Association of a variant in the muscarinic acetylcholine receptor 2 gene (CHRM2) with nicotine addiction.

Genetic factors contribute to the overall risk of developing nicotine addiction, which is the major cause of preventable deaths in western countries. However, knowledge regarding specific polymorphisms influencing smoking phenotypes remains scarce. In the present study we provide evidence that a common single nucleotide polymorphism (SNP) in the 5' untranslated region of CHRM2, the gene coding for the muscarinic acetylcholine receptor 2 is associated with nicotine addiction. CHRM2 was defined as a candidate gene for nicotine addiction based on previous evidence that linked variations in CHRM2 to alcohol and drug dependence. A total of more than 5,500 subjects representative of the German population were genotyped and assessed regarding their smoking habits. The impact of three SNPs in CHRM2 on smoking behavior/nicotine addiction was investigated using logistic regression models or a quasi-Poisson regression model, respectively. We found the T allele of SNP rs324650 to be associated with an increased risk of smoking/nicotine dependence according to three different models, the recessive models of regular or heavy smokers vs. never-smokers (odds ratio 1.17 in both analyses) and according to the Fagerström index of nicotine addiction. In the analysis stratified by gender this association was only found in females. Our data provide further evidence that variations in CHRM2 may be associated with the genetic risk of addiction in general or with certain personality traits that predispose to the development of addiction. Alternatively, variations in CHRM2 could modulate presynaptic auto-regulation in cholinergic systems and may thereby affect an individual's response to nicotine more specifically.

No evidence for variation in colorectal cancer risk associated with different types of postmenopausal hormone therapy.

Little is known about the effects of various types, modes, and routes of hormone replacement therapy (HRT) on the risk of colorectal cancer (CRC) among postmenopausal women. We conducted a population-based case-control study with validation of self-reported hormone use and no upper age limit. In 1,456 postmenopausal women aged 45-94 years (546 cases, 910 controls), the use of HRT was associated with reduction in CRC risk among ever users (adjusted odds ratio (OR) 0.65, 95% confidence interval 0.50-0.84), current users, and recent users. There was no evidence that risk reduction among current users varies by age. Risk reduction was seen both in estrogen-only therapy (0.42, 0.23-0.78) and in combination therapy (0.60, 0.41-0.87), the latter regardless of the mode of therapy, whether with hormone patches (0.40, 0.17-0.90) or with oral tablets (0.59, 0.39-0.90). In combination with estrogen, progestagens of the norethisterone and levonorgestrel families were associated with strong reduction in CRC risk.

Serum oestrogen receptor alpha and beta bioactivity are independently associated with breast cancer: a proof of principle study.

BACKGROUND: Oestrogens play a crucial role in breast carcinogenesis. Earlier studies have analysed the serum levels of endogenous hormones measured by conventional assays. In this study, we analysed the capacity of serum from breast cancer cases and controls to transactivate the oestrogen receptor alpha (ER-alpha) and beta (ER-beta). METHODS: We used a receptor oestrogen-responsive element (ERE) -- the green fluorescent protein (GFP)-reporter test system in Saccharomyces cerevisiae. Oestrogen receptor-alpha or ER-beta bioactivity was determined in serum from 182 randomly chosen postmenopausal women with breast cancer and from 188 age-matched controls. RESULTS: High serum ER-alpha and ER-beta bioactivity were independently associated with the presence of breast cancer. Women whose levels of serum ER-alpha and ER-beta bioactivity were in the highest quintile among controls had a 7.57-(95% confidence interval (CI): 2.46-23.32; P=0.0004) and a 10.14 (95% CI: 3.19-32.23; P<0.0001)-fold risk for general and oestrogen receptor-positive breast cancer, respectively. CONCLUSION: The use of serum ER-alpha and ER-beta bioactivity assays as clinical tools in the management of breast cancer warrants further research. Future studies will dictate whether surrogate markers of ER-alpha and ER-beta bioactivity will provide a means to monitor the efficacy of anti-endocrine, adjuvant and chemopreventive strategies.

