Cardiovascular and cancer mortality in relation to dietary polychlorinated biphenyls and marine polyunsaturated fatty acids: a nutritional-toxicological aspect of fish consumption.

BACKGROUND: Co-exposure to environmental contaminants present in fish could mitigate the beneficial effects of fish consumption and possibly explain the lack of association observed for mortality in some geographical regions. OBJECTIVE: To assess the independent associations of dietary exposure to polychlorinated biphenyls (PCBs) and long-chain omega-3 fish fatty acids intake with cardiovascular and cancer mortality. METHODS: We used the prospective population-based Swedish Mammography Cohort and the Cohort of Swedish Men comprising 32 952 women and 36 545 men, free from cancer, cardiovascular disease and diabetes at baseline in 1998. Validated estimates of dietary PCBs and long-chain omega-3 fish fatty acids [i.e. eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA)] intake were obtained via a food frequency questionnaire at baseline. Information on death was ascertained through register linkage. RESULTS: During a mean follow-up of 15.5 years, we ascertained 16 776 deaths. We observed for cardiovascular mortality, comparing extreme quintiles in multivariable models mutually adjusted for PCBs and EPA-DHA, dose-dependent associations for dietary PCB exposure, hazard ratio (HR) 1.31 (CI 95%: 1.08 to 1.57; P-trend 0.005) and for dietary EPA-DHA intake, HR 0.79 (CI 95%: 0.66 to 0.95; P-trend 0.041). For cancer mortality, no clear associations were discerned. CONCLUSION: The beneficial effect of fish consumption on the cardiovascular system seems compromised by co-exposure to PCBs - one likely explanation for the inconsistent associations observed between fish consumption and mortality.

A pilot study on the feasibility of European harmonized human biomonitoring: Strategies towards a common approach, challenges and opportunities.

In 2004 the European Commission and Member States initiated activities towards a harmonized approach for Human Biomonitoring surveys throughout Europe. The main objective was to sustain environmental health policy by building a coherent and sustainable framework and by increasing the comparability of data across countries. A pilot study to test common guidelines for setting up surveys was considered a key step in this process. Through a bottom-up approach that included all stakeholders, a joint study protocol was elaborated. From September 2011 till February 2012, 17 European countries collected data from 1844 mother-child pairs in the frame of DEMOnstration of a study to COordinate and Perform Human Biomonitoring on a European Scale (DEMOCOPHES).(1) Mercury in hair and urinary cadmium and cotinine were selected as biomarkers of exposure covered by sufficient analytical experience. Phthalate metabolites and Bisphenol A in urine were added to take into account increasing public and political awareness for emerging types of contaminants and to test less advanced markers/markers covered by less analytical experience. Extensive efforts towards chemo-analytical comparability were included. The pilot study showed that common approaches can be found in a context of considerable differences with respect to experience and expertize, socio-cultural background, economic situation and national priorities. It also evidenced that comparable Human Biomonitoring results can be obtained in such context. A European network was built, exchanging information, expertize and experiences, and providing training on all aspects of a survey. A key challenge was finding the right balance between a rigid structure allowing maximal comparability and a flexible approach increasing feasibility and capacity building. Next steps in European harmonization in Human Biomonitoring surveys include the establishment of a joint process for prioritization of substances to cover and biomarkers to develop, linking biomonitoring surveys with health examination surveys and with research, and coping with the diverse implementations of EU regulations and international guidelines with respect to ethics and privacy.

Gender differences in cadmium and cotinine levels in prepubertal children.

Susceptibility to environmental stressors has been described for fetal and early childhood development. However, the possible susceptibility of the prepubertal period, characterized by the orchestration of the organism towards sexual maturation and adulthood has been poorly investigated and exposure data are scarce. In the current study levels of cadmium (Cd), cotinine and creatinine in urine were analyzed in a subsample 216 children from 12 European countries within the DEMOCOPHES project. The children were divided into six age-sex groups: boys (6-8 years, 9-10 years and 11 years old), and girls (6-7 years, 8-9 years, 10-11 years). The number of subjects per group was between 23 and 53. The cut off values were set at 0.1 µg/L for Cd, and 0.8 µg/L for cotinine defined according to the highest limit of quantification. The levels of Cd and cotinine were adjusted for creatinine level. In the total subsample group, the median level of Cd was 0.180 µg/L (range 0.10-0.69 µg/L), and for cotinine the median wet weight value was 1.50 µg/L (range 0.80-39.91 µg/L). There was no significant difference in creatinine and cotinine levels between genders and age groups. There was a significant correlation between levels of cadmium and creatinine in all children of both genders. This shows that even at such low levels the possible effect of cadmium on kidney function was present and measurable. An increase in Cd levels was evident with age. Cadmium levels were significantly different between 6-7 year old girls, 11 year old boys and 10-11 year old girls. As there was a balanced distribution in the number of subjects from countries included in the study, bias due to data clustering was not probable. The impact of low Cd levels on kidney function and gender differences in Cd levels needs further investigation.

