Beyond the bladder: poor sleep in women with overactive bladder syndrome.

BACKGROUND: Nocturnal bladder symptoms and sleep disruption commonly coexist in middle-aged and older women. Although sleep disruption is often attributed to nocturnal bladder symptoms in women with overactive bladder syndrome, nonbladder factors also may influence sleep in this population. Many women with overactive bladder are eager to identify nonpharmacologic strategies for both bladder symptoms and sleep disruption, given the potential adverse effects of sedative and anticholinergic bladder medications in this population. OBJECTIVES: To provide greater insight into the complex relationship between nighttime overactive bladder symptoms and sleep disruption, and to evaluate the effects of a guided slow-paced respiration intervention on sleep outcomes in women with overactive bladder. STUDY DESIGN: We conducted an ancillary study within a randomized trial of slow-paced respiration in women with overactive bladder symptoms. Ambulatory community-dwelling women who reported ≥3 episodes/day of urgency-associated voiding or incontinence were randomized to use either a portable biofeedback device (RESPeRATE; Intercure, Ltd) to practice guided slow-paced respiration exercises daily for 12 weeks (N=79) or an identical-appearing device programmed to play nonrhythmic music without guiding breathing (N=82). At baseline and after 12 weeks, bladder symptoms were assessed by voiding diary, sleep duration, and disruption were assessed by sleep diary corroborated by wrist actigraphy, and poor sleep quality was determined by a Pittsburgh Sleep Quality Index global score >5. RESULTS: Of the 161 women randomized, 31% reported at least twice-nightly nocturia, 26% nocturnal incontinence, and 70% poor sleep quality at baseline. Of the 123 reporting any nighttime awakenings, 89% averaged 1 or more nighttime awakenings, and 83% attributed at least half of awakenings to using the bathroom. Self-reported wake time after sleep onset increased with increasing frequency of nocturnal bladder symptoms (P=.01 for linear trend). However, even among women without nocturia, average sleep quality was poor (Pittsburg Sleep Quality Index global score mean of 7.3; 95% confidence interval, 6.0-8.6). Over 12 weeks, women assigned to slow-paced respiration (N=79) experienced modest improvements in mean nocturnal voiding frequency (0.4 fewer voids/night), sleep quality (1.1 point score decrease), and sleep disruption (1.5% decreased wake time after sleep onset). However, similar improvements were detected in the music control group (N=81), without significant between-group differences. CONCLUSIONS: Many women with overactive bladder syndrome experience disrupted sleep, but not all nocturnal awakenings are attributable to bladder symptoms, and average sleep quality tends to be poor even in women without nocturia. Findings suggest that clinicians should not assume that poor sleep in women with overactive bladder syndrome is primarily caused by nocturnal bladder symptoms. Guided slow-paced respiration was associated with modest improvements in nocturia frequency and sleep quality in this trial, but the results do not support clinician recommendation to use this technique over other behavioral relaxation techniques for improving sleep.

A Randomized Controlled Trial of Device Guided, Slow-Paced Respiration in Women with Overactive Bladder Syndrome.

PURPOSE: We evaluated the effects of device guided, slow-paced respiration on urgency associated urinary symptoms, perceived stress and anxiety, and autonomic function in women with overactive bladder syndrome. MATERIALS AND METHODS: We performed a randomized, parallel group trial of slow-paced respiration to improve perceived stress and autonomic dysfunction as potential contributors to overactive bladder. Ambulatory women who reported at least 3 voiding or incontinence episodes per day associated with moderate to severe urgency were randomized to use a portable biofeedback device to practice daily, slow, guided breathing exercises or a control device which appeared identical and was reprogrammed to play music without guiding breathing. During 12 weeks we evaluated changes in urinary symptoms by voiding diaries, perceived stress and anxiety by validated questionnaires, and autonomic function by heart rate variability and impedance cardiography. RESULTS: In the 161 randomized participants, including 79 randomized to paced respiration and 82 randomized to the control group, the average ± SD baseline frequency of voiding or incontinence associated with moderate to severe urgency was 6.9 ± 3.4 episodes per day. Compared to controls the participants randomized to paced respiration demonstrated greater improvement in perceived stress (average Perceived Stress Scale score decrease 2.8 vs 1.1, p=0.03) but not in autonomic function markers. During 12 weeks the average frequency of voiding or incontinence associated with moderate to severe urgency, which was the study primary outcome, decreased by a mean of 0.9 ± 3.2 episodes per day but no significant between group difference was detected. CONCLUSIONS: Among women with overactive bladder slow-paced respiration was associated with a modest improvement in perceived stress during 12 weeks. However, it was not superior to a music listening control for reducing urinary symptoms or changing autonomic function.

