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Robert D Langer

Publications and source records attributed to Robert D Langer.

35 records · Page 2Linked to original sources

Baseline associations between postmenopausal hormone therapy and inflammatory, haemostatic, and lipid biomarkers of coronary heart disease. The Women's Health Initiative Observational Study.

Clinical trials of postmenopausal hormone therapy (PHT) have found an early increase in cardiovascular events, and have not demonstrated the reduction in coronary heart disease (CHD) predicted from changes in conventional risk factors or found in observational studies, suggesting that PHT may increase coronary risk through other pathways. We compared baseline levels of C-reactive protein (CRP), interleukin-6 (IL-6), sICAM-1, tissue plasminogen activator antigen (tPA-antigen), D-dimer, homocysteine, triglycerides, total-, HDL- and LDL- cholesterol in 304 cases with incident CHD and 304 controls, according to self-reported use of PHT. Subjects were selected from the 75,343 participants in the WHI Observational Study without baseline cardiovascular disease or cancer. PHT was associated with higher CRP, HDL and triglycerides, and lower tPA-antigen and homocysteine. CRP was highest in users of unopposed conjugated equine estrogen. Levels of IL-6,sICAM-1,D-dimer and total cholesterol did not differ between PHT users and non-users. Transdermal estrogen users had low levels of D-dimer and CRP. Among users of estrogen plus progestin (EP), CRP, IL-6, tPA-antigen, D-dimer, total cholesterol and triglycerides were higher in women with incident coronary events than controls. Estrogen alone (E) controls shared only the tPA-antigen association, but had higher HDL and lower LDL than E cases. In non-users CRP, tPA-antigen and D-dimer were associated with incident CHD. In summary, risk markers differed by PHT category. Some associations differed between women with and without incident CHD, especially for EP, where inflammatory and thrombotic markers were higher in cases. These associations remain speculative pending confirmation in randomized trials.

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Tissue plasminogen activator antigen and D-dimer as markers for atherothrombotic risk among healthy postmenopausal women.

BACKGROUND: Plasma markers of fibrinolytic function are associated with incident coronary events among several, but not all, prospective epidemiologic investigations of healthy individuals. Few studies have evaluated this relationship in women. In addition, although menopausal hormone therapy (HT) may alter markers of fibrinolytic function, the relevance of this effect for coronary risk assessment has not been studied. METHODS AND RESULTS: In a prospective, nested case-control study among 75 343 postmenopausal women without prior cardiovascular disease or cancer, we evaluated the relationships of elevated tissue plasminogen activator (tPA) antigen and D-dimer with subsequent first coronary heart disease events over a median period of 2.9 years. Baseline levels of both biomarkers were higher among 304 cases compared with 304 controls matched on age, smoking status, ethnicity, and length of follow-up; median values were 9.0 versus 7.4 ng/mL (P<0.001) for tPA antigen and 27.6 versus 23.4 ng/mL (P=0.001) for D-dimer. In matched-pairs analyses, the odds ratio in the highest versus lowest quartile of tPA antigen was 3.5 (95% CI, 2.1 to 5.8; P trend <0.001) and for D-dimer was 2.0 (95% CI, 1.2 to 3.2; P trend=0.005). After adjustment for lipid and nonlipid risk factors, including C-reactive protein, tPA antigen remained a significant predictor. Multivariable-adjusted associations for D-dimer, although attenuated, largely remained statistically significant. When stratified by HT, the relationship between tPA antigen and incident coronary heart disease was similar among nonusers, estrogen-only users, and current users of any HT. CONCLUSIONS: Elevated tPA antigen and, to a lesser extent, D-dimer are independently associated with incident coronary events among postmenopausal women. In analyses stratified by HT, tPA antigen remained a consistent marker of increased coronary risk.

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Effects of conjugated equine estrogen in postmenopausal women with hysterectomy: the Women's Health Initiative randomized controlled trial.

