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1.  Dynamic changes of the endogenous cannabinoid and opioid mesocorticolimbic systems during adolescence: THC effects 
Adolescence is a critical phase of active brain development often characterized by the initiation of marijuana (Cannabis sativa) use. Limited information is known regarding the endogenous cannabinoid system of the adolescent brain as well as related neurotransmitters that appear sensitive to cannabis exposure. We recently observed that adult rats pre-exposed to Δ-9-tetrahydrocannabinol (THC) during adolescence self-administered higher amounts of heroin and had selective impairments of the enkephalin opioid system within the nucleus accumbens (NAc) implicated in reward-related behavior. To explore the ontogeny of the cannabinoid and opioid neuronal systems in association with adolescence THC exposure, rats were examined at different adolescent stages during an intermittent THC paradigm (1.5 mg/kg i.p. every third day) from postnatal days (PNDs) 28–49. Rat brains were examined 24 hours after injection at PND 29 (early adolescence), PND 38 (mid adolescence) and PND 50 (late adolescence) and analyzed for endocannabinoids (anandamide and 2-arachidonoylglycerol), Met-enkephalin, cannabinoid CB1 receptors and µ opioid receptors (µOR) in the NAc, caudate-putamen and prefrontal cortex (PFC). Of the markers studied, the endocannabinoid levels had the most robust alterations throughout adolescence and were specific to the PFC and NAc. Normal correlations between anandamide and 2-arachidonoylglycerol concentrations in the NAc (positive) and PFC (negative) were reversed by THC. Other significant THC-induced effects were confined to the NAc — increased anandamide, decreased Met-enkephalin and decreased µORs. These findings emphasize the dynamic nature of the mesocorticolimbic endocannabinoid system during adolescence and the selective mesocorticolimbic disturbance as a consequence of adolescent cannabis exposure.
doi:10.1016/j.euroneuro.2008.06.009
PMCID: PMC2745315  PMID: 18674887
anandamide; 2-arachidonoylglycerol; mu opioid receptor; enkephalin; ontogeny; nucleus accumbens
2.  Chemotherapy versus chemotherapy plus irradiation in limited small cell lung cancer. Results of a controlled trial with 5 years follow-up. 
British Journal of Cancer  1986;54(1):7-17.
One hundred and forty-five patients with limited stage small cell lung cancer were included in a randomized trial to evaluate the effect of chemotherapy with or without chest irradiation. Seventy-six patients were allotted chemotherapy alone while 69 patients received the same chemotherapy plus radiotherapy, 40 Gy in split-course, administered in weeks 6 and 10 after the initiation of chemotherapy. The chemotherapy consisted of lomustine, cyclophosphamide, vincristine and methotrexate. Patients treated with chemotherapy alone survived for a median of 52 weeks compared to 44 weeks in patients receiving the combined regimen (P = 0.055). After exclusion of five early deaths and one patient refusing the irradiation plus 14 completely resected patients, the remaining 65 patients receiving chemotherapy alone and the 60 patients treated with chemotherapy plus radiotherapy were included in a new analysis. The difference in survival duration which could be ascribed to treatment with or without chest irradiation thereby diminished (P = 0.24). Eighteen months' disease-free survival was obtained in 9.2% of the 65 patients and in 9.8% of the 60 patients. The complete remission rates were 37% and 46%, respectively, (P = 0.33) and the median durations of complete remission were 40 weeks and 52 weeks (P = 0.67). Treatment failure of the primary tumour occurred in 85% of patients treated with chemotherapy alone in contrast to 61% of patients receiving the combined regimen (P = 0.005). Seventy-nine of these patients underwent autopsy at which no residual chest disease was observed in 17% and 37%, respectively (P = 0.045). The combined regimen was more toxic than chemotherapy alone resulting in significantly greater dose reductions and more pronounced thrombocytopenia. Lung and pericardial fibrosis was responsible for four deaths among the complete responders in the radiotherapy group. The combined regimen thus tended to be more efficacious with respect to tumour control at the expense, however, of increased toxicity which per se, eliminated a potential improvement of the overall therapeutical results.
PMCID: PMC2001661  PMID: 3015184
3.  Efficacy of an adapted granzyme B-based anti-CD30 cytolytic fusion protein against PI-9-positive classical Hodgkin lymphoma cells in a murine model 
Blood Cancer Journal  2013;3(3):e106-.
