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.

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.

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.

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.

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.

Characteristics of primary amphetamine users in Sweden: a criminal justice population examined with the Addiction Severity Index.

BACKGROUND/AIMS: Characteristics of primary amphetamine, heroin and cocaine users were compared in a criminal justice population. METHODS: 7,085 clients with suspected or reported substance use were studied using the Addiction Severity Index. Variables separating amphetamine, heroin and cocaine users were analyzed in stepwise logistic regression. RESULTS: There were considerably more primary amphetamine users (n = 1,396) than heroin (n = 392) and cocaine (n = 119) users. Amphetamine users were older, a more rural population, and less likely to be non-Nordic immigrants. Compared with heroin, amphetamine use was associated with older age, Nordic origin, nonurban residence, memory/concentration problems, parental alcohol problems, and less history of other opioid use, overdose and detoxification. Compared with cocaine, amphetamine use was associated with older age, Nordic origin, nonurban residence, injecting, tobacco and institution treatment. Overlap of drug use between groups was relatively uncommon. CONCLUSION: This pattern of amphetamine use, common among Swedish criminals, has relatively distinct boundaries from heroin and cocaine use, commonly involves injecting, and differs from other countries. Psychiatric problems and alcohol heredity were common, and evidence-based treatment for amphetamine users is needed. The connection between amphetamine use and criminal behavior is insufficiently understood and should be further addressed.

Phenotypic protein profiling of different B cell sub-populations using antibody CD-microarrays.

Antibody microarrays enable extensive protein expression profiling, and provide a valuable complement to DNA microarray-based gene expression profiling. In this study, we used DotScan antibody microarrays that contain antibodies against 82 different cell surface antigens, to determine phenotypic protein expression profiles for human B cell sub-populations. We then demonstrated that the B cell protein profile can be used to delineate the relationship between normal B cells and malignant counterparts. Principle component analysis showed that the lymphomas did not cluster with the normal memory B cells or germinal centre B cells, but they did cluster with germinal centre founder cells and naïve B cells.

Toll-like receptor cross-hyporesponsiveness is functional in interleukin-1-receptor-associated kinase-1 (IRAK-1)-deficient macrophages: differential role played by IRAK-1 in regulation of tumour necrosis factor and interleukin-10 production.

Signalling downstream Toll-like receptors (TLR) is regulated at several levels in order to activate the immune response and prevent excessive inflammation. Altered intracellular signalling may be one reason that repeated stimulation of various TLRs results in hyporesponsiveness and cross-tolerance. We report that TLR cross-tolerance is inducible in the absence of interleukin-1 receptor-associated kinase-1 (IRAK-1) in peritoneal macrophages. Similar to wild-type macrophages, IRAK-1-deficient macrophages respond with decreased tumour necrosis factor (TNF) production to a secondary TLR stimulation, but in opposite to IRAK-1(+/+), IRAK-1(-/-) macrophages display increased interleukin (IL)-10 production at TLR restimulation. IRAK-1-deficient peritoneal macrophages have a defective TNF and IL-10 production in response to lipoteichoic acid stimulation as well as a defective IL-10-but a normal TNF production in response to high concentration of lipopolysaccharide. Our results demonstrate that IRAK-1 is not necessary for induction of TLR cross-tolerance as judged by TNF production.

Factors associated with history of non-fatal overdose among opioid users in the Swedish criminal justice system.

BACKGROUND: Overdose (OD) is a common cause of death in opioid users. Also, many current opioid users report a history of non-fatal OD. The present study aimed to identify factors associated with a history of non-fatal OD. METHODS: A sample of 7085 Swedish criminal justice clients with alcohol or drug misuse was assessed, using the Addiction Severity Index. Subjects reporting use of opioids during the 30 days prior to incarceration were included (n=1113). Relevant variables of misuse pattern, heredity, psychiatric symptoms and previous criminal charges were analysed in a logistic regression model. RESULTS: A history of non-fatal OD was reported by 55% (n=604). The estimated contribution to the variance in OD history was 25% for variables describing misuse pattern, compared to 10% for psychiatric symptoms, 8% for heredity, and 8% for previous criminal charges. The final model included the following variables: history of injection drug use (OR 3.28), history of heroin use (OR 2.87), history of suicide attempt (OR 1.92), history of tranquilliser use (OR 1.91), being born in Sweden or other Nordic countries (OR 1.74), difficulty in controlling violent behaviour (OR 1.68), and paternal alcohol problems (OR 1.57). CONCLUSIONS: Suicide attempts and difficulty in controlling violent behaviour were associated with history of non-fatal OD, independent of variables of misuse pattern. This may indicate a possible association with impulse control disturbances, and may have clinical applications. Country of birth and heredity of alcohol problems also had some influence. As expected, severity of misuse most strongly contributed to history of non-fatal OD.

Serum interleukin-1 receptor antagonist is an early indicator of colitis onset in Galphai2-deficient mice.

AIM: To study the serum concentration of IL-1beta, IL-1 receptor antagonist (IL-1Ra) and IL-18 in Galphai2-deficient mice at the age of 6 (healthy), 12 (pre-colitic) and 24 wk (colitic) and in healthy control mice. METHODS: At the time of killing, serum samples were collected and IL-1beta, IL-1Ra and IL-18 levels were measured using enzyme-linked immunosorbent assays. RESULTS: Serum concentration of IL-1Ra was significantly increased in pre-colitic (median: 524 ng/L; P=0.02) and colitic (450 ng/L; P=0.01), but not in healthy (196 ng/L) Galphai2-deficient mice as compared with controls (217 ng/L). Serum concentrations of IL-1beta did not differ between Galphai2-deficient mice and their controls, irrespective of age, IL-18 was significantly increased in colitic, but not in pre-colitic mice compared with controls (510 ng/L vs 190 ng/L; P=0.05). CONCLUSION: The increased serum concentrations of IL-18 and IL-1Ra in established diseases are suggested as markers of ongoing colitis. Interestingly, the significantly increased serum concentration of IL-1Ra in pre-colitic mice is found to be an early marker of disease progression.

