Disease-modifying antirheumatic drug-free sustained remission in rheumatoid arthritis: an increasingly achievable outcome with subsidence of disease symptoms.

OBJECTIVE: Disease-modifying antirheumatic drug (DMARD)-free sustained remission, the sustained absence of synovitis after cessation of DMARD therapy, is a relevant long-term outcome of rheumatoid arthritis (RA) if (1) its occurrence is promoted by treatment and (2) this status reflects resolution of symptoms and disability. This study investigated both items. METHODS: 1007 patients with RA diagnosed between 1993 and 2011, included in the Leiden Early Arthritis Clinic, were studied on achieving DMARD-free sustained remission. Patients included in 1993-1995 were initially treated with non-steroidal anti-inflammatory drugs, in 1996-1998 mild DMARDs were started early, from 1999 onwards methotrexate was initiated promptly and from 2005 onwards disease activity score (DAS)-steered treatment was common. Remission rates were compared using Kaplan-Meier curves and Cox proportional regression. RESULTS: In total, 155 patients achieved DMARD-free sustained remission. Specific treatment strategies were significantly associated with achieving remission (p<0.001). Cox regression adjusted for anticitrullinated protein antibody/rheumatoid factor, swollen joint count, erythrocyte sedimentation rate, C-reactive protein revealed HRs for DMARD-free sustained remission of 1.13 (95% CI 0.48 to 2.64) in patients diagnosed in 1996-1998, 2.39 (1.07 to 5.32) in patients treated with early methotrexate (inclusion 1999-2004) and 3.72 (1.60 to 8.62) in those treated early with methotrexate and DAS-steered therapy (inclusion 2005-2011). At the time of remission, the Health Assessment Questionnaire was at the level of the general population (median 0.13, IQR 0-0.63). Also, patient-rated visual analogue scale (VAS) morning stiffness, fatigue, pain and disease activity were low (median (IQR) mm, 14 (2-27), 10 (0-47), 6 (0-20), 7 (0-20), respectively). CONCLUSIONS: More intensive treatment strategies increased the chance for DMARD-free sustained remission, indicating that RA chronicity can be influenced. Patients with RA achieving DMARD-free sustained remission have a normalised functional status.

Anticitrullinated protein antibodies and rheumatoid factor are associated with increased mortality but with different causes of death in patients with rheumatoid arthritis: a longitudinal study in three European cohorts.

OBJECTIVE: Patients with rheumatoid arthritis (RA)-related autoantibodies have an increased mortality rate. Different autoantibodies are frequently co-occurring and it is unclear which autoantibodies associate with increased mortality. In addition, association with different causes of death is thus far unexplored. Both questions were addressed in three early RA populations. METHODS: 2331 patients with early RA included in Better Anti-Rheumatic Farmaco-Therapy cohort (BARFOT) (n=805), Norfolk Arthritis Register (NOAR) (n=678) and Leiden Early Arthritis Clinic cohort (EAC) (n=848) were studied. The presence of anticitrullinated protein antibodies (ACPA), rheumatoid factor (RF) and anticarbamylated protein (anti-CarP) antibodies was studied in relation to all-cause and cause-specific mortality, obtained from national death registers. Cox proportional hazards regression models (adjusted for age, sex, smoking and inclusion year) were constructed per cohort; data were combined in inverse-weighted meta-analyses. RESULTS: During 26 300 person-years of observation, 29% of BARFOT patients, 30% of NOAR and 18% of EAC patients died, corresponding to mortality rates of 24.9, 21.0 and 20.8 per 1000 person-years. The HR for all-cause mortality (95% CI) was 1.48 (1.22 to 1.79) for ACPA, 1.47 (1.22 to 1.78) for RF and 1.33 (1.11 to 1.60) for anti-CarP. When including all three antibodies in one model, RF was associated with all-cause mortality independent of other autoantibodies, HR 1.30 (1.04 to 1.63). When subsequently stratifying for death cause, ACPA positivity associated with increased cardiovascular death, HR 1.52 (1.04 to 2.21), and RF with increased neoplasm-related death, HR 1.64 (1.02 to 2.62), and respiratory disease-related death, HR 1.71 (1.01 to 2.88). CONCLUSIONS: The presence of RF in patients with RA associates with an increased overall mortality rate. Cause-specific mortality rates differed between autoantibodies: ACPA associates with increased cardiovascular death and RF with death related to neoplasm and respiratory disease.