Tumors develop when infiltrating immune cells contribute growth stimuli, and cancer cells are selected to survive within such a cytotoxic microenvironment. One possible immune-escape mechanism is the upregulation of PI-9 (Serpin B9) within cancer cells. This serine proteinase inhibitor selectively inactivates apoptosis-inducing granzyme B (GrB) from cytotoxic granules of innate immune cells. We demonstrate that most classical Hodgkin lymphoma (cHL)-derived cell lines express PI-9, which protects them against the GrB attack and thereby renders them resistant against GrB-based immunotherapeutics. To circumvent this disadvantage, we developed PI-9-insensitive human GrB mutants as fusion proteins to target the Hodgkin-selective receptor CD30. In contrast to the wild-type GrB, a R201K point-mutated GrB construct most efficiently killed PI-9-positive and -negative cHL cells. This was tested in vitro and also in vivo whereby a novel optical imaging-based tumor model with HL cell line L428 was applied. Therefore, this variant, as part of the next generation immunotherapeutics, also named cytolytic fusion proteins showing reduced immunogenicity, is a promising molecule for (targeted) therapy of patients with relapsing malignancies, such as cHL, and possibly other PI-9-positive malignancies, such as breast or lung carcinoma.
doi:10.1038/bcj.2013.4
PMCID: PMC3615217  PMID: 23524591
targeted cancer therapy; serine protease; treatment resistance; Serpin B9; immunotoxin
4.  Lung nodule volumetry: segmentation algorithms within the same software package cannot be used interchangeably 
European Radiology  2010;20(8):1878-1885.
Objective
We examined the reproducibility of lung nodule volumetry software that offers three different volumetry algorithms.
Methods
In a lung cancer screening trial, 188 baseline nodules >5 mm were identified. Including follow-ups, these nodules formed a study-set of 545 nodules. Nodules were independently double read by two readers using commercially available volumetry software. The software offers readers three different analysing algorithms. We compared the inter-observer variability of nodule volumetry when the readers used the same and different algorithms.
Results
Both readers were able to correctly segment and measure 72% of nodules. In 80% of these cases, the readers chose the same algorithm. When readers used the same algorithm, exactly the same volume was measured in 50% of readings and a difference of >25% was observed in 4%. When the readers used different algorithms, 83% of measurements showed a difference of >25%.
Conclusion
Modern volumetric software failed to correctly segment a high number of screen detected nodules. While choosing a different algorithm can yield better segmentation of a lung nodule, reproducibility of volumetric measurements deteriorates substantially when different algorithms were used. It is crucial even in the same software package to choose identical parameters for follow-up.
doi:10.1007/s00330-010-1749-z
PMCID: PMC2899012  PMID: 20306082
Pulmonary nodules; Volumetry; Segmentation; Reproducibility; Computed tomography
5.  Heterogeneity in cancer guidelines: should we eradicate or tolerate? 
Annals of Oncology  2008;19(12):2067-2078.
Background: Heterogeneity in aspects of development, structure and context of oncology guidelines was not evaluated. We analysed and critically examined its implications.
Materials and methods: Nine cancer clinical practice guidelines were selected on the basis of popularity among oncologists. The relevant Web sites and publications on three tumours were examined and characteristics grouped in the data domains: producing organisation, methodology, guideline structure and content, implementation and evaluation and scientific agreement.
Results: ASCO, ESMO, NICE, SIGN, START, NHMRC, NCI, NCCN and CCO guidelines were examined. Development was initiated by stakeholders or authorised bodies, run by task forces with varying degrees of multidisciplinarity, with rare endorsement of external guidelines. Recommendation formulation was on the basis of evidence, shaped via interactive processes of expert review and public consultation-based modifications. Guidelines varied in comprehensiveness per tumour type, number, size, format, grading of evidence, update and legal issues. Orientation for clinic use or as reference document, end-users and binding or elective nature also varied. Standard dissemination strategies were used, though evaluation of adoption and of impact on health outcomes was implemented with considerable heterogeneity.
Conclusions: Heterogeneity in development, structure, user and end points of guidelines is evident, though necessary in order to meet divergent demands. Crucial for their effectiveness are adherence to methodological standards, a clear definition of what the guideline intends to do for whom and a systematic evaluation of their impact on health care.
doi:10.1093/annonc/mdn418
PMCID: PMC2733109  PMID: 18662954
cancer; clinical practice; guidelines; oncology
7.  Cancer incidence among Danish seafarers: a population based cohort study 
Aims: Seafarers aboard oil and chemical tankers may be exposed to many chemicals, including substances like benzene that are known to be carcinogenic. Other seafarers are exposed to engine exhaust, different oil products, and chemicals used aboard and some years ago asbestos was also used extensively in ships. The aim of this study was to study cancer morbidity among Danish seafarers in relation to type of ship and job title.
