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Background & aims: Genome-wide association studies in primary biliary cholangitis (PBC) have failed to find X chromosome (chrX) variants associated with the disease. Here, we specifically explore the chrX contribution to PBC, a sexually dimorphic complex autoimmune disease. Methods: We performed a chrX-wide association study, including genotype data from 5 genome-wide association studies (from Italy, United Kingdom, Canada, China, and Japan; 5244 case patients and 11,875 control individuals). Results: Single-marker association analyses found approximately 100 loci displaying P < 5 × 10-4, with the most significant being a signal within the OTUD5 gene (rs3027490; P = 4.80 × 10-6; odds ratio [OR], 1.39; 95% confidence interval [CI], 1.028-1.88; Japanese cohort). Although the transethnic meta-analysis evidenced only a suggestive signal (rs2239452, mapping within the PIM2 gene; OR, 1.17; 95% CI, 1.09-1.26; P = 9.93 × 10-8), the population-specific meta-analysis showed a genome-wide significant locus in East Asian individuals pointing to the same region (rs7059064, mapping within the GRIPAP1 gene; P = 6.2 × 10-9; OR, 1.33; 95% CI, 1.21-1.46). Indeed, rs7059064 tags a unique linkage disequilibrium block including 7 genes: TIMM17B, PQBP1, PIM2, SLC35A2, OTUD5, KCND1, and GRIPAP1, as well as a superenhancer (GH0XJ048933 within OTUD5) targeting all these genes. GH0XJ048933 is also predicted to target FOXP3, the main T-regulatory cell lineage specification factor. Consistently, OTUD5 and FOXP3 RNA levels were up-regulated in PBC case patients (1.75- and 1.64-fold, respectively). Conclusions: This work represents the first comprehensive study, to our knowledge, of the chrX contribution to the genetics of an autoimmune liver disease and shows a novel PBC-related genome-wide significant locus.

Abortion is common. Data on abortion rates are inexact but can be used to explore trends. Globally, the estimated rate in the period 2010-2014 was 35 abortions per 1000 women (aged 15-44 years), five points less than the rate of 40 for the period 1990-1994. Abortion laws vary around the world but are generally more restrictive in developing countries. Restrictive laws do not necessarily deter women from seeking abortion but often lead to unsafe practice with significant mortality and morbidity. While a legal framework for abortion is a prerequisite for availability, many laws, which are not evidence based, restrict availability and delay access. Abortion should be available in the interests of public health and any legal framework should be as permissive as possible in order to promote access. In the absence of legal access, harm reduction strategies are needed to reduce abortion-related mortality and morbidity. Abortion can be performed surgically (in the first trimester, by manual or electric vacuum aspiration) or with medication: both are safe and effective. Cervical priming facilitates surgery and reduces the risk of incomplete abortion. Diagnosis of incomplete abortion should be made on clinical grounds, not by ultrasound. Septic abortion is a common cause of maternal death almost always following unsafe abortion and thus largely preventable. While routine follow-up after abortion is unnecessary, all women should be offered a contraceptive method immediately after the abortion. This, together with improved education and other interventions, may succeed in reducing unintended pregnancy.

Whatever the outcome, pregnancy provides the opportunity to offer effective contraception to couples motivated to avoid another pregnancy. This narrative review summarizes the evidence for health providers, drawing attention to current guidelines on which contraceptive methods can be used, and when they should be started after pregnancy, whatever its outcome. Fertility returns within 1 month of the end of pregnancy unless breastfeeding occurs. Breastfeeding, which itself suppresses fertility after childbirth, influences both when contraception should start and what methods can be used. Without breastfeeding, effective contraception should be started as soon as possible if another pregnancy is to be avoided. Interpregnancy intervals of at least 6 months after miscarriage and 1-2 years after childbirth have long been recommended by the World Health Organization in order to reduce the chance of adverse pregnancy outcome. Recent research suggests that this may not be necessary, at least for healthy women

Background Perfluoroalkyl substances (PFAS), a heterogeneous group of highly stable man-made chemicals, have been widely used since 1960s and can be detected almost ubiquitously in all environmental matrices. In Italy, on January 2014, drinking water contamination in an area of the Veneto Region was detected mainly due to the drain of fluorinated chemicals by a manufacturing company operating since 1964. Methods The present ecological mortality study was aimed at comparing mortality for some causes of death selected on the basis of previous reported associations, during the period 1980-2013, in municipalities with PFAS contaminated and uncontaminated drinking water on the basis of the levels indicated by the Italian National Health Institute (ISS). Sex-specific number, standardized mortality rates and rate ratios (RR) for PFAS contaminated and uncontaminated areas were computed for each cause of death through the ENEA epidemiological database. Results In both sexes, statistically significant RRs were detected for all causes mortality, diabetes, cerebrovascular diseases, myocardial infarction and Alzheimer's disease. In females, RRs significantly higher than 1.0 were also observed for kidney and breast cancer, and Parkinson's disease. Increased risk, although not statistically significant, was observed for bladder cancer in both sexes, and for testicular cancer, pancreatic cancer and leukemia in males only. Conclusions Higher mortality levels for some causes of death, possibly associated with PFAS exposure, were detected in contaminated municipalities in comparison with uncontaminated ones with similar socioeconomic status and smoking habits. These results warrant further individual level analytic studies to delineate casual associations. © 2015 The Author.

Common childhood infectious diseases have been associated with a reduced risk of following haematopoietic malignancies, but investigations on multiple myeloma (MM) are scarce. Information about 213 MM cases and 1128 healthy controls were obtained from a multicentre population-based Italian case-control study. The association between chickenpox, measles, mumps, pertussis and rubella and the MM risk was estimated by unconditional logistic regression, adjusting for age, gender and residence area. No association was found between MM risk and any considered infectious disease. The number of infections was slightly inversely associated with the risk of MM, but statistical significance was not reached (OR 0.87, 95% CI 0.55–1.4 for 1-2 diseasesvs.none and OR 0.68, 95% CI 0.41–1.1 for 3-5 diseases, respectively,P= 0.131). We did not find a clear evidence that common infections during childhood are associated with the subsequent risk of developing MM.

Since 1960, incidence of non-Hodgkin's lymphoma (NHL) has been increasing in most industrialized countries, but causes of this trend remain unclear. A role of the decreased exposure to infectious agents during childhood has been proposed. Our study evaluates the association between common childhood infectious diseases and the risk of NHL and its major subtypes by a reanalysis of the Italian multicenter case-control study. After exclusion of next-of-kin interviews, 1,193 cases, diagnosed between 1990 and 1993, and 1,708 population-based controls were included in the analyses. OR estimates were obtained by logistic regression, adjusting for gender, age, residence area, education, smoking habit and exposure to radiations, pesticides and aromatic hydrocarbons. Among B-cell lymphomas (n = 1,102) an inverse association was observed for rubella (OR = 0.80, 95% CI: 0.65-0.99), pertussis (OR = 0.74, 95% CI: 0.62-0.88) and any infection (OR = 0.75, 95% CI: 0.61-0.93). A negative trend by number of infections was observed, which was more evident among mature B-cell lymphoma (OR = 0.66 for three infections or more, 95% CI: 0.48-0.90). Our results indicate a potential protective role of common childhood infections in the etiology of B-cell NHL.

Non-Hodgkin lymphoma (NHL) is the most common hematologic malignancy and the fifth most common type of cancer in more developed regions of the world (1). Numerous NHL subtypes with distinct combinations of morphologic, immunophenotypic, genetic, and clinical features are currently recognized (2,3). The incidence of NHL subtypes varies substantially by age, sex, and race/ethnicity (4–7). However, the etiological implications of this biological, clinical, and epidemiological diversity are incompletely understood. The importance of investigating etiology by NHL subtype is clearly supported by research on immunosuppression, infections, and autoimmune diseases, which are the strongest and most established risk factors for NHL. Studies of solid organ transplant recipients and individuals infected with HIV demonstrate that risks are markedly increased for several—but not all—NHL subtypes (8–13). Some infections and autoimmune diseases are associated with a single specific subtype [eg, human T-cell lymphotropic virus, type I (HTLV-I) with adult T-cell leukemia/lymphoma (14), celiac disease with enteropathy-type peripheral T-cell lymphoma (PTCL) (15–17)], whereas others [eg, Epstein–Barr virus, hepatitis C virus (HCV), Sjogren’s syndrome (18–21)] have been associated with multiple subtypes. In the last two decades, reports from individual epidemiological studies of NHL have suggested differences in risks among NHL subtypes for a wide range of risk factors, but most studies have lacked the statistical power to assess any differences quantitatively and have not systematically evaluated combinations of subtypes. One study assessed multiple risk factors and found support for both etiologic commonality and heterogeneity for NHL subtypes, with risk factor patterns suggesting that immune dysfunction is of greater etiologic importance for diffuse large B-cell lymphoma (DLBCL) and marginal zone lymphoma than for chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL) and follicular lymphoma (22). However, that analysis was limited to approximately 1300 NHL cases and considered only the four most common NHL subtypes. Pooling data from multiple studies through the International Lymphoma Epidemiology Consortium (InterLymph) have provided substantial insight into associations between specific risk factors and NHL subtypes, with evidence that family history of hematologic malignancy, autoimmune diseases, atopic conditions, lifestyle factors (smoking, alcohol, anthropometric measures, and hair dye use), and sun exposure are associated with NHL risk (19,21,23–32). However, no previous study has compared patterns of risk for a range of exposures for both common and rarer NHL subtypes. We undertook the InterLymph NHL Subtypes Project, a pooled analysis of 20 case–control studies including 17 471 NHL cases and 23 096 controls, to advance understanding of NHL etiology by investigating NHL subtype-specific risks associated with medical history, family history of hematologic malignancy, lifestyle factors, and occupation. The detailed risk factor profiles for each of 11 NHL subtypes appear in this issue (15–17,33–40). In this report, we assess risk factor heterogeneity among the NHL subtypes and identify subtypes that have similar risk factor profiles.