Interpreting biomarker data from the COPHES/DEMOCOPHES twin projects: Using external exposure data to understand biomarker differences among countries.

In 2011 and 2012, the COPHES/DEMOCOPHES twin projects performed the first ever harmonized human biomonitoring survey in 17 European countries. In more than 1800 mother-child pairs, individual lifestyle data were collected and cadmium, cotinine and certain phthalate metabolites were measured in urine. Total mercury was determined in hair samples. While the main goal of the COPHES/DEMOCOPHES twin projects was to develop and test harmonized protocols and procedures, the goal of the current paper is to investigate whether the observed differences in biomarker values among the countries implementing DEMOCOPHES can be interpreted using information from external databases on environmental quality and lifestyle. In general, 13 countries having implemented DEMOCOPHES provided high-quality data from external sources that were relevant for interpretation purposes. However, some data were not available for reporting or were not in line with predefined specifications. Therefore, only part of the external information could be included in the statistical analyses. Nonetheless, there was a highly significant correlation between national levels of fish consumption and mercury in hair, the strength of antismoking legislation was significantly related to urinary cotinine levels, and we were able to show indications that also urinary cadmium levels were associated with environmental quality and food quality. These results again show the potential of biomonitoring data to provide added value for (the evaluation of) evidence-informed policy making.

Dietary exposure to polychlorinated biphenyls is associated with increased risk of stroke in women.

OBJECTIVE: The potentially beneficial effects of fish consumption on stroke may be modified by major food contaminants in fish. Polychlorinated biphenyls (PCBs) in particular are proposed to play a role in the aetiology of stroke. The aim of this study was to assess the association between dietary PCB exposure and stroke risk with the intake of long-chain omega-3 fish fatty acids and fish consumption. DESIGN: The prospective population-based Swedish Mammography Cohort was examined. It was comprised of 34,591 women free of cardiovascular diseases and cancer at baseline in 1997 and followed up for 12 years. Validated estimates of dietary PCB exposure were obtained via a food frequency questionnaire at baseline. Incident cases of stroke were ascertained through register linkage. RESULTS: During 12 years of follow-up (397,309 person-years), there were 2015 incident cases of total stroke (1532 ischaemic strokes, 216 intracerebral haemorrhages, 94 subarachnoid haemorrhages and 173 unspecified strokes). Multivariable-adjusted relative risks (RR), controlled for known stroke risk factors and fish consumption, were 1.67 [95% confidence interval (CI), 1.29-2.17] for total stroke, 1.61 (95% CI, 1.19-2.17) for ischaemic stroke and 2.80 (95% CI, 1.42-5.55) for haemorrhagic stroke for women in the highest quartile of dietary PCB exposure (median 288 ng day(-1) ) compared with women in the lowest quartile (median 101 ng day(-1) ). CONCLUSION: Dietary exposure to PCBs was associated with an increased stroke risk in women, especially haemorrhagic stroke. The results provide important information regarding the risk-benefit analysis of fish consumption, particularly for cerebrovascular disease prevention.

Freedom and confinement: patients' experiences of life with home haemodialysis.

Patients with chronic end stage renal disease need dialysis to survive; however, they also need a treatment that suits their life situation. It is important that healthcare providers provide reliable, up-to-date information about different dialysis treatment options. Since home haemodialysis is a relatively new treatment, it is necessary to gather more knowledge about what the treatment entails from the patient's perspective. The aim of this study was to describe patients' experiences of having home haemodialysis. To gain access to the patients' experiences, they were asked to write narratives, which describe both their good and bad experiences of life with the treatment. The narratives were analysed with a qualitative method. The results of this analysis are subdivided into five themes: freedom to be at home and control their own treatment, feeling of being alone with the responsibility, changes in the home environment, need for support, and security and well-being with home haemodialysis. The conclusion is that home haemodialysis provides a certain level of freedom, but the freedom is limited as the treatment itself is restrictive. In order to improve patients' experiences with home haemodialysis, more research based on patients' experiences is needed and it is necessary to involve the patients in the development of the care.

