Hemoglobin A1c Serum Level Predicts 5-year Mortality in Patients with Cognitive Impairment.

Background: Subjective cognitive decline (SCD) and mild cognitive impairment (MCI) may occur as preclinical stages of Alzheimer's disease (AD), ultimately leading to dementia. Glycated hemoglobin A1c (HbA1c) is a diagnostic marker for diabetes mellitus and indicates mortality risk. Objectives: This university-based, exploratory retrospective study examined the impact of HbA1c serum level on 5-year mortality among individuals with cognitive impairment. Methods: Included were 1076 subjects aged at least 50 years who visited the Memory Outpatient Clinic of the Medical University of Vienna due to memory problems. Participants were diagnosed with SCD, MCI, or AD subsequent to neurological examination, standard laboratory blood tests, and neuropsychological testing. Survival was compared between diagnostic subgroups and with respect to HbA1c categories using log-rank tests based on Kaplan-Meier functions. The Neuropsychological Test Battery Vienna (NTBV) was dimensionally reduced, and a principal component analysis (PCA) was performed to further analyze results. Corresponding factor scores, HbA1c values, and baseline characteristics were included in Cox proportional hazards models to assess 5-year mortality risk. Results: During the observation period, 323 patients (30%) died at a mean age comparable between diagnostic subgroups (SCD 84.2 ± 10.1, MCI 81.2 ± 8.3, AD 82.2 ± 7.4 years). Individuals with normal serum HbA1c levels had significant advantages in survival within the MCI (12.9 ± .3 vs. 10.0 ± .8 years) and the AD subgroups (8.2 ± .4 vs. 5.5 ± .6 years), and metric HbA1c predicted 5-year mortality (HR 1.24). Conclusion: This study demonstrates an association between abnormal HbA1c serum levels and increased mortality.

First-trimester occupational exposures and hypertensive disorders of pregnancy among US nurses.

BACKGROUND: Limited and conflicting data exist regarding the impact of first-trimester nursing occupational exposures on hypertensive disorders of pregnancy (HDP). AIMS: To investigate whether first-trimester night shift work, work hours and work-related activities are associated with HDP. METHODS: We conducted a cross-sectional analysis of 6610 women within the Nurses' Health Study II. We used multiple logistic regression to estimate the odds ratios (ORs) and 95% confidence intervals (CIs) for the relation of occupational exposures to HDP. RESULTS: Nine per cent of respondents reported an HDP in the index pregnancy (gestational hypertension: n = 354, 5%, preeclampsia: n = 222, 3%). First-trimester fixed or rotating night shift work was not significantly associated with gestational hypertension or preeclampsia compared to day shift work only. Compared to those working 21-40 h/week, working overtime (≥41 h/week) was not associated with gestational hypertension but was associated with 43% higher odds of preeclampsia (95% CI 1.02, 2.00). For part-time work (≤20 h/week), the OR was 0.76 (95% CI 0.56, 1.02) for gestational hypertension and 0.64 (95% CI 0.43, 0.97) for preeclampsia. The odds of preeclampsia were 3% higher per additional hour worked per week (95% CI 1.01-1.04). Compared to 0-4 h spent standing or walking per day, standing or walking ≥9 h daily was associated with 32% lower odds of gestational hypertension (95% CI 0.47, 0.99) but was not significantly associated with preeclampsia. Frequency of heavy lifting was not associated with either hypertensive disorder or pregnancy. CONCLUSIONS: Among nurses, working overtime was associated with higher odds of preeclampsia.

Reducing nighttime light exposure in the urban environment to benefit human health and society.

Nocturnal light pollution can have profound effects on humans and other organisms. Recent research indicates that nighttime outdoor lighting is increasing rapidly. Evidence from controlled laboratory studies demonstrates that nocturnal light exposure can strain the visual system, disrupt circadian physiology, suppress melatonin secretion, and impair sleep. There is a growing body of work pointing to adverse effects of outdoor lighting on human health, including the risk of chronic diseases, but this knowledge is in a more nascent stage. In this Review, we synthesize recent research on the context-specific factors and physiology relevant to nocturnal light exposure in relation to human health and society, identify critical areas for future research, and highlight recent policy steps and recommendations for mitigating light pollution in the urban environment.

