Stressful life-events in childhood and risk of multiple sclerosis: a Danish nationwide cohort study.

BACKGROUND: Current knowledge concerning the association between exposure to stressful life-events (SFLEs) in childhood and later risk of multiple sclerosis (MS) is sparse. OBJECTIVES: We studied the associations between SFLEs in childhood and subsequent risk of MS in a nationwide cohort of 2.9 million Danes born from 1968 to 2011. METHODS: A SFLE in childhood was defined as exposure before age 18 years to parental divorce, parental death, or death of a sibling, using information from the Danish Civil Registration System. MS cases in the cohort were identified in the Danish Multiple Sclerosis Registry. Associations of SFLE with MS risk were evaluated by incidence rate ratios (RR) of MS obtained in log-linear Poisson regression models. RESULTS: Persons exposed to any SFLE in childhood were at 11% elevated risk of MS (RR = 1.11; 95% confidence interval: 1.03-1.20), compared to non-exposed persons. Stratification by subtype of SFLE showed that parental death and death of a sibling were not associated with MS risk. However, persons exposed to parental divorce were at 13% increased risk of developing MS compared to non-exposed (RR = 1.13; 1.04-1.23). CONCLUSIONS: Associations of SFLEs in childhood with risk of MS are weak. However, parental divorce is somehow associated with modestly increased risk of MS.

Socioeconomic factors in childhood and the risk of multiple sclerosis.

In a national cohort comprising 1.5 million Danes born from 1966 to 1992, we studied the association between childhood socioeconomic status (SES) and the risk of multiple sclerosis (MS) from 1981 to 2007 using information about household income and parental educational levels at the person's 15th birthday. The association between childhood SES and MS was evaluated using MS incidence rate ratios with 95% confidence intervals obtained in log-linear Poisson regression analyses. We found no strong association between childhood SES and MS but did observe a tendency toward a reduced risk of MS among children from households with more highly educated parents, particularly mothers. Children whose mothers had a secondary (rate ratio = 0.95, 95% confidence interval: 0.86, 1.04) or higher (rate ratio = 0.86, 95% confidence interval: 0.76, 0.97) education had reduced risks of MS (5% and 14%, respectively) compared with children of mothers with a basic education (P for trend = 0.02). Results were practically unchanged in an analysis restricted to persons aged 15-29 years, among whom the possible effect of own SES on MS risk is considered limited. Overall, SES in childhood seems of no major importance for the subsequent risk of MS; however, offspring of well-educated mothers may be at a slightly reduced risk of MS.

Cesarean section and offspring's risk of multiple sclerosis: a Danish nationwide cohort study.

BACKGROUND: Apart from a recent study reporting a 2- to 3-fold increased risk of multiple sclerosis (MS) among women and men who were delivered by Cesarean section (C-section), little attention has been given to the possible association between mode of delivery and the risk of MS. OBJECTIVES: We studied the association between C-section and risk of MS, in a cohort of 1.7 million Danes born from 1973 to 2005. METHODS: Information on C-section and MS was obtained from the Danish Medical Birth Register and the Danish MS Register, respectively. The association between C-section and MS was evaluated by means of MS incidence rate ratios (RR) with 95% confidence intervals (CI) obtained in log-linear Poisson regression analyses. RESULTS: There were 930 cases of MS in the study cohort, of whom 80 (9%) were delivered by C-section. Overall, we found there was no significant association between C-section and risk of MS (RR = 1.17; 0.92-1.46). Analyses stratified by sex revealed no unusual risk of MS for women (RR = 1.08: 0.80-1.42) nor men (RR = 1.37: 0.91-1.98). A supplementary sibling-matched Cox regression analysis likewise suggested there was no excess risk of MS in persons delivered by C-section (HR = 1.03; 0.63-1.69). CONCLUSIONS: Mode of delivery appears to be unimportant in relation to MS development in the offspring.

Reproductive history and risk of multiple sclerosis.