Role of microRNAs and microRNA machinery in the pathogenesis of diffuse large B-cell lymphoma.

Deregulation of microRNA (miRNA) expression has been documented in diffuse large B-cell lymphoma (DLBCL). However, the impact of miRNAs and their machinery in DLBCL is not fully determined. Here, we assessed the role of miRNA expression and their processing genes in DLBCL development. Using microarray and RT-qPCR approaches, we quantified global miRNAs and core components of miRNA-processing genes expression in 75 DLBCLs (56 de novo and 19 transformed) and 10 lymph nodes (LN). Differential miRNA signatures were identified between DLBCLs and LNs, or between the de novo and transformed DLBCLs. We also identified subsets of miRNAs associated with germinal center B-cell phenotype, BCL6 and IRF4 expression, and clinical staging. In addition, we showed a significant over-expression of TARBP2 in de novo DLBCLs as compared with LNs, and decreased expression of DROSHA, DICER, TARBP2 and PACT in transformed as compared with de novo cases. Interestingly, cases with high TARBP2 and DROSHA expression had a poorer chemotherapy response. We further showed that TARBP2 can regulate miRNA-processing efficiency in DLBCLs, and its expression inhibition decreases cell growth and increases apoptosis in DLBCL cell lines. Our findings provide new insights for the understanding of miRNAs and its machinery in DLBCL.

An LCA researcher's wish list--data and emission models needed to improve LCA studies of animal production.

The last decade has seen an increase in environmental systems analysis of livestock production, resulting in a significant number of studies with a holistic approach often based on life-cycle assessment (LCA) methodology. The growing public interest in global warming has added to this development; guidelines for carbon footprint (CF) accounting have been developed, including for greenhouse gas (GHG) accounting of animal products. Here we give an overview of methods for estimating GHG emissions, with emphasis on nitrous oxide, methane and carbon from land use change, presently used in LCA/CF studies of animal products. We discuss where methods and data availability for GHGs and nitrogen (N) compounds most urgently need to be improved in order to produce more accurate environmental assessments of livestock production. We conclude that the top priority is to improve models for N fluxes and emissions from soils and to implement soil carbon change models in LCA/CF studies of animal products. We also point at the need for more farm data and studies measuring emissions from soils, manure and livestock in developing countries.

All-cause mortality in criminal justice clients with substance use problems--a prospective follow-up study.

BACKGROUND: Mortality in previously incarcerated individuals is known to be elevated, with high proportions of drug-related deaths. However, there is less documentation of whether specific substance use patterns and other clinical characteristics predict increased mortality in the group. METHODS: This is a follow-up study of mortality and causes of death in ex-prisoners with substance use problems prior to incarceration (N=4081), who were followed during an average of 3.6 years from release from prison until death or until data were censored. Baseline predictors of mortality, derived from interviews with Addiction Severity Index (ASI) in prison, were studied in a Cox regression analysis. RESULTS: During follow-up, 166 subjects (4.1%) died. Standardized mortality ratios were 7.0 (3.6-12.2) for females and 7.7 (5.6-9.0) for males. In 84% of cases, deaths were unnatural or due to substance-related disease. Most common causes of death were accidental poisoning (27%), transport accidents (13%), poisoning/injury with undetermined intent (12%), and suicide (10%). Death was positively predicted by heroin use, overdose, and age, and negatively predicted by a history of depression. CONCLUSIONS: A vast majority of deaths after release from prison in individuals with substance use are due to violent or substance-related causes. Significant predictors identified were mainly related to patterns of drug use, and need to be addressed upon incarceration as risk factors of death. The findings have implications for referral and treatment upon release from prison.

U-2932: two clones in one cell line, a tool for the study of clonal evolution.

Genetic heterogeneity is common in tumors, explicable by the development of subclones with distinct genetic and epigenetic alterations. We describe an in vitro model for cancer heterogeneity, comprising the diffuse large B-cell lymphoma cell line U-2932 which expresses two sets of cell surface markers representing twin populations flow-sorted by CD20 vs CD38 expression. U-2932 populations were traced to subclones of the original tumor with clone-specific immunoglobulin IgVH4-39 hypermutation patterns. BCL6 was overexpressed in one subpopulation (R1), MYC in the other (R2), both clones overexpressed BCL2. According to the combined results of immunoglobulin hypermutation and cytogenetic analysis, R1 and R2 derive from a mother clone with genomic BCL2 amplification, which acquired secondary rearrangements leading to the overexpression of BCL6 (R1) or MYC (R2). Some 200 genes were differentially expressed in R1/R2 microarrays including transcriptional targets of the aberrantly expressed oncogenes. Other genes were regulated by epigenetic means as shown by DNA methylation analysis. Ectopic expression of BCL6 in R2 variously modulated new candidate target genes, confirming dual silencing and activating functions. In summary, stable retention of genetically distinct subclones in U-2932 models tumor heterogeneity in vitro permitting functional analysis of oncogenes against a syngenic background.

