[Physicians and scientific research: slight decline of the numbers of physicians with a doctoral degree]. / Artsen en wetenschappelijk onderzoek: lichte teruggang van het aantal gepromoveerde artsen.

OBJECTIVE: To establish whether the number of physicians interested in a career in academia (i.e. research) is declining. DESIGN: Descriptive. METHOD: The researchers analysed the pre- and post-doctoral careers of PhD students at 3 university medical centres (VU Amsterdam, Nijmegen and Maastricht) in 4 separate reference years (1989, 1994, 1999 and 2003), using information from doctoral dissertations and the Dutch medical address book. The researchers recorded the gender of the students and the timing of the doctorate in relation to specialist training, university education and employment, as applicable. RESULTS: The total number of dissertations produced at the 3 medical faculties in the 4 reference years increased gradually by nearly a factor of 2 (1989: 112; 1994: 152; 1999: 198; 2003: 213). In terms of absolute numbers, the number of dissertations authored by physicians increased from 1989 to 1994 and again in 1999 (64, 90 and 105), but decreased slightly in 2003 (96). The percentage of female physicians obtaining a doctorate doubled during this period (1989: 9/64 (14); 2003: 28/96 (29)). Increasingly, physicians prepared their dissertation before or during their training as specialists or general practitioners (1989: 15/64 (23%); 2003: 51/96 (53%)). Ofthe clinical specialists who had received their doctorate, approximately half continued to work in an academic setting after obtaining their degree. This percentage remained approximately the same in all reference years (1989: 13/26 (50); 1994:19/35 (54); 1999: 21/45 (47); 2003: 21/40 (53)). CONCLUSION: Although the number of physicians performing scientific research as part of their doctoral degree project declined slightly in 2003 following an initial rise, our data indicate no cause for major concern. One reason may be increased interest in Clinical Research Fellow programmes. However, the future of medical research would look brighter if young physicians with doctorates had better career prospects within academic centres. To follow the academic careers of clinicians in The Netherlands, a national registry is needed to collect the type of data analysed in this study continually.

Trends in live birth prevalence of down syndrome in the Northern Netherlands 1987-96: the impact of screening and prenatal diagnosis.

In the Northern Netherlands, we examined the live birth prevalence of Down syndrome (DS) and the impact of maternal serum screening (MSS) and prenatal cytogenetic diagnosis (PCD) during the period 1987-96. In this period the live birth prevalence, based on the maternal age distribution and the age specific risk of delivering a child with DS was expected to increase from 1.26 in 1987 to 1.62 in 1996. The introduction of MSS in 1991 made PCD available to women of all ages. Nevertheless, the utilization of PCD remained very stable. In 1991, 4.7% of pregnant women underwent a diagnostic test. In 1996 this percentage was 6.4%. As a result of MSS and PCD, the live birth prevalence of DS was 19% lower than expected (p<0.01). Despite utilization of PCD based on opting-in and a discouraging government policy regarding the offer of MSS, the percentage of DS cases detected by PCD increased from of 17% during the period 1987-90 to 27% in the period 1991-96 when MSS was available. The percentages have been corrected for spontaneous pregnancy loss. From a medical and financial point of view, MSS was the most cost-effective indication for PCD. However, the potential of reducing the birth prevalence of DS is limited by the low utilization of MSS and PCD by pregnant women.

[The SGO Health Research Promotion Program. XIII. Evaluation of the section 'Addiction Research']. / Het Stimuleringsprogramma Gezondheidsonderzoek (SGO). XIII. Evaluatie van het deelprogramma 'Verslavingsonderzoek'.

As a part of the SGO Health Research Promotion Programme a research programme on addiction research was realized. Aim of the programme was to strengthen and concentrate the Dutch research into addiction. Within the Amsterdam Institute for Addiction Research (AIAR), a structural collaboration between the Jellinek Treatment Centre for Addiction, the University of Amsterdam and the Academic Hospital of the University of Amsterdam, strategic research programmes were developed on the borderland of addiction and psychiatry, notably 'Clinical epidemiology addiction' and 'Developmental disorders, addiction and psychotraumas'. The institution of a co-ordinating platform of research groups conducting socio-epidemiological addiction research improved the co-ordination of research lines in this field.

[The SGO Health Research Promotion Program. XIV. Final evaluation]. / Het stimuleringsprogramma Gezondheidsonderzoek (SGO). XIV. Eindevaluatie.

In the Netherlands, the SGO Health Research Promotion Programme was carried out from 1986 until 1997. The aim of the programme was to strengthen patient-oriented clinical research in specific fields of medicine. Some of the programme sections certainly produced a number of good publications in established national and international journals, but the programme advisory committee's main objective was to bring about a cultural change in the field of health care investigation: awareness of the principle that scientific and notably patient-centred investigation has a place in its own right in research, education and care. This resulted in a large diversity of methods of stimulation ranging from stimulation of co-operation between researchers, training of physician researchers, support of methodology development, stimulation of education and postgraduate training, to establishment of actual institutes for clinical scientific research. Patient-oriented research is the necessary link within the continuum of health research, medical education and care. Changing social and demographic developments ask for continuous innovation of this type of research. Top-down steering, as practised by the SGO, can be necessary and effective to reach this innovation.

[The Health Research Promotion program (SGO). XII. Evaluation of the section 'Health Care Research-experimental postgraduate training of general practitioners']. / Het stimuleringsprogramma Gezondheidsonderzoek (SGO). XII. Evaluatie van het deelprogramma 'Gezondheidszorgonderzoek-Experimentele kaderopleiding huisartsen'.

As a part of the SGO Health Research Promotion Programme, programme section Health Care Research, an experimental core training was instituted for general practitioners. The aim of the training was to provide a small number of family physicians with clinical and medical expertise relevant to general practice that would enable them to play a leading role in the development of academic general practice medicine. Seven general physicians followed a self-composed training programme of 2 to 3 years, consisting of active participation in patient care in Dutch clinics and clinics in other countries. The experiences gained during the SGO programme were used by the Dutch College of General Practitioners to develop a nationwide superior professional training course.

Women's opinions and the implications of first- versus second-trimester screening for fetal Down's syndrome.

Two groups of pregnant women were questioned regarding their opinions on serum screening for Down's syndrome in the first trimester of pregnancy. One group comprised 83 women attending our antenatal clinic who were questioned at the time of the existing second-trimester screening test. Seventy-six per cent of those who participated in the second-trimester screening programme would have preferred the test to have been in the first trimester, mainly because of the easier termination of pregnancy and/or the earlier reassurance provided. The remaining 24 per cent could see no advantage in the earlier time frame. Of the 49 women who had declined second-trimester screening, only two would have participated in screening had it been in the first trimester. The other group comprised those women attending our antenatal diagnosis clinic who were considering chorionic villus sampling (CVS). Forty-four per cent of these women would have allowed serum screening in the first trimester to influence their decision as to whether to undergo definitive prenatal diagnostic testing. In general, those women who made use of second-trimester serum screening would also do so in the first trimester. Those who declined the existing screening programme would also decline first-trimester screening. Many women currently deciding to undergo CVS would allow a first-trimester screening test to influence their decision.

[AGIKO (Clinical Research Fellow); a training model aimed at enhancement of clinical scientific research]. / 'Assistent-geneeskundige in opleiding tot klinisch onderzoeker' (AGIKO); opleidingsmodel ter versterking van klinisch-wetenschappelijk onderzoek door huisarts en specialist.

The enhancement of clinical scientific research in the Netherlands is being stimulated to a substantial extent by the introduction and stimulation of a training model aimed at the combined training of physicians to both a general practitioner or specialist and a clinical researcher, the AGIKO (Clinical Research Fellow). The model has been recognized by the Central College for Recognition and Registration of Medical Specialists. Extra stimulation by the section Medical Sciences of the Netherlands Organization for Scientific Research (MW-NWO) makes it possible to appoint AGIKOs on second or third flows of funds but also within the first flow of funds. During the last two years, 25 AGIKO applications from ten medical specialisms have been approved. The AGIKO model may help to meet (expected) needs for future clinical-medical research workers in specific research areas.

Maternal urinary beta-core hCG in chromosomally abnormal pregnancies in the first trimester.

We evaluated urinary beta-core human chorionic gonadotropin (beta-core hCG) in the detection of fetal Down's syndrome (DS) in the first trimester of pregnancy. Urine was collected prior to performing chorionic villous sampling (CVS) between 10 and 12 completed weeks from the last menstrual period. In the 9 months of the study, there were 15 chromosomal abnormalities detected by CVS: five trisomy 21, four monosomy X, two trisomy 18, and four cases of confined placental mosaicism (CPM). In these 15 aneuploid pregnancies, the levels of urinary beta-core hCG were expressed as multiples of the median (MOM) of the ratio of beta-core hCG/creatinine for gestational age. The MOMs of this ratio in each of the five DS pregnancies were 0.2, 0.5, 1.3, 1.4, and 1.7. No difference was found between fetuses with DS or any of the other chromosomal abnormalities tested and normal fetuses. Contrary to optimistic reports of urinary beta-core hCG in the second-trimester detection of fetal DS, our data suggest that this is not a useful screening test for DS in the first trimester of pregnancy.

[Stimulation Program Health Research. XI. Evaluation of the section 'Rehabilitation Medicine']. / Het Stimuleringsprogramma Gezondheidsonderzoek (SGO). XI. Evaluatie van het deelprogramma 'Revalidatiegeneeskunde'.