BACKGROUND: It has been suggested that reproductive factors may be involved in the etiology of multiple sclerosis (MS). We studied associations of reproductive history with MS risk in a population-based setting. METHODS: Using national databases, we established a cohort comprising 4.4 million Danish men and women born between 1935 and 1989 and alive in 1968 or later. We obtained information about their live-born children, pregnancy losses, pregnancy complications, and infertility diagnoses. MS cases in the cohort were identified through 2004 in the Danish Register of Multiple Sclerosis. Associations between reproductive factors and MS risk were evaluated using rate ratios (RRs) obtained in log-linear Poisson regression analysis. RESULTS: MS was diagnosed in 6332 women and 3426 men. In both sexes, parents had a lower risk of MS compared with childless persons (in women, RR = 0.76 [95% confidence interval = 0.71-0.82]; in men, 0.89 [0.80-0.98]). RRs were inversely associated with number of children, age at first childbirth, and proximity in time since most recent birth. Among women, MS risk was unrelated to histories of pregnancy loss, pregnancy complications, or infertility. A supplementary analysis in which the date of MS diagnosis was backdated by 5 years to address the possibility of reverse causality did not confirm a protective effect of parenthood (in women, 0.95 [0.88-1.03]; in men, 1.08 [0.98-1.20]). CONCLUSIONS: Similar findings in women and men argue against a biologic role of pregnancy in the etiology of MS. Moreover, the observed differences in childbearing patterns were restricted to the 5 years before MS diagnosis, suggesting that reverse causality (ie, reduced reproductive activity in persons with yet-undiagnosed MS) might explain the observed associations.

The co-occurrence of endometriosis with multiple sclerosis, systemic lupus erythematosus and Sjogren syndrome.

BACKGROUND: In a previous study, women with endometriosis were found to be at a 7-24-fold increased risk of multiple sclerosis (MS), systemic lupus erythematosus (SLE) and Sjögren syndrome (SS). We examined these associations in a large population-based cohort study. METHODS: We followed 37 661 women registered with endometriosis in the Danish Hospital Discharge Register 1977-2007 for subsequent hospitalizations with MS, SLE or SS. As measures of relative risk, we used ratios of observed to expected incidence rates of first hospitalizations for MS, SLE and SS among women with endometriosis, i.e. standardized incidence ratios (SIR) with accompanying 95% confidence intervals (CIs). RESULTS: During slightly more than 456 000 person-years of follow-up, we identified 130, 54 and 86 cases of MS, SLE and SS, respectively, yielding SIRs of 1.2 (95% CI 1.05-1.5) for MS, 1.6 (1.2-2.1) for SLE and 1.6 (1.3-2.0) for SS. In a supplementary analysis restricted to 9191 women with laparoscopy or laparotomy confirmed endometriosis, associations were unchanged for MS (SIR = 1.4; 1.04-1.9), but lost statistical significance for SLE (SIR = 1.1; 0.6-2.1) and SS (SIR = 1.4; 0.9-2.3). CONCLUSIONS: Our national cohort-based findings do not support prior claims of markedly increased risks of MS, SLE and SS in women with endometriosis. However, whether women with endometriosis are truly at a modestly (20-60%) elevated risk of one or more of the studied autoimmune diseases must await clarification in future large-scale prospective studies.

Associations of unhealthy lifestyle factors with sexual inactivity and sexual dysfunctions in Denmark.

INTRODUCTION: Studies have linked obesity, a sedentary lifestyle, and tobacco smoking to erectile dysfunction, but the evidence linking unhealthy lifestyle factors to other sexual dysfunctions or to sexual inactivity is conflicting. AIM: To examine associations between unhealthy lifestyle factors and sexual inactivity with a partner and four specific sexual dysfunctions in each sex. METHODS: We used nationally representative survey data from 5,552 Danish men and women aged 16-97 years in 2005. Cross-sectional associations of lifestyle factors with sexual inactivity and sexual dysfunctions were estimated by logistic regression-derived, confounder-adjusted odds ratios (ORs). MAIN OUTCOME MEASURES: We calculated ORs for sexual inactivity with a partner and for sexual dysfunction and sexual difficulties overall in both sexes, for erectile dysfunction, anorgasmia, premature ejaculation, and dyspareunia in men, and for lubrication insufficiency, anorgasmia, dyspareunia, and vaginismus in women. RESULTS: Obesity (body mass index [BMI]≥30 kg/m(2) ) or a substantially increased waist circumference (men ≥102 cm; women ≥88 cm), physical inactivity, and, among women, tobacco smoking were each significantly associated with sexual inactivity in the last year. Among sexually active men, both underweight (BMI <20 kg/m(2) ) and obesity, a substantially increased waist circumference, physical inactivity in leisure time, high alcohol consumption (>21 alcoholic beverages/week), tobacco smoking, and use of hard drugs were each significantly positively associated with one or more sexual dysfunctions (ORs between 1.71 and 22.0). Among sexually active women, the only significant positive association between an unhealthy lifestyle factor and sexual dysfunction was between hashish use and anorgasmia (OR 2.85). CONCLUSION: In both sexes, several unhealthy lifestyle factors were associated with sexual inactivity with a partner in the last year. Additionally, among sexually active participants, men with unhealthy lifestyles were significantly more likely to experience sexual dysfunctions. Considering the importance of a good sex life, our findings may be useful in attempts to promote healthier lifestyles.

