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STUDY OBJECTIVE AND DESIGN: In Aalsmeer, a horticultural community near the main international airport in The Netherlands, a more than fourfold increase in the incidence of haematopoietic malignancies in young people was observed between 1980 and 1985. In a population based case-control study, the association with local environmental factors was investigated. For each patient younger than 40 years of age (n = 14) diagnosed between 1975 and 1989, four age and sex matched controls were selected via local general practitioners. All parents of patients and controls completed a questionnaire on their lifestyle, living conditions, and health, for several years preceding each individual diagnosis. Odds ratios (ORs) with 95% confidence intervals (CI) were calculated, matched, and, if necessary, stratified for neighbourhood. Increased ORs were recorded for intensive use of petroleum products and pesticides by the patients themselves and their fathers: OR petroleum products: 8.0 (95% CI 2.2, 129.9) and 9.0 (1.0, 66.1) respectively; OR pesticides: 6.0 (0.6, 49.3) and 3.2 (1.0, 10.1) respectively. Swimming in a local pond was also significantly associated with the disease: OR = 5.3 (1.3, 17.4). In the 1970s this pond had been polluted by petroleum products and pesticides. The increased incidence of childhood haematopoietic malignancies in Aalsmeer may have been associated with several specific local environmental factors. Interpretation of the results, however, should take into account the fact that confidence intervals were wide because of the limited number of cases. [ABSTRACT FROM AUTHOR]

Background Cellular actions of advanced glycation end-products (AGE) are mediated by a receptor for AGE (RAGE), a novel integral membrane protein. Immunohistochemical studies show only low-level RAGE antigen expression in endothelial cells. Design It was the purpose of the study to compare expression of RAGE antigen by endothelial cells in non-diabetic uraemic patients (n=8) with non-uraemic controls (n=11). Samples of arterial tissue were obtained at the time of renal transplantation (in uraemic patients) and abdominal surgery (in controls). RAGE antigen was visualized using guinea-pig anti-RAGE IgG and PAP technique. Results Marked staining for RAGE was noted in endothelial cells, both arterial endothelium and endothelium of vasa vasorum of normoglycaemic uraemic patients, but was not demonstrable in endothelial cells of large arteries and only faintly expressed in vasa vasorum of non-uraemic individuals. Conclusion Normal endothelial cells do not constitually express RAGE antigen; in contrast it is expressed by arterial and capillary endothelial cells of uraemic patients. The observation is of note in view of the putative role of AGE of causing atherosclerotic and non-atherosclerotic vascular lesions. [ABSTRACT FROM PUBLISHER]

Abstract Background Previous research by the authors found evidence that up to 10% of particular household categories may be exposed to elevated carbon monoxide (CO) concentrations from poor quality gas appliance installations. The literature suggests certain neurological symptoms are linked to exposure to low levels of CO. This paper addresses the hypothesis that certain self-reported neurological symptoms experienced by a householder are linked to an estimate of their CO exposure. Methods Between 27 April and 27 June 2006, 597 homes with a mains supply of natural gas were surveyed, mainly in old, urban areas of London. Qualified gas engineers tested all gas appliances (cooker, boiler, gas fire, and water heater) and reported, according to the Gas Industry Unsafe Situations Procedure, appliances considered At Risk (AR), Immediately Dangerous (ID) or Not to Current Standards (NCS). Five exposure risk categories were defined based on measurement of CO emitted by the appliance, its features and its use, with "high or very high" exposure category where occupants were considered likely to be exposed to levels greater than 26 ppm for one hour. The prevalence of symptoms at each level of exposure was compared with that at lowest level of exposure. Results Of the households, 6% were assessed as having a "high or very high" risk of exposure to CO. Of the individuals, 9% reported at least one neurological symptom. There was a statistically significant association between "high or very high" exposure risk to CO and self-reported symptoms compared to "no exposure" likelihood, for households not in receipt of benefit, controlling for "number of residents" and presence of pensioners, OR = 3.23 (95%CI: 1.28, 8.15). Risk ratios across all categories of exposure likelihood indicate a dose-response pattern. Those households in receipt of benefit showed no dose-response pattern. Conclusion This study found an association between risk of CO exposure at low concentration, and prevalence of self-reported neurological symptoms in the community for those households not in receipt of benefit. As health status was self-reported, this association requires further investigation.