Methods: A cohort of all Danish seafarers during 1986–1999 (33 340 men; 11 291 women) registered by the Danish Maritime Authority with an employment history was linked with the nationwide Danish Cancer Registry and followed up for cancer until the end of 2002. The number of person years at risk was 517 518. Standardised incidence ratios (SIR) were estimated by use of the corresponding national rates.
Results: The SIR of all cancers combined was higher than expected: 1.26 (95% CI 1.19 to 1.32) for men and 1.07 (95% CI 0.95 to 1.20) for women. This was mainly due to an excess of cancer of the larynx, lung, tongue, mouth, pharynx, oesophagus, pancreas, kidney, urinary bladder, colon, and bone as well as skin melanomas among men (the three latter borderline significantly increased), and an excess of cancer of the lung, rectum, and cervix uteri among women. The differences in risk pattern for lung cancer between the different job categories among men ranged in terms of SIR from 1.2 (95% CI 0.9 to 1.7) (engine officers) to 2.3 (1.6 to 3.3) (engine room crew), and 4.1 (2.1 to 7.4) among maintenance crew. Non-officers had a 1.5 times higher lung cancer risk than officers. No increased occurrence of all lymphatic and haematopoietic malignancies combined was found for employees on tankers, but the number of cases was limited to a total of 7.
Conclusions: Danish seafarers, especially men, face an increased overall cancer risk, in particular a risk for lung cancer and other tobacco associated cancers.
doi:10.1136/oem.2005.020818
PMCID: PMC1740901  PMID: 16234401
8.  Suicide among Danes with multiple sclerosis 
Methods: The study was based on linkage of the Danish Multiple Sclerosis Registry to the Cause of Death Registry. It comprised all 10 174 persons in whom multiple sclerosis was diagnosed in the period 1953 to 1996. The end of follow up was 1 January 1999. Standardised mortality ratios (SMRs) were calculated for various times after diagnosis and for age and calendar period of diagnosis.
Results: In all, 115 persons (63 men, 52 women) had taken their own lives, whereas the expected number of suicides was 54.2 (29.1 men, 25.1 women). Thus the suicide risk among persons with multiple sclerosis was more than twice that of the general population (SMR = 2.12). The increased risk was particularly high during the first year after diagnosis (SMR = 3.15).
Conclusions: The risk of suicide in multiple sclerosis was almost twice as high as expected more than 20 years after diagnosis. The excess suicide risk has not declined since 1953.
doi:10.1136/jnnp.2004.056747
PMCID: PMC1739366  PMID: 16170097
9.  Relation between policies and work related assault: Minnesota Nurses' Study 
Aims: To assess the relation between violence prevention policies and work related assault.
Methods: From Phase 1 of the Minnesota Nurses' Study, a population based survey of 6300 Minnesota nurses (response 79%), 13.2% reported experiencing work related physical assault in the past year. In Phase 2, a case-control study, 1900 nurses (response 75%) were questioned about exposures relevant to violence, including eight work related violence prevention policy items. A comprehensive causal model served as a basis for survey design, analyses, and interpretation. Sensitivity analyses were conducted for potential exposure misclassification and the presence of an unmeasured confounder.
Results: Results of multiple regression analyses, controlling for appropriate factors, indicated that the odds of physical assault decreased for having a zero tolerance policy (OR = 0.5, 95% CI 0.4 to 0.8) and having policies regarding types of prohibited violent behaviours (OR = 0.5, 95% CI 0.3 to 0.9). Analyses adjusted for non-response and non-selection resulted in wider confidence intervals, but no substantial change in effect estimates.
Conclusions: It appears that some work related violence policies may be protective for the population of Minnesota nurses.
doi:10.1136/oem.2004.014134
PMCID: PMC1740877  PMID: 16169912
10.  Hospitalisations among seafarers on merchant ships 
Aims: To study morbidity among active seafarers in the merchant navy in order to clarify possible work related morbidity and the morbidity related to work and lifestyle where possible preventive measures may be initiated.
Methods: From a register in the Danish Maritime Authority a cohort of Danish merchant seafarers who had been actively employed at sea in 1995 was identified. For each seafarer, information on all employment periods at sea, charge aboard, and ship was available. The cohort was linked with the National In-patient Register in Denmark. Standardised hospitalisation ratios (SHRs) were calculated for all major diagnostic groups using all gainfully employed as reference.