Background: Chromosomal instability in peripheral blood mononuclear cells has a role in the onset of primary biliary cirrhosis. We hypothesized that patients with primary biliary cirrhosis may harbour telomere dysfunction, with consequent chromosomal instability and cellular senescence. Aim: To evaluate the clinical significance of telomerase activity and telomere length in peripheral blood mononuclear cells from patients with primary biliary cirrhosis. Study design: In this population-based case control study, 48 women with primary biliary cirrhosis (25 with cirrhosis), 12 with chronic hepatitis C matched by age and severity of disease, and 55 age-matched healthy women were identified. Mononuclear cells from the peripheral blood of patients and controls were isolated. Telomere length and telomerase activity were measured. Results: Telomere length and telomerase activity did not differ between cases (5.9±1.5kb) and controls (6.2±1.4kb, pc=0.164). Telomere shortening and advanced-stage disease strongly correlated with telomerase activity. Patients with advanced disease retained significantly less telomerase activity than those with early-stage disease (0.6±0.9 OD vs. 1.5±3.7 OD, p=0.03). Telomere loss correlated with age, suggesting premature cellular ageing in patients with primary biliary cirrhosis. Conclusion: Our data strongly support the telomere hypothesis of human cirrhosis, indicating that telomere shortening and telomerase activity represent a molecular mechanism in the evolution of human cirrhosis in a selected population of patients. © 2013 Editrice Gastroenterologica Italiana S.r.l

to re-evaluate the meaning of attributable risk assessing the event advancement as an individual effect indicator.mortality descriptive study of cardiovascular and respiratory causes in two populations exposed to different emission levels from a coal-fired power plant.people residing in 23 Italian municipalities (100,725 subjects) aged 35-84 years observed from 2000 to 2007.age-specific death rates and death anticipation by age.a higher mortality among the exposed corresponds to a median death anticipation from 25 to 20 months among people aged 65-74 and of 6 months for people aged 75-84.for the set of the considered causes of death, a higher mortality among the exposed corresponds to a median anticipation of all deaths occurred among exposed people.

The ABCB4 gene encodes the MDR3 protein. Mutations of this gene cause progressive familial intrahepatic cholestasis type 3 (PFIC3) in children, but their clinical relevance in adults remains ill defined. The study of a well-characterized adult patient series may contribute to refining the genetic data regarding cholangiopathies of unknown origin. Our aim was to evaluate the impact of ABCB4 mutations on clinical expression of cholestasis in adult patients. We consecutively evaluated 2602 subjects with hepatobiliary disease. Biochemical evidence of a chronic cholestatic profile (CCP) with elevated serum gamma-glutamyltransferase activity or diagnosis of intrahepatic cholestasis of pregnancy (ICP) and juvenile cholelithiasis (JC) were inclusion criteria. The personal/family history of additional cholestatic liver disease (PFH-CLD), which includes ICP, JC, or hormone-induced cholestasis, was investigated. Mutation screening of ABCB4 was carried out in 90 patients with idiopathic chronic cholestasis (ICC), primary biliary cirrhosis (PBC), primary sclerosing cholangitis (PSC), ICP, and JC. Eighty patients had CCP. PSC and ICC patients with PFH-CLD had earlier onset of disease than those without it (p = 0.003 and p = 0.023, respectively). The mutation frequency ranged from 50 % (ICP, JC) to 17.6 % (PBC). Among CCP patients, presence or absence of PFH-CLD was associated with ABCB4 mutations in 26.8 vs 5.1 % (p = 0.013), respectively; in the subset of ICC and PSC patients, the corresponding figures were 44.4 vs 0 % (p = 0.012) and 28.6 vs 8.7 % (p = 0.173). Cholangiopathies attributable to highly penetrant ABCB4 mutant alleles are identifiable in a substantial proportion of adults that generally have PFH-CLD. In PSC and ICC phenotypes, patients with MDR3 deficiency have early onset of disease.

background: Venous thromboembolism (VTE) is a specific reproductive health risk for women. methods: Searches were performed in Medline and other databases. The selection criteria were high-quality studies and studies relevant to clinical reproductive medicine. Summaries were presented and discussed by the European Society of Human Reproduction and Embryology Workshop Group. results: VTE is a multifactorial disease with a baseline annual incidence around 50 per 100 000 at 25 years and 120 per 100 000 at age 50. Its major complication is pulmonary embolism, causing death in 1-2% of patients. Higher VTE risk is associated with an inherited thrombophilia in men and women. Changes in the coagulation system and in the risk of clinical VTE in women also occur during pregnancy, with the use of reproductive hormones and as a consequence of ovarian stimulation when hyperstimulation syndrome and conception occur together. In pregnancy, the risk of VTE is increased 5-fold, while the use of combined hormonal contraception (CHC) doubles the risk and this relative risk is higher with the more recent pills containing desogestrel, gestodene and drospirenone when compared with those with levonorgestrel. Similarly, hormone replacement therapy (HRT) increases the VTE risk 2-to 4-fold. There is a synergistic effect between thrombophilia and the various reproductive risks. Prevention of VTE during pregnancy should be offered to women with specific risk factors. In women who are at high risk, CHC and HRT should be avoided. conclusions: Clinicians managing pregnancy or treating women for infertility or prescribing CHC and HRT should be aware of the increased risks of VTE and the need to take a careful medical history to identify additional co-existing risks, and should be able to diagnose VTE and know how to approach its prevention.

Emergency contraception (EC) prevents pregnancy after unprotected sex or contraceptive failure. Use of EC has increased markedly in countries where a product is available over the counter, yet barriers to availability and use remain. Although effective in clinical trials, it has not yet been possible to show a public health benefit of EC in terms of reduction of unintended pregnancy rates. Selective progesterone receptor modulators developed as emergency contraceptives offer better effectiveness than levonorgestrel, but still EC is less effective than use of ongoing regular contraception. Methods which inhibit ovulation whenever they are taken or which act after ovulation to prevent implantation and strategies to increase the uptake of effective ongoing contraception after EC use would prevent more pregnancies.

Background & Aims: Life expectancy of patients with compensated hepatitis C virus (HCV) cirrhosis achieving sustained virologic response (SVR) is limited by liver events as compared to the general population. Thus, survival benefit of SVR remains to be measured. Methods: The study includes prospective surveillance data from three cohorts of Italian patients with compensated HCV cirrhosis who achieved SVR on an interferon-based (IFN) regimen, compared to simultaneously observed non-SVR, untreated and decompensated patients. Overall survival was calculated from the date of start of IFN to death. The number of deaths expected during the at-risk period was determined by applying age- and sex-specific mortality rates recorded in Italy for person-years adequate for the enrolment period. The standardized mortality ratio (SMR) determined the relative risk of death over that of the age and sex matched general population. Results: Overall, 28/181 patients followed-up for a median period of 9.6 years (range 1–25 years) died. The 10 and 20-year overall survival rates for the whole series were 90.9% (95% CI, 84.3–94.8) and 62.9% (95% CI, 45.9–75.9), respectively. The number of expected deaths in the corresponding age and sex matched general population was 28.1, corresponding to a SMR = 1.00 (95% CI, 0.72–1.35), with an SMR for non-SVR patients of 3.85 (95% CI, 3.43–4.30), for untreated of 3.01 (95% CI, 2.64–3.42) and for decompensated of 6.70 (95% CI, 5.39–8.22). Conclusions: Patients with compensated HCV cirrhosis achieving SVR by IFN obtain a main benefit levelling their survival curve to that of the general population. Wider applicability of IFN-free regimens will possibly make this achievement more generalizable.

