AGT M235T genotype/anxiety interaction and gender in the HyperGEN study.

BACKGROUND: Both anxiety and elevated heart rate (HR) have been implicated in the development of hypertension. The HyperGen cohort, consisting of siblings with severe and mild hypertension, an age-matched random sample of persons from the same base populations, and unmedicated adult offspring of the hypertensive siblings (N = 1,002 men and 987 women), was analyzed for an association of the angiotenisinogen AGTM235T genotype (TT, MT, MM) with an endophenotype, heart rate (HR) in high and low anxious groups. METHODOLOGY: The interaction of AGTM genotype with anxiety, which has been independently associated with hypertension, was investigated adjusting for age, hypertension status, smoking, alcohol consumption, beta blocker medication, body mass index, physical activity and hours of television viewing (sedentary life style). PRINCIPAL FINDINGS: Although there was no main effect of genotype on HR in men or women, high anxious men with the TT genotype had high HR, whereas high anxious men with the MM genotype had low HR. In women, HR was inversely associated with anxiety but there was no interaction with genotype. CONCLUSION/SIGNIFICANCE: The results suggest that high anxiety in men with the TT genotype may increase risk for hypertension whereas the MM genotype may be protective in high anxious men. This type of gene x environment interaction may be one reason why genome wide association studies sometimes fail to replicate. The locus may be important only in combination with certain environmental factors.

Cross-sectional correlates of fasting hyperinsulinaemia in post-menopausal women of different ethnic origin.

AIMS: In a large ethnically diverse nationwide sample of post-menopausal women we explored the relationship between fasting insulin levels, ethnicity, and a wide range of anthropometric, socio-economic, and lifestyle factors. METHODS: Subjects were post-menopausal women aged 50-79 years without diagnosed diabetes mellitus comprising a subsample (n = 3500) of the Women's Health Initiative (WHI) Clinical Trial and Observational Study. In a cross-sectional survey at baseline, we analysed the association between ethnicity and fasting insulin using analysis of covariance procedures and identified independent correlates of hyperinsulinaemia, defined by the 75th percentile cut point for each ethnic group. RESULTS: Fasting insulin levels were higher among African-American and Hispanic women than among non-Hispanic White or Asian women. These differences persisted after adjustment for age, educational attainment, total and central body obesity, adult weight change, family history of diabetes, smoking status, alcohol consumption, use of menopausal hormone therapy and physical activity. Higher levels of body mass index, waist-hip ratio, adult weight gain, and lower levels of total and moderate or strenuous recreational activity were independent correlates of fasting hyperinsulinaemia. Habitual walking was also inversely associated with fasting insulin. CONCLUSIONS: In this cross-sectional analysis, fasting insulin levels were higher among African-American and Hispanic post-menopausal women as compared with non-Hispanic White and Asian women. In addition, obesity, adult weight gain, and low levels of moderate or strenuous physical activity were independently associated with hyperinsulinaemia.

Cardiovascular reactivity to mental stress in the Stockholm Female Coronary Risk Study.

OBJECTIVE: This study evaluated the ability of mental stress testing to discriminate between women with and without CHD, and among women with different disease manifestations, taking into account history of hypertension and beta-blocker use. METHODS: Analyses were based on data from a community-based case-control study of women aged 65 years or younger. The study group consisted of 292 women who were hospitalized for an acute event of CHD, either AMI or unstable AP in Stockholm between 1991 and 1994. Controls were matched to cases by age and catchment area. Cardiovascular reactivity and emotional response to an anagram task solved under time pressure were measured 3 to 6 months after hospitalization. RESULTS: Patients reacted with smaller increases in heart rate (4 bpm) than their controls (7 bpm). Results for the rate-pressure product were similar. Cardiovascular reactions did not distinguish patients with AP from those with AMI. History of hypertension (present in 50% of patients and 11% of controls) was related to enhanced diastolic blood pressure reactivity. Patients on beta-blockers (66%) had lower heart-rate levels throughout testing, but did not differ in their cardiovascular stress reactions when compared with the remaining participants. CONCLUSIONS: Women with heart disease have somewhat lower heart-rate responses to stress than healthy age-matched controls. History of hypertension is related to enhanced diastolic blood pressure reactivity to mental stress in both patients and controls.

Amiodarone and radiation therapy sequelae.

