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In this study, we tested the hypothesis that patients with early and continuously treated phenylketonuria (PKU) are selectively impaired in cognitive functions dependent on the prefrontal cortex (PFC) over a wide age range. Thirty-six patients with PKU between 8 and 20 years of age and 36 controls matched for age, sex, and educational level of both parents performed computerized versions of tests shown to be sensitive to PFC functions. To assess specificity, we selected within each test measures shown to be specifically impaired by PFC damage as well as measures not specifically impaired by damage to the PFC (control measures). A contrast sensitivity test was administered to obtain additional and independent evidence for the mechanism proposed to underlie the specific PFC deficits. Patients with early and continuously treated PKU demonstrated impairments on 3 of the 4 PFC measures but not on any of the control measures. Furthermore, they were found to be significantly less sensitive to contrast than were the matched controls. Together, these results seem to confirm that specific deficits in PFC functions persist in older patients with early and continuously treated PKU. The results with respect to the biochemical mechanism underlying these deficits were less clear. They do suggest, however, that some of the deficits may be ameliorated by stricter dietary treatment.

Objective - To investigate the role of stromelysin (MMP-3) activity in synovial fluid (SF) at different stages of development and in common joint disorders in the horse. Methods - Stromelysin activity was determined with a fluorogenic enzyme activity assay in SF of normal joints of fetal, juvenile and adult horses, and in SF of horses suffering from the developmental orthopaedic disease osteochondrosis (OC) or osteoarthritis (OA). Additionally, MMP-3 activity was expressed as a ratio of previously reported general MMP activity in the same SF samples. Results - The levels of active stromelysin were 30-fold to 80-fold higher in SF from fetal horses than in SF from juvenile and mature animals (p<0.001). Juvenile horses (5 and 11 months of age) showed a twofold to threefold higher stromelysin activity than adult horses (p<0.05). In OC joints, stromelysin activity was not significantly different from the activity in normal, age matched, control joints. In OA joints the activity was about four times higher than in normal joints (p<0.001). The ratio MMP-3 activity/general MMP activity did not change with age in normal, healthy joints. This ratio was more then twofold increased in OA joints compared with normal joints, indicating selective upregulation of gene expression or activation of proMMP-3, or both, in OA pathology. Conclusions - The significantly higher stromelysin activity in young individuals parallels the higher metabolic activity occurring at rapid growth and differentiation at early age. In OC, MMP-3 mediated matrix degradation appears to be not different from normal joints. The increased stromelysin activity in OA joints is in agreement with pathological matrix degradation. In these joints MMP-3 activity is selectively increased compared with normal joints.

The number of recently published papers on motion sickness may convey the impression that motion sickness is far from being understood. The current review focusses on a concept which tends to unify the different manifestations and theories of motion sickness. The paper highlights the relations between ergonomic principles to minimise motion sickness and the concept predictions. The clinical management of sufferers from motion sickness in terms of selection, pharmacological measures and desensitisation courses is treated as well.

On October 1, 1997, a 1 day hot-topic workshop on C-reactive protein (CRP) was organized in Leiden, the Netherlands, aiming at further evaluating the importance of inflammation as a critical mechanism in cardiovascular disease. C-reactive protein (CRP) is an acute phase protein that is associated with risk of cardiovascular events in healthy individuals and patients with angina pectoris. At the workshop, several investigators who are the pioneers in studies on CRP as a cardiovascular risk factor presented the latest data and their views on the topic. The discussions were designed to evaluate where we stand at present, and what should be done in the near future to promote evidence-based diagnostics and evidence-based intervention/ prevention strategies. The discussion focussed on the association between CRP and cardiovascular disease (CVD), a possible causal role of CRP in CVD, the effect of drugs on CRP levels, the role of infectious agents in the relation between CRP and CVD, and the measurement of low levels of CRP. Although many questions remained, the meeting resulted in a better insight into the role of CRP in cardiovascular disease and a basis for further studies in this area. © Harcourt Brace and Co. Ltd 1998.