DRD4 genotype predicts longevity in mouse and human.

Longevity is influenced by genetic and environmental factors. The brain's dopamine system may be particularly relevant, since it modulates traits (e.g., sensitivity to reward, incentive motivation, sustained effort) that impact behavioral responses to the environment. In particular, the dopamine D4 receptor (DRD4) has been shown to moderate the impact of environments on behavior and health. We tested the hypothesis that the DRD4 gene influences longevity and that its impact is mediated through environmental effects. Surviving participants of a 30-year-old population-based health survey (N = 310; age range, 90-109 years; the 90+ Study) were genotyped/resequenced at the DRD4 gene and compared with a European ancestry-matched younger population (N = 2902; age range, 7-45 years). We found that the oldest-old population had a 66% increase in individuals carrying the DRD4 7R allele relative to the younger sample (p = 3.5 × 10(-9)), and that this genotype was strongly correlated with increased levels of physical activity. Consistent with these results, DRD4 knock-out mice, when compared with wild-type and heterozygous mice, displayed a 7-9.7% decrease in lifespan, reduced spontaneous locomotor activity, and no lifespan increase when reared in an enriched environment. These results support the hypothesis that DRD4 gene variants contribute to longevity in humans and in mice, and suggest that this effect is mediated by shaping behavioral responses to the environment.

Adaptive statistical iterative reconstruction reduces patient radiation dose in neuroradiology CT studies.

INTRODUCTION: Adaptive statistical iterative reconstruction (ASIR) can decrease image noise, thereby generating CT images of comparable diagnostic quality with less radiation. The purpose of this study is to quantify the effect of systematic use of ASIR versus filtered back projection (FBP) for neuroradiology CT protocols on patients' radiation dose and image quality. METHODS: We evaluated the effect of ASIR on six types of neuroradiologic CT studies: adult and pediatric unenhanced head CT, adult cervical spine CT, adult cervical and intracranial CT angiography, adult soft tissue neck CT with contrast, and adult lumbar spine CT. For each type of CT study, two groups of 100 consecutive studies were retrospectively reviewed: 100 studies performed with FBP and 100 studies performed with ASIR/FBP blending factor of 40 %/60 % with appropriate noise indices. The weighted volume CT dose index (CTDIvol), dose-length product (DLP) and noise were recorded. Each study was also reviewed for image quality by two reviewers. Continuous and categorical variables were compared by t test and free permutation test, respectively. RESULTS: For adult unenhanced brain CT, CT cervical myelography, cervical and intracranial CT angiography and lumbar spine CT both CTDIvol and DLP were lowered by up to 10.9 % (p < 0.001), 17.9 % (p = 0.005), 20.9 % (p < 0.001), and 21.7 % (p = 0.001), respectively, by using ASIR compared with FBP alone. Image quality and noise were similar for both FBP and ASIR. CONCLUSION: We recommend routine use of iterative reconstruction for neuroradiology CT examinations because this approach affords a significant dose reduction while preserving image quality.

Efficacy of Continuous Transdermal Nitroglycerin for Treating Hot Flashes by Inducing Nitrate Cross-tolerance in Perimenopausal and Postmenopausal Women: A Randomized Clinical Trial.

