Risk assessment of coccidostatics during feed cross-contamination: animal and human health aspects.

Coccidiosis, an intestinal plasmodium infection, is a major infectious disease in poultry and rabbits. Eleven different coccidiostats are licensed in the EU for the prevention of coccidiosis in these animal species. According to their chemical nature and main biological activity, these compounds can be grouped as ionophoric (monensin, lasalocid sodium, salinomycin, narasin, maduramicin and semduramicin) or non-ionophoric (robenidine, decoquinate, nicarbazin, diclazuril, and halofuginone) substances. Coccidiostats are used as feed additives, mixed upon request into the compounded feed. During the technical process of commercial feed production, cross-contamination of feed batches can result in the exposure of non-target animals and induce adverse health effects in these animals due to a specific sensitivity of mammalian species as compared to poultry. Residue formation in edible tissues of non-target species may result in unexpected human exposure through the consumption of animal products. This review presents recent risk assessments performed by the Scientific Panel on Contaminants in the Food Chain (CONTAM) of the European Food Safety Authority (EFSA). The health risk to non-target species that would result from the consumption of cross-contaminated feed with coccidostats at levels of 2, 5 or 10% was found to be negligible for most animal species with the exception of salinomycin and monensin in horses because of the particular sensitivity for which toxicity may occur when cross-contamination exceeds 2% and 5% respectively. Kinetic data and tissue analyses showed that residues of coccidiostats may occur in the liver and eggs in some cases. However, the level of residues of each coccidiostat in edible animal tissues remained sufficiently low that the aggregate exposure of consumers would not exceed the established acceptable daily intake (ADI) of each coccidiostat. It could be concluded that technical cross-contamination of animal feeds would not be expected to adversely affect the health of consumers.

[Stroke--and then? Considerable need of assistance two year after stroke according to a large nation-wide study]. / Slaganfall--och sedan? Omfattande hjälpbehov två år efter slaganfallet, visar stor nationell studie.

The National Board of Health and Welfare together with Riks-Stroke (the Swedish National Registry for Quality Assessment of Acute Stroke Care) were commissioned by the government to study the circumstances of 4,023 stroke patients, two years after the event. Both physical and psychological impairments together with psychosocial consequences were common. Approximately one fifth of the patients did not receive enough help and support, and the most common reason for this was the high cost. Instead many were dependent upon next-of-kin. This indicates that the long-term care of stroke patients needs to be improved.

[Stroke unit care saves lives. The Swedish national quality assessment registry of stroke care is the first of its kind in the world]. / Vård på stroke-enhet räddar liv. Sverige först i världen med nationellt kvalitetsregister för slaganfall.

Meta-analyses of randomised trials of acute stroke treated in specialised stroke units have yielded convincing evidence of benefits in terms of reduced mortality rates, as compared with treatment in a general ward. However, no studies had been performed to ascertain whether the promising results could be reproduced in routine clinical practice. Accordingly, a comparison of routine care of acute stroke patients in stroke units (SUs) with that in general wards (GWs) was made on the basis of data for the 14,300 cases of acute stroke from 87 units in 80 Swedish hospitals registered in 1996 at the Swedish national stroke registry, the first of its kind in the world. Among patients capable of independent daily life and fully conscious at admission, the mortality rate was lower in the SU than in the GW subgroup, both at discharge from hospital and three months after the stroke event; and three months after stroke, a greater proportion of SU patients had been discharged to their homes, and a smaller proportion were in long-term care. However, no such subgroup differences were found among patients with impaired consciousness at admission. Thus, the promising results of the randomised trials of SU treatment would appear to be reproducible in routine clinical practice, though the beneficial effect is smaller in magnitude.

Assessment of side effects induced by injection of different adjuvant/antigen combinations in rabbits and mice.