Results: Seafarers were shown to be inhomogeneous, with significant differences in SHRs for the same disease groups between different groups of seafarers depending on charge and ship type. SHRs for lifestyle related diseases were high, although rates for acute conditions, such as acute myocardial infarction, were low, probably due to referral bias, as acute conditions are likely to cause hospitalisation abroad, and thus are not included in the study. SHRs for injury and poisoning were high, especially for ratings and officers aboard small ships.
Conclusion: Despite pre-employment selection, a large proportion of the seafarers constitute a group of workers with evidence of poor health probably caused by lifestyle. The subgroups with high risk of hospitalisation due to lifestyle related diseases also had an increased risk of hospitalisation due to injury and poisoning.
doi:10.1136/oem.2004.014779
PMCID: PMC1740984  PMID: 15723878
11.  Impact of smoking on the social gradient in health expectancy in Denmark 
Study objective: Health expectancy is arrived at by dividing life expectancy into average lifetime in different states of health. The purpose of the study was to estimate health expectancy among never smokers and smokers in groups at high, medium, and low educational levels in Denmark.
Design: Life tables for never smokers and smokers with a high, medium, and low educational level were constructed on the basis of Statistics Denmark registers and combined with data from the Danish Health Interview Survey 2000. Health expectancy was calculated by Sullivan's method.
Main results: Life expectancy at age 30 differs on average by 8.5 years between never smokers and heavy smokers. Expected lifetime in self rated good health was 39.4 years for a never smoking man corresponding to 82.0% of the rest of his life. For male lifelong heavy smokers these figures were reduced to 27.3 years and 69.2%. The proportion of expected lifetime in self rated good health was 89.5% and 71.3% among male never smokers and lifelong heavy smokers with a high educational level, respectively; and the proportion among male never smokers and heavy smokers with a low educational level was 73.4% and 63.6%, respectively. Similar results were seen as regards expected lifetime without longstanding illness. For women the social gradient in health expectancy was intensified among smokers.
Conclusions: Within each educational group smoking reduces expected lifetime in a healthy state. The social gradient in health expectancy cannot be explained by a reverse social gradient in smoking prevalence.
doi:10.1136/jech.2003.012955
PMCID: PMC1732832  PMID: 15194724
12.  An epidemiological study of the magnitude and consequences of work related violence: the Minnesota Nurses' Study 
Aims: To identify the magnitude of and potential risk factors for violence within a major occupational population.
Methods: Comprehensive surveys were sent to 6300 Minnesota licensed registered (RNs) and practical (LPNs) nurses to collect data on physical and non-physical violence for the prior 12 months. Re-weighting enabled adjustment for potential biases associated with non-response, accounting for unknown eligibility.
Results: From the 78% responding, combined with non-response rate information, respective adjusted rates per 100 persons per year (95% CI) for physical and non-physical violence were 13.2 (12.2 to 14.3) and 38.8 (37.4 to 40.4); assault rates were increased, respectively, for LPNs versus RNs (16.4 and 12.0) and males versus females (19.4 and 12.9). Perpetrators of physical and non-physical events were patients/clients (97% and 67%, respectively). Consequences appeared greater for non-physical than physical violence. Multivariate modelling identified increased rates for both physical and non-physical violence for working: in a nursing home/long term care facility; in intensive care, psychiatric/behavioural or emergency departments; and with geriatric patients.
Conclusions: Results show that non-fatal physical assault and non-physical forms of violence, and relevant consequences, are frequent among both RNs and LPNs; such violence is mostly perpetrated by patients or clients; and certain environmental factors appear to affect the risk of violence. This serves as the basis for further analytical studies that can enable the development of appropriate prevention and control efforts.
doi:10.1136/oem.2003.007294
PMCID: PMC1763639  PMID: 15150388
13.  Multicentre, randomised, double blind, placebo controlled, phase III study of weekly, low dose, subcutaneous interferon beta-1a in secondary progressive multiple sclerosis 
Objective: Interferon (IFN) beta has repeatedly shown benefit in multiple sclerosis (MS) in reducing the rate of relapse, the disease activity as shown with magnetic resonance imaging and, to some degree, the progression of disability; however, it is unknown how much the therapeutic response depends on the dose, the subgroup involved, and the disease stage. This multicentre, double blind, placebo controlled study explored the dose–response curve by examining the clinical benefit of low dose IFN beta-1a (Rebif®), 22 µg subcutaneously once weekly, in patients with secondary progressive MS.