Meta-analysis: longitudinal studies of serum vitamin D and colorectal cancer risk.

BACKGROUND: In 1980, Garland hypothesized that lower levels of vitamin D resulting from much weaker UV-B radiation at higher latitudes may account for the striking geographical pattern of cancer mortality. Further research has been conducted over the past 20 years. AIM: To perform a systematic review and meta-analysis of longitudinal studies on the association between serum 25 hydroxyvitamin D (25(OH)D) and the risk of colorectal cancer (CRC). METHODS: Relevant studies published until September 2008 were identified by systematically searching Ovid Medline, EMBASE, and ISI Web of Knowledge databases and by cross-referencing. Due to the heterogeneity of studies in categorizing serum vitamin D levels, all results were recalculated for an increase of serum 25(OH)D by 20 ng/mL. Summary odds ratios (ORs) were calculated using meta-analysis methods. RESULTS: Overall, eight original articles reporting on the association between serum 25(OH) D and CRC risk were included. In meta-analyses, summary ORs (95% confidence intervals) for the incidence of CRC, colon cancer and rectal cancer associated with an increase of 25(OH)D by 20 ng/mL were 0.57 (0.43-0.76), 0.78 (0.54-1.13) and 0.41 (0.11-1.49). No indication for publication bias was found. CONCLUSIONS: Our results support suggestions that serum 25(OH)D is inversely related to CRC risk.

Association of nicotinic acetylcholine receptor subunit alpha 4 polymorphisms with nicotine dependence in 5500 Germans.

Polymorphisms in the CHRNA4 gene coding the nicotinic acetylcholine receptor subunit alpha 4 have recently been suggested to play a role in the determination of smoking-related phenotypes. To examine this hypothesis, we conducted a genetic association study in three large samples from the German general population (N(1)=1412; N(2)=1855; N(3)=2294). Five single-nucleotide polymorphisms in CHRNA4 were genotyped in 5561 participants, including 2707 heavily smoking cases (regularly smoking at least 20 cigarettes per day) and 2399 never-smoking controls (

Changes in Escherichia coli resistance patterns during and after antibiotic therapy: a longitudinal study among outpatients in Germany.

There is worldwide concern about the appearance and rise of bacterial resistance to commonly used antibiotics. Although the gut is an important reservoir for resistant Escherichia coli, data from large-scale epidemiological studies concerning the colonisation dynamics of the normal gut flora with resistant E. coli during and after antibiotic therapy are sparse. Accordingly, a large community-based study was conducted to ascertain changes in the prevalence of resistant E. coli during and after antibiotic treatment. Stool samples before, during and after antibiotic therapy were obtained from 541 patients (aged >/=40 years) with a febrile infection who attended a general practitioner in southern Germany. The MICs of commonly prescribed antibiotics for E. coli isolates from the stools were determined. The prevalence of resistance to the corresponding antibiotics rose from 18% to 38%, from 29% to 58% and from 33% to 67% during treatment with beta-lactam antibiotics, doxycycline and co-trimoxazole, respectively. Prevalences of resistance in the E. coli isolates also rose for other antibiotic classes. With the exception of co-trimoxazole resistance, prevalences of resistance returned to baseline levels in <2 weeks after the cessation of antibiotic therapy. Thus, there was a substantial, but rapidly reversible, increase in the prevalence of resistant E. coli isolates during antibiotic treatment.

Hormone replacement therapy, body mass, and the risk of colorectal cancer among postmenopausal women from Germany.

