Effects of estrogen replacement on the progression of coronary-artery atherosclerosis

BACKGROUND: Heart disease is a major cause of illness and death in women. To understand better the role of estrogen in the treatment and prevention of heart disease, more information is needed about its effects on coronary atherosclerosis and the extent to which concomitant progestin therapy may modify these effects. METHODS: We randomly assigned a total of 309 women with angiographically verified coronary disease to receive 0.625 mg of conjugated estrogen per day, 0.625 mg of conjugated estrogen plus 2.5 mg of medroxyprogesterone acetate per day, or placebo. The women were followed for a mean (+/-SD) of 3.2+/-0.6 years. Base-line and follow-up coronary angiograms were analyzed by quantitative coronary angiography. RESULTS: Estrogen and estrogen plus medroxyprogesterone acetate produced significant reductions in low-density lipoprotein cholesterol levels (9.4 percent and 16.5 percent, respectively) and significant increases in high-density lipoprotein cholesterol levels (18.8 percent and 14.2 percent, respectively); however, neither treatment altered the progression of coronary atherosclerosis. After adjustment for measurements at base line, the mean (+/-SE) minimal coronary-artery diameters at follow-up were 1.87+/-0.02 mm, 1.84+/-0.02 mm, and 1.87+/-0.02 mm in women assigned to estrogen, estrogen plus medroxyprogesterone acetate, and placebo, respectively. The differences between the values for the two active-treatment groups and the value for the placebo group were not significant. Analyses of several secondary angiographic outcomes and subgroups of women produced similar results. The rates of clinical cardiovascular events were also similar among the treatment groups. CONCLUSIONS: Neither estrogen alone nor estrogen plus medroxyprogesterone acetate affected the progression of coronary atherosclerosis in women with established disease. These results suggest that such women should not use estrogen replacement with an expectation of cardiovascular benefit.     

Expression of superoxide dismutase and xanthine oxidase in myometrium, fetal membranes and placenta during normal human pregnancy and parturition

Superoxide, an agent which attenuates the half-life of nitric oxide, is metabolized and synthesized by superoxide dismutase (SOD) and xanthine oxidase, respectively. Over the last few years much work has focused on the role of nitric oxide in human parturition. The aim of this study was to determine whether the onset of human parturition is associated with a change in the expression of copper/zinc superoxide dismutase (Cu/Zn SOD), manganese superoxide dismutase (Mn SOD) or xanthine oxidase within the uterus. Samples of myometrium, placenta, decidua and fetal membranes were obtained from women before and after the onset of labour at term. Immunocytochemistry was used to localize Cu/Zn SOD, Mn SOD and xanthine oxidase and measure SOD enzyme activity. Cu/Zn and Mn SOD-like immunoreactivity was detected in syncytiotrophoblast cells, villous stromal cells and endothelial cells of blood vessels in the placenta. In the myometrium Cu/Zn and Mn SOD were localized to myocytes and endothelial cells and to some vascular smooth muscle cells. In the fetal membranes we observed staining for Cu/Zn SOD and Mn SOD in the amnion, chorion, extravillous trophoblast and decidua. There was no difference in SOD enzyme activity or staining intensity for SOD between different cell types before and during labour. Xanthine oxidase immunoreactivity was identified in each of the tissues examined and again there was no difference in immunostaining in tissues obtained from women delivered before or after the onset of labour. These results show that the pregnant uterus is capable of both synthesizing and degrading superoxide and suggest that superoxide dismutase and xanthine oxidase may play a role in the maintenance of uterine quiescence during pregnancy, but not in the initiation of parturition.      

Usefulness of an enzyme-linked immunosorbent assay for detection of Giardia antigen in feces.

The usefulness of a recently developed enzyme-linked immunosorbent assay which detects Giardia lamblia antigen in feces was determined in experimentally infected humans. Giardia antigen was determined in serially collected fecal specimens from humans inoculated with two Giardia isolates, GS/M and Isr. A total of 277 stools from 18 volunteers were tested, 74 from Isr-inoculated volunteers and 203 from GS/M-inoculated volunteers. None of the five Isr-inoculated volunteers became infected, and none of their stools contained Giardia antigen. In contrast, all of the 13 GS/M-inoculated volunteers became infected, and Giardia antigen was present one or more times in the stools of each. Of 203 stools from GS/M-inoculated volunteers, 73 contained Giardia cysts, and 69 of these (94.5%) had detectable antigen. In contrast, 108 of the 203 specimens were positive for Giardia antigen and only 73 had cysts. Most antigen-positive but cyst-negative specimens occurred during treatment, but during patency 71 stools contained antigen and 65 had cysts. The enzyme-linked immunosorbent assay is infections and is easier to perform.     