Methods: A total of 371 patients with clinically definite SPMS were randomised to receive either placebo or subcutaneous IFN beta-1a, 22 µg once weekly, for 3 years. Clinical assessments were performed every 6 months. The primary outcome was time to sustained disability, as defined by time to first confirmed 1.0 point increase on the Expanded Disability Status Scale (EDSS). Secondary outcomes included a sensitive disability measure and relapse rate.
Results: Treatment had no beneficial effect on time to confirmed progression on either the EDSS (hazard ratio (HR) = 1.13; 95% confidence interval (CI) 0.82 to 1.57; p = 0.45 for 22 µg v placebo) or the Regional Functional Status Scale (HR = 0.93; 95% CI 0.68 to 1.28; p = 0.67). Other disability measures were also not significantly affected by treatment. Annual relapse rate was 0.27 with placebo and 0.25 with IFN (rate ratio = 0.90; 95% CI 0.64 to 1.27; p = 0.55). The drug was well tolerated with no new safety concerns identified. No significant gender differences were noted.
Conclusions: This patient population was less clinically active than SPMS populations studied in other trials. Treatment with low dose, IFN beta-1a (Rebif®) once weekly did not show any benefit in this study for either disability or relapse outcomes, including a subgroup with preceding relapses. These results add a point at one extreme of the dose–response spectrum of IFN beta therapy in MS, indicating that relapses in this phase may need treatment with higher doses than in the initial phases.
doi:10.1136/jnnp.2003.010090
PMCID: PMC1763573  PMID: 15090564
14.  Human transforming growth factor α (TGF-α) is digested to a smaller (1–43), less biologically active, form in acidic gastric juice 
Gut  2002;51(6):787-792.
Background: Transforming growth factor α (TGF-α) is a 50 amino acid peptide with potent proliferative and cytoprotective activity present in gastric mucosa and juice.
Aims: To determine the forms and biological activity of natural and recombinant TGF-α following incubation with acid pepsin.
Patients: Human gastric juice was obtained under basal conditions from patients taking acid suppressants and from volunteers undergoing intragastric neutralisation.
Methods: Samples were analysed using mass spectroscopy and/or high pressure liquid chromatography with radioimmunoassay. Biological activity was determined using thymidine incorporation into rat hepatocytes and an indomethacin/restraint induced gastric damage rat model.
Results: TGF-α1–50 is cleaved to TGF-α1–43 by acid pepsin and this is the predominant form in normal gastric juice. However, intragastric neutralisation or taking acid suppressants caused the predominant form to be TGF-α1–50. TGF-α1–43 had only half of the ability to maximally stimulate [3H]thymidine incorporation into primary rat hepatocytes (28 177 (1130) DPM/well for 2.16 nM TGF-α1–43 v 63 184 (3536) DPM/well for TGF-α1–50; p<0.001). A similar reduced potency was seen when used in an indomethacin induced rat gastric damage model (0.18 μmol/kg/h of TGF-α1–43 reduced ulcer area by 19% whereas TGF-α1–50 reduced area by 62%; p<0.001).
Conclusions: TGF-α1–50 is cleaved to the TGF-α1–43 form by acid pepsin, causing 2–5-fold loss of biological activity. Such changes may have relevance to the actions of acid suppressants and the importance of this peptide in both normal and abnormal growth.
PMCID: PMC1773459  PMID: 12427777
transforming growth factor; gastric juice
15.  Occupational accidents aboard merchant ships 
Objectives: To investigate the frequency, circumstances, and causes of occupational accidents aboard merchant ships in international trade, and to identify risk factors for the occurrence of occupational accidents as well as dangerous working situations where possible preventive measures may be initiated.
Methods: The study is a historical follow up on occupational accidents among crew aboard Danish merchant ships in the period 1993–7. Data were extracted from the Danish Maritime Authority and insurance data. Exact data on time at risk were available.
Results: A total of 1993 accidents were identified during a total of 31 140 years at sea. Among these, 209 accidents resulted in permanent disability of 5% or more, and 27 were fatal. The mean risk of having an occupational accident was 6.4/100 years at sea and the risk of an accident causing a permanent disability of 5% or more was 0.67/100 years aboard. Relative risks for notified accidents and accidents causing permanent disability of 5% or more were calculated in a multivariate analysis including ship type, occupation, age, time on board, change of ship since last employment period, and nationality. Foreigners had a considerably lower recorded rate of accidents than Danish citizens. Age was a major risk factor for accidents causing permanent disability. Change of ship and the first period aboard a particular ship were identified as risk factors. Walking from one place to another aboard the ship caused serious accidents. The most serious accidents happened on deck.
