Osteoprotegerin gene polymorphisms in men with coronary artery disease

Osteoprotegerin (OPG) antagonizes receptor activator of nuclear factor-kappaB ligand (RANKL), the principal regulator of osteoclasts. Of note, OPG-deficient mice display osteoporosis and arterial calcification. Recently, OPG gene polymorphisms have been associated with osteoporosis and early predictors of cardiovascular disease. In this study, we examined OPG gene polymorphisms in 468 men who had absence of coronary artery disease (CAD) or single-, double-, or triple-vessel disease on coronary angiography. Denaturing gradient gel electrophoresis followed by DNA sequencing revealed nucleotide substitutions 149 T-->C, 163 A-->G, 209 G-->A, 245 T-->G, 950 T-->C (all promoter), 1181 G-->C (exon 1), and 6890 A-->C (intron 4), respectively. Although single polymorphisms were not associated with CAD, linkage of polymorphisms 950 and 1181 revealed that haplotypes were overrepresented in men with CAD (chi(2) = 17.05; P = 0.03) with an increased risk of CAD in carriers of genotypes 950 TC/1181 GC and 950 CC/1181 CC (odds ratio, 1.67; 95% confidence interval, 1.02-2.72; P = 0.04). Furthermore, serum OPG levels were correlated with the presence of a C allele at position 950 (P = 0.02). In summary, linkage of genetic variations of the OPG gene at positions 950 and 1181 may confer an increased risk of CAD in Caucasian men.     

Further delineation of the KBG syndrome caused by ANKRD11 aberrations

Loss-of-function variants in ANKRD11 were identified as the cause of KBG syndrome, an autosomal dominant syndrome with specific dental, neurobehavioural, craniofacial and skeletal anomalies. We present the largest cohort of KBG syndrome cases confirmed by ANKRD11 variants reported so far, consisting of 20 patients from 13 families. Sixteen patients were molecularly diagnosed by Sanger sequencing of ANKRD11, one familial case and three sporadic patients were diagnosed through whole-exome sequencing and one patient was identified through genomewide array analysis. All patients were evaluated by a clinical geneticist. Detailed orofacial phenotyping, including orthodontic evaluation, intra-oral photographs and orthopantomograms, was performed in 10 patients and revealed besides the hallmark feature of macrodontia of central upper incisors, several additional dental anomalies as oligodontia, talon cusps and macrodontia of other teeth. Three-dimensional (3D) stereophotogrammetry was performed in 14 patients and 3D analysis of patients compared with controls showed consistent facial dysmorphisms comprising a bulbous nasal tip, upturned nose with a broad base and a round or triangular face. Many patients exhibited neurobehavioural problems, such as autism spectrum disorder or hyperactivity. One-third of patients presented with (conductive) hearing loss. Congenital heart defects, velopharyngeal insufficiency and hip anomalies were less frequent. On the basis of our observations, we recommend cardiac assessment in children and regular hearing tests in all individuals with a molecular diagnosis of KBG syndrome. As ANKRD11 is a relatively common gene in which sequence variants have been identified in individuals with neurodevelopmental disorders, it seems an important contributor to the aetiology of both sporadic and familial cases.     

Effects of estrogen and medroxyprogesterone acetate on subpopulations of triglyceride-rich lipoproteins and high-density lipoproteins

Hormonal replacement therapy (HRT) in postmenopausal women has been shown to increase both triglyceride (TG) and high-density lipoprotein (HDL) cholesterol levels. To better understand the effects of conjugated equine estrogen (CEE) and medroxyprogesterone acetate (MPA), the 2 most commonly prescribed hormones in HRT, on the different subpopulations of TG-rich and HDL lipoproteins, we conducted a placebo-controlled, double-blind, randomized, crossover study consisting of 3 different phases in 14 postmenopausal women. The 3 phases, each 8-week long, included: (1) placebo, (2) CEE 0.625 mg/d, and (3) CEE 0.625 mg/d and MPA 2.5 mg/d. Slight and statistically nonsignificant elevations in TG levels were observed during the CEE treatment. While very-low-density lipoprotein (VLDL) cholesterol levels were not significantly affected by CEE and CEE + MPA, both HRT treatments lowered remnant lipoprotein (RLP) cholesterol (-14% and -37%, respectively). Compared with placebo, CEE caused a significant increase in HDL, HDL(2), apolipoprotein (apo) A-I, LpAI, alpha1, and prealpha1 levels (12%, 27%, 17%, 26%, 60%, and 102%, respectively). The combination therapy blunted the CEE effect on all HDL parameters, resulting in HDL, HDL(2), and LpAI levels being no longer significantly different from placebo. Apo A-I levels and alpha1, and prealpha1 levels were still significantly higher than placebo (+11%, +50%, and +112%, respectively). These results indicate that HRT has beneficial effects on RLP levels and that, while the estrogen component of HRT has a beneficial effect on the HDL subpopulations mostly associated with coronary heart disease (CHD) protection, MPA partially inhibits this effect.     