Importance: Due to the potential risks of long-term systemic estrogen therapy, many menopausal women are interested in nonhormonal treatments for vasomotor symptoms. Physiologic studies indicate that nitric oxide plays a key role in mediating hot flash-related vasodilation, suggesting that nonhormonal medications that induce nitrate tolerance in the vasculature may offer therapeutic benefit for vasomotor symptoms. Objective: To determine whether uninterrupted administration of transdermal nitroglycerin (NTG) to induce nitrate cross-tolerance decreased the frequency or severity of menopause-related hot flashes. Design, Setting, and Participants: This randomized, double-blinded, placebo-controlled clinical trial included perimenopausal or postmenopausal women reporting 7 or more hot flashes per day who were recruited from northern California by study personnel at a single academic center. Patients were randomized between July 2017 and December 2021, and the trial ended in April 2022 when the last randomized participant completed follow-up. Interventions: Uninterrupted daily use of transdermal NTG (participant-directed dose titration from 0.2-0.6 mg/h) or identical placebo patches. Main Outcome Measures: Validated symptom diaries assessing changes in any hot flash frequency (primary outcome) and moderate-to-severe hot flash frequency over 5 and 12 weeks. Results: Among the 141 randomized participants (70 NTG [49.6%], 71 placebo [50.4%]; 12 [85.8%] Asian, 16 [11.3%] Black or African American, 15 [10.6%] Hispanic or Latina, 3 [2.1%] multiracial, 1 [0.7%] Native Hawaiian or Pacific Islander, and 100 [70.9%] White or Caucasian individuals), a mean (SD) of 10.8 (3.5) hot flashes and 8.4 (3.6) moderate-to-severe hot flashes daily was reported at baseline. Sixty-five participants assigned to NTG (92.9%) and 69 assigned to placebo (97.2%) completed 12-week follow-up (P = .27). Over 5 weeks, the estimated change in any hot flash frequency associated with NTG vs placebo was -0.9 (95% CI, -2.1 to 0.3) episodes per day (P = .10), and change in moderate-to-severe hot flash frequency with NTG vs placebo was -1.1 (95% CI, -2.2 to 0) episodes per day (P = .05). At 12 weeks, treatment with NTG did not significantly decrease the frequency of any hot flashes (-0.1 episodes per day; 95% CI, -1.2 to 0.4) or moderate-to-severe hot flashes (-0.5 episodes per day; 95% CI, -1.6 to 0.7) relative to placebo. In analyses combining 5-week and 12-week data, no significant differences in change in the frequency of any hot flashes (-0.5 episodes per day; 95% CI, -1.6 to 0.6; P = .25) or moderate-to-severe hot flashes (-0.8 episodes per day; 95% CI, -1.9 to 0.2; P = .12) were detected with NTG vs placebo. At 1 week, 47 NTG (67.1%) and 4 placebo participants (5.6%) reported headache (P < .001), but only 1 participant in each group reported headache at 12 weeks. Conclusions and Relevance: This randomized clinical trial found that continuous use of NTG did not result in sustained improvements in hot flash frequency or severity relative to placebo and was associated with more early but not persistent headache. Trial Registration: Clinicaltrials.gov Identifier: NCT02714205.

Weight loss to treat urinary incontinence in overweight and obese women.

