An incidence study of diagnosed autism-spectrum disorders among immigrants to the Netherlands.

OBJECTIVE: To estimate the risk of developing autism-spectrum disorder (ASD) in children born to immigrants as compared with children of Dutch-born parents. METHOD: Retrospective, population-based cohort study of all live births (n = 106 953) between 1998 and 2007 in a circumscribed geographical region in the Netherlands. Cohort members were linked to the Psychiatric Case Register to identify diagnosed cases. RESULTS: A total of 518 cases of ASD were identified, including 150 children with autism and 368 children with Asperger syndrome or Pervasive Developmental Disorder Not Otherwise Specified (PDD-NOS). Children born to migrants from developing countries were at significantly lower risk of ASD [rate ratio (RR) = 0.6, 95% confidence interval (CI) 0.5-0.9] than children of Dutch-born parents. Within the ASD group, the risk for the subgroup with Asperger syndrome and PDD-NOS was reduced (RR = 0.4, 95% CI 0.3-0.6), whereas that for narrowly defined autism was non-significantly increased (RR = 1.4, 95% CI 0.9-2.4). Migrant groups did not differ in age at diagnosis. CONCLUSION: The results echo Swedish findings indicating a reversal of risk gradient in children of parents from developing countries, specifically a decreased risk for high-functioning and increased risk for low-functioning autism.

Risk of psychiatric treatment for mood disorders and psychotic disorders among migrants and Dutch nationals in Utrecht, The Netherlands.

PURPOSE: While there are consistent reports of a high psychosis rate among certain groups of migrants in Europe, there is little information on their risk for mood disorders. The aim of this study was to investigate the risk of receiving psychiatric treatment for mood disorders or psychotic disorders, comparing migrants and Dutch nationals in an ethnically mixed catchment area. A second aim was to calculate the 1-year prevalence rates of psychotic disorders in first-generation migrants. METHOD: A psychiatric registry provided information on treatments at all in- and outpatient facilities. Statistics Netherlands provided annual population figures. RESULTS: The risk of receiving treatment for unipolar depressive disorder was increased for the Turkish-Dutch (first and second generation combined; age- and sex-adjusted relative risk 4.9; 95% CI: 4.4-5.5), Moroccan-Dutch (RR = 3.6; 3.3-4.0) and Surinamese-Dutch (RR=1.8; 1.5-2.2). The risk of being treated for bipolar disorder was not significantly increased for any group, except for the Turkish-Dutch of the second generation. The risk of treatment for non-affective psychotic disorder was very high for the Turkish-Dutch, Moroccan-Dutch and Surinamese-Dutch of the second generation. There was a large difference in the relative risk of this disorder between the Turkish-Dutch of the first (RR = 1.3; 1.0-1.8) and the second generation (RR = 8.7; 5.5-13.9). The 1-year prevalence rates of treated psychotic disorders were highest for Surinamese-Dutch (2.1%) and Moroccan-Dutch males (1.2%) of the first generation. Migrants from western-European countries were not at increased risk for any of these disorders. CONCLUSIONS: The stressful position of non-Western migrants in Dutch society has negative consequences on their mental health.

[A case study; ethnicity and clozapine, a risky combination?]. / Etniciteit en clozapine: wees bedacht op benigne etnische neutropenie.

Agranulocytosis is a very serious side-effect of treatment with clozapine. For this reason, the Dutch guidelines state the specific values of leukocyte and neutrophil counts at which treatment with clozapine should be discontinued. We focus on a patient with a benign ethnic neutropenia who, despite a low neutrophil count, was allowed to continue taking clozapine. We discuss a number of important practical considerations that can affect the way in which leukocyte and neutrophil counts are interpreted in relation to the use of clozapine.

Low treatment adherence with antipsychotics is associated with relapse in psychotic disorders within six months after discharge.

OBJECTIVE: The aim of this study was to assess the association between treatment adherence with antipsychotics and schizophrenia relapse on a continuous scale. METHOD: A cohort study with a total of 477 patients with schizophrenia who were recently discharged from an inpatient clinic was performed. RESULTS: In the 160 people who relapsed within the six months after discharge the average medication possession ratio was 0.50. This was 0.59 in the 317 persons who were not readmitted. The resulting hazard ratio for the medication possession ratio on relapse risk was 0.60 (95% confidence interval: 0.42-0.88). CONCLUSION: The found hazard ratio indicates that the risk of relapse is substantially decreased when a patient is properly adherent to the antipsychotic therapy that was prescribed at the inpatient clinic.