Previous studies have reported inconsistent results regarding the modifying effect of hormone replacement therapy (HRT) on the association of body mass index (BMI) and the risk of colorectal cancer (CRC) among postmenopausal women. We assessed the use of HRT and BMI in 208 postmenopausal women with histologically confirmed incident CRC and 246 controls in a population-based case-control study in Germany (DACHS study). Ever use of HRT was strongly associated with reduction of CRC risk (adjusted odds ratio 0.41, 95% confidence interval 0.25-0.67). Among nonusers of HRT, risk of CRC was strongly increased in women with BMI 27 to <30 kg m(-2) (2.76, 1.07-7.12) and obese women (3.30, 1.25-8.72), when compared with women with BMI <23 kg m(-2) (P for trend <0.01). BMI was not associated with risk of CRC among HRT users (P for interaction <0.01). In contrast to most other studies, a positive association of BMI and CRC risk was found among nonusers of HRT, but not among users of HRT. The reasons for the inconsistency of results regarding the potential risk modifying effect of postmenopausal hormones in the association of BMI with CRC remain inconclusive and require further study.

Pain and high sensitivity C reactive protein in patients with chronic low back pain and acute sciatic pain.

BACKGROUND: The severity of pain from musculoskeletal disorders might be associated with high sensitivity C reactive protein (hsCRP), a sensitive marker of low grade systemic inflammation. OBJECTIVE: To study the association between pain as assessed by a visual analogue scale (VAS) and hsCRP in patients with chronic low back pain and acute sciatic pain. METHODS: Information on pain severity, determinants of hsCRP, and hsCRP values were obtained prospectively at up to 10 time points during six months in 72 consecutive patients (mean age 43.3 years; 59.7% female): 41 with chronic low back pain and 31 with acute sciatic pain. The association between severity of pain and raised (highest quartile) hsCRP values at any time point was estimated by multivariable logistic regression using generalised estimating equations to adjust odds ratios (OR) and their confidence intervals (CI) for intraindividual dependence of measurements. RESULTS: Mean intensity of pain (VAS 0-10) at baseline was 4.9 and 5.5 in patients with chronic low back and acute sciatic pain, respectively. Highest v lowest tertile of average intensity of pain during the last 24 hours was associated with increased hsCRP levels among patients with acute sciatic pain (adjusted OR = 3.4 (95% CI, 1.1 to 10), but not in patients with chronic low back pain (adjusted OR = 0.87 (0.25 to 3.0)). CONCLUSIONS: Mean intensity of pain during the previous 24 hours as assessed by VAS was independently associated with high levels of hsCRP in patients with acute sciatic pain but not in those with chronic low back pain.

Standardised work-up programme for fever of unknown origin and contribution of magnetic resonance imaging for the diagnosis of hidden systemic vasculitis.

BACKGROUND: Fever of unknown origin (FUO) is a diagnostic challenge. Rheumatologists are often in charge of patients with FUO because the vasculitides, especially, are potential and common causes of FUO. OBJECTIVE: To evaluate the value of a standardised investigation to identify the cause of FUO. METHODS: A standardised work-up programme for patients with FUO was started at the beginning of September 1999. The rate of identified causes of FUO was compared between all patients with FUO admitted to a tertiary care centre of rheumatology between January 1996 and August 1999 (control group) and September 1999 and January 2003 (work-up group). In January 2002 magnetic resonance imaging (MRI) was added to the investigation. RESULTS: 67 patients with FUO were identified--32 before and 35 after institution of the work-up programme. Before implementation 25% of all patients with FUO remained undiagnosed, after implementation 37%. After institution of the investigation the percentage of patients with vasculitides increased significantly from 6% (n = 2) to 26% (n = 9, p = 0.047, Fisher's exact test). This increase could be attributed to the addition of MRI in 2002. When all patients with FUO before 2002 (n = 55) and thereafter (n = 12) were compared the prevalence of systemic vasculitis increased from 11% (n = 6) to 42% (n = 5, p = 0.021). CONCLUSION: Implementation of a standardised work-up programme for FUO did not improve the overall rate of diagnosis. Addition of MRI significantly increased the diagnosis of systemic vasculitis as the underlying cause of FUO. MRI should be included in the investigation of patients with FUO when vasculitis is suspected.