Homocysteine - A predictor for five year-mortality in patients with subjective cognitive decline, mild cognitive impairment and Alzheimer's dementia.

BACKGROUND: Subjective Cognitive Decline (SCD) and Mild Cognitive Impairment (MCI) are preclinical stages of Alzheimer's Disease (AD), which is the most common entity of dementia. Homocysteine is an amino acid in the methionine cycle, and many studies revealed a significant association between elevated homocysteine serum levels and the progression of dementia. The primary objective of this retrospective study was to investigate whether elevated homocysteine serum levels could be associated with mortality and neuropsychological test results in individuals suffering from SCD, MCI or AD. METHODS: This study is a single-center explorative retrospective data analysis with 976 data protocols from the Memory Outpatient's Clinic of the Medical University of Vienna included. All patients underwent a neurological examination, a laboratory blood test, and neuropsychological testing to establish a diagnosis of either SCD, MCI, or AD. Data was evaluated by Kaplan-Meier functions, factor analysis, and binary logistic regression models. RESULTS: Patients with AD showed significantly higher mean homocysteine levels (SCD 12.15 ± 4.71, MCI 12.80 ± 4.81, AD 15.0 ± 6.44 µmol/L) compared to those with SCD and MCI (p ≤ .001). The mean age of patients with AD (75.2 ± 7.8) was significantly older at the time of testing than of patients with MCI (69.1 ± 9.6) or SCD (66.8 ± 9.3). Since homocysteine levels increase with age, this could be a possible explanation for the higher levels of AD patients. The age at death did not differ significantly between all diagnostic subgroups, resulting in the shortest survival times for AD patients. Homocysteine levels were negatively associated with in Mini-Mental State Examination (MMSE) and Neuropsyhcological Test Battery Vienna (NTBV) factors F1-F4 (F1 = attention, F2 = memory, F3 = executive functions, F4 = naming/verbal comprehension). Moreover, higher homocysteine levels significantly predicted shorter five-year survival in the logistic regression models, even after adjusting for age, diagnostic subgroups, sex, years of education and results of neuropsychological testing. CONCLUSION: The results of this study suggest that homocysteine levels are independently associated with impaired cognitive function and increased five-year mortality.

Shift work tolerance.

BACKGROUND: Shift work is widespread due to 24-h work in many occupations. Understanding differences in individual shift work tolerance (SWT) can help develop coping strategies for shift workers. AIMS: This in-depth qualitative review elucidates the architecture of SWT, providing an overview of the research advances in the last decade (2011-2021). METHODS: We searched Google Scholar, PubMed and Medline for different word combinations concerning SWT. Genome-wide association studies (GWAS) for the potential genetic basis of SWT were additionally searched in GWAS Central and GWAS Catalogue. RESULTS: Eleven new studies were published since 2011, with the proportion of longitudinal studies on SWT having more than doubled in the past decade. They consolidate prior findings (e.g. hardiness most consistently associated with SWT) and discovered additional aspects of SWT like resistance to change and job stress. The 15 large-scale GWAS identified, most of which using UK Biobank (UKB) and 23andMe data, involved mapped genes showing overlap especially within analysis of the same phenotype (e.g. PER2/3 for morningness, PAX8 for sleep duration and LINGO1 for neuroticism). Individual GWAS for additional traits such as resilience have also been published though assessments of gene overlap are not yet possible. CONCLUSIONS: Progress regarding longitudinal studies on SWT has been made though a more consistent definition of SWT remains crucial for future research. Non-genetic studies on SWT suggest several important traits and factors; many of which have now also been explored using GWAS. Such evidence could serve as basis for individualized risk prediction and disease prevention approaches for night-shift workers.

Drivers of Infectious Disease Seasonality: Potential Implications for COVID-19.