CONTEXT: Despite decades of use and considerable research, the role of estrogen alone in preventing chronic diseases in postmenopausal women remains uncertain. OBJECTIVE: To assess the effects on major disease incidence rates of the most commonly used postmenopausal hormone therapy in the United States. DESIGN, SETTING, AND PARTICIPANTS: A randomized, double-blind, placebo-controlled disease prevention trial (the estrogen-alone component of the Women's Health Initiative [WHI]) conducted in 40 US clinical centers beginning in 1993. Enrolled were 10 739 postmenopausal women, aged 50-79 years, with prior hysterectomy, including 23% of minority race/ethnicity. INTERVENTION: Women were randomly assigned to receive either 0.625 mg/d of conjugated equine estrogen (CEE) or placebo. MAIN OUTCOME MEASURES: The primary outcome was coronary heart disease (CHD) incidence (nonfatal myocardial infarction or CHD death). Invasive breast cancer incidence was the primary safety outcome. A global index of risks and benefits, including these primary outcomes plus stroke, pulmonary embolism (PE), colorectal cancer, hip fracture, and deaths from other causes, was used for summarizing overall effects. RESULTS: In February 2004, after reviewing data through November 30, 2003, the National Institutes of Health (NIH) decided to end the intervention phase of the trial early. Estimated hazard ratios (HRs) (95% confidence intervals [CIs]) for CEE vs placebo for the major clinical outcomes available through February 29, 2004 (average follow-up 6.8 years), were: CHD, 0.91 (0.75-1.12) with 376 cases; breast cancer, 0.77 (0.59-1.01) with 218 cases; stroke, 1.39 (1.10-1.77) with 276 cases; PE, 1.34 (0.87-2.06) with 85 cases; colorectal cancer, 1.08 (0.75-1.55) with 119 cases; and hip fracture, 0.61 (0.41-0.91) with 102 cases. Corresponding results for composite outcomes were: total cardiovascular disease, 1.12 (1.01-1.24); total cancer, 0.93 (0.81-1.07); total fractures, 0.70 (0.63-0.79); total mortality, 1.04 (0.88-1.22), and the global index, 1.01 (0.91-1.12). For the outcomes significantly affected by CEE, there was an absolute excess risk of 12 additional strokes per 10 000 person-years and an absolute risk reduction of 6 fewer hip fractures per 10 000 person-years. The estimated excess risk for all monitored events in the global index was a nonsignificant 2 events per 10 000 person-years. CONCLUSIONS: The use of CEE increases the risk of stroke, decreases the risk of hip fracture, and does not affect CHD incidence in postmenopausal women with prior hysterectomy over an average of 6.8 years. A possible reduction in breast cancer risk requires further investigation. The burden of incident disease events was equivalent in the CEE and placebo groups, indicating no overall benefit. Thus, CEE should not be recommended for chronic disease prevention in postmenopausal women.

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Ethnicity, sleep, mood, and illumination in postmenopausal women.

BACKGROUND: This study examined how ethnic differences in sleep and depression were related to environmental illumination and circadian rhythms. METHODS: In an ancillary study to the Women's Health Initiative, 459 postmenopausal women were recorded for one week in their homes, using wrist monitors. Sleep and illumination experience were estimated. Depression was self-rated with a brief adjective check list. Affective diagnoses were made using the SCID interview. Sleep disordered breathing was monitored with home pulse oximetry. RESULTS: Hispanic and African-American women slept less than European-American women, according to both objective recordings and their own sleep logs. Non-European-American women had more blood oxygen desaturations during sleep, which accounted for 26% of sleep duration variance associated with ethnicity. Hispanic women were much more depressed. Hispanic, African-American and Native-American women experienced less daily illumination. Less daily illumination experience was associated with poorer global functioning, longer but more disturbed sleep, and more depression. CONCLUSIONS: Curtailed sleep and poor mood were related to ethnicity. Sleep disordered breathing was a factor in the curtailed sleep of minority women. Less illumination was experienced by non-European-American women, but illumination accounted for little of the contrasts between ethnic groups in sleep and mood. Social factors may be involved.

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Estrogen plus progestin and the risk of peripheral arterial disease: the Women's Health Initiative.