BACKGROUND: Obesity is an established and modifiable risk factor for urinary incontinence, but conclusive evidence for a beneficial effect of weight loss on urinary incontinence is lacking. METHODS: We randomly assigned 338 overweight and obese women with at least 10 urinary-incontinence episodes per week to an intensive 6-month weight-loss program that included diet, exercise, and behavior modification (226 patients) or to a structured education program (112 patients). RESULTS: The mean (+/-SD) age of the participants was 53+/-11 years. The body-mass index (BMI) (the weight in kilograms divided by the square of the height in meters) and the weekly number of incontinence episodes as recorded in a 7-day diary of voiding were similar in the intervention group and the control group at baseline (BMI, 36+/-6 and 36+/-5, respectively; incontinence episodes, 24+/-18 and 24+/-16, respectively). The women in the intervention group had a mean weight loss of 8.0% (7.8 kg), as compared with 1.6% (1.5 kg) in the control group (P<0.001). After 6 months, the mean weekly number of incontinence episodes decreased by 47% in the intervention group, as compared with 28% in the control group (P=0.01). As compared with the control group, the intervention group had a greater decrease in the frequency of stress-incontinence episodes (P=0.02), but not of urge-incontinence episodes (P=0.14). A higher proportion of the intervention group than of the control group had a clinically relevant reduction of 70% or more in the frequency of all incontinence episodes (P<0.001), stress-incontinence episodes (P=0.009), and urge-incontinence episodes (P=0.04). CONCLUSIONS: A 6-month behavioral intervention targeting weight loss reduced the frequency of self-reported urinary-incontinence episodes among overweight and obese women as compared with a control group. A decrease in urinary incontinence may be another benefit among the extensive health improvements associated with moderate weight reduction. (ClinicalTrials.gov number, NCT00091988.)

A cardiovascular safety study of LibiGel (testosterone gel) in postmenopausal women with elevated cardiovascular risk and hypoactive sexual desire disorder.

Evaluation of the safety of hormonal preparations for the treatment of female sexual dysfunction is important to assess the benefit-to-risk profile of these drugs and has been strongly encouraged by the Food and Drug Administration. LibiGel (Biosante Pharmaceuticals, Inc., Lincolnshire, IL), a low-dose testosterone gel, is under development for the treatment of hypoactive sexual desire disorder (HSDD) in oophorectomized women. To evaluate the long-term effects of LibiGel on risk for cardiovascular (CV) events, breast cancer, and general safety, a randomized, placebo-controlled clinical study using a novel adaptive design to optimize sample size and power is being conducted. The primary end point of the BioSante LibiGel Safety Study (BLISS) is a composite of CV events including death, nonfatal myocardial infarction, nonfatal stroke, coronary revascularization, hospitalized unstable angina, and venous thromboembolic events. Breast cancer is a coprimary end point. Postmenopausal women (both surgically and naturally) with HSDD and increased risk for CV events will be followed up for up to 5 years postrandomization with an interim data analysis for regulatory approval after the last woman enrolled has been on therapy for at least 12 months. Determination of the number of subjects to enroll is based on an adaptive design that uses interim data to estimate the predictive probability of study success. In agreement with the Food and Drug Administration, LibiGel will be declared safe if the upper limit of the 97.2% CI of the hazard ratio is ≤2.0 or the upper bound of the 97.2% CI for the absolute difference between CV event rates per 100 person-years is ≤1% and the observed hazard ratio is ≤2.0. The BLISS study will define the CV safety profile of low-dose testosterone therapy in the formulation of LibiGel for postmenopausal women with HSDD, and the trial design may provide a paradigm for studies that aim to document long-term safety when the proposed outcome under study is an uncommon adverse event.

Effects of the selective estrogen receptor modulator raloxifene on coronary outcomes in the Raloxifene Use for The Heart trial: results of subgroup analyses by age and other factors.

BACKGROUND: The Raloxifene Use for The Heart (RUTH) trial showed that raloxifene, a selective estrogen receptor modulator, had no overall effect on the incidence of coronary events in women with established coronary heart disease or coronary heart disease risk factors. We provide detailed results of the effect of raloxifene on coronary outcomes over time and for 24 subgroups (17 predefined, 7 post hoc). METHODS AND RESULTS: Postmenopausal women (n=10 101; mean age, 67 years) were randomized to raloxifene 60 mg/d or placebo for a median of 5.6 years. Coronary outcomes were assessed by treatment group in women with coronary heart disease risk factors and those with established coronary heart disease. Raloxifene had no effect on the incidence of coronary events in any subgroup except in the case of a post hoc age subgroup analysis using age categories defined in the Women's Health Initiative randomized trials. The effect of raloxifene on the incidence of coronary events differed significantly by age (interaction P=0.0118). The incidence of coronary events in women <60 years of age was significantly lower in those assigned raloxifene (50 events) compared with placebo (84 events; hazard ratio, 0.59; 95% confidence interval, 0.41 to 0.83; P=0.003; absolute risk reduction, 36 per 1000 women treated for 1 year). No difference was found between treatment groups in the incidence of coronary events in women > or =60 and <70 or > or =70 years of age. CONCLUSIONS: In postmenopausal women at increased risk of coronary events, the overall lack of benefit of raloxifene was similar across the prespecified subgroups.