Not 1 year has passed since the emergence of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the causative agent of coronavirus disease 2019 (COVID-19). Since its emergence, great uncertainty has surrounded the potential for COVID-19 to establish as a seasonally recurrent disease. Many infectious diseases, including endemic human coronaviruses, vary across the year. They show a wide range of seasonal waveforms, timing (phase), and amplitudes, which differ depending on the geographical region. Drivers of such patterns are predominantly studied from an epidemiological perspective with a focus on weather and behavior, but complementary insights emerge from physiological studies of seasonality in animals, including humans. Thus, we take a multidisciplinary approach to integrate knowledge from usually distinct fields. First, we review epidemiological evidence of environmental and behavioral drivers of infectious disease seasonality. Subsequently, we take a chronobiological perspective and discuss within-host changes that may affect susceptibility, morbidity, and mortality from infectious diseases. Based on photoperiodic, circannual, and comparative human data, we not only identify promising future avenues but also highlight the need for further studies in animal models. Our preliminary assessment is that host immune seasonality warrants evaluation alongside weather and human behavior as factors that may contribute to COVID-19 seasonality, and that the relative importance of these drivers requires further investigation. A major challenge to predicting seasonality of infectious diseases are rapid, human-induced changes in the hitherto predictable seasonality of our planet, whose influence we review in a final outlook section. We conclude that a proactive multidisciplinary approach is warranted to predict, mitigate, and prevent seasonal infectious diseases in our complex, changing human-earth system.

Increased risk of death associated with the use of proton-pump inhibitors in patients with dementia and controls - a pharmacoepidemiological claims data analysis.

BACKGROUND AND PURPOSE: The use of proton-pump inhibitors (PPIs) was reported to be associated with increased mortality risk and has been proposed as a potential risk factor for neurodegenerative diseases. We aimed to assess the impact of PPI use on survival in patients with dementia as compared with controls. METHODS: This register-based control-matched cohort study included 28 428 patients with dementia ascertained by the prescription of antidementia drugs and two control individuals matched by sex, age and area of residence for each patient with dementia during the study period from 1 January 2005 to 30 June 2016. Cumulative defined daily doses (DDDs) of PPIs were extracted from the health insurance prescription registries. A multivariate Cox regression model for non-proportional hazards was used to analyse mortality risk in dependence of PPI exposure, which was limited to 1 year preceding the date of cohort entry (index date) in order to avoid immortal time bias. RESULTS: The PPI exposure of 100 DDDs in the year before the index date was associated with an increased mortality risk in patients with dementia (adjusted hazard ratio, 1.07; 95% confidence intervals, 1.03-1.12), but also in controls (adjusted hazard ratio, 1.47; 95% confidence intervals, 1.31-1.64). The mortality risk in relation to PPI use was significantly lower in patients with dementia as compared with controls (P < 0.0001) and highest in the first 2 years after the index date in both cohorts. CONCLUSIONS: Our findings promote more stringent pharmacovigilance strategies to avoid PPI use in cases lacking a clear indication for therapy or where potential risks outweigh the benefits.

Maternal rotating night shift work before pregnancy and offspring stress markers.

BACKGROUND: Recent studies suggest an intergenerational influence of stress such that maternal exposure even before pregnancy could impact offspring health outcomes later in life. In humans, investigations on the impact of maternal stressors on offspring health outcomes, including stress-sensitive biomarkers, have largely been limited to extreme stressors. Prior studies have not addressed more moderate maternal stressors, such as rotating night shift work, on offspring stress markers in young adulthood. METHODS: We investigated the association between maternal rotating night shift work before conception and offspring salivary cortisol and alpha amylase (sAA) patterns in young adulthood among mothers enrolled in the Nurses' Health Study II (NHSII) and their offspring participating in the Growing Up Today Study 2 (GUTS2). Our sample included over 300 mother-child pairs where, between 2011 and 2014, the children provided 5 saliva samples over the course of one day. We used piecewise linear mixed models to compare awakening responses, overall slopes as well as several other diurnal patterns of cortisol and sAA between offspring born to shift working versus non-shift working mothers. RESULTS: Offspring born to shift working mothers had a flattened late decline in cortisol (percent differences in slope (%D): 2.1%; 95%CI: 0.3, 3.8) and their sAA awakening response was steeper (%D -37.4%; 95%CI: -59.0, -4.4), whereas sAA increase before bedtime appeared less pronounced (%D -35.9%; 95%CI: -55.3, -8.3), compared to offspring born to mothers without shift work. For cortisol, we observed a significant difference in the Area Under the Curve (AUC) (%D 1.5%; 95%CI: 0.3, 2.7) with higher AUC for offspring of mothers who worked rotating night shifts. In offspring-sex-stratified analyses we found differences primarily among males. CONCLUSION: Our results provide some - albeit modest - evidence that maternal rotating night shift work-a moderate stressor-influences offspring stress markers. Future studies with larger samples sizes, more detailed exposure assessment (particularly during maternal pregnancy), and multiple offspring biomarker assessments at different developmental stages are needed to further investigate these associations.