Evaluating relationships between symptom duration and persistence of rheumatoid arthritis: does a window of opportunity exist? Results on the Leiden early arthritis clinic and ESPOIR cohorts.

BACKGROUND: A prolonged symptom or disease duration at treatment initiation is associated with unfavourable outcomes in rheumatoid arthritis (RA). It is unknown whether this relation is linear, referring to a common 'the-earlier-the-better principle', or whether a transient time frame in which the disease is more susceptible to treatment exists, referring to a 'window of opportunity'. To elucidate this, we evaluated the shape of the associations of symptom duration with persistence of RA. METHODS: Patients with 1987 RA treated with disease modifying antirheumatic drugs (DMARDs) in the Leiden Early Arthritis Clinic (EAC, n=738) and Evaluation et Suivi de POlyarthrites Indifférenciées Récentes (ESPOIR) (n=533) were studied. Cox proportional hazards regression models using natural cubic splines were performed; the log-HR on DMARD-free sustained remission (the opposite of RA persistence) during 5-year follow-up was plotted against symptom duration. Discrimination was measured using time-dependent receiver operator characteristic curves. Subanalyses were performed stratified for the DMARDs used (methotrexate or other conventional DMARDs) and for anticitrullinated peptide antibody (ACPA). RESULTS: 11.5% (85/738) and 5.4% (29/533) of EAC and ESPOIR RA patients achieved DMARD-free sustained remission. In both cohorts and all analyses, the curves depicting the log-HRs on remission in relation to symptom duration were not linear. The symptom duration with optimal discriminative ability was 14.9 weeks (95% CI 12.3 to 16.0; area under the curve (AUC) 0.61) in the EAC and 19.1 weeks (95% CI 12.3 to 28.0; AUC 0.59) in ESPOIR. For ACPA-positive RA, this was 11.4 weeks (95% CI 7.7 to 79.0; AUC 0.56) and for ACPA-negative RA 15.0 weeks (95% CI 9.7 to 48.7; AUC 0.56). CONCLUSIONS: The association between symptom duration and RA persistence is not linear, suggesting the presence of a confined period in which RA is more susceptible to treatment.

What is the evidence for the presence of a therapeutic window of opportunity in rheumatoid arthritis? A systematic literature review.

OBJECTIVE: Initiation of DMARD-therapy in the 'window of opportunity' is thought to result in a more effective modification of the processes underlying rheumatoid arthritis (RA). We questioned whether this effect is true or hyped and performed a systematic literature review. METHODS: Medical literature databases up to June 2012 were systematically reviewed for cohort studies and randomised controlled trials reporting outcome data of early RA in relation with symptom duration at treatment initiation. The quality of these studies was assessed by two independent reviewers using a criteria scoring system of 15 items. Studies were dichotomised with the median score (79%) as cut-off. Best-evidence synthesis was applied to determine the level of evidence per outcome category. A meta-analysis was performed on the studies reporting on achieving DMARD-free sustained remission (the reverse of disease persistency). RESULTS: Out of 836 screened articles, 18 fulfilled the selection criteria and were not duplicates. Ten were scored as high quality. Remission (various definitions) and radiographic progression were frequently studied outcomes. There was strong evidence for an association between symptom duration and radiographic progression. A meta-analysis on datasets evaluating DMARD-free sustained remission showed that symptom duration was independently associated with such remission; HR 0.989 (95% CI 0.983 to 0.995) per week increase in symptom duration. A moderate level of evidence was observed for other remission outcomes. CONCLUSIONS: Even when heterogeneity of patients is taken into account, prolonged symptom duration is associated with radiographic progression and a lower chance on DMARD-free sustained remission. These data may support the presence of a 'window of opportunity'.