With the aging of our population, amiodarone, a cardiac antiarrhythmic, is being used with increasing frequency. Anecdotal reports have appeared describing unexpected mucosal as well as cutaneous toxicity in patients treated concurrently with external beam radiotherapy and oral amiodarone. We retrospectively reviewed 12 years of experience at the University of Iowa Hospitals and Clinics and found 10 cases wherein amiodarone was taken concurrently with external beam radiation therapy. In our series, there were no missed treatment fractions because of unexpected acute sequelae. We conclude that amiodarone use does not preclude the delivery of therapeutic radiotherapy.

The Aspergillus nidulans homoaconitase gene lysF is negatively regulated by the multimeric CCAAT-binding complex AnCF and positively regulated by GATA sites.

In beta-lactam-antibiotic-producing fungi, such as Aspergillus (Emericella) nidulans, L-alpha-aminoadipic acid is the branching point of the lysine and penicillin biosynthesis pathways. To obtain a deeper insight into the regulation of lysine biosynthesis genes, the regulation of the A. nidulans lysF gene, which encodes homoaconitase, was studied. Band-shift assays indicated that the A. nidulans multimeric CCAAT-binding complex AnCF binds to two of four CCAAT motifs present in the lysF promoter region. AnCF consists at least of three different subunits, designated HapB, HapC, and HapE. In both a delta hapB and a delta hapC strain, the expression of a translational lysF-lacZ gene fusion integrated in single copy at the chromosomal argB gene locus was two to three-fold higher than in a wild-type strain. These data show that AnCF negatively regulates lysF expression. The results of Northern blot analysis and lysF-lacZ expression analysis did not indicate a lysine-dependent repression of lysF expression. Furthermore, mutational analysis of the lysF promoter region revealed that two GATA sites matching the GATA consensus sequence HGATAR positively affected lysF-lacZ expression. Results of Northern blot analysis also excluded that the global nitrogen regulator AreA is the responsible trans-acting GATA-binding factor.

Hostility, social support, and carotid artery atherosclerosis in the National Heart, Lung, and Blood Institute Family Heart Study.

This cross-sectional study investigates the association of hostility and social support (measured by standardized instruments) to carotid artery atherosclerosis in men and women with a high familial risk for coronary heart disease (CHD) and those with low to medium risk. The hypothesis was that high hostility and low social support would have a stronger association in subjects with a familial predisposition to CHD. There were 535 low- to medium-risk women, 491 low- to medium-risk men, 1,950 high-risk women, and 1,667 high-risk men in the study. The extent of carotid artery atherosclerosis was assessed by B-mode ultrasound imaging. A lesion was defined as an intimal-medial far wall thickness of 1 mm in the common, internal, or carotid bifurcation, or identification of plaque at any site. Odds ratios and their 95% confidence intervals were calculated using generalized estimating equations (GEE) for logistic regression. Family was specified as the clustering variable, and robust SEEs were obtained that account for dependence of the data within families. After controlling for age, education, body mass index, ever having smoked, ever drinking > 5 drinks a day, and metabolic index, hostility was significantly associated with increased odds of carotid lesions in only high-risk women. High-risk women showed a significantly reduced odds of carotid lesions with high social support, but the extent of this protection was reduced when age and education were included in the equation. A combination of high hostility and low social support was associated with higher odds than hostility alone in both high-risk men and women. These results suggest that women with a high familial predisposition for CHD may be more vulnerable to cardiovascular influences from hostility and social support than high-risk men or men and women with low to medium risk.

Why do men get more heart disease than women? An international perspective.

Biological, behavioral, and psychosocial contributions to the gender gap in coronary heart disease (CHD) are discussed. Although CHD is the Number 1 cause of death for both sexes in the industrialized world, CHD mortality rates between these countries are larger than those between men and women, suggesting that biological factors are not the sole influences on the gender gap in CHD. Traditional coronary risk factors cannot explain the rapid increase in CHD mortality among middle-aged men in many of the newly independent states of eastern Europe. However, eastern European men score higher on stress-related psychosocial coronary risk factors (e.g., social isolation, vital exhaustion) than men living in the West. Comparisons between the sexes also reveal gender differences in psychosocial and behavioral coronary risk factors, including excessive alcohol consumption and smoking, favoring women. Overall, it appears that men's coping with stressful events may be less adaptive physiologically, behaviorally, and emotionally, contributing to their increased risk for CHD.

Familial resemblance for hostility: the National Heart, Lung, and Blood Institute Family Heart Study.