OBJECTIVES: The identification of prognostic factors associated with mortality is crucial in any clinical setting. METHODS: We enrolled in a prospective study 352 patients with compensated hepatitis C virus (HCV)-induced cirrhosis, consecutively observed between 1989 and 1992. At entry, patients underwent upper endoscopy to detect esophageal varices, and were then surveilled by serial clinical and ultrasonographic examination. The model for end-stage liver disease (MELD) score was calculated with information collected at enrollment. Baseline predictors and intercurrent events associated with mortality were assessed using the Cox regression model. RESULTS: During a median follow-up of 14.4 years, 194 subjects received a single course of interferon monotherapy, 131 patients developed decompensation (ascites, bleeding, hepatic encephalopathy), 109 patients had hepatocellular carcinoma (HCC), 9 had liver transplant, and 158 died. Esophageal varices were associated with development of decompensation (hazard ratio (HR), 2.09; 95% confidence interval (CI), 1.33-3.30) and liver-related death (HR, 2.27; 95% CI, 1.41-3.66). A MELD score of > 10 predicted overall mortality (HR, 2.15; 95% CI, 1.50-3.09). Overall survival of patients with MELD < or = 10 was 80% at 10 years. HCC occurrence increased the risk of decompensation fivefold (HR, 5.52; 95% CI, 3.77-8.09). Hepatic and overall mortality hazard ratios were 8.62 (95% CI, 5.57-13.3) and 3.80 (95% CI, 2.67-5.42), respectively, for patients who developed HCC, and 16.9 (95% CI, 9.97-28.6) and 7.08 (95% CI, 4.88-10.2) for those who experienced decompensation. CONCLUSIONS: In patients with compensated HCV-induced cirrhosis, the presence of esophageal varices at baseline predicted decompensation and mortality. The development of HCC during follow-up strongly hastens the occurrence of decompensation, which is the main determinant of death. Patients with a MELD score < or = 10 at study entry had a prolonged life expectancy.

Background Cholesterol elimination occurs through bile acid synthesis that starts within the liver from 7α-hydroxylation or in extrahepatic tissues from 27-hydroxylation. This study was aimed at investigating in vivo these two pathways in patients with chronic liver disease. Methods Serum concentrations of 7α- and 27-hydroxycholesterol were measured in 54 patients (29 with primary biliary cirrhosis and 25 with chronic hepatitis C) and 18 controls. The rate of oxysterol plasma appearance was calculated after intravenous infusions of deuterated 7α- and 27-hydroxycholesterol in patients ( n = 8) and control subjects ( n = 8) who gave consent. The expression of sterol 27-hydroxylase was evaluated in macrophages isolated from 20 subjects. Results In patients with liver disease, the rate of plasma appearance of 7α-hydroxycholesterol was significantly reduced (1.44 ± 0.96 vs . 2.75 ± 1.43 mg/hour, p = 0.03), the degree of reduction being related with the severity of the disease ( p = 0.01) whereas that of 27-hydroxycholesterol was unaffected. The rate of plasma appearance of 27-hydroxycholesterol was significantly related to its serum concentrations ( r = 0.54, p = 0.03) and to its release from cultured macrophages ( r = 0.85, p = 0.03). Conclusions In liver disease 7α-hydroxylation of cholesterol seems to be impaired while 27-hydroxylation is unaffected. Serum concentrations of 27-hydroxycholesterol are useful to obtain information on the activity of this alternative pathway.

Epidemiological studies have shown the association between the exposure to air pollution and several adverse health effects. To evaluate the possible acute health effects of air pollution due to the emissions of a cement plant in two small municipalities in Italy (Mazzano and Rezzato), a case–control study design was used. The risks of hospital admission for cardiovascular or respiratory diseases for increasing levels of exposure to cement plant emissions were estimated, separately for adults (age>34 years) and children (0–14 years). Odds ratios (OR) were estimated using unconditional regression models. Attributable risks were also calculated.Statistically significant risks were found mainly for respiratory diseases among children: OR 1.67 (95% CI 1.08–2.58) for the moderately exposed category (E1), OR 1.88 (95% CI 1.19–2.97) for the highly exposed category (E2), with an attributable risk of 38% of hospital admissions due to the exposure to cement plant exhausts. Adults had a weaker risk: OR 1.38 (95% CI 1.18–1.61) for group E1, OR 1.31 (95% CI 1.10–1.56) for group E2; the attributable risk was 23%. Risks were higher for females and for the age group 35–64. These results showed an association between the exposure to plant emissions and the risk of hospital admission for cardiovascular or respiratory causes; this association was particularly strong for children. Keywords: Cement plant, Health effects, Air pollution, Nitrogen oxides, GIS

Genetic factors are critical in determining susceptibility to primary biliary cirrhosis (PBC), but there has not been a clear association with human leukocyte antigen (HLA) genes. We performed a multicenter case-control study and analyzed HLA class II DRB1 associations using a large cohort of 664 well-defined cases of PBC and 1992 controls of Italian ancestry. Importantly, healthy controls were rigorously matched not only by age and sex, but also for the geographical origin of the proband four grandparents (Northern, Central, and Southern Italy). After correction for multiple testing, DRB1*08 [odds ratio (OR), 3.3; 95% confidence interval (CI), 2.4-4.5] and DRB1*02 (OR 0.9; 95% CI 0.8-1.2) were significantly associated with PBC, whereas alleles DRB1*11 (OR 0.4; 95% CI 0.3-0.4) and DRB1*13 (OR 0.7; 95% CI 0.6-0.9) were protective. When subjects were stratified according to their grandparental geographical origin, only the associations with DRB1*08 and DRB1*11 were common to all three areas. Associated DRB1 alleles were found only in a minority of patients, whereas an additive genetic model is supported by the gene dosage effect for DRB1*11 allele and the interaction of DRB1*11,*13, and *08. Lastly, no significant associations were detected between speci fic DRB1 alleles and relevant clinical features represented by the presence of cirrhosis or serum autoantibodies. In conclusion, we confirm the role for HLA to determine PBC susceptibility and suggest that the effect of HLA is limited to patient subgroups. We suggest that a large whole-genome approach is required to identify further genetic elements contributing to the loss of tolerance in this disease. Copyright © 2008 by the American Association for the Study of Liver Diseases.

Serous, endometrioid, clear cell and mucinous histotypes are the most common epithelial ovarian cancer. Most serous cancers appear to originate from precursor lesions at the fimbriated tubal end, whereas most endometrioid and clear cell cancers seem to derive from atypical endometriosis. Data regarding hormonal factors and associated gynaecologic conditions were critically analysed with the objective of defining a carcinogenic model for sporadic epithelial ovarian cancer complying with epidemiologic and pathologic findings. Oral contraceptives and tubal ligation substantially reduce the risk of serous, endometrioid and clear cell subgroups, but have no significant effect on mucinous tumours, which probably follow a different oncogenic pathway. We hypothesize that serous, endometrioid and clear cell cancers share a common pathogenic mechanism, i.e. iron-induced oxidative stress derived from retrograde menstruation. Fimbriae floating in bloody peritoneal fluid are exposed to the action of catalytic iron and to the genotoxic effect of reactive oxygen species, generated from haemolysis of erythrocytes by pelvic macrophages. This would explain the distal site of tubal intraepithelial neoplasia. Collection of blood inside endometriomas would lead to the same type of genotoxic insult on gonadal endometrial implants. This would explain why endometriosis-associated cancers develop much more frequently in the ovary than at extragonadal sites. In women not seeking conception, bilateral salpingectomy could be advised whenever planning surgery for independent indications, thus possibly reducing cancer risk, while preserving ovarian function. The use of oral contraceptives should be favoured for prolonged periods of time, especially in women with endometriosis, a population at doubled risk of gonadal malignancy.

The association between cancer incidence and the residence near polluting facilities in an industrial area nearby Taranto has been investigated. Age, sex and occupational exposure were controlled as confounding variables in a case-control study (658 cases, 2092 controls). High risks were evidenced close to the steel mill (OR: 3.54), coke plant (OR: 4.80), mineral deposit (OR: 3.33) and shipbuilding (OR: 4.29) for pleural neoplasm, and to the steel mill (OR: 1.65) and shipbuilding (OR: 1.79) for lung cancer. After adjustment for occupational exposure, increasing trends of risk were observed both for lung and bladder cancers. Cancer risks were evidenced near industrial sites and the introduction of "occupational exposure" as a confounder modified significantly the risks with respect to distance from the source of pollution, particularly for pleural, lung and bladder cancers.

Objective To investigate compliance, satisfaction, and preference in women using a transdermal contraceptive patch. Methods Women (18–6 years) from eight European countries used contraceptive patches (norelgestromin 6 mg, ethinylestradiol 600 μg for six, 4-week treatment cycles. Compliance, satisfaction, and preference were assessed after 3 and 6 cycles and study completion using self-report methods. Results Of the 778 participants, 36.8% (n = 287) used no contraception at baseline. The most common methods were oral contraceptives (67.9%, n = 334) and barrier methods (21.5%, n = 106). Of oral contraception users, 63.5% (n = 212) were satisfied or very satisfied with their previous method, but compliance was poor with 77.8% (n = 260) reporting missed doses. After 3 and 6 cycles, > 80% of all included women were satisfied or very satisfied with the patch. At study completion, most participants (73.7%) reported a preference for the patch compared to their previous method. Of 4107 cycles, 3718 (90.5%) were completed with perfect compliance. Two pregnancies occurred during this study, representing a Pearl Index of 0.63. No new safety issues were identified and the patch was well tolerated. Conclusion Women were highly satisfied with transdermal contraception and preferred this form of family planning over their previous method. Transdermal contraception represents a valuable addition to contraceptive options with potential to offer high compliance and efficacy.