BACKGROUND: Observational studies have reported less frequent carotid atherosclerosis in healthy women taking postmenopausal hormone therapy. Estrogen with progestin did not reduce peripheral arterial events among women with preexisting coronary heart disease. This analysis evaluates clinical peripheral arterial disease among generally healthy women in the Women's Health Initiative randomized trial of estrogen plus progestin. METHODS AND RESULTS: The Estrogen Plus Progestin trial assigned 16 608 postmenopausal women, mean age 63.3+/-7.1 years, to daily conjugated estrogens (0.625 mg) with medroxyprogesterone acetate (2.5 mg) or placebo and documented health outcomes over an average of 5.6 years of follow-up. Hospitalization for peripheral arterial disease was infrequent, with annualized rates of 0.08%, 0.06%, and 0.02% for carotid disease, lower extremity arterial disease, and abdominal aortic aneurysm, respectively. The incidence of peripheral arterial events did not differ between treatment groups (hazard ratio [HR] 0.89, 95% confidence interval 0.63, 1.25). The risk was slightly greater among women assigned to active estrogen with progestin in years 1 (HR 1.33) and 2 (HR 1.27), and was slightly lower in later years (HR 0.85 and 0.87 in years 5 and > or =6). Among adherent participants, the hazard ratio for peripheral arterial events was 1.23 (95% confidence interval 0.79, 1.91) over the 5.6 years of follow up. Subgroup analysis identified no significant interactions between estrogen with progestin and baseline characteristics with regard to peripheral arterial disease risk. CONCLUSIONS: Among generally healthy postmenopausal women, conjugated estrogens with progestin did not confer protection against peripheral arterial disease.

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Naps and circadian rhythms in postmenopausal women.

BACKGROUND: Napping patterns and relationships among naps, circadian rhythms, and nocturnal sleep were evaluated in postmenopausal women. Naps and nocturnal sleep were compared between depressed women and healthy volunteers. METHODS: The study included 436 postmenopausal women between the ages of 50 and 81 years. Psychiatric interviews were conducted using the Structured Clinical Interview for DSM-IV Axis I Disorders. Each participant wore a wrist-activity monitor and kept a daily sleep log at home for 1 week. The major urinary melatonin metabolite (6-sulfatoxymelatonin [aMT6s]) was measured for two 24-hour periods at home. RESULTS: There was no significant difference in naps and nocturnal sleep patterns between depressed participants (n = 30) and those with no history of mental disorder (n = 222). Three peaks occurred in the timing of napping: approximately 1 hour before bedtime, 8 to 9 hours after wake-up time, and 2 hours after waking, in descending order of magnitude. Significant inverse correlations were observed between evening nap duration and both wake-up time and aMT6s acrophase. The onset time of aMT6s excretion was advanced by 32 minutes in evening nappers. CONCLUSIONS: Evening napping, a characteristic of these postmenopausal women, may be related to an advance of circadian rhythms in this age group. Relationships between evening napping and earlier wake-up time may be a common manifestation of advanced circadian rhythms or may be a homeostatic effect.

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Chronic venous disease in an ethnically diverse population: the San Diego Population Study.

In a 1994-1998 cross-sectional study of a multiethnic sample of 2,211 men and women in San Diego, California, the authors estimated prevalence of the major manifestations of chronic venous disease: spider veins, varicose veins, trophic changes, and edema by visual inspection; superficial and deep functional disease (reflux or obstruction) by duplex ultrasonography; and venous thrombotic events based on history. Venous disease increased with age, and, compared with Hispanics, African Americans, and Asians, non-Hispanic Whites had more disease. Spider veins, varicose veins, superficial functional disease, and superficial thrombotic events were more common in women than men (odds ratio (OR) = 5.4, OR = 2.2, OR = 1.9, and OR = 1.9, respectively; p < 0.05), but trophic changes and deep functional disease were less common in women (OR = 0.7 for both; p < 0.05). Visible (varicose veins or trophic changes) and functional (superficial or deep) disease were closely linked; 92.0% of legs were concordant and 8.0% discordant. For legs evidencing both trophic changes and deep functional disease, the age-adjusted prevalences of edema, superficial events, and deep events were 48.2%, 11.3%, and 24.6%, respectively, compared with 1.7%, 0.6%, and 1.3% for legs visibly and functionally normal. However, visible disease did not invariably predict functional disease, or vice versa, and venous thrombotic events occurred in the absence of either.

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Influence of estrogen plus progestin on breast cancer and mammography in healthy postmenopausal women: the Women's Health Initiative Randomized Trial.