Sexual dysfunctions and difficulties in denmark: prevalence and associated sociodemographic factors.

Sexual dysfunctions and difficulties are common experiences that may impact importantly on the perceived quality of life, but prevalence estimates are highly sensitive to the definitions used. We used questionnaire data for 4415 sexually active Danes aged 16-95 years who participated in a national health and morbidity survey in 2005 to estimate the prevalence of sexual dysfunctions and difficulties and to identify associated sociodemographic factors. Overall, 11% (95% CI, 10-13%) of men and 11% (10-13%) of women reported at least one sexual dysfunction (i.e., a frequent sexual difficulty that was perceived as a problem) in the last year, while another 68% (66-70%) of men and 69% (67-71%) of women reported infrequent or less severe sexual difficulties. Estimated overall frequencies of sexual dysfunctions among men were: premature ejaculation (7%), erectile dysfunction (5%), anorgasmia (2%), and dyspareunia (0.1%); among women: lubrication insufficiency (7%), anorgasmia (6%), dyspareunia (3%), and vaginismus (0.4%). Highest frequencies of sexual dysfunction were seen in men above age 60 years and women below age 30 years or above age 50 years. In logistic regression analysis, indicators of economic hardship in the family were positively associated with sexual dysfunctions, notably among women. In conclusion, while a majority of sexually active adults in Denmark experience sexual difficulties with their partner once in a while, approximately one in nine suffer from frequent sexual difficulties that constitute a threat to their well-being. Sexual dysfunctions seem to be more common among persons who experience economic hardship in the family.

Can the tight co-speciation between reed beetles (Col., Chrysomelidae, Donaciinae) and their bacterial endosymbionts, which provide cocoon material, clarify the deeper phylogeny of the hosts?

In most mutualistic symbioses of insects and intracellular bacteria, the endosymbionts provide additional nutrients to a host that feeds on an unbalanced diet. A strictly vertical transmission leads to co-speciation between the two partners. We have investigated an insect-bacteria relationship with a non-nutritional basis. The reed beetles (Donaciinae) harbor bacteria that produce a secretion used by the larvae for building a cocoon for pupation in mud underwater. The 16S rRNA of the bacteria and the cytochrome c oxidase I and elongation factor 1alpha of the beetles have been partially sequenced. The bacterial and the host phylogeny were highly congruent. Larger taxonomic units (genera) and host species groups/pairs have been recovered in the bacterial phylogeny. The symbiont data still cannot clarify the hitherto unresolved deeper phylogeny of the hosts, which is interpreted as a sign of rapid adaptive radiation of the reed beetles soon after their origin. The rate of sequence evolution among/within host species is discussed.

Ultrastructural and molecular characterization of endosymbionts of the reed beetle genus Macroplea (Chrysomelidae, Donaciinae), and proposal of "Candidatus Macropleicola appendiculatae" and "Candidatus Macropleicola muticae".

Intracellular bacterial symbionts are known from various insect groups, particularly from those feeding on unbalanced diets, where the bacteria provide essential nutrients to the host. In the case of reed beetles (Coleoptera: Chrysomelidae, Donaciinae), however, the endosymbionts appear to be associated with specialized "glands" that secrete a material used for the beetles' unusual water-tight cocoon. These glands were discovered over a century ago, but the bacteria they contain have yet to be characterized and placed in a phylogenetic context. Here, we describe the ultrastructure of two endosymbiotic species ("Candidatus Macropleicola appendiculatae" and "Candidatus Macropleicola muticae") that reside in cells of the Malpighian tubules of the reed beetle species Macroplea appendiculata and Macroplea mutica, respectively. Fluorescent in situ hybridization using oligonucleotides targeting the 16S rRNA gene specific to Macroplea symbionts verified the localization of the symbionts in these organs. Phylogenetic analysis of 16S rRNA placed "Candidatus Macropleicola" in a clade of typically endosymbiotic Enterobacteriaceae (gamma-proteobacteria). Finally, we discuss the evidence available for the hypothesis that the beetle larvae use a secretion produced by the bacteria for the formation of an underwater cocoon.

