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This study aimed to determine disease activity patterns in juvenile systemic lupus erythematosus (jSLE) and its relation to early treatment. All jSLE patients who visited the outpatient departments of three Dutch university hospitals for at least 6 months were included. Data were retrospectively collected from each patient visit and hospitalization. Patient characteristics, clinical and laboratory findings categorized in organ systems, flare rate, medication use and disease course were analysed. Included were 35 patients (female 77%; White 47%) with a total follow-up of 142 years. Median age at diagnosis was 12.8 years. Flare rate was 0.45/patient-year. An organ system not earlier involved was affected in 34% of flares. Identifiable disease activity patterns were: chronic active (49%), relapse remitting (14%) and long quiescence (37%), with no significant difference in organ involvement at diagnosis. Positive anti-Sm and non-White ethnicity were significantly associated with a chronic active pattern. In 14 patients with severe symptoms at diagnosis, treatment with intravenous cyclophosphamide and/or biologics and/or intravenous methylprednisone in the first 6 months resulted in a long quiescence pattern in seven patients. In conclusion, distinct disease activity patterns are identifiable in children. Suppression of disease with early aggressive treatment may decrease the rate of progression. Lupus (2010) 19, 1550-1556.

Objective:To evaluate changes in health-related quality of life (HRQoL) in patients with refractory juvenile idiopathic arthritis (JIA) who are being treated with etanercept.Methods:53 patients with JIA from seven Dutch centres were included. HRQoL was measured by the Childhood Health Assessment Questionnaire (CHAQ), Child Health Questionnaire (CHQ) and Health Utilities Index mark 3 (HUI3) at the start and after 3, 15 and 27 months of treatment. At the same time points the following JIA disease activity variables were collected; physician’s global assessment through the visual analogue scale (VAS), number of active and limited joints and erythrocyte sedimentation rate. A statistical method linear mixed models was used to assess outcomes over time.Results:During etanercept treatment both disease-specific and generic HRQoL outcomes improved dramatically. Significant improvements were shown after 3 months and these improvements continued at least up to 27 months of treatment. The disease-specific CHAQ, including VAS pain and wellbeing, showed a significant improvement in all domains. The generic health-profile measure CHQ improved for all the health concepts except for “family cohesion”, which was normal. The generic preference-based HUI3 showed impairment and, subsequently, significant improvement in the more specific domains (“pain”, “ambulatory”, “dexterity”). In accordance disease activity variables also improved significantly over time.Conclusion:This study shows that the HRQoL of patients with refractory JIA can be substantially improved by the use of etanercept for all aspects impaired by JIA. Information on HRQoL is crucial to understand the complete impact of etanercept treatment on patients with JIA and their families.

OBJECTIVES: Most clinical studies use paper case record forms (CRFs) to collect data. In the Dutch multi-centre observational study on biologicals we encountered several disadvantages of using the paper CRFs. These are delay in data collection, lack of overview in collected data and difficulties in obtaining up-to-date interim reports. Therefore, we wanted to create a more effective method of data collection compared with CRFs on paper in a multi-centre study.METHODS: We designed a web-based register with the intention to make it easy to use for participating physicians and at the same time accurate and up-to-date. Security demands were taken into account to secure the safety of the patient data.RESULTS: The web-based register was tested with data from 161 juvenile idiopathic arthritis patients from nine different centres. Internal validity was obtained and user-friendliness guaranteed. To secure the completeness of the data automatically generated e-mail alerts were implemented into the web-based register. More transparency of data was achieved by including the option to automatically generate interim reports of data in the web-based register. The safety was tested and approved.CONCLUSIONS: By digitalizing the CRF we achieved our aim to provide easy, rapid and safe access to the database and contributed to a new way of data collection. Although the web-based register was designed for the current multi-centre observational study, this type of instrument can also be applied to other types of studies. We expect that especially collaborative study groups will find it an efficient tool to collect data.

This exploratory study examines the relationship between design and competitive advantage in a technology-driven sector. The sector chosen as a research setting is the Dutch information technology (IT) sector. The research on managerial perceptions of the benefits and costs of design focused on the design dimensions of usability and aesthetics. Semi-structured interviews with managers from eight IT companies were conducted to collect empirical data and two feedback sessions were organized to verify the conclusions drawn. As expected, it was found that design is a relatively under-utilized strategic tool in the Dutch IT sector. Sensitivity to usability and aesthetics throughout the NPD process, however, seems necessary considering the tendency towards price competition in the IT sector as a consequence of overcapacity and standardization of IT technology and functionality, and an increasingly critical attitude of customers towards the costs of IT. The only solution to this cost trap would seem to ...