The impact of maternal education on intrauterine growth: a comparison of former West and East Germany.

BACKGROUND: Objective of this re-analysis of datasets from former East and West Germany was to examine the influence of maternal education on intrauterine growth in two different political and social systems. METHODS: Information on socio-demographic or lifestyle factors and pregnancy outcome was available for 3374 liveborn singletons from West Germany (1987/88) and 3070 from East Germany (1990/91). Multiple logistic regression was used to estimate the association between maternal education and the risk of delivering a small-for-gestational-age (SGA) newborn below the 10th percentile of birthweight. RESULTS: Women with the lowest education had a significantly elevated risk of SGA newborns compared to women with the highest education in West (odds ratio [OR] = 2.58, 95% CI : 1.17-5.67) and East Germany (OR = 2.77, 95% CI : 1.54- 5.00). The distribution of factors known to influence intrauterine growth varied with education in both states. After adjusting for these factors, women with the lowest educational level still had a higher risk of SGA birth: OR (West) = 2.02, 95% CI : 0.87-4.72; OR (East) = 1.95, 95% CI : 1.02-3.74. CONCLUSIONS: Our findings support the assumption that in former socialist countries health inequalities as a result of social inequalities existed.

Infection of human monocyte-derived macrophages with Chlamydia trachomatis induces apoptosis of T cells: a potential mechanism for persistent infection.

Viruses can escape T-cell surveillance by infecting macrophages and thereby induce apoptosis of noninfected T cells. This ability had not been demonstrated for bacteria. We investigated whether infection of macrophages with the important human pathogen Chlamydia trachomatis can induce T-cell apoptosis. Because Chlamydia-Mycoplasma coinfection is a frequent event, the ability of Mycoplasma fermentans-infected macrophages to induce T-cell apoptosis was also studied. Infected macrophages were cocultivated with autologous T cells in different activation states. Propidium iodide-based fluorescence-activated cell sorter analysis demonstrated that macrophages infected with viable chlamydiae induced T-cell death. Apoptosis was identified as the mode of death induction by using a terminal deoxynucleotidyltransferase-mediated dUTP-biotin nick end labeling assay. Induction of T-cell death was macrophage dependent. Incubation of T cells with infectious chlamydiae in the absence of macrophages did not lead to T-cell apoptosis. UV irradiation of chlamydiae diminished the ability to induce death. T-cell death was induced by a cell-free supernatant of infected macrophages. Not only phytohemagglutinin-preactivated T cells but also non-mitogen-preactivated T cells were susceptible to C. trachomatis-induced apoptosis. In contrast, M. fermentans infection of macrophages did not induce T-cell death. Coinfection had no additional effect. In summary, intracellular chlamydial infection of macrophages can induce T-cell apoptosis. Apoptosis induction by chlamydiae possibly explains how persistently infected macrophages escape T-cell surveillance and why the Chlamydia-specific T-cell response is diminished during persistent chlamydial infection.

Maternal occupational exposure to chemical substances and the risk of infants small-for-gestational-age.

BACKGROUND: The association between maternal occupational exposure to specific chemical substances (organic solvents, carbon tetrachloride, herbicides, chlorophenols, polychlorinated biphenyls, aromatic amines, lead and lead compounds, mercury and mercury compounds) and birth of small-for-gestational-age (SGA) infants was evaluated using data from a prospective cohort study of 3,946 pregnant women in West Germany from 1987 to 1988. METHODS: Occupational, medical, and psychosocial information was gathered through a questionnaire from pregnant women who were recruited between 15 and 28 gestational weeks. Exposure to chemical substances at the current workplace was assessed by a job-exposure matrix constructed by Pannett in 1985 and weighted for the number of working hours per week. Women not working at the time of the interview, women with multiple births, and women with stillbirths were excluded from analysis. Data were analyzed using dichotomous and polytomous logistic regression to control for age, smoking status, alcohol consumption, body mass index, and number of former births. RESULTS: The results of the dichotomous logistic regression analysis suggest that leather work might be associated with the birth of infants small-for-gestational-age through exposure to chlorophenols (P = 0.02) and aromatic amines (P = 0.05). In the polytomous logistic regression analysis, only the association between exposure to mercury and growth retardation reached statistical significance (P = 0.02); however, the power of the study is limited. Further adjustment for income, shift work, and heavy physical work had no substantial effect on the results. CONCLUSIONS: These findings suggest that maternal exposure to specific chemicals at work may be a risk factor for the birth of SGA infants.

