[Weight gain and treatment with psychotropic drugs : Background and management]. / Gewichtszunahme unter Therapie mit Psychopharmaka : Hintergründe und Management.

Psychotropic drug-induced weight gain (PIWG) is a well-known and frequent side effect which is relevant for the prognosis of patients. Individual medications have varying risks for the occurrence of PIWG, and at the same time there are individual risk factors on the part of patients, such as age, gender, metabolic and genetic factors. As the metabolic changes in the context of PIWG result in increased mortality in the long term, it is important to prevent PIWG by appropriate prevention and to intervene in a targeted manner if PIWG has already occurred. Appropriate monitoring is therefore essential. This article provides an overview of underlying mechanisms, risk constellations and possible countermeasures.

Effects of Radiation Exposure on the Cost-Effectiveness of CT Angiography and Perfusion Imaging in Aneurysmal Subarachnoid Hemorrhage.

BACKGROUND AND PURPOSE: CT angiography and perfusion imaging is an important prognostic tool in the management of patients with aneurysmal subarachnoid hemorrhage. The purpose of this study was to perform a cost-effectiveness analysis of advanced imaging in patients with SAH, incorporating the risks of radiation exposure from CT angiography and CT perfusion imaging. MATERIALS AND METHODS: The risks of radiation-induced brain cancer and cataracts were incorporated into our established decision model comparing the cost-effectiveness of CT angiography and CT perfusion imaging and transcranial Doppler sonography in SAH. Cancer risk was calculated by using National Cancer Institute methodology. The remaining input probabilities were based on literature data and a cohort at our institution. Outcomes were expected quality-adjusted life years gained, costs, and incremental cost-effectiveness ratios. One-way, 2-way, and probabilistic sensitivity analyses were performed. RESULTS: CT angiography and CT perfusion imaging were the dominant strategies, resulting in both better health outcomes and lower costs, even when incorporating brain cancer and cataract risks. Our results remained robust in 2-way sensitivity analyses varying the prolonged latency period up to 30 years, with either brain cancer risk up to 50 times higher than the upper 95% CI limit or the probability of cataracts from 0 to 1. Results were consistent for scenarios that considered either symptomatic or asymptomatic patients with SAH. Probabilistic sensitivity analysis confirmed our findings over a broad range of selected input parameters. CONCLUSIONS: While risks of radiation exposure represent an important consideration, CT angiography and CT perfusion imaging remained the preferred imaging compared with transcranial Doppler sonography in both asymptomatic and symptomatic patients with SAH, with improved health outcomes and lower health care costs, even when modeling a significantly higher risk and shorter latency period for both cataract and brain cancer than that currently known.

Continuous Combined Estrogen Plus Progestin and Endometrial Cancer: The Women's Health Initiative Randomized Trial.

BACKGROUND: While progestin addition to estrogen mitigates endometrial cancer risk, the magnitude of the effect on incidence, specific endometrial cancer histologies, and endometrial cancer mortality remains unsettled. These issues were assessed by analyses after extended follow-up of the Women's Health Initiative (WHI) randomized clinical trial evaluating continuous combined estrogen plus progestin use. METHODS: The WHI enrolled 16 608 postmenopausal women into a randomly assigned, double-blind, placebo-controlled trial. Women age 50 to 79 years with intact uteri with normal endometrial biopsy at entry were randomly assigned to once-daily 0.625 mg conjugated equine estrogen plus 2.5mg medroxyprogesterone acetate (n = 8506) as a single pill or matching placebo (n = 8102). Follow-up beyond the original trial completion date required reconsent, obtained from 12 788 (83%) of surviving participants. Analyses were by intent-to-treat. All statistical tests were two-sided. RESULTS: After 5.6 years' median intervention and 13 years' median cumulative follow-up, there were fewer endometrial cancers in the combined hormone therapy compared with the placebo group (66 vs 95 case patients, yearly incidence, 0.06% vs 0.10%; hazard ratio [HR] = 0.65, 95% confidence interval [CI] = 0.48 to 0.89, P = .007). While there were somewhat fewer endometrial cancers during intervention (25 vs 30, respectively; HR = 0.77, 95% CI = 0.45 to 1.31), the difference became statistically significant postintervention (41 vs 65, respectively; HR = 0.59, 95% CI = 0.40 to 0.88, P = .008), but hazard ratios did not differ between phases (P difference = .46). There was a statistically nonsignificant reduction in deaths from endometrial cancer in the estrogen plus progestin group (5 vs 11 deaths, HR = 0.42, 95% CI = 0.15 to 1.22). CONCLUSION: In postmenopausal women, continuous combined estrogen plus progestin decreases endometrial cancer incidence.

