Gene expression analysis of precision-cut human liver slices indicates stable expression of ADME-Tox related genes.

In the process of drug development it is of high importance to test the safety of new drugs with predictive value for human toxicity. A promising approach of toxicity testing is based on shifts in gene expression profiling of the liver. Toxicity screening based on animal liver cells cannot be directly extrapolated to humans due to species differences. The aim of this study was to evaluate precision-cut human liver slices as in vitro method for the prediction of human specific toxicity by toxicogenomics. The liver slices contain all cell types of the liver in their natural architecture. This is important since drug-induced toxicity often is a multi-cellular process. Previously we showed that toxicogenomic analysis of rat liver slices is highly predictive for rat in vivo toxicity. In this study we investigated the levels of gene expression during incubation up to 24 h with Affymetrix microarray technology. The analysis was focused on a broad spectrum of genes related to stress and toxicity, and on genes encoding for phase-I, -II and -III metabolizing enzymes and transporters. Observed changes in gene expression were associated with cytoskeleton remodeling, extracellular matrix and cell adhesion, but for the ADME-Tox related genes only minor changes were observed. PCA analysis showed that changes in gene expression were not associated with age, sex or source of the human livers. Slices treated with acetaminophen showed patterns of gene expression related to its toxicity. These results indicate that precision-cut human liver slices are relatively stable during 24h of incubation and represent a valuable model for human in vitro hepatotoxicity testing despite the human inter-individual variability.

Estimation and prediction of the HIV-AIDS-epidemic under conditions of HAART using mixtures of incubation time distributions.

The estimation of the HIV-AIDS epidemic by means of back-calculation (BC) has been difficult since the introduction of highly active anti-retroviral therapy (HAART) because the incubation time distributions needed for BC were poorly known. Moreover, it has been assumed that if the general public is aware that effective treatments are available then the majority of infected people would be known, and therefore a hidden epidemic was assumed not to exist. Nevertheless, it was suspected that not every infected person would come to the attention of health-care providers, and therefore estimates independent of the patients' registration were necessary. In this paper, the incubation time distributions for HIV treated with the HAART regimen are derived from a cohort study. By using estimates of the proportion treated according to the HAART regimen and the incubation time distributions estimated in the era before the implementation of HAART (pre-HAART), new marginal population incubation time distributions for each of the three risk groups (homosexuals, drug users and others) were constructed. The BC was performed using an empirical Bayesian approach based on the latter incubation time distribution.

Mixed plaques: statistical evidence how plaque assays may underestimate virus concentrations.

Even at very low concentrations human pathogenic viruses may result in infection and possibly subsequent disease. Ideally, viruses are quantified by use of cell culture assays to determine their infectivity. Plaque assays are common tools for enumeration of viruses in inocula and this process is straightforward when a plaque results from the offspring of a single infectious virus particle. In the course of a study on the usefulness of sewage monitoring for surveillance of polio-virus transmission, sewage samples containing a mixture of two live polio vaccine strains (type 1 and type 3) were analyzed. The total poliovirus concentration in plaque forming units (pfu) was estimated by means of a monolayer plaque assay on L20B cells. Subsequent typing of virus directly by neutralisation of virus from excised plaques revealed the occurrence of plaques containing both type 1 and type 3 virus. This means that there must be plaques that originate from more than one initial infectious virus particle. As a consequence, the estimated virus concentration is incorrect. We present statistical methods that utilize these mixed plaque counts to estimate the concentrations of either virus type in our sewage samples. We can also calculate a correction factor for the error in virus concentration, which would result from equating a pfu to a single infectious particle. Since many quantitative methods in microbiology are based on colony counts, we conclude that such counts should be interpreted with caution, especially when data are used in quantitative microbial risk assessment to estimate the public health impact.

Dose dependency of adjuvant activity of particulate matter from five European sites in three seasons in an ovalbumin-mouse model.