Interphase cytogenetics using biotin and digoxigenin labelled probes II: Simultaneous differential detection of human and papilloma virus nucleic acids in individual nuclei.

A method was developed for the simultaneous detection of viral and human DNA in contrasting colours in routine formalin fixed, paraffin wax embedded biopsy specimens. This was achieved by non-isotopic in situ hybridisation (NISH) with a biotinylated Y chromosome probe and digoxigenin labelled probe for human papilloma virus type 6 (HPV 6). The tissues studied were peripheral lymphocytes, tonsil, and penile warts. The hybridisation signals produced by biotinylated probes were visualised in red using streptavidin peroxidase and those produced by digoxigenin labelled probes as a blue/black colour using anti-digoxigenin alkaline phosphatase. In lymphocytes and tonsil 95-100% of cells had a detectable Y chromosome; in warts only 60-70% of infected keratinocytes near the skin surface had a demonstrable Y chromosome. This suggests that this chromosome is lost or occluded in cell maturation. In simultaneous double hybridisation with both probes, HPV and Y sequences were demonstrable within the same nucleus in penile warts. This technique permits the simultaneous differential detection of two nuclei acid sequences in interphase nuclei and will have application in analysis of putative dual HPV infections and in determining the intranuclear spatial relations between nucleic acids in interphase nuclei.     

Detection of human papillomavirus in matched cervical smears and biopsy specimens by non-isotopic in situ hybridisation.

AIMS: To determine the relative diagnostic sensitivity of non-isotopic in situ hybridisation (NISH) for the diagnosis of human papillomavirus (HPV) on matched smears and biopsy specimens; to compare the NISH signal type in the two samples; and to correlate the NISH data with the morphological diagnosis. METHODS: HPV samples were assayed individually by NISH with digoxigenin labelled probes (HPV6, 11, 16, 18, and 33) on routinely collected paraffin wax embedded cervical biopsy specimens and for high risk HPVs with a cocktail of similarly labelled probes (HPV16, 18, 33) on matched smears. These were taken at the same colposcopic examination from 32 patients investigated for an abnormal cervical Papanicolaou (PAP) stained smear. RESULTS: An HPV signal was present in 18 (56%) biopsy specimens and in 14 (44%) smears. There was higher concordance of sets of data in the presence of cytopathic wart virus changes. The superiority of biopsy over smear in detecting HPV was mainly the result of examining the entire cervical biopsy specimen rather than cells scraped from the cervical surface. The NISH signal type in both biopsy specimen and smear was similar; it has been shown that NISH type 1 signal correlates with episomal viral replication and type 2 and 3 signals with viral integration. CONCLUSIONS: These data show that NISH on cervical smears is a worthwhile primary screen for HPV infection. The NISH signal types in cervical smears are similar to those previously described in cervical biopsy specimens.     

Volunteer studies of deletion mutants of Vibrio cholerae O1 prepared by recombinant techniques

Vibrio cholerae O1 A-B- vaccine strain JBK 70 and A-B+ CVD 101 prepared by recombinant DNA techniques from pathogenic EI Tor Inaba N16961 and classical Ogawa 395, respectively, were fed to 38 volunteers in single doses of 10(4) to 10(10). Although severe diarrhea did not occur in any vaccine, more than one-half developed mild diarrhea. These attenuated strains colonized well and elicited prominent vibriocidal and antitoxic (CVD 101) antibody responses. Recipients of a single dose of JBK 70 were significantly protected when challenged with 10(6) wild-type N16961. Diarrhea occurred in 7 of 8 controls but in only 1 of 10 vaccines (P less than 0.003, 89% vaccine efficacy), demonstrating the potency of immune mechanisms that do not involve cholera antitoxin. Further derivatives were prepared to explore the pathogenesis of the residual diarrhea, considering that either intestinal colonization by the vaccine itself or accessory toxins might be responsible. CVD 102, an auxotrophic mutant of CVD 101, did not cause diarrhea but colonized poorly and elicited feeble immune responses. Derivatives of JBK 70 and CVD 101 (CVD 104 and 105) deleted of genes encoding the EI Tor hemolysin still caused mild diarrhea. Genetically engineered strains can be colonizing, highly immunogenic, and protective single-dose oral vaccines, but they must be further attenuated before they can be considered for use as public health tools.     