CONTEXT: The Women's Health Initiative trial of combined estrogen plus progestin was stopped early when overall health risks, including invasive breast cancer, exceeded benefits. Outstanding issues not previously addressed include characteristics of breast cancers observed among women using hormones and whether diagnosis may be influenced by hormone effects on mammography. OBJECTIVE: To determine the relationship among estrogen plus progestin use, breast cancer characteristics, and mammography recommendations. DESIGN, SETTING, AND PARTICIPANTS: Following a comprehensive breast cancer risk assessment, 16 608 postmenopausal women aged 50 to 79 years with an intact uterus were randomly assigned to receive combined conjugated equine estrogens (0.625 mg/d) plus medroxyprogesterone acetate (2.5 mg/d) or placebo from 1993 to 1998 at 40 clinical centers. Screening mammography and clinical breast examinations were performed at baseline and yearly thereafter. MAIN OUTCOME MEASURES: Breast cancer number and characteristics, and frequency of abnormal mammograms by estrogen plus progestin exposure. RESULTS: In intent-to-treat analyses, estrogen plus progestin increased total (245 vs 185 cases; hazard ratio [HR], 1.24; weighted P<.001) and invasive (199 vs 150 cases; HR, 1.24; weighted P =.003) breast cancers compared with placebo. The invasive breast cancers diagnosed in the estrogen plus progestin group were similar in histology and grade but were larger (mean [SD], 1.7 cm [1.1] vs 1.5 cm [0.9], respectively; P =.04) and were at more advanced stage (regional/metastatic 25.4% vs 16.0%, respectively; P =.04) compared with those diagnosed in the placebo group. After 1 year, the percentage of women with abnormal mammograms was substantially greater in the estrogen plus progestin group (716 [9.4%] of 7656) compared with placebo group (398 [5.4%] of 7310; P<.001), a pattern which continued for the study duration. CONCLUSIONS: Relatively short-term combined estrogen plus progestin use increases incident breast cancers, which are diagnosed at a more advanced stage compared with placebo use, and also substantially increases the percentage of women with abnormal mammograms. These results suggest estrogen plus progestin may stimulate breast cancer growth and hinder breast cancer diagnosis.

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Sex and time differences in the associations of non-high-density lipoprotein cholesterol versus other lipid and lipoprotein factors in the prediction of cardiovascular death (The Rancho Bernardo Study).

Non-high-density lipoprotein (HDL) cholesterol (total cholesterol [TC] minus HDL cholesterol) has been suggested as the preferred lipid fraction to predict cardiovascular disease. We compared the ability of lipids, lipoproteins, the ratio of total to HDL cholesterol (TC/HDL), and non-HDL cholesterol to predict fatal coronary heart disease (CHD) and cardiovascular disease in 1,386 women and 1,094 men (mean age 69 years). After 10 years, there were more deaths in men (n = 310) than women (n = 268), but the proportions of deaths attributed to CHD (23% and 25%, respectively) and cardiovascular disease (48% and 47%) were similar. In men, age-adjusted values for non-HDL cholesterol, TC/HDL ratio, and triglycerides each predicted a significantly increased risk of CHD and cardiovascular disease; none of these associations was independent of pack-years of smoking, systolic blood pressure, fasting plasma glucose, body mass index, and physical activity. In women, age-adjusted non-HDL cholesterol levels did not predict CHD or cardiovascular disease events before or after adjusting for these covariates and for estrogen replacement therapy. In women, only the ratio of TC to HDL cholesterol predicted CHD and cardiovascular disease deaths independent of estrogen use and other risk factors. Observed associations were sensitive to time, being evident in women at 3 and 5 years, and lost thereafter, but not apparent before 10 years in men. Thus, non-HDL cholesterol is not superior to individual lipids, lipoproteins, or their ratios in the prediction of cardiovascular death in older adults.

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Quantified duplex augmentation in healthy subjects and patients with venous disease: San Diego population study.