Non-steroidal anti-inflammatory drugs and the risk of psychosis.

The objective of the current research was to examine the relation between non-steroidal anti-inflammatory drugs (NSAID) use and risk of psychosis. To this end we performed a longitudinal case-control study using prescription data from a Dutch health insurance company. Men aged 25 years or over and women aged 30 years or over were excluded to prevent inclusion of non-incident cases. This resulted in eighty-two cases and 359 randomly selected controls from the same population. The overall relative risk of incident antipsychotic use for NSAID users, adjusted for age and prescription frequency, was 0.80 (95% CI: 0.48-1.33). After stratification for gender the risk of psychosis was significantly lower (59%) in male NSAID users only. The relative risks for male and female subjects were 0.41 (95% CI: 0.17-0.97) and 1.31 (95% CI: 0.65-2.64), respectively. These results suggest that in men NSAIDs may lower the risk of psychosis.

No therapeutic effect of plasmin antagonist tranexamic acid in rheumatoid arthritis. A double-blind placebo-controlled pilot study.

OBJECTIVE: In the present study, the effects of plasmin antagonist tranexamic acid (TEA) on urinary pyridinoline excretion rates were investigated in rheumatoid arthritis (RA) patients. METHODS: The study was set up as a double-blind placebo-controlled pilot study. Ten patients received tranexamic acid and 9 received placebo for 12 weeks. Urinary excretion rates of hydroxylysylpyridinoline (HP) and lysylpyridinoline (LP) were used as molecular markers of articular cartilage and bone degradation. In addition, clinical parameters of disease activity were assessed and CRP levels were measured. RESULTS: Treatment with TEA did not reduce pyridinoline excretion, nor was any effect observed on clinical parameters of disease activity or on CRP levels. CONCLUSION: The results of the present pilot study show no beneficial effect of TEA as adjuvant therapy in RA patients with respect to joint destruction or disease activity.

Reliability of spot samples for assessment of urinary excretion of pyridinoline in patients with rheumatoid arthritis.

OBJECTIVE: To determine how well a spot urine sample of patients with active rheumatoid arthritis (RA) can predict 24-hour urinary pyridinoline and deoxypyridinoline excretion. METHODS: Urine samples of 11 hospitalized RA patients taken on 2 consecutive days at 8 a.m. and 4 p.m. were compared with samples from 24-hour collections (gold standard). High-performance liquid chromatography was used to measure the collagen crosslink concentrations. RESULTS: Sampling time was the only significant factor (repeated measurement ANOVA). Significant differences were found between morning and 24-hour samples and between morning and afternoon samples, but not between afternoon and 24-hour samples. CONCLUSIONS: Samples collected in the afternoon (4 p.m.) give the best approximation of 24-hour urinary pyridinoline excretion in patients with active rheumatoid arthritis. In longitudinal studies the sampling time should be fixed.

Validity and reliability of the Katz-15 scale to measure unfavorable health outcomes in community-dwelling older people.

OBJECTIVES: To predict the risk of future unfavourable health outcomes in older people it is common to assess the level of both basic and instrumental activities of daily living. To accomplish this, the commonly used Katz-6 and the Lawton IADL questionnaires can be combined to form the 'Modified Katz ADL' scale, also known as the Katz-15 scale. So far, the validity and reliability of the Katz-15 scale is unknown. The objective of the current study is to investigate how well the Katz-15 is able to predict future unfavorable health outcomes and how this is related to the existing Katz-6 scale. DESIGN: We performed a follow-up study using data from a group of 60 year and older participants from a large Dutch clinical trial. PARTICIPANTS: We included 2321 participants in the analysis. The average age of the study population was 74 years and 44% was male. MEASUREMENTS: We studied the relation between the Katz-15 scale and a number of unfavourable health outcomes, such as hospitalization, admission to a nursing home, admission to a home for the aged and death within one year of follow-up. RESULTS: We found the Katz-15 to be both internally consistent and strongly associated with quality of life measures. We observed moderate to strong associations between the Katz-15 and the unfavourable health outcomes All associations studied were stronger for the Katz-15 scale as compared to the Katz-6 scale. CONCLUSION: The results of our study indicate that the Katz-15 scale is able to reliably and validly predict future unfavorable health outcomes. This makes the scale a valuable measure in determining both basic and instrumental activities of daily living.