Objective: To assess the link between enuresis nocturna and the severity of behavioural and/or emotional problems in Dutch children and the course of these problems. Setting: West-Mine Region in the Netherlands: Subjects and methods: Prospective cohort study involving 66 of the 80 bedwetting children from all 1652 children born in 1983 in this region. After 1 y, contact was still possible with 64 of the enuretics. We used the Dutch version of the Child Behaviour Checklist (CBCL) and a questionnaire about bedwetting. Results: The mean T-score for Total Problems (CBCL score) in 1992 (M1; mean age 8,6) was 52.1, and 1 y later was 49.2 (M2). There was no significant difference in the CBCL scores for M1, M2 and a matching group from the Dutch CBCL norm population, either in the group who remained wet or in the group who became dry. There were no differences between the sexes. There was no link between the severity of behavioural and emotional problems and the frequency of bedwetting. However, more children with bedwetting than expected were in the clinical range. Conclusion: There was no difference in behavioural and/or emotional problems between the first and the second measurement and the matching group from the CBCL norm group. There were no differences in behavioural and/or emotional problems between primary and secondary bedwetters, nor were there any consequences related to the frequency of bedwetting.

Dietary energy restriction may protect against cancer. In parts of the Netherlands, mostly in larger cities, periods of chronically impaired nutrition and even severe famine (Hunger Winter 1944-1945) existed during the 1930s and World War II (1940-1945). We studied the association between energy restriction during childhood and early adulthood on the risk of ovarian cancer later in life. In 1986, the Netherlands Cohort Study was initiated. A self-administered questionnaire on dietary habits and other cancer risk factors was completed by 62,573 women aged 55-69 years at baseline. Follow-up for cancer was established by record linkage to the Netherlands Cancer Registry. After 16.3 years of follow-up, 364 invasive epithelial ovarian cancer cases and 2220 subcohort members (sampled from the total cohort directly after baseline) with complete information confounders were available for case-cohort analyses. In multivariable analysis, ovarian cancer risk was lower for participants with an unemployed father during the 1930s (Hazard Ratio (HR), 0.70; 95% Confidence Interval (CI), 0.47-1.06) compared to participants with an employed father as well as for participants living in a city during World War II (HR, 0.69; 95% CI, 0.54-0.90) compared to participants living in the country-side. Residence in a Western City during the famine (Hunger Winter) was not associated with a decreased risk. Our results show a relation between proxy variables for modest energy restriction over a longer period of time during childhood or early adulthood and a reduced ovarian cancer risk. © 2011 Schouten et al.

Acrylamide, a potential human carcinogen, has been discovered in a variety of heat-treated carbohydrate-rich food products. Previously, dietary acrylamide intake was shown to be associated with endocrine-related cancers in humans. We assessed the association between dietary acrylamide intake and risk of postmenopausal breast cancer stratified by estrogen and progesterone receptor status. This study was embedded within the Netherlands Cohort Study on diet and cancer, which was initiated in 1986 enrolling 62,573 women aged 55-69 years at baseline. After 13.3 years of follow-up, 2225 incident breast cancer cases were ascertained, with hormone receptor status information for 43%. Cox proportional hazards analysis was applied to determine hazard ratios in quintiles of dietary acrylamide intake stratifying on estrogen receptor (ER) and progesterone receptor (PR) and smoking status. No association was observed for overall breast cancer or receptor-negative breast cancer risk, irrespective of smoking status. A statistically non-significantly increased risk of ER positive, PR positive and joint receptor-positive breast cancer was found in never-smoking women. The multivariable-adjusted hazard ratios were 1.31 (95% CI: 0.87-1.97, P _trend = 0.26) for ER+, 1.47 (0.86-2.51, P _trend = 0.14) for PR+, and 1.43 (0.83-2.46, P _trend = 0.16) for ER+PR+, when comparing women in the highest quintile of acrylamide intake (median 36.8 μg/day) to women in the lowest (median 9.5 μg/day). This study showed some indications of a positive association between dietary acrylamide intake and receptor-positive breast cancer risk in postmenopausal never-smoking women. Further studies are needed to confirm or refute our observations. © 2009 Springer Science+Business Media, LLC.