Long-term outcome of rheumatoid arthritis defined according to the 2010-classification criteria.

OBJECTIVE: The 2010 American College of Rheumatology/European League Against Rheumatism (ACR/EULAR) criteria for rheumatoid arthritis (RA) have been thoroughly studied for the test characteristics but it is unclear whether '2010 RA' has a different phenotype than '1987 RA' when assessing the severity of the disease course. Therefore this study compared two long-term disease outcomes. METHODS: 1502 early arthritis patients that had no other diagnoses than RA or undifferentiated arthritis (UA) were studied on fulfilling the 1987 ACR criteria, 2010 criteria or both. The severity of joint damage was studied with yearly radiographs over 7 years. Achieving disease-modifying anti-rheumatic drug (DMARD)-free sustained remission was assessed over 10-years follow-up. Multivariate normal regression and Cox-proportional hazard regression were used, adjusting for age, gender and treatment. RESULTS: 550 patients fulfilled the 1987 criteria, 788 patients the 2010 criteria and 489 both criteria sets. Patients fulfilling the 2010 criteria developed less severe radiological joint damage (p=0.023) and achieved DMARD-free sustained remission more often (HR=1.18 (0.93-1.50)) than patients fulfilling the 1987 criteria, though the latter was not statistically significant. All 1987+2010- patients were anti-citrullinated peptide antibody (ACPA)-negative. When also applying the radiologic criterion of the 2010-criteria, half of the 1987+2010- patients became 2010 criteria positive, but results on the long-term outcome remained similar. CONCLUSIONS: '2010 RA' has a milder disease course than '1987 RA'. This may have important implications for basic scientific studies and clinical trials in RA.

MRI-detected subclinical joint inflammation is associated with radiographic progression.

BACKGROUND: We recently demonstrated that MRI inflammation is prevalent in clinically non-swollen joints of early arthritis patients. In this study, we assessed the relevance of this subclinical inflammation with regard to radiographic progression. METHODS: 1130 joints (unilateral metacarpophalangeal 2-5, wrist and metatarsophalangeal 1-5) of 113 early arthritis patients underwent clinical examination and 1.5 T MRI at baseline, and radiographs at baseline and 1 year. Two readers scored the MRIs for synovitis, bone marrow oedema (BME) and tenosynovitis according to Rheumatoid Arthritis (RA) Magnetic Resonance Imaging (MRI) Scoring System (RAMRIS). Radiographic progression over 1 year was determined using the Sharp-van der Heijde scoring method. RESULTS: On patient level, BME, synovitis and tenosynovitis were associated with radiographic progression, independent of known risk factors (p=0.003, 0.001 and 0.011, respectively). Of all non-swollen joints (n=932), 232 joints (26%) had subclinical inflammation (≥1 MRI-inflammation feature present). These joints were distributed among 91% of patients. Radiographic progression was present in 4% of non-swollen joints with subclinical inflammation compared to 1% of non-swollen joints without subclinical inflammation (relative risks (RR) 3.5, 95% CI 1.3 to 9.6). Similar observations were done for BME (RR5.3, 95% CI 2.0 to 14.0), synovitis (RR3.4, 95% CI 1.2 to 9.3) and tenosynovitis (RR3.0, 95% CI 0.7 to 12.7) separately. CONCLUSIONS: Radiographic progression was infrequent, but joints with subclinical inflammation had an increased risk of radiographic progression within year 1. This demonstrates the relevance of MRI-detected subclinical inflammation.

Smoking as a risk factor for the radiological severity of rheumatoid arthritis: a study on six cohorts.