Various particulate matter (PM) samples were tested for their adjuvant potency in an animal model of allergy (ovalbumin) in the European Union study entitled Respiratory Allergy and Inflammation Due to Ambient Particles. Coarse and fine ambient particles were collected during spring, summer, and winter in Rome, Oslo, Lodz, Amsterdam, and De Zilk. De Zilk, at the Dutch seaside, has mainly westerly winds and served as a negative pollution control. EHC-93 (Ottawa dust) was used as a positive control. We studied the adjuvant potency of the particle antibody responses to ovalbumin and histopathological changes in the lung. After a sensitization phase by coexposure to EHC-93 and ovalbumin, the antibody response to ovalbumin and inflammatory responses in the lung were huge. There was more adjuvant activity in reaction to 9-mg/ml samples than to 3-mg/ml samples. A best-fit analysis of these samples shows that the ambient coarse and fine particles at these sites, in combination with allergens, have severe to mild adjuvant activity in the order Lodz, Rome, Oslo, and Amsterdam. A high dose of the fine fraction was more potent than a high dose of the coarse fraction, except at De Zilk, where the reverse was true. Spring and winter PM was more potent than summer PM. Depending on the site, either a water-soluble or a water-insoluble fraction was responsible for the adjuvant activity. A concentration of 3 mg/ml is effective for screening high-activity samples, as is a concentration of 9 mg/ml for screening low-activity samples in the ovalbumin-mouse model.

Adjuvant activity of ambient particulate matter of different sites, sizes, and seasons in a respiratory allergy mouse model.

In the framework of an EU project entitled, "Respiratory Allergy and Inflammation due to Ambient Particles (RAIAP)", various ambient particulate matter samples were tested for their adjuvant potency in an animal allergy model to ovalbumin. Coarse (2.5-10 microm) and fine (0.15-2.5 microm) particles were collected during the spring, summer, and winter in Rome, Oslo, Lodz, and Amsterdam. Coarse and fine particles were also collected near a seaside location in the Netherlands, where prevailing winds are westerly. These latter particles served as a control, with a minimum contribution by traffic. Ottawa dust (EHC-93) was used as a standard reference sample. Immunoglobulins (IgE, IgG1, and IgG2a), histopathological changes in the lung, cytokines, and the number of cells and their differentiation in lung lavages were used as effect parameters to study the adjuvant potency of these particles. The particles (3 mg/ml) were mixed with ovalbumin (0.4 mg/ml) and intranasally administered during the sensitization or the challenge phase. Intranasal administration of ovalbumin only induced very little antibody response, but introduced a minor inflammatory response in the lung or BAL during the sensitization and challenge phase. On the contrary, after coexposure to EHC-93 and ovalbumin, a major increase was found in immunoglobulin levels specific for ovalbumin, and a major inflammatory response in lung and BAL was induced. Coexposure to ovalbumin with 4 out of 12 collected PM samples (3 mg/ml) resulted in an increase of mainly IgE and IgG1. The histopathological changes consisted of a small to severe peribronchial and perivascular inflammatory response, a hypertrophy of bronchiolar mucous cells and an increase in eosinophils and neutrophils in the BAL. Statistical evaluation of the above-mentioned parameters showed associations with PMx (coarse and fine), site, season, season x PMx, season x site and (PMx) x site. In addition, adjuvant activity of the PMx can be ranked as Lodz > Rome = Amsterdam > Oslo. When the different seasons were compared for IgE, PM from winter was found more active compared to PM from spring and summer. Only for the histopathological lesions, statistically significant difference in effects was found between coarse and fine (coarse > fine). No associations were found between the endotoxin content and the biological effects parameters, although endotoxin was much more confined to the coarse fraction. In conclusion, PM, both coarse and fine, and from various geographic sites, was found to differ in adjuvant activity; furthermore, winter was found more active than spring and summer.

Acute effect of air pollution on respiratory complaints, exhaled NO and biomarkers in nasal lavages of allergic children during the pollen season.