Reproduction and hybrid load in all-hybrid populations of Rana esculenta water frogs in Denmark.

All-hybrid populations of the water frog, Rana esculenta, are exceptional in consisting of independently and to some extent sexually reproducing interspecific hybrids. In most of its range R. esculenta reproduces hemiclonally with one of the parental species, R. lessonae or R. ridibunda, but viable populations of diploid and triploid hybrids, in which no individuals of the parental species have been found, exist in the northern part of the range. We test the hypothesis that nonhybrids arise every year in these all-hybrid populations, but die during larval development. Microsatellite markers were used to determine the genotypes of adults and abnormal and healthy offspring in three all-hybrid populations of R. esculenta in Denmark. Of all eggs and larvae, 63% developed abnormally or died, with some being nonhybrid (genomes matching one of the parental species), many being aneuploid (with noninteger chromosome sets), a few being tetraploid, and many eggs possibly being unfertilized. The 37% surviving and apparently healthy froglets were all diploid or triploid hybrids. In all three populations, gametogenesis matched the pattern previously described for all-hybrid R. esculenta populations in which most triploid adults have two R. lessonae genomes. This pattern was surprising for the one population in which triploid adults had two R. ridibunda genomes, because here it leads to a deficiency of gametes with an R. lessonae genome and should compromise the stability of this population. We conclude that faulty gametogenesis and mating between frogs with incompatible gametes induce a significant hybrid load in all-hybrid populations of R. esculenta, and we discuss compensating advantages and potential evolutionary trajectories to reduce this hybrid load.

Lung function in Greenlandic and Danish children and adolescents.

Respiratory morbidity in Inuit children is high. However, little is know regarding lung function measures in this population. The forced expiratory volumes in one second (FEV(1)) and forced vital capacity (FVC) in 888 Greenlandic Inuits (N=888) and Danes (N=477) aged 6-18 years were compared. Furthermore, associations between level of lung function and atopy and lifestyle factors were estimated in Greenlanders. The effect of height on FEV(1) and FVC was significantly different in Greenlanders and Danes, this difference in lung function increased with increasing height, and could not be explained by differences in age weight and BMI. Thus, Greenlanders taller than 130 cm had up to 300-400 ml higher FEV(1) and FVC compared with Danes of the same height. Among Greenlanders, those living in settlements had the highest levels of both FEV(1) and FVC. Greenlanders had elevated levels of FEV(1) and FVC compared with Danes. The Inuit having a shorter limb length in relation to trunk height may account for these differences. However, our finding that Greenlanders living in settlements had the highest lung function level also suggests a possible role of factors in the traditional Greenlandic lifestyle.

Multiple human papilloma virus types in cervical infections: competition or synergy?

Coinfection with multiple human papilloma virus (HPV) types is common in cervical HPV infection. To evaluate if infections with different HPV types occur independently, we examined 3558 women above 15 years of age suspected of cervical HPV infection. Among them, 1842 (52%) women were HPV negative and 1716 (48%) were HPV positive as analysed by a PCR-based commercial microarray assay for mucosal types. Of the HPV-positive samples, 824 (48%) had single infections, while 892 (52%) had multiple infections. Observed numbers of concurrent HPV types differed from expected numbers under the assumption of independence between infections by the various HPV types. Significant positive associations were observed for 16 pairs of HPV types in statistical analysis accounting for mass significance. Significant negative associations were also found, i.e. women with HPV-16 infection had 0.4 times the odds of having HPV-51 compared with women not infected with HPV-16. HPV-16 was the only type with odds ratios <1 for all pairwise combinations. While our findings of statistically significant coexistence do not prove biological dependence among HPV types, they do suggest that infections with some HPV types may depend on the existence of certain other HPV types. Any interaction between coexisting HPV types could either decrease or increase the efficacy of current HPV vaccines that offer mainly type-specific protection, depending on whether the types vaccinated against compete with other HPV types or not.