Background: Data-driven classification of long-term psychotic symptom trajectories and identification of associated risk factors could assist treatment planning and improve long-term outcomes in psychosis. However, few studies have used this approach, and knowledge about underlying mechanisms is limited. Here, we identify long-term psychotic symptom trajectories and investigate the role of illness-concurrent cannabis and stimulant use., Methods: 192 participants with first-episode psychosis were followed up after 10 years. Psychotic symptom trajectories were estimated using growth mixture modeling and tested for associations with baseline characteristics and cannabis and stimulant use during the follow-up (FU) period., Results: Four trajectories emerged: (1) Stable Psychotic Remission (54.2 %), (2) Delayed Psychotic Remission (15.6 %), (3) Psychotic Relapse (7.8 %), (4) Persistent Psychotic Symptoms (22.4 %). At baseline, all unfavorable trajectories (2-4) were characterized by more schizophrenia diagnoses, higher symptom severity, and longer duration of untreated psychosis. Compared to the Stable Psychotic Remission trajectory, unstable trajectories (2,3) showed distinct associations with cannabis/stimulant use during the FU-period, with dose-dependent effects for cannabis but not stimulants (Delayed Psychotic Remission: higher rates of frequent cannabis and stimulant use during the first 5 FU-years; Psychotic Relapse: higher rates of sporadic stimulant use throughout the entire FU-period). The Persistent Psychosis trajectory was less clearly linked to substance use during the FU-period., Conclusions: The risk for an adverse long-term course could be mitigated by treatment of substance use, where particular attention should be devoted to preventing the use of stimulants while the use reduction of cannabis may already yield positive effects., Competing Interests: Declaration of competing interest The authors have no conflicts of interest to disclose., (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)

Background: Early identification of treatment non-response in first-episode psychosis (FEP) is essential to outcome. Despite indications that exposure to childhood trauma (CT) can have adverse effects on illness severity, its impact on treatment non-response and the interplay with other pre-treatment characteristics is sparsely investigated. We use a lack of clinical recovery as an early indicator of treatment resistance to investigate the relationship between CT and treatment resistance status at one-year follow-up and the potential mediation of this effect by other pre-treatment characteristics., Methods: This prospective one-year follow-up study involved 141 participants recruited in their first year of treatment for a schizophrenia-spectrum disorder. We investigated clinical status, childhood trauma (CT), premorbid adjustment (PA), and duration of untreated psychosis (DUP) at baseline and clinical status at one-year follow-up. Ordinal regression analyses were conducted to investigate how PA and DUP affected the relationship between CT and one-year outcome in FEP., Results: 45 % of the FEP sample reported moderate to severe CT, with significantly higher levels of CT in the early treatment resistant group compared to participants with full or partial early recovery. Ordinal regression analysis showed that CT was a significant predictor of being in a more severe outcome group (OR = 4.59). There was a partial mediation effect of PA and a full mediation effect of DUP on the effect of CT on outcome group membership., Discussion: Our findings indicate that reducing treatment delays may mitigate the adverse effects of CT on clinical outcomes and support the inclusion of broad trauma assessment in FEP services., Competing Interests: Declaration of competing interest We hereby declare that we have no conflicts of interest or financial relationships to disclose. The funding bodies were not involved in the data analysis, writing, or submission of this manuscript for publication., (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)

Pulsed field ablation (PFA) is an emerging technology for the treatment of atrial fibrillation (AF), for which pre-clinical and early-stage clinical data are suggestive of some degree of preferentiality to myocardial tissue ablation without damage to adjacent structures. Here in the MANIFEST-17K study we assessed the safety of PFA by studying the post-approval use of this treatment modality. Of the 116 centers performing post-approval PFA with a pentaspline catheter, data were received from 106 centers (91.4% participation) regarding 17,642 patients undergoing PFA (mean age 64, 34.7% female, 57.8% paroxysmal AF and 35.2% persistent AF). No esophageal complications, pulmonary vein stenosis or persistent phrenic palsy was reported (transient palsy was reported in 0.06% of patients; 11 of 17,642). Major complications, reported for ~1% of patients (173 of 17,642), were pericardial tamponade (0.36%; 63 of 17,642) and vascular events (0.30%; 53 of 17,642). Stroke was rare (0.12%; 22 of 17,642) and death was even rarer (0.03%; 5 of 17,642). Unexpected complications of PFA were coronary arterial spasm in 0.14% of patients (25 of 17,642) and hemolysis-related acute renal failure necessitating hemodialysis in 0.03% of patients (5 of 17,642). Taken together, these data indicate that PFA demonstrates a favorable safety profile by avoiding much of the collateral damage seen with conventional thermal ablation. PFA has the potential to be transformative for the management of patients with AF., (© 2024. The Author(s).)