Glycemic index, glycemic load, and the risk of pancreatic cancer among postmenopausal women in the women's health initiative observational study and clinical trial.

BACKGROUND: Several reports have suggested that conditions associated with hyperinsulinemia and insulin resistance, such as diets high in carbohydrates, may influence the risk of pancreatic cancer, although results from prior studies have been mixed. METHODS: We utilized data from the population-based women's health initiative (WHI) cohort to determine whether dietary factors that are associated with increased postprandial blood glucose levels are also associated with an increased risk of pancreatic cancer. The WHI included 161,809 postmenopausal women of ages 50-79, in which 332 cases of pancreatic cancer were identified over a median of 8 years of follow-up; 287 of these cases met the criteria for analysis. A validated 122-item food frequency questionnaire was used to estimate dietary glycemic load (GL), glycemic index (GI), total and available carbohydrates, fructose and sucrose. Baseline questionnaires and physical exams provided information on demographic, medical, lifestyle, and anthropometric characteristics. Cox proportional hazards models were used to estimate hazard ratios (HR) and 95% confidence intervals (CI) for the association between the exposures of interest and pancreatic cancer risk, with adjustment for potential confounders. RESULTS: Dietary GL, GI, carbohydrates, fructose, and sucrose were not associated with increased risk of pancreatic cancer. The multivariable adjusted HR for the highest vs. the lowest quartile of GL was 0.80 (95% CI = 0.55-1.15, trend p = 0.31) and 1.13 (95% CI = 0.78-1.63, trend p = 0.94) for GI. The results remained negative when individuals with a history of diabetes were excluded. CONCLUSIONS: Our results do not support the hypothesis that dietary intake of carbohydrates is associated with increased risk of pancreatic cancer.

A study of association between common variation in the growth hormone-chorionic somatomammotropin hormone gene cluster and adult fasting insulin in a UK Caucasian population.

BACKGROUND: Reduced growth during infancy is associated with adult insulin resistance. In a UK Caucasian cohort, the CSH1.01 microsatellite polymorphism in the growth hormone-chorionic somatomammotropin hormone gene cluster was recently associated with increases in adult fasting insulin of approximately 23 pmol/l for TT homozygote males compared to D1D1 or D2D2 homozygotes (P = 0.001 and 0.009; n = 206 and 92, respectively), but not for females. TT males additionally had a 547-g lower weight at 1 year (n = 270; P = 0.008) than D2D2 males. We sought to replicate these data in healthy UK Caucasian subjects. We genotyped 1396 subjects (fathers, mothers and children) from a consecutive birth study for the CSH1.01 marker and analysed genotypes for association with 1-year weight in boys and fasting insulin in fathers. RESULTS: We found no evidence for association of CSH1.01 genotype with adult male fasting insulin concentrations (TT/D1D1 P = 0.38; TT/D2D2 P = 0.18) or weight at 1 year in boys (TT/D1D1 P = 0.76; TT/D2D2 P = 0.85). For fasting insulin, our data can exclude the previously observed effect sizes as the 95 % confidence intervals for the differences observed in our study exclude increases in fasting insulin of 9.0 and 12.6 pmol/l for TT relative to D1D1 and D2D2 homozygotes, respectively. Whilst we have fewer data on boys' 1-year weight than the original study, our data can exclude a reduction in 1-year weight greater than 557 g for TT relative to D2D2 homozygotes. CONCLUSION: We have not found association of the CSH1.01 genotype with fasting insulin or weight at 1 year. We conclude that the original study is likely to have over-estimated the effect size for fasting insulin, or that the difference in results reflects the younger age of subjects in this study relative to those in the previous study.