Appendicitis, mesenteric lymphadenitis, and subsequent risk of ulcerative colitis: cohort studies in Sweden and Denmark.

OBJECTIVE: To determine whether the repeatedly observed low risk of ulcerative colitis after appendicectomy is related to the appendicectomy itself or the underlying morbidity, notably appendicitis or mesenteric lymphadenitis. DESIGN: Nationwide cohort studies. SETTING: Sweden and Denmark. PARTICIPANTS: 709 353 Swedish (1964-2004) and Danish (1977-2004) patients who had undergone appendicectomy were followed up for subsequent ulcerative colitis. The impact of appendicectomy on risk was also studied in 224 483 people whose parents or siblings had inflammatory bowel disease. MAIN OUTCOME MEASURES: Standardised incidence ratios and rate ratios as measures of relative risk. RESULTS: During 11.1 million years of follow-up in the appendicectomy cohort, 1192 patients developed ulcerative colitis (10.8 per 100 000 person years). Appendicectomy without underlying inflammation was not associated with reduced risk (standardised incidence ratio 1.04, 95% confidence interval 0.95 to 1.15). Before the age of 20, however, appendicectomy for appendicitis (0.45, 0.39 to 0.53) or mesenteric lymphadenitis (0.65, 0.46 to 0.90) was associated with significant risk reduction. A similar pattern was seen in those with affected relatives, whose overall risk of ulcerative colitis was clearly higher than the background risk (1404 observed v 446 expected; standardised incidence ratio 3.15, 2.99 to 3.32). In this cohort, appendicectomy without underlying appendicitis did not modify risk (rate ratio 1.04, 0.66 to 1.55, v no appendicectomy), while risk after appendicectomy for appendicitis was halved (0.49, 0.31 to 0.74). CONCLUSIONS: In individuals with or without a familial predisposition to inflammatory bowel disease, appendicitis and mesenteric lymphadenitis during childhood or adolescence are linked to a significantly reduced risk of ulcerative colitis in adulthood. Appendicectomy itself does not protect against ulcerative colitis.

Reproductive factors and risk of systemic lupus erythematosus: nationwide cohort study in Denmark.

OBJECTIVE: The female predominance in systemic lupus erythematosus (SLE) suggests the possible involvement of reproductive factors in its etiology. We evaluated the relationship between parity and pregnancy losses and subsequent risk of SLE in a population-based cohort study. METHODS: We followed 4.4 million Danes aged 15-69 years for first inpatient hospitalizations for SLE between 1977 and 2004. As measures of relative risk, we used Poisson regression-derived hospitalization rate ratios (RR) with 95% confidence intervals (CI) for cohort members with different reproductive histories. RESULTS: Overall, 1614 women and 274 men were hospitalized with SLE during 88.9 million person-years of followup. Number of children was unrelated to SLE risk in men, but women with at least one liveborn child were at lower risk than nulliparous women (RR 0.74; 95% CI 0.64-0.86), and women with 2 or more children were at lower risk than 1-child mothers. Recurrent idiopathic pregnancy losses, including spontaneous abortions, missed abortions, and stillbirths, were associated with markedly increased SLE risk (RR 3.50; 95% CI 2.38-4.96, for 2+ vs none; p < 0.001). CONCLUSION: Nulliparous women, 1-child mothers, and women who experience spontaneous abortions, missed abortions, or stillbirths are at increased SLE risk. Theoretically, immunological processes involved in subfertility or idiopathic pregnancy losses might act as initiating or contributing factors in some cases of SLE. However, considering the well established excess of pregnancy complications in women with established SLE, the observed associations more likely reflect the effect of subclinical immunological processes in women destined to develop SLE.

Fatherhood status and prostate cancer risk.