As a part of the SGO Health Research Promotion Programme a research programme on rehabilitation medicine was realized. Aim of the programme was to strengthen clinical research in this field by training clinical researchers and improving clinical research infrastructure. Three clinical specialists have been trained to become senior clinical researchers by a 4-year training programme, concentrated within 2 clusters of a medical faculty, a university hospital and one or more centres for rehabilitation medicine. As a follow-up to the programme a 6-week educational course was developed for intending MDs in rehabilitation medicine and five intending rehabilitation medicine specialists receive a PhD research training during their clinical specialisation.

Severe neutropenia in T-large granular lymphocyte leukemia corrected by intensive immunosuppression.

Optimum treatment of severe neutropenia, a major factor for morbidity and mortality in T-large granular lymphocyte (LGL) leukemia, is undefined. We observed a rapid improvement of the neutrophil count in a patient with T-LGL leukemia and severe neutropenia after the combined administration of antilymphocyte-globulin (ALG), cyclosporin A, prednisone, and granulocyte colony-stimulating factor (G-CSF). Although G-CSF treatment was terminated after 7 days, the neutrophil count has persisted above 1.0 x 10(9)/1 for up to 6 months now. Oral methotrexate is given continuously as treatment for T-LGL leukemia. The response to this immunosuppressive regimen suggests a T-cell-mediated mechanism as the underlying cause for neutropenia in T-LGL leukemia.

Selective conversion and esterification of monohydroxyeicosatetraenoic acids by human vascular smooth muscle cells: relevance to smooth muscle cell proliferation.

5-, 12-, and 15-hydroxyeicosatetraenoic acid (HETE), lipoxygenase metabolites of arachidonic acid that may modulate cell proliferation, were examined for their ability to affect the [3H]thymidine incorporation of human umbilical artery smooth muscle cells. We found that these hydroxy fatty acids inhibited the serum-induced [3H]thymidine incorporation of growth-arrested vascular smooth muscle cells in a similar dose-dependent manner. The inhibitory effect was dependent on the serum concentration used to stimulate cell growth. The higher the serum concentration, the lower the inhibitory effect of the HETE. In parallel experiments, the incorporation of HETEs into lipids of the smooth muscle cells was examined. After 20 h of incubation, we found that in the presence of 0.4% serum 70% of 3H-labeled 5-HETE was esterified into human vascular smooth muscle cell lipids. Twelve and eight percent, respectively, of 12- and 15-HETE were incorporated into smooth muscle cell lipids. Furthermore, we found that during the 20-h incubation of human umbilical artery smooth muscle cells with 12- and 15-HETE, these compounds were converted into metabolites with a chromatographic behavior on HPLC similar to that of diHETEs. 5-HETE was not converted into these polar metabolites. Increasing the serum concentration resulted in a decreased metabolism of all HETEs tested. Thus, the distinct differences between the metabolism of different HETEs by vascular smooth muscle cells does not reflect the proliferation inhibitory effect of these HETEs.

Involvement of cyclooxygenase- and lipoxygenase-mediated conversion of arachidonic acid in controlling human vascular smooth muscle cell proliferation.

We observed that the growth of human umbilical artery smooth muscle cells was inhibited by the phospholipase A2 inhibitors p-bromophenacylbromide and mepacrine. These findings suggest that fatty acid metabolism might be integrated in the control mechanism of vascular smooth muscle cell proliferation. To identify eicosanoids possibly involved in this process, we studied both the metabolism of arachidonic acid of these cells in more detail and the effect of certain arachidonic acid metabolites on smooth muscle cells growth. We found no evidence for the conversion of arachidonic acid via the lipoxygenase pathway. In contrast, arachidonic acid was rapidly converted via the cyclooxygenase pathway. The following metabolites were identified: prostaglandin E2 (PGE2), 6-keto-prostaglandin F1 alpha (6-k-PGF1 alpha), prostaglandin F2 alpha (PGF2 alpha), 12-hydroxyheptadecatrienoic acid (12-HHT) and 11-hydroxyeicosatetetraenoic acid (11-HETE). PGE2 was the major metabolite detected. Arachidonic acid metabolites were only found in the culture medium, not in the cell. After synthesis, 11-HETE was cleared from the culture medium. We have previously reported that PGE2 inhibits the serum-induced [3H]-thymidine incorporation of growth-arrested human umbilical artery smooth muscle cells. Here we show that also 11-HETE exerts this inhibitory property. Thus, our data suggests that human umbilical artery smooth muscle cells convert arachidonic acid only via the cyclooxygenase pathway. Certain metabolites produced by this pathway, including PGE2 and 11-HETE, may inhibit vascular smooth muscle cell proliferation.