OBJECTIVE Some obese individuals have normal insulin sensitivity. It is controversial whether this phenotype is associated with increased all-cause mortality risk. RESEARCH DESIGN AND METHODS Fifteen-year all-cause mortality data were obtained through the Regional Health Registry for 2,011 of 2,074 Caucasian middle-aged individuals of the Cremona Study, a population study on the prevalence of diabetes in Italy. Individuals were divided in four categories according to BMI (nonobese: RESULTS Obese insulin-sensitive subjects represented 11% (95% CI 8.1–14.5) of the obese population. This phenotype had similar BMI but lower waist circumference, blood pressure, fasting glucose, triglycerides, and fibrinogen and higher HDL cholesterol than obese insulin-resistant subjects. In the 15-year follow-up, 495 deaths (cardiovascular disease [CVD]: n = 221; cancer: n = 180) occurred. All-cause mortality adjusted for age and sex was higher in the obese insulin-resistant subjects (hazard ratio 1.40 [95% CI 1.08–1.81], P = 0.01) but not in the obese insulin-sensitive subjects (0.99 [0.46–2.11], P = 0.97) when compared with nonobese insulin-sensitive subjects. Also, mortality for CVD and cancer was higher in the obese insulin-resistant subjects but not in the obese insulin-sensitive subjects when compared with nonobese insulin-sensitive subjects. CONCLUSIONS In contrast to obese insulin-resistant subjects, metabolically healthy obese individuals are less common than previously thought and do not show increased all-cause, cancer, and CVD mortality risks in a 15-year follow-up study.

INTRODUCTION: Although fertility rates are falling in many countries, Europe is the continent with the lowest total fertility rate (TFR). This review assesses trends in fertility rates, explores possible health and social factors and reviews the impact of health and social interventions designed to increase fertility rates.METHODS: Searches were done in medical and social science databases for the most recent evidence on relevant subject headings such as TFR, contraception, migration, employment policy and family benefits. Priorities, omissions and disagreements were resolved by discussion.RESULTS: The average TFR in Europe is down to 1.5 children per woman and the perceived ideal family size is also declining. This low fertility rate does not seem directly caused by contraception since in Northern and Western Europe the fertility decline started in the second half of the 1960s. Factors impacting on lower fertility include the instability of modern partnerships and value changes. Government support of assisted human reproduction is beneficial for families, but the effect on TFR is extremely small. Government policies that transfer cash to families for pregnancy and child support also have small effects on the TFR.CONCLUSIONS: Societal support for families and for couples trying to conceive improves the lives of families but makes no substantial contribution to increased fertility rates.

A population-based case–control study of 649 leukemia cases and 1771 controls carried out in 11 Italian areas, offered the opportunity to evaluate the relationship between alcohol consumption and leukemia risk. For all leukemias, acute lymphocytic leukemia (ALL), acute myeloid leukemia (AML), and chronic lymphocytic leukemia (CLL), we found a non-significantly inverse association for moderate levels of total alcohol and wine intake, but increased risks at high levels, with, in most cases, significant trend effects (odd ratios (OR) for all leukemias in the lowest quartile of total alcohol consumption [0.1–9.0 g/day of ethanol] versus never-drinker = 0.73; 95% confidence intervals (95% CI) = 0.51–1.03; OR in the highest quartile [> 31.7 g/day] = 1.15; 95% CI = 0.82–1.63; p of the linear trend test = 0.007). For chronic myeloid leukemia (CML), we found a non-significantly positive association for all levels of total alcohol and wine intake, and a significant positive linear trend effect (p = 0.03) for wine intake (OR for 0.1–9.0 g/day of ethanol intake from wine = 1.34; 95% CI = 0.61–2.94; OR in the highest quartile of wine intake [> 27.7 g/day] = 2.13; 95% CI = 1.01–4.50). No consistent dose–response was detected analysing duration of alcohol consumption for any leukemia subtypes. In conclusion, even though our study did not show a clear association between alcohol intake and leukemia risk, some of the patterns of the risk estimates (a possible J-shaped dose–response curve between alcohol intake and ALL, AML, and CLL risks, and the positive association between alcohol and CML), may be suggestive.

Objective: Diabetes frequently complicates cystic fibrosis (CF) without fasting hyperglycemia or despite spontaneous hypoglycemia (anecdotally ascribed to malnutrition), whose prevalence, clinical meaning, and relationship with glucose tolerance and clinical/nutritional status were not previously investigated. The relationship of CF genotype with insulin secretion control is also unclear. Design and methods: A total of 129 CF patients without stable diabetes received 188 oral glucose tolerance tests. Distribution of fasting plasma glucose (FPG), glucose, insulin and C-peptide responses, clinical/nutritional variables, and their relationships were analyzed. Results: FPG < 60 mg/dl (3.3 mmo/l) was detected in 14% of studies and reactive hypoglycemia (PG < 50 mg/dl (2.8 mmo/l)) in 15%. OGTT-based diabetes frequency was similar in the lowest quartile (Q1) and Q2–3 for FPG (10 and 8%), with higher glucose increment and area under the curve in Q1. Insulin and C-peptide levels were similar among FPG quartiles. Class I cystic fibrosis transmembrane conductance regulator mutation carriers had higher insulin concentrations than class II, especially in Q1 for FPG. Age, sex, nutritional, and anthropometric parameters including fat and lean body mass were unrelated to FPG. Lower FPG was associated with more frequent hospitalization rates (P = 0.002) and lower Shwachman scores (P = 0.041). Steroids weaning was accurately evaluated but then excluded as a possible cause of hypoglycemia. Conclusions/interpretation: Fasting asymptomatic hypoglycemia is frequent and possibly related to inappropriate insulin secretion control in class I mutation carriers. Low FPG does not exclude impaired glucose tolerance (IGT) and diabetes in CF and reflects worse clinical status.

Background: Few studies have analysed the association between alcohol intake and Hodgkin's lymphoma (HL) or multiple myeloma (MM) risks. Materials and methods: A multicentre population-based case–control study of 363 HL, 270 MM cases, and 1771 controls offered the opportunity to evaluate the relationship between alcohol and HL/MM risks. Unconditional logistic regression was carried out to estimate odds ratios (ORs) and 95% confidence intervals (CIs), associated with alcohol intake (servings per week, grams per day of ethanol intake) or duration of exposure (year). Results: For HL, considering nonsmokers only, ever drinkers had a significantly decreased risk than never drinkers (OR = 0.46). Significantly lower risks in all levels of total alcohol intake were also detected, considering servings per week (OR for one to four servings per week = 0.51, 95% CI 0.32–0.82; OR for five to nine servings per week = 0.39, 95% CI 0.21–0.73; OR for 10–19 servings per week = 0.26, 95% CI 0.12–0.54; OR for ≥20 servings per week = 0.34, 95% CI 0.15–0.79) and grams per day of ethanol intake (OR for 0.1–9.0 g/day = 0.45, 95% CI 0.27–0.74; OR for 9.1–17.9 g/day = 0.52, 95% CI 0.30–0.90; OR for 18.0–31.7 g/day = 0.27, 95% CI 0.13–0.57; OR for >31.7 g/day = 0.35, 95% CI 0.15–0.79). In the analysis for ever-smoking HL cases and controls, ever drinkers had the same risk as never drinkers. For MM, ever drinkers had a non-significantly decreased risk than non-drinkers (OR = 0.74), and ORs in almost all consumption levels were not significant (OR for 0.1–9.0 g/day = 0.93; OR for 9.1–17.9 g/day = 0.82; OR for 18.0–31.7 g/day = 0.47; 95% CI 0.28–0.81; OR for >31.7 g/day = 0.68). For HL and MM, the beverage type did not affect the risk significantly, and no consistent dose–response relationships were found, considering intensity or duration of alcohol consumption. Conclusions: Our study indicates a protective effect of alcohol consumption for nonsmoking HL cases.