OBJECTIVE: The purpose of this study was to assess the relationship between road traffic noise exposure at home and the prevalence of hypertension. METHODS: We conducted cross-sectional analyses in a large random sample (N = 40,856) of inhabitants of Groningen City, and in a subsample (the Prevention of Renal and Vascular End-Stage Disease [PREVEND]) study cohort; N = 8592). RESULTS: Before adjustment for confounders, road traffic noise exposure was associated with self-reported use of antihypertensive medication in the city of Groningen sample (odds ratio [OR] = 1.31 per 10-dB increase in Lden). Adjusted odds ratios were significant for the subjects between 45 and 55 years old in the full model when adjusted for PM10 (OR = 1.19) and at higher exposure (Lden >55 dB) only (OR = 1.21; with adjustment for PM10, OR = 1.31). In the PREVEND cohort, the unadjusted odds ratio was 1.35 for hypertension (systolic and diastolic blood pressure >140 and >90 mm Hg, respectively, or use of antihypertensive medication). Again, the adjusted odds ratio was significant for subjects between 45 and 55 years old (OR = 1.27; with adjustment for PM10, OR = 1.39). CONCLUSIONS: Exposure to road traffic noise may be associated with hypertension in subjects who are between 45 and 55 years old. Associations seemed to be stronger at higher noise levels. ©2007The American College of Occupational and Environmental Medicine.

Background: Because of their influence on insulin concentrations, we hypothesized that both physical activity and energy restriction may reduce the risk of pancreatic cancer. Objective: We examined the associations between physical activity, proxies for energy restriction, and pancreatic cancer risk. Design: The Netherlands Cohort Study consisted of 120,852 individuals who completed a baseline questionnaire in 1986. After 13.3 y of follow-up, 408 cases were available for analysis. Self-reported information on physical activity was collected. Three indicators were used as proxies for energy restriction: father's employment status during the Economic Depression (1932-1940) and place of residence during the World War II years (1940-1944) and the Hunger winter (1944-1945). Results: For past sports activities, we observed a significantly decreased risk of pancreatic cancer (HR: 0.80; 95% CI: 0.64, 0.99). Proxies for energy restriction were not related to pancreatic cancer risk. When the results for energy restriction were stratified by height, a significant multiplicative interaction was observed for the Economic Depression period (P = 0.002). Shorter individuals (height less than the sex-specific median adult height) with an unemployed father during the Economic Depression period had a significantly lower cancer risk (HR: 0.31; 95% CI: 0.14, 0.66) than did taller individuals with an employed father. No significant interactions were observed for exposure to energy restriction during the World War II years and the Hunger winter. Conclusions: Our results suggest a modestly decreased risk of pancreatic cancer associated with past sports activity. With respect to proxies for energy restriction, our findings suggest that shorter individuals exposed to energy restriction during adolescence may have a reduced risk, whereas taller individuals may not. © 2011 American Society for Nutrition.

Insulin requirement affects the careers of diabetic professionals who do safety-sensitive jobs. In most cases, insulin-treated individuals are automatically banned from safety-sensitive jobs because the risk of hypoglycaemia is regarded as incompatible with safety. Recent developments—such as diabetes self-management education, self-monitoring of blood glucose, continuous glucose monitoring, and shortacting and longacting insulin analogues—enable better achievement of individual glycaemic target ...

Cisplatin (CDDP) is an extremely active drug in the treatment of germ- cell tumours. Earlier, we found an unexpected inverse correlation between the total amount of sulfhydryl groups and CDDP sensitivity in a panel of 3 human germ-cell tumour and 3 colon-carcinoma cell lines. Major components of the sulfhydryl groups are glutathione and metallothionein (MT). We further investigated a possible role of MT in the CDDP sensitivity of germ-cell tumours. MT levels and functionality of the germ-cell-tumour and colon- carcinoma cell lines were found to be inversely correlated with CDDP sensitivity. No difference in sub-cellular localization of MT could be observed among the types of cell lines. In agreement with the in vitro data, immunohistochemical detection of MT was high in 11/14 primary human germ- cell tumours and low in 7/7 human colon carcinomas. MT-protein expression in primary germ-cell tumours did not discriminate between responding and non- responding patients. As compared with the primary tumours, MT-protein expression decreased in 5/7 post-chemotherapy residual vital tumours or remained undetectable (2/7). MT-protein expression in the germ-cell tumours was not related to total p53-protein expression. In summary, over-expression of MT was found in germ-cell tumours, both in cell lines and in human tumours. Although MT-protein over-expression seems to be associated with the CDDP sensitivity of germ-cell tumours, MT-protein expression in primary germ-cell tumours did not differ between responding and non-responding patients and therefore cannot be used to predict response to chemotherapy. (C) 2000 Wiley-Liss, Inc.

Organo psycho syndrome (OPS) or chronic toxic encephalopathy (CTE) is a neurotoxic condition reported following long-term exposure to paints containing organic solvent and to other solvents. Lactate esters are finding wider use as solvents. Lactate esters have been well studied in standard toxicity tests, but specific neurotoxicity studies have not been conducted. No clinical signs of chronic neurotoxicity have been observed in standard toxicity tests. Lactate esters are rapidly hydrolyzed in the body to lactic acid and the corresponding alcohol. Alcohols have been reported to have acute neurotoxic effects, usually following high levels of ingestion. The literature on alcohols was reviewed to establish the no-observed-adverse-effect level (NOAEL) for acute neurotoxicity and to look for any evidence of chronic neurotoxicity from the alcohols produced by hydrolysis of the lactate esters. The NOAELs were compared with the potential amounts of alcohol produced by hydrolysis of different lactate esters at 200 mg/m3 (the NOAEL for most of the lactate esters). In all cases neither acute nor chronic neurotoxicity would be expected based on the amounts of alcohol produced by hydrolysis of the lactate esters at their NOAELs. L-Lactic acid is a normal metabolite in the body and is not considered neurotoxic. Based on this information there is no evidence to suggest that L-lactate esters can cause any chronic neurotoxicity, OPS, or CTE. © 2001 Academic Press.

Objectives: To assess the association between bullying behavior and a wide variety of psychosomatic health complaints and depression. Study design: In a cross-sectional study, 2766 elementary school children age 9 to 12 years filled out a questionnaire on bullying behavior and health complaints. Three groups - bullied children, active bullies, and children who both bully and are bullied - were compared with the group of children not involved in bullying behavior. Subsequently, risks for psychosomatic symptoms and depression were calculated by means of odds ratios. Results: Bully victims had significantly higher chances for depression and psychosomatic symptoms compared with children not involved in bullying behavior. Odds ratios were as follows: headache, 3.0; sleeping problems, 2.4; abdominal pain, 3.2; bedwetting, 2.9; feeling tired, 3.4; and depression, 7.7. Children who actively bullied did not have a higher chance for most of the investigated health symptoms. Conclusions: Being bullied is strongly associated with a wide range of psychosomatic symptoms and depression. These associations are similar to the complaints known to be associated with child abuse. Therefore, when such health complaints are presented, pediatricians and other health care workers should also be aware of the possibility that a child is being bullied to take preventive measures.

BACKGROUND AND PURPOSE: Psychosocial stress at work has been proposed to be a risk factor for cardiovascular disease. However, its role as a risk factor for stroke is uncertain. METHODS: We conducted an individual-participant-data meta-analysis of 196 380 males and females from 14 European cohort studies to investigate the association between job strain, a measure of work-related stress, and incident stroke. RESULTS: In 1.8 million person-years at risk (mean follow-up 9.2 years), 2023 first-time stroke events were recorded. The age- and sex-adjusted hazard ratio for job strain relative to no job strain was 1.24 (95% confidence interval, 1.05;1.47) for ischemic stroke, 1.01 (95% confidence interval, 0.75;1.36) for hemorrhagic stroke, and 1.09 (95% confidence interval, 0.94;1.26) for overall stroke. The association with ischemic stroke was robust to further adjustment for socioeconomic status. CONCLUSION: Job strain may be associated with an increased risk of ischemic stroke, but further research is needed to determine whether interventions targeting job strain would reduce stroke risk beyond existing preventive strategies.

Background: In the Netherlands, there is a very low incidence of sudden infant death syndrome (SIDS) due to effective preventive campaigns. Methods: During the period September 1996 to August 2002, nationwide 161 deaths from SIDS (about 85% of all cases of SIDS during that time) were investigated by the Cot Death Committee of the Dutch Paediatric Association. Results and Discussion: Over 10% of cases of SIDS took place during some type of child care. From a national survey carried out in 2000/01 information was available on the child care attendance of 2000 Dutch infants aged 3-6 months. Based on the hours usually spent in child care by these infants, the number of similarly aged infants that died from SIDS while attending child care was 4.2 times higher than expected. Remarkably, the prevalence of known risk factors for SIDS, such as sleeping position and parental smoking, was favourable in the SIDS cases in child care settings. The adherence of child care facilities to the safe sleeping recommendations is high in the Netherlands, and no explanation as to why child care settings may be associated with an increased risk of SIDS is apparent. The possibility of other explanations, such as stress and change in routine care, is hypothesised.

Context: Inconsistent findings from observational studies have continued the controversy over the effects of dietary fiber on colorectal cancer. Objective: To evaluate the association between dietary fiber intake and risk of colorectal cancer. Design, Setting, and Participants: From 13 prospective cohort studies included in the Pooling Project of Prospective Studies of Diet and Cancer, 725 628 men and women were followed up for 6 to 20 years across studies. Study- and sex-specific relative risks (RRs) were estimated with the Cox proportional hazards model and were subsequently pooled using a random-effects model. Main Outcome Measure: Incident colorectal cancer. Results: During 6 to 20 years of follow-up across studies, 8081 colorectal cancer cases were identified. For comparison of the highest vs lowest study- and sex-specific quintile of dietary fiber intake, a significant inverse association was found in the age-adjusted model (pooled RR=0.84; 95% confidence interval [CI], 0.77-0.92). However, the association was attenuated and no longer statistically significant after adjusting for other risk factors (pooled multivariate RR=0.94; 95% CI, 0.86-1.03). In categorical analyses compared with dietary fiber intake of 10 to <15 g/d, the pooled multivariate RR was 1.18 (95% CI, 1.05-1.31) for less than 10 g/d (11% of the overall study population); and RR, 1.00 (95% CI, 0.85-1.17) for 30 or more g/d. Fiber intake from cereals, fruits, and vegetables was not associated with risk of colorectal cancer. The pooled multivariate RRs comparing the highest vs lowest study- and sex-specific quintile of dietary fiber intake were 1.00 (95% CI, 0.90-1.11) for colon cancer and 0.85 (95% CI, 0.72-1.01) for rectal cancer (P for common effects by tumor site=.07). Conclusions: In this large pooled analysis, dietary fiber intake was inversely associated with risk of colorectal cancer in age-adjusted analyses. However, after accounting for other dietary risk factors, high dietary fiber intake was not associated with a reduced risk of colorectal cancer. ©2005 American Medical Association. All rights reserved.