From primary photochemistry to biological function in the blue-light photoreceptors PYP and AppA.

To properly respond to changes in fluency conditions, Nature has developed a variety of photosensors that modulate gene expression, enzyme activity and/or motility. Dedicated types have evolved, which can be classified in six families: rhodopsins, phytochromes, xanthopsins, cryptochromes, phototropins and BLUF-proteins. The photochemistry of the first three families is based on cis/trans isomerization of an ethylene bond. Surprisingly, the latter three all use flavin as their chromophore, but each with very different photochemistry. In this contribution we will discuss the molecular basis of signal generation in a xanthopsin (Photoactive Yellow Protein (PYP) from Halorhodospira halophila), a photoreceptor for negative phototaxis, and in a BLUF protein (AppA from Rhodobacter sphaeroides), a transcriptional anti-repressor. PYP is activated through trans/cis isomerization of the 7,8-vinyl bond of its 4-hydroxycinnamic acid chromophore. This initiates a photocycle with multiple intermediates, like pB, which is formed after intramolecular proton transfer. The negative charge thus formed in the interior of the protein triggers formation of a partially unfolded signaling state. For AppA much less is known about the underlying photochemistry. Available evidence suggests that it is based on a light-induced change in the hydrogen-bonding of its flavin chromophore and/or a change in hydrophobic stacking between the flavin and/or nearby aromatic amino acids like Y 21. A signaling state is formed within microseconds, which recovers with a rate of approximately 10(-3) s(-1). The change in conformation between receptor- and signaling-state in AppA, however, appear to be minute as compared to those in PYP. Here we review the underlying chemistry in the various steps of the photocycle of these two photoreceptor proteins and provide new data on their mechanism and function.

Therapeutic suggestion has not effect on postoperative morphine requirements.

This study was designed to confirm the effect of therapeutic intraoperative auditory suggestion on recovery from anesthesia, to establish the effect of preoperative suggestion, and to assess implicit memory for intraoperative information using an indirect memory task. Sixty consenting unpremedicated patients scheduled for elective gynecologic surgery were randomly divided into three equal groups: Group 1 received a tape of therapeutic suggestions preoperatively, and the story of Robinson Crusoe intraoperatively; Group 2 heard the story of Peter Pan preoperatively and therapeutic suggestions intraoperatively; Group 3 heard the Crusoe story preoperatively and the Peter Pan story intraoperatively. A standardized anesthetic technique was used with fentanyl, propofol, isoflurane, and nitrous oxide. After surgery, all patients received patient-controlled analgesia (PCA) with a standardized regimen. In the 24 h postsurgery, morphine use was recorded every 6 h and at 24 h an indirect memory test (free association) was used to test for memory of the stories. Anxiety scores were measured before surgery and at 6 and 24 h postsurgery. There were no significant differences between groups for postoperative morphine use, pain or nausea scores, anxiety scores, or days spent in hospital after surgery. Seven of 20 patients who heard the Pan story intraoperative gave a positive association with the word "Hook," whereas 2 of 20 who did not hear the story gave such an association. Indirect memory for the Pan story was established using confidence interval (CI) analysis. (The 95% CI for difference in proportion did not include zero). No indirect memory for the Crusoe story could be demonstrated. This study did not confirm previous work which suggested that positive therapeutic auditory suggestions, played intraoperatively, reduced PCA morphine requirements. In contrast, a positive implicit memory effect was found for a story presented intraoperatively.

Lack of effect of doxycycline on disease activity and joint damage in patients with rheumatoid arthritis. A double blind, placebo controlled trial.

OBJECTIVE: To investigate the effects of doxycycline on disease activity and joint destruction in patients with rheumatoid arthritis (RA). METHODS: A 36 week double blind, placebo controlled crossover trial was conducted. Patients (n = 66) received 50 mg doxycycline or placebo twice a day during 12, 24, or 36 weeks. Patient assessments were performed before the treatment was administered, at 6, 12, 24 and 36 weeks of treatment, and finally at 4 weeks after cessation of treatment. Patient assessments, swollen and tender joint counts, duration of morning stiffness, erythrocyte sedimentation rate, and Modified Disease Activity Score were used as measures of disease activity. Effects on joint destruction were assessed by urinary excretion of the pyridinolines hydroxylysylpyridinoline and lysylpyridinoline and by scoring radiographic damage of hands and feet before and after treatment. RESULTS: The changes of clinical or laboratory disease activity measures, pyridinoline excretion, or progression of radiographic joint damage during doxycycline or placebo treatment did not differ significantly. CONCLUSION: The results indicate that 50 mg doxycycline twice a day provided no therapeutic benefit for patients with RA.

Glutathione conjugation of 1,2-dibromo-1-phenylethane in rats in vivo.

The metabolism of 1,2-dibromo-1-phenylethane (DBPE) was studied in rats. Administration of DBPE orally, in doses of 0.25-1.25 mmol/kg (66-330 mg/kg), to male Wistar rats resulted in the excretion of a single mercapturic acid in urine. The methyl esters of three potential mercapturic acid metabolites were synthesized: N-acetyl-S-(2-oxo-2-phenylethyl)-L-cysteine methyl ester (O),N-acetyl-S-(2-hydroxy-1-phenylethyl)-L-cysteine methyl ester (I), and N-acetyl-S-(2-hydroxy-2-phenylethyl)-L-cysteine methyl ester (II). GC/MS analysis showed that the methyl ester of the excreted mercapturic acid was identical with II. Quantitative measurement of II in urine by GLC showed that, after 24 hr, excretion of the mercapturic acid was almost complete and amounted to 41% of the administered dose. At doses higher than 1.00 mmol/kg, the excretion no longer increased. Inhibition of the oxidative pathways by ip injection of 1-phenylimidazole resulted in an excretion decrease of about 40%. (Pre)treatment with diethyl maleate lowered the excretion of mercapturic acid by 30-60%. Glutathione conjugates synthesized from DBPE and styrene oxide were separated by HPLC. Both compounds can produce the same two pairs of diastereomers, viz. (R)- and (S)-(2-hydroxy-1-phenyl-ethyl)glutathione ((R)-1 and (S)-1), and (R)- and (S)-(2-hydroxy-2-phenylethyl)glutathione ((R)-2 and (S)-2). These could be separated in the order (R)-2, (R)-1, (S)-1, and (S)-2 within 20 min. This method was also applied to examine glutathione conjugates excreted in bile after DBPE administration.(ABSTRACT TRUNCATED AT 250 WORDS)

Modulation of fibroblast-mediated cartilage degradation by articular chondrocytes in rheumatoid arthritis.

OBJECTIVE: To determine the role of chondrocytes and factors released from chondrocytes in cartilage destruction by fibroblast-like synoviocytes (FLS) derived from patients with rheumatoid arthritis (RA). METHODS: RA FLS from 2 patients were implanted into SCID mice, together with fresh articular cartilage or with cartilage that had been stored for 24 hours at 4 degrees C or at 37 degrees C. The invasion of the same RA FLS into the fresh and stored cartilage was compared histologically using a semiquantitative scoring system. In addition, we investigated whether protein synthesis in chondrocytes affects the invasion of RA FLS in vitro. A 3-dimensional cartilage-like matrix formed by cultured chondrocytes was labeled with 35S. After formation of the cartilage-like matrix, protein synthesis was blocked with cycloheximide. The invasion of RA FLS from 6 patients into cycloheximide-treated and untreated matrix was assessed by measuring the released radioactivity in coculture with and without interleukin-1beta (IL-1beta) and tumor necrosis factor alpha (TNFalpha). RESULTS: The SCID mouse experiments showed a significant invasion of RA FLS into the cartilage (overall mean score 3.2) but revealed significant differences when the invasion of the same RA FLS into fresh and stored cartilage was compared. RA FLS that were implanted with fresh articular cartilage showed a significantly higher invasiveness than those implanted with pieces of cartilage that had been stored for 24 hours (overall mean score 2.3). Storage at 37 degrees C and 4 degrees C resulted in the same reduction of invasion (35% and 37%, respectively). In the in vitro experiments, RA FLS rapidly destroyed the cartilage-like matrix. Blocking of chondrocyte protein biosynthesis significantly decreased the invasion of RA FLS, as shown by a decreased release of radioactivity. Addition of IL-1beta, but not TNFalpha, to the cocultures partially restored the invasiveness of RA FLS. CONCLUSION: These data underline the value of the SCID mouse in vivo model of rheumatoid cartilage destruction and demonstrate that chondrocytes contribute significantly to the degradation of cartilage by releasing factors that stimulate RA FLS. Among those, IL-1beta-mediated mechanisms might be of particular importance.

Bone turnover, joint damage and bone mineral density in early rheumatoid arthritis treated with combination therapy including high-dose prednisolone.

OBJECTIVES: Exploration of bone metabolism changes at different levels of disease activity, both with and without oral corticosteroid therapy, and prediction of changes in joint damage and bone density from the observed changes in markers of bone turnover. METHODS: Data analysis from a randomized clinical trial with 155 rheumatoid arthritis (RA) patients; median age 50 yr, early and active disease (diagnosis < 2 yr); one group treated with a combination of sulphasalazine (SSZ; 2000 mg/day), methotrexate (MTX; 7.5 mg/week) and prednisolone (initially 60 mg/day, tapered in six weekly steps to 7.5 mg/day), the other group with SSZ alone. Prednisolone and MTX were tapered and stopped after weeks 28 and 40, respectively, while SSZ was continued. Urine and serum samples were collected at baseline and weeks 16, 28, 40 and 56. Measurements of urinary pyridinoline (PYD) and deoxypyridinoline (DPD) and serum alkaline phosphatase (tAP) and osteocalcin (OC) were performed, as well as standard clinimetry and bone densitometry. RESULTS: Over time and in both treatment groups, bone formation and bone resorption markers showed a pattern similar to erythrocyte sedimentation rate (ESR): a significant decrease compared with baseline and a larger decrease with combined treatment at weeks 16 and 28. PYD excretion, tAP, OC, and joint damage scores were significantly lower in the combined treatment group. Changes in bone density (of spine and hips) did not significantly differ between treatment groups. Mainly cumulative ESR explained progression of joint damage. CONCLUSIONS: Prednisolone and disease-modifying anti-rheumatic drug therapy in patients with early and active RA are both independently associated with decreased levels of urinary excretion of bone collagen resorption markers PYD and DPD. Markers of bone formation and resorption closely followed changes in ESR in both treatment groups. Reduced bone resorption together with reduced bone formation-initially at a somewhat faster pace-resulted in less bone turnover and explain the observed (non-significant and partially reversible) extra bone loss in the lumbar spine associated with prednisolone (combined treatment).

Cartilage degradation and invasion by rheumatoid synovial fibroblasts is inhibited by gene transfer of a cell surface-targeted plasmin inhibitor.

OBJECTIVE: Joint destruction in rheumatoid arthritis (RA) is a result of degradation and invasion of the articular cartilage by the pannus tissue. The present study was undertaken to examine the role of the plasminogen activation system in cartilage degradation and invasion by synovial fibroblasts and investigate a novel gene therapeutic approach using a cell surface-targeted plasmin inhibitor (ATF.BPTI). METHODS: Adenoviral vectors were used for gene transfer. The effects of ATF.BPTI gene transfer on RA synovial fibroblast-dependent cartilage degradation were studied in vitro, and cartilage invasion was studied in vivo in the SCID mouse coimplantation model. RESULTS: The results indicate that cartilage matrix degradation by rheumatoid synovial fibroblasts is plasmin mediated and depends on urokinase-type plasminogen activator for activation. Targeting plasmin inhibition to the cell surface of the fibroblasts by gene transfer of a cell surface-binding plasmin inhibitor resulted in a significant reduction of cartilage matrix degradation in vitro and of cartilage invasion in vivo. Compared with uninfected rheumatoid synovial fibroblasts, the mean +/-SEM cartilage degradation in vitro was reduced to 87.9+/-0.9% after LacZ gene transfer versus a reduction to 24.0+/-1.6% after ATF.BPTI gene transfer (P<0.0001). The mean +/- SEM in vivo cartilage invasion score was 3.1+/-0.4 in the control-transduced fibroblasts and 1.8+/-0.4 in the ATF.BPTI-transduced fibroblasts (P<0.05). CONCLUSION: These results indicate a role of the plasminogen activation system in synovial fibroblast-dependent cartilage degradation and invasion in RA, and demonstrate an effective way to inhibit this by gene transfer of a cell surface-targeted plasmin inhibitor.