Rotating night shift work and menopausal age.

STUDY QUESTION: How are rotating night shift schedules associated with age at menopause among a large, national cohort of shift working nurses? SUMMARY ANSWER: Our findings suggest that working rotating night shifts with sufficient frequency may modestly accelerate reproductive senescence among women who may already be predisposed to earlier menopause. WHAT IS KNOWN ALREADY: Younger age at menopause has been associated with increased risk of adverse health outcomes, particularly those linked to reproduction. Night work has been associated with reproductive dysfunction, including disruption of menstrual cycle patterns. STUDY DESIGN, SIZE, DURATION: This cohort study was conducted among 80 840 women of the Nurses' Health Study 2 (NHS2), with prospective follow-up from 1991 through 2013. Loss-to-follow-up of the NHS2 is estimated to be <10%. PARTICIPANTS/MATERIALS, SETTING, METHODS: We assessed the association between cumulative and current rotating night shift work and age at natural menopause over 22 years of follow-up (1991-2013). Cox proportional hazards models were used to estimate hazard ratios (HR) for menopause, adjusted for age, smoking status, body mass index, physical activity, alcohol consumption, reproductive factors and exogenous hormone use. MAIN RESULTS AND THE ROLE OF CHANCE: Over follow-up, 27 456 women (34%) reached natural menopause. Women who worked 20 or more months of rotating night shifts in the prior 2-year had an increased risk of earlier menopause (multivariable-adjusted (MV)-HR = 1.09, 95% CI: 1.02-1.16) compared to women without rotating night shift work. This risk was stronger among women undergoing menopause or otherwise censored under age 45 years (MV-HR = 1.25, 95% CI: 1.08-1.46), than it was for those continuing in the study when >45 years old (MV-HR = 1.05, 95% CI: 0.99-1.13). Working 10 or more years of cumulative rotating night work was also associated with higher risk of menopause among women reaching menopause under age 45 (MV-HR10-19 years = 1.22, 95% CI: 1.03-1.44; MV-HR≥20 years = 1.73, 95% CI: 0.90-3.35), though not over the age of 45 years (MV-HR10-19 years = 1.04, 95% CI: 0.99-1.10; MV-HR≥20 years = 1.01, 95% CI: 0.89-1.15). LIMITATIONS, REASONS FOR CAUTION: The degree to which observed effects of rotating night shifts on age at natural menopause are due to circadian disruption, rather than fatigue and stress associated with working more demanding schedules, is uncertain due to potential residual confounding by these factors. WIDER IMPLICATIONS OF THE FINDINGS: This is the first study to assess the effects of night work on menopausal timing among a larger national cohort of shift working women. Women already prone to earlier menopause may further truncate their reproductive lifetime by working schedules comprising day as well as night shifts. STUDY FUNDING/COMPETING INTEREST(S): This study was supported by Center for Disease Control and Prevention/The National Institute for Occupational Safety and Health Grant 5R01OH009803 (PI: Schernhammer E), as well as UM1 CA176726 from the National Institute of Health. The funding sources had no role in the design and conduct of the study; collection, management, analysis and interpretation of the data; preparation, review or approval of the article; and decision to submit the article for publication. The authors have no conflicts of interest.

A Review of Data of Findings on Night Shift Work and the Development of DM and CVD Events: a Synthesis of the Proposed Molecular Mechanisms.