Reproductive factors and subtypes of breast cancer defined by hormone receptor and histology.

Reproductive factors are associated with reduced risk of breast cancer, but less is known about whether there is differential protection against subtypes of breast cancer. Assuming reproductive factors act through hormonal mechanisms they should protect predominantly against cancers expressing oestrogen (ER) and progesterone (PR) receptors. We examined the effect of reproductive factors on subgroups of tumours defined by hormone receptor status as well as histology using data from the NIHCD Women's Contraceptive and Reproductive Experiences (CARE) Study, a multicenter case-control study of breast cancer. We estimated odds ratios (ORs) and 95% confidence intervals (CIs) as measures of relative risk using multivariate unconditional logistic regression methods. Multiparity and early age at first birth were associated with reduced relative risk of ER + PR + tumours (P for trend=0.0001 and 0.01, respectively), but not of ER - PR - tumours (P for trend=0.27 and 0.85), whereas duration of breastfeeding was associated with lower relative risk of both receptor-positive (P for trend=0.0002) and receptor-negative tumours (P=0.0004). Our results were consistent across subgroups of women based on age and ethnicity. We found few significant differences by histologic subtype, although the strongest protective effect of multiparity was seen for mixed ductolobular tumours. Our results indicate that parity and age at first birth are associated with reduced risk of receptor-positive tumours only, while lactation is associated with reduced risk of both receptor-positive and -negative tumours. This suggests that parity and lactation act through different mechanisms. This study also suggests that reproductive factors have similar protective effects on breast tumours of lobular and ductal origin.

Radial bone density and breast cancer risk in white and African-American women.

A number of different models for assessing individual risk of breast cancer use known risk factors such as age, age at menarche, age at first live birth, previous breast biopsies, and family history. High bone mass in white women is also associated with an increased breast cancer risk; however, bone mass as a risk factor has not been studied in African-American women. We conducted a case-control study to evaluate bone mineral density as a risk factor for breast cancer in white and African-American women. We recruited 221 women with newly diagnosed breast cancer from a comprehensive breast cancer center at a large university hospital, and 197 control women who were frequency matched for ethnicity and age. Odds ratios were based on proximal and distal radial bone density measured by peripheral bone densitometry (Norland pDEXA) and expressed as a standardized "Z-score" (age and ethnicity specific). Logistic regression models were fitted controlling for body mass index, menopausal status, age, and HRT use (ever/never and duration). With proximal bone density Z-score included in the model as a continuous variable, a one-unit increase in radial shaft bone density increased the risk of breast cancer by 25% (p=0.02). When proximal bone density Z-score was analyzed as a dichotomous variable (< or = 0, > 0) the odds ratio was 1.98 (95% CI, 1.32 to 2.97); that is, having an above average proximal bone density (age-specific) doubles the risk of breast cancer. There were no significant interactions with, and no appreciable confounding effects by, other covariates. An above-average radial shaft Z-score is a significant risk factor for breast cancer in both white and African-American women. The present study extends the association between bone mass and breast cancer risk to African-Americans, and suggests another potential application for bone density testing.

Lack of support for a role of the insulin gene variable number of tandem repeats minisatellite (INS-VNTR) locus in fetal growth or type 2 diabetes-related intermediate traits in United Kingdom populations.