During 2 months of the pollen season, the acute and putative adjuvant effect of traffic-related air pollution on respiratory health was investigated in children sensitised to grass pollen or house dust mite (HDM). Respiratory complaints were objectified via measurement of exhaled NO and inflammatory mediators in nasal lavage (NAL). During the study children, skin prick negative (n = 31) or positive to grass pollen (n = 22), HDM (n = 34) or grass pollen + HDM (n = 32), kept a daily diary on respiratory symptoms, and NAL and exhaled air was sampled twice a week. The level of air pollutants and pollen was monitored continuously. Like children sensitised to HDM, those sensitised to pollen reported respiratory complaints (shortness of breath, itchy eyes or blocked nose) more frequently than non-sensitised children during (but not before) the pollen season; the respiratory complaints of sensitised children were independent of the pollen level. In addition, exposure to increased levels of PM(10) induces 'shortness of breath' in pollen- and HDM-sensitised children, whereas ozone induces a blocked nose in HDM-sensitised children. Combined exposure to PM(10) + pollen and O(3) + pollen induces a blocked nose in both HDM-sensitised children and children sensitised to pollen + HDM. Significant positive associations were found between eNO and the levels of NO(2), CO, PM(2.5) and pollen in both sensitised and non-sensitised children. At the start of the pollen season, the NAL concentration of eosinophils and ECP in pollen-sensitised children was increased compared to winter, but their levels were not further affected by increased exposure to pollen or air pollution. In conclusion, during the pollen season, sensitised children continuously report a high prevalence of respiratory complaints which coincides with increased levels of upper and lower airway inflammatory markers. No additional pro-inflammatory effect of air pollution was observed, which indicates that air pollution does not facilitate allergen-induced inflammatory responses.

A Bayesian approach to parameter estimation in HIV dynamical models.

In the context of a mathematical model describing HIV infection, we discuss a Bayesian modelling approach to a non-linear random effects estimation problem. The model and the data exhibit a number of features that make the use of an ordinary non-linear mixed effects model intractable: (i) the data are from two compartments fitted simultaneously against the implicit numerical solution of a system of ordinary differential equations; (ii) data from one compartment are subject to censoring; (iii) random effects for one variable are assumed to be from a beta distribution. We show how the Bayesian framework can be exploited by incorporating prior knowledge on some of the parameters, and by combining the posterior distributions of the parameters to obtain estimates of quantities of interest that follow from the postulated model.

Natural history of primary sclerosing cholangitis and prognostic value of cholangiography in a Dutch population.

BACKGROUND: Median survival of patients with primary sclerosing cholangitis (PSC) has been estimated to be 12 years. Cholangiography is the gold standard for diagnosis but is rarely used in estimating prognosis. AIMS: To assess the natural history of Dutch PSC patients and to evaluate the prognostic value of a cholangiographic classification system. PATIENTS: A total of 174 patients with established PSC attending a university hospital and three teaching hospitals from 1970 to 1999. METHODS: Charts were reviewed for validity and time of diagnosis, concurrent inflammatory bowel disease, interventions, liver transplantation, occurrence of cholangiocarcinoma, and death. Follow up data were obtained from the charts and from the attending clinician or family physician. Median follow up was 76 months (range 1-300). The earliest available cholangiography was scored using a radiological classification system for the severity of sclerosis, developed in our institution. Survival curves were computed by the Kaplan-Meier method. Cholangiographic staging was used to construct a prognostic model, applying Cox proportional hazards analysis. RESULTS: The estimated median survival from time of diagnosis to death from liver disease or liver transplantation was 18 years. Cholangiocarcinoma was found in 18 (10%) patients. Fourteen patients (8%) underwent liver transplantation. Cholangiographic scoring was inversely correlated with survival. A combination of intrahepatic and extrahepatic scoring, together with age at endoscopic retrograde cholangiopancreatography, proved strongly predictive of survival. CONCLUSIONS: The observed survival was considerably better than reported in earlier series from Sweden, the UK, and the USA. Classification and staging of cholangiographic abnormalities has prognostic value.