OBJECTIVE: This study was undertaken to determine the quantitative augmentation response in several veins examined in a cohort assembled to permit comparisons by sex, age, and ethnicity, under normal conditions and in the presence of obstruction, with and without trophic changes. METHOD: The common femoral vein, superficial femoral vein, sapheno-femoral junction, popliteal vein, sapheno-popliteal junction, and posterior tibial vein were studied with duplex ultrasonographic scanning. Augmentation response was elicited with use of an automated cuff inflator. Mean level of each response was analyzed according to patient sex, age, and ethnicity, each adjusted for the other two. Normal values were compared with those obtained from legs with venous obstructive disease, with or without signs of trophic changes. RESULTS: Decreased augmentation response was noted only in the sapheno-femoral junction and sapheno-popliteal junction, and was smaller in women. Augmentation response was slightly increased in the oldest age group (>70 years) in the common femoral vein, superficial femoral vein, popliteal vein, and posterior tibial vein. The highest augmentation response was found in Asian subjects, in the common and superficial femoral veins and the sapheno-femoral and sapheno-popliteal junctions; and the smallest augmentation response was found in African American subjects, in these same veins and junctions. Differences in vein diameters may explain these findings, ie, smaller diameters in Asians and larger diameters in African Americans. Most important, compared with normal values, augmentation response was decreased in legs with venous obstructive disease only when trophic changes were present. CONCLUSION: Like quantification of reflux, quantitative evaluation of the augmentation response may help in diagnosis of venous obstructive disease when trophic changes are present.

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Postmenopausal hormone therapy and migraine headache.

BACKGROUND: Estrogen withdrawal has been described as a trigger for migraine headache, and some studies suggest that estrogen and progestin may exacerbate migraine. No population-based studies have examined the association between hormone therapy (HT) and migraine among postmenopausal women. METHODS: To examine the association between HT and migraine headache in postmenopausal women, we used self-report of HT use, HT characteristics, and migraine headache within the past year among 17,107 postmenopausal female health professionals enrolled in the Women's Health Study. RESULTS: Analyses were restricted to the 17,107 of 21,788 postmenopausal women who were postmenopausal at baseline and who were never (38.5%) or current (61.5%) users of HT. Of these, 1,909 (11.2%) experienced migraine headache within the last year. Women with migraine headache were significantly younger, had a younger age at menopause, were more likely to have had a surgical menopause, and were more likely to be current users of HT. After adjusting for age, race, smoking, alcohol use, ever use of oral contraception, age at menopause, and menopause type, the odds ratio (OR) for migraine headache was 1.42 (95% CI 1.24-1.62) for women who were current users of HT compared with never users. ORs were similar for users of estrogen alone (OR 1.39, 95% CI 1.14-1.69) and users of both estrogen and progestin (OR 1.41, 95% CI 1.22-1.63). CONCLUSIONS: In this cross-sectional study, current HT use was associated with higher rates of migraine headache than nonuse. Clinical trials are needed to determine if HT increases the incidence of migraine in postmenopausal women.

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Hormone replacement and the prevention of cardiovascular disease.

Recently, there has been considerable discussion about the benefits and risks of using hormone replacement therapy (HRT) for cardiovascular protection in postmenopausal women. Numerous studies have addressed this issue, with conflicting results. Observational studies strongly suggest a benefit of HRT for primary prevention of cardiovascular disease (CVD), whereas controlled trials that tested a single common regimen of estrogen plus progestin found no effect on CVD events or angiographic progression in older women with established CVD. More recently a primary prevention trial in high risk patients found reduced carotid atheroma with estrogen alone. A variety of combination therapies with various estrogens and progestins are now available. These formulations have significantly different effects on cardiovascular risk markers, which independently affect outcomes. This information should be considered when deciding whether to use HRT in an individual woman, and if so, which formulation to use.

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Stability of electrocardiographic classification pre- and postglucose challenge.

Because of validity concerns, electrocardiograms (ECGs) in epidemiologic studies are usually taken in fasting subjects. It would be preferable logistically to record ECGs throughout the day. The authors investigated the stability of ECGs taken while fasting and approximately 1 hour after a 75-g glucose load on the same morning in 89 older men and women who were participants in the Rancho Bernardo (California) Chronic Disease Study between 1984 and 1995. A reader blinded to this comparison classified ECGs using the Minnesota code and Whitehall criteria. Of 75 initially normal tracings, 27% changed to possible ischemia postglucose. Of 12 tracings initially indicating possible ischemia, two reverted to normal (kappa = 0.40, 95% confidence interval: 0.21, 0.59). The two tracings initially scored as probable ischemia remained in that category postglucose. More ECGs worsened than improved, and the variability pre- and postglucose was at least as great as that between clinic visits conducted 8 years apart.

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Bleeding patterns of the hormone replacement therapies in the postmenopausal estrogen and progestin interventions trial.