PURPOSE OF REVIEW: Night shift work has become highly prevalent in our 24/7 societies, with up to 18% of the US work force working alternate shift schedules. However, studies indicate that there may be adverse health effects of chronic night work across diverse populations. These effects are likely due to misalignment of the circadian system with work schedules, mediated by the system's primary marker melatonin as well as other downstream molecules. RECENT FINDINGS: Melatonin has multiple biologic actions that are relevant to cardiometabolic disease, including modulation of oxidative stress, inflammation, and (via the melatonin receptor) vasoconstriction. Behavioral traits, such as chronotype and meal timing, have recently been shown to interact with the effects of night work on cardiometabolic health. Together with recent findings suggesting a role for circadian genes in cardiometabolic risk, the interactions of night shift work and behavioral traits are likely to facilitate novel treatment and prevention approaches for cardiovascular disease and type 2 diabetes, incorporating aspects of clock and timing.

A randomized controlled trial of oral melatonin supplementation and breast cancer biomarkers.

We examined compliance with and the effects of melatonin supplementation on breast cancer biomarkers (estradiol, insulin-like growth factor I (IGF-1), insulin-like growth factor-binding protein 3 (IGFBP-3), and the IGF-1/IGFBP-3 ratio) in postmenopausal breast cancer survivors. In a double-blind, placebo-controlled study, postmenopausal women with a prior history of stages 0-III breast cancer who had completed active cancer treatment (including hormonal therapy) were randomly assigned to either 3 mg oral melatonin (n = 48) or placebo daily for 4 months. Plasma samples were collected at baseline and after the completion of the intervention. The primary endpoints were compliance and change in estradiol and IGF-1/IGFBP-3 levels. Ninety-five women were randomized (48 to melatonin and 47 to placebo). Eighty-six women (91%) completed the study and provided pre- and postintervention bloods. Melatonin was well tolerated without any grade 3/4 toxicity and compliance was high (89.5%). Overall, among postmenopausal women with a prior history of breast cancer, a 4-month course of 3 mg melatonin daily did not influence circulating estradiol, IGF-1, or IGFBP-3 levels. Compliance was comparable between the two groups. Short-term melatonin treatment did not influence the estradiol and IGF-1/IGBBP-3 levels. Effects of longer courses of melatonin among premenopausal women are unknown. Low baseline estradiol levels in our study population may have hindered the ability to detect any further estradiol-lowering effects of melatonin.

Autoimmune disease and risk for Parkinson disease: a population-based case-control study.

OBJECTIVE: Inflammatory mediators are increased in autoimmune diseases and may activate microglia and might cause an inflammatory state and degeneration of dopaminergic neurons in the brain. Thus, we evaluated whether having an autoimmune disease increases the risk for developing Parkinson disease (PD). METHODS: A population based case-control study was conducted in Denmark of 13,695 patients with a primary diagnosis of PD recorded in the Danish National Hospital Register during the period 1986-2006. Each case was matched on year of birth and sex to 5 population controls selected at random from among inhabitants of Denmark who were alive at the date of the patient's diagnosis. The main exposure measure was a hospital diagnosis of 1 of 32 selected autoimmune diseases recorded 5 or more years before the index date in the files of the Danish Hospital Register. RESULTS: We observed no overall association between a diagnosis of autoimmune disease and risk for subsequent PD (odds ratio 0.96, 95% confidence interval 0.85-1.08). In a subgroup of patients with autoimmune diseases with systemic involvement, primarily rheumatoid arthritis, we saw a decrease in risk for PD of 30%. CONCLUSIONS: Our results do not support the hypothesis that autoimmune diseases increase the risk for Parkinson disease. The decreased risk observed among patients with rheumatoid arthritis might be explained by underdiagnosis of movement disorders such as Parkinson disease in this patient group or by a protective effect of the treatment with anti-inflammatory drugs over prolonged periods.

Nightshift work and fracture risk: the Nurses' Health Study.