Towards understanding and managing the learning process in mail sorting.

OBJECTIVE: This paper was based on case study research at the Swedish Mail Service Division and it addresses learning time to sort mail at new districts and means to support the learning process on an individual as well as organizational level. PARTICIPANTS: The study population consisted of 46 postmen and one team leader in the Swedish Mail Service Division. METHODS: Data were collected through measurements of time for mail sorting, interviews and a focus group. RESULTS: The study showed that learning to sort mail was a much more complex process and took more time than expected by management. Means to support the learning process included clarification of the relationship between sorting and the topology of the district, a good work environment, increased support from colleagues and management, and a thorough introduction for new postmen. CONCLUSIONS: The identified means to support the learning process require an integration of human, technological and organizational aspects. The study further showed that increased operations flexibility cannot be reinforced without a systems perspective and thorough knowledge about real work activities and that ergonomists can aid businesses to acquire this knowledge.

Associations between polysubstance use and psychiatric problems in a criminal justice population in Sweden.

BACKGROUND: Polysubstance use is common in substance users, and may complicate their clinical course. This study, in a criminal justice setting in Sweden, examines the association between the number of concurrently used substance types and psychiatric symptoms during 30 days before incarceration, while controlling for background variables such as family history (drug and alcohol problems, psychiatric problems, criminality), demographic data and history of emotional, physical or sexual abuse. METHODS: The data material comprised 5659 criminal justice clients reporting a substance use problem, examined with the Addiction Severity Index. Variables were compared in a multinomial regression analysis, comparing clients reporting one (n=1877), two (n=1408), three (n=956), four (n=443) and five or more (n=167) substance types. RESULTS: The 30-day prevalence of most psychiatric symptoms included in the study (depression, anxiety, cognitive problems, hallucinations, difficulty controlling violent behaviour, suicidal ideation, suicide attempts) was higher in individuals with a higher number of concurrent substance types used. In multinomial regression analysis, while controlling for background variables, these associations remained for concurrent suicidal ideation, cognitive problems, hallucinations and violent behaviour, with the latter two being associated with the higher numbers of substance types. Binge alcohol drinking, tranquilizers, opioids and the number of substance types reported were associated with several of the psychiatric symptoms. CONCLUSIONS: In the present criminal justice setting in Sweden, the use of multiple substance types and concurrent psychiatric symptoms appear to be associated, and a sub-group reporting particularly high numbers of concurrent substance types are particularly likely to report potentially severe psychiatric problems.

Growth factor and protease expression during different phases of healing after rabbit deep flexor tendon repair.

The purpose of the study was to contribute to the mapping of molecular events during flexor tendon healing, in particular the growth factors insulin-like growth factor-1 (IGF-1), vascular endothelial growth factor (VEGF) and nerve growth factor (NGF), matrix metalloproteinases (MMP-3 and MMP-13) and their inhibitors (tissue inhibitors of metalloproteinases, TIMP-1 and TIMP-3, and the protease cathepsin K. In a rabbit model of flexor tendon injury, the mRNA expression for the growth factors, MMPs and TIMPs were measured in tendon and tendon sheath tissue at several time points (3, 6, 21, and 42 days) representing different phases of the healing process. We found that MMP-13 remained increased during the study period, whereas MMP-3 returned to normal levels within the first week after injury. TIMP-3 was down-regulated in the tendon sheaths. Cathepsin K was up-regulated in tendons and sheaths after injury. NGF was present in both tendons and sheaths, but unaltered. IGF-1 exhibited a late increase in the tendons, while VEGF was down-regulated at the later time points. In conclusion, we have demonstrated the presence of NGF in flexor tendons. MMP-13 expression appears to play a more protracted role in flexor tendon healing than MMP-3. The relatively low levels of endogenous IGF-1 and VEGF mRNA following injury support their potential beneficial role as exogenous modulators to optimize tendon healing and strength without increasing adhesion formation.

Prediction of irinotecan and 5-fluorouracil toxicity and response in patients with advanced colorectal cancer.