Conclusions: It was possible to clearly identify work situations and specific risk factors for accidents aboard merchant ships. Most accidents happened while performing daily routine duties. Preventive measures should focus on workplace instructions for all important functions aboard and also on the prevention of accidents caused by walking around aboard the ship.
doi:10.1136/oem.59.2.85
PMCID: PMC1740248  PMID: 11850550
16.  Do CA125 response criteria overestimate tumour response in second-line treatment of epithelial ovarian carcinoma? 
British Journal of Cancer  2004;90(2):377-382.
doi:10.1038/sj.bjc.6601501
PMCID: PMC2409573  PMID: 14735180
ovarian neoplasms; recurrence; second-line treatment; chemotherapy; CA125; response
17.  Severe intracellular magnesium and potassium depletion in patients after treatment with cisplatin 
British Journal of Cancer  2003;89(9):1633-1637.
doi:10.1038/sj.bjc.6601344
PMCID: PMC2394419  PMID: 14583761
cisplatin; side effects; hypomagnesaemia; magnesium; potassium; depletion
18.  Abstention from smoking extends life and compresses morbidity: a population based study of health expectancy among smokers and never smokers in Denmark 
Tobacco Control  2001;10(3):273-278.
OBJECTIVE—To estimate health expectancy— that is, the average lifetime in good health—among never smokers, ex-smokers, and smokers in Denmark.
DESIGN—A method suggested by Peto and colleagues in 1992 for estimating smoking attributable mortality rates was used to construct a life table for never smokers. This life table and relative risks for death for ex-smokers and smokers versus never smokers were used to estimate life tables for ex-smokers and smokers. Life tables and prevalence rates of health status were combined and health expectancy was calculated by Sullivan's method.
SETTING—The Danish adult population.
MAIN OUTCOME MEASURES—The expected lifetime in self rated good health or without longstanding illness for never smokers and smokers.
RESULTS—The expected lifetime of a 20 year old man who will never begin to smoke is 56.7 years, 48.7 (95% confidence interval (CI), 46.8 to 50.7) years of which are expected to be in self rated good health. The corresponding figures for a man who smokes heavily are 49.5 years, 36.5 (95% CI 35.0 to 38.1 ) years of which are in self rated good health. A 20 year old woman who will never begin to smoke can expect to live a further 60.9 years, with 46.4 (95% CI 44.9 to 47.8) years in self rated good health; if she is a lifelong heavy smoker, her expected lifetime is reduced to 53.8 years, 33.8 (95% CI 31.7 to 35.9) years of which are in self rated good health. Health expectancy based on long standing illness is reduced for smokers when compared with never smokers.
CONCLUSIONS—Smoking reduces the expected lifetime in good health and increases the expected lifetime in poor health.


Keywords: life expectancy; health expectancy
doi:10.1136/tc.10.3.273
PMCID: PMC1747595  PMID: 11544393
19.  Use of GIS and Exposure Modeling as Tools in a Study of Cancer Incidence in a Population Exposed to Airborne Dioxin 
Environmental Health Perspectives  2004;112(9):1032-1036.
In environmental health research there is a recognized need to develop improved epidemiologic and statistical methods for rapid assessment of relationships between environment and health. Exposure assessment is identified as a major challenge needing attention. In this study an exposure simulation model was used to delimit almost exactly in space and time an urban population exposed to airborne dioxin. A geographic information system (GIS) was used as the electronic environment in which to link the exposure model with the demographic, migration, and cancer data of the exposed population. This information is available in Denmark on an individual basis. Standardized incidence ratios (SIRs) for both men and women in 10-year age bands were calculated for three different exposure areas. Migration patterns were outlined. SIRs showed no excess of cancer incidences during the time span chosen (13 years; 1986–1998) in the whole exposed area or in the medium or higher polluted areas. The exposure model appeared very useful in selection of the appropriate exposure areas. The integration of the model in a GIS together with individual data on addresses, sex, age, migration, and information from routine health statistics (Danish Cancer Registry) proved its usefulness in demarking the exposed population and identifying the cancers related to that population. Less than one-third of the study population lived at the same address after 13 years of observation, and only half were still residing in the area, indicating migration of people as a major misclassification.
doi:10.1289/ehp.6739
PMCID: PMC1247197  PMID: 15198924
air pollution; cancer; dioxin; environmental epidemiology; exposure model; GIS; health registers; migration
20.  Immunological and clinical follow up of hepatitis C virus associated cryoglobulinaemic vasculitis 
Annals of the Rheumatic Diseases  2001;60(4):385-390.