A phase 1B dose escalation trial of Scutellaria barbata (BZL101) for patients with metastatic breast cancer.

The purpose of this study was to determine the safety and maximum tolerated dose (MTD) of BZL101 (FDA IND# 59,521), an orally delivered aqueous extract from the herb Scutellaria barbata, in women with metastatic breast cancer (MBC). The trial was an open-label, phase 1B, multicenter, dose escalation study. Eligible patients had histologically confirmed breast cancer and measurable stage IV disease. The standard phase 1 "3 + 3" study design was used to determine the MTD. Primary endpoints were toxicity and MTD of BZL101. Secondary outcomes included efficacy based on RECIST criteria. A total of 27 women with a median of 2 prior chemotherapy treatments for metastatic disease were treated in four different dose cohorts. Grade 3 and 4 adverse events (AEs) were uncommon. Dose-limiting toxicities included the following: grade 4 AST elevation, grade 3 diarrhea, grade 3 fatigue, and grade 3 rib pain. Fourteen patients were evaluable according to Response Evaluation Criteria in Solid Tumors. Investigator assessment classified three patients with stable disease for >120 days (21%). One patient was on BZL101 for 449 days and remains stable for 700 + days. Independent radiology review identified three patients with objective tumor regression (>0% and <30%). The MTD was not reached, thus per protocol, the MTD was defined as the maximum administered dose of BZL101 40 g/day. In conclusion, oral administration of BZL101 was safe, well tolerated, and showed promising clinical evidence of anticancer activity in this heavily pretreated population of women with MBC.

Effect of weight loss on urinary incontinence in overweight and obese women: results at 12 and 18 months.

PURPOSE: Initial weight loss improves urinary incontinence in overweight and obese women. In this study we examined the longer term effects of a weight loss intervention on urinary incontinence. MATERIALS AND METHODS: Overweight and obese women (mean +/- SD age 53 +/- 10 years) with 10 or more urinary incontinence episodes weekly were randomized to an 18-month behavioral weight loss intervention (226) or control group (112). Outcome measures were collected at 12 and 18 months. RESULTS: At baseline women had a mean body mass index of 36 +/- 6 kg/m(2) and reported a mean of 24 +/- 18 incontinence episodes weekly. Of the patients 86% completed 18-month measurements. The percent weight loss in the intervention group averaged 8.0%, 7.5% and 5.5% at 6, 12 and 18 months, respectively, vs approximately 1.5% in the control group (all values p <0.001). Compared with controls at 12 months the intervention group reported a greater percent reduction in weekly stress urinary incontinence episodes (65% vs 47%, p <0.001), and a greater proportion achieved at least a 70% decrease in weekly total and stress urinary incontinence episodes. At 18 months a greater proportion of women in the weight loss intervention group had more than 70% improvement in urge incontinence episodes but there were no significant differences between the groups for stress or total urinary incontinence. The intervention group also reported greater satisfaction with changes in urinary incontinence than the control group at 6, 12 and 18 months. CONCLUSIONS: Weight loss intervention reduced the frequency of stress incontinence episodes through 12 months and improved patient satisfaction with changes in incontinence through 18 months. Improving weight loss maintenance may provide longer term benefits for urinary incontinence.

The day-to-day impact of urogenital aging: perspectives from racially/ethnically diverse women.