Irinotecan and 5-fluorouracil (5-FU) are used to treat metastatic colorectal cancer. Irinotecan's active metabolite is inactivated by UDP-glucuronosyltransferase 1A1 (UGT1A1), which is deficient in Gilbert's syndrome. Irinotecan and metabolites are transported by P-glycoprotein, encoded by ABCB1. 5-FU targets folate metabolism through inhibition of thymidylate synthase (TYMS). Methylenetetrahydrofolate reductase (MTHFR) generates active folate necessary for haematopoiesis. We retrospectively genotyped 140 Swedish and Norwegian irinotecan and 5-FU-treated colorectal cancer patients from the Nordic VI clinical trial for selected variants of UGT1A1, ABCB1, TYMS and MTHFR. We found an increased risk of clinically relevant early toxicity in patients carrying the ABCB1 3435 T/T genotype, Odds ratio (OR)=3.79 (95% confidence interval (CI)=1.09-13.2), and in patients carrying the UGT1A1(*)28/(*)28 genotype, OR=4.43 (95% CI=1.30-15.2). Patients with UGT1A1(*)28/(*)28 had an especially high risk of neutropenia, OR=6.87 (95% CI=1.70-27.7). Patients who had reacted with toxicity during the first two cycles were in total treated with fewer cycles (P<0.001), and less often responded to treatment (P<0.001). Genetic variation in ABCB1 was associated with both early toxicity and lower response to treatment. Carriers of the ABCB1 1236T-2677T-3435T haplotype responded to treatment less frequently (43 vs 67%, P=0.027), and survived shorter time, OR=1.56 (95% CI=1.01-2.45).

Efficacy of mobile telephone contact for follow-up in injecting heroin users.

BACKGROUND: Prospective follow-up of heroin users is known to be difficult due to their unstable lifestyle, and high follow-up rates have usually demanded major tracking efforts. In Sweden, mobile telephones are commonly used by heavy drug users for drug trading. OBJECTIVES: This methodology study aims to examine the efficacy of mobile telephone contact for prospective follow-up interviews with injecting heroin users recruited at the syringe exchange program of Malmö, Sweden. METHODS: Seventy-eight heroin users with mobile telephone numbers were included. Subjects reported using heroin for 28 days of the previous 30 days, and only 8% reported they had recently been engaged in work or studies. Clients were contacted between 15 and 21 times over 2 years, with each contact attempt generally involving two telephone calls on consecutive days. RESULTS: During follow-up, 68% of subjects had been successfully contacted for at least one follow-up interview (on average 6.9 interviews), and 25% of follow-up attempts were successful. In 23% of the sample (n=18), at least 50% of follow-up attempts were successful, and these subjects tended to be older (p=.05) and more likely to be female (p=.07), whereas follow-up rates were unrelated to baseline heroin use. CONCLUSIONS AND SCIENTIFIC SIGNIFICANCE: Despite limited effort, and despite the severe situation of intravenous heroin users, mobile telephone contact can be used with heavy drug users in the present setting.

Assessment of early-life lead exposure in rural Bangladesh.

Lead is a well-known neurotoxic metal and one of the most toxic chemicals in a child's environment. The aim of this study was to assess early-life lead exposure in a pristine rural area of Bangladesh. The exposure was expected to be very low because of the absence of vehicle traffic and polluting industries. Lead was measured in erythrocytes, urine, and breast milk of 500 randomly selected pregnant women, participating in a randomized food and micronutrient supplementation trial in Matlab (MINIMat). Lead was also measured in urine of their children at 1.5 and 5 years of age, and in rice, well water, cooking pots, and materials used for walls and roof. All measurements were performed using ICPMS. We found that the women had relatively high median erythrocyte lead levels, which increased considerably from early pregnancy to late lactation (81-136microg/kg), probably due to release from bone. Urinary lead concentrations were unchanged during pregnancy (median approximately 3.5microg/L) and non-linearly associated with maternal blood lead levels. Children, at 1.5 and 5 years of age, had a median urinary lead concentration of 4microg/L, i.e., similar to that in their mothers. Rice, the staple food in Matlab, collected from 63 homes of the study sample, contained 1-89microg/kg (median 13microg/kg) dry weight and seems to be an important source of lead exposure. Other sources of exposure may be cooking pots and metal sheet roof material, which were found to release up to 380 and 4200microg/L, respectively, into acidic solutions. Based on breast milk lead concentrations (median 1.3microg/L) a median daily intake of 1.2microg was estimated for 3 months old infants. However, alternatives to breast-feeding are likely to contain more lead, especially rice-based formula. To conclude, lead exposure in women and their children in a remote unpolluted area was found to be surprisingly high, which may be due to their living conditions.