Visual hallucinations in psychosis are under-researched despite associations with increased illness severity, functional impairments, and suicidality in the few existing studies. Further, there are no long-term longitudinal studies, making it impossible to conclude if these associations are state or trait phenomena. In the current prospective longitudinal study, 184 individuals with first-episode psychosis were assessed with semi-structured clinical interviews and self-report questionnaires at baseline and 10-year follow-up. Participants were grouped based on lifetime experience of visual hallucinations: before or at baseline (VH+/+), first during follow-up (VH-/+), or never (VH-/-). Associations with functioning, suicide attempts, childhood trauma and other markers of illness severity were tested using multinomial logistic regression analysis. At baseline, the VH+/+ group (37.5%), but not VH-/+ (12.5%), had poorer functioning, higher symptom severity, a lower age at onset, and included more individuals with a history of multiple suicide attempts than the VH-/- group (50%). At follow-up, the VH-/+ group, but not VH+/+, had poorer functioning and higher symptom severity than the VH-/- group. However, the number of participants who committed multiple suicide attempts during the follow-up period was again significantly higher in the VH+/+ group. There was no association with childhood trauma. Hence, visual hallucinations are associated with impaired functioning and higher symptom severity, but only in the short-term. However, visual hallucinations that arise early in the course of illness are a risk indicator for repeated suicide attempts throughout the illness course. These findings highlight the relevance of assessing visual hallucinations and monitoring their development over time., (© 2024. The Author(s).)

Aberrant belief updating due to misestimation of uncertainty and an increased perception of the world as volatile (i.e., unstable) has been found in autism and psychotic disorders. Pupil dilation tracks events that warrant belief updating, likely reflecting the adjustment of neural gain. However, whether subclinical autistic or psychotic symptoms affect this adjustment and how they relate to learning in volatile environments remains to be unraveled. We investigated the relationship between behavioral and pupillometric markers of subjective volatility (i.e., experience of the world as unstable), autistic traits, and psychotic-like experiences in 52 neurotypical adults with a probabilistic reversal learning task. Computational modeling revealed that participants with higher psychotic-like experience scores overestimated volatility in low-volatile task periods. This was not the case for participants scoring high on autistic-like traits, who instead showed a diminished adaptation of choice-switching behavior in response to risk. Pupillometric data indicated that individuals with higher autistic- or psychotic-like trait and experience scores differentiated less between events that warrant belief updating and those that do not when volatility was high. These findings are in line with misestimation of uncertainty accounts of psychosis and autism spectrum disorders and indicate that aberrancies are already present at the subclinical level., (© 2023. The Author(s).)

Background: Pulmonary vein isolation (PVI) ablation is a standard therapy for paroxysmal atrial fibrillation (PAF). Lesion Index (LSI) is a metric to guide radiofrequency (RF) ablation using the TactiCath Ablation Catheter, Sensor Enabled with the EnSite Cardiac Mapping System (Abbott)., Objective: This study (NCT-03906461) was designed to capture best practices using LSI-guided catheter ablation to treat PAF subjects in a real-world setting., Methods: This prospective single-arm observational study enrolled 143 PAF subjects in the United States, Europe, and Japan undergoing de novo PVI with RF ablation. PVI lesions were assigned to 10 anatomically defined segments. Mean LSIs achieved for all lesions were analyzed. Follow-up was conducted between 3-6 months and 12 months after the procedure., Results: Pulmonary veins were isolated in all subjects. The mean achieved LSI was 4.9, with lower values in Europe (4.4) and Japan (4.5) than the United States (5.5). First-pass success, defined as no gaps requiring touch-up ablation after 20 minutes post isolation, was achieved in 76.2% of subjects. Use of high LSI (≥5) resulted in shorter procedure, RF, and fluoroscopy times and fewer touch-up ablations compared to low LSI (<5). At 12 months, 99.3% of subjects were free from procedure- or device-related serious adverse events and 95.7% (112/117) (35.0% on antiarrhythmic drugs) were free from recurrence and/or a repeat ablation procedure for atrial fibrillation / atrial flutter / atrial tachycardia., Conclusion: LSI-guided ablation strategies proved safe and effective despite differences in LSI workflows. Use of high LSI values resulted in shorter procedure, RF, and fluoroscopy times and fewer touch-up ablations compared to low LSI., (© 2022 Heart Rhythm Society. Published by Elsevier Inc.)

Aberrant attribution of salience to in fact little informative events might explain the emergence of positive symptoms in schizophrenia and has been linked to belief uncertainty. Uncertainty is thought to be encoded by neuromodulators, including norepinephrine. However, norepinephrinergic encoding of uncertainty, measured as task-related pupil dilation, has rarely been explored in schizophrenia. Here, we addressed this question by comparing individuals with a disorder from the schizophrenia spectrum to a non-psychiatric control group on behavioral and pupillometric measures in a probabilistic prediction task, where different levels of uncertainty were introduced. Behaviorally, patients performed similar to controls, but their belief uncertainty was higher, particularly when instability of the task environment was high, suggesting an increased sensitivity to this instability. Furthermore, while pupil dilation scaled positively with uncertainty, this was less the case for patients, suggesting aberrant neuromodulatory regulation of neural gain, which may hinder the reduction of uncertainty in the long run. Together, the findings point to abnormal uncertainty processing and norepinephrinergic signaling in schizophrenia, potentially informing future development of both psychopharmacological therapies and psychotherapeutic approaches that deal with the processing of uncertain information., (Copyright © 2021 The Authors. Published by Elsevier B.V. All rights reserved.)