We evaluated the side effects induced by injection of Freund's adjuvant (FA) and alternative adjuvants combined with different antigens. Rabbits and mice were injected subcutaneously, intramuscularly (rabbits) and intraperitoneally (mice) with different adjuvants (FA, Specol, RIBI, TiterMax, Montanide ISA50) in combination with several types of antigens (synthetic peptides, autoantigen, glycolipid, protein, mycoplasma or viruses). The effects of treatment on the animals' well-being were assessed by clinical and behavioural changes (POT and LABORAS assays) and gross and histopathological changes. In rabbits, treatment did not appear to induce acute or prolonged pain and distress. Mice showed behavioural changes immediately after (predominantly secondary) immunization. Injection of several adjuvant/antigen mixtures resulted in severe pathological changes, depending on adjuvant, type of antigen, animal species used and route of injection. Both rabbits and mice showed pathological changes ranging from marked to severe after injection of FA, and ranging from minimal to marked after Specol and Montanide injections. Pathological changes after RIBI injections were severe in rabbits, though slight in mice. After TiterMax injections, pathological changes were moderate in rabbits, though severe in mice. In conclusion, injection of FA according to present guidelines resulted mostly in severe pathological changes, whereas only very few clinical and behavioural signs indicated prolonged severe pain. Our findings indicate that Montanide ISA50 and Specol induce acceptable antibody titres, and cause fewer pathological changes than FA. Thus they are effective alternatives to FA.

Risk assessment on the carcinogenic potential of hybridoma cell DNA: implications for residual contaminating cellular DNA in biological products.

The aim of this study was to evaluate the possible carcinogenic potential of residual DNA derived from immortalized and possibly tumorigenic cell lines due to activated oncogenic sequences (oncogenes). These cell lines have been used for the production of biologicals, i.e. monoclonal antibodies, lymphokines and vaccines. The authors used hybridoma DNA as a first model. For this reason experiments in two species were performed, namely in 3-4 week-old female Balb/c mice and newborn Riv:TOX rats. Doses of 250 micrograms DNA, derived from Balb/c hybridoma cells, were injected subcutaneously (s.c.) in 200 mice. These mice also received a s.c. injection of the solvent only (TE buffer) at another site of the back skin (negative control for local tumour development). An additional group of 50 mice was treated intraperitoneally (i.p.) with the solvent only to serve as a negative control group for possible systemic tumorigenic effects. Doses of 5 micrograms plasmid pPy1 DNA, containing the entire Polyoma virus genome, served as positive control and were injected s.c. and i.p. in 20 and 50 mice, respectively. Doses of 50 micrograms hybridoma DNA or 5 micrograms pPy1 DNA were injected s.c. in rats too, using nine animals per group. During the experiment, animals were observed weekly, especially for the occurrence of subcutaneous tumours at the injection sites. The mouse study was terminated after more than 2 years, the rat study after 1 year. Gross necropsy was performed on all animals and histopathological examination of grossly suspected neoplastic lesions was performed. In the mouse experiment, tumour development at the s.c. injection site of the DNA was observed in one out of 20 animals in the pPy1-treated positive control group (neurofibrosarcoma) and one out of 200 animals in the hybridoma DNA-treated group (haemangioma-like lesion). Tumour development at or near the s.c. injection site of the solvent only was observed in two out of 200 animals. In the rat study none out of nine hybridoma DNA-treated rats developed tumours at the injection site, while three out of nine rats of the positive control group, injected with the pPy1 DNA, showed local tumour development (benign and malignant soft tissue tumours.) It is concluded that, at the high dose and numbers of animals tested, parenteral administration of hybridoma DNA does not induce local tumour development. Furthermore, no indications were found for systemic carcinogenic potential of the hybridoma DNA used. Based on a worst case approach of our data, the oncogenic risk of 100 pg residual DNA was estimated to be 2 x 10(-9), a value intermediate of the estimations of the WHO (1987) and the Dutch Health Council (1988) 5 x 10(-11) and 2 x 10(-7), respectively. Therefore, it is unlikely that the risk of 100 pg of DNA derived from other immortalized cell lines will exceed the level of generally accepted cancer risk of 10(-6).

Costs of stroke in Sweden. A national perspective.

BACKGROUND AND PURPOSE: Cost-effectiveness analyses of stroke management are hampered by paucity of economic data. We made an update of the direct and indirect costs of stroke in Sweden (population, 8.5 million). METHODS: Direct costs (ie, the costs for hospital and outpatient care and social services) were estimated on the basis of two prospective population-based studies of stroke and of two nationwide cross-sectional inventories of bed-days and diagnoses. Indirect costs (ie, the costs for loss of productivity and early retirement) were based on official statistics. RESULTS: The direct annual costs of care for stroke patients in 1991 equaled 7836 million Swedish krona (SKr) ($1306 million in US dollars), and the indirect costs, 2430 million SKr ($405 million). The cost of stroke care was 1208 SKr ($201) per inhabitant in Sweden. The expected direct costs per patient from first stroke to death were 440,000 SKr ($73,333). When prestroke costs for other diseases and advanced age were subtracted, the sum was reduced to 180,000 SKr ($30,000). CONCLUSIONS: Costs for hospital and outpatient care and social services accounted for 76% of Swedish stroke costs and for 24% of costs for loss of production and early retirement. Only 41% of direct costs were stroke-related.