OBJECTIVE Malabsorptive bariatric surgery (biliopancreatic diversion and biliointestinal bypass [BIBP]) reduces serum cholesterol levels more than restrictive surgery (adjustable gastric banding [AGB]), and this is thought to be due to greater weight loss. Our aim was to evaluate the changes of cholesterol metabolism induced by malabsorptive and restrictive surgery independent of weight loss. RESEARCH DESIGN AND METHODS In a nonrandomized, self-selected, unblinded, active-comparator, bicenter, 6-month study, glucose metabolism (blood glucose and serum insulin levels and homeostasis model assessment of insulin resistance [HOMA-IR] index) and cholesterol metabolism (absorption: serum campesterol and sitosterol levels; synthesis: serum lathosterol levels; catabolism: rate of appearance and serum concentrations of serum 7-α- and serum 27-OH-cholesterol after infusions of deuterated 7-α- and 27-OH-cholesterol in sequence) were assessed in grade 3 obesity subjects undergoing BIBP (n = 10) and AGB (n = 10). Evaluations were performed before and 6 months after surgery. RESULTS Subjects had similar values at baseline. Weight loss was similar in the two groups of subjects, and blood glucose, insulin levels, HOMA-IR, and triglycerides decreased in a similar way. In contrast, serum cholesterol, LDL cholesterol, non-HDL cholesterol, serum sitosterol, and campesterol levels decreased and lathosterol levels increased only in BIBP subjects, not in AGB subjects. A significant increase in 7-α-OH-cholesterol occurred only with BIBP; serum 27-OH-cholesterol decreased in both groups. CONCLUSIONS Malabsorptive surgery specifically affects cholesterol levels, independent of weight loss and independent of glucose metabolism and insulin resistance. Decreased sterol absorption leads to decreased cholesterol and LDL cholesterol levels, accompanied by enhanced cholesterol synthesis and enhanced cholesterol catabolism. Compared with AGB, BIBP provides greater cholesterol lowering.

Objective This study was undertaken to ascertain whether the incidence of pregnancy is increased and time-to-conception is reduced in infertile women with rectovaginal endometriosis undergoing conservative surgery compared with those on expectant management. Study design A total of 105 infertile women under the age of 40 years with rectovaginal endometriosis and no other associated major infertility factor underwent first-line conservative surgery at laparotomy or expectant management according to a shared decision-making approach. Results Among the 44 women who had resection of rectovaginal endometriosis, 15 became pregnant, compared with 22 of the 61 women who choose expectant management (24-month cumulative probabilities, 44.9% and 46.8%, respectively; log-rank test, χ 2 1 = 0.75; P = .38). One major and 9 minor postoperative complications occurred. Significant differences in pain-free survival time in favor of the surgery group were observed for dysmenorrhea, dyspareunia, and dyschezia. Conclusion Conservative surgery for rectovaginal endometriosis in infertile women does not modify the reproductive prognosis although it does increase pain-free survival time.

A number of studies have shown possible associations between occupational exposures, particularly solvents, and lymphomas. The present investigation aimed to evaluate the association between exposure to solvents and lymphomas (Hodgkin and non-Hodgkin) in a large population-based, multicenter, case-control study in Italy.All newly diagnosed cases of malignant lymphoma in men and women age 20 to 74 years in 1991-1993 were identified in 8 areas in Italy. The control group was formed by a random sample of the general population in the areas under study stratified by sex and 5-year age groups. We interviewed 1428 non-Hodgkin lymphoma cases, 304 Hodgkin disease cases, and 1530 controls. Experts examined the questionnaire data and assessed a level of probability and intensity of exposure to a range of chemicals.Those in the medium/high level of exposure had an increased risk of non-Hodgkin lymphoma with exposure to toluene (odds ratio = 1.8; 95% confidence interval = 1.1-2.8), xylene 1.7 (1.0-2.6), and benzene 1.6 (1.0-2.4). Subjects exposed to all 3 aromatic hydrocarbons (benzene, toluene, and xylene; medium/high intensity compared with none) had an odds ratio of 2.1 (1.1-4.3). We observed an increased risk for Hodgkin disease for those exposed to technical solvents (2.7; 1.2-6.5) and aliphatic solvents (2.7; 1.2-5.7).This study suggests that aromatic and chlorinated hydrocarbons are a risk factor for non-Hodgkin lymphomas, and provides preliminary evidence for an association between solvents and Hodgkin disease.

BACKGROUND The association between lesion type, disease stage and severity of pain was studied in a large group of women with endometriosis to verify whether endometrial implants at different sites determine specific complaints and to evaluate the validity of the current classification system in women with symptomatic disease. METHODS A total of 1054 consecutive women with endometriosis undergoing first-line conservative or definitive surgery were included. Data on age at surgery, disease stage according to the revised American Fertility Society (AFS) classification, anatomical characteristics of endometriotic lesions, and type and severity of pain symptoms were collected and analysed by multiple logistic regression. RESULTS Minimal endometriosis was present in 319 patients, mild in 139, moderate in 292 and severe in 304. A significant inverse relationship was demonstrated between age at surgery and moderate-to-severe dysmenorrhoea, dyspareunia and non-menstrual pain. A strong association was found between posterior cul-de-sac lesions and pain at intercourse [Wald chi (2) = 17.00, P = 0.0001; odds ratio (OR) = 2.64, 95% confidence interval (CI) = 1.68-4.24]. A correlation between endometriosis stage and severity of symptoms was observed only for dysmenorrhoea (Wald chi (2) = 5.14, P = 0.02) and non-menstrual pain (Wald chi (2) = 5.63, P = 0.018). However, the point estimates of ORs were very close to unity (respectively, 1.33, 95% CI = 1.04-1.71, and 1.01, 95% CI = 1.00-1.03). CONCLUSIONS The association between endometriosis stage and severity of pelvic symptoms was marginal and inconsistent and could be demonstrated only with a major increase in study power.

BACKGROUND: To assess the predictive value of the current classification of endometriosis in terms of response to surgical treatment, we studied to what extent disease stage, lesion type and lesion site were associated with post-operative pregnancy rate, symptom recurrence and disease relapse. METHODS: A total of 729 women with endometriosis undergoing first-line conservative laparoscopic surgery were included. Data on age at surgery, disease stage according to the revised American Fertility Society (AFS) classification, anatomical characteristics of endometriotic lesions, fertility status and types and severity of pain symptoms were collected. RESULTS: Minimal endometriosis was present in 222 patients, mild in 106, moderate in 197 and severe in 204. The cumulative probability of pregnancy at 3 years from surgery in 537 infertile women was 47% (51 % at stage 1,45% at stage II, 46% at stage III and 44% at stage IV; log-rank test, Χ 2 3 = 1.50, P = 0.68). The cumulative probability of moderate or severe dysmenorrhoea recurrence in 425 symptomatic subjects was 24% (32% at stage I, 24% at stage II, 21% at stage III and 19% at stage IV; log-rank test, Χ 2 3 = 6.39, P = 0.094). The cumulative probability of disease relapse was 12% (3% at stage I, 11% at stage II, 11% at stage III and 23% at stage IV; log-rank test, Χ 2 3 = 24.95, P = 0.0001). Using Cox's multivariate proportional hazards regression analysis, no association was observed between endometriosis stage or lesion type and lesion site and any of the considered study outcomes. CONCLUSIONS: The current classification of endometriosis has an inadequate predictive value with regard to the major clinical outcomes.

Objective To employ protocols of mild ovarian stimulation to prevent an excessively elevated rate of high-order multiple pregnancies. Design Case series. Setting University hospital. Patient(s) Six hundred and twenty one consecutive patients undergoing 1,259 controlled ovarian hyperstimulation and intrauterine insemination cycles. Intervention(s) Patients received 50 IU per day of recombinant follicle-stimulating hormone (FSH) starting the third day of the cycle, then a gonadotropin-releasing hormone (GnRH) antagonist on the day in which a follicle ≥13 mm was visualized. Cycles were canceled if three or more follicles ≥16 mm and/or five or more follicles ≥11 mm were detected. Main Outcome Measure(s) Rate of high-order multiple pregnancies. Result(s) The clinical pregnancy rate per initiated cycle was 9.2% (95% confidence interval, 7.5–11.1%). The incidence of twins and high-order multiple pregnancies was 9.5% (95% CI, 5.3–16.2%) and 0 (0.0–3.2%), respectively. Conclusion(s) In controlled ovarian hyperstimulation and intrauterine insemination cycles, a protocol of 50 IU of recombinant FSH daily combined with the use of GnRH antagonists and a policy of strict cancellation based on echographic criteria are associated with a satisfactory pregnancy rate per initiated cycle and a low risk of high-order multiple pregnancies.