Background and Objectives: A plethora of studies has investigated and compared social cognition in autism and schizophrenia ever since both conditions were first described in conjunction more than a century ago. Recent computational theories have proposed similar mechanistic explanations for various symptoms beyond social cognition. They are grounded in the idea of a general misestimation of uncertainty but so far, almost no studies have directly compared both conditions regarding uncertainty processing. The current study aimed to do so with a particular focus on estimation of volatility, i.e. the probability for the environment to change., Methods: A probabilistic decision-making task and a visual working (meta-)memory task were administered to a sample of 86 participants (19 with a diagnosis of high-functioning autism, 21 with a diagnosis of schizophrenia, and 46 neurotypically developing individuals)., Results: While persons with schizophrenia showed lower visual working memory accuracy than neurotypical individuals, no significant group differences were found for metamemory or any of the probabilistic decision-making task variables. Nevertheless, exploratory analyses suggest that there may be an overestimation of volatility in subgroups of participants with autism and schizophrenia. Correlations revealed relationships between different variables reflecting (mis)estimation of uncertainty, visual working memory accuracy and metamemory., Limitations: Limitations include the comparably small sample sizes of the autism and the schizophrenia group as well as the lack of cognitive ability and clinical symptom measures., Conclusions: The results of the current study provide partial support for the notion of a general uncertainty misestimation account of autism and schizophrenia., Competing Interests: The authors have declared that no competing interests exist.

Background and Objective: Goal-directed behavior is a central feature of human functioning. It requires goal appraisal and implicit cost-benefit analyses, i.e., how much effort to invest in the pursuit of a certain goal, against its value and a confidence judgment regarding the chance of attainment. Persons with severe mental illness such as psychosis often struggle with reaching goals. Cognitive deficits, positive symptoms restricting balanced judgment, and negative symptoms such as anhedonia and avolition may compromise goal attainment. The objective of this study was to investigate to what degree symptom severity is related to cognitive abilities, metacognition, and effort-based decision-making in a visual search task., Methods: Two studies were conducted: study 1: N = 52 (healthy controls), and study 2: N = 46 (23 patients with psychosis/23 matched healthy controls). Symptoms were measured by the CAPE-42 (study 1) and the PANSS (study 2). By using a visual search task, we concomitantly measured (a) accuracy in short-term memory, (b) perceived accuracy by participants making a capture area or confidence interval, and (c) effort by measuring how long one searched for the target. Perseverance was assessed in trials in which the target was omitted and search had to be abandoned., Results: Higher levels of positive symptoms, and having a diagnosis of psychosis, were associated with larger errors in memory. Participants adjusted both their capture area and their search investment to the error of their memory. Perseverance was associated with negative symptoms in study 1 but not in study 2., Conclusion: By simultaneously assessing error and confidence in one's memory, as well as effort in search, we found that memory was affected by positive, not negative, symptoms in healthy controls, and was reduced in patients with psychosis. However, impaired memory did not concur with overconfidence or less effort in search, i.e., goal directed behavior was unrelated to symptoms or diagnosis. Metacognition and motivation were neither affected by cognitive abilities nor by negative symptoms. Clinically, this could indicate that struggles with goal directed behavior in psychosis may not solely be dependent on primary illness factors., (Copyright © 2020 Hegelstad, Kreis, Tjelmeland and Pfuhl.)

Background and Objectives: Performance on cognitive tasks is often impaired in individuals with schizophrenia (SCZ), possibly resulting from either cognitive deficits (e.g., limited working memory capacity) or diminished mental effort or both. Investment of mental effort itself can be affected by cognitive resources, task load, and motivational factors and has thus proven difficult to measure. Pupil dilation during task performance has been proposed as an objective measure, but it remains unclear to what extent this converges with self-reports of perceived task demands, motivation, and invested effort. The current study tried to elucidate this question., Methods: A visual version of the digit span task was administered in a sample of 29 individuals with a diagnosis from the SCZ spectrum and 30 individuals without any psychiatric disorder. Pupil size was recorded during the task, whereas self-reported invested effort and task demand were measured afterward., Results: No group difference was found for working memory capacity, but individuals with SCZ showed diminished trial-by-trial recall accuracy, showed reduced pupil dilation across all task load conditions, and reported higher perceived task demands., Conclusion: Results indicate reduced effort investment in patients with SCZ, but it remains unclear to what extent this alone could explain the lower recall performance. The lack of a direct link between objective and subjective measures of effort further suggests that both may assess different facets of effort. This has important implications for clinical and research settings that rely on the reliability of neuropsychological test results when assessing cognitive capacity in this patient group., (Copyright © 2020 Kreis, Moritz and Pfuhl.)