BACKGROUND: Urogenital symptoms affect up to half of women after menopause, but their impact on women's day-to-day functioning and wellbeing is poorly understood. METHODS: Postmenopausal women aged 45 to 80 years reporting urogenital dryness, soreness, itching, or pain during sex were recruited to participate in in-depth focus groups to discuss the impact of their symptoms. Focus groups were homogenous with respect to race/ethnicity and stratified by age (for White or Black women) or language (for Latina women). Transcripts of sessions were analyzed according to grounded theory. RESULTS: Six focus groups were conducted, involving 44 women (16 White, 14 Black, 14 Latina). Five domains of functioning and wellbeing affected by symptoms were identified: sexual functioning, everyday activities, emotional wellbeing, body image, and interpersonal relations. For some participants, symptoms primarily affected their ability to have and enjoy sex, as well as be responsive to their partners. For others, symptoms interfered with everyday activities, such as exercising, toileting, or sleeping. Participants regarded their symptoms as a sign that they were getting old or their body was deteriorating; women also associated symptoms with a loss of womanhood or sexuality. Additionally, participants reported feeling depressed, embarrassed, and frustrated about their symptoms, and expressed reluctance to discuss them with friends, family, or health care providers. CONCLUSIONS: Urogenital symptoms can have a marked impact on sexual functioning, everyday activities, emotional wellbeing, body image, and interpersonal relations after menopause. Clinicians may need to question women actively about these symptoms, as many are reluctant to seek help for this problem.

The sequence and analysis of duplication-rich human chromosome 16.

Human chromosome 16 features one of the highest levels of segmentally duplicated sequence among the human autosomes. We report here the 78,884,754 base pairs of finished chromosome 16 sequence, representing over 99.9% of its euchromatin. Manual annotation revealed 880 protein-coding genes confirmed by 1,670 aligned transcripts, 19 transfer RNA genes, 341 pseudogenes and three RNA pseudogenes. These genes include metallothionein, cadherin and iroquois gene families, as well as the disease genes for polycystic kidney disease and acute myelomonocytic leukaemia. Several large-scale structural polymorphisms spanning hundreds of kilobase pairs were identified and result in gene content differences among humans. Whereas the segmental duplications of chromosome 16 are enriched in the relatively gene-poor pericentromere of the p arm, some are involved in recent gene duplication and conversion events that are likely to have had an impact on the evolution of primates and human disease susceptibility.

Effect of raloxifene on stroke and venous thromboembolism according to subgroups in postmenopausal women at increased risk of coronary heart disease.

BACKGROUND AND PURPOSE: Raloxifene, a selective estrogen receptor modulator, reduces risk of invasive breast cancer and osteoporosis, but the effect on risk for stroke and venous thromboembolism in different patient subgroups is not established. The purpose of this analysis was to evaluate the effect of raloxifene on the incidence of all strokes, stroke deaths, and venous thromboembolic events according to participant subgroups. METHODS: This was a secondary end point analysis of an international, randomized, placebo-controlled clinical trial of 10 101 postmenopausal women with or at increased risk of coronary heart disease followed a median of 5.6 years. Strokes, venous thromboembolic events, and deaths were adjudicated by expert centralized committees. Strokes were categorized as ischemic, hemorrhagic, or undetermined and venous thromboembolic events were subclassified. RESULTS: The incidences of all strokes did not differ between raloxifene (incidence rate per 100 woman-years=0.95) and placebo (incidence rate=0.86) treatment groups (P=0.30). In women assigned raloxifene versus placebo, there was a higher incidence of fatal strokes (incidence rates=0.22 and 0.15, respectively, P=0.0499) and venous thromboembolic events (incidence rates=0.39 and 0.27, respectively, P=0.02). No significant subgroup interactions were found except that there was a higher incidence of stroke associated with raloxifene use among current smokers. CONCLUSIONS: In postmenopausal women at increased risk for coronary events, the incidences of venous thromboembolism and fatal stroke but not all strokes were higher in those assigned raloxifene versus placebo. Raloxifene's effect did not differ across subgroups, except that the risk of stroke differed by smoking status. Treatment decisions about raloxifene should be based on a balance of projected absolute risks and benefits.