Idiopathic Colonic Varices: An Unusual Cause of Massive Lower Gastrointestinal Hemorrhage

We report a patient with massive lower gastrointestinal bleeding, probably from extensive colonic varices. Despite lengthy investigation, the etiology of the colonic varices was not determined. There are numerous reports in the literature of bleeding from cotonic varices attributed to portal hypertension from cirrhosis or venous obstruction. However, bleeding from colonic varices Iocated in the entire colon without demonstrable cause have only rarely been reported.     

Diabetes,plasma insulin,and cardiovascular disease: subgroup analysis from the Department of Veterans Affairs high-density lipoprotein intervention trial (VA-HIT)

BACKGROUND: Diabetes mellitus, impaired fasting glucose level, or insulin resistance are associated with increased risk of cardiovascular disease. OBJECTIVES: To determine the efficacy of gemfibrozil in subjects with varying levels of glucose tolerance or hyperinsulinemia and to examine the association between diabetes status and glucose and insulin levels and risk of cardiovascular outcomes. METHODS: Subgroup analyses from the Department of Veterans Affairs High-Density Lipoprotein Intervention Trial, a randomized controlled trial that enrolled 2531 men with coronary heart disease (CHD), a high-density lipoprotein cholesterol level of 40 mg/dL or less (/=271 pmol/L) was associated with a 31% increased risk of events (P =.03). Gemfibrozil was effective in persons with diabetes (risk reduction for composite end point, 32%; P =.004). The reduction in CHD death was 41% (HR, 0.59; 95% CI, 0.39-0.91; P =.02). Among individuals without diabetes, gemfibrozil was most efficacious for those in the highest fasting plasma insulin level quartile (risk reduction, 35%; P =.04). CONCLUSION: In men with CHD and a low high-density lipoprotein cholesterol level, gemfibrozil use was associated with a reduction in major cardiovascular events in persons with diabetes and in nondiabetic subjects with a high fasting plasma insulin level.     

Apolipoprotein A-I and A-II kinetic parameters as assessed by endogenous labeling with [(2)H(3)]leucine in middle-aged and elderly men and women

The purpose of our study was to investigate high density lipoprotein (HDL) apolipoprotein (apo) A-I and apoA-II kinetics in a state of constant feeding after a primed-constant infusion of [5,5, 5-(2)H(3)]L-leucine in 32 normolipidemic older men and postmenopausal women (aged 41 to 79 years). ApoA-I and apoA-II were isolated from plasma HDL, and enrichment was determined by gas chromatography/mass spectrometry. The fractional secretion rate was obtained by using a monoexponential equation calculated with the SAAM II program (Department of Bioengineering, University of Washington, Seattle). Mean HDL cholesterol (HDL-C) and total triglyceride levels were 23% higher and 27% lower, respectively, in women than in men. Mean plasma apoA-I levels were 10% greater in women than in men, whereas mean apoA-II levels were similar. HDL size, estimated by gradient-sizing gels and by the HDL-C/apoA-I+apoA-II ratio, was significantly higher in women than in men. Mean apoA-I secretion rates (SRs) were similar in men and women (12.28+/-3.64 versus 11.96+/-2.92 mg/kg per day), whereas there was a trend toward a lower (-13%) apoA-I fractional catabolic rate (FCR) in women compared with men (0.199+/-0.037 versus 0. 225+/-0.062 pools per day, P=0.11). Mean apoA-II SRs (2.21+/-0.57 versus 2.27+/-0.91 mg/kg per day) and FCRs (0.179+/-0.034 versus 0. 181+/-0.068 pools per day) were similar in men and women. For the group as a whole, there was an inverse association between the HDL-C/apoA-I+apoA-II ratio and apoA-I FCR and between the ratio and triglyceride levels. Plasma levels of apoA-I and apoA-II were correlated with their respective SRs but not FCRs. These data suggest a major role for apoA-I and apoA-II SRs in regulating the plasma levels of these proteins, whereas apoA-I FCR might be an important factor contributing to the differences in apoA-I levels between men and postmenopausal women. Moreover, plasma triglyceride levels are important determinants of HDL size and apoA-I catabolism.     

Human herpesvirus 6 is an important pathogen in infectious lung disease after allogeneic bone marrow transplantation

Two hundred and ten bronchoalveolar lavage (BAL) samples were obtained from 50 patients 10 days before and on defined days after allogeneic bone marrow transplantation (BMT). The samples were examined for human cytomegalovirus (HCMV) and human herpesvirus-6 (HHV-6) by polymerase chain reaction (PCR). Fifteen patients (30%) had a positive result for HCMV in at least one sample and 25 (50%) were positive for HHV-6 in at least one sample. Five patients developed HCMV-associated interstitial pneumonia (HCMV-IP) within 100 days after allogeneic BMT. Four of these patients were positive for both HCMV and HHV-6. Conspicuous HHV-6 positivity was detected in BAL samples obtained because of respiratory symptoms. No association was found between detection of HHV-6 and acute graft-versus-host disease. Engraftment failure or a delay in engraftment was observed in none of the 50 patients. The data from this study indicate that HHV-6 is a pathogen in HCMV-associated, as well as in non-HCMV-associated infectious lung disease after BMT.