OBJECTIVE: To explore whether significant differences exist between bleeding patterns with common regimens of hormone replacement therapy using two different progestogens. METHODS: A total of 875 women in the Postmenopausal Estrogen and Progestin Interventions Trial took either placebo, conjugated equine estrogen 0.625 mg, conjugated equine estrogen 0.625 mg plus medroxyprogesterone acetate 2.5 mg in a continuous fashion, or conjugated equine estrogen 0.625 mg daily plus either cyclical medroxyprogesterone acetate 10 mg or cyclical micronized progesterone 200 mg/day for 12 days per month. Bleeding days, amounts, and episodes were recorded in diaries and aggregated by 6-month intervals for 3 years for the 596 participants with a uterus. Any bleeding for women on continuous regimens, or more than 6 episodes of bleeding per 6-month period for cyclical regimens, was considered excess. RESULTS: Conjugated equine estrogen plus micronized progesterone cyclical was associated with fewer excess episodes of bleeding than conjugated equine estrogen plus medroxyprogesterone acetate continuous in the first 6 months. Quantities of bleeding for conjugated equine estrogen plus micronized progesterone cyclical were less than for conjugated equine estrogen plus medroxyprogesterone acetate cyclical through 30 months and for the number of bleeding days through study end. The 3-year cumulative quantities, days, and episodes of bleeding were significantly lower for conjugated equine estrogen plus micronized progesterone cyclical than for conjugated equine estrogen plus medroxyprogesterone acetate cyclical. Placebo treated women had scant bleeding and conjugated equine estrogen had modest amounts relative to the combination therapies. CONCLUSION: The bleeding measures for conjugated equine estrogen plus micronized progesterone cyclical showed consistent advantages over those for cyclical conjugated equine estrogen plus medroxyprogesterone acetate in terms of quantity, length, and episodes of bleeding. In the first 6 months, conjugated equine estrogen plus micronized progesterone cyclical had fewer excess bleeding episodes than continuous conjugated equine estrogen plus medroxyprogesterone acetate.

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Depression and endogenous melatonin in postmenopausal women.

BACKGROUND: Previous reports on melatonin secretion in depression are numerous but conflicting. There are very few studies relating the duration of the nocturnal melatonin peak to depression, and the results of those studies have been equivocal. METHODS: We studied mood disorders and urinary melatonin excretion in 382 postmenopausal women. Psychiatric diagnoses and global assessment of functioning (GAF) scores were determined based on a Structured Clinical Interview for DSM-IV Axis I Disorders (SCID). Urinary 6-sulfatoxymelatonin (6-SMT) samples were collected for two 24-h periods at home. RESULTS: A positive family history of depression was significantly related to a longer duration of 6-SMT excretion. There were marginally significant associations between current major depression and delayed offset of 6-SMT excretion and between later acrophase and lifetime major depression, even with control for age, ethnicity, season, and several medications. LIMITATIONS: The subjects were studied in their home environments, where light effects were not controlled. Data were restricted to postmenopausal women, including a limited number of subjects with current major depression. CONCLUSIONS: These results suggest that there might be a familial vulnerability in the endogenous melatonin signal in subjects prone to depression, and an abnormality in the duration of the melatonin signal in those with current major depression.

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Evening light exposure: implications for sleep and depression.

OBJECTIVES: To examine whether dim illumination in the evening is a factor in sleep disturbances of aging, depression, and circadian phase advance. DESIGN: One-week continuous recordings were made to record illumination exposure and to infer 24-hour sleep patterns from wrist activity. SETTING: Recordings took place during normal home and community activities. PARTICIPANTS: Complete data of 154 postmenopausal women, mean age 66.7, were selected from a larger study of participants in the Women's Health Initiative. MEASUREMENTS: Illumination in lux was averaged for 4 hours before bedtime and over 24 hours. Mood was measured using a brief eight-item screen. RESULTS: Illumination in the 4 hours before bedtime was quite dim: median 24 lux. Nevertheless, evening light exposure was not significantly related to sleep amount (in bed or out of bed) sleep efficiency, sleep latency, wake within sleep, or mood. In contrast, the overall amount of light throughout the 24 hours was negatively correlated with sleep latency, wake within sleep, and depressed mood. CONCLUSIONS: Low evening lighting does not appear to be a crucial factor in sleep and mood disturbances of aging, but overall lighting may contribute to these disturbances.

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