Palliative chemotherapy or watchful waiting? A vignettes study among oncologists.

PURPOSE: To determine the preferences of oncologists for palliative chemotherapy or watchful waiting and the factors considered important to that preference. METHODS: Sixteen vignettes (paper case descriptions), varying on eight patient and treatment characteristics, were designed to assess the oncologists' preferences. Their strength of preference was rated on a 7-point scale. An orthogonal main effects design provided a subset of all possible combinations of the characteristics, allowing estimations of the relative weights of the presented characteristics. A written questionnaire was sent to a random sample of oncologists (N = 1,235). RESULTS: The response rate was 67%, and 697 questionnaires were available for analysis. Eighty-one percent of the respondents were male. The mean age was 46 years. We found considerable variation among the oncologists. No major associations between physician characteristics and preferences were found. Of the patient and treatment characteristics affecting treatment preference, age was the strongest predictor, followed by the patient's wish to be treated and the expected survival gain. Other patient and treatment characteristics had a limited effect on preferences, except for psychologic distress, which had no independent impact. CONCLUSION: Patients will encounter different decisions depending on their oncologists' preferences and their own personal background. Therefore, to ensure adequate information for decision-making processes, decision aids are proposed.

Role of nitric oxide in gastric motor and sensory functions in healthy subjects.

BACKGROUND AND AIMS: Impaired accommodation and hypersensitivity to distension of the proximal stomach are considered to be important factors in the pathogenesis of dyspeptic complaints. As fundus relaxing agents may be effective in the treatment of these symptoms, insight into the mediators involved in fundic accommodation and associated perceptual responses is important. Therefore, we studied the effect of nitric oxide (NO) synthase inhibition by N(G)-monomethyl-L-arginine (L-NMMA) on fundic tone, postprandial sensations, and gastric perception in healthy volunteers. SUBJECTS AND METHODS: Eighteen healthy volunteers participated in a double blind, placebo controlled, randomised study. They underwent a gastric barostat study to evaluate the effect of L-NMMA on meal and distension induced sensations and on fundic relaxation in response to oral meal intake, intraduodenal lipid, and glucagon administration. RESULTS: Compared with placebo, L-NMMA decreased fundic volume after oral meal intake (438 (55) v 304 (67) ml; n=8; p<0.05) and during intraduodenal lipid infusion (384 (37) v 257 (43) ml; n=10; p<0.05) but not after glucagon injection (570 (62) v 540 (52) ml; n=4; p=0.4). In addition, basal fundic volume was significantly reduced by L-NMMA. Scores for nausea and satiation were decreased by L-NMMA after oral meal intake but not during intraduodenal lipid infusion. Perception scores to gastric distension were not altered by L-NMMA. CONCLUSIONS: NO is involved in maintaining basal fundic tone and in meal induced fundic relaxation in humans, but not in visceral perception.

The proximal stomach and postprandial symptoms in functional dyspeptics.

OBJECTIVES: It remains unclear whether postprandial symptom profiles in patients with visceral hypersensitivity and in those with impaired fundic accommodation differ. Therefore, we evaluated the postprandial symptoms in functional dyspepsia (FD) patients classified according to proximal stomach function. In addition, the effect of gastric relaxation induced by sumatriptan on postprandial symptoms was studied in FD patients with impaired fundic accommodation. METHODS: Twenty-five healthy volunteers (HVs) and 44 FD patients filled out a disease-specific questionnaire (Nepean Dyspepsia Index) and underwent a gastric barostat study to evaluate visceral sensitivity, meal-induced fundic relaxation, and postprandial symptoms. Postprandial symptoms evoked by a drink test or reported during the barostat study were compared between FD patients subdivided according to the underlying pathophysiological mechanism. Finally, the effect of sumatriptan on postprandial symptoms evoked by a drink test was investigated in HVs and in FD patients with impaired fundic accommodation. RESULTS: There was no clear relationship between any of the 15 Nepean Dyspepsia Index symptoms and proximal stomach function. Postprandial symptoms evoked during the barostat study or after the drink tests were significantly higher in FD patients than in HVs; however, no clear differences in symptom profile could be demonstrated between the different subclasses of FD. Sumatriptan did not affect the maximal ingested volume or the postprandial symptoms in HVs or FD patients after a drink test. CONCLUSIONS: No clear relationship could be demonstrated between postprandial symptoms and proximal stomach function.