BACKGROUND: Whether fatherhood status affects prostate cancer risk remains controversial. Recently, it was proposed that childless men are at lower prostate cancer risk than men with children and that men with sons may be at lower risk than men with daughters only. METHODS: National population-based register data were used to address these associations between fatherhood status and prostate cancer risk. The cohort comprised all men born in Denmark between 1935 and 1988, among whom 3400 developed prostate cancer during a total of 51.6 million person-years of follow-up between 1968 and 2003. RESULTS: Childless men were found to be at a 16% reduced risk of prostate cancer compared with fathers (rate ratio [RR] of 0.84; 95% confidence interval [95% CI], 0.73-0.95). The sex of the offspring did not affect prostate cancer risk (fathers with sons vs fathers without sons: RR of 0.99; 95% CI, 0.90-1.08). Among fathers, a significant trend was observed of gradually reduced prostate cancer risk with increasing number of children (P = .009), a pattern applying to both sons (P = .01) and daughters (P = .04). CONCLUSIONS: Our national cohort study corroborates the view that men without children constitute a group that is at a moderately reduced risk of prostate cancer. Among men with children, there appears to be a linear decline in prostate cancer risk with increasing number of children that is independent of the sex of the offspring.

The risk of developing Crohn's disease after an appendectomy: a population-based cohort study in Sweden and Denmark.

BACKGROUND: The relationship between appendectomy and Crohn's disease is controversial. A Swedish-Danish cohort study was conducted to assess the risk of developing Crohn's disease after an appendectomy. METHODS: 709 353 appendectomy patients in Sweden (since 1964) and Denmark (since 1977) were followed for first hospitalisations for Crohn's disease to 2004. Standardised incidence ratios (SIR) served as relative risks. RESULTS: Overall, 1655 Crohn's disease cases were observed during 11.1 million person-years of follow-up. Whereas appendectomy before the age of 10 years was not associated with the risk of Crohn's disease (SIR 1.00; 95% CI 0.80-1.25), the overall SIR of developing Crohn's disease was 1.52 (95% CI 1.45-1.59), being highest in the first 6 months (SIR 8.69; 95% CI 7.68-9.84). SIR diminished rapidly thereafter, with the risk of Crohn's disease reaching background levels after 5-10 years for Crohn's disease overall, as well as for Crohn's ileitis, ileocolonic Crohn's disease, Crohn's colitis and other/unspecified Crohn's disease. A long-term increased risk of Crohn's disease up to 20 years after the appendectomy was seen only in appendectomy patients without appendicitis or mesenteric lymphadenitis. CONCLUSION: The transient increased risk of Crohn's disease after an appendectomy is probably explained by diagnostic bias.

Strong combined gene-environment effects in anti-cyclic citrullinated peptide-positive rheumatoid arthritis: a nationwide case-control study in Denmark.

OBJECTIVE: To study the role of shared epitope (SE) susceptibility genes, alone and in combination with tobacco smoking and other environmental risk factors, for risk of subtypes of rheumatoid arthritis (RA) defined by the presence or absence of serum antibodies against cyclic citrullinated peptides (CCPs). METHODS: To address these issues, a nationwide case-control study was conducted in Denmark during 2002-2004, comprising incident cases of RA or patients with recently diagnosed RA (309 seropositive and 136 seronegative for IgG antibodies against CCP) and 533 sex- and age-matched population controls. Associations were evaluated by logistic regression analyses, in which odds ratios (ORs) served as measures of relative risk. RESULTS: Compared with individuals without SE susceptibility genes, SE homozygotes had an elevated risk of anti-CCP-positive RA (OR 17.8, 95% confidence interval [95% CI] 10.8-29.4) but not anti-CCP-negative RA (OR 1.07, 95% CI 0.53-2.18). Strong combined gene-environment effects were observed, with markedly increased risks of anti-CCP-positive RA in SE homozygotes who were heavy smokers (OR 52.6, 95% CI 18.0-154), heavy coffee drinkers (OR 53.3, 95% CI 15.5-183), or oral contraceptive users (OR 44.6, 95% CI 15.2-131) compared with SE noncarriers who were not exposed to these environmental risk factors. CONCLUSION: Persons who are homozygous for SE susceptibility genes, notably those who are also exposed to environmental risk factors, have a markedly and selectively increased risk of anti-CCP-positive RA. A distinction between anti-CCP-positive RA and anti-CCP-negative RA seems warranted, because these RA subtypes most likely represent etiologically distinct disease entities.

Environmental risk factors differ between rheumatoid arthritis with and without auto-antibodies against cyclic citrullinated peptides.