Changing social patterns of risk factors for cardiovascular disease in a Swedish community intervention programme.

Since 1985 a small-scale community-based cardiovascular disease (CVD) preventive programme has been in operation in an inland municipality, Norsjö, in Northern Sweden. The aim of this study was to assess the development of the relationship between social position and CVD risk factors in repeated cross-sectional surveys (1985-1990) among all men and women aged 30, 40, 50 and 60 years in the study area, using an age-stratified random sample from the Northern Sweden MONICA Study of 1986 and 1990 as reference population. These multiple cross-sectional surveys comprised a self-administered questionnaire and a health examination. Of the study population 95% (n = 1499) and 80% of those in the reference area (n = 3208) participated. Subjects were classified with regard to demographic, structural and social characteristics in relation to CVD risk factors and self-reported health status. Time trends in classical risk factor occurrence were assessed in terms of age- and sex- adjusted odds ratios using Mantel-Haenszel procedures. When simultaneously adjusting for several potential confounders we used a logistic regression analysis. Initially, more than half of the study population, both males and females, had and elevated (> or = 6.5 mmol/l) serum cholesterol level. After adjustments had been made for age and social factors it was found that the relative risk of hypercholesterolaemia dropped substantially and significantly among both sexes during the 6 years of CVD intervention in the study area. However, the probability of being a smoker was significantly reduced only in highly educated groups. Among other risk factors no single statistically significant change over time could be found. In the reference area there were no changes over time for the selected CVD risk factors. People in the study area had a less favourable perception of their health than those in the reference area. Social differences were found when perceived good health was measured, especially in variables indicating emotional and social support. When sex, age and social factors had been accounted for there was not clear change over the years in perceived good health.

The cost-effectiveness of treating hypertension in elderly people--an analysis of the Swedish Trial in Old Patients with Hypertension (STOP Hypertension).

OBJECTIVES: The aim of this study was to estimate the cost-effectiveness of antihypertensive treatment in elderly people based on the results of the Swedish Trial in Old Patients with Hypertension (STOP Hypertension). DESIGN: The STOP Hypertension study was a randomized trial comparing active antihypertensive treatment with a placebo. The risk of stroke, cardiovascular disease and total mortality was significantly reduced in the actively treated group compared to placebo. SETTING: One hundred and sixteen primary health care centres in Sweden. SUBJECTS: A total of 1627 hypertensive patients aged 70-84. No patient was lost to follow-up. INTERVENTIONS: Antihypertensive treatment with beta blockers and diuretics for a mean follow-up of 25 months. MAIN OUTCOME MEASURE: The cost-effectiveness ratio estimated as the net cost (the treatment cost minus saved costs of reduced cardiovascular morbidity) divided by the number of life-years gained (the increase in life expectancy from treatment). RESULTS: The cost per life-year gained was estimated as SEK 5000 for men and SEK 15,000 for women ($1 = SEK 6; 1 pound = SEK 10). The cost per life-year gained did not exceed SEK 100,000 in any of the sensitivity analyses. CONCLUSIONS: It is concluded that treatment of elderly hypertensive patients with beta blockers and/or diuretics is cost-effective according to the results of the STOP Hypertension study.

Simultaneous liquid chromatographic determination of seventeen of the major monoamine neurotransmitters, precursors and metabolites. II. Assessment of human brain and cerebrospinal fluid concentrations.

The optimized chromatographic method procedure presented in Part I was employed for the assessment of human brain and cerebrospinal fluid neurotransmitters levels. The optimized sample preparation and chromatographic conditions permitted a rapid (less than 25 min), sensitive and semi-automated high-performance liquid chromatographic analysis which measures all major monoamine neurotransmitters, precursors and metabolites in human brain and cerebrospinal fluid. The brain specimen was deproteinized with perchloric acid (containing Na2EDTA and sodium sulphite), the internal standard and heparin were added and the samples were sonicated, centrifuged, filtered and injected directly into the chromatographic system. Cerebrospinal fluid was handled in a similar manner except that sonication was excluded. The regional distribution of monoamine neurotransmitter concentrations in human brain and cerebrospinal fluid is presented.