Impaired drinking capacity in patients with functional dyspepsia: relationship with proximal stomach function.

BACKGROUND & AIMS: Impaired fundic accommodation to a meal and hypersensitivity to distention are increasingly recognized as important mechanisms underlying functional dyspepsia (FD). In the present study, we evaluated whether a drink test can predict such abnormalities and thus represent a noninvasive tool to study proximal stomach motor function. METHODS: Healthy volunteers (HV), nonconsulters with mild dyspeptic symptoms (MS), and patients with FD filled out a disease-specific questionnaire and underwent a drink test with either water or with a high calorie fluid. The maximal ingested volume and the subsequent symptoms were meticulously recorded. In addition, all subjects underwent a gastric barostat study assessing meal-induced relaxation and sensation to distention. RESULTS: Drinking capacity was not significantly related to any particular dyspeptic symptom. FD were able to consume less water (893 +/- 70 mL) and caloric liquid (767 +/- 50 mL) compared with HV (water, 1764 +/- 120 mL; caloric liquid, 1308 +/- 96 mL) or MS (water, 1645 +/- 120 mL; caloric liquid, 973 +/- 45 mL). Approximately half of the FD had an abnormal water or Nutridrink test compared with 9% of MS and 4% of HV. Furthermore, FD developed significantly more symptoms than MS or HV after both drink tests. The drinking capacity did not predict impaired fundic accommodation or visceral hypersensitivity. CONCLUSIONS: FD, but not MS, have an impaired drinking capacity to both water and a nutrient liquid. The drinking capacity is not related to a specific dyspeptic symptom and does not predict proximal stomach motor function.

Effect of preoperative oral immune-enhancing nutritional supplement on patients at high risk of infection after cardiac surgery: a randomised placebo-controlled trial.

BACKGROUND: Elderly patients and those with poor ventricular function have increased morbidity and mortality rates when undergoing surgery. We aimed to ascertain whether an oral immune-enhancing nutritional supplement could improve preoperative host defence, and subsequently lower postoperative infections and organ dysfunction in patients undergoing elective cardiac surgery who are at high risk of infection. METHODS: In this prospective, randomised, double-blind, placebo-controlled study, we randomly assigned 50 patients who were scheduled to undergo coronary artery bypass to receive either an oral immune-enhancing nutritional supplement containing L-arginine, omega3 polyunsaturated fatty acids, and yeast RNA (n=25), or a control (n=25) for a minimum of 5 days. Patients were included if they were aged 70 years or older, or had an ejection fraction of less than 0.4, or were scheduled to undergo mitral valve replacement. The main outcome was preoperative host defence (delayed-type hypersensitivity response to recall antigens, expression of HLA-DR epitopes on monocytes, and concentration of interleukin 6 in plasma). Analysis was per protocol. FINDINGS: Five patients (two in the treatment group) were excluded because they did not take the minimum dose. Preoperative expression of HLA-DR epitopes on monocytes was significantly higher in patients given the study treatment (109% [95% CI 92-128]) than those given the control (69% [58-82]) compared with baseline (100%) (p=0.02, repeated measures ANOVA). However, concentration of interleukin 6 was significantly lower in the treatment group (0.90 pg/L [0.69-1.18]) than in the control group (1.94 pg/L [1.45-2.59]) (p=0.032, repeated measures ANOVA). Additionally, delayed-type hypersensitivity response to recall antigens improved preoperatively and remained better until hospital discharge. INTERPRETATION: Intake of an oral immune-enhancing nutritional supplement for a minimum of 5 days before surgery can improve outlook in high-risk patients who are undergoing elective cardiac surgery.

