Socio-demographic factors, reproductive history and risk of osteoarthritis in a cohort of 4.6 million Danish women and men.

OBJECTIVE: Studies addressing possible socio-demographic and reproductive factors in the aetiology of osteoarthritis (OA) are few. We studied possible influences of educational level, household income, marital status and parenting patterns on OA risk overall and at anatomical sites. METHOD: We linked national register data about socio-demographic variables, reproductive histories and OA hospital contacts to a cohort of 4.6 million Danes. Ratios of first OA hospitalisation rates (RRs) were calculated using Poisson regression. RESULTS: Overall, 100,437 women and 92,020 men had a first OA hospital contact during 91.5 million person-years between 1982 and 2008. Short education, low income and married status were significantly associated with increased OA risk, and persons with children were at higher risk of OA(overall) (RR=1.10 in women; RR=1.22 in men), OA(knee) (RRs 1.14; 1.28), OA(back) (RRs 1.18; 1.33), and OA(hand) (RRs 1.21; 1.43), but not of OA(hip) (RRs 0.96; 1.00) than persons without children. The RR of OA(overall) increased by a factor of 1.05 in women and 1.04 in men per additional child, most notably for OA(knee) in women (1.10 per child). CONCLUSION: Risk of OA hospitalisation was highest among married persons and persons with short education or low income. The similar or even stronger associations with reproductive factors in men than women suggest that unmeasured lifestyle factors rather than biological factors associated with pregnancy might explain the higher OA risk in persons with children. However, the particularly strong association between parity and risk of OA(knee) in women is compatible with a role of pregnancy-associated factors.

The Agersoe cattle: the last remnants of the Danish island cattle (Bos taurus)?

A phenotypically interesting strain of cattle existed on the small island of Agersoe, on the west coast of Zealand, Denmark, in the beginning of the last decade. The cattle share a great resemblance to the extinct Danish breed, the Island cattle. The objective of this study was to genetically characterize the Agersoe cattle, using microsatellites, amplified fragment length polymorphism (AFLP) and mtDNA markers, and analyse the genetic variability within the breed and the genetic relationship to 14 European breeds with focus on the Red Danish and Jutland breed. The results show diversity in nuclear markers comparable to that of modern breeds and that the Agersoe cattle are separable from the two native breeds. The absence of inbreeding and the degree of genetic diversity are taken as a sign of recent admixture. The Agersoe cattle did not exhibit a consistent association with any of the European breeds. Several arguments based on this survey have been put forward in favour of characterizing the Agersoe cattle as being the last remnants of the Danish Island Cattle.

National cohort study of reproductive risk factors for rheumatoid arthritis in Denmark: a role for hyperemesis, gestational hypertension and pre-eclampsia?

OBJECTIVES: While reproductive factors might plausibly be involved in the aetiology of rheumatoid arthritis (RA), the female predominance remains unexplained. A study was undertaken to address the possible impact of live births, pregnancy losses and pregnancy complications on the subsequent risk of RA in a nationwide cohort study. METHODS: National register data were used to link reproductive histories and later RA hospitalisations in a cohort of 4.4 million Danes. As a measure of relative risk associated with different reproductive histories, ratios of first inpatient RA hospitalisation rates (RRs) were used with 95% confidence intervals (CIs) obtained by Poisson regression analysis. RESULTS: Overall, 7017 women and 3041 men were admitted to hospital with RA in 1977-2004 (88.8 million person-years). The risk of RA was inversely associated with age at birth of first child in both women and men (p for trend <0.001). Overall, nulliparity and a history of pregnancy loss were not associated with RA risk but, compared with one-child mothers, women with two (RR 0.84; 95% CI 0.78 to 0.90) or three (RR 0.83; 95% CI 0.77 to 0.91) children were at reduced risk. The risk of RA was increased in women with a history of hyperemesis (RR 1.70; 95% CI 1.06 to 2.54), gestational hypertension (RR 1.49; 95% CI 1.06 to 2.02) or pre-eclampsia (RR 1.42; 95% CI 1.08 to 1.84). CONCLUSIONS: One-child mothers and young parents are at increased risk of RA later in life, possibly due to socioeconomic factors. The novel finding of a significantly increased risk of RA in women whose pregnancies were complicated by hyperemesis, gestational hypertension or pre-eclampsia might reflect reduced immune adaptability to pregnancy in women disposed to RA or a role of fetal microchimerism in the aetiology of RA.

Risk factors for male breast cancer--a case-control study from Scandinavia.

We report a population-based case-control study on risk factors for male breast cancer. Data on a broad range of previously suggested risk factors were collected in a set of Scandinavian breast cancer cases and matched controls. Incident cases (n = 282) with histologically verified carcinomas of the breast were identified from notification to the cancer registries of Denmark, Norway and Sweden over a 4-year period 1987-1991 and of these cases, 156 men could be approached and responded. Controls were identified through national central population registers and were matched individually for country, sex and year of birth. Controls with a diagnosis of breast cancer were excluded; 468 of 780 controls responded. Data on risk factors were collected by self-administered questionnaires mailed to the cases between land 2 years after diagnosis and to controls during the same period. The findings were compatible with an increased risk associated with family history of breast cancer (odds ratio (OR) = 3.3, 95% confidence interval (CI) 2.0-5.6), obesity 10 years before diagnosis (OR = 2.1, 95% CI 1.0-4.5) for BMI > 30, diabetes (OR = 2.6, 95% CI 1.3-5.3) and the use of digoxin and methyldopa (OR = 2.0 and 2.1, respectively). The association with family history of breast cancer has been repeated in several studies, while the relation to anthropometric measures has been equivocal. We could not substantiate some associations seen in other studies; namely those with high education, fertility, marital status, testicular injury, liver disease and religion. The detailed questions about gynaecomastia indicated that many cases reported signs of breast cancer as a gynaecomastia. This type of misunderstanding may explain the strong association with gynaecomastia seen in other studies. Several patients died before contact. Thus, risk factors related to a more aggressive male breast cancer or related to high risk of dying (e.g. liver cirrhosis, heavy smoking) may have been missed.

Diversity of Plasmodium falciparum populations and complexity of infections in relation to transmission intensity and host age: a study from the Usambara Mountains, Tanzania.

Diversity and complexity of infections with Plasmodium falciparum were described from cross-sectional surveys in November-December 1996 in 6 villages in the Usambara Mountains, Tanzania, where transmission ranged markedly from 0.03 to 91 infective bites per individual per year. Forty-eight samples, stratified for age and parasite densities, were examined from each village (n = 288). Genotyping was performed by a nested PCR method using primers specific for allele families of genes for the merozoite surface protein 1 (msp-1) and merozoite surface protein 2 (msp-2). A high degree of genetic diversity was found within each village but there were no differences found among the 6 villages. Poisson regressions showed significant effects of host age, village and interaction between host age and village on the complexity of infection. There was a positive, non-linear relationship between complexity of infection and transmission intensity with a maximal number of genotypes found per individual even at high transmission intensities. Furthermore there was a significantly lower complexity found in adults (> 15 years) as compared to children (< 15 years) in the lowland village. This difference was not found as transmission intensity decreased. By comparing data from the same geographical area, using the same methods, and taking into account confounding factors, the present study provides evidence for an effect of both age and transmission intensity on complexity of infection with P. falciparum.

A phylogenetic analysis of cuckoo bumblebees (Psithyrus, Lepeletier) and bumblebees (Bombus, Latreille) inferred from sequences of the mitochondrial gene cytochrome oxidase I.

PCR amplification and direct sequencing of a 532-bp region of the mt CO-1 (cytochrome oxidase I) gene from five true bumblebee species and six cuckoo bumblebee species were performed. The sequences were then aligned to the corresponding sequence in the honey bee. Phylogenetic analyses based on parsimony and maximum likelihood indicate that the cuckoo bumblebees form a monophyletic group within the true bumblebees. The Bombus lucorum group (subgenus Bombus) falls out as the sister group to a clade comprising the cuckoo bumblebees and the remaining true bumblebees. A strong A + T bias (A + T = 75%) was recorded. Comparisons of all the sequences show a high-transversion bias (A<-->T) even among closely related species. The bias is most pronounced in third positions.

Influence of indoor climate on the sick building syndrome in an office environment. The Danish Indoor Climate Study Group.

The influence of indoor climate factors on symptoms of the sick building syndrome was investigated in Greater Copenhagen, Denmark. Altogether, 2369 office workers in 14 buildings, where indoor climate measurements were made, filled out a questionnaire. Multivariate logistic regression analyses of the multifactorial effects on the prevalence of work-related mucosal irritation and work-related general symptoms among the office workers showed that the concentration of macromolecular organic floor dust, the floor covering, the number of workplaces in the office, the age of the building, the type of ventilation, and two easily recognizable factors, the shelf factor and the fleece factor, were associated with the prevalence of symptoms.

Influence of personal characteristics, job-related factors and psychosocial factors on the sick building syndrome. Danish Indoor Climate Study Group.

The influence of personal characteristics, life-style, job-related factors, and psychosocial work factors on symptoms of the sick building syndrome was investigated in Greater Copenhagen, Denmark. The buildings were not characterized beforehand as "sick" or "healthy." Of the 4369 employees sent a questionnaire, 3507 returned them. Multivariate logistic regression analyses of the multifactorial effects on the prevalence of work-related mucosal irritation and work-related general symptoms among the office workers showed that sex, job category, work functions (handling of carbonless paper, photocopying, work at video display terminals), psychosocial factors of work (dissatisfaction with superiors or colleagues and quantity of work inhibiting job satisfaction) were associated with work-related mucosal irritation and work-related general symptoms, but these factors could not account for the differences between the buildings as to the prevalence of the symptoms. The building factor (i.e., the indoor climate) was strongly associated with the prevalence of the symptoms.

Quality control of patho-anatomical diagnosis of carcinoma of the breast.

Three pathologists, especially interested in breast cancer, reexamined 379 random specimens of invasive breast cancer initially diagnosed at 27 pathological institutes; these were obtained from the computer register of the Danish Breast Cancer Cooperative Group (DBCG). The degree of variation between a) the primary diagnosis (the country as a whole) and each of the 3 pathologists and b) between the 3 pathologists mutually, has been studied with regard to the 2 main groups of carcinoma--infiltrating duct carcinoma (IDC) and infiltrating lobular carcinoma (ILC). The degree of variation was found to be similar between each of the 3 pathologists and the country as a whole, with a kappa value of approx. 0.3 for both types of carcinoma, and a considerably better interobserver variation between the 3 pathologists with a kappa value of approx. 0.7. The most important reason was that the 3 pathologists agreed on the occurrence of more than twice as many cases primarily diagnosed as ILC. A partial explanation is in fact that since the start of DBCG, reports have appeared of variants of ILC not previously known. The diagnosis of malignancy (carcinoma) was almost completely unambiguous.

Histologic malignancy grading of invasive ductal breast carcinoma. A regression analysis of prognostic factors in low-risk carcinomas from a multicenter trial.

In a prospective adjuvant trial including patients with primary operable breast cancer, invasive carcinomas of ductal type were subjected to histological malignancy grading. The parameters investigated were tubule formation, number of mitoses and cell pleomorphism. A Cox regression model for survival data was applied to evaluate the impact of the histological parameters on prognosis in 1809 patients with low-risk carcinomas. Cell pleomorphism proved superior to the other histologic tumor characteristics. It was found that low-risk invasive ductal carcinomas with severe cell pleomorphism had an excess recurrence intensity of 209% relative to carcinomas with no pleomorphism. It is therefore suggested that polymorphous invasive ductal breast carcinomas, other things being equal, should be regarded as high-risk tumors in future clinical trials. Finally it was found that the tripartite malignancy grading 1, 2 and 3 characterizing each of the histological parameters was not equidistant. Consequently, the traditional tripartite histologic scoring needs reconsideration.

Updating prognosis and therapeutic effect evaluation in cirrhosis with Cox's multiple regression model for time-dependent variables.

A multivariate Cox regression analysis with time-dependent variables has been performed on the data of 415 patients with cirrhosis included in a controlled clinical trial of 10-15 mg prednisone daily versus placebo. The analysis showed that a poor prognosis was associated with a low prothrombin index, marked ascites, GI bleeding, high age, high daily alcohol consumption, high bilirubin and alkaline phosphatase and low albumin values, little liver connective tissue inflammation, and poor nutritional status. Prothrombin index and ascites showed significant interaction with the treatment in such a manner that high prothrombin index and absence of ascites were associated with a beneficial effect of prednisone, whereas low prothrombin index and presence of ascites were associated with a harmful effect of prednisone treatment. The final model was validated in independent patients by comparing their actual survival with that predicted from the model, using a split-sample testing technique. The prognostic factors were combined with an index that can be used to update prognosis whenever changes occur in the clinical status of a patient during the course of the disease. The probability of surviving the next 3 or 6 months can be estimated from the prognostic index at any time during the course. The index may be of value for the correct timing of special therapeutic procedures such as liver transplantation.

Probability of false negative nodal staging in conjunction with partial axillary dissection in breast cancer.

There is a risk of overlooking lymph node metastases and thereby contributing to inaccurate nodal staging when performing partial axillary dissection in conjunction with total mastectomy in female breast cancer. The Danish Breast Cancer Cooperative Group (DBCG) analysed this risk in a prospective nation-wide adjuvant trial dealing with primary operable breast carcinoma. The series comprised 3114 patients, initially found to have lymph node negative axillae, followed for a median of 24 months (quartiles 12-40). It was found that the probability of early ipsilateral axillary relapse of cancer, estimated by means of the life table method, decreased with the number of nodes removed. After 2 years the recurrence rate was 12 per cent for patients with no lymph nodes removed, 7 per cent with one or two nodes removed and 2 per cent with three or more nodes removed. It is concluded that the risk of false negative nodal staging in conjunction with partial axillary dissection is modest, provided at least three lymph nodes are removed and found to be negative on histological examination.

Prognostic value of surface antigens in primary human breast carcinomas, detected by monoclonal antibodies.

Three monoclonal antibodies, raised against human milk fat globule membranes, have been applied to 194 primary human breast carcinomas. The detected antigenic sites were found to be heterogeneously distributed. A statistical association with estrogen receptor content and grade of anaplasia was found for two of the antigens, Mam 3a and Mam 3b. The presence of all three antigens was independent of menopausal status, age, primary lymph node metastases, and progesterone receptor status. Life table analysis showed a better survival for patients with tumors positive for Mam 3b. The effect of these variables on recurrence-free survival has been analyzed using a Cox regression model. It is found that the most important prognostic factors are the number of positive lymph nodes, the estrogen receptor content, and the menopausal status of the high-risk patients. The ability of a model based on these factors to predict recurrence is not significantly improved by including any of the three surface antigens.

Elastosis in relation to prognosis in primary breast carcinoma.

The content of elastic tissue has been evaluated in 171 primary breast carcinomas. Of the tumors, 35% had no or very little elastic tissue in the malignant areas, 42% presented with medium elastosis, and 22% had gross elastosis. The occurrence of elastin has been related to different prognostic factors. An increasing amount of elastin was found with increasing amounts of estrogen receptor (p = 0.0003), while there was only a slight correlation to the progesterone receptor content. Furthermore, the highly differentiated tumors contained more elastin in their tumor tissue than the poorly differentiated tumors (p = 0.003), and parous women had significantly more elastin than nonparous women (p = 0.02). The presence of elastin was not, however, of any demonstrable prognostic significance.

Beneficial effect of adjuvant tamoxifen therapy in primary breast cancer patients with high oestrogen receptor values.

Oestrogen receptor concentrations were measured in primary tumours of 291 postmenopausal breast cancer patients with high risk of recurrence. These patients were a subset of the 1650 patients participating in the Danish Breast Cancer Cooperative Group's trial of adjuvant treatment with tamoxifen (30 mg daily for one year). A cut-off point of 10 fmol/mg cytosol protein and the use of a Cox proportional hazards model distinguished between patients with long recurrence-free survivals and those with early recurrent disease. The use of this model also showed that patients with an oestrogen-receptor content below 100 fmol/mg did not benefit from the endocrine therapy, while those with concentrations above 100 fmol/mg had a significantly longer recurrence-free survival. This finding is consistent with the response of advanced breast cancer to endocrine treatment.

Estrogen and progesterone receptor profile patterns in primary breast cancer.

Estrogen (ER) and progesterone receptor (PgR) analyses have been performed in 884 primary, malignant human breast tumor biopsies. Receptor contents were evaluated with respect to age and menopausal status. The frequency of ER+ tumors was found to be significantly higher in postmenopausal than in pre/perimenopausal women. Age rather than menopausal status was found to be associated with this difference. The significant association with age was found in the post- but not the pre/perimenopausal women. The frequency of PgR+ tumors was found to be significantly lower in the postmenopausal than in the pre/perimenopausal women. Neither age nor menopausal status alone could account for this difference, which appears to be due to a compound effect of the two factors. The distribution of receptor profile patterns is described according to menopausal status. The patterns differ significantly in pre- and postmenopausal women. PgR dominates in the premenopausal tumor while ER dominates in the postmenopausal tumor. This difference is apparent within the subgroup of ER + PgR + patients as well. The current tenets for prediction of recurrent disease utilizing steroid hormone receptor determinations are discussed for the group of ER + PgR + patients.