SUMMARY: Nightshift work suppresses melatonin production and has been associated with an increased risk of major diseases including hormonally related tumors. Experimental evidence suggests that light at night acts through endocrine disruption likely mediated by melatonin. To date, no observational study has addressed the effect of night work on osteoporotic fractures, another condition highly sensitive to sex steroid exposure. Our study, to our knowledge, the first to address this question, supports the hypothesis that nightshift work may negatively affect bone health, adding to the growing list of ailments that have been associated with shift work. INTRODUCTION: We evaluated the association between nightshift work and fractures at the hip and wrist in postmenopausal nurses. METHODS: The study population was drawn from Nurses' Health Study participants who were working full or part time in nursing in 1988 and had reported their total number of years of rotating nightshift work. Through 2000, 1,223 incident wrist and hip fractures involving low or moderate trauma were identified among 38,062 postmenopausal women. We calculated multivariate relative risks (RR) of fracture over varying lengths of follow-up in relation to years of nightshift work. RESULTS: Compared with women who never worked night shifts, 20+ years of nightshift work was associated with a significantly increased risk of wrist and hip fractures over 8 years of follow-up [RR = 1.37, 95% confidence interval (CI), 1.04-1.80]. This risk was strongest among women with a lower body mass index (<24) who never used hormone replacement therapy (RR = 2.36; 95% CI, 1.33-4.20). The elevated risk was no longer apparent with 12 years of follow-up after the baseline single assessment of nightshift work. CONCLUSIONS: Long durations of rotating nightshift work may contribute to risk of hip and wrist fractures, although the potential for unexplained confounding cannot be ruled out.

Time trends of the prevalence of asthma and allergic disease in Austrian children.

After a substantial increase in the prevalence of atopic disease in Europe, recent studies indicate that a plateau has been reached. However, variation across countries and age groups exists. We studied the prevalence and time trends of asthma and allergic disease among schoolchildren in Austria, a country with traditionally low rates of asthma, hay fever, and eczema. As part of the International Study of Asthma and Allergies in Childhood (ISAAC), symptoms and physician diagnoses of asthma and allergic disease of 13,399 Austrian children aged 6-7 yr and 1516 children aged 12-14 yr were surveyed between 1995 and 1997. A similar survey was conducted between 2001 and 2003. Among children aged 6-7 yr, significant increases were seen in the prevalence of physician-diagnosed asthma (+16%; p = 0.013), hay fever (+22%; p < 0.001), and eczema (+37%; p < 0.001) between 1995 and 2003. These changes were paralleled by an increase in the prevalence of symptoms typical for hay fever (itchy eyes and runny nose), but not by an increase in wheeze. Among children aged 12-14 yr, the lifetime prevalence of diagnosed asthma increased by 32%, of hay fever by 19%, and of eczema by 28% (all, p < 0.001). These changes were paralleled by increases in the prevalence of wheezing as documented by both questions before and after a video showing wheezing children but not by symptoms typical for hay fever such as itchy eyes and runny nose. In conclusion, in Austria, contrary to other European countries, the prevalence of asthma and allergic disease increased among schoolchildren. Additional studies are needed to continue monitoring the dynamics of the prevalence of asthma and allergic disease in Austria and to explore trends in their risk factors.

Circulating insulin-like growth factor axis and the risk of pancreatic cancer in four prospective cohorts.

Insulin-like growth factor (IGF)-I induces growth in pancreatic cancer cells and blockade of the IGF-I receptor has antitumour activity. The association of plasma IGF-I and IGF binding protein-3 (IGFBP-3) with pancreatic cancer risk has been investigated in two small studies, with conflicting results. We conducted a nested case-control study within four large, prospective cohorts to investigate whether prediagnostic plasma levels of IGF-I, IGF-II, and IGFBP-3 were associated with pancreatic cancer risk. Plasma levels in 212 cases and 635 matched controls were compared by conditional logistic regression, with adjustment for other known pancreatic cancer risk factors. No association was observed between plasma levels of IGF-I, IGF-II, or IGFBP-3 and incident diagnosis of pancreatic cancer. Relative risks for the highest vs the lowest quartile of IGF-I, IGF-II, and IGFBP-3 were 0.94 (95% confidence interval (CI), 0.60-1.48), 0.96 (95% CI, 0.61-1.52), and 1.21 (95% CI, 0.75-1.92), respectively. The relative risk for the molar ratio of IGF-I and IGFBP-3, a surrogate measure for free IGF-I, was 0.84 (95% CI, 0.54-1.31). Additionally, no association was noted in stratified analyses or when requiring longer follow-up. In four prospective cohorts, we found no association between the risk of pancreatic cancer and prediagnostic plasma levels of IGF-I, IGF-II, or IGFBP-3.