The aim of this study was to evaluate new and previously hypothesised non-genetic risk factors for serologic subtypes of rheumatoid arthritis (RA) defined by the presence or absence of auto-antibodies to cyclic citrullinated peptides (CCP). In a national case-control study, we included 515 patients recently diagnosed with RA according to the American College of Rheumatology 1987 classification criteria and 769 gender- and age-matched population controls. Telephone interviews provided information about non-genetic exposures, and serum samples for patients were tested for anti-CCP-antibodies. Associations between exposure variables and risk of anti-CCP-positive and anti-CCP-negative RA were evaluated using logistic regression. A series of RA subtype-specific risk factors were identified. Tobacco smoking (odds ratio [OR] = 1.65; 95% confidence interval: 1.03-2.64, for > 20 versus 0 pack-years) was selectively associated with risk of anti-CCP-positive RA, whereas alcohol consumption exhibited an inverse dose-response association with this RA subtype (OR = 1.98, 1.22-3.19, for 0 versus > 0-5 drinks per week). Furthermore, coffee consumption (OR = 2.18; 1.07-4.42, for > 10 versus 0 cups per day), ever use of oral contraceptives (OR = 1.65; 1.06-2.57) and having a first-degree relative with schizophrenia (OR = 4.18; 1.54-11.3) appeared more strongly associated with risk of anti-CCP-positive RA. Obesity was selectively associated with risk of anti-CCP-negative RA, with obese individuals being at more than 3-fold increased risk of this subtype compared with normal-weight individuals (OR = 3.45; 1.73-6.87). Age at menarche was the only examined factor that was significantly associated with both serologic subtypes of RA (p-trends = 0.01); women with menarche at age > or = 15 years had about twice the risk of either RA subtype compared with women with menarche at age < or = 12 years. Major differences in risk factor profiles suggest distinct etiologies for anti-CCP-positive and anti-CCP-negative RA.

Reproductive patterns and non-Hodgkin lymphoma risk in Danish women and men.

Reproductive patterns have been inconsistently linked to risk of non-Hodgkin lymphoma (NHL) in women, and fathering patterns in relation to NHL risk have not been studied. The authors conducted a register-based cohort study of 4.1 million Danes to investigate associations of livebirths with subsequent NHL incidence (85 million person-years, 3819 NHL cases). The impact of induced abortions, ectopic pregnancies, spontaneous abortions, missed abortions, stillbirths, and hydatidiform moles on subsequent NHL incidence was studied in a subcohort of 1.2 million women. Ratios of NHL incidence rates, accompanying trend tests and two-sided p-values were calculated by log-linear Poisson regression analyses. Pregnancies, whether ending in livebirths or not, were unrelated to NHL incidence in women. The only statistically significant finding in women was that, among parous women, age at first child-birth was inversely associated with NHL incidence (p-trend = 0.001). In men, there was no overall difference in NHL incidence between fathers and non-fathers. However, in men with children, NHL risk declined with increasing number of children (p-trend = 0.02) and increased with time since birth of the most recent child (p-trend < 0.001). Pregnancies have limited impact, if any, on subsequent NHL risk in women. Our findings in men need replication, but, if verified, they may reflect lymphomagenesis-associated male subfertility prior to NHL diagnosis.

A comparison of risk factors for wheeze and recurrent cough in preschool children.

In a study of 2,978 Danish children aged 5 years from two suburban counties of Copenhagen, carried out in 1998, the authors compared risk factor profiles for wheeze and recurrent cough without wheeze by using polytomous logistic regression to clarify whether the two conditions are likely to have the same etiology. Data were obtained 1) by a mailed parental questionnaire (International Study of Asthma and Allergies in Childhood questions and supplementary questions on cough, sociodemography, perinatal factors, and environmental exposure); 2) through general practitioners (familial allergic disease); and 3) from the National Medical Birth Register (birth weight). Wheeze (WH) was defined as more than one episode of wheeze within the last 12 months (irrespective of cough status) and recurrent cough without WH (RC) as cough occurring outside colds and usually lasting for periods of more than 1 week in children with no more than one attack of wheeze within the last 12 months. Risk factors for comparison were selected as those that, after repeated stepwise logistic regression, remained significant for children with WH or RC. Significant differences were found for gender (p = 0.003), gestational age (p = 0.0002), maternal history of asthma (p = 0.0008), and standard of housing condition (p = 0.04)-all risk factors for WH but not RC. Results may suggest that the two conditions have different etiologies.