BACKGROUND: Smoking is a risk factor for the development of anti -citrullinated protein antibodies (ACPA) positive rheumatoid arthritis (RA). Whether smoking predisposes to severe joint damage progression is not known, since deleterious, protective and neutral observations have been made. OBJECTIVE: To determine the effect of smoking on joint damage progression. METHODS: Smoking status was assessed in 3158 RA patients included in six cohorts (Leiden Early Arthritis Clinic (Leiden-EAC), BARFOT, Lund, Iceland, NDB and Wichita). In total 9412 radiographs were assessed. Multivariate normal regression and linear regression analyses were performed. Data were summarised in a random effects inverse variance meta-analysis. RESULTS: When comparing radiological progression for RA patients that were never, past and current smokers, smoking was significantly associated with more severe joint damage in Leiden-EAC (p=0.042) and BARFOT (p=0.015) RA patients. No significant associations were found in the other cohorts, though a meta-analysis on the six cohorts showed significantly more severe joint damage progression in smokers (p=0.01). Since smoking predisposes to ACPA, analyses were repeated with ACPA as additional adjustment factor. Then the association was lost (meta-analysis p=0.29). CONCLUSIONS: This multi-cohort study indicated that the effect of smoking on joint damage is mediated via ACPA and that smoking is not an independent risk factor for radiological progression in RA.

Association of genetic variants in the IL4 and IL4R genes with the severity of joint damage in rheumatoid arthritis: a study in seven cohorts.

OBJECTIVE: The progression of joint destruction in rheumatoid arthritis (RA) is determined by genetic factors. Changes in IL4 and IL4R genes have been associated with RA severity, but this finding has not been replicated. This study was undertaken to investigate the association between IL4- and IL4R-tagging single-nucleotide polymorphisms (SNPs) and the progression rate of joint damage in RA in a multicohort candidate gene study. METHODS: IL4- and IL4R-tagging SNPs (n = 8 and 39, respectively) were genotyped in 600 RA patients for whom 2,846 sets of radiographs of the hands and feet were obtained during 7 years of followup. Subsequently, SNPs significantly associated with the progression of joint damage were genotyped and studied in relation to 3,415 radiographs of 1,953 RA patients; these included data sets from Groningen (The Netherlands), Lund (Sweden), Sheffield (UK), the North American Rheumatoid Arthritis Consortium (US), Wichita (US), and the National Data Bank (US). The relative increase in progression rate per year in the presence of a genotype was determined in each cohort. An inverse variance weighting meta-analysis was performed on the 6 data sets that together formed the replication phase. RESULTS: In the discovery phase, none of the IL4 SNPs and 7 of the IL4R SNPs were significantly associated with the joint damage progression rate. In the replication phase, 2 SNPs in the IL4R gene were significantly associated with the joint damage progression rate (rs1805011 [P = 0.02] and rs1119132 [P = 0.001]). CONCLUSION: Genetic variants in IL4R were identified, and their association with the progression rate of joint damage in RA was independently replicated.

[What to do when elder abuse is suspected?] / Wat te doen als je ouderenmishandeling vermoedt?

Elder abuse is a worldwide problem with serious consequences for individuals and society. The recognition of elder abuse is complex due to a lack of awareness and knowledge. We present a case of a patient with signs of elder abuse. This case concerns a patient who showed signs of neglect and physical abuse as a result of possible derailed informal care provision. The mandatory reporting code on domestic violence of The Royal Dutch Medical Association was followed and measures were taken by the general practitioner. In the discussion, information on signs and types of elder abuse were provided, together with the description of risk factors.

Two point-of-care test-based approaches for the exclusion of deep vein thrombosis in general practice: a cost-effectiveness analysis.