Background: Severe acute pancreatitis is a common diagnosis in emergency general surgery and can be a cause of significant morbidity and mortality. A consequence of severe acute pancreatitis is thrombus in the splanchnic veins. These thrombi can potentially lead to bowel ischemia or hepatic failure. However, another complication of severe acute pancreatitis is retroperitoneal bleeding. At this time, it is unclear if treating patients for splanchnic vein thrombosis in the context of severe acute pancreatitis is associated with any outcome benefit. A systematic review might clarify this question., Data Sources: A two-fold search strategy (one broad and one precise) looked at all published literature. The review was registered on PROSPERO (ID: CRD42018102705). MEDLINE, EMBASE, PubMed, Cochrane and Web of Science databases were searched and potentially relevant papers were reviewed independently by two researchers. Any disagreement was reviewed by a third independent researcher. Primary outcome was reestablishment of flow in the thrombosed vein versus bleeding complications., Results: Of 1462 papers assessed, a total of 16 papers were eligible for inclusion. There were no randomized controlled trials, 2 were case series, 5 retrospective single-center studies and 9 case reports. There were a total of 198 patients in these studies of whom 92 (46.5%) received anticoagulation therapy. The rates of recanalization of veins in the treated and non-treated groups was 14% and 11% and bleeding complications were 16% and 5%, respectively. However, the included studies were too heterogeneous to undertake a meta-analysis., Conclusions: The systematic review highlights the lack evidence addressing this clinical question. Therefore a randomized controlled trial would be appropriate to undertake., (Copyright © 2020 First Affiliated Hospital, Zhejiang University School of Medicine in China. Published by Elsevier B.V. All rights reserved.)

Background: Oral antiseptics reduce nosocomial infections and ventilator-associated pneumonia in critically ill medical and surgical patients intubated for prolonged periods. However, the role of oral antiseptics given before and after planned surgery is not clear. The aim of this systematic review and meta-analysis is to determine the effect of oral antiseptics (chlorhexidine or povidone-iodine) when administered before and after major elective surgery., Methods: Searches were conducted of the MEDLINE, EMBASE and Cochrane databases. The analysis was performed using the random-effects method and the risk ratio (RR) with 95 % confidence interval (CI)., Results: Of 1114 unique identified articles, perioperative chlorhexidine was administered to patients undergoing elective surgery in four studies. This identified 2265 patients undergoing elective cardiac surgery, of whom 1093 (48.3 %) received perioperative chlorhexidine. Postoperative pneumonia and nosocomial infections were observed in 5.3 and 20.2 % who received chlorhexidine compared to 10.4 and 31.3 % who received a control preparation, respectively. Oral perioperative chlorhexidine significantly reduced the risk of postoperative pneumonia (RR = 0.52; 95 % CI 0.39-0.71; p < 0.01) and overall nosocomial infections (RR = 0.65; 95 % CI 0.52-0.81; p < 0.01), with no effect on in-hospital mortality (RR = 1.01; 95 % CI 0.49-2.09; p = 0.98)., Conclusions: Perioperative oral chlorhexidine significantly decreases the incidence of nosocomial infection and postoperative pneumonia in patients undergoing elective cardiac surgery. There are no randomised controlled studies of this simple and cheap intervention in patients undergoing elective non-cardiac surgery., Trial Registration: This systematic review was registered with the International prospective register of systematic reviews (PROSPERO). The registration number is CRD42015016063.

Perfluorooctane sulphonate (PFOS) is a persistent organic pollutant that is toxic, bioaccumulative and undergoes wide transportation across all environmental media. It has been widely detected in environmental samples but there is limited information about the health effects on humans from environmental exposure. This paper presents the findings of a review of the literature on the impact of PFOS on the health of the general population. Fifteen relevant epidemiological studies were identified that looked at the association between human PFOS exposure and a range of health related outcomes. Small but statistically significant associations have been reported with PFOS and total cholesterol, glucose metabolism, body mass index (BMI), thyroid function, infertility, breast feeding, uric acid and attention deficit/hyperactivity disorder (ADHD). The true significance of these findings is uncertain due to the inconsistencies in some of the study results and the limitations of the literature. The majority of studies were cross-sectional and considered surrogate markers of health (e.g. cholesterol levels). The available literature is also limited in ascertaining the link between PFOS concentrations in the environment, exposure pathways and health effects. We conclude that the current evidence is inconclusive and further large-scale prospective cohort studies would be useful to assess the association between environmental exposure to PFOS, appropriate biomarkers (e.g. serum levels of PFOS) and health outcomes.