Hydrosalpinges adversely affect markers of endometrial receptivity

While in-vitro fertilization (IVF) was initially developed in women with tubal factor infertility, recent clinical studies have suggested that the presence of hydrosalpinges lowers implantation and pregnancy rates. We postulated that these hydrosalpinges cause impaired endometrial receptivity. A total of 103 women with hydrosalpinges were prospectively evaluated, and compared with 55 infertile and 44 fertile controls. All women had endometrial biopsies during the window of implantation, analysed by conventional histological criteria, and also stained for three integrin markers of endometrial receptivity (alpha1beta1, alpha4beta1 and alpha vbeta3). Women with hydrosalpinges (cases) expressed significantly less of the alpha vbeta3 integrin compared with controls. There was no difference in expression of alpha1beta1 or alpha4beta1 among groups. A significantly greater number of cases had out of phase histology and missing alpha vbeta3 (type I defects) and absent integrin expression despite normal histological maturation (type II) defects, compared with controls. Of 20 women with impaired endometrial receptivity who were also biopsied after hydrosalpinx surgery, 70% demonstrated increased alpha vbeta3 expression. Seventy-seven percent of type I and 57% of type II defects were corrected postoperatively. Using markers of endometrial receptivity, this study demonstrates that inflammatory hydrosalpinges have an adverse effect on endometrial receptivity, which in some cases may be overcome by surgical treatment of the hydrosalpinx.      

<Emphasis Type="Italic">TCF7L2</Emphasis>variant genotypes and type 2 diabetes risk in Brazil: significant association,but not a significant tool for risk stratification in the general population

Background  

Genetic polymorphisms of the TCF7L2 gene are strongly associated with large increments in type 2 diabetes risk in different populations worldwide. In this study, we aimed to confirm the effect of the TCF7L2 polymorphism rs7903146 on diabetes risk in a Brazilian population and to assess the use of this genetic marker in improving diabetes risk prediction in the general population.     

Reliability of the acetabular teardrop as a landmark

Summary This study investigated the effect of tilt and observer reliability on radiographic measurements of the position of a prosthetic acetabular cup in seven dry bone pelves using the teardrop as a landmark. Coronal or sagittal tilt of more than five degrees was easily recognisable and there was effectively no observer variation in the measurements up to this limit. In addition, 90 out of 100 randomly selected antero-posterior pelvic radiographs from an outpatient department were not significantly rotated and 93 demonstrated a clearly defined teardrop. Measurements about the teardrop on routine radiographs are therefore sufficiently accurate to allow assessment of prosthetic position.

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La valeur du sourcil cotyloidien comme repère d'analyse radiologique

Résumé Cette étude, conduite sur 7 bassins secs, apprécie l'effet de l'inclinaison du bassin sur la qualité de l'analyse radiographique de la position d'une cupule prothétique de hanche en utilisant le sourcil cotyloïdien comme repère. Une inclinaison du bassin dans les plans coronal et sagittal est aisément détectable et il n'existe pas de variation d'analyse entre les différents observateurs en dessous de 5° d'inclinaison. De plus, sur 100 radiographies antéro-postérieures de bassin choisies au hasard dans les dossiers de consultation, 90 avaient été réalisées sans incidence particulièrement adaptée et l'on pouvait repérer facilement le sourcil sur 93% d'entre elles. Les mesures faites sur des radios de routine sont donc suffisamment précises pour permettre l'évaluation de la position d'une prothèse à partir du sourcil cotyloïdien.

     

Heritability and Expression of C-Reactive Protein in Type 2 Diabetes in the Diabetes Heart Study

Elevated C-reactive protein (CRP) levels are associated with both prevalent and incident cardiovascular disease. In this study, familial aggregation was estimated, and we tested for association between serum CRP levels and polymorphisms within the CRP and APOE genes in sib-ships with type 2 diabetes mellitus, a population at increased risk for cardiovascular disease. CRP levels were determined in 461 diabetes-affected subjects from 224 sibships from the Diabetes Heart Study (DHS). Heritability estimates of CRP levels were obtained using variance component models. Genetic influence on serum CRP levels by single nucleotide polymorphisms (SNPs) in the CRP and APOE genes was evaluated by association analysis using mixed models. Subjects were Caucasian American (84%) and African-American (16%), 53% female, and had an average age of 62.2 ± 9.2 years. The median CRP level was 3.3 mg/L (range 0 to 59.3 mg/L), and estimated heritability for CRP was approximately 40%. Estimates of heritability were significantly greater than zero (P < 0.0001) and relatively constant, despite adjustments for important modifiers (age, sex, ethnicity, diabetes duration, statin-use and anti-inflammatory use) of CRP. There was no significant evidence for association of CRP levels with CRP gene SNPs; however, consistent with previous reports, there was significant evidence of association of CRP levels with polymorphisms within the APOE gene. These data indicate CRP levels are significantly influenced by genetic (and/or environmental) factors that are shared within DHS families. While the APOE locus shows evidence of contributing to CRP levels, no evidence of CRP gene polymorphism association with CRP levels was observed.