BACKGROUND: In the diagnostic work-up of deep vein thrombosis (DVT), the use of point-of-care-test (POCT) D-dimer assays is emerging as a promising patient-friendly alternative to regular D-dimer assays, but their cost-effectiveness is unknown. We compared the cost-effectiveness of two POCT-based approaches to the most common, laboratory-based, situation. METHODS: A patient-level simulation model was developed to simulate the diagnostic trajectory of patients presenting with symptoms of DVT at the general practitioner (GP). Three strategies were defined for further diagnostic work-up: one based on current guidelines ('regular strategy') and two alternative approaches where a POCT for D-dimer is implemented at the 1) phlebotomy service ('DVT care pathway') and 2) GP practice ('fast-POCT strategy'). Probabilities, costs and health outcomes were obtained from the literature. Costs and effects were determined from a societal perspective over a time horizon of 6 months. Uncertainty in model outcomes was assessed with a one-way sensitivity analysis. RESULTS: The Quality-Adjusted Life Years (QALYs) scores for the three DVT diagnostic work-up strategies were all around 0.43 across a 6 month-time horizon. Cost-savings of the two POCT-based strategies compared to the regular strategy were €103/patient for the DVT care pathway (95% CI: -€117-89), and €87/patient for the fast-POCT strategy (95% CI: -€113-67). CONCLUSIONS: Point-of-care-based approaches result in similar health outcomes compared with regular strategy. Given their expected cost-savings and patient-friendly nature, we recommend implementing a D-dimer POCT device in the diagnostic DVT work-up.

Explanatory models and openness about dementia in migrant communities: A qualitative study among female family carers.

Background The prevalence of dementia is increasing among people with a Turkish, Moroccan and Surinamese-Creole background. Because informal care is very important in these communities, it is pertinent to see what explanations female family carers have for dementia and whether they can discuss dementia openly within the community and the family. Method Forty-one individual interviews and six focus group interviews ( n = 28) were held with female Turkish, Moroccan and Surinamese Creole family carers who are looking after a close relative with dementia, and who live in The Netherlands. Qualitative analysis has been carried out, supported by the software MaxQda. Results The dominant explanations of dementia given by the female family carers interviewed are in line with what Downs et al. describe as the explanatory models 'dementia as a normal ageing process' and 'dementia as a spiritual experience'. In addition, some female family carers gave explanations that were about an interplay between various factors. Turkish and Moroccan informal caregivers ascribe the causes of dementia relatively often to life events or personality traits, whereas Surinamese Creole caregivers frequently mention physical aspects, such as past dehydration. However, the explanatory model 'dementia as a neuropsychiatric condition', which is dominant in Western cultures, was rarely expressed by the informal caregivers. The female family carers generally talked openly about the dementia with their close family, whereas particularly in the Turkish and Moroccan communities open communication within the broader communities was often hampered, e.g. by feelings of shame. Conclusions Female family carers of Turkish, Moroccan or Surinamese Creole backgrounds often consider dementia as a natural consequence of ageing, as a spiritual experience, and/or as an interplay between various factors. They feel they can talk openly about dementia within their close family, while outside the close family this is often more difficult.

Family care for immigrants with dementia: The perspectives of female family carers living in The Netherlands.

BACKGROUND: The prevalence of dementia is increasing among non-western immigrants. It is known that family care is provided relatively often among immigrant groups. Until now, however, relatively little was known about how relatives of people with dementia in the immigrant communities perceive family care. This study therefore focuses on describing the perspectives of female Turkish, Moroccan and Surinamese Creole family carers in the Netherlands about providing family care to a close relative with dementia. METHODS: Forty-one individual interviews and six focus group interviews (n=28) were held with female Turkish, Moroccan and Surinamese Creole family carers who are looking after a close relative with dementia. A qualitative analysis of the interviews has been carried out, supported by the software MaxQda. RESULTS: Related to their cultural and religious backgrounds, female family carers with Turkish, Moroccan or Surinamese Creole origins see family care as a task that they should carry out with respect and love. They feel that family care is superior to professional care and that it is principally a task for women. If men do have a role in family care, then it generally covers non-physical aspects. Despite the fact that the family carers interviewed listed aspects that make caring for a close relative with dementia difficult, they do say that they get a great deal of satisfaction from providing this care. In Turkish and Moroccan families in particular this type of care leads to more recognition and appreciation of the daughter or daughter-in-law who is giving it. CONCLUSION: Family carers of Turkish, Moroccan or Surinamese Creole origin derive a great deal of satisfaction from giving family care to a relative with dementia. This fulfilment largely outweighs the burden of care. Professional support or information for these family carers can be improved by also focusing on the positive aspects of providing family care instead of an exclusive focus on reducing the burden.