Purpose Cisplatin was found to radiosensitize SW-1573 cells by inhibition of PLDR. Therefore, it was investigated whether cisplatin combined with γ-radiation leads to an increase in the number of chromosomal aberrations or apoptotic cells compared with radiation alone. Methods Confluent cultures of the human lung carcinoma cell line SW-1573 were treated with 1 μM cisplatin for 1 h, 4 Gy γ-radiation, or a combination of both. Cell survival was studied by the clonogenic assay. Aberrations were analysed by FISH in prematurely condensed chromosomes (PCC) and the induction of apoptosis by counting fragmented nuclei. Results A radiosensitizing effect of cisplatin on cell survival was observed if time for PLDR was allowed. An increased number of chromosomal fragments were observed immediately after irradiation compared with 24 h after irradiation whereas color junctions are only formed 24 h after irradiation. No increase in chromosomal aberrations was found after combined treatment, but a significantly enhanced number of fragmented nuclei were observed when confluent cultures were replated after allowing PLDR. Conclusion The inhibition of PLDR by cisplatin in delayed plated SW-1573 cells did not increase chromosomal aberrations, but increased the induction of apoptosis.

Background: In children with severe rheumatic disease (RD), treatment with corticosteroids (CS) is frequently needed and growth retardation and osteopenia may develop. A beneficial effect of human growth hormone (hGH) has been reported but mostly in trials without a control group.Aims: To study the effect of hGH on growth, bone mineral density (BMD), and body composition, taking the disease activity and CS use into account.Methods: Randomised controlled trial on 17 prepubertal RD patients with growth retardation and/or decreased BMD. The hGH group (n = 10) received treatment with hGH 4 IU/m(2)/day (similar to 0.045 mg/kg/ day) during two years. The controls (n = 7) received no GH treatment.Results: During the two year study period the disease activity, and use of CS and methotrexate (MTX) did not differ between the groups. There was a significant mean increase in height standard deviation score ( HSDS) in the hGH group (0.42 +/- 0.16 SDS) and a non-significant decrease in the controls (-0.18 +/- 0.11 SDS). Change in BMD did not differ significantly between the groups, although the increase in BMD for lumbar spine within the hGH group was significant. Lean body mass improved significantly in the hGH group compared to controls (0.64 +/- 0.19 SDS versus -0.20 +/- 0.17 SDS), while the decrease in percentage fat was not significant.Conclusions: There was a significant effect of hGH on growth and lean body mass, but a longer duration of treatment might be necessary to evaluate the effect of hGH on BMD.

Objective: To evaluate the safety and efficacy of autologous stem cell transplantation (ASCT) for refractory juvenile idiopathic arthritis (JIA). Design: Retrospective analysis of follow up data on 34 children with JIA who were treated with ASCT in nine different European transplant centres. Rheumatological evaluation employed a modified set of core criteria. Immunological reconstitution and infectious complications were monitored at three month intervals after transplantation. Results: Clinical follow up ranged from 12 to 60 months. Eighteen of the 34 patients (53%) with a follow up of 12 to 60 months achieved complete drug-free remission. Seven of these patients had previously failed treatment with anti-TNF. Six of the 34 patients (18%) showed a partial response (ranging from 30% to 70% improvement) and seven (21%) were resistant to ASCT. Infectious complications were common. There were three cases of transplant related mortality (9%) and two of disease related mortality (6%). Conclusions: ASCT in severely ill patients with JIA induces a drug-free remission of the disease and a profound increase in general wellbeing in a substantial proportion of patients, but the procedure carries a significant mortality risk. The following adjustments are proposed for future protocols: (1) elimination of total body irradiation from the conditioning regimen; (2) prophylactic administration of antiviral drugs and intravenous immunoglobulins until there is a normal CD4+ T cell count.

In juvenile idiopathic arthritis (JIA) patients there is a lack of markers that predict severe disease. Although anticitrullinated protein antibodies (ACPA) have contributed substantially to the understanding of rheumatoid arthritis (RA),1 their detection in JIA has not been equally useful as incidence rates in JIA patients are low2 and merely confined to the polyarticular immunoglobulin (Ig)M-rheumatoid factor (RF)-positive category resembling RA. Recently, anticarbamylated protein (anti-CarP) antibodies were detected in 45% of RA patients and importantly also in 16%–20% ACPA-negative patients.3–5 Within the ACPA-negative patients, anti-CarP antibodies were associated with more severe radiographic progression.3 Since most JIA patients are ACPA-negative we investigated whether anti-CarP antibodies are present in the sera of JIA patients and how they are related to ACPA and IgM-RF. JIA patients from three Dutch sources were included: the BeSt for Kids trial (NTR 1574, a treatment strategy study) (n=33), a previously described cohort6 (n=48) and the Arthritis and Biologicals in Children (ABC) register7 (n=153). Healthy controls (n=107) (mean age/range 11/(2–20)) are stem-cell graft …