This study compared the effectiveness and safety of a new subcutaneous formulation of depot medroxyprogesterone acetate delivering 104 mg per 0.65 mL (DMPA-SC 104) every 3 months with those of leuprolide-a widely used and effective treatment for pain from endometriosis-in a dose of 3.75 mg per month (or 11.25 mg every 3 months). Bone mineral density (BMD) was estimated after 6 months of treatment and again at a 12-month follow-up assessment. Clinical end points included dysmenorrhea, dyspareunia, pelvic pain and tenderness, and induration. In addition, productivity was monitored at 6 and 18 months. Both treatments began in the first 5 days of a normal menstrual cycle. Participants were 299 women with laparoscopically diagnosed endometriosis; 153 were randomized to receive DMPA-SC 104, and 146 leuprolide. Between two thirds and three fourths of patients in both groups completed 12 months of follow up. The 2 treatment groups were initially similar in nearly all respects. All signs and symptoms of endometriosis were lessened as effectively by treatment with DMPA-SC 104 as with leuprolide. More than three fourths of patients in each treatment group maintained improvement at 12 months. Patients reported a higher quality of life with either treatment, and those in both treatment groups were satisfied with their results. Productivity also improved significantly in both groups. Patients taking leuprolide had significant reductions from baseline BMD in the total hip and lumbar spine regions after 6 months of treatment. A similar change occurred, in the spine only, in patients given DMPA-SC 104. At 12 months, BMD values were normal at both sites in the latter group, whereas women treated with leuprolide continued to have declining values at both sites. Hot flushes were less frequent in the DMPA-SC 104 group as was amenorrhea. Serious adverse events occurred in 4% of the DMPA-SC 104 group and 2% of patients given leuprolide. The most common side effect during follow-up was breast pain, which was slightly more frequent in the DMPA-SC 104 group. There were no clinically important changes in hematologic values, biochemical assays, or urinalysis. Although further long-term trials will be needed, the present findings suggest that DMPA-SC 104 may be suitable as a first-line treatment for women having pain caused by endometriosis. (Several investigators, including my colleagues and I.

Missing information about reproductive processes is an important barrier to conception and live birth among infertile couples. In vitro and genetic techniques have been informative, but not enough is known about potential defects in fertilization, implantation and early embryo development to define explicit infertility diagnoses and direct specific treatment. Study of gamete quality is needed because endocrine and ultrasound measurements in the female cannot determine oocyte quality and semen analysis in the male is a limited predictor of fertilizing ability. Also, more study would help in understanding the conditions in the Fallopian tube and elsewhere that foster fertilization and embryo development. Research in related subjects is also needed: after many years of enquiry, there exists little or no evidence to determine how and if endometriosis causes subfertility. In contrast, the recently described impact of smoking in males is large, clinically important and possibly reversible. Missing information limits the choice of specific treatment, puts a ceiling on the overall prognosis, increases the likelihood of persistent infertility and forms a barrier to understanding the broader meanings of success in the management of infertility.

BACKGROUND Residual ovarian function after laparoscopic excision of endometriotic ovarian cysts is a major and still unsolved topic. Ultrasonographic evaluation of ovarian response to ovulation stimulation represents a simple yet poorly employed tool to assess residual ovarian function after surgery. METHODS Data from patients referred for IVF or ICSI between January 2001 and December 2002 were reviewed. Patients were included who previously underwent laparoscopic excision of a monolateral endometriotic ovarian cyst. The operated ovary and contralateral intact ovary were compared in terms of number of follicles with a mean diameter >15 mm at the time of hCG administration. Basal volume of the two ovaries before initiating stimulation was also compared. A paired Student's t-test was used to investigate differences between the two ovaries. RESULTS In total, 32 patients and 46 cycles were identified. The mean (+/- SD) number of follicles >15 mm was 4.2 +/- 2.5 in the control ovary and 2.0 +/- 1.5 in the previously operated ovary (P < 0.001); this corresponded to a mean reduction of 53% (95% CI 35-72%) but did not seem to be related to the dimension of the excised ovarian cyst. The basal volume of the operated ovaries was also statistically significantly diminished, though this reduction was less relevant. CONCLUSIONS Excision of endometriotic ovarian cysts is associated with a significant reduction in ovarian reserve. Further studies are required to clarify whether the damage is related to the surgical procedure or to the previous presence of a cyst.

Background This prospective study evaluated the effect of weight reduction on anthropometric indices and ovarian morphology in anovulatory overweight patients with polycystic ovary syndrome (PCOS). Methods Thirty-three anovulatory overweight patients with PCOS were enrolled in the study. All had patent Fallopian tubes and chronic anovulation: 27 of them were oligo-amenorrhoeic. The partners were normospermic. Patients were prescribed a 1200 kcal/day diet, and physical exercise was recommended. Anthropometric indices and ovarian imaging parameters were assessed at baseline and after weight loss of 5 and 10%. Results Twenty-five patients (76%) lost at least 5% of their body weight. Eleven of these patients (33%) reached a 10% decrease in weight. Waist circumference at the umbilical level, hip circumference, four skin folds, body mass index and fatty mass ratio were significantly reduced after 5 and 10% weight loss. Ovarian morphology changed during the diet: we observed a significant reduction in ovarian volume and in the number of microfollicles per ovary. Among the 27 patients with oligo-amenorrhoea, 18 had a resumption of regular cycles and 15 experienced spontaneous ovulation; 10 spontaneous pregnancies occurred in patients who lost at least 5% of their weight. Conclusions Weight loss through a controlled low-calorie diet improves anthropometric indices in obese PCOS patients, reduces ovarian volume and microfollicle number and can restore ovulatory cycles, allowing spontaneous pregnancy.

Laparoscopic surgery is often carried out in women with endometriosis who experience dysmenorrhea. The results are not consistently good, and affected women often have recurrent pain. This open-label, parallel-group, randomized trial evaluated an intrauterine device (IUD) that releases levonorgestrel (a Lng-IUD), a potent 19-nortestosterone derivative progestin that can induce amenorrhea. Twenty parous women with endometriosis and moderate or severe dysmenorrhea received the Lng-IUD after operative laparoscopy, whereas 20 others had only surgery. The participants, who were 40 years of age or younger and did not want a child, were reevaluated after 12 months. Conservative surgery was performed using only mechanical instruments and electrosurgery. Adhesions were sectioned, the ovaries were mobilized, and areas of endometriosis were either excised or coagulated. The Lng-IUD that was inserted into the uterine cavity releases 20μg of levonorgestrel daily over 5 years. In one case, the Lng-IUD was displaced. After 12 months, amenorrhea was described by 28% of women given the Lng-IUD and dysmenorrhea or spotting by another 50%; 22% of these women had normal menstrual flow. Dysmenorrhea continued at a moderate or severe level in 45% of women treated by surgery alone. The absolute risk reduction of recurrent dysmenorrhea in the Lng-IUD group was 35%. Dyspareunia and nonmenstrual pain also were less frequent in the IUD group. Tolerable side effects developed in 8 of 20 women assigned to receive the IUD. At follow-up, 75% of women in the Lng-IUD group and 50% of those in the surgery-only group were satisfied or very satisfied with their treatment. This pilot study suggests that, in women with symptomatic endometriosis, inserting a Lng-IUD after conservative laparoscopic surgery reduces the chance of recurrent dysmenorrhea and provides a high level of patient satisfaction, at least over the medium term.

Objective To evaluate the efficacy of laparoscopic resection of the uterosacral ligaments in women with endometriosis and predominantly midline dysmenorrhea. Design Randomized controlled trial. Setting Two academic departments. Patient(s) One hundred eighty patients undergoing operative laparoscopy as first-line therapy for stage I to IV symptomatic endometriosis. Intervention(s) Operative laparoscopy including uterosacral ligament resection or conservative surgery alone. Main outcome measure(s) Proportion of women with recurrence of moderate or severe dysmenorrhea 1 year after surgery. Result(s) No complications occurred. Among the patients who were evaluable 1 year after operative laparoscopy, 23 of 78 (29%) women who had uterosacral ligament resection and 21 of 78 (27%) women who had conservative surgery only reported recurrent dysmenorrhea. The corresponding numbers of patients at 3 years were 21 of 59 (36%) women and 18 of 57 (32%) women, respectively. Time to recurrence was similar in the two groups. Pain was substantially reduced, and patients in both groups experienced similar and significant improvements in health-related quality of life, psychiatric profile, and sexual satisfaction. Overall, 68 of 90 (75%) patients in the uterosacral ligament resection group and 67 of 90 (74%) patients in the conservative surgery group were satisfied at 1 year. Conclusion(s) Addition of uterosacral ligament resection to conservative laparoscopic surgery for endometriosis did not reduce the medium- or long-term frequency and severity of recurrence of dysmenorrhea.

Objective To ascertain whether adjuvant gonadotropin-releasing hormone (GnRH) agonist therapy decreases blood loss during abdominal myomectomy. Design Randomized controlled trial. Setting Academic reproductive surgery center. Patient(s) One hundred premenopausal women requiring first-line conservative surgery for symptomatic intramural or subserous fibroids. Intervention(s) Eight weeks of treatment with depot triptorelin before myomectomy or immediate surgery. Main outcome measure(s) Intraoperative blood loss, operating time, degree of difficulty of the procedure, and short-term rate of fibroid recurrence. Result(s) Mean (±SD) intraoperative blood loss was 265 ± 181 mL in triptorelin recipients and 296 ± 204 in patients who had immediate surgery (mean difference, −31 mL [95% CI, −108 to 46 mL]). No significant differences were observed in blood loss according to uterine volume, number of fibroids removed, or total length of myometrial incisions. Most procedures in either group were of routine difficulty. On ultrasonography 6 months after myomectomy, four women in the GnRH agonist group and one in the immediate surgery group had tumor recurrence. Conclusion(s) Treatment with a GnRH agonist before abdominal myomectomy has no significant effect on intraoperative blood loss. Thus, systematic use of medical therapy before abdominal myomectomy does not seem to be justified.