The human transcriptome map: clustering of highly expressed genes in chromosomal domains.

The chromosomal position of human genes is rapidly being established. We integrated these mapping data with genome-wide messenger RNA expression profiles as provided by SAGE (serial analysis of gene expression). Over 2.45 million SAGE transcript tags, including 160,000 tags of neuroblastomas, are presently known for 12 tissue types. We developed algorithms to assign these tags to UniGene clusters and their chromosomal position. The resulting Human Transcriptome Map generates gene expression profiles for any chromosomal region in 12 normal and pathologic tissue types. The map reveals a clustering of highly expressed genes to specific chromosomal regions. It provides a tool to search for genes that are overexpressed or silenced in cancer.

USAGE: a web-based approach towards the analysis of SAGE data. Serial Analysis of Gene Expression.

MOTIVATION: SAGE enables the determination of genome-wide mRNA expression profiles. A comprehensive analysis of SAGE data requires software, which integrates (statistical) data analysis methods with a database system. Furthermore, to facilitate data sharing between users, the application should reside on a central server and be accessed via the internet. Since such an application was not available we developed the USAGE package. RESULTS: USAGE is a web-based application that comprises an integrated set of tools, which offers many functions for analysing and comparing SAGE data. Additionally, USAGE includes a statistical method for the planning of new SAGE experiments. USAGE is available in a multi-user environment giving users the option of sharing data. USAGE is interfaced to a relational database to store data and analysis results. The USAGE query editor allows the composition of queries for searching this database. Several database functions have been included which enable the selection and combination of data. USAGE provides the biologist increased functionality and flexibility for analysing SAGE data. AVAILABILITY: USAGE is freely accessible for academic institutions at http://www.cmbi.kun.nl/usage/. The source code of USAGE is freely available for academic institutions on request from the first author.

Back-calculation by birth cohort, incorporating age- specific disease progression, pre-AIDS mortality and change in European AIDS case definition. European Union Concerted Action on Multinational AIDS Scenarios.

OBJECTIVES: To adapt and improve methodology for back-calculation of AIDS in Europe and to examine the feasibility of estimating past HIV incidence by birth cohort. METHODS: Empirical Bayesian back-calculation (EBBC) used Markov disease progression models, modified to allow for three diseases added to the AIDS case definition in 1993 and for pre-AIDS mortality, and estimation by penalized maximum likelihood with a neighbour prior. EBBC by 5-year birth cohort assumed a minimum age at infection and age-dependent progression rates; three versions, with varying age effects, were investigated using AIDS cases diagnosed prior to the introduction of highly active antiretroviral therapies (HAART). RESULTS: Compared with the no age-effect version, EBBC by birth cohort tended to produce flattened HIV incidence curves in country-exposure groups with < 1000 AIDS cases, reflecting effects of the neighbour prior when data become sparse. Otherwise, birth cohort analysis, with moderate effects of age on progression, gave initially increasing incidence curves and consistent patterns across countries, with the 1960-1964 cohort most affected. In the European Union, incidence is estimated to have peaked in 1983 among homosexual men and in 1988 among injecting drug users; 460000 persons were estimated to be living with HIV/AIDS at the end of 1995. CONCLUSIONS: Our improved methodology deals effectively with the change in AIDS case definition and has allowed quantitative assessments of the HIV epidemic by birth cohort using all AIDS cases diagnosed before 1996, thus providing a sound basis for public health policy at a time when estimation of more recent prevalence is compromised by the effects of HAART.

Evidence for VIP(1)/PACAP receptors in the afferent pathway mediating surgery-induced fundic relaxation in the rat.

