zinc-finger domain are involved in a wide range of developmental and cellular controls. Some of these functions have been hypothesized to involve protein dimerization. In the present report we demonstrate, using both in vitro and cell-based studies, that a representative LIM protein, human cysteine-rich protein (hCRP), can efficiently homodimerize. The dimerization ability of hCRP is mapped to the LIM domains, can be transferred to an unrelated protein by fusion of a single minimal LIM/double zinc-finger segment, occurs in the absence as well as the presence of DNA, and appears to depend on coordination of two zinc atoms in the finger doublet. These observations support a specific role for protein dimerization in the function of proteins containing the LIM/double zinc-finger domain and expand the general spectrum of potential interactions mediated by zinc-finger motifs.     

Targeted Physician Education and Standardizing Documentation Improves Documented Reporting with Inflammatory Bowel Disease Quality Measures in a Large Academic and Private Practice

Background

Prior studies have shown poor compliance with quality measures for IBD at academic and private practices. We sought to provide focused interventions to improve compliance and documentation with the IBD measures.

Methods

Two centers, academic practice (AP) and private practice (PP), initially reviewed their compliance with eight established IBD quality measures in consecutive charts. A multi-faceted intervention was developed to improve awareness and documentation of these measures. The initial data and the quality measures were reviewed at a group meeting. Following this, a handout summarizing the measures was placed in each exam room. The AP added a new screen to the EHR that summarized the relevant IBD history, while the PP added a new template that was filled out and imported into the charts. Three months after this intervention, charts were reviewed for compliance with the measures.

Results

The intervention cohort consisted of 768 patients (AP = 569/PP = 199) compared to the initial cohort of 566 patients (AP = 367/PP = 199). Improvement was seen throughout all measures compared to the initial cohort. The AP reported compliance with all relevant measures in 21% and the PP in 60% compared to 7 and 10% in the initial cohort. PP had ≥ 75% compliance with every measure, of which only assessment for bone loss and pneumococcal vaccination was under 80%. In contrast, the AP compliance ranged from 35 to 100% with assessment for bone loss, influenza, and pneumococcal vaccination scoring lowest.

Conclusion

Our study demonstrates that focused low-cost interventions can significantly improve compliance with IBD quality measures in different practice settings.

     

Increased expression of the G gamma and A gamma globin genes associated with a mutation in the A gamma enhancer

We have previously described a unique type of delta beta-thalassemia in a Chinese family characterized by increased expression of the G gamma and A gamma fetal globin genes in the absence of a large deletion in the beta-globlin gene cluster. Our earlier study of the beta-globin gene on this delta beta-thalassemia chromosome showed a promoter mutation in the TATA box. In this report, we describe the results of our study of the fetal globin domain of this delta beta-thalassemia chromosome. We have cloned a 13-kb DNA fragment that includes the G gamma and the A gamma genes and the 3' A gamma enhancer element of this delta beta-thalassemia chromosome. DNA sequence analysis of the G gamma and A gamma-globin genes including their promoters did not show any mutations, but analysis of the putative enhancer element downstream from the A gamma-globin gene showed a C to T substitution 2,401 nucleotides downstream from the A gamma cap site. We performed DNA linkage analysis to determine if this mutation is unique to this chromosome or represents a common polymorphism. Our linkage analysis showed that this mutation is not a common polymorphism and that it is also not an intrinsic part of the haplotype of the chromosome on which it was found. We also studied the interaction of nuclear proteins from erythroid and nonerythroid cells with the DNA sequences surrounding this mutation. We have shown by in vitro DNase I footprinting that this mutation falls within a region that is occupied by a novel DNA-binding protein that binds to this site in nuclear extracts from erythroid, but not nonerythroid cells. The binding of this nuclear protein to DNA appears to be dependent on GATA-1 binding to an adjacent GATA-1 site. We have also developed a new functional assay to compare the activity of the normal and mutant A gamma enhancer elements in erythroid cells. Analysis of the activity of the mutant enhancer shows that the mutation completely eliminates all enhancer activity in this assay. These findings suggest that this mutation of the A gamma enhancer on a chromosome that carries a partially inactivated beta-globin gene may be responsible for the increased expression of both gamma-globin genes seen in this condition.     

Relation between coronary artery calcium and incident chest pain in a community-dwelling screening population

Incident chest pain occurred in 30.3% of 1,743 asymptomatic healthy men and women who were followed for up to 4 years. Proportions of patients who had coronary artery calcium were similar among those who had no chest pain, noncardiac pain, atypical pain, or cardiac chest pain. Incident chest pain is common and should be examined according to a patient's pretest probability of developing coronary artery disease, without excessive influence of the presence of coronary artery calcium.     

Platelets stimulate expression of endothelin mRNA and endothelin biosynthesis in cultured endothelial cells

Modulation of the biosynthesis of the vasoconstrictor peptide endothelin was studied in cultured endothelial cells. Immunoreactive endothelin (irET) levels were significantly elevated in conditioned medium from bovine pulmonary artery endothelial (BPAE) or human umbilical vein endothelial cells when coincubated with washed human platelets. Platelets (approximately 200,000 cells/microliters) enhanced irET levels approximately 250% over basal levels. Stimulation of irET levels in BPAE cell-conditioned medium by platelets was time and platelet number dependent. Platelets, as well as thrombin and transforming growth factor-beta 1, stimulated the expression of preproendothelin-1 mRNA in a time-dependent manner. Coincubation of low doses of thrombin (0.1 unit/ml) and subthreshold concentrations of platelets with BPAE cells resulted in a further enhancement of irET levels in conditioned medium. Platelet-mediated stimulation of irET production was not significantly affected by indomethacin (1 microM) or the platelet-activating factor receptor antagonist WEB 2086 (1 microM); however, coincubation of endotoxin (100 ng/ml) with platelets and BPAE cells resulted in significantly higher levels of irET. Whether direct contact or adhesion between platelets and endothelial cells is necessary for stimulating irET release was studied by separating platelets from BPAE cells with a 0.4 microns permeable membrane. Under these conditions, platelets still produced significant elevations (approximately 190% over basal levels) in irET levels in BPAE cell-conditioned medium. In addition, platelet-free buffer from agonist-induced platelet aggregation also significantly enhanced irET production (200% over basal values). These data indicate that a platelet-derived regulatory factor can induce the biosynthesis of endothelin from cultured endothelial cells and also suggest that platelets might play a role in vasomotor regulation via a novel intercellular interaction with the endothelium.