OBJECTIVE—To study immunological markers and compare these markers with standard measures for the clinical and immunological follow up of vasculitis activity in hepatitis C virus (HCV) associated cryoglobulinaemic vasculitis (CV).
METHODS—Serial serum samples from eight patients with newly diagnosed HCV associated CV were followed during interferon α treatment induced remission of the CV. Vasculitis activity and disease extent were evaluated with the Birmingham vasculitis activity score (BVAS) and disease extent index (DEI). Cryoglobulinaemia, complement levels (C3c, C4, and CH50), rheumatoid factor (RF), autoantibodies such as antinuclear antibodies, soluble interleukin 2 receptor (sIL2r), soluble intercellular adhesion molecule-1 (sICAM-1), and soluble CD30 (sCD30) were determined.
RESULTS—All patients achieved either complete or partial remission of their CV during interferon α treatment. There was a significant reduction in vasculitis activity and disease extent (BVAS, DEI), cryoglobulinaemia, RF, sIL2r, sICAM-1, and sCD30. Complement C3c levels increased significantly during this period. Erythrocyte sedimentation rate and levels of complement C4 and CH50 did not change significantly. Both clinical measures (BVAS and DEI) correlated significantly only with C3c and sCD30.
CONCLUSIONS—Although this study was of only a small group of patients, it shows that BVAS and DEI as clinical measures and C3c and sCD30 as immunological markers may be useful in the follow up of disease activity of HCV associated CV. The data indicate that activity of the humoral (cryoglobulinaemia, RF, autoantibodies) and cellular (sIL2r, sICAM-1, sCD30) immune response and endothelial damage (sICAM-1) are found in HCV associated CV.


doi:10.1136/ard.60.4.385
PMCID: PMC1753599  PMID: 11247870
22.  Socioeconomic status and trends in risk factors for cardiovascular diseases in the Danish MONICA population, 1982-1992 
STUDY OBJECTIVE—The decline in cardiovascular mortality in Denmark during the 1980s has been greatest in the highest socioeconomic groups of the population. This study examines whether the increased social inequality in cardiovascular mortality has been accompanied by a different trend in cardiovascular risk factors in different educational groups.
DESIGN—Data from three cross sectional WHO MONICA surveys conducted in 1982-84, 1987, and 1991-92, were analysed to estimate trends in biological (weight, height, body mass index, blood pressure, and serum lipids) and behavioural (smoking, physical activity during leisure, and eating habits) risk factors in relation to educational status.
SETTING—County of Copenhagen, Denmark.
PARTICIPANTS—6695 Danish men and women of ages 30, 40, 50, and 60 years.
MAIN RESULTS—The prevalence of smoking and heavy smoking decreased during the study but only in the most educated groups. In fact, the prevalence of heavy smoking increased in the least educated women. There was no significant interaction for the remaining biological and behavioural risk factors between time of examination and educational level, indicating that the trend was the same in the different educational groups. However, a summary index based on seven cardiovascular risk factors improved, and this development was only seen in the most educated men and women.
CONCLUSION—The difference between educational groups in prevalence of smoking increased during the 1980s, and this accounted for widening of an existing social difference in the total cardiovascular risk.


Keywords: cardiovascular risk factors; socioeconomic status; time trends
doi:10.1136/jech.54.2.108
PMCID: PMC1731611  PMID: 10715743
23.  Asymptomatic bronchial hyperresponsiveness to exercise in childhood and the development of asthma related symptoms in young adulthood: the Odense Schoolchild Study 
Thorax  1999;54(7):587-589.
BACKGROUND—Exercise testing may be of value in identifying a group of children at high risk of subsequently developing respiratory symptoms. As few longitudinal studies have investigated this issue, the bronchial hyperresponsiveness to exercise in asymptomatic children was evaluated as a risk factor for developing asthma related symptoms in young adulthood.