The insulin gene variable number of tandem repeats minisatellite (INS-VNTR) class III allele is associated with altered fetal growth, type 2 diabetes risk (especially when paternally inherited), and insulin and IGF2 gene expression. Further studies are needed to establish the role of the INS-VNTR in fetal growth and assess whether its effects depend on the parent of origin. We analyzed the INS-VNTR-linked -23 Hph1 polymorphism in 2283 subjects, comprising 1184 children and 1099 parents. There were no differences (P < 0.05) in birth weight between offspring of the three genotypes: III/III (n = 108) vs. I/I (n = 558), effect size, -8 g (P = 0.87); and I/III (n = 464) vs. I/I, effect size, -19 g (P = 0.54). We observed no differences in head circumference [III/III (n = 95) vs. I/I (n = 470), effect size, -0.14 cm; P = 0.31] or birth length. No differences were observed when stratifying by postnatal growth realignments [nonchangers III/III (n = 37) vs. I/I (n = 170), effect size, -43 g; P = 1.00] or by parent of origin of the class III allele (presence of paternal III allele effect size, -15 g; P = 0.74). INS-VNTR was nominally associated (P < 0.05) with body mass index and insulin resistance, but not with beta-cell function, in young adults. In the largest study to date, we found a lack of support for a role for INS-VNTR in fetal growth and nominal association with type 2 diabetes-related intermediate traits.

Genetic variation in the small heterodimer partner gene and young-onset type 2 diabetes, obesity, and birth weight in U.K. subjects.

The orphan receptor small heterodimer partner (SHP, NR0B2) modulates the transcription activity of the MODY1 gene HNF4a. Mutations in SHP were found in 7% of Japanese obese young-onset type 2 diabetic patients and were associated with moderate obesity and increased birth weight. We investigated SHP in 1927 U.K. subjects, examining relationships with type 2 diabetes, obesity, and birth weight. Sequencing of the coding region of SHP in 122 obese, young-onset type 2 diabetic patients detected the polymorphism G171A. The polymorphism was not associated with diabetes in case control or familial association studies. The A allele (frequency 0.07) was not associated with obesity in type 2 diabetic subjects (n = 348), their parents (n = 272), or young nondiabetic adults (n = 925). However, the rare (<1%) AA homozygotes had a raised BMI in each cohort; this was significant when all cohorts were combined (Z score = 0.67 AA vs. -0.05 G/x, P = 0.02). There was no association with corrected birth weight in 382 normal babies, but the only AA baby was 4,069 g. Our study suggests that genetic variation in SHP is unlikely to be common in the predisposition to diabetes, obesity, or increased birth weight in U.K. Caucasians.

The role of transcription factors in maturity-onset diabetes of the young.

The study of maturity-onset diabetes of the young (MODY), an autosomal dominant form of early-onset diabetes mellitus characterised by defective insulin secretion has been extremely successful in two ways. Firstly it has enabled definitive diagnosis for patients. This allows more accurate prediction of disease and treatment requirements. Secondly it has facilitated an increased understanding of the genes and pathways that are crucial for normal beta-cell function. Five of the six MODY genes, TCF1 (encoding HNF-1alpha), TCF2 (encoding HNF-1beta) HNF4A, insulin promoter factor (IPF)1, and NEUROD1, are transcription factors that operate in a complex network of gene regulation. Several genes have been shown to be regulated by the MODY transcription factors in a beta-cell specific manner. This includes the co-regulation of HNF-1alpha and HNF-4alpha by each other. The exact mechanism of how mutations in these transcription factors result in diabetes in humans remains unknown. However, current opinion favours pleiotropic adverse effects on many genes; extensive in vitro and in vivo studies of these genes has highlighted their importance in both glucose sensing-insulin secretion coupling and maintaining the fully differentiated beta-cell phenotype.

The role of the HNF4alpha enhancer in type 2 diabetes.

The genetic causes of type 2 diabetes are not well understood. The disease has been linked to chromosome 20q12-q13.1 a region which harbors the transcription factor HNF4alpha. Mutations in the coding region of HNF4alpha cause maturity onset diabetes of the young, an autosomal dominant form of diabetes, but do not account for the linkage to this region. An enhancer element has recently been characterized 6 kb 5' of the HNF4alpha P1 promoter containing binding sites for the transcription factors HNF1, HNF4, HNF3, and C/EBP, which are overlapped by glucocorticoid consensus sites. We hypothesized that variation in the enhancer element disrupts HNF4alpha expression in the liver and increases susceptibility to type 2 diabetes. We screened for variants of the enhancer element in 39 white UK young onset diabetic subjects, giving >95% power to identify variants with minor allele frequencies of >5%. No variants of the enhancer element were found in this population. We conclude that variation in the HNF4alpha enhancer element is not a common cause of susceptibility to type 2 diabetes.