ObjectivesEvidence suggests that certain occupations and related exposures may increase the risk of malignant lymphoma. Farming, printing and paper industry, wood processing, meat handling and processing, welding, shoe and leather manufacturing and teaching profession are among the categories that have been implicated in previous studies. The relationship between occupation and malignant lymphoma has been investigated in a large European prospective study.MethodsWe investigated occupational risks for lymphomas in the European Prospective Investigation into Cancer and Nutrition (EPIC). The mean follow-up time for 348 555 subjects was 9 years (SD: 2 years). The analysis was based on 866 and 48 newly diagnosed cases of non-Hodgkin's lymphoma (NHL) and Hodgkin's lymphoma (HL). These were identified in the EPIC subcohorts with occupational data. Data on 52 occupations were collected through standardised questionnaires. Cox proportional hazard models were used to explore the association between occupation and risk of malignant lymphoma.ResultsThe following occupations were positively associated with malignant NHL after adjustment for study centre, age, sex, socioeconomic status (SES), smoking and alcohol: butchers (HR=1.53, 95% CI 1.05 to 2.48, including multiple myeloma/plasmacytoma; HR=1.30, 95% CI 1.00 to 2.66, excluding multiple myeloma/plasmacytoma) and car repair workers (HR=1.50, 95% CI 1.01 to 2.00, including multiple myeloma/plasmacytoma; HR=1.51, 95% CI 1.01 to 2.31, excluding multiple myeloma/plasmacytoma). HL was associated with gasoline station occupation (HR=4.59, 95% CI 1.08 to 19.6).ConclusionThe findings in this current study of a higher risk of NHL among car repair workers and butchers and a higher risk of HL among gasoline station workers suggest a possible role from occupationally related exposures, such as solvents and zoonotic viruses, as risk factors for malignant lymphoma.

Incidence of liver disease (LD) associated with cystic fibrosis (CF) and its clinical characterization still is unsettled. We have assessed prospectively the incidence and risk factors of this complication, and its impact on the clinical course of CF. Between 1980 and 1990, we enrolled 177 CF patients without LD in a systematic clinical, laboratory, ultrasonography screening program of at least a 10-year duration. During a 14-year median follow-up (2,432 patient-years), 48 patients developed LD, with cirrhosis already present in 5. Incidence rate (number of cases per 100 patient-years) was 1.8% (95% confidence interval: 1.3-2.4), with sharp decline after the age of 10 years and higher risk in patients with a history of meconium ileus (incidence rate ratio, 5.5; 2.7-11), male sex (2.5; 1.3-4.9), or severe mutations (2.4; 1.2-4.8) at multivariate analysis. Incidence of cirrhosis was 4.5% (2.3-7.8) during a median period of 5 years from diagnosis of liver disease. Among the 17 cirrhotic patients, 13 developed portal hypertension, 4 developed esophageal varices, 1 developed liver decompensation requiring liver transplantation. Development of LD did not condition different mortality (death rate ratio, 0.4; 0.1-1.5) or higher incidence of other clinically relevant outcomes. In conclusion, LD is a relatively frequent and early complication of CF, whose detection should be focused at the first life decade in patients with history of meconium ileus, male sex, or severe genotype. Although LD does not condition a different clinical course of CF, in some patients it may progress rapidly and require liver transplantation.

"BACKGROUND: A previous explorative record-linkage study suggested a putative role of employment in electrical manufacturing in increasing female breast cancer risk in the Province of Milan (Italy). We deepened the understanding of this possible association in a single large electrical manufacturing plant located in Lombardy in the Province of Milan. METHODS: We carried out a nested case-control study within a cohort of women employed in a large electrical manufacturing plant. All incident cases during 2002 to 2009 of female breast cancer in individuals who worked at least a 1 year in the factory and resided in Lombardy, Italy, were selected. Controls were randomly sampled from all women who worked in the same plant and resided in Lombardy as of December 31, 2005. Odds ratios (ORs) and corresponding 95% confidence intervals (CIs) were calculated using multiple logistic regression models, taking into consideration only female workers as ever/never exposed to physical/chemical agents and their longest occupational period. ORs were adjusted for several potential confounders, namely, other known risk factors. RESULTS: The ORs for female breast cancer were significantly increased for exposure to chlorinated solvents (OR 1.65, 95% CI 1.04-2.62), and there was a twofold increase (OR 2.10, 95% CI 1.21-3.66) among women exposed for at least 10 years. We found no other significantly increased OR by exposure or job title. CONCLUSIONS: Our results suggest an increased risk of breast cancer after exposure to chlorinated solvents among women employed in the electrical manufacturing industry."

The role of occupational exposures in breast cancer development is still uncertain. A recent paper showed increased risks in some occupational sectors in Lombardy, Italy. We deepened this analysis at the level of single provinces of the same Italian region.Based on administrative data, a case-control study was carried out recruiting all incident cases of female breast cancer in the period 2002-2009, aged between 35 and 69 years, residing in Lombardy, Italy. Controls were randomly sampled from all women residing in Lombardy as of December 31, 2005. Occupational histories, including blue collar status, were available from 1974 through record linkage with a social security pension database, and were obtained for 11188 cases and 25329 controls. Adjusted odds ratios (ORs) and corresponding 90% confidence intervals (CIs) were calculated using multiple unconditional logistic regression models. Analyses were performed also by single provinces of Lombardy, Italy. Multiple comparisons were accounted for according to the Benjamini-Hochberg method.The ORs for female breast cancer were modestly but significantly increased for employment in electrical manufacturing (OR 1.12, 90% CI 1.04-121), textile (OR 1.08, 90% CI 1.02-1.15), paper (OR 1.25, 90% CI 1.06-1.46) and rubber (OR 1.26, 90% CI 1.03-1.54) industries. Analysis by province showed significantly increased ORs for electrical manufacturing in the Milano province. After adjustment for multiple comparisons no estimates remained statistically significant, except OR for electrical manufacturing in the Milano province.Although with several limitations, our results point to a possible role of exposures in electrical manufacturing, textile, paper and rubber industries in the process leading to breast cancer. An in-dept study for the electrical manufacturing industry has been already planned in Milano province.

As a part of the Occupational Cancer Monitoring (OCCAM) project, a routine analysis based on Umbria region cancer registry (RTUP) database in 2002-2008 was performed. Among other results, the incidental finding of brain cancer increased risk in steel foundry workers in Terni province (Italy), lead us to deepen the analysis, focusing on this specific industrial sector.A monitoring study, based on Umbria Regional Cancer Registry data, was recently carried out. Brain cancer cases and controls identified within this preliminary study were selected. Therefore, we considered all incident cases (in Umbria region 2002-2008) of brain cancer occurred among workers occupied for at least one year in private companies since 1974 and controls randomly sampled from the same population. Afterwards, taking in to account results from steel foundry in Terni province, we further deepened our analysis, focusing on this productive sector. Odds ratios (ORs) and corresponding 90% confidence intervals (CIs) were calculated using multiple logistic regression models, adjusted by age at diagnosis or sampling, sex and province of residence, when appropriate.Statistical analyses were carried out on 14913 subjects, 56 cases and 14857 controls. Significantly increased ORs were observed for garment, mechanical manufacturing and chemical industries. Moreover, the risk estimates were strongly correlated with exposures in iron and steel foundries and a cluster of 14 cases in the same foundry in Terni was observed (OR 9.59, 90% CI 2.76-33.34).Results of this explorative study showed increased ORs of brain cancer in some productive branches, involving possible exposures to chemical compounds and/or solvents. Moreover, our results pointed out a significantly increased risk in Terni foundry workers, determining an interesting brain cancer cluster (14 cases). Further studies on this industrial sector are needed with improved definitions of tasks and exposures.

Assisted Reproduction Treatment (ART) is here to stay. This review addresses the parental background of birth defects, before, during and after conception and focuses both on the underlying subfertility and on the question whether ART as a treatment is an additional contributing factor. Searches were performed in Medline and other databases. Summaries were discussed in a Delphi panel set-up by the European Society of Human Reproduction and Embryology (ESHRE). Several birth defects and adult diseases arise during the earliest stages of ovarian development and oocyte differentiation: this is the case of cleft palate disorders in offspring from female rat exposed to Dioxin during fetal life or the polycystic ovary diseases in female offspring (primates) exposed to elevated androgen concentration during fetal life. Human oocytes and embryos often fail to stop the propagation of aneuploid cells but maintain their ability to repair DNA damages including those introduced by the fertilizing sperm. There is a 29 % increased risk of birth defects in the newborns spontaneously conceived by subfertile couples and the risk is further increased (34 %) when conception is achieved by treating infertlity with ART (Danish IVF Registry). Periconceptional conditions are critical for ART babies: their birth weight is in general smaller (Norvegian Registry) but a more prolonged culture time doubled the number of large babies (Finnish Registry). The long-term developmental effects of ART on child and subsequent health as an adult remains a subject worthy of futher monitoring and investigation.