This study aims to describe the epidemiology of unintentional non-fire related CO fatalities in the UK and to relate this information to sources of CO. Data from the CO-Gas Safety Society (COGSS) database was analysed and compared with data from the English House Condition Survey (EHCS). There were 462 deaths from the COGSS database, from 1 January 1996 to 31 December 2007 inclusive. The relative risk for death due to non-gas vs gas fuels was 10.52 (95% CI 7.71-14.34). The main weakness of the study is the likely underascertainment of CO deaths in the database. However, this study has identified specific risk factors for CO-related deaths in the UK; the use of non-gas fuels has not previously been highlighted as a significant cause of CO poisoning, and the relative risk (although not the absolute risk) of CO-related fatalities from these fuels is substantial.

Background: Previous research by the authors found evidence that up to 10% of particular household categories may be exposed to elevated carbon monoxide (CO) concentrations from poor quality gas appliance installations. The literature suggests certain neurological symptoms are linked to exposure to low levels of CO. This paper addresses the hypothesis that certain self-reported neurological symptoms experienced by a householder are linked to an estimate of their CO exposure., Methods: Between 27 April and 27 June 2006, 597 homes with a mains supply of natural gas were surveyed, mainly in old, urban areas of London. Qualified gas engineers tested all gas appliances (cooker, boiler, gas fire, and water heater) and reported, according to the Gas Industry Unsafe Situations Procedure, appliances considered At Risk (AR), Immediately Dangerous (ID) or Not to Current Standards (NCS). Five exposure risk categories were defined based on measurement of CO emitted by the appliance, its features and its use, with "high or very high" exposure category where occupants were considered likely to be exposed to levels greater than 26 ppm for one hour. The prevalence of symptoms at each level of exposure was compared with that at lowest level of exposure., Results: Of the households, 6% were assessed as having a "high or very high" risk of exposure to CO. Of the individuals, 9% reported at least one neurological symptom. There was a statistically significant association between "high or very high" exposure risk to CO and self-reported symptoms compared to "no exposure" likelihood, for households not in receipt of benefit, controlling for "number of residents" and presence of pensioners, OR = 3.23 (95%CI: 1.28, 8.15). Risk ratios across all categories of exposure likelihood indicate a dose-response pattern. Those households in receipt of benefit showed no dose-response pattern., Conclusion: This study found an association between risk of CO exposure at low concentration, and prevalence of self-reported neurological symptoms in the community for those households not in receipt of benefit. As health status was self-reported, this association requires further investigation.

Factor VIIa/tissue factor (FVIIa/TF) interaction has been reported to induce intracellular signalling in cells constitutively expressing TF, independently of downstream activation of the coagulation cascade. It is unknown, however, whether binding of FVII to its cofactor TF alters the gene expression profile in cells which inducible express TF under inflammatory conditions. To address this issue, gene expression patterns in cultured LPS-stimulated monocyte-derived macrophages with or without exposure to FVIIa were compared by cDNA macro-array analysis. Of the 1176 genes examined on the array, a small set of six genes (IL-6, IL-8,TNF-a, GRO-beta alpha-thymosin, cathepsin H) were consistently up-regulated and one gene suppressed (alpha-antitrypsin) in response to FVIIa in activated monocyte-derived macrophages. Among the seven genes identified by array analysis, five genes were finally confirmed by real-time RT-PCR. Interestingly, all of these genes differentially regulated in response to FVIIa (GRO-beta, IL-6, IL-8, TNF-alpha and alpha-antitrypsin) are critical in inflammation. The changes in gene expression were reflected by corresponding changes in the protein concentrations of IL-6 and IL-8 as demonstrated by ELISA. Active site-inhibited FVIIa had no effect on gene expression indicating that FVIIa-induced gene alteration is dependent on the proteolytic activity of FVIIa. The FVIIa-induced alterations in gene expression were found to be TF-dependent but independent of downstream coagulation proteins like thrombin and FXa. In summary, this study demonstrates that binding of FVIIa to its cofactor TF enhances restricted pro-inflammatory genes in activated monocyte-derived macrophages. By up-regulation of chemokines critical for leukocyte recruitment, FVIIa/TF interaction on activated monocyte-derived macrophages could be relevant to prepare monocytes/macrophages for extravasation and may represent a novel amplification loop of leukocyte recruitment.