We previously reported activation of an inhibitory adrenergic and a non-adrenergic non-cholinergic (NANC) pathway during abdominal surgery relaxing the rat gastric fundus. In the present study, we investigated the possible role of nitric oxide (NO) and vasoactive intestinal polypeptide (VIP) in the NANC part of the surgery-induced fundic relaxation. The effect of the NO biosynthesis inhibitor N(G)-nitro-L-arginine (L-NOARG), the non-selective VIP receptor antagonist [D-p-Cl-Phe(6),Leu(17)]-VIP and the selective VIP(1) receptor antagonist [Acetyl-His(1),D-Phe(2),Lys(15),Arg(16), Leu(17)]-VIP was investigated on the non-adrenergic fundic relaxation induced by manipulation of the small intestine followed by resection of the caecum. Guanethidine partly reduced the manipulation-induced fundic relaxation. Addition of L-NOARG reduced this non-adrenergic component, whereas the non-selective VIP receptor antagonist had no significant effect. Combination of L-NOARG and the non-selective VIP antagonist however further reduced the relaxation to manipulation. The selective VIP(1) receptor antagonist reduced the mean and maximal relaxation induced by abdominal surgery in the presence of guanethidine. When combined with L-NOARG, the relaxation of the gastric fundus was almost completely abolished. The VIP(1) receptor antagonist alone had no significant effect on the mean and maximal relaxation, but enhanced recovery of fundic tone. In conclusion, as VIP(1) receptors are not present in the rat gastric fundus, these results suggest that the NANC inhibitory pathway activated during abdominal surgery involves VIP(1) receptors, most likely in the afferent limb. The inhibitory neurotransmitters released at the level of the gastric fundus smooth muscle are NO and a substance different from VIP.

Neuroendocrine reactivity and recovery from work with different physical and mental demands.

OBJECTIVES: The purpose of this study was to examine the extent to which the type or nature (physical, mental or mixed mental and physical) of work and work characteristics is related to the course of neuroendocrine reactivity and recovery from work. METHODS: Neuroendocrine reactivity and recovery were studied by measuring the urinary excretion of adrenaline, noradrenaline, and cortisol during and after 3 workdays, 1 consecutive day off, and a baseline day. The assessment was made in 3 groups of Dutch male workers (N=60) who differed in the nature (mental, physical, and combined mental and physical demands) of their work. Multilevel analyses were performed to fit linear mixed-effects models for each hormone. RESULTS: Main or interaction effects with time of day were found between the workers in combined mental and physical work and the 2 other groups of workers for cortisol, adrenaline, and noradrenaline excretion. In addition, the baseline levels of the 3 hormones were higher in the workers with combined mental and physical work when compared with the other 2 groups. The excretion rates during the workdays were higher than those on the day off, but a trend towards mobilizing less activity was found from the 1st to the 3rd workday. Job demands were negatively related to cortisol excretion. Job control and social demands at work did not affect the excretion rates of the hormones. CONCLUSIONS: Unfavorable effects on cortisol and adrenaline reactivity or recovery was found for workers with combined mental and physical demands when compared with workers doing mainly mental or mainly physical work. The results of the present study are in accordance with the cognitive activation theory and the allostatic load model.

Assessing health impact of environmental pollution sources using space-time models.

We used disease mapping for health impact assessment of the national airport of the Netherlands. Spatio-temporal models were used to relate hospital discharge data for acute myocardial infarction and bronchitis in 1991, 1992 and 1993 to noise and distance from the airport. To compare models a discrepancy measure (expected predictive deviance) proposed by Carlin and Louis was used. The best fitting model was the most general one with inclusion of spatial and temporal components. Results on the effects of the covariates noise and distance from the airport were somewhat inconsistent between men and women and between the two diseases: for women no association between bronchitis and distance from the airport was found, whereas for men no association between acute myocardial infarction and noise was found.