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Purpose. It is assumed that osteosarcomas of the jaws mainly occur at older ages, whereas the most prominent sites, that is, the long bones, are more affected at ages <20. Jaw-localized tumors are less malignant and have lower metastatic spread rates. Patients and Methods. This study analyses the nationwide data of the Dutch Cancer Registry on osteosarcoma during the period from 1991 to 2010. Age-corrected incidence rates were calculated. Results. In 949, 38 patients had tumors in the maxilla and in 58 in the mandible. Median age for maxilla, mandible, and other localizations was 45.5,49, and 23 years, respectively. Age-corrected incidence for osteosarcomas increased after a steep decline for the age cohorts from 20 to 60 years to nearly the same level as the younger patients. The incidence for maxillary lesions showed a steady increase from 0.46 to 1.60 per million over all age ranges; the highest incidence for mandibular lesions was found in the age cohort from 60 to 79 years. In respect to histology, no shifts for age were found, except for Paget's disease-related osteosarcoma. In older patients, chemotherapy was omitted more often. Overall survival was similar for all age groups, except for extragnatic tumor patients in the age range of 60-79 years. Conclusions. Osteosarcomas have comparable incidences below the age of 20 as compared with ages >60 years. Poorer outcome in older people is likely due to refraining from chemotherapy. [ABSTRACT FROM AUTHOR]

The quality of drinking water in the Netherlands has to comply with the Dutch Drinking Water Directive: less than one infection in 10,000 persons per year may occur due to consumption of unboiled drinking water. Since virus concentrations in drinking waters may be below the detection limit but entail a public health risk, the infection risk from drinking water consumption requires the assessment of the virus concentrations in source waters and of the removal efficiency of treatment processes. In this study, samples of source waters were taken during 4 years of regular sampling (1999 to 2002), and enteroviruses, reoviruses, somatic phages, and F-specific phages were detected in 75% (range, 0.0033 to 5.2 PFU/liter), 83% (0.0030 to 5.9 PFU/liter), 100% (1.1 to 114,156 PFU/liter), and 97% (0.12 to 14,403 PFU/liter), respectively, of 75 tested source water samples originating from 10 locations for drinking water production. By endpoint dilution reverse transcription-PCR (RT-PCR), 45% of the tested source water samples were positive for norovirus RNA (0.22 to 177 PCR- detectable units [PDU]/liter), and 48% were positive for rotavirus RNA (0.65 to 2,249 PDU/liter). Multiple viruses were regularly detected in the source water samples. A significant correlation between the concentrations of the two phages and those of the enteroviruses could be demonstrated. The virus concentrations varied greatly between 10 tested locations, and a seasonal effect was observed. Peak concentrations of pathogenic viruses occur in source waters used for drinking water production. If seasonal and short-term fluctuations coincide with less efficient or failing treatment, an unacceptable public health risk from exposure to this drinking water may occur. [ABSTRACT FROM AUTHOR]

The use of roof-collected rainwater as a freely available and sustainable alternative to drinking water produced by drinking water companies increases worldwide. Initially, rainwater is free of microbial contamination, but it may become contaminated by animals and humans or, alternatively, human pathogens may grow in stored rainwater resulting in a significant human health risk from infectious diseases. This three-year study demonstrated that rainwater stored in different reservoirs in The Netherlands was frequently faecally contaminated and incidentally contained potential human pathogens such as Campylobacter, Cryptosporidium, Giardia, Aeromonas hydrophila and Legionella. Analysis of samples during a period with variable weather conditions showed a correlation between rainfall intensity and faecal indicator counts and increased detection of pathogens after heavy rainfall incidents. Outside temperature had a limited effect on both the temperature and the microbiological quality of the water in the reservoirs, which did not comply with Dutch drinking water legislation and should thus not be consumed without treatment. In general, a health risk may arise from exposure to pathogens when contaminated droplets are inhaled, ingested or come into contact with the skin. Health risks may be reduced by regular cleaning of the collection, storage and transport means, but to assess their efficacy field intervention studies are required. [ABSTRACT FROM AUTHOR]

In 1995, AAFACT®, a new monoclonal purified factor VIII concentrate (FVIII), derived from human plasma, was introduced in the Netherlands. The monoclonal purification based production process includes a viral inactivation step by solvent/detergent treatment. Products manufactured according to this procedure, for example Hemofil M® are used worldwide. The aim of the present study was to assess inhibitor development in a large cohort of previously treated patients (PTPs) who were followed up for 10 years. In addition, efficacy, HIV and hepatitis C virus (HCV) transmission, and allergic reactions were monitored. All 165 patients with severe haemophilia A (FVIII < 1%) known at the van Creveldkliniek who ever used AAFACT® during the period from October 1995 to September 2005 were included. Two of them were previously untreated patients (PUPs) and two others had <50 exposure days. Data on FVIII consumption, number of exposures, bleedings and hospitalization days were collected from start of AAFACT® until last clinical and laboratory evaluation while on this product. At the end of follow-up, 91 patients were still using this plasma-derived FVIII. Median age at start of follow-up was 26 years (range 1–52). None of the patients reported lack of efficacy. Median FVIII consumption per patient during follow-up was 2058 IU kg−1 bodyweight per year, and median number of exposures was 148 per year. During 1029 patient-years of follow-up, one inhibitor was diagnosed in a previously treated patient PTP. This patient developed high titre inhibitor following surgery for which he, during 1 week, had been treated with continuous infusion with recombinant FVIII. No inhibitor occurred during 68 cases of surgery using continuous infusion with AAFACT®. No viral transmissions or other adverse events occurred during 10 years of follow-up; AAFACT® appeared to be an effective and safe FVIII product. [ABSTRACT FROM AUTHOR]

Summary. AAFACT® , a monoclonal purified, solvent/detergent treated human plasma-derived coagulation factor VIII concentrate obtained from plasma of voluntary, non-remunerated blood donors, is manufactured and marketed in the Netherlands by Sanquin Plasma Products since 1995. In a postmarketing surveillance study, 70 previously treated haemophilia A patients were included (73% severe, 14% moderate and 13% mild haemophilia A). Most of these patients were followed during 4 years for the appearance of adverse events, possible transmissions of blood-borne viruses and the occurrence of antibodies against FVIII. The efficacy of treatment was determined in each patient by the in vivo recovery of FVIII. During this study, only six adverse events, possibly related to the use of AAFACT® , were reported. None of these were indicated as serious. Transmissions of HIV, HAV, HBV and HCV in the seronegative patients have not been observed. In none of the patients, inhibitors to FVIII were detected. The in vivo recovery of FVIII during this study was not different from the in vivo recovery observed in eight patients during the preregistration study. There was a correlation of in vivo recovery with age and body weight. From these results, we conclude that the clinical usage of this human plasma-derived FVIII product is efficient and safe. [ABSTRACT FROM AUTHOR]

The demand for patient information in modern medical care is increasing and sound information for patients is becoming a necessity. For haemophilia patients, information about their disease and its complications is already widely available. In order to increase the organization of this information, a ‘Patient Information Dossier’ (PID) and communication check lists were developed at the Dutch National Hemophilia Center, the Van Creveldkliniek, in cooperation with the Department of Patient Education of the University Medical Center Utrecht. The PID has an unique double function: (1) it contains patient tailored information about the practical facts of hospital care; and (2) it provides a communication checklist used by various members of the comprehensive care team, in order to supply patients with more uniform information. In order to gain a better insight of the gaps in information supply, according to patients and healthcare workers, the Department of Patient Education formulated a questionnaire. The PID itself was written by a study group consisting of members of the comprehensive care team. The entire process was developed, edited and coordinated by an advisor of the Department of Patient Education. The above-mentioned study group developed a specific PID on haemophilia care. Its 10 chapters provide information and guidelines, and advise patients where to find more information about this subject. Each chapter includes a checklist for patients, enabling them to prepare subjects for discussion during clinical visits. The team also developed a communication checklist to be used by various team members during a patient’s visit to the clinic, as well as specific checklists covering the possible problem subjects of the PID. The PID is the lifelong property of the patient, and can be used during each visit to the clinic. The PID was implemented in February 2000, and within 4 months, was distributed among 200 patients visiting the Van Creveldkliniek. Evaluation by use of a questionnaire showed that most patients found the information in the PID sufficient and in accordance with that which they had received previously. [ABSTRACT FROM AUTHOR]

The aim of this pilot study was to examine the usefulness of the Dutch version of the Arthritis Impact Measurement Scales 2 (D-AIMS2)in assessing the health status of Dutch individuals with haemophilia. Sixty-eight individuals with mild, moderate, and severe haemophilia attending our clinic for their annual check-up participated. They first completed the Canadian Occupational Performance Measure (COPM). The D-AIMS2 was filled in afterwards at home. With the COPM, individuals rated their specific problematic activities of daily life (ADL), as well as the severity and importance of each problem. The D-AIMS2 is a comprehensive, self-administered questionnaire that evaluates functional health status. Fifty-seven individuals completed and returned the D-AIMS2. Reliability analysis demonstrated good internal consistency for the scales (Cronbach’s α=0.76–1.00), as well as for the components (α=0.80–0.88), except for the component ‘social interaction’ (α=0.44). Criterion validity of the D-AIMS2 was assessed by comparison with COPM outcomes; 80% of the problematic ADLs were included in the questionnaire, 20% were missing. Correlations between the D-AIMS2 components ‘physical health’ and ‘symptoms’ with predicted scores of those individuals by a highly experienced physiotherapist (r=0.63 and 0.53, respectively) substantiated its concurrent validity. Based on these results we concluded that the D-AIMS2, with minor adjustments, can be an appropriate tool for assessing the health status of Dutch haemophilia patients. [ABSTRACT FROM AUTHOR]

The article summarizes research findings on the characteristics and suitability of a new method for employing the "hard core" unemployed. The findings contradict the myth of the "unemployable" people. This article contains a summary of research findings on the value of a new type of employment service especially developed for the benefit of unemployed people for whom the standard methods of help have failed to produce any practical results. It starts with an explanation of the problems of so-called "unemployable" people and seek an answer to the question of why some unemployed people are more "difficult-to-place" than others. Next it looks at the situation of various categories of unemployed people on the Dutch labor market, inasmuch as it has distinctive features in comparison with other Western countries. This is followed by a description of the "tailor-made" method: a type of employment service developed by the Helmond Job Opportunities Project to find suitable work for "unemployable" people in Helmond, a provincial town in the south of the Netherlands.

In the Netherlands, there is a free choice of product for the treatment of haemophilia. Which product is chosen depends on the following considerations: medical, psychological, availability of clotting products, economics and government guidelines. Since the introduction of recombinant product in 1995, the percentage of Dutch patients treated with it has increased from 8% in 1995 to 20% in 1998. In 1999, an average of 48% of patients visiting the Van Creveldkliniek were treated with recombinant product. Children are more often treated with recombinant product than adults; 93% of children between 0 and 5 years, 53% of children between 6 and 20 years and 40% of adults are treated with recombinant product. [ABSTRACT FROM AUTHOR]

Presents information regarding the treatment of hemophilia in the Netherlands. Cases where prophylaxis of the disease is started in patients; Treatment schedule of bleeding episodes in the disease; Products used for treatment of the disease in the country.

Background In the Netherlands, seclusion is historically the measure of first choice in dealing with aggressive incidents. In 2010, the Mediant Mental Health Trust in Eastern Netherlands introduced a policy prioritising the use of enforced medication to manage aggressive incidents over seclusion. The main goal of the study was to investigate whether prioritising enforced medication over seclusion leads to a change of aggressive incidents and coercive measures. Methods The study was carried out with data from 2764 patients admitted between 2007 and 2013 to the hospital locations of the Mediant Mental Health Trust in Eastern Netherlands, with a catchment area of 500,000 inhabitants. Seclusion, restraint and enforced medications as well as other coercive measures were gathered systematically. Aggressive incidents were assessed with the SOAS-R. An event sequence analysis was preformed, to assess the whether seclusion, restraint or enforced medication were used or not before or after aggressive incidents. Results Enforced medication use went up by 363% from a very low baseline. There was a marked reduction of overall coercive measures by 44%. Seclusion hours went down by 62%. Aggression against staff or patients was reduced by 40%. Conclusions When dealing with aggression, prioritising medication significantly reduces other coercive measures and aggression against staff, while within principles of subsidiarity, proportionality and expediency. [ABSTRACT FROM AUTHOR]

Prophylactic treatment in severe hemophilia is very effective but limited by cost-issues. The implementation of two different prophylactic regimens in the Netherlands and Sweden since the 1970s may be considered as a 'natural experiment'. We compared costs and outcome of Dutch intermediate- and Swedish high-dose prophylactic regimens for patients with severe hemophilia (FVIII/IX <1IU/dl) born 1970-1994 using prospective standardised outcome assessment and retrospective collection of cost data. 78 Dutch and 50 Swedish patients, median age 24 (range14-37) were included. Intermediate-dose prophylaxis used less factor concentrates [median (IQR) Netherlands 2100 IU/kg/yr (1400-2900) vs Sweden 4000 IU/kg/yr (3000-4900); p<0.01]. Clinical outcome was slightly inferior for the intermediate-dose regimen (p<0.01): 5-year bleeding [median 1.3 (0.8-2.7) vs 0 (0.0-2.0) joint bleeds/yr] and joint health [HJHS score over 10/144 points in 46% vs 11%], while social participation and quality of life (EQ-5D) were similar. Annual total costs were 66% higher for high-dose prophylaxis: mean 180 (95%CI 163-196) × US$1000 USD for Dutch vs 298 (95%CI 271-325) × US$1000 USD for Swedish patients (p<0.01). At group level, the incremental benefits of high dose prophylaxis appear limited. At patient level, prophylaxis should be tailored individually and many patients may do well on lower doses of concentrate without compromising safety. [ABSTRACT FROM AUTHOR]

Background: Cabazitaxel has been shown to improve overall survival (OS) in metastatic castration-resistant prostate cancer (mCRPC) patients after docetaxel in the TROPIC trial. However, trial populations may not reflect the real-world population. We compared patient characteristics and outcomes of cabazitaxel within and outside trials (standard of care, SOC)., Patients and Methods: mCRPC patients treated with cabazitaxel directly after docetaxel therapy before 2017 were retrospectively identified and followed to 2018. Patients were grouped on the basis of treatment within a trial or SOC. Outcomes included OS and prostate-specific antigen (PSA) response., Results: From 3616 patients in the CAPRI registry, we identified 356 patients treated with cabazitaxel, with 173 patients treated in the second line. Trial patients had favorable prognostic factors: fewer symptoms, less visceral disease, lower lactate dehydrogenase, higher hemoglobin, more docetaxel cycles, and longer treatment-free interval since docetaxel therapy. PSA response (≥ 50% decline) was 28 versus 12%, respectively (P = .209). Median OS was 13.6 versus 9.6 months for trial and SOC subgroups, respectively (hazard ratio = 0.73, P = .067). After correction for prognostic factors, there was no difference in survival (hazard ratio = 1.00, P = .999). Longer duration of androgen deprivation therapy treatment, lower lactate dehydrogenase, and lower PSA were associated with longer OS; visceral disease had a trend for shorter OS., Conclusion: Patients treated with cabazitaxel in trials were fitter and showed outcomes comparable to registration trials. Conversely, those treated in daily practice showed features of more aggressive disease and worse outcome. This underlines the importance of adequate estimation of trial eligibility and health status of mCRPC patients in daily practice to ensure optimal outcomes., (Copyright © 2019 Elsevier Inc. All rights reserved.)

In the Netherlands, safe and sufficient drinking water is provided to the general population by ten drinking water companies. To guarantee safe drinking water the World Health Organization (WHO) developed a Water Safety Plan (WSP), a Risk Assessment and a Risk Management (RA/RM) framework. The objective of the study was to identify legally required RA approaches, to document application of RA/RM activities at Dutch drinking water companies and to determine to what extent these RA/RM activities as a whole cover all the elements of the WHO WSP approach. This study could be of interest to both managers of large water utilities and decision makers. The assessment was performed by means of a policy review and interviews with two to four staff members involved in RA/RM from all ten Dutch drinking water companies combined with a joint workshop. The drinking water companies are well aware of the potential hazards and risks that can influence the drinking water quality. To guarantee the supply of safe and sufficient drinking water, the Dutch drinking water sector uses six different legally required RA/RM approaches. This study shows that by using the six legally required RA/RM approaches, all WSP steps are covered. WSP entails a generic risk assessment for identifying all hazards and hazardous events from source to tap, whereas the six legally required RA/RM each focus on specific risks at an advanced level. Each risk assessment provides information on specific hazards and hazardous events covering a part of the water supply chain. These legal requirements are complemented with additional RA/RM activities at sector and water company level such as codes of practices and standard operating procedures. The outcomes of all RA/RM approaches combined provide information from source to tap. When using multiple RA/RM approaches, it is crucial to share and combine information derived from the different activities., (Copyright © 2019 The Authors. Published by Elsevier GmbH.. All rights reserved.)

Objective: To gain insight into the differences in emergency care offered to elderly (65+ years) and younger patients (20-64 years). The emergency care pathway includes: out-of-hours general practitioner cooperatives, regional ambulance services, psychiatric emergency medical services, accident and emergency departments and acute cardiac care units., Design: Retrospective cohort study., Method: We used data from all emergency care contacts from the Emergency Care Monitor of April 2015 and April 2016 from an emergency care region in the east of the Netherlands ('Acute Zorgregio Oost'); this involved 84,647 care contacts with 55,061 patients. We defined pathway emergency care contacts as multiple emergency care contacts with different healthcare providers within the emergency care pathway, and differentiated between single or repeated care contacts with a single emergency healthcare provider. We investigated differences in presenting symptoms, diagnoses, lead time, hospital admissions and mortality in the chain care., Results: Emergency care contact was more often pathway contact in elderly than in younger patients (26% vs. 16%; p < 0.0001). Elderly patients more often received a diagnosis of CVA, pneumonia or exacerbation of COPD, while younger patients more often had simple contusions or abdominal symptoms. Pathway lead time was longer in elderly than in younger patients (median difference: 33 minutes; 95% CI: 25-40. Elderly patients were admitted to hospital more often (71% vs. 39%, p < 0.0001) and their mortality rate was higher (2.0% vs. 0.5%; p < 0.0001)., Conclusion: Elderly patients in the emergency care pathway have more frequent and longer pathway contact and present themselves with a more complicated and life-threatening clinical picture than younger patients. New solutions should be explored to ensure that the emergency care pathway remains accessible and available and offers sufficient quality for the increasing number of elderly.

Introduction: Adjuvant chemotherapy still is a controversial therapy for rectal cancer patients. The aim of this study was to analyze the effect of adjuvant chemotherapy on recurrence-free survival (RFS) for patients with stage III rectal cancer treated in clinical practice, taking into account which neo-adjuvant treatment patients received., Methods: Patients from regions in the Netherlands diagnosed between 1996 and 2013 with pathological stage III rectal cancer who received short-course radiotherapy, chemoradiation or no neo-adjuvant treatment and who underwent surgery were included. After stratification by neo-adjuvant treatment, 5-year RFS according to adjuvant chemotherapy receipt was calculated using Kaplan-Meier curves. Cox regression was used to discriminate the independent effect of adjuvant chemotherapy on the risk of recurrence/death., Results: The study population consisted of 829 patients, of whom 537 (65%) patients received short-course radiotherapy, 128 (15%) patients received chemoradiation and 164 (20%) patients received no neo-adjuvant treatment. Adjuvant chemotherapy was administered to 152 (18%) patients. Adjuvant chemotherapy was associated with improved 5-year RFS for patients who received short-course radiotherapy (61% vs. 46%, p = 0.005) and for patients who did not receive any neo-adjuvant treatment (70% vs. 28%, p < 0.0001). In multivariable analyses, adjuvant chemotherapy was associated with a reduced risk of recurrence/death for patients treated with short-course radiotherapy (HR 0.65, 95% CI 0.46-0.93) and for patients without neo-adjuvant treatment (HR 0.35, 95% CI 0.18-0.71), but not for patients treated with chemoradiation (HR 1.11, 95% CI 0.51-2.41)., Conclusion: Among patients with stage III rectal cancer, the effect of adjuvant chemotherapy on RFS seems to vary by neo-adjuvant treatment., (Copyright © 2015 Elsevier Ltd. All rights reserved.)

Aim: High-dose-rate brachytherapy (HDRBT) appears to be associated with less treatment-related toxicity compared with external beam radiotherapy in patients with rectal cancer. The present study compared the effect of preoperative treatment strategies on overall survival, cancer-specific deaths, and local recurrences between a Dutch and Canadian expert center with different preoperative treatment strategies., Patients and Methods: We included 145 Dutch and 141 Canadian patients with cT3, non-metastasized rectal cancer. All patients from Canada were preoperatively treated with HDRBT. The preoperative treatment strategy for Dutch patients consisted of either no preoperative treatment, short-course radiotherapy, or chemoradiotherapy. Cox proportional hazards models were used to estimate hazard ratios (HR) with 95% confidence intervals (CIs) comparing overall survival. We adjusted for age, cN stage, (y)pT stage, comorbidity, and type of surgery. Primary endpoint was overall survival. Secondary endpoints were cancer-specific deaths and local recurrences., Results: Five-year overall survival was 70.9% (95% CI 62.6%-77.7%) in Dutch patients compared with 86.9% (80.1%-91.6%) in Canadian patients, resulting in an adjusted HR of 0.70 (95% CI 0.39-1.26; p = 0.233). Of 145 Dutch patients, 6.9% (95% CI 2.8%-11.0%) had a local recurrence and 17.9% (95% CI 11.7%-24.2%) patients died of rectal cancer, compared with 4.3% (95% CI 0.9%-7.5%) local recurrences and 10.6% (95% CI 5.5%-15.7%) rectal cancer deaths out of 141 Canadian patients., Conclusion: We did not detect statistically significant differences in overall survival between a Dutch and Canadian expert center with different treatment strategies. This finding needs to be further investigated in a randomized controlled trial., (Copyright © 2015 Elsevier Ltd. All rights reserved.)

In fish spas, clients may submerge their hands, feet or whole body in basins with Garra rufa fish, for dead skin removal. Skin infections may result from using these spas, transmitted from fish to clients, through either fish or water, or from client to client. The microbiological water quality was determined in 24 fish spas in 16 companies in the Netherlands through analysis of a single water sample per fish spa. Water samples were tested for the presence of Aeromonas spp., Vibrio spp.,Pseudomonas aeruginosa, nontuberculous mycobacteria,and faecal indicator bacteria by using standard culture methods. The majority of the examined fish spas contained Aeromonas spp. (n = 24), P. aeruginosa(n = 18), Vibrio spp. (n = 16) including V. cholerae non-O1/O139 and V. vulnificus, and several rapid growing Mycobacterium spp. (n = 23) including M. fortuitum, M.conceptionense, M. abscessus and M. chelonae. Faecal contamination of the fish spa water was low. Based on the detected concentrations of Aeromonas spp., Vibriospp., and P. aeruginosa, the detected Mycobacteriumspp., and the health implications of these bacteria, the health risk from using fish spas is considered limited for healthy people with an intact skin and no underlying disease.

Swimming pool-related Pseudomonas aeruginosa infections mainly result in folliculitis and otitis externa. P. aeruginosa forms biofilms on surfaces in the swimming pool environment. The presence of P. aeruginosa on inflatables and foam teaching aids in 24 public swimming pools in the Netherlands was studied. Samples (n = 230) were taken from 175 objects and analysed for P. aeruginosa by culture. Isolated P. aeruginosa were tested for antibiotic resistance by disk diffusion. P. aeruginosa was detected in 63 samples (27%), from 47 objects (27%) in 19 (79%) swimming pools. More vinyl-canvas objects (44%) than foam objects (20%) were contaminated, as were wet objects (43%) compared to dry objects (13%). Concentrations were variable, and on average higher on vinyl-canvas than on foam objects. Forty of 193 (21%) P. aeruginosa isolates from 11 different objects were (intermediate) resistant to one or more of 12 clinically relevant antibiotics, mostly to imipenem and aztreonam. The immediate risk of a P. aeruginosa infection from exposure to swimming pool objects seems limited, but the presence of P. aeruginosa on pool objects is unwanted and requires attention of pool managers and responsible authorities. Strict drying and cleaning policies are needed for infrequently used vinyl-canvas objects.

Background: Since the Dutch Mental Health Act of 1984 came into effect, seclusion has often been used as the measure of choice for dealing with aggressive or dangerous patients. In 2012 the Ministry of Health formulated a policy whereby seclusion was to be phased out, but not replaced by involuntary medication. In 2007, within the framework of the Mental Health Act, the Argus system of registering coercive measures was introduced in order to monitor the reduction in the use of seclusion and involuntary medication. This article describes, in a longitudinal cohort study, the effect of the policy to reduce aggression by replacing seclusion through the use of involuntary medication or other measures., Aim: To investigate whether, in the long run, a reduction in the use of seclusion will lead to a proportional increase in the use of involuntary medication, and to assess whether this policy can really be termed 'substitution., Method: We performed this study by analysing Argus data for the period 2007-2011, relating to 1843 patients being treated by Mediant. ESULTS The changing proportions of seclusion and involuntary medication over time demonstrated that the use of involuntary medication did result in patients being secluded for a shorter period of time., Conclusion: In the case of dangerous psychiatric patients, medication, administered forcibly when necessary, is preferable to seclusion as far as subsidiarity, proportionality and expediency are concerned. A strategy whereby medication provides appropriate treatment and seclusion is kept within reasonable limits cannot be termed 'substitution'.

Osteosarcoma of the cranio-facial structures and skull is rare. In children, only 5.6% of cases are localized in these areas. It is claimed that the mean age at presentation is at least 10-15 years higher than for osteosarcomas in other parts of the body. However these reports are based on data from single institutions or compiled from several registries. It is further claimed that tumours in the mandible and maxilla are less malignant, as based on observations of a better prognosis and lower incidence of metastatic spread as compared with osteosarcomas arising elsewhere. We report all histologically proven cranio-facial osteosarcomas in The Netherlands occurring over a 20-year period, based on the national registration covering all Dutch pathology laboratories (PALGA). The age-corrected incidence of primary osteosarcoma ranged from 0.33 to 0.41 per million across the age ranges. The mandible was the most frequent site of involvement. Only 61% had a high malignant histological grading. Our data indicate that the age-corrected incidence of primary osteosarcomas is similar across all age ranges. In respect to histology, a lower grade of malignancy is more frequent. Maxillary lesions significantly more often have a lower histological grade of malignancy., (Copyright © 2013 International Association of Oral and Maxillofacial Surgeons. Published by Elsevier Ltd. All rights reserved.)

In 2009, four bathing sites in The Netherlands were monitored for potentially human pathogenic Vibrio species to observe possible associations with environmental conditions and health complaints. Three slightly different enrichment procedures were used to isolate Vibrio species with different growth requirements. Waters were generally positive for Vibrio from May until October; median Vibrio concentrations ranged from 4 to 383 MPN per litre (maximum 10(5) MPN per litre). Isolated Vibrio species included V. alginolyticus (50.6%) and V. parahaemolyticus (8.5%) from bathing sites with salinities ranging between 2.8 and 3.5% and V. cholerae non-O1/O139 (6.9%) from sites with salinities ranging between 0.007 and 0.08%. Although more samples were positive for Vibrio at elevated water temperatures, a quantitative relation between Vibrio numbers in water samples and the water temperature was not observed which may be explained by maximum water temperatures of 21 ° C. Active surveillance yielded one case of a recreational water related Vibrio infection. V. cholerae non-O1/O139 was cultured from the patient's wound and the implicated recreational water; PFGE profiles of the water and patient isolates were not identical. The number of patients that contract a Vibrio infection through exposure to Dutch recreational waters seems low, but may be underestimated. The common occurrence of Vibrio species in these waters stresses the need for providing information on Vibrio to risk groups to prevent infections., (Copyright © 2011 Elsevier GmbH. All rights reserved.)

Aim: Paediatric drug prescriptions are known for their high percentages of off-label and unlicensed use. In paediatric oncology data available are scarce. The aim of this paper is an analysis of the licensing and labelling status of all prescribed medication over a 2 week period in a Dutch paediatric oncology centre., Methods: An analysis of the delivery of medication by the hospital pharmacy to patients admitted to the paediatric oncology centre was carried out., Results: In total 268 precriptions were filed for 39 patients. In 87% of children unlicensed medication was used. Fifty-nine per cent of the children received at least two unlicensed drugs. In total 72% of the drugs were used licensed and on-label was found in 57% of the prescriptions. There was a trend that in younger children percentages were lower. International and local guidelines necessitated in many cases unlicensed use, e.g. intrathecal prednisolone, low dose medication such as heparin, ethanol and vancomycin for locking intravenous devices and higher intravenous vancomycin dosages. There were no major differences with respect to type of malignancy., Conclusion: Our figures are substantially higher than the figures reported from adult oncology. Comparison with other paediatric reports are cumbersome, due to different percentages of diseases in the reports and other rules to dispense medication in the outpatient setting. Our data are in line with reports mentioning the higher percentages of unlicensed and off-label use. Our data further underpin the need for more research on suitable formulations, dosages, safety and efficacy in these children., (© 2011 The Authors. British Journal of Clinical Pharmacology © 2011 The British Pharmacological Society.)

Background: We report on the treatment of children and adolescents with acute lymphoblastic leukemia (ALL) in first relapse. The protocol focused on: (1) Intensive chemotherapy preceding allogeneic stem cell transplantation (SCT) in early bone marrow relapse; (2) Rotational chemotherapy in late relapse, without donor; (3) Postponement of cerebro-spinal irradiation in late isolated CNS relapse; and (4) Treatment in very late bone marrow relapse with chemotherapy only., Methods: From January 1999 until July 2006 all 158 Dutch pediatric patients with ALL in first relapse were recorded. Ninety-nine patients were eligible; 54 patients with early and 45 with late relapse. Eighteen patients had an isolated extra-medullary relapse; 69 patients had bone marrow involvement only., Results: Five-years EFS rates for early and late relapses were 12% and 35%, respectively. For early relapses 5 years EFSs were 25% for patients transplanted; 0% for non-transplanted patients. For late relapses 5 years EFS was 64% for patients treated with chemotherapy only, and 16% for transplanted patients. For very late relapses EFS was 58%., Conclusions: Our data suggest the superiority of SCT for early relapse patients. For late relapses a better outcome is achieved with chemotherapy only using the rotational chemotherapy scheme. The most important factor for survival was interval between first CR and occurrence of the first relapse., (Copyright © 2011 Wiley-Liss, Inc.)

Background: A population-based cohort of children aged 1-18 years with acute lymphoblastic leukaemia (ALL) was treated with a dexamethasone-based protocol (Dutch Childhood Oncology Group [DCOG] ALL-9). We aimed to confirm the results of the most effective DCOG ALL protocol for non-high-risk (NHR) patients to date (ALL-6), compare results with ALL-7 and ALL-8, and study prognostic factors in a non-randomised setting., Methods: From Jan 1, 1997, until Nov 1, 2004, patients with ALL were treated according to the ALL-9 protocol in eight Dutch academic centres with their affiliated peripheral hospitals. Patients were stratified into NHR and high risk (HR) groups. HR criteria were white-blood-cell count of 50,000 cells per microL or more, T-cell phenotype, mediastinal mass, CNS or testicular involvement, and Philadelphia chromosome or MLL rearrangement; patients who did not fulfil these criteria were deemed to be NHR. The NHR group was treated with a three-drug induction (dexamethasone, vincristine, and asparaginase) for 6 weeks, medium-dose methotrexate for 3 weeks, then maintenance therapy. HR patients received a four-drug induction (as for the NHR patients plus daunorubicin) for 6 weeks, high-dose methotrexate for 8 weeks, and two intensification courses before receiving maintenance therapy. Triple intrathecal medication was given 13 times in NHR patients, 15 times in HR patients (17 times for patients with initial CNS involvement). No patient received cranial irradiation. Maintenance therapy was given until 109 weeks for all patients and consisted of mercaptopurine and methotrexate for 5 weeks, alternated with dexamethasone and vincristine for 2 weeks. Kaplan-Meier analysis was done on an intention-to-treat basis with event-free survival as the primary endpoint. This trial is registered at trialregister.nl, number NTR460/SNWLK-ALL-9., Findings: 859 patients were recruited to the study. Complete remission was achieved in 592 (98.5%) of the 601 patients in the NHR group and 250 (96.9%) of the 258 in the HR group. Five patients in the NHR group and four in the HR group died during induction. Median follow-up for patients alive was 72.2 (range 4.8-132.7) months as of August, 2008. 5-year event-free survival was 81% (SE 1%) in all patients: 84% (2%) in NHR patients, and 72% (3%) in HR patients. Isolated CNS relapses occurred in 22 (2.6%) of 842 patients. In a multivariate analysis, DNA index was the strongest predictor of outcome (<1.16 vs >or=1.16; relative risk 0.42, 95% CI 0.22-0.78), followed by age (1-9 vs >or=10 years; 2.23, 1.60-3.11) and white-blood-cell count (<50,000 vs >or=50,000 cells per microL; 1.60, 1.13-2.26)., Interpretation: The overall results of the dexamethasone-based DCOG ALL-9 protocol are better than those of our previous Berlin-Frankfurt-Münster-based protocols ALL-7 and ALL-8. The results for NHR patients were achieved with high cumulative doses of dexamethasone and vincristine, but without the use of anthracyclines, etoposide, cyclophosphamide, or cranial irradiation, therefore minimising the risk of side-effects., Funding: Dutch Health Insurers.

Purpose: We assessed the long-term risk of breast cancer (BC) after treatment for Hodgkin's lymphoma (HL). We focused on the volume of breast tissue exposed to radiation and the influence of gonadotoxic chemotherapy (CT)., Patients and Methods: We performed a cohort study among 1,122 female 5-year survivors treated for HL before the age of 51 years between 1965 and 1995. We compared the incidence of BC with that in the general population. To assess the risk according to radiation volume and hormone factors, we performed multivariate Cox regression analyses., Results: After a median follow-up of 17.8 years, 120 women developed BC (standardized incidence ratio [SIR], 5.6; 95% CI, 4.6 to 6.8), absolute excess risk 57 per 10,000 patients per year. The overall cumulative incidence 30 years after treatment was 19% (95% CI, 16% to 23%); for those treated before age 21 years, it was 26% (95% CI, 19% to 33%). The relative risk remained high after prolonged follow-up (> 30 years after treatment: SIR, 9.5; 95% CI, 4.9 to 16.6). Mantle field irradiation (involving the axillary, mediastinal, and neck nodes) was associated with a 2.7-fold increased risk (95% CI, 1.1 to 6.9) compared with similarly dosed (36 to 44 Gy) mediastinal irradiation alone. Women with >or= 20 years of intact ovarian function after radiotherapy at young ages (< 31 years) experienced significantly higher risks for BC than those with fewer than 10 years of intact ovarian function., Conclusion: Reduction of radiation volume appears to decrease the risk for BC after HL. In addition, shorter duration of intact ovarian function after irradiation is associated with a significant reduction of the risk for BC.

Background: Histological examination of bone tumors is one of the most difficult subjects in pathology. In this manuscript, correctness of initial histological diagnosis in pediatric bone tumors and tumorlike lesions was investigated., Procedure: All 262 bone tumor specimens of children up to the age of 19 years reviewed from 1999 to 2003 by the Netherlands Committee on Bone Tumors were included. Initial diagnosis and diagnosis after review were compared., Results: Only 60% of original diagnoses proved to be correct. After classification according to the main categories of the World Health Organization classification, only 75% of tumors were correctly categorized. Thirteen of the 60 malignant tumors were not recognized as malignant. Seven of 198 benign lesions were reclassified as malignant. Kappa values were indicative for good agreement in the (by the Ministry of Health designated) bone tumor centers. For nondesignated hospital kappa values, a substantial lower level of agreement was noted. Agreement was almost perfect in Ewing/primitive neuroectodermal tumors. For cartilaginous, osteogenic, and fibrous tumors, agreement was lower. Adamantinomas were not recognized in non-bone tumor centers. For the remaining group composed of miscellaneous tumors, poor levels of agreement were noted., Conclusions: We conclude that correct diagnosis of childhood bone tumors requires review by a multidisciplinary team of experts. Specifically in non-bone tumor centers, the correctness of the initial diagnosis can be questioned.

Introduction: Data on childhood bone tumors are mainly confined to reports on malignant tumors or on institutional registries. Incidence figures on both benign and malignant bone tumors in childhood are lacking., Methods: From January 1999 to December 2003, 1474 newly diagnosed bone tumors in children up to 18 years were registered in Pathologisch Anatomisch Landelijk Geautomatiseerd Archief (the nationwide network and registry of histopathology and cytopathology in The Netherlands). Data provided were diagnosis, date of birth, age at diagnosis, and localization. For incidence calculations, data on age and sex in each year of investigation were obtained from the StatLine database of Statistics Netherlands (www.cbs.nl)., Results/conclusions: Incidence of pathology-proven bone tumors in children is low. Incidence of pathology-proven bone tumors in The Netherlands is 79.3 per 1,000,000. From the very first year of life, incidence increases from 3.9 per 1,000,000 to a peak at 13 to 15 years of 142.9 per 1,000,000. Osteochondromas are the most prevalent tumors, followed by aneurysmal bone cysts. The overall incidence is higher for male compared with female patients, mainly due to different frequencies found in aneurysmal bone cysts, Ewing sarcoma, and osteochondroma. Shifts in incidence differ among the various tumors. In infants, bone tumors are mainly chondromas and fibrous dysplasia, which both show a steady increase at older ages. Tumors most prevalent at older ages are osteochondromas, osteosarcomas, osteoid osteomas, and chondromas. A peak incidence at approximately the age of 10 is noted for solitary bone cysts, nonossifying fibromas, and osteoblastomas. Small children more often have localizations in the skull and facial bones. Comparison with literature data showed significant differences due to referral-based institutionally bias, whereas tumor registries only give data for specific tumor types.

Introduction: Childhood cancer survivors are known to be at increased risk for second malignancies., Patients and Methods: The risk of second malignancies was assessed in 1368 5-year survivors of childhood cancer treated in the Emma Children's Hospital AMC in Amsterdam. The median follow-up time was 16.8 years., Results: Sixty two malignancies were observed against 5.4 expected, yielding a standardised incidence ratio (SIR) of 11.2 (95% confidence interval: 8.53-14.4; absolute excess risk: 3.2 per 1000 person-years). New observations were the strongly increased risks of meningiomas (SIR=40) and basal cell carcinomas (SIR=9). Patients whose treatment involved radiotherapy had a 2-fold increased second cancer risk compared to patients with chemotherapy alone., Discussion: The relative risk of second malignancies does not decrease till at least 30 years of follow-up. With aging of the survivor cohort this results in a strong increase of the AER, due to the rising background risk of cancer with age.

Faecally impacted surface waters used for drinking water production may encompass risk for norovirus infections. To be able to assess a possible health risk, noroviruses should be quantified and fluctuations identified. In 2001, norovirus concentrations in the river Meuse displayed a seasonal distribution with high peaks during wintertime as determined by RT-PCR on serially diluted RNA. An intensified day-by-day sampling scheme in the winter of 2002/2003 revealed that the winter peak consisted of several peaks of varying duration and magnitude, possibly due to contamination events in the catchment. The highest estimated concentration was 1700 PCR-detectable units per litre (95% CI 250-8000), which if coinciding with failing treatment could lead to significant numbers in drinking water. Adaptive dynamic filtering was shown to adequately predict subsequent sample concentrations. If valid, such analyses could prove to be useful as early warning systems in risk management of water sources.

We investigated the influence of age and co-morbidity on treatment, the occurrence of serious non-urological complications of treatment and prognosis for prostate cancer patients diagnosed and treated in community hospitals. Additional information from a random sample of 505 prostate cancer patients (aged 40 years or older) from the Eindhoven Cancer Registry diagnosed between 1995 and 1999 was collected. In all, 43% of the prostate cancer patients aged 40-69 years and 64% of those aged 70 or older suffered from one or more serious concomitant disease that barely affected primary treatment choice. However, compared to patients without co-morbidity, patients with cardiovascular diseases underwent radical prostatectomy less often (P=0.01). In all, 38% of the patients undergoing radical prostatectomy suffered from complications during the first year after diagnosis versus about 20% of those receiving radiotherapy. The number of complications did not seem to be affected by co-morbidity. After adjustment for age, stage, grade, prostate-specific antigen level and treatment, the cumulative risk of death was almost two times higher for patients with two or more concomitant diseases than for patients without co-morbidity. After adjustment for age, prostate cancer patients with co-morbidity were not treated differently, did not suffer from more complications but had a worse prognosis, compared to those without co-morbidity.

Prophylaxis is the treatment of choice for children with severe haemophilia. As prophylaxis is especially important during the period of growth, the need for continued prophylaxis in adulthood should be considered. The aim of this study was to describe the incidence and outcome of stopping prophylaxis in patients with severe haemophilia who were offered prophylaxis during childhood. All patients with severe haemophilia (factor VIII/IX <0.01 IU/ml), born 1970-80, treated in two Danish and one Dutch treatment centre were studied. Data on discontinuation of prophylaxis, treatment, joint bleed frequency, clinical scores and radiological scores were collected. Eighty patients were studied. Median follow-up was 19 years (range 7-29). A total of 35% of patients discontinued prophylaxis at a median age of 21.5 years [interquartile range (IQR) 18.4-24.4], experiencing only three joint bleeds per year (IQR 1.4-8.7). Median clinical scores were similar in patients who discontinued prophylaxis [4 points (IQR 0-6)] and those who continued [3 points (IQR 1-6)], as were median Pettersson scores at 13 (IQR 1-24) vs. 13 points (IQR 5-23) respectively. In conclusion one-third of young adults with severe haemophilia on a prophylactic regimen discontinued prophylaxis in early adulthood, while maintaining a low joint bleed frequency and similar arthropathy after 4 years.

Human noroviruses cause gastroenteritis in humans, leading to high virus loads in sewage. Norovirus concentrations in raw and treated sewage samples from two sewage treatment plants (STP) were studied, along with virus removal and genetic diversity. Over one year, the average norovirus concentrations in raw sewage were approximately 10(5) pcr detectable units (pdu) per liter compared with 10(3) pdu/l of treated sewage. Similar sewage treatment processes at STP-A and STP-B led to 2.7 and 2.0 log(10)-units of virus removal, respectively. In total, 11 different norovirus variants were detected in 49 out of 53 sewage samples, with up to four different norovirus strains in a single sewage sample. Along with GGI.6 Sindlesham and GGII.2 Melksham, the GGIIb variant was one of the most prevalent noroviruses in both raw and treated sewage. This strain emerged among populations in Europe in 2000 and 2001. Treated sewage containing 10(2)-10(3) norovirus pdu is discharged into the surface water. The use of such fecally contaminated surface waters for shellfish culture, drinking water production and recreational purposes poses a potential health risk. We showed the presence of multiple norovirus strains in raw and treated sewage, confirming the need to clone before sequencing the RT-PCR products. Exposure to multiple norovirus strains in sewage contaminated food or water may lead to the occurrence of norovirus recombinants, which may be more virulent and pathogenic than the norovirus strains already circulating in the population.

Severe haemophilia (factor [F]VIII/FIX activity < 0.01 IU mL(-1)) is characterized by repeated haemarthroses resulting in severe arthropathy in adulthood. In 1958, Professor Nilsson in Sweden introduced prophylactic infusions with clotting factor concentrates at regular intervals in order to maintain clotting factor levels above 0.01 IU mL(-1) and to prevent bleeding. Since then, evidence of the long-term beneficial effects of prophylactic treatment for severe haemophilia has been increasing and it has become the recommended treatment strategy for children with severe haemophilia by both the World Health Organization and the US National Hemophilia Foundation Medical and Scientific Advisory Committee. However, the implementation of this recommendation has been hampered by issues of cost and venous access. The high costs of prophylaxis have largely prevented its use in major parts of the world. The question therefore is whether the current models of replacement of clotting factor concentrates, while certainly being effective, are also optimal. Can the data on outcome at different levels of factor replacement be used to assess their cost-effectiveness?

SPICES criteria (Student-centred, Problem-based, Integrated, Community-based, Electives, Systematic) are used to describe educational strategies applied in medical schools. Application of SPICES criteria often can be just a statement since various forms of teaching with large variations are incorporated in a curriculum. In this paper a system of rating SPICES criteria is presented in which also quantitative aspects (in respect of hours of scheduling of the various educational strategies) are considered. Application of this system provides a score on application of SPICES criteria for the curriculum as whole. In addition, comparison of various curricula can be done in a more objective manner.

A balanced diet based on the Guidelines of the Netherlands Nutrition Centre provides a suitable basis for the maintenance of good health. However, there are a number of situations where supplementation with vitamins is clearly indicated. These include infants (vitamin A, D and K), young children, and pregnant and lactating women (vitamin D), future expectant mothers (folic acid) and the elderly (vitamin D). If doubts exist about a sufficient vitamin intake via the regular diet, a daily supplement supplying all vitamins at the level of the recommended daily allowance (RDA) is considered to be a responsible and safe choice. Epidemiological research indicates that the incidence of certain diseases is lower if the intake of vitamins is significantly higher than the RDA. However to date, targeted intervention studies have provided little unequivocal evidence to support this argument. For certain vitamins (A, D, folic acid, B6, nicotinic acid and beta-carotene) excessive intakes are associated with a health risk or clear toxicity. In the case of vitamin B6, nicotinic acid, folic acid and beta-carotene this risk is mainly limited to the use of high-dose supplements.

Objectives: To report an outbreak of nosocomial influenza in thirteen out of twenty-two admitted patients suffering from severe lung emphysema., Methods: Acute-phase and convalescent serum samples of nine patients were collected. An antihaemagglutinin assay was performed to detect a rise in antibodies against influenza A virus. Further information about vaccination history of the patients and healthcare workers was included., Results: The majority of these twenty-two patients was vaccinated with a trivalent vaccine six months earlier. The immunological response showed that the influenza A (H3N2) strain which caused these infections is similar to the vaccine strain A/Sydney/5/97., Conclusions: The staff of our institute which was not systematically vaccinated may have been the source of infection. The time elapsed between the vaccination and the infection is the probable explanation of this event.

Both Sweden and the Netherlands have a long experience with primary prophylaxis in children with severe haemophilia. In these countries it has been offered to all children for the last 3-4 decades. In Sweden prophylaxis is generally started at an earlier age with a higher dosage and frequency than in the Netherlands. Patients in the Netherlands receive a more individually tailored regimen, with prophylaxis now started after the first one or two joint bleeds and dosages are increased when breakthrough bleeds occur. The current study evaluated the effect prophylaxis on long-term outcomes and the consumption of clotting factor concentrates in Dutch and Swedish cohorts. Our results show that the orthopaedic outcome in the oldest groups of patients from Sweden and the Dutch cohorts were comparable, although the Swedish patients used twice as much clotting products per year. In the youngest patients, joint status is very good and further follow-up is necessary to demonstrate the benefits of either strategy. In conclusion, more individually tailored regimens aimed at preventing bleeding prevent joint damage in children with severe haemophilia, while clotting factor consumption is about half of that in previously described regimens.

We investigated whether haemophilic children who are on prophylactic therapy differ from their healthy peers in terms of motor performance and disability. Thirty-nine children, aged 4-12 years, with moderate (eight) and severe (31) haemophilia were included. Patients with severe haemophilia received primary prophylactic therapy that was individually tailored. The number of target joints, amount of swelling, range of motion, muscular strength and pain were measured, as well as motor skills and disability. The scores were compared to the normal population. No patients had target joints. Normal range of motion in all joints was seen in 97% (38/39) of the patients. Strength of elbow, knee, and ankle muscles were within the normal ranges. Ninety-five percent (37/39) of the patients had normal motor performance. Although 90% of our patients (35/39) had no disabilities in activities of daily living (ADL), 79% (31/39) of them reported that the disease impacted on their lives. Seventy-two percent (28/39) of the patients had pain, and in 21% (6/28) of them this was mainly caused by injections. Restrictions in sports or gymnastics were seen in 56% (22/39) of the patients. Those who indicated that they experienced pain and those who indicated restrictions in sports had a higher chance of experiencing disease impact compared to those who did not have these limitations. There were no significant differences between patients with moderate and severe haemophilia. In general, Dutch children with moderate or severe haemophilia are comparable with their healthy peers with regard to motor performance and ADL. However, a majority of the patients perceive an impact of their disease associated with pain and restrictions in sports.

The aim of this study was to investigate the validity of the Dutch Arthritis Impact Measurement Scales 2 (D-AIMS2). Hence, D-AIMS2 data of individuals with severe haemophilia were correlated with clinical and perceived health-related quality of life data. Patients with severe haemophilia, who visit the Van Creveldkliniek on a regular basis, were administered the D-AIMS2. In addition, health-related quality of life was measured by the Sickness Impact Profile (SIP). As clinical indices, range of movement (which was converted into Joint Alignment and Motion scores) and muscle strength were recorded during the routine visit. Extensive descriptive and correlational (linear) analyses between corresponding datasets were performed. Thirty-one individuals with severe haemophilia were included. Their scores on the D-AIMS2 demonstrated moderate to very high internal consistency for scales and components (Cronbach's alpha = 0.62-0.92). The physical health components of the D-AIMS2 and the SIP were significantly correlated (Pearson's r = 0.53; P < 0.05). The psychological health and social interaction components of the D-AIMS2 did not correlate significantly with the psychosocial component of the SIP. The physical health component of the D-AIMS2 correlated significantly with the clinical data for the lower extremities (r = 0.52 and r = -0.45; P < 0.05). These data support the reliability and validity of the physical aspects of the D-AIMS2 in patients with severe haemophilia. The next step should be to extend the investigation of psychometric qualities of this health-related questionnaire in a larger population.

We describe a new structural mutant of the beta-globin chain in a 17-year-old Dutch Caucasian girl. The mutant is associated with a severe pathology as a consequence of hyper-instability of the hemoglobin tetramer. The proband, whose parents had no history of hemolysis, was admitted to the hospital at 5 months of age with hemolytic anemia and splenomegaly. No indications for autoimmune defects or enzymopathies were found. Repeated hemoglobin electrophoresis on cellulose acetate revealed no abnormalities. At the age of 17 years, a minor abnormal band of less than 1% was detected on starch gel electrophoresis, migrating slightly faster than Hb A2. Sequencing of the beta-globin gene revealed heterozygosity for a 4 bp deletion (GCTA) in combination with a 1 bp insertion (T) at codons 138/139. This event eliminates two amino acids (Ala-Asn) and introduces a new residue (Tyr). We discuss the hematological and the pathophysiological consequences of this mutant, which is fully expressed as a gene product, and apparently assembled into unstable tetramers that precipitate shortly after.

Background and Objectives: Human parvovirus B19 is a potential risk to hemophiliac patients receiving blood products., Materials and Methods: To determine the prevalence of the corresponding antibody in patients with hemophilia A or B von Willebrand's disease, we tested 326 hemophilia patients for anti-B19 IgG. The results were compared with those of 203 age-matched controls (male blood donors and children)., Results: The overall prevalence of B19 IgG in the hemophilia patients was 302/326, and in the controls 123/203. Below the age of 10, hemophilia patients had a higher prevalence of B19 IgG (76%, 42/55) than the controls (23%, 11/48; p < 0.00001). In those below the age of 5 who had been treated exclusively with monoclonally purified concentrate, it made no difference whether the product was pasteurized or solvent-detergent treated. There was significantly lower incidence in patients who were rarely treated., Conclusion: Parvovirus B19 if frequently transmitted in blood products. Existing virus-inactivating methods do not prevent transmission.

Objective: To assess the dietary, physical, biochemical and lifestyle determinants of vitamin B6 status parameters among healthy adults., Design and Subjects: Dietary intake and status variables as well as other relevant characteristics were determined among 444 adults, aged 20-79 y and stratified for sex and 10-years age classes with a randomly selected control group (n = 300) and an over representation of persons with a low habitual vitamin B6 intake (n = 144)., Results and Conclusions: The direct status parameters (plasma pyridoxal-5'-phosphate (PLP), plasma pyridoxal + PLP (PL + PLP), and 4-pyridoxic acid (4-PA) excretion) were clearly related to dietary variables and plasma concentrations of vitamin C (women only), vitamin B12 and folate. The total percentage of variance in p-PLP explained in multivariate regression analysis was 41 and 30% in men and women, respectively. The most important explaining variables besides vitamin B6 intakes were variables closely related to PLP-metabolism: albumin and alkaline phosphatase. Biochemical function related status parameters showed less statistically significant correlations with dietary variables. Four to 24% of the variance in the stimulation coefficients of erythrocyte aspartate aminotransferase (alpha-EAST) and erythrocyte alanine aminotransferase (alpha-EALT) and change in homocysteine excretion after a methionin load was explained by a combination of dietary, physiological and lifestyle related variables. The low percentages explained for some variables, notably alpha-EAST (women) and the change in homocysteine excretion after a methionin load (men), suggests that these parameters are not sensitive to the level of vitamin B6 intake as found in the present study. Alcohol contributed in many of the explaining models for vitamin B6 status parameters. Therefore, when assessing the vitamin B6 status of a population, it is important to estimate the level of alcohol intake as well. Furthermore, the results illustrate the importance of sex related differences in the metabolism of some parameters, especially homocysteine excretion. The variance in the clinical function related status parameter measured in the present study, handgripstrength, was explained for 50% by a combination of age, body weight and Quetelet Index (QI) with no important contribution of dietary variables.

Objective: To describe the rationale, design and methods for a nutrition surveillance study with special reference to vitamin B6 and other micronutrients., Rationale and Design: Several studies in the Netherlands have shown that differences in dietary intake and in nutritional status indicators are relatively small among various socio-demographic groups, so that the relevance of this traditional risk group identification in terms of public health and nutrition policy is limited. Therefore, it was decided to use the diet itself as primary selection criterion for a study on the adequacy of the vitamin B6 supply. The first Dutch national food consumption survey in 1987/88 showed, among other things, that mean vitamin B6 intake (per gram of protein) was substantially below the adequate level for all age-gender groups studied. Since the potential impact on public health of this observation may be relatively large, intake of vitamin B6 was chosen as first selection criterion. A study design that creates the largest possible distinction in vitamin B6 intake would be most efficient to study the health risks as a consequence of a low vitamin B6 intake. Several arguments, such as the need to estimate the prevalence of an inadequate status of vitamin B6 and other micronutrients, led to the decision to use a random population sample as a reference group for comparison with the group with low habitual vitamin B6 intake. Other major arguments underlying the study design and the selection of the nutritional status indicators, as well as the framework of the Dutch Nutrition Surveillance System, are discussed. Finally, the design and methods of the study are described in detail (except food consumption methods).

Objective: To assess the adequacy of folate intake and status among adults in the Netherlands., Design and Subjects: Dietary intake was measured by 3 d diet records among 444 adults, aged 20-79 y, stratified for sex and 10 y age classes, with an overrepresentation of people with a low habitual intake of vitamin B6. Serum folate and other physical, biochemical and lifestyle characteristics were determined, and interrelationships were evaluated by bi- and multivariate regression analysis., Results: Mean folate intake was 325 and 308 microg/d in men aged 20-49 and 50-79 y, respectively. In both younger and older women mean folate intake was 270 microg/d. The prevalence of intakes below the lower limit of the recommended range (200-300 microg/d) was 10-20% among different age-gender groups. No intakes below the average minimum requirement of 100 microg/d were observed. The recommendation of 400 microg folate/d for women who wish to become pregnant was not met by 95% of the women aged 20-49 y. Potatoes, vegetables and fruit provided 36% of folate in the diet; other important sources were bread (18%) and dairy products (16%). Mean serum folate levels were 11.3 and 12.1 nmol/l in younger and older men, respectively. In younger and older women these levels were 12.2 and 14.2 nmol/l, respectively. Serum folate levels below 5 nmol/l (the 2.5 percentile of healthy blood donors) were present in 4% of the older men, but not in the other age-gender-groups. Serum folate levels were clearly influenced by recent folate intake. Furthermore, physiological and lifestyle variables, notably alcohol and tobacco use, were important determinants of serum folate., Conclusion: The folate intake among adult men and women was adequate in view of recommended daily intakes. However, the folate intake among women did not meet the recommendation for those who want to become pregnant. According to criteria derived from homocysteine metabolism as related to cardiovascular disease, folate status may not be adequate in 60-79% of adult age-sex groups.

Objective: To assess the adequacy of micronutrient status among the adult population, with special reference to vitamin B6 status., Design and Subjects: Micronutrient status was assessed among a random sample of the adult Dutch population (reference group, n = 300), aged 20-79 y, stratified for age and gender, and among a group with a low vitamin B6 intake (n = 144)., Results: Low vitamin B6 groups had lower mean levels of erythrocyte and plasma pyridoxal (PL) and pyridoxal-5'-phosphate (PLP), urinary excretion of 4-pyridoxic acid, basal and stimulated erythrocyte aspartate aminotransferase (EAST) and erythrocyte alanine aminotransferase (EALT) activities and EAST stimulation coefficients but not of EALT stimulation coefficients, handgripstrength and 24 h homocysteine excretion before and after a methionin load test. Besides, plasma levels of vitamin C, B12 and folate were lower among low B6 than among reference groups indicating a combined low vitamin status. Direct biomarkers of vitamin B6 intake (plasma PLP and 4-pyridoxic acid excretion) were significantly related to more functional parameters (EAST, EALT and alpha-EAST). Among random reference groups the prevalence of plasma PLP values below 19 nmol/l was 3-7% for different age-gender groups, with the highest value of 16% among men aged 50-79 years. The prevalence of high values of erythrocyte glutathion reductase stimulation coefficient (alpha-EGR) and low levels of serum vitamin B12 and C was not more than 5% among different age-gender reference groups., Conclusions: Direct biomarkers of vitamin B6 intake confirmed the preselection of a group with a low vitamin B6 intake. The results suggest that the sensitivity of vitamin B6 status parameters for low vitamin B6 intake was highest for the direct vitamin B6 status parameters and lowest for handgripstrength and homocysteine excretion after a methionin load; results for enzyme stimulation coefficients were intermediate. The prevalence of below adequate status parameters for vitamin B2, B6, B12 and C was not more than 7% among the different age-gender groups, with the exception of a value of 16% for plasma PLP levels below 19 nmol/l among men aged 50-79.