Cyclin D1 A870G polymorphism and the risk of colorectal cancer and adenoma.

Cyclin D1 (CCND1) plays a key role in cell cycle control, particularly in the transition from G1 to S phase, which is regulated by cyclin-dependent kinases. A common adenine to guanine polymorphism (A870G) in the CCND1 gene has been associated with a longer-life protein and an increased risk of colorectal cancer and adenoma in some studies. Among subjects with hereditary nonpolyposis colorectal cancer, the A870G polymorphism has also been associated with a younger age of onset of colorectal cancer. We analysed 181 colorectal cancer cases and 475 matched controls and 524 adenoma cases and 517 matched controls within women in the Nurses' Health Study (NHS) cohort, 171 colorectal cancer cases and 347 matched controls and 372 adenoma cases and 712 matched controls nested within men in the Health Professionals' Follow-Up Study (HPFS) cohort, and 258 colorectal cancer cases and 415 matched controls within men in the Physicians' Health Study (PHS) cohort to assess the risk associated with the CCND1 A870G genotype. Moreover, we assessed whether CCND1 genotype modified the effect of a sporadic (nonsyndromic) family history of colorectal cancer as well as the effect of other dietary and lifestyle risk factors for colorectal cancer and adenoma. In all cohorts combined, the CCND1 polymorphism did not show statistically significant associations to risk of colorectal cancer (odds ratio (OR) for A allele carriers, 1.04; 95% confidence interval (95% CI), 0.82-1.32) or adenoma (OR, 0.96; 95% CI, 0.79-1.18). The CCND1 A870G genotype was associated with a modest, although nonsignificantly elevated risk of colorectal cancer (OR, 1.59; 95% CI, 0.98-2.57) in women. In contrast, the polymorphism was not associated with increased risk of adenoma in either men or women. Among participants with the A870G genotype, a family history of colorectal cancer conferred a substantially greater risk of colorectal cancer in the women (P for interaction=0.06) and adenoma in the men (P for interaction=0.02). Current postmenopausal hormone (PMH) use was associated with a significant reduction in the risk of colorectal cancer and adenoma among women with the A870G genotype, whereas there was no effect of PMH use among those with the GG genotype. The CCND1 polymorphism appeared to confer a modest elevation in the risk of colorectal cancer among women. Moreover, the A870G genotype may enhance the protective effect of postmenopausal oestrogen use on the development of colorectal neoplasia.

Phase I/II study of oral etoposide plus GM-CSF as second-line chemotherapy in platinum-pretreated patients with advanced ovarian cancer.

The aim of this phase I/II study was to determine the maximum tolerated dose (MTD) and the dose-limiting toxicities of chronic oral etoposide given on days 1-10 followed by rescue with subcutaneous (s.c.) granulocyte-macrophage colony-stimulating factor (GM-CSF) on days 12-19 as second-line chemotherapy in platinum-pretreated patients (pts) with advanced ovarian carcinoma. Cohorts of three to six pts were treated with doses of oral etoposide from 750 mg m(-2) cycle(-1) escalated to 1250 mg m(-2) cycle(-1) over 10 days, every 3 weeks. Subcutaneous GM-CSF, 400 mug once daily, days 12-19, was added if dose-limiting granulocytopenia was encountered. In total, 18 pts with a median Karnofsky index of 80% (range, 70-100%) and a median time elapsed since the last platinum dose of 10 months (range, 1-24 months), 30% of whom showed visceral metastases, were treated at four dose levels (DLs) of oral etoposide on days 1-10 of each cycle as follows: DL 1, 750 mg m(-2) cycle(-1), without GM-CSF, three pts; DL 2, 1000 mg m(-2) cycle(-1), without GM-CSF, three pts; DL 3, 1000 mg m(-2) cycle(-1), with GM-CSF, six pts; and DL 4, 1250 mg m(-2) cycle(-1), with GM-CSF, six pts. All pts were assessable for toxicity and 16 pts for response. Dose-limiting toxicity (DLT) was reached at DL 4 by three of six pts, showing World Health Organization (WHO) toxicity grade 4. One patient died from gram-negative sepsis associated with granulocytopenia grade 4. Two more pts developed uncomplicated granulocytopenia grade 4. Thus, we recommend that DL 3 can be used for further phase II evaluation (i.e. oral etoposide 1000 mg m(-2) cycle(-1), days 1-10, followed by s.c. GM-CSF 400 mug, days 12-19). The clinical complete or partial responses in each patient cohort were: DL 1, one of three pts; DL 2, one of three pts; DL 3, three of five pts; and DL 4, two of five pts. In conclusion, in this phase I/II study, we defined the MTD and the dose recommended for the therapy with oral etoposide given over 10 days followed by s.c. GM-CSF in platinum-pretreated patients with advanced ovarian cancer. Our data demonstrate encouraging activity of this regimen and strongly support its further investigation in a phase II study.