IL2RA is associated with persistence of rheumatoid arthritis.

INTRODUCTION: Although rheumatoid arthritis (RA) is generally a chronic disease, a proportion of RA-patients achieve disease-modifying antirheumatic drug (DMARD)-free sustained remission, reflecting loss of disease-persistence. To explore mechanisms underlying RA-persistence, we performed a candidate gene study. We hypothesized that variants associating with lack of radiographic progression also associate with DMARD-free sustained remission. METHODS: 645 Dutch RA-patients were studied on DMARD-free sustained remission during a maximal follow-up duration of 10-years. Variants associated with radiographic progression under an additive model in the total RA-population (Human Leukocyte Antigens (HLA)-DRB1-shared epitope (SE), Dickkopf-1 (DKK1)-rs1896368, DKK1-rs1896367, DKK1-rs1528873, C5Orf30-rs26232, Interleukin-2 receptor-α (IL2RA)-rs2104286, Matrix metalloproteinase-9 (MMP-9)-rs11908352, rs451066 and Osteoprotegerin (OPG)-rs1485305) were studied. Cox-regression analyses were performed and Bonferroni correction applied. Soluble IL2Rα (sIL2Rα)-levels were studied. For replication, 622 RA-patients included in the French Evaluation et Suivi de POlyarthrites Indifférenciées Récentes cohort (ESPOIR)-cohort were investigated. Results were combined in inverse-variance weighted meta-analysis. RESULTS: Similar as previously reported, the SE-alleles associated with less remission (hazard ratio (HR) = 0.57, 95 % confidence interval (95 % CI) = 0.42-0.77, p = 2.72×10(-4)). Variants in DKK-1, C5orf30, MMP-9 and OPG were not associated with remission. The IL2RA-rs2104286 minor allele associated with a higher chance on remission (HR = 1.52, 95 % CI = 1.16-1.99, p = 2.44×10(-3)). The rs2104286 minor allele associated with lower sIL2Rα-levels (p = 1.44×10(-3)); lower sIL2Rα-levels associated with a higher chance on remission (HR per 100 pg/L = 0.81, 95 % CI = 0.68-0.95, p = 0.012). When including rs2104286 and sIL2Rα-levels in one analysis, the HR for rs2104286 was 2.27 (95 % CI = 1.06-4.84, p = 0.034) and for sIL2Rα 0.83 (95 % CI = 0.70-0.98, p = 0.026). Within ESPOIR, the HR of rs2104286 was 1.31 (95 % CI = 0.90-1.90). The meta-analysis revealed a p-value of 1.01×10(-3). CONCLUSION: IL2RA-rs2104286 and sIL2Rα-level associated with RA-persistence. IL2RA variants are known to protect against multiple sclerosis, diabetes mellitus and RA. Besides HLA-SE, IL2RA-rs2104286 is thus far the only known genetic variant associated with both joint destruction and RA-persistence. This underlines the relevance of IL2RA for RA.

Effects of intrahippocampally-injected naloxone and morphine upon behavioural responses to novelty in mice from two selectively-bred lines.

To examine the peptidergic regulation of behavioural responses to novelty, 5-month-old male mice from the inbred selection lines SRH (selected for rearing frequency: high) and SRL (selected for rearing frequency: low) were intrahippocampally micro-injected (0.5 microliter) with either the opiate antagonist naloxone (0.3 microgram), or the opiate agonist morphine (1.0 microgram), or saline vehicle alone, given 15 min prior to individual exposure to 20-min exploration tests in a novel environment. Naloxone exerted opposite effects upon various exploratory acts and locomotor activity in the two strains, that is, it decreased the scores in SRH and augmented them in SRL, while morphine depressed the scores in both. It is suggested that an excess of opioids in SRