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A balanced robertsonian translocation (rob) results from fusion of 2 acrocentric chromosomes. Carriers are phenotypically normal and are often diagnosed because of recurrent miscarriages, infertility, or aneuploid offspring. Mortality and site-specific cancer risks in carriers have not been prospectively investigated. We followed 1,987 carriers diagnosed in Great Britain for deaths and cancer risk, over an average of 24.1 years. Standardized mortality and incidence ratios were calculated comparing the number of observed events against population rates. Overall mortality was higher for carriers diagnosed before age 15 years (standardized mortality ratio (SMR) = 2.00, 95% confidence interval (CI): 1.09, 3.35), similar for those diagnosed aged 15–44 years (SMR = 1.06, 95% CI: 0.86–1.28), and lower for those diagnosed aged 45–84 years (SMR = 0.81, 95% CI: 0.68, 0.95). Cancer incidence was higher for non-Hodgkin lymphoma (standardized incidence ratio (SIR) = 1.90, 95% CI: 1.01, 3.24) and childhood leukemia (SIR = 14.5, 95% CI: 1.75, 52.2), the latter particularly in rob(15;21) carriers (SIR = 447.8, 95% CI: 11.3, 2,495). Rob(13;14) carriers had a higher breast cancer risk (SIR = 1.58, 95% CI: 1.12, 2.15). Mortality risks relative to the population in diagnosed carriers depend on age at cytogenetic diagnosis, possibly reflecting age-specific cytogenetic referral reasons. Carriers might be at greater risk of childhood leukemia and non-Hodgkin lymphoma and those diagnosed with rob(13;14) of breast cancer.

SUMMARYLittle is known about the main routes of human cytomegalovirus (HCMV) transmission in young adult populations. This study investigated risk factors for HCMV transmission in young adults attending university over a 3-year period. Blood samples were tested for HCMV specific viral capsid antigen IgG by enzyme immunoassay. Being born in a developing country and having lived in Africa were associated with HCMV seropositivity at study onset. No risk factors were associated with HCMV seroconversion over the 3-year follow-up. In contrast to previous reports, sexual activity was not associated with HCMV seroprevalence or seroconversion.

A large number of melanocytic nevi is the strongest known risk factor for melanoma in whites, but its relationship to sun exposure overseas among young white women living in temperate climates is unclear. A total of 754 white English women aged 18–46 years were recruited into a cross-sectional study in 1997–2000 to investigate the effect of ultraviolet exposures on numbers of nevi and atypical nevi, and on skin aging as measured by microtopography. Having ever holidayed in hotter countries was associated with a greater age- and phenotype-adjusted mean number of whole-body nevi (percent increase=74; 95% confidence interval: 24, 144; P=0.001), particularly for holidays taken at ages 18–29 years and for counts of the trunk and lower limbs. Having ever lived overseas was not associated with nevus counts, but was inversely associated with number of atypical nevi (P=0.02). Skin aging was not associated with residence or holidays abroad. The association of holidays overseas with an increased nevus count in young white women, which was stronger in the anatomical sites intermittently exposed to sunlight, supports the hypothesis that intermittent sun exposure is of relevance in the etiology of nevi and, hence, melanoma. The findings are of public health relevance given the growing popularity of foreign holidays.

Turner syndrome is characterized by complete or partial X chromosome monosomy. It is associated with substantial morbidity, but mortality risks and causes of death are not well described.Our objective was to investigate mortality and causes of death in women with Turner syndrome.We constructed a cohort of women diagnosed with Turner syndrome at almost all cytogenetic centers in Great Britain and followed them for mortality.A total of 3,439 women diagnosed between 1959-2002 were followed to the end of 2006.Standardized mortality ratios (SMRs) and absolute excess risks were evaluated.In total, 296 deaths occurred. Mortality was significantly raised overall [SMR = 3.0; 95% confidence interval (CI) = 2.7-3.4] and was raised for nearly all major causes of death. Circulatory disease accounted for 41% of excess mortality, with greatest SMRs for aortic aneurysm (SMR = 23.6; 95% CI = 13.8-37.8) and aortic valve disease (SMR = 17.9; 95% CI = 4.9-46.0), but SMRs were also raised for other circulatory conditions. Other major contributors to raised mortality included congenital cardiac anomalies, diabetes, epilepsy, liver disease, noninfectious enteritis and colitis, renal and ureteric disease, and pneumonia. Absolute excess risks of death were considerably greater at older than younger ages.Mortality in women with Turner syndrome is 3-fold higher than in the general population, is raised for almost all major causes of death, and is raised at all ages, with the greatest excess mortality in older adulthood. These risks need consideration in follow-up and counseling of patients and add to reasons for continued follow-up and preventive measures in adult, not just pediatric, care.

Summary Background Turner syndrome, one of the most common cytogenetic abnormalities, is characterised by complete or partial X-chromosome monosomy. Cancer risks in women with Turner syndrome have not been clearly established. We aimed to compare the risk of cancer in women with this syndrome with that of the general population. Methods We formed a national cohort of 3425 women who were cytogenetically diagnosed with Turner syndrome in Great Britain between 1959 and 2002. Identifying information for these patients was sent to the National Health Service Central Register (NHSCR) for England and Wales and to the NHSCR for Scotland. Individuals who were identified on this register were followed-up for cancer incidence. Standardised incidence ratios (SIRs) and 95% CIs were calculated on the basis of the number of cancers observed compared with that expected based on national incidence rates. Cumulative risk estimates were obtained by use of the Kaplan-Meier method. Findings A total of 58 299 person-years were accrued during the study, with a mean of 17·0 years (SD 8·6) follow-up per patient. 73 malignancies other than non-melanoma skin cancer occurred (SIR 0·9 [95% CI 0·7–1·2]). Risks were significantly increased for tumours of the CNS (n=13; 4·3 [2·3–7·4]), especially for meningioma (n=7; 12·0 [4·8–24·8]) and childhood brain tumours (n=3; 10·3 [2·1–30·1]), and for cancers of the bladder and urethra (n=5; 4·0 [1·3–9·2]) and eye (n=2; 10·5 [1·3–37·9]), compared with the general population. However, the risk of breast cancer was significantly decreased (n=10; 0·3 [0·2–0·6]). The SIR for cutaneous melanoma was 2·2 (95% CI 1·0–4·4; n=8), and one of the ocular cancers was a melanoma. The risk of corpus uteri cancer was significantly increased at ages 15–44 years (n=3; 8·0 [1·6–23·2]). During follow-up, five women, all with a Y-chromosome lineage, developed gonadoblastoma of the ovary, corresponding to a cumulative risk of 7·9% (95% CI 3·1–19·0) by age 25 years in this group. Interpretation This study shows that, in addition to having an increased risk of gonadoblastoma, women with Turner syndrome seem to be at increased risk for meningioma and childhood brain tumours, and possibly bladder cancer, melanoma, and corpus uteri cancer, but are at a decreased risk for breast cancer. Reasons for these risks might relate to genetic and hormonal factors or to the effects of hormonal treatments given to women with Turner syndrome.

We present the results of a multicenter clinical trial using Epstein-Barr virus (EBV)–specific cytotoxic T lymphocytes (CTLs) generated from EBV-seropositive blood donors to treat patients with EBV-positive posttransplantation lymphoproliferative disease (PTLD) on the basis of the best HLA match and specific in vitro cytotoxicity. Thirty-three PTLD patients who had failed on conventional therapy were enrolled. No adverse effects of CTL infusions were observed and the response rate (complete or partial) in 33 patients was 64% at 5 weeks and 52% at 6 months. Fourteen patients achieved a complete remission, 3 showed a partial response, and 16 had no response at 6 months (5 died before completing treatment). At 5 weeks, there was a significant trend toward better responses with higher numbers of CD4+ cells in infused CTL lines (P = .001) that were maintained at 6 months (P = .001). Patients receiving CTLs with closer HLA matching responded better at 6 months (P = .048). Female patients responded better than male patients, but the differences were not statistically significant. Our results show that allogeneic CTLs are a safe and rapid therapy for PTLD, bypassing the need to grow CTLs for individual patients. The response rate in this poor prognosis patient group is encouraging.

Purpose To assess long-term site-specific risks of second malignancy following non-Hodgkin's lymphoma (NHL) in relation to treatment and demographic factors. Patients and Methods A cohort of 2,456 patients with NHL who were first treated from 1973 to 2000 and were younger than 60 years from centers in the British National Lymphoma Investigation were observed, and occurrences of second malignancy was compared with expectations based on general population cancer rates in England and Wales. Results In total, 123 second malignancies occurred. Relative risks (RRs) were significantly elevated for all malignancies combined (RR = 1.3; 95% CI, 1.1 to 1.6) and for leukemia (RR = 8.8; 95% CI, 5.1 to 14.1) and lung cancer (RR = 1.6; 95% CI, 1.1 to 2.3). RRs of malignancy overall diminished significantly with increasing age at first treatment. Leukemia risk was significantly increased after chemotherapy (RR = 10.5; 95% CI, 5.0 to 19.3) and mixed-modality treatment (RR = 13.0; 95% CI, 5.2 to 26.7). Relative risks of lung (RR = 1.9; 95% CI, 1.1 to 3.1) and colorectal (RR = 2.1; 95% CI, 1.1 to 3.6) cancers were significantly raised following chemotherapy. Conclusion NHL patients are at elevated risk of developing second malignancy, particularly leukemia and lung cancer. The relative risk is greater with patients who are younger at first treatment. Chemotherapy predisposes patients toan increased risk of leukemia, and possibly lung and colorectal cancers. The role of specific drug treatments in the etiology of solid cancers after NHL deserves further investigation.

Birthweight and other pregnancy outcomes in a cohort of women with pre-gestational insulin-treated diabetes mellitus, Scotland, 1979-95 Aims To assess pregnancy outcomes, in particular birthweight, in a large population-based cohort of women in Scotland with pre-gestational insulin-treated diabetes mellitus. Methods Data about diabetes from the Diabetes UK cohort were linked to data on births from the Scottish Hospital In-Patient Record System. This identified 1112 eligible singleton deliveries during 1979- 95 to 706 insulin-treated women. Results One thousand and eighty-four (97.5%) deliveries resulted in a live-born infant and 28 (2.5%) in a stillbirth. There were 13 (1.2%) neonatal deaths. The mean birthweight of the live-born infants was 3421 g, 1.06 standard deviations greater than that of infants in the Scottish general population after correcting for sex and gestational age. Forty-three per cent of live-born babies in the study were large (> Scottish 90th percentile) and 4% small ( = 4000 g, occurred in 23% live-born babies and its prevalence was significantly inversely related to duration of maternal diabetes. However, the mean birthweight of infants born to mothers with diabetes for 20 or more years was still 0.90 standard deviations greater than in the general population. Prevalence of macrosomia increased with increasing number of previous pregnancies, but was not associated with maternal height or smoking habits. Stillbirth and neonatal death rates were, respectively, 4.7 (95% confidence interval = 3.3, 6.8) and 2.4 (1.4, 4.1), times higher than those in the general population. Conclusions The frequency of adverse pregnancy outcomes in women with pre- existing insulin-treated diabetes was much higher than in the Scottish general population, and changed little during the study period. A detailed quantification of the independent effect of duration of mother's diabetes on birthweight revealed a continuous inverse correlation between these two variables.

Risk of lymphoid neoplasia after cardiothoracic transplantation: the influence of underlying disease and human leukocyte antigen type and matching. Background. It has been known for more than 20 years that there is an increased risk of lymphoid neoplasia after cardiothoracic transplantation. Recent studies have demonstrated the importance of primary Epstein-Barr virus (EBV) infection and type of immunosuppressive therapy to the cause of these neoplasms, but the contribution of other factors remains equivocal. Methods. The authors followed 1,562 patients undergoing cardiothoracic transplantation at Harefield Hospital, United Kingdom, and used standard cohort methods of analysis to examine whether posttransplant lymphoma risk was related to the underlying disease requiring transplantation or the human leukocyte antigen (HLA) type and matching. Lymphomas were categorized into EBV-associated lymphoproliferative disease (LPD) and EBV-negative non-Hodgkin's lymphoma(NHL), and the authors carried out separate analyses of these. Results. The authors found no significant association between the underlying disease necessitating transplantation and the risk of lymphoid neoplasia. There was also no evidence of a relation of lymphoma risk with the presence or absence of any particular HLA antigen, although significant protective effects of HLA-B14 and -B57 were found when analyses were conducted without adjustment for multiple testing. Risk of LPD was not associated with degree of HLA mismatching, but there was a significant effect of mismatching on risk of EBV-negative tumors. Conclusions. The differential effect of HLA mismatching on the risks of LPD and EBV-negative NHL provides further evidence that these two tumors are distinct etiologic entities. The authors' results suggest that the immunologic cause of EBV-negative NHL may be different from that of LPD. Investigation of the relation of risk of EBV-negative NHL to degree of immunosuppression is needed.

To determine the role of sexual contact in transmission of Epstein-Barr virus (EBV) and occurrence of infectious mononucleosis (IM), a cross-sectional study was undertaken of EBV serologic testing and histories of IM and sexual behavior among 1006 new students at Edinburgh University. Prevalence of EBV seropositivity was significantly greater among women (79.2%) than among men (67.4%; P

Summary Background Growth hormone raises serum concentrations of insulin-like growth factor IGF-I, which is mitogenic and antiapoptotic. There is evidence that raised endogenous levels of growth hormone and IGF-I might be associated with increased risk of certain solid cancers, but there have been no data on long-term risks of solid cancers after growth hormone treatment. Methods We did a cohort study to investigate cancer incidence and mortality in 1848 patients in the UK who were treated during childhood and early adulthood with human pituitary growth hormone during the period from 1959 to 1985. Patients were followed up for cancer incidence to December, 1995 and for mortality to December, 2000. Risk of cancer in the cohort was compared with that in the general population, controlling for age, sex, and calendar period. Findings Patients treated with human pituitary growth hormone had significantly raised risks of mortality from cancer overall (standardised mortality ratio 2·8, 95% CI 1·3–5·1; ten cases), colorectal cancer (10·8, 1·3–38·8; two cases), and Hodgkin's disease (11·4, 1·4–41·3; two cases). Incidence of colorectal cancer was also greatly raised (7·9, 1·0–28·7). After exclusion of patients whose original diagnosis rendered them at high risk of cancer, the significance and size of the risks of colorectal cancer incidence and mortality, and of Hodgkin's disease mortality were increased. Interpretation Although based on small numbers, the risk of colorectal cancer is of some concern and further investigation in other cohorts is needed. We have no evidence as to whether growth hormone in modern dosage regimens is associated with an increased risk of colorectal cancer.

If infections are involved in the aetiology of childhood leukaemia then seasonal variation in the birth or onset dates of the malignancy may be apparent. Previous studies that have examined seasonality of these dates have produced conflicting results. Using population-based data from the National Registry of Childhood Tumours we conducted a larger study than any to date of 15 835 cases of childhood leukaemia born and diagnosed in the UK between 1953–95. We found no evidence of seasonality in either month of birth or month of diagnosis overall or in any subgroups by age, sex, histology or immunophenotype. We did however find a significant (P= 0.01) February peak in month of birth for cases born before 1960 and a significant (P= 0.02) August peak in month of diagnosis for those diagnosed before 1962. Whilst these findings may be due to chance they are also consistent with changes over time in the seasonality of exposure, or immunological response, to a relevant infection. Changes in the seasonal variation in the fatality rate of a pre-leukaemic illness, such as pneumonia, could be another explanation. © 2001 Cancer Research Campaign http://www.bjcancer.com

GH is increasingly used for treatment of children and adults. It is mitogenic, however, and there is therefore concern about its safety, especially when used to treat cancer patients who have become GH deficient after cranial radiotherapy. We followed 180 children with brain tumors attending three large hospitals in the United Kingdom and treated with GH during 1965-1996, and 891 children with brain tumors at these hospitals who received radiotherapy but not GH. Thirty-five first recurrences occurred in the GH-treated children and 434 in the untreated children. The relative risk of first recurrence in GH-treated compared with untreated patients, adjusted for potentially confounding prognostic variables, was decreased (0. 6; 95% confidence interval, 0.4-0.9) as was the relative risk of mortality (0.5; 95% confidence interval, 0.3-0.8). There was no significant trend in relative risk of recurrence with cumulative time for which GH treatment had been given or with time elapsed since this treatment started. The relative risk of mortality increased significantly with time since first GH treatment. The results, based on much larger numbers than previous studies, suggest that GH does not increase the risk of recurrence of childhood brain tumors, although the rising trend in mortality relative risks with longer follow-up indicates the need for continued surveillance.

BACKGROUND Organ transplantation is associated with a greatly increased risk of Epstein-Barr virus (EBV)-associated lymphoproliferative disease (LPD), which is often fatal. There has been little epidemiological analysis, however, of the risk factors for LPD in transplant patients and none on whether the risks of non-EBV-associated lymphoid neoplasms are also increased. METHODS The risk of lymphoid neoplasia was assessed in a cohort of 1563 patients who underwent cardiothoracic transplantation at Harefield Hospital, UK from 1980 to 1994 and were followed until December 1995. EBV antibody was assessed in the patients before transplantation, and lymphoid neoplasms were assessed for EBV RNA and latent EBV gene expression. RESULTS Thirty cases of LPD occurred during follow-up. One lymphoma of unknown EBV status occurred. There were also six cases of EBV-negative non-Hodgkin's lymphoma (EBV-negative NHL), a highly significant excess over expectations from the general population rates of NHL (standardized incidence ratio 10.2 [95% confidence interval, 4.6-22.8]). The risk of LPD was significantly 10-fold raised in individuals who were EBV seronegative before transplantation; independently of this, it decreased steeply with age at transplantation and was greatest in the first year after transplantation. The risk was significantly raised in young seronegative recipients if the donor was older than the recipient. EBV-negative NHL occurred entirely in men 45 years old and older who were EBV seropositive before transplantation, and risk was not related to duration since transplantation. CONCLUSIONS The risk factors found for LPD accord with EBV etiology and with greater hazard from primary infection than from reactivation. A second non-Hodgkin's lymphoid neoplasm, not related to EBV, seems also to be a consequence of transplantation and immunosuppression but is unlikely to be due to first infection by a ubiquitous agent. Its etiology and prevention need investigation separately from LPD.

Purpose We investigated the long-term risk of second primary malignancy after chemotherapy for Hodgkin's lymphoma (HL) in a much larger cohort than any yet published, to our knowledge. Patients and Methods We followed 5,798 patients with HL treated with chemotherapy in Britain from 1963 to 2001—of whom 3,432 also received radiotherapy—to assess second primary malignancy risks compared with general population-based expectations. Results Second malignancies occurred in 459 cohort members. Relative risk (RR) of second cancer was raised after chemotherapy alone (RR, 2.0; 95% CI, 1.7 to 2.4) but was much lower than after combined modalities (RR, 3.9; 95% CI, 3.5 to 4.4). After chemotherapy alone, there were significantly raised risks of lung cancer, non-HL, and leukemia, each contributing approximately equal absolute excess risk. After combined modalities, there were raised risks of these and several other cancers. Second cancer risk peaked 5 to 9 years after chemotherapy alone, but it remained raised for 25 years and longer after combined modalities. Risk was raised after each common chemotherapy regimen except, based on limited numbers and follow-up, adriamycin, bleomycin, vinblastine, and dacarbazine. The age and time-course relations of lung cancer differed between chemotherapy alone and combined modalities. Conclusion Although chemotherapy alone leads to raised risk of second malignancy, this risk is lower and affects fewer anatomic sites than that after combined modalities, and it is slight if at all after 15 years follow-up. The mechanism of lung cancer etiology may differ between chemotherapy and radiotherapy.

Background. Infectious mononucleosis (IM) is common among university students. We undertook to analyze the clinical features and sequelae of the disease in a cohort of students at Edinburgh University. Methods. Consecutive IM case patients were recruited from 2000 through 2002 at the University Health Service after diagnosis of IM. Results. IM resulted in marked reductions in student study time, physical exercise, and non-exercise-related social activities, and sustained increases in reported number of hours of sleep. The disease profile differed between the sexes, with significantly more females reporting fatigue, which was more likely to be prolonged (P = .003) and to lead to loss of study time (P = .013). Female case patients were more likely to discontinue their studies following IM (16% vs 0%; P = .056). Within the typically elevated lymphocyte counts in IM, we identified an elevated gamma delta T cell component that may contribute to the disease pathogenesis. Conclusions. IM results in substantial morbidity among university students, reported as more profound in females, and affecting academic studies, physical exercise, and social activities. Immunization to prevent IM and strategies to reduce post-IM disability would be beneficial in this population.

Myocardial infarction is a major cause of excess long-term mortality in survivors of Hodgkin disease, but limited information exists on the effects of specific chemotherapy regimens used to treat these patients on their risk of death from myocardial infarction.We followed a cohort of 7033 Hodgkin disease patients who were treated in Britain from November 1, 1967, through September 30, 2000, and compared their risk of myocardial infarction mortality with that in the general population of England and Wales. All statistical tests were two-sided.A total of 166 deaths from myocardial infarction occurred in the cohort, statistically significantly more than expected (standardized mortality ratio [SMR] = 2.5, 95% confidence interval [CI] = 2.1 to 2.9), with an absolute excess risk of 125.8 per 100,000 person-years. Standardized mortality ratios decreased sharply with older age at first treatment, but absolute excess risks of death from myocardial infarction increased with older age up to age 65 years at first treatment. The statistically significantly increased risk of myocardial infarction mortality persisted through to 25 years after first treatment. Risks were increased statistically significantly and independently for patients who had been treated with supradiaphragmatic radiotherapy, anthracyclines, or vincristine. Risk was particularly high for patients treated with the doxorubicin, bleomycin, vinblastine, and dacarbazine regimen (SMR = 9.5, 95% CI = 3.5 to 20.6). Risk at 20 or more years after first treatment was particularly great for patients who had received supradiaphragmatic radiotherapy and vincristine without anthracyclines (SMR = 14.8, 95% CI = 4.8 to 34.5).The risk of death from myocardial infarction after treatment for Hodgkin disease remains high for at least 25 years. The increased risks are related to supradiaphragmatic radiotherapy but may also be related to anthracycline and vincristine treatment.

BACKGROUND: A vaccine against Epstein-Barr virus (EBV) infection is in clinical trials. Up-to-date information on risk factors for EBV infection and infectious mononucleosis (IM) among young adults is required to inform a vaccination strategy. METHODS: We carried out a prospective study on a cohort of university students. All EBV-seronegative students were asked to report symptoms of IM and were followed up 3 years later to undergo repeat EBV testing and to complete a lifestyle questionnaire. EBV typing was performed for these subjects, as well as for students who were EBV seropositive at enrollment and for additional students with IM. RESULTS: A total of 510 students (25%) who took part in the study were EBV seronegative when they entered the university; of the 241 who donated a second blood sample 3 years later, 110 (46%) had seroconverted to EBV, 27 (25%) of whom developed IM [corrected] Penetrative sexual intercourse was a risk factor for EBV seroconversion (P = .004), but neither condom use nor oral sex significantly altered the rate of seroconversion. EBV type 1 was significantly overrepresented in IM, compared with silent seroconversion (P = .001). CONCLUSIONS: Our findings suggest that acquisition of EBV is enhanced by penetrative sexual intercourse, although transmission could occur through related sexual behaviors, such as "deep kissing." We also found that EBV type 1 infection is significantly more likely to result in IM. Overall, the results suggest that a large EBV type 1 load acquired during sexual intercourse can rapidly colonize the B cell population and induce the exaggerated T cell response that causes IM. Thus, IM could, perhaps, be prevented with a vaccine that reduces the viral load without necessarily inducing sterile immunity.

Context: Klinefelter syndrome is characterized by hypogonadism and infertility, consequent on the presence of extra X chromosome(s). There is limited information about long-term mortality in this syndrome because there have been no large cohort studies. Objective: Our objective was to investigate mortality in men with Klinefelter syndrome. Design and Setting: We obtained data about patients diagnosed with Klinefelter syndrome at almost all cytogenetics centers in Britain, as far back as records were available, and conducted a cohort study of their mortality, overall and by karyotype. Patients: We assessed 3518 patients diagnosed since 1959, followed to mid-2003. Outcome Measure: The outcome measure was standardized mortality ratio (SMR). Results: A total of 461 deaths occurred. There was significantly raised mortality overall [SMR, 1.5; 95% confidence interval (CI), 1.4–1.7] and from most major causes of death including cardiovascular disease (SMR, 1.3; 95% CI, 1.1–1.5), nervous system disease (SMR, 2.8; 95% CI, 1.6– 4.6), and respiratory disease (SMR, 2.3; 95% CI, 1.8–2.9). Mortality was particularly raised from diabetes (SMR, 5.8; 95% CI, 3.4–9.3), epilepsy (SMR,7.2;95%CI,3.1–14.1),pulmonaryembolism(SMR,5.7;95%CI, 2.5–11.3), peripheral vascular disease (SMR, 7.9; 95% CI, 2.9–17.2), vascular insufficiency of the intestine (SMR, 12.3; 95% CI, 4.0–28.8), renal disease (SMR, 5.0; 95% CI, 2.0–10.3), and femoral fracture (SMR, 39.4; 95% CI, 4.8–142.3). Mortality from ischemic heart disease was significantly decreased (SMR, 0.7; 95% CI, 0.5–0.9). Conclusions: Patients diagnosed with Klinefelter syndrome have raised mortality from several specific causes. This may reflect hormonal and genetic mechanisms. (J Clin Endocrinol Metab 90: 6516–6522, 2005)

Background: Men with Klinefelter syndrome have one or more extra X chromosomes and have endocrine abnormalities. Case reports have led to suggestions that men with Klinefelter syndrome have elevated risks of several cancers, but published cohort studies have been relatively small. We conducted a nationwide cohort study to examine these risks. Methods: We followed a cohort of 3518 men who had been cytogenetically diagnosed with Klinefelter syndrome in Britain from 1959 through 2002 and compared their cancer incidence and mortality with that of men in the national population. All statistical tests were two-sided. Results: The standardized mortality ratio (SMR) for all cancers was 1.2 (95% confidence interval [CI] = 1.0 to 1.4). Compared with the general population, men with Klinefelter syndrome had higher mortality from lung cancer (SMR = 1.5, 95% CI = 1.0 to 2.0), breast cancer (SMR = 57.8, 95% CI = 18.8 to 135.0), and non-Hodgkin lymphoma (SMR = 3.5, 95% CI = 1.6 to 6.6) and lower mortality from prostate cancer (SMR = 0, 95% CI = 0 to 0.7). The standardized mortality ratios were particularly high for breast cancer among men with 47,XXY mosaicism (SMR = 222.8, 95% CI = 45.9 to 651.0) and for non-Hodgkin lymphoma among men with a 48,XXYY constitution (SMR = 36.7, 95% CI = 4.4 to 132.5). The cancer incidence data corroborated these associations. Conclusions: These results support a hormonal etiology for breast cancer in men and for prostate cancer and suggest that men with Klinefelter syndrome may be at substantially elevated risks for non-Hodgkin lymphoma, breast cancer, and, perhaps, lung cancer.

We investigated the relative validity of an interview-administered FFQ to estimate phytoestrogen intake among South Asian women in the UK. A population-based sample of 108 healthy South Asian women completed random repeated monthly 24-h recalls [with a subsample (n = 58) also providing multiple plasma samples] over a period of 1 y followed by administration of the FFQ. The FFQ produced slightly higher estimates of phytoestrogen intake than the 24-h recalls, but the percentage of women classified into the same +/- 1 quartile by the 2 methods was high for all phytoestrogens (from 81 to 94%) with only a small percentage (

Objective: To investigate risk factors for Creutzfeldt-Jakob disease (CJD) in patients in the United Kingdom treated with human pituitary growth hormone (hGH). Methods: Incidence rates of CJD, based on person-year denominators, were assessed in a cohort of 1,848 patients treated with hGH in the United Kingdom from 1959 through 1985 and followed to the end of 2000. Results: CJD developed in 38 patients. Risk of CJD was significantly increased by treatment with hGH prepared by the Wilhelmi method of extraction from human pituitaries. Risk was further raised if this treatment was administered at ages 8 to 10 years. The peak risk of CJD was estimated to occur 20 years after first exposure, and the estimated lifetime cumulative risk of CJD in Wilhelmi-treated patients was 4.5%. Conclusions: Size-exclusion chromatography, used in non-Wilhelmi preparation methods, may prevent CJD infection. Susceptibility to CJD may vary with age, and susceptibility may be present in only a few percent of the population.

OBJECTIVES—Workers in the steel industry are exposed to various severe hazards. This study investigated risk factors for non-fatal injury occurring in the workplace and during travel to and from work in steelworkers in Brazil. METHODS—Non-fatal work related injuries during employment from January 1977 to September 1992 were analysed in a cohort of 21 732 male workers in the steel plant of USIMINAS, Brazil. RESULTS—There were 14 972 non-fatal injuries during follow up, with 10 891 injuries in the workplace and 4081 during travel to and from work (travel to work injury). The rate of injury in the workplace was 5.6/100 person-years and that of travel to work injury was 2.1/100 person-years. The most common injuries were to hands, arms, and eyes, with 90% of the eye injuries caused by a foreign body. Both rates of workplace and travel to work injury increased significantly with the number of injuries previously experienced, and decreased with number of years in employment and calendar period. The rates of travel to work injury also seemed to decrease with age, but age was not an independent predictor of workplace injury when we controlled for duration of employment. The rate of workplace injury was increased eightfold for workers who had experienced more than six previous injuries compared with those with no previous workplace injuries after adjusting for duration of employment and calendar period. Labourers were most at risk of workplace injury, with about eight injuries per 100 person-years. Travel to work injury was most common among support workers, with nearly half of the travel to work injuries affecting the eyes. CONCLUSION—The rate of injury was high in these steelworks, both for workplace and travel to work injuries. Characteristics of the work areas and the employees can identify high risk groups; protective measures, safety, health training, and injury programmes should concentrate particularly on these groups. Prevention of eye injury needs special attention in steelworks. Keywords: steel workers; injuries

Objective: To determine mortality in patients with congenital adrenal hyperplasia (CAH) compared with that in the general population. Design: We identified 333 children with CAH, treated at several pediatric endocrinology departments in the United Kingdom since 1964, and monitored their mortality to mid 1996. Standardized mortality ratios were calculated, comparing mortality in the cohort with that in the general population, adjusted for sex, age, and calendar period. Results: All-cause mortality in the cohort was 3 times that expected. Mortality was significantly increased at ages 1 to 4 years (standardized mortality ratio=18.3) but not at older ages and was significantly increased in patients of Indian-subcontinent ethnicity (standardized mortality ratio=20.4), particularly in girls. From case notes and death certificates, it appears that most deaths were caused by adrenal crisis, often after infection. Conclusions: Although survival of patients with CAH has greatly improved since steroid therapy has been used, this disease can still have fatal consequences. The high mortality rate in Indian ethnic girls may well reflect lack of parental acceptance and understanding of the disease, as well as of the action required when their child becomes acutely ill. Better communication with and education of parents of children with CAH, especially those from immigrant ethnic minorities, is important. (J Pediatr 1998;133:516-20)

OBJECTIVES: In a cohort of 21,816 Brazilian steelworkers we found mortality from motor-vehicle injury was twice that in the State population. A nested case-control study was therefore undertaken to investigate possible socio-demographic, medical and occupational risk factors for this increased risk. METHODS: Cases were defined as all steelworkers in the cohort who died of motor-vehicle injury during employment in the period 1977-1992. For each case, four controls were selected at random from workers in the cohort who were employed at the time of death of the case, and who were born in the same year as the case. Data on socio-demographic factors, and medical and occupational histories were obtained from personnel, industrial hygiene and medical records, and the relation of these factors to risk of motor-vehicle injury was analysed using conditional logistic regression. RESULTS: In a multivariate analysis, the risk of death from motor-vehicle injury was independently associated with being unmarried (odds ratio [OR] compared to married = 3.21, 95% confidence interval [CI]: 1.84-5.59), having a hearing defect (OR = 2.28, 95% CI: 1.10-4.74) and exposure to moderate (OR = 1.71, 95% CI: 1.03-2.83) or high (OR = 2.00, 95% CI: 1.18-3.39) levels of noise at work. The risk of fatal motor-vehicle injury increased with intensity of occupational noise exposure (P = 0.004). CONCLUSIONS: The raised risk of motor-vehicle injury death associated with single marital status is likely to relate to selective factors in the types of individual who remain single, and behaviours associated with being unmarried. The raised risks in relation to hearing defects and exposure to occupational noise, factors that do not appear to have been examined previously, imply that occupational noise exposures might be a cause of fatal motor-vehicle accidents outside the workplace. This finding may have widespread public health consequences since high levels of noise in the workplace and occupationally acquired hearing deficits are prevalent in several occupations. Further investigation is needed to confirm the associated and its mechanisms and, if it is causal, to develop preventive strategies. Language: en

OBJECTIVES: To estimate the relative risk of death from work related injury in a steelworks, associated with exposure to various occupational hazards, sociodemographic factors, and medical history. MATERIAL AND METHODS: The study was a nested case-control design. It was based on a cohort of men employed in the steel plant of USIMINAS, Brazil between January 1977 and August 1990, who were followed up to November 1992. The cases were defined as all workers in the cohort who died from injury in the study period and whose death had been notified to the Brazilian Ministry of Labour as being related to work. Four controls per case, matched to cases on year of birth, were randomly selected from among workers employed in the plant at the time of death of the matching case. Data on potential risk factors for occupational injury were extracted from company records; for the controls these data were abstracted for the period preceding the death of the matching case. RESULTS: There were 37 deaths related to work injuries during the study period. Four surviving workers were selected as controls for each case, but for eight the personnel records were incomplete, leaving 140 controls in all. Significantly increased risk of fatal injury related to work was associated with exposure to noise, heat, dust and fumes, gases and vapours, rotating shift work, being a manual worker, and working in the steel mill, coke ovens, blast furnaces, and energy and water supply areas. Risk of fatal injury related to work increased with intensity of exposure to noise (P (trend) = 0.004) and heat (P < 0.001), and increased greatly with a hazard score that combined information on noise, heat, dust, and gas exposure (P < 0.001). Number of years of schooling (P = 0.03) and salary level (P = 0.03) were both negatively associated with risk. In a multivariate analysis including all these significant factors, only hazard score and area of work remained associated with death from injury related to work. The highest risks were for men exposed to all four environmental hazards (odds ratio (OR) 19.4; 95% confidence interval (95% CI) 1.1 to 352.1) and those working in the energy supply area (OR 18.0; 1.6 to 198.1). CONCLUSIONS: The study identified parts of the steelworks and types of hazard associated with greatly increased risk of fatal accident. Research and measures to prevent accidents need to concentrate on these areas and the people working in them. The use of a hazard score was successful in identifying high risk, and similar scoring might prove useful in other industrial situations.

OBJECTIVES: Injury is the leading cause of death in the male working population of Brazil. An important fraction of these deaths are work related. Very few cohort studies of steel workers, and none from developing countries, have reported on mortality from injuries. This paper analyses mortality from work and non-work related injuries among Brazilian steel workers. METHODS: Deaths during employment from 1 January 1977 to 30 November 1992 were analysed in a cohort of 21,816 male steel workers. Mortality rates specific for age and calendar year among the workers were compared with those of the male population of the state where the plant is located. Work related injuries were analysed by comparing the mortality rates for different subgroups of the cohort. RESULTS: The number of deaths (391) was less than half that expected based on death rates of the general population. Over 60% (242) of deaths were due to injuries. Mortality from most causes was substantially below that in the general population, but that from unintentional injury, was 50% above that of the general population. Standardised mortality ratios (SMRs) were highest for the youngest and the oldest employees and for labourers and clerical workers. Mortality from motor vehicle injury was twice that expected from population rates (SMR = 209, 95% confidence interval (95% CI) 176-244). There was a 67% fall in the age adjusted mortality from occupational injuries in the study period. CONCLUSION: The healthy worker effect in this cohort was greater than that commonly found in studies of occupational groups in developed countries, probably because of a greater socioeconomic gap between employed and unemployed populations in Brazil, and unequal distribution of health care resources. Mortality was especially high for motor vehicle injuries. The fall in mortality from occupational injuries during the study period was probably due to improvement in safety standards, increased automation, and better medical care. There is a need to investigate risk factors for unintentional injuries among steel workers, especially those due to motor vehicle injuries. Prevention of occupational and nonoccupational injuries should be a main priority in Brazil.

Background Studies suggest that routine variations in public drinking water turbidity may be associated with endemic gastrointestinal illness. We systematically reviewed the literature on this topic. Methods We searched databases and websites for relevant studies in industrialized countries. Studies investigating the association between temporal variations in drinking water turbidity and incidence of acute gastrointestinal illness were assessed for quality. We reviewed good quality studies for evidence of an association between increased turbidity and gastrointestinal illness. Results We found six relevant good quality studies. Of five studies investigating effluent water turbidity, two found no association. Two studies from Philadelphia reported increased paediatric and elderly hospital use on specific days after increased turbidity. A fifth study reported more telephone health service calls on specific days after peak turbidity. There were differences between studies affecting their comparability, including baseline turbidity and adjustment for seasonal confounders. Conclusion It is likely that an association between turbidity and GI illness exists in some settings or over a certain range of turbidity. A pooled analysis of available data using standard methods would facilitate interpretation.

Objective: To determine the risk of testicular cancer in relation to undescended testis and its treatment based on recorded details of the maldescent, treatment, and biopsy from case notes. Design: Cohort study. Setting: Hospital for Sick Children, Great Ormond Street, London. Subjects: 1075 boys with cryptorchidism treated by orchidopexy or hormones at the hospital during 1951-64. Main outcome measures: Relative risk of testicular cancer in the cohort compared with men in the general population. Results: 12 testicular cancers occurred in 11 of the patients during follow up to mid-1990 (relative risk of cancer in males with cryptorchidism=7.5 (95% confidence interval 3.9 to 12.8)). The relative risk fell significantly beyond 15 years after orchidopexy but did not decrease with younger age at orchidopexy. Risk was significantly raised in testes that had had biopsy samples removed during orchidopexy (relative risk=66.7 (23.9 to 143.3) compared with a testis in a man in the general population) and was significantly greater in these testes than in undescended testes that had not had biopsy samples taken at orchidopexy (6.7 (2.7 to 13.5)). No reasons for biopsy or distinguishing clinical aspects of the testes that had had biopsy samples taken and later developed malignancies were evident in the case notes. No histological abnormalities were evident at initial biopsy except in one testis that had features of dysgenesis. Conclusions: Biopsy seems to be a stronger risk factor for testicular cancer than any factor previously identified. The trauma of open biopsy may contribute substantially to risk of malignancy or the testes may have been selected for biopsy on the basis of clinical factors predictive of malignancy but not mentioned in the case notes. Key messages The reasons for increased risk of testicular cancer in cryptorchidism are unclear Risk of testicular cancer was determined in follow up of 1075 boys with cryptorchidism treated during 1951-64 The relative risk of testicular cancer in the cohort compared with men in the general population was 7.5 and did not decrease with younger age at orchidopexy Risk was much greater in undescended testes from which a biopsy sample had been taken during orchidopexy than in those with no biopsy Biopsy was a stronger risk factor for testicular cancer than any factor previously identified

Background Researchers commonly employ strategies to increase participation in health studies. These include use of incentives and intensive reminders. There is, however, little evidence regarding the quantitative effect that such strategies have on study results. We present an analysis of data from a case-control study of Campylobacter enteritis in England to assess the usefulness of a two-reminder strategy for control recruitment. Methods We compared sociodemographic characteristics of participants and non-participants, and calculated odds ratio estimates for a wide range of risk factors by mailing wave. Results Non-participants were more often male, younger and from more deprived areas. Among participants, early responders were more likely to be female, older and live in less deprived areas, but despite these differences, we found little evidence of a systematic bias in the results when using data from early reponders only. Conclusions We conclude that the main benefit of using reminders in our study was the gain in statistical power from a larger sample size.