OBJECTIVE: The purpose of this study was to examine whether several aspects of hostility as measured by the Cook-Medley Hostility Scale (ie, aggressive responding, hostile affect, cynicism, and overall hostility score) were determined in part by family factors (ie, genes and/or familial environments). METHODS: Analyses were based on 680 European-American families (2525 individuals) from the NHLBI Family Heart Study (FHS), a population-based study of genetic and nongenetic determinants of CHD, atherosclerosis, and cardiovascular risk factors. The influence of family relationships, age, and education on the variation in each of the four hostility scores were estimated. RESULTS: Significant familial resemblance in all hostility scores was found, accounting for 42% of the variance in total hostility, 30% in cynicism, 38% in aggressive responding, and 18% in hostile affect. Very little of this resemblance could be explained by similarities in education. Familial resemblance for cynicism was solely due to significant parent-offspring and sibling correlations (ie, no spouse resemblance), suggesting the possibility of genetic influences. Gender and generation differences were also evident in the familial correlations. CONCLUSIONS: Hostility aggregates in families. Both family environmental and genetic sources of resemblance are suggested for hostility.

Late effects in children treated with radiation therapy for Wilms' tumor.

PURPOSE: To determine the frequency and types of late effects in children receiving radiation therapy (RT) for Wilms' tumor. MATERIALS AND METHODS: From 1968 to 1994, 55 children received megavoltage RT at our institution as part of treatment for Wilms' tumor. A total of 42 (76.4%) have survived and have a minimum follow-up of 5 years. There were 25 female and 17 male patients with a median age at diagnosis of 48 months (range, 7-126 months). There were 12 Stage I, eight Stage II, 15 Stage III, six Stage IV, and one Stage V patient. RT was delivered to the hemiabdomen in 36 and whole abdomen in six patients. RT dose was 1000-1200 cGy (Group A) in 12, 1201-2399 cGy (Group B) in 11, and 2400-4000 cGy (Group C) in 19. Whole-lung RT was delivered to 13 patients either at diagnosis or pulmonary relapse. All patients received chemotherapy; the most common agents were actinomycin-D/vincristine/adriamycin in 13 and actinomycin-D/vincristine in 18. Median follow-up was 181 months (range, 60-306 months). RESULTS: Of 42 patients, 13 (31.0%) did not have late effects of treatment. The number of patients who developed muscular hypoplasia, limb length inequality, kyphosis, and iliac wing hypoplasia were seven (16.7%), five (11.9%), three (7.1%), and three (7.1%), respectively. Scoliosis was seen in 18 (42.9%) with only one patient requiring orthopedic intervention. Median time to development of scoliosis was 102 months, with a range of 16-146 months. The actuarial incidence of scoliosis at 5, 10, and 15 years after RT was 4.8 +/- 3.3%, 51.8 +/- 9.0%, and 56.7 +/- 9.3%, respectively. Only one of 12 Group A patients developed scoliosis. The 10- and 15-year actuarial incidences of scoliosis for Group A and B patients were 37.7 +/- 12.4% and 37.7 +/- 12.4%, whereas for Group C patients the incidences were 65.8 +/- 12.0% and 74.4 +/- 11. 7% (p = 0.03, log rank test). The actuarial incidence of bowel obstruction at 5, 10, and 15 years was 9.5 +/- 4.5%, 13.0 +/- 5.6%, and 17.0 +/- 6.5%. Of 23 patients, five irradiated within 10 days of surgery and one of 19 irradiated after 10 days developed bowel obstruction (p = 0.09, log rank test). Three patients developed hypertension with normal blood urea nitrogen (BUN) and creatinine levels; another patient had chronic renal insufficiency in a nonirradiated kidney. One patient developed diffuse interstitial pneumonitis. Of the 19 female patients who have reached puberty, three have given birth, and 15 have regular and one has irregular menstrual periods. Four patients developed benign neoplasms; three were in the RT field (two osteochondroma, one lipoma) and one outside (cervical intraepithelial neoplasia II). There were three second malignancies (chronic myelogenous leukemia at 9 years, osteosarcoma at 11 years, and breast cancer at 25 years after initial diagnosis of nephroblastoma); both solid malignancies occurred in the RT field. CONCLUSIONS: Late effects of therapy were seen in more than two thirds of children treated for Wilms' tumor. Children treated with lower doses (<2400 cGy) had a lower incidence of scoliosis compared with those who received more than 2400 cGy. There is also a suggestion that the incidence is lower in patients who received 1000-1200 cGy. Severe physical and functional deformity from RT was uncommon.