Background: In the last decades, the incidence of oesophageal and gastric cardia adenocarcinoma has increased rapidly in the Western world. We investigated the association between body mass index (BMI), height and risk of oesophageal and gastric cardia adenocarcinoma. Methods: The Netherlands Cohort Study was initiated in 1986. All participants (n = 120 852), aged 55-69 years, completed a self administered questionnaire. Cases were identified through annual record linkage with the Netherlands Cancer Registry. After 13.3 years of follow-up, excluding the first follow-up year, complete data from 4552 subcohort members, 133 oesophageal and 163 gastric cardia adenocarcinomas were available for case-cohort analyses. Incidence rate ratios (RRs) and corresponding 95% confidence intervals were estimated using Cox proportional hazard models. Results: The RRs (95% CI) of oesophageal adenocarcinoma were 1.40 (0.95 to 2.04) and 3.96 (2.27 to 6.88) for overweight (BMI 25.0-29.9 kg/m2) and obese subjects (BMI ≥ 30.0 kg/m2), respectively, compared to subjects with normal weight (BMI 20.0-24.9 kg/m2). For gastric cardia adenocarcinoma, these RRs were 1.32 (0.94 to 1.85) and 2.73 (1.56 to 4.79). Also change in BMI during adulthood was positively associated with the risk of oesophageal and gastric cardia adenocarcinoma (p trend 0.001 and 0.02, respectively), while no association was found with BMI in early adulthood (p trend 0.17 and 0.17, respectively). None of the tumour types investigated was significantly associated with height. Conclusions: These results confirm higher risks of oesophageal and gastric cardia adenocarcinoma with increasing BMI. This implies that the increasing prevalence of obesity may be one of the explanations for the rising incidence of oesophageal and gastric cardia adenocarcinoma in the Western world.

Objective To determine possible patterns of synovitis on contrast-enhanced magnetic resonance imaging (CE-MRI) and its relation to pain and severity in patients with radiographic knee osteoarthritis (OA). Methods In total, 86 patients (mean age 62 years, 66% women, median body mass index 29 kg/m2) with symptomatic knee OA (Kellgren/Lawrence radiographic score 3) were included. T1-weighted, gadolinium-chelate-enhanced MRI with fat suppression was used to semiquantitatively score the extent of synovitis at 11 knee sites (total score range 0-22). Self-reported pain was assessed with 3 standardized questionnaires. Principal components analysis (PCA) was used to investigate patterns (the location and severity) of synovitis. Subsequently, these patterns were assessed for associations with pain measures and radiographic severity in adjusted logistic regression models. Results Synovitis was observed in 86 patients and was found to be generally mild on CE-MRI (median total synovitis score 7, range 0-16). The median pain scores were 53 (range 0-96) on the visual analog scale for pain, 51.4 (range 2.8-97.2) on the Knee Injury and Osteoarthritis Outcome Score (KOOS) for pain, 35 (range 0-75) on the Intermittent and Constant Osteoarthritis Pain (ICOAP) score for constant pain, and 40.6 (range 0-87.5) on the ICOAP score for intermittent pain. PCA resulted in extraction of 3 components, explaining 53.4% of the variance. Component 1 was characterized by synovitis at 7 sites (mainly medial parapatellar involvement) and was associated with scores on the KOOS pain subscale and the ICOAP constant pain subscale. Component 2 was characterized by synovitis at 4 sites (mainly the site adjacent to the anterior cruciate ligament), but was not associated with pain measures or with radiographic severity. Component 3, characterized by synovitis at 3 sites (mainly at the loose body site), was associated with radiographic severity. Conclusion Different patterns of synovitis in knee OA were observed. The pattern that included several patellar sites was associated with pain, whereas other patterns showed no association, suggesting that pain perception in patients with knee OA is a localized response. Copyright © 2015 by the American College of Rheumatology.