Effects of raloxifene on cardiovascular events and breast cancer in postmenopausal women.

BACKGROUND: The effect of raloxifene, a selective estrogen-receptor modulator, on coronary heart disease (CHD) and breast cancer is not established. METHODS: We randomly assigned 10,101 postmenopausal women (mean age, 67.5 years) with CHD or multiple risk factors for CHD to 60 mg of raloxifene daily or placebo and followed them for a median of 5.6 years. The two primary outcomes were coronary events (i.e., death from coronary causes, myocardial infarction, or hospitalization for an acute coronary syndrome) and invasive breast cancer. RESULTS: As compared with placebo, raloxifene had no significant effect on the risk of primary coronary events (533 vs. 553 events; hazard ratio, 0.95; 95 percent confidence interval, 0.84 to 1.07), and it reduced the risk of invasive breast cancer (40 vs. 70 events; hazard ratio, 0.56; 95 percent confidence interval, 0.38 to 0.83; absolute risk reduction, 1.2 invasive breast cancers per 1000 women treated for one year); the benefit was primarily due to a reduced risk of estrogen-receptor-positive invasive breast cancers. There was no significant difference in the rates of death from any cause or total stroke according to group assignment, but raloxifene was associated with an increased risk of fatal stroke (59 vs. 39 events; hazard ratio, 1.49; 95 percent confidence interval, 1.00 to 2.24; absolute risk increase, 0.7 per 1000 woman-years) and venous thromboembolism (103 vs. 71 events; hazard ratio, 1.44; 95 percent confidence interval, 1.06 to 1.95; absolute risk increase, 1.2 per 1000 woman-years). Raloxifene reduced the risk of clinical vertebral fractures (64 vs. 97 events; hazard ratio, 0.65; 95 percent confidence interval, 0.47 to 0.89; absolute risk reduction, 1.3 per 1000). CONCLUSIONS: Raloxifene did not significantly affect the risk of CHD. The benefits of raloxifene in reducing the risks of invasive breast cancer and vertebral fracture should be weighed against the increased risks of venous thromboembolism and fatal stroke. (ClinicalTrials.gov number, NCT00190593 [ClinicalTrials.gov].).

In vivo binding of active heat shock transcription factor 1 to human chromosome 9 heterochromatin during stress.

Activation of the mammalian heat shock transcription factor (HSF)1 by stress is a multistep process resulting in the transcription of heat shock genes. Coincident with these events is the rapid and reversible redistribution of HSF1 to discrete nuclear structures termed HSF1 granules, whose function is still unknown. Key features are that the number of granules correlates with cell ploidy, suggesting the existence of a chromosomal target. Here we show that in humans, HSF1 granules localize to the 9q11-q12 heterochromatic region. Within this locus, HSF1 binds through direct DNA-protein interaction with a nucleosome-containing subclass of satellite III repeats. HSF1 granule formation only requires the DNA binding competence and the trimerization of the factor. This is the first example of a transcriptional activator that accumulates transiently and reversibly on a chromosome-specific heterochromatic locus.

Oophorectomy as a risk factor for coronary heart disease.

OBJECTIVE: The objective of the study was to examine the relationship between bilateral oophorectomy (BSO) and risk of coronary heart disease (CHD). STUDY DESIGN: We searched PubMed, EMBASE, meeting abstracts, and reference lists for studies that compared women with BSO at the time of hysterectomy with: (1) women with hysterectomy and ovarian conservation, (2) naturally menopausal women, (3) premenopausal women, or (4) women with no history of hysterectomy or BSO but unreported menopausal status. The primary outcome was fatal or nonfatal CHD. RESULTS: We reviewed 1956 citations. Seven observational studies met inclusion criteria. Heterogeneity among studies precluded formal metaanalysis. Four studies reported BSO increases risk for CHD but only in some subgroups of women or not in fully adjusted multivariate models. Three studies found no increased risk of CHD following BSO, but these studies had significant limitations. CONCLUSION: The existing evidence is inconclusive to determine the effect of BSO on risk of CHD.