Radiation field simulation of gynecologic malignancies: localization of the cervix and vagina with a flexible vaginal localizer contrast tampon.

The authors evaluated a flexible vaginal localizer contrast tampon for radiation therapy simulation. In 51 patients, the degree of cervical or vaginal cuff displacement secondary to the contrast tampon was evaluated by comparing simulation radiographs (with tampon) and initial portal radiographs (without tampon). The same comparisons were made on the radiographs obtained in 25 control subjects who underwent simulation without a tampon. Mean displacement in the group who underwent simulation with a tampon was minimal (< or = 5 mm in each direction) and similar to that in the control group. This technique provides reliable cervical and vaginal cuff localization.

Hostility, social support, and coronary heart disease in the National Heart, Lung, and Blood Institute Family Heart Study.

This cross-sectional study investigated the association of hostility and social support to coronary heart disease (CHD) in 2 groups of men and women: those with a familial predisposition for CHD (high-risk sample) and a randomly selected group. The hypothesis was that hostility and low social support would be associated with CHD, and would have a greater effect in the high-risk group. The random sample contained 2,447 individuals (47.1% male) from 576 families, and the high-risk sample consisted of 2,300 people (45.5% male) from 542 families. Odds ratios (OR) and their 95% confidence intervals were calculated using generalized estimating equations (GEE) for logistic regression. Family was specified as the clustering variable, and robust SEEs were obtained to account for dependence of the data within families. After controlling for age, education, body mass index, exercise, smoking history, drinking history, and drinking >5 drinks a day, hostility was associated with a history of coronary bypass surgery or coronary angioplasty in high-risk men (OR 1.21) and a history of myocardial infarction in high-risk women (OR 1.39). High-risk women with high social support had reduced odds of a previous myocardial infarction (OR 0.76), whereas women with high network adequacy in the random sample had reduced risk of myocardial infarction (OR 0.41) and angina (OR 0.49). A ratio of high hostility to low social support was associated with past myocardial infarction in high-risk women (OR 2.47) and a history of angina (OR 2.02) in the random sample men. These results suggest that high hostility and low social support are associated with some manifestations of CHD after controlling for adverse health behaviors.

The use of laminarias for osmotic dilation of the cervix in gynecological brachytherapy applications.

PURPOSE: Osmotic dilators (laminarias) have been used for gradual nontraumatic dilation of the cervical canal for various intrauterine procedures; however, this technique has not been well accepted in gynecological brachytherapy. The purpose of this study was to evaluate the efficacy of osmotic cervical dilation for brachytherapy in gynecologic cancer patients, without the use of general/regional anesthesia, and to assess patient tolerance, complications, and outcome. METHODS AND MATERIALS: Thirteen brachytherapy procedures were performed in 6 patients with clinical Stages I and II endometrial (5) and Stage IB cervical cancer (1), who were unable to tolerate general/regional anesthesia because of severe medical problems. An osmotic dilator (synthetic laminaria) was inserted into the cervical os 10-12 h before each brachytherapy procedure and removed just before the procedure. Standard Fletcher-Suit-Delclos tandem insertions with vaginal colpostats or cylinders were then performed. Degree of cervical dilation, patient discomfort, procedure time, intra- and postoperative complications were recorded, and local control and survival were assessed. Median follow-up was 31 months (range: 8-35 months). RESULTS: The diameter of the dilated cervical os after laminaria removal was adequate (> or = 5 mm) for tandem insertion, and no additional mechanical dilation was required in all but one procedure (1 of 13). All procedures were performed without general/regional anesthesia. The mean duration of the procedures was 44 min (range, 20-60 min). Discomfort was minimal in all cases. There were no intra- or postoperative complications. All patients maintained local control until death (1 of metastatic disease, 2 of intercurrent disease) or last follow-up (2 with no evidence of disease, 1 alive with metastatic disease). CONCLUSION: This preliminary study suggests that osmotic cervical dilation with a synthetic laminaria is a useful technique to facilitate intrauterine tandem insertion in patients who cannot tolerate general/regional anesthesia. This technique may reduce treatment-associated morbidity, shorten procedure time, and allow the delivery of adequate radiation therapy in this uncommon but challenging patient population.

Development of a homologous transformation system for the human pathogenic fungus Aspergillus fumigatus based on the pyrG gene encoding orotidine 5'-monophosphate decarboxylase.