Melatonin and cancer risk: does light at night compromise physiologic cancer protection by lowering serum melatonin levels?

The suprachiasmatic nuclei in the hypothalamus, one of the most important physiological determinants of alertness and performance, drive a circadian pacemaker in mammals, with an intrinsic period averaging 24 h. Light is the primary stimulus to the disruption and resetting of this pacemaker, which is expressed in changing melatonin rhythms. Melatonin production in humans decreases when people are exposed to light at night. Since melatonin shows potential oncostatic action in a variety of tumours, it is possible that lowered serum melatonin levels caused by exposure to light at night enhance the general tumour development. Cancer is the second leading cause of death in industrialised countries like the United States, where a significant proportion of workers engage in shift work, making a hypothesised relation between light exposure at night and cancer risk relevant. Observational studies support an association between night work and cancer risk. We hypothesise that the potential primary culprit for this observed association is the lack of melatonin, a cancer-protective agent whose production is severely diminished in people exposed to light at night.

Cholecystectomy and the risk for developing colorectal cancer and distal colorectal adenomas.

Earlier work describes a modest association between cholecystectomy and the risk of colorectal cancer. We conducted a prospective study of 85 184 women, 36-61 years old, who had no history of cancer to evaluate whether known risk factors for colorectal cancer, including dietary history, that have not been controlled for in previous analyses can help explain the observed association. During 16 years of follow-up, 877 cases of colorectal cancer were documented and 1452 women who underwent endoscopy during the follow-up time were diagnosed with distal adenomas. After adjustment for age and other known or suspected risk factors, we found a significant, positive association between cholecystectomy and the risk of colorectal cancer (multivariate relative risk RR 1.21, 95% CI 1.01-1.46). The risk was highest for cancers of the proximal colon (RR 1.34, 95% CI 0.97-1.88) and the rectum (RR 1.58, 95% CI 1.05-2.36). However, we did not observe a significant association between cholecystectomy and distal colorectal adenomas. In this large prospective cohort study, a history of cholecystectomy appears to increase modestly the risk of colorectal cancer, even after adjustment for other colorectal cancer risk factors.

Gallstones, cholecystectomy, and the risk for developing pancreatic cancer.

We examined the relation between gallstones, cholecystectomy, and the development of pancreatic cancer in the Nurses' Health Study and the Health Professionals Follow-up Study. Among 104,856 women and 48,928 men without cancer at baseline, we documented 349 cases of pancreatic cancer during up to 16 years of follow-up. Participants were classified according to a history of gallstones or cholecystectomy. The age-adjusted relative risk of pancreatic cancer following cholecystectomy or diagnosis of gallstones was 1.31 (95% CI, 0.93-1.83). However, adjustment for other pancreatic cancer risk factors attenuated the association (RR=1.11, 95% CI, 0.78-1.56); this risk did not increase with increasing time following cholecystectomy or gallstones. Gallstones or cholecystectomy do not appear to be significant risk factors for pancreatic cancer.