The course of central nervous system systemic lupus erythematosus (CNS-SLE) is largely unknown. New imaging techniques are available to assist in monitoring the disease course.To report a case of juvenile CNS-SLE, in which magnetic resonance imaging (MRI) was used to assess disease activity.A 10-year-old female patient with SLE presented with convulsions; MRI and computed tomography (CT) of the cerebrum disclosed abnormalities. Despite adequate treatment, two years later she had a generalised convulsion, and MRI showed new lesions. MR spectroscopy (MRS) indicated neuronal loss, inflammation, and metabolically compromised tissue; magnetisation transfer imaging (MTI) showed an increase in whole brain lesion load. After exclusion of a malignancy, CNS-SLE was the most likely diagnosis, and cyclophosphamide pulses were administered. Initially, multiple sclerosis (MS)-like lesions regressed, but despite maximal immunosuppressive drugs, new lesions formed and disappeared. When immunosuppressive drugs had been stopped for six months MRI showed improved lesions and MTI histograms.In this case report, the anatomical substrate, metabolic aspect, neuroimaging, and clinical course of MS-like lesions in a child with CNS-SLE are described. The way in which radiological techniques can support clinical decision making in this young patient with progressive CNS-SLE is illustrated.

Objective: Juvenile idiopathic arthritis (JIA) is a chronic disorder in which both genetic and environmental factors are involved. Recently, we identified the TRAF1/C5 region (located on chromosome 9q33–34) as a risk factor for rheumatoid arthritis (RA) (p combined = 1.4×10 −8 ). In the present study the association of the TRAF1/C5 region with the susceptibility to JIA was investigated. Methods: A case–control association study was performed in 338 Caucasian patients with JIA and 511 healthy individuals. We genotyped the single nucleotide polymorphism rs10818488 as a marker for the TRAF1/C5 region. Results: The A allele was associated with the susceptibility to rheumatoid factor-negative polyarthritis with an 11% increase in allele frequency (OR 1.54, 95% CI 1.09 to 2.18; p = 0.012). This association was stronger when combining subtypes with a polyarticular phenotype (OR 1.46, 95% CI 1.12 to 1.90; p = 0.004). In addition, we observed a trend towards an increase in A allele frequency in patients with extended oligoarthritis versus persistent oligoarthritis (49%, 38% respectively); p = 0.055. Conclusions: Apart from being a well replicated risk factor for RA, TRAF1/C5 also appears to be a risk factor for the rheumatoid factor-negative polyarthritis subtype of JIA and, more generally, seems to be associated with subtypes of JIA characterised by a polyarticular course.

Objective. To assess the efficacy, tolerability, and safety of sulfasalazine (SSZ) in the treatment of juvenile chronic arthritis (JCA). Methods. We conducted a 24-week randomized, placebo-controlled, double- blind, multicenter study of patients with active JCA of both oligoarticular and polyarticular onset. Patients were treated with a dosage of 50 mg/kg/day of SSZ (maximum 2,000 mg/day) or placebo. The efficacy variables were joint scores, physician's, parents', and patient's overall assessments, and laboratory parameters of inflammation. Results. Of the 69 patients enrolled, 52 (75%) completed the trial. Six patients (18%) withdrew from the placebo group, and 11 (31%) withdrew from the SSZ group (P = 0.18). In the intention- to-treat analysis of end point efficacy, between-group differences were significant for the overall articular severity score (P = 0.02), all global assessments (P = 0.01), and the laboratory parameters (P < 0.001). Adverse events occurred more frequently in the SSZ group and were the main reason for withdrawal (P < 0.001), but in all instances, these events were transient or reversible upon cessation of treatment. Conclusion. The results of this first placebo-controlled study show that SSZ is effective and safe in the treatment of children with oligoarticular- and polyarticular-onset JCA, although it was not well tolerated in one-third of the patients.

Female sex hormones affect susceptibility to systemic lupus erythematosus (SLE). To determine the effect of female sex hormones at onset of SLE on the survival of these patients, a retrospective survey was performed. The charts of 168 female SLE patients were evaluated to study the disease course, in particular the presence and kind of SLE criteria. Patients were classified as either belonging to the 'high female sex hormone at onset (HH)' or 'low female sex hormone at onset (LH)' group according to age at diagnosis. The statistics of the Dutch population, matched for age, were used to control for differences in life expectancy in these groups. A Cox regression model revealed that the relative mortality risk of HH patients vs HH controls was 4.2 times higher than the relative mortality risk of LH patients compared to LH controls. No differences in the frequency of SLE criteria between HH and LH patients were found that could explain the observed difference in mortality risk.

The time dependence of the kink power in weakly index guided high power stripe lasers in the AlGaAs system are investigated. A periodic dependence of the kink power on the length of the laser is observed in continuous and pulsed modes, but the pulsed mode kink curve is shifted with respect to the continuous one. This is observed to be proportional to 1/τ, where τ is the pulse width. The kink is due to phase locking of the modes of the waveguide resulting from a shift of the effective indexes, which is driven by self-heating due to free-carrier absorption of the laser mode.

To assess the efficacy, tolerability, and safety of sulfasalazine (SSZ) in the treatment of juvenile chronic arthritis (JCA).We conducted a 24-week randomized, placebo-controlled, double-blind, multicenter study of patients with active JCA of both oligoarticular and polyarticular onset. Patients were treated with a dosage of 50 mg/kg/day of SSZ (maximum 2,000 mg/day) or placebo. The efficacy variables were joint scores, physician's, parents', and patient's overall assessments, and laboratory parameters of inflammation.Of the 69 patients enrolled, 52 (75%) completed the trial. Six patients (18%) withdrew from the placebo group, and 11 (31%) withdrew from the SSZ group (P = 0.18). In the intention-to-treat analysis of end point efficacy, between-group differences were significant for the overall articular severity score (P = 0.02), all global assessments (P = 0.01), and the laboratory parameters (P0.001). Adverse events occurred more frequently in the SSZ group and were the main reason for withdrawal (P0.001), but in all instances, these events were transient or reversible upon cessation of treatment.The results of this first placebo-controlled study show that SSZ is effective and safe in the treatment of children with oligoarticular- and polyarticular-onset JCA, although it was not well tolerated in one-third of the patients.

Connective tissue remodelling has been studied at the fine structural level at the periphery of skin wounds repairing by both first and second intention. The periphery of such wounds was studied as it was predicted that not only would remodelling between old and new connective tissue be taking place, but that the fibroblast would be involved. Excisional and incisional wounds were made in the skin of adult mice and biopsied 14 days later. Our results showed that numerous fibroblasts in the junctional zone between old and new connective tissue exhibited intracellular collagen within vesicles. These findings indicate that the fibroblast is capable of phagocytosing and degrading collagen and has a fundamental role to play in connective tissue remodelling.

First molar tooth germs were dissected from one-day-old mice; placed for one hour in McCoy's medium containing 10 μc tritiated thymidine and transplanted subcutaneously into young adult animals of the same strain. Seven, 14, 21 and 28 days after implantation the host animals were sacrificed and the transplants harvested. The transplants were then serially sectioned and autoradiographs prepared. Control sections were prepared of first molar tooth germs in situ, after dissection from the jaws and after labelling with tritiated thymidine. Forty-nine of the 115 transplanted tooth germs continued development with the formation of enamel, dentine, cement, periodontal ligament and bone. In some instances the transplanted tooth germs “erupted” through the skin with the establishment of an epithelial attachment. Examination of control sections showed that the transplants consisted of dental organ, dental papilla and a layer of ectomesenchymal cells continuous with the dental papilla and investing the dental organ. Examination of autoradiographs of the transplants showed labelling of cementoblasts and periodontal ligament fibroblasts, thereby establishing their origin from the ectomesenchymal cells investing the tooth germ.

Seventy-five- to one-hundred-micron slices of undemineralized human teeth were examined by transmitted light, incident light and polarized light microscopy, to determine the nature of Tomes' granular layer in root dentine. Transmitted light examination showed that the granules occupied differing levels within the section. Incident light microscopy showed that the granules were true spaces and polarized light microscopy showed that fibre orientation was not the cause of the granular layer. When thin sections (1 μ-0.75μ) of a tooth slice containing Tomes' granular layer were examined by light and electron microscopy no evidence of any spaces were found in the region where they had been demonstrated in the thick 75-100 μ section. Looping of the terminal portions of the dentinal tubules was found. A model system has been used to show that sectioning of this loop region could produce a space visible in thick sections and corresponding to a granule of Tomes' layer. It is suggested that this looping of dentinal tubules in root dentine, and not in the dentine beneath enamel, is the result of different rates of dentine deposition in these two areas.