A homologous transformation system for the opportunistic fungal pathogen Aspergillus fumigatus was developed. It is based on the A. fumigatus pyrG gene, encoding orotidine 5'-monophosphate decarboxylase, which was cloned and sequenced. Transformation of both Aspergillus (Emericella) nidulans and A. fumigatus pyrG mutant strains by the use of protoplasts or electroporation established the functionality of the cloned gene. DNA sequencing of the A. fumigatus pyrG1 mutant allele revealed that it encodes a truncated, non-functional, PyrG protein. Transformation of an A. fumigatus pyrG1 mutant with a plasmid carrying the novel pyrG2 allele constructed by in vitro mutagenesis yielded prototrophic transformants following recombination between both mutation sites. Analysis of transformants carrying the entire plasmid showed that up to 45% of integration had occurred at the pyrG locus. This provides a tool to target defined genetic constructs at a specific locus in the A. fumigatus genome in order to study gene regulation and function.

The Aspergillus nidulans lysF gene encodes homoaconitase, an enzyme involved in the fungus-specific lysine biosynthesis pathway.

In filamentous fungi, lysine is synthesized via the alpha-aminoadipate pathway. In order to gain insight into this fungus-specific pathway (to date, no genes for enzymes of this pathway in filamentous fungi have been cloned) the lysine auxotrophic mutant LysF88 of Aspergillus nidulans was studied. HPLC and 1H-NMR analyses revealed that LysF88 accumulated homocitric acid in the culture supernatant. In addition, both the LysF88 mutant strain and LysF deletion strain (LysFKO) described here showed hardly any homoaconitase activity, indicating that lysF encodes homoaconitase. The lysF gene was cloned by complementation of the LysF88 mutant and sequenced. It has a size of 2397 bp, including a single intron of 72 bp. The two exons encode an open reading frame (ORF) of 2325 bp. The calculated M(r) of the homoaconitase protein (775 amino acids) is 83,943. A major and a minor transcript begin at positions -28 and -32, respectively. The 3' end of the lysF cDNA showed a poly(A) tail commencing at position +2647 following a 250 bp untranslated region after the lysF stop codon. A putative polyadenylation signal sequence (TATAAA) is located 49 bp upstream of the polyadenylation site. Computer analysis revealed 55% amino acid sequence identity between the products of the putative homoaconitase ORF of A. nidulans and that of the recently sequenced homologous Saccharomyces cerevisiae. The similarity was particularly obvious in a region of cysteine residues, which are characteristic of an iron-sulfur cluster, implying that homoaconitase contains such a cluster. The homoaconitases of A. nidulans and S. cerevisiae share only 20% sequence identity with S. cerevisiae aconitase. The pH optimum for the activity of A. nidulans homoaconitase in 0.1 M potassium phosphate buffer is between pH 8.1 and pH 8.6. Homoaconitase exhibited an apparent K(m) of 1.1 mM toward homoisocitric acid. The specific activity of homoaconitase was reduced by up to six-fold in mycelia grown in the presence of L-lysine, suggesting that it is regulated by lysine.

Relationship of job strain to standard coronary risk factors and psychological characteristics in women and men of the Family Heart Study.

This study reports on standard coronary risk factors (plasma lipids and lipoproteins, blood pressure, heart rate, age, body mass index) and psychosocial variables (job strain, Type A behavior, hostility, illnesses, medical and psychological symptoms, health-damaging behavior) in a community sample of 324 employed men, 203 employed women, and 155 female homemakers. Employed women reported less hostility and fewer illnesses than homemakers and had lower cholesterol levels than homemakers and men. Job characteristics were unrelated to standard coronary risk factor levels in both sexes, but predicted medical symptoms and health-damaging behavior in men. These findings suggest that employment is associated with enhanced medical and physical well-being among women and point to possible behavioral and psychological pathways by which job strain may adversely influence men's health.

Molecular characterization of the genes encoding pyruvate formate-lyase and its activating enzyme of Clostridium pasteurianum.

Formate is the major source of C1 units in many species of the genus Clostridium. In this study we have cloned and characterized the genes encoding pyruvate formate-lyase and its activating enzyme of Clostridium pasteurianum. The genetic and transcriptional organizations of the genes and the high level of homology exhibited by the respective gene products to their Escherichia coli counterparts indicate strong evolutionary conservation of these enzymes.