METHODS—A community based sample of 1369 schoolchildren, first investigated in 1985 at a mean age of 9.7 years, was followed up after a mean of 10.5 years. Nine hundred and twenty children (67%) were asymptomatic in childhood and 777 (84.9%) of these were re-investigated at follow up. At the first examination a maximum progressive exercise test on a bicycle ergometer was used to induce airway narrowing. The forced expiratory volume in one second (FEV1) after exercise was considered abnormal if the percentage fall in FEV1 was more than 5% of the highest fall in the reference subjects characterised by having no previous history of asthma or asthma related symptoms. The threshold for a positive test was 8.6% of pre-exercise FEV1.
RESULTS—One hundred and three subjects (13%) had wheeze within the last year at follow up and, of these, nine (9%) had been hyperresponsive to exercise in 1985. One hundred and seventy subjects (22%) had non-infectious cough within the previous year, 11 of whom (6%) had been hyperresponsive to exercise in 1985. Multiple regression analysis showed that subjects with hyperresponsiveness to exercise had an increased risk of developing wheeze compared with subjects with a normal response to exercise when the fall in FEV1 after exercise was included as a variable (threshold odds ratio (OR) 2.3 (95% CI 1.1 to 5.5)). The trend was not significant when exercise induced bronchospasm was included as a continuous variable (OR 1.02 (95% CI 0.97 to 1.06)).
CONCLUSIONS—Asymptomatic children who are hyperresponsive to exercise are at increased risk of developing new symptoms related to wheezing but the predictive value of exercise testing for individuals is low.


PMCID: PMC1745513  PMID: 10377202
24.  How good is the Prevent model for estimating the health benefits of prevention? 
STUDY OBJECTIVE: Prevent is a public health model for estimating the effect on mortality of changes in exposure to risk factors. When the model is tested by simulating a development that has already taken place, the results may differ considerably from the actual situation. The purpose of this study is to test the Prevent model by applying it to a synthetic cohort in which the development is unaffected by concealed factors. DESIGN: A micro-simulation model was developed to create basic data for Prevent and give "exact" results as to changes in risk factor prevalences and mortality. The estimates of Prevent simulations were compared with the "exact" results. MAIN RESULTS: Modelling one risk factor related to a cause specific mortality gave fairly similar results by the two methods. Including two risk factors Prevent tends slightly to overestimate the health benefits of prevention. CONCLUSIONS: The differences between the "exact" mortality and the Prevent estimates will be small for realistic scenarios and Prevent provide reasonable estimates of the health benefits of prevention.
 
PMCID: PMC1756876  PMID: 10396537
25.  Underlying cause of death in Danish patients with multiple sclerosis: results from the Danish Multiple Sclerosis Registry 
OBJECTIVES—To determine the underlying causes of death in a large population based register series of patients with multiple sclerosis.
METHODS—The Danish Multiple Sclerosis Registry, which contains virtually all diagnosed cases of multiple sclerosis in Denmark who were alive in 1949 plus cases with onset of multiple sclerosis in the period 1949-93, who have been diagnosed and notified by 1 January 1994, was linked with the Danish Registry of Causes of Death, in which ICD codes for causes of death from the death certificate are stored for all Danish citizens.
RESULTS—6068 register cases of multiple sclerosis, who had died in the period 1951-93, were included. Multiple sclerosis was noted on the death certificate as the underlying cause of death in 55.4%; cardiac or vascular diseases in 17.6%; cancers in 8.6%; respiratory or infectious diseases in 5.1%; other natural causes in 9.5%; accident or suicide in 3.8%. The distribution varied with age at death. Standardised mortality ratios (SMRs) were computed on the basis of the 8142 incident cases, who had onset of multiple sclerosis within the period 1951-93; the SMRs for causes of death other than multiple sclerosis were highest for infectious or pulmonary diseases: 2.46 (95% confidence interval (95% CI) 2.04-2.94); suicide: 1.62 (95% CI 1.29-2.01); cardiac or vascular diseases: 1.34 (95% CI 1.22-1.48); accidents 1.34 (95% CI 1.02-1.71); and significantly lower than unity for cancers: 0.79 (95% CI 0.70-0.90), lower for men than for women.
CONCLUSIONS—More than half of the patients with multiple sclerosis die from multiple sclerosis or complications of the disease. Among other causes, patients with multiple sclerosis have an increased risk of dying from heart or vascular diseases but a reduced risk of dying from cancer. An increased risk of death from suicide and accidents can be indirectly attributed to multiple sclerosis. The diminished risk of dying from cancer may be a result of incomplete ascertainment of cancers in disabled patients with multiple sclerosis.


PMCID: PMC2170172  PMID: 9667561

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