A putative functional polymorphism in the IGF-I gene: association studies with type 2 diabetes, adult height, glucose tolerance, and fetal growth in U.K. populations.

IGF-I has a critical role in growth and metabolism. A microsatellite polymorphism 1 kb upstream to the IGF-I gene has recently been associated with several adult phenotypes. In a large Dutch cohort, the absence of the commonest allele (Z) was associated with reduced serum IGF-I levels, reduced height, and an increased risk of type 2 diabetes and myocardial infarction. This result has not been replicated, and the role of this polymorphism in these traits in U.K. subjects is not known. We sought further evidence for the involvement of this variant in type 2 diabetes using a case-control study and IGF-I and diabetes-related traits in a population cohort of 640 U.K. individuals aged 25 years. Absence of the common allele was not associated with type 2 diabetes (odds ratio 0.70, 95% CI 0.47-1.04 for X/X versus Z/Z genotype, chi(2) test for trend across genotypes, P = 0.018). In the population cohort, the common allele (Z) was associated with decreased IGF-I levels (P = 0.01), contrary to the Dutch study, but not with adult height (P = 0.23), glucose tolerance (P = 0.84), oral glucose tolerance test-derived values of beta-cell function (P = 0.90), or insulin resistance (P = 0.66). There was no association with measures of fetal growth, including birth weight (P = 0.17). Our results do not support the previous associations and suggest that the promoter microsatellite is unlikely to be functionally important.

The effect of patient reminders on the use of screening mammography in an urban health department primary care setting.

Mammography screening continues to be under-utilized, especially among women from lower socioeconomic groups. In order to determine whether having direct access to health care services has an effect on mammography use among low income women, we conducted a randomized trial of two alternative letter reminders among 1,717 women who were enrolled at two locations of a multi-site inner city health department in Detroit. All participants were 39(1/2) years of age and older and were due for a screening mammogram at randomization. A physician-directed reminder form was placed in each of the participant's medical records at the beginning of the study. In addition participants were randomized to receive either a letter directing them to visit their primary care physician, a letter directing them to contact the clinic directly to schedule a mammogram, or no letter. Study participants were predominantly African-American, two-thirds of whom were over age 50, and who had minimal health insurance coverage. During the intervention year, mammograms were completed by 179 out of 967 study women at site one (18.5%), and 90 out of 750 study women at site two (12%). A multivariate model controlling for the simultaneous effect of age, insurance type, visit history and past mammography use, showed no significant independent effect of either type of letter reminder on mammography completion during the study year. In conclusion, letters targeted at women due for screening mammograms did not have a beneficial effect on mammography utilization above and beyond that of a physician medical record reminder.

Levels of 5-hydroxymethyl-2'-deoxyuridine in DNA from blood of women scheduled for breast biopsy.

Systemic oxidative stress is thought to contribute to risk of various cancers, including breast cancer. DNA repair ability also has been associated with breast cancer risk. In this work, we examined levels of oxidative DNA damage as an indication of breast cancer risk in women because oxidative DNA damage levels should reflect the net balance of oxidative stress and DNA repair ability. Levels of 5-hydroxymethyl-2'-deoxyuridine, one form of oxidative DNA damage, were measured in DNA from blood of women scheduled for breast biopsy. The blood samples analyzed included women whose biopsy results indicated invasive breast cancer, high-risk lesions (atypical hyperplasia or carcinoma in situ), or benign lesions. Mean levels of 5-hydroxymethyl-2'-deoxyuridine were significantly higher in blood of women who had high risk or invasive breast lesions versus women with benign lesions. If atypical hyperplasia or carcinoma in situ are precursor lesions for breast cancer, then these results suggest that oxidative DNA damage may be involved in the cancer process before invasive cancer develops.

Comparison of dietary assessment methods in a low-fat dietary intervention program.