Objective: To assess the reliability of the most widely used clinical methods for predicting or confirming ovulation. Methods: We monitored spontaneous cycles in 101 infertile women using basal body temperature (BBT), transvaginal ultrasound, a urinary stick system for LH surge, and three serum progesterone measurements in the midluteal phase. Transvaginal ultrasound monitoring was standard for ovulation detection and sensitivity. We calculated specificity and accuracy of each method compared with that standard. Results: Follicular development and ultrasound evidence of ovulation were confirmed in 97 of 101 cycles (96%). Urinary LH surge preceded follicular rupture assessed by ultrasonography in all cycles and showed concordance with ultrasound-evidenced ovulation in 98 of 101 cases. The timing of BBT nadir had wide variability, and BBT and ultrasonography agreed in a similar percentage of cases (74%). Midluteal serum progesterone assessments showed ovulatory values in 93 subjects, and ovulation was concordant with ultrasonography in 90 subjects. Conclusion: Urinary LH was accurate in predicting ovulation with ultrasonography as the standard for detection, but time varied widely. The nadir of BBT predicted ovulation poorly. The BBT chart was less accurate for confirming ovulation, whereas a single serum progesterone assessment in midluteal phase seemed as effective as repeated serum progesterone measures.

Background As weight gain is one of the most frequently cited reasons for not using and for discontinuing hormonal contraceptives, in an open-label, single-arm, multicentre clinical study we evaluated the effect of the ethinylestradiol/norelgestromin contraceptive patch (EVRA, Janssen-Cilag International, Belgium) on body composition using bioelectrical impedance analysis (BIA). Methods Body weight and impedance vector components (resistance (R) and reactance (Xc), at 50 kHz frequency, Akern-RJL Systems analyzer) were recorded before entry, after 1, 3 and 6 months in 182 Italian healthy women aged 29 yr (18 to 45), and with BMI 21.8 kg/m2 (16 to 31). Total body water (TBW) was estimated with a BIA regression equation. Vector BIA was performed with the RXc mean graph method and the Hotelling's T2 test for paired and unpaired data. Results After 6 months body weight increased by 0.64 kg (1.1%) and TBW increased by 0.51 L (1.7%). The pattern of impedance vector displacement indicated a small increase in soft tissue hydration (interstitial gel fluid). Body composition changes did not significantly differ among groups of previous contraceptive methods. Arterial blood pressure did not significantly change over time. Conclusion After 6 months of treatment with the ethinylestradiol/norelgestromin contraceptive patch we found a minimal, clinically not relevant, increase in body weight less than 1 kg that could be attributed to an adaptive interstitial gel hydration. This fluctuation is physiological as confirmed by the lack of any effect on blood pressure. This could be useful in increasing women's choice, acceptability and compliance of the ethinylestradiol/norelgestromin contraceptive patch.

Background: No information is available on the hepatic and extrahepatic pathways of bile acid synthesis in normal children and in pediatric cholestatic liver diseases. Methods: To explore the changes of the two pathways of bile acid synthesis during development, plasma concentrations of 7α-hydroxycholesterol and 27-hydroxycholesterol were measured in 50 healthy children (1 month-14 years) and compared to 18 adult controls. We also measured plasma oxysterols in 31 patients with pediatric cholestatic liver disease. Results: A progressive increase of plasma concentrations of both 27-hydroxycholesterol and 7α-hydroxycholesterol was found with age. In children with cystic fibrosis-associated liver disease plasma concentrations of 27-hydroxycholesterol were significantly lower compared to age-matched controls (5.6 ± 0.5 vs. 12.8 ± 1.1 μg/dl; p < 0.001) and paralleled significantly lower concentrations of total cholesterol. In infants with biliary atresia plasma concentrations of 27-hydroxycholesterol were significantly higher compared to age-matched controls (8.8 ± 0.8 vs. 4.4 ± 0.6 μg/dl, p < 0.001) paralleling significantly higher concentrations of total cholesterol while 7α-hydroxycholesterol resulted significantly lower (1.2 ± 0.2 vs. 2.3 ± 0.3 μg/100 mg of total cholesterol; p = 0.011). Conclusions: Our data suggest that both pathways of bile acid synthesis reach a state of maturity only after the age of 4 years and are significantly influenced also in children by liver function and intestinal absorption of cholesterol. © 2008 Elsevier B.V. All rights reserved.

BACKGROUND—The annual incidence of non-Hodgkin's lymphomas (NHL) is increasing by 3%-4% in different parts of the developed world. Excesses of NHL have been observed in populations exposed to immunosuppressants and to HIV, but these causes do not explain the increasing trends. It is suggested that delayed infection could explain NHL trends, through an impairment of the Th1/Th2 lymphocyte patterns. METHODS—In a population-based study on 1388 patients with NHL, 354 with Hodgkin's disease (HD) and 1718 healthy controls, the age of first occurrence of bacterial and viral diseases was investigated. Clinical records were perused in one centre to check the anamnestic data. FINDINGS—The age of occurrence of bacterial and viral diseases was significantly higher among NHL patients than in the controls. The association between later age at first bacterial or viral disease was limited to small families (OR= 1.95; 95% confidence intervals 1.26, 3.00, for age 4-8 at first infection; OR=1.91; 1.19, 3.06, for age 9+, compared with less than 4). The association was more obvious for bacterial diseases (possibly for the lower degree of misclassification). High grade lymphomas showed the strongest association. The later age of occurrence of bacterial or viral diseases in NHL patients is consistent with a higher incidence of lymphomas observed in higher social groups. No clear association was found between HD and age at first bacterial or viral diseases. INTERPRETATION—It is proposed that delayed infection could explain the increasing NHL trends, through an impairment of the Th1/Th2 lymphocyte patterns. The model of delayed infection has been proposed also to explain increasing prevalence rates of asthma.

High-resolution cytogenetic analysis of a large number of women with premature ovarian failure (POF) identified six patients carrying different Xq chromosome rearrangements. The patients (one familial and five sporadic cases) were negative for Turner's stigmata and experienced a variable onset of menopause. Microsatellite analysis and fluorescent in situ hybridization (FISH) were used to define the origin and precise extension of the Xq anomalies. All of the patients had a Xq chromosome deletion as the common chromosomal abnormality, which was the only event in three cases and was associated with partial Xp or 9p trisomies in the remaining three. Two of the Xq chromosome deletions were terminal with breakpoints at Xq26.2 and Xq21.2, and one interstitial with breakpoints at Xq23 and Xq28. In all three cases, the del(X)s retained Xp and Xq specific telomeric sequences. One patient carries a psu dic(X) with the deletion at Xq22.2 or Xq22.3; the other two [carrying (X;X) and (X;9) unbalanced translocations, respectively] showed terminal deletions with the breakpoint at Xq22 within the DIAPH2 gene. Furthermore, the rearranged X chromosomes were almost totally inactivated, and the extent of the Xq deletions did not correlate with the timing of POF. In agreement with previous results, these findings suggest that the deletion of a restricted Xq region may be responsible for the POF phenotype. Our analysis indicates that this region extends from approximately Xq26.2 (between markers DXS8074 and HIGMI) to Xq28 (between markers DXS 1113 and ALD) and covers approximately 22 Mb of DNA. These data may provide a starting point for the identification of the gene(s) responsible for ovarian development and folliculogenesis.

A systematic literature review of the last two decades was performed to evaluate the effect of pelvic denervations in addition to conservative surgery on dysmenorrhoea and deep dyspareunia associated with endometriosis. Chronic pelvic pain relief after hysterectomy or adhesiolysis was also assessed. In the five non-comparative studies on the effect of pre-sacral neurectomy, the frequency of dysmenorrhoea recurrence or persistence after treatment ranged from 4 to 40%. The pooled frequency of non-responders at the end of follow-up was 23% (95% confidence interval (CI), 19 to 27%). Only two of the three comparative, non-randomized trials demonstrated a significant treatment benefit of pre-sacral neurectomy, and the results of the two identified randomized controlled trials are discordant. Significant quantitative heterogeneity among studies prevented pooling of data on dysmenorrhoea. The common odds ratio of deep dyspareunia persistence was 0.69 (95% CI, 0.31 to 1.54). In the 10 non-comparative studies on the effect of uterosacral ligament resection, the frequency of dysmenorrhoea and deep dyspareunia persistence after treatment ranged, respectively, from 0 to 50% and from 6 to 42%. The pooled frequency of non-responders at the end of follow-up was 23% (95% CI, 20 to 27%) and 13% (95% CI, 8 to 18%), respectively. Routine performance of complementary denervating procedures cannot be recommended based on the quality of the evidence available. The results of the five studies on the effect of hysterectomy on chronic pelvic pain of presumed uterine origin consistently demonstrated that 83-97% of operated women reported pain relief or improvement 1 year after surgery. There is no consensus on the outcome of adhesiolysis in patients with chronic pain, and the role of pelvic adhesions in causing symptoms is under scrutiny.