Two types of health care systems and their influence on the introduction of perinatal care: an epidemiological twin model in Berlin from 1950 to 1990.

OBJECTIVES: When perinatal medicine emerged as a new medical discipline in the 1960s, Berlin was as one of the world's leading centers. During that time, the city was separated into two parts, each fostering its own health care system. After the destruction of the Berlin Wall, it was possible to speak with the citizens of East Berlin and to access their database systems. This created the singular opportunity to objectively compare the development of perinatal care in both parts of Berlin. METHODS: Rates of maternal, perinatal, and infant mortality as well as the rate of preterm deliveries were evaluated over time and between East and West Berlin. The timing of introduction of 20 specific perinatal interventions was evaluated across 18 hospitals with more than 500 deliveries (11 in West Berlin and 7 in East Berlin). Interviews were conducted with 100 gynecologists, 100 midwives, and 100 women who had recently delivered their first child from each side of the city regarding their opinions of the importance of these interventions for the quality of perinatal medicine and how they would distribute a budget to improve maternity care. RESULTS: Maternal, perinatal, and infant mortality decreased in both parts of Berlin until 1990 (p < 0.0001), without significant differences between East and West Berlin, though the preterm delivery rate was slightly lower in East Berlin compared with West Berlin (p < 0.06). Some new clinical techniques and treatments--such as cardiotocography, ultrasound, tocolytic therapy, and peridural anesthesia--were introduced earlier in West Berlin. In contrast, certain public health measures--such as maternal transport, screening programs for diabetes, and support of breastfeeding--were introduced much earlier in East Berlin. There were significant differences between the beliefs of gynecologists, midwives, and mothers in East and West Berlin. In general, citizens of East Berlin were more enthusiastic about technological medical advances, whereas citizens of West Berlin were more supportive of public health and alternative methods. In addition, there were significant differences between female and male physicians in their beliefs about how to improve health care, regardless of whether they resided in East or West Berlin. CONCLUSIONS: The results of this study may serve as a basis for reflection on how different social circumstances and health care policies can influence the improvement of maternal and child health care.

Contamination of human breast milk with organochlorine residues: a comparison between East and West Germany through sentinel practice networks.

STUDY OBJECTIVE: The aim of the study was to assess and compare the contamination of human breast milk with organochlorine residues through two sentinel practice networks in Lower Saxony, a state of former West Germany, and Saxony-Anhalt, a state of former East Germany. DESIGN: Eligible women were enrolled in this cross sectional study by a network of 51 paediatric practices in Lower Saxony and 44 in Saxony-Anhalt when bringing their babies for a regular screening examination four to six weeks after delivery. Sociodemographic, lifestyle, and exposure factors were determined by questionnaire. Milk samples were analysed for hexachlorocyclohexane (HCH), hexachlorbenzole (HCB), DDT, dieldrin, polychlorinated biphenyls (PCB), and heptachlorepoxid (HCE); half the samples were also analysed for dioxin. Analytic statistics were computed using multiple logistic regression. SETTING: The study was conducted in Lower Saxony, Germany, from July 1992 to June 1993, and in Saxony-Anhalt, Germany, from January to June 1995. PARTICIPANTS: 156 primiparous, breast-feeding women from Lower Saxony and 113 from Saxony-Anhalt were studied, who either were born and raised in former West or East Germany, respectively. MAIN RESULT: Mean age of mothers and children differed significantly between the two study groups. In Lower Saxony all but two milk samples were well below the tolerable concentrations established by the German Research Council (Deutsche Forschungsgemeinschaft (DFG)). In Saxony-Anhalt no participant had concentrations above those recommended by the DFG. After adjustment for age of mother and child, occupational and non-occupational pesticide contact, DDT and beta-HCH concentrations were significantly lower in Lower Saxony; HCE and dieldrin concentrations were lower in Saxony-Anhalt. No differences between the two states were found for PCB, HCB, gamma-HCH, and dioxin. CONCLUSIONS: Breast milk contamination levels in former East German Saxony-Anhalt exceeded the contamination in Lower Saxony only for DDT and beta-HCH.