Suicide in alcoholism. A prospective study of 88 suicides: I. The multidimensional diagnosis at first admission.

A series of 1,312 alcoholics admitted to the Department of Psychiatry, University Hospital, Lund, Sweden, from 1949 through 1969, were followed up until Dec 31, 1980. Eighty-eight (16%) of a total of 537 deaths were officially registered as suicides. The conditions of all alcoholics were evaluated with a multidimensional diagnostic rating schedule at first admission. Alcoholics who later committed suicide had a higher rate of depressive and dysphoric symptoms and were more brittle and sensitive than the others, while the frequencies of cognitive impairment and delirium tremens were similar. Peptic ulcers were more frequent in the suicide group (21% v 7%). The ratings did not differentiate between those who committed suicide early or late after admission.

Regional cerebral blood flow during alcohol withdrawal.

Serial bilateral measurements of regional cerebral blood flow (rCBF) by the xenon Xe 133 inhalation method were made during 13 withdrawal periods in 12 male alcoholics with pronounced physical dependence. A significant global reduction of rCBF was found during the first two days of withdrawal. The largest decreases were seen in cases with clouded sensorium and with an extended preceding drinking period. An rCBF distribution with relatively high temporal and low parietal flows during the first two days was coupled to aggravated symptoms. In two men who reported auditory and visual hallucinations during the measurements, elevated rCBF values were found in the temporal, Sylvian, and occipital regions.

Chaos-related deterministic regulation of heart rate variability in time- and frequency domains: effects of autonomic blockade and exercise.

OBJECTIVES: To study non-linear complexity or chaotic behaviour of heart rate in short time series and its dependence on autonomic tone. METHODS: Ten healthy individuals (5 men, mean age 44 years) were investigated at rest, after intravenous injections of propranolol (0.15 mg/kg), followed by atropine (0.03 mg/kg). On another occasion, investigation was made during exercise on a bicycle ergometer at 40% and at 70% of maximal working capacity. Heart rate variability was assessed by: local sensitive dependence on initial conditions as quantitated by the dominant Lyapunov exponent, coefficient of variation of heart rate, power spectral analysis of high- and low-frequency bands and the 1/f-slope of the very-low-frequency band and time domain analysis. RESULTS: The approximate dominant Lyapunov exponent was positive at rest and remained positive during autonomic blockade and during exercise. The exponent decreased significantly with propranolol+atropine and even more so during exercise but did not attain zero. At baseline approximate predictability was lost after about 30 s whereas after autonomic blockade or exercise it was lost after about 60 s. The 1/f-slope remained unaltered around -1. As expected, power in high- and low-frequency bands as well as time domain index decreased significantly with autonomic blockade. The low-frequency band and time domain index were affected by exercise. CONCLUSIONS: Heart rate variability of sinus rhythm in healthy individuals has characteristics suggestive of low-dimensional chaos-like determinism which is modulated but not eliminated by inhibition of autonomic tone or by exercise. The dominant Lyapunov exponent characterises heart rate variability independent or the other investigated measures.

Organotellurium compounds as efficient retarders of lipid peroxidation in methanol.

Diaryl tellurides were found efficiently to retard azo-initiated lipid peroxidation of linoleic acid in methanol. The most efficient compounds, 31 and 39, contained one and two hydroxyl groups, respectively, in the para positions and methyl groups in all four positions ortho to tellurium. As determined by the values of n.kinh, these materials were as effective retarders of lipid peroxidation as vitamin E. Contrary to the conventional antioxidants examined, diaryl tellurides were found to inhibit peroxidation for long times, seemingly with an autocatalytic mechanism. Diaryl tellurides were found to be partially oxidized during the peroxidation. The reduction of tellurium (IV) compounds to the divalent state during the conditions of the experiment is discussed. The reactivity of some diaryl chalcogenides toward 2,2-diphenyl-1-picrylhydrazyl (DPPH) in methanol was studied. All compounds investigated were less reactive than vitamin E. One of the most active organotellurium compounds, bis(4-aminophenyl) telluride, reacted considerably faster with DPPH than the corresponding selenide or sulfide. It was concluded that mechanisms involving both hydrogen atom transfer and electron transfer were operative in the reaction of organotellurides with DPPH.

Chicken neuropeptide Y receptor Y2: structural and pharmacological differences to mammalian Y2(1).

Here we report the molecular cloning of the chicken (Gallus gallus) neuropeptide Y (NPY) receptor Y2, the first non-mammalian Y2 receptor. It displays 75-80% identity to mammalian Y2 and has a surprisingly divergent cytoplasmic tail. Expression of the receptor protein in a cell line showed that the receptor did not bind the mammalian Y2 selective antagonist BIIE0246. Furthermore, porcine [Leu(31), Pro(34)]NPY, which binds poorly to mammalian Y2, exhibited an unexpectedly high affinity for chicken Y2. In situ hybridisation revealed expression in the hippocampus. Thus, the chicken Y2 receptor exhibits substantial differences with regard to sequence and pharmacological profile in comparison to mammalian Y2 receptors, while the expression pattern in the central nervous system resembles that observed in mammals.