The food frequency questionnaire (FFQ) is commonly utilized for assessment of dietary fat intake, but its validity among individuals following a low-fat diet is unclear. We evaluated the agreement of nutrient estimates derived from FFQ, 24-h recall, and 3-day food records obtained from 104 participants in a randomized trial of a low-fat dietary intervention for women at elevated breast cancer risk. Comparisons were made for total calories, percent calories from fat, and total fat after 1 yr. Correlation was assessed using standard methods based on a null hypothesis of no agreement between instruments as well as by a methodology based on a null hypothesis that the instruments should be in agreement. With the use of standard methods, FFQ estimates for women on the low-fat diet were significantly correlated to records only for percent calories from fat (r = 0.39), whereas recall and record estimates were significantly correlated for all three dietary variables. Using the new method, we found no significant correlation between FFQ and either recalls or records for women following a low-fat diet but significant correlation between recall and record estimates for total calories (r = 0.67). Traditional correlation testing may overestimate the extent of agreement in dietary instruments among women on a low-fat diet. We found empirical support for the nontraditional method.

Recruitment for a pilot case control study of oxidative DNA damage and breast cancer risk.

Oxidative DNA damage (ODD) can result from numerous endogenous metabolic processes as well as from exposure to environmental and dietary oxidants. One important type of ODD that may have a role in carcinogenesis is the formation of hydroxylated DNA bases. Our major purpose was to determine the potential for subject accrual for a multisite case-control study of ODD and breast cancer risk within a large urban university medical center. We examined the levels of a hydroxylated thymine residue, 5-hydroxymethyl-2'-deoxyuridine in DNA obtained from the peripheral blood of 26 women with breast cancer and an age-matched group of 29 control women without breast cancer. The isolated DNA was analyzed for levels of 5-hydroxymethyl-2'-deoxyuridine by gas chromatography with mass spectral detection. Our recruitment methods resulted in a relatively high yield of eligible cases (72%) and a lower yield of controls (46%). We evaluated the dose-response relationship of ODD level to breast cancer risk, using quartiles of ODD. The covariate-adjusted odds ratio of breast cancer exceeded 2.0 for women in the highest quartile of ODD (compared with the lowest quartile), although this result was not statistically significant. ODD levels were significantly more variable among African-American controls (SD = 224.1) than among white controls (SD = 57.5), p < 0.001. Overall, these results suggest a possible slight increase in breast cancer risk among women in the highest ODD quartile, after adjusting for race, menopausal status, and family history of breast cancer.

Follow-up among women with an abnormal mammogram in an HMO: is it complete, timely, and efficient?

OBJECTIVE: To describe the extent to which women with seriously abnormal mammograms complete indicated follow-up, the timeliness of this follow-up, and variations in the pattern of use of diagnostic procedures. STUDY DESIGN: Retrospective chart review. PATIENTS AND METHODS: Ninety-two women enrolled in a single urban health maintenance organization (HMO) with an abnormal index mammogram (mass or suspicious calcifications) during 1995 or 1996 were identified by review of all HMO mammography reports. Data were abstracted from medical records concerning all clinical services received over the 11 months after the date of the abnormal mammogram. Procedure costs were estimated based on 1997 Medicare relative-value units. Logistic regression and a multivariate accelerated failure-time model were used to evaluate the association between predictor variables and the occurrence and timing of completion of follow-up. RESULTS: Follow-up was not completed by 31 (34%) of the 92 study women and was delayed beyond 60 days for another 32 (35%). In adjusted analysis, factors associated with completion within 60 days included age less than 50 years and inclusion of a specific follow-up recommendation in the mammogram report. Completion by the end of the study (a minimum of 11 months after the index mammogram) was associated only with the presence of a specific follow-up recommendation. The follow-up process (i.e., the diagnostic procedures used) was highly variable but almost always included surgical evaluation. The average cost among those completing follow-up was about $1900 (in 1997 dollars). CONCLUSIONS: Incomplete follow-up after a potentially seriously abnormal mammogram constitutes an important barrier to breast cancer control efforts in the study HMO, but its explanation remains incompletely understood. The follow-up process itself is highly variable, and improvement in its efficiency and timely completion will require a better understanding of its determinants.