[Predictors of follow-up course of asthma complaints in early childhood--results of a follow-up study]. / Prädiktoren der Verlaufsentwicklung asthmatischer Beschwerden im frühen Kindesalter--Ergebnisse einer Follow-up-Untersuchung.

A follow-up study was undertaken to determine the predictors of the course of recurrent wheezing episodes in children (between 0 to 8 years). In 1991, 600 children with wheezing episodes had been recorded by physicians who participated in a sentinel practice network. On each consultation with the same physicians from October 1994 until June 1995, parents of these children were questioned again about the course of their respiratory symptoms (n = 218). Associations between the course of disease and predictors (recorded by physicians in 1991) were analysed using polytomous logistic regression. The following factors were significantly associated with the frequency of asthmatic episodes (odds ratio (OR) > 1 indicates an unfavourable course of disease in comparison with the reference category, [95% confidence interval]): indoor cigarette smoking: OR = 1.7; [1.0-3.0], older than 1 year of age (reference: < 1 year): OR = 3.0; [1.1-8.5], more than 5 asthmatic episodes during the year before the first registration: OR = 2.7; [1.3-5.6], infect-associated asthma: OR = 0.4 [0.2-1.0], paediatrician as recording physician (reference: general practitioner): OR = 0.4 (0.2-0.8). No significant association with the course of disease was found for sex, education of the parents, region, parental asthma, hospital admissions because of obstructive symptoms. In correspondence with other studies, the majority of children showed a favourable course of their obstructive respiratory symptoms: for only 7% the frequency of episodes increased during 3 years after the first contact. Indoor smoking and severity of asthma are known as predictors of the course of the disease. The better prognosis of infect-associated obstructive symptoms supports the thesis that the majority of infants with asthmatic symptoms have narrow, infect-mediated airways obstructions, but no increased risk for bronchial asthma in their later lives. An early identification of children at risk may allow a specific and intensified therapy to improve the course of disease.

Renal hemodynamics in recent-onset type II diabetes.

Glomerular hyperfiltration is thought to play an important role in the genesis of diabetic nephropathy. While hyperfiltration is well documented in early type I diabetes, the evidence for hyperfiltration in type II diabetes is conflicting. We investigated 16 nonproteinuric patients with recently diagnosed type II diabetes. Glomerular filtration rate (GFR) and effective renal plasma flow (ERPF) were measured as inulin clearance (CIN) and p-aminohippuric acid clearance (CPAH) using a constant infusion technique. Lean body mass was measured by densitometry (weighing under water). Renal hemodynamics were also measured in 31 healthy volunteers and six obese nondiabetic individuals. Median GFR in diabetics (133 mL/min/1.73 m2; range, 95 to 165) was significantly (P < 0.01) higher than in obese nondiabetic controls (median, 118; range, 95 to 139). Elevated GFR (ie, > 95th percentile of nonobese healthy controls) was found in 44% of patients. When GFR was factored for lean body mass, it was elevated in 50%. GFR did not correlate with fasting glucose, hemoglobin A1C (HbA1C), insulin-like growth factors, IGF-1 and IGF-2, or somatomedin-binding protein (SMBP). The findings document that hyperfiltration is common in recent-onset type II diabetics.