Objectives: To investigate a cluster of leukaemia among young people and assess the plausibility of a disease-exposure relationship., Design: Descriptive analysis of population-based leukaemia incidence data, review of evidence related to the causation of leukaemia, assessment of environmental exposures to known leukaemogens, and resulting risks of leukaemia., Setting: Illawarra region of New South Wales, Australia, focusing on suburbs between the Port Kembla industrial complex and Lake Illawarra (the Warrawong area)., Main Outcome Measures: Standardised incidence ratios (SIRs) for leukaemia; current measured and past estimated ambient air benzene concentrations; and expected leukaemia cases attributable to estimates of ambient air benzene concentrations., Results: In 1989-1996, 12 leukaemia cases among Warrawong residents aged less than 50 years were observed, more than the 3.49 cases expected from the rate in the rest of the Illawarra region (SIR, 343.8; 99% CI, 141.6-691.7). These people lived in suburbs immediately to the south-southwest of a coke byproducts plant (a major industrial source of benzene, one of the few known leukaemogens). The greatest excess was among 15-24-year-olds (SIR, 1085.6; 99% CI, 234.1-3072.4). In 1996, ambient air concentrations of benzene averaged less than 1 part per billion (ppb). Since 1970, ambient air concentrations of benzene were estimated to have averaged up to 3 ppb, about one-thousandth of the level at which leukaemia risk has been identified in occupational epidemiological studies. Using the risk assessment model developed by the US Environmental Protection Agency, we estimate that past benzene levels in the Warrawong area could have resulted in 0.4 additional cases of leukaemia in 1989-1996., Conclusions: The excess occurrence of leukaemia in the Warrawong area in 1989-1996 is highly unusual. Current environmental benzene exposure and the reconstructed past environmental benzene exposure level are too low to explain the large excess of leukaemia. The cause of the cluster is uncertain.

Background: The deposition of protein Z was investigated in atherosclerotic vascular lesions of patients with diabetes mellitus or atherosclerotic vascular disease without diabetes in comparison to controls., Patients and Methods: Protein Z antigen was evidenced by immunohistochemistry in arteries of 5 healthy control patients, 11 diabetic patients with arterio-occlusive disease and 7 patients suffering from arterio-occlusive disease without diabetes. For immunohistochemistry, a commercially available antibody was taken as first antibody, and immunopositivity was evaluated independently by two investigators (J.G.; I.K.) as negative (0), positive (+) and strongly positive (++). The results were assessed by the Whitney-Mann-Wilcoxon test., Results: Macrovascular endothelial cells were stained positive for protein Z in all arteries studied. Arteries of controls did not show significant immunopositivity in cells other than macrovascular endothelial cells, while the microvascular endothelial cells of control arteries were largely negative. The proliferating subendothelial space in atherosclerotic vascular lesions showed significant immunopositivity for protein Z. In contrast to control arteries, the microvascular endothelial cells of the proliferating areas stained positive. The staining pattern of the subendothelial space was similar in atherosclerotic vessels independent of the risk factor for atherosclerosis. Plaques were immunopositive for protein Z, too., Conclusions: Protein Z is present in atherosclerotic vascular lesions of diabetic and non-diabetic patients, but not in the subendothelial space and microvascular endothelial cells of healthy controls. Since protein Z-positivity was detected in microvascular endothelium as well as in extra-vascular deposits around plaques, it may play a role in the development of these lesions.

Resistance to activated protein C [1,2,3,4,5,6] is the most frequent hereditary cause of thromboses and is widespread through-out the population. Women with APC resistance have an enhanced risk of thrombosis compared to the total population. The risk increase, with the intake of oral contraceptives.

The Dutch part of Kempenland has been exposed to cadmium pollution since the last century. Experimental data suggest effects by cadmium on reproduction such as diminished fertility, decreased foetal growth, and specific malformations. Use was made of a historical cohort of dairy cows, ascertained from a surveillance program conducted by the regional Veterinary Health Service between 1976 and 1986. Ten dairy farms in the cadmium region were matched by size with 40 dairy farms from a reference area. Logistic models were used to calculate Odds (OR) and Rate Ratios (RR) and their 95% confidence interval. In total 4,039 exposed and 15,552 reference gestations were compared. The reasons for the slaughter of 574 exposed and of 2,824 reference cows were ascertained. A lower twinning rate [OR = 0.63 (0.47-0.84)] was found and more birth complications, for both calves [OR = 1.50 (1.25-1.80)] and cows [OR = 1.49 (1.24-1.79)]. More inseminations [OR = 1.20 (1.01-1.43)] were needed for conception in the exposed area. Deaths among twins [OR = 1.66 (0.90-3.07)] were not significantly higher. Perinatal death, premature death, age at, or reasons for, slaughter were not consistently different. These results are consistent with those of other observational and experimental studies. Extrapolation from these large domestic animals to humans is problematic, as is the more frequent extrapolation from rodents to humans. It can be concluded that longterm exposure to low levels of cadmium is associated with impaired reproduction in dairy cows.

In Aalsmeer, a horticultural community near the main international airport in the Netherlands, an incidence of haematopoietic malignancies in young people over four times the national mean was observed in the period 1980-1985. A population based case-control study investigated the association with local environmental factors. For each case younger than 40 years of age (n = 14), diagnosed between 1975 and 1989, four controls, matched for age and gender, were selected via local general practitioners. All parents of patients and controls completed a questionnaire on their life style, living conditions and health for several years preceding each individual diagnosis. Odds ratios (ORs) were calculated, matched and--if necessary--stratified for neighbourhood. Increased ORs were recorded for intensive use of petroleum products and pesticides, by the patients themselves and their fathers (OR petroleum products: 8.0, resp. 9.0; OR pesticides: 6.0, resp. 3.2). Most of these increases were statistically significant. Swimming in a local pond was also significantly associated with the disease (OR = 5.3); in the seventies this pond had been polluted by accidents with petroleum products and pesticides. contributed to the increase of the disease: ORs for several indirect exposure parameters were all above 2. It can be concluded that the increased incidence of childhood haematopoietic malignancies in Aalsmeer may have been associated with several specific local environmental factors. However, interpretation of the results should take into account that confidence intervals were wide, due to the necessarily limited number of cases.

Research in 1984 indicated that the cadmium body burden was higher in a village where the soil is contaminated with cadmium (Luyksgestel) than in a control village (Zeeland). The distribution of kidney function parameters also differed between the two villages. The aim of this study is to estimate the lifetime accumulated cadmium intake from food for the people from both villages. Various data sets describing dietary patterns in the Netherlands were used. The assessed average lifetime accumulated cadmium intake from food by the study subjects (aged 30-69 years) was 435 mg (+/- 131 mg) in Luyksgestel and 394 (+/- 113 mg) in Zeeland. The estimated lifetime accumulated cadmium intake for a hypothetical allotment gardener of 55 years was 520 mg from vegetables grown on uncontaminated soil, and 655 mg for lifelong consumption of vegetables from contaminated soil. The Luyksgestel subjects' estimated cadmium intake from food was well below the provisional tolerable weekly intake as proposed by the WHO, of 400-500 micrograms or 1124-1404 mg for the lifelong intake by a 55-year-old man.

Patterns in the occurrence of influenza-like symptoms after increases in ambient sulphur dioxide (SO2) concentrations, have been investigated. Three routinely collected sets of data were used: (a) air pollution, including SO2, as measured continuously by the National Air Monitoring System; (b) ambient outdoor air temperature as measured hourly by the Royal Dutch Meteorological Institute and (c) weekly influenza incidence as monitored by the Dutch Sentinel Practice Network. The region investigated has been confined to the three western provinces of the Netherlands. The data were expressed as weekly average values. To correct for autocorrelation the 'Box-Jenkins approach' to model time series was used. After correction for seasonal patterns and a log transformation the ARMA (autoregressive and moving average) models were identified. The relation between the time series has been assessed by a transfer function model. After correction for temperature and with a delay of two weeks, a significant association could be ascertained between the hourly SO2 concentration and influenza incidence. An association between lower temperature and increased influenza incidence one week later was established as well. A relation of air pollution and influenza with a delay of about two weeks is quite possible. However, 12 years may have been too short a period to correct for secular patterns and SO2 was probably only an indicator of air pollution. Further investigation seems warranted.

The border region between Belgium and The Netherlands, the Kempen, was found to be polluted with cadmium. The main route of pollution had been by air but some cadmium came by way of surface-water and solid waste. This resulted in an increase in the cadmium content of locally grown vegetables. The consequential exposure to cadmium of humans living in the area has been estimated using various methods and is approximately the FAO/WHO maximum allowable daily intake, smoking disregarded. Several studies of possible effects on public health were conducted. Among these studies were two geographic studies, one on hospital admissions for various non-malignant diseases and one on cancer-incidence. Two cohort studies on possible teratogenic effects in a non-occupationally exposed, non-smoking vegetarian population with a high fertility and good registration were also conducted. A survey on cadmium content of the urine and kidney damage in a longtime but non-occupationally exposed rural population and a reference population formed the main study. Also, a survey on cadmium content of the kidney samples of autopsied patients in a population based study and a reference population was conducted. Together these studies showed that the extra exposure had lead to an additional body-burden of cadmium resulting in various signs of malfunction. In consequence of the findings the Netherlands Ministry for Housing, Physical Planning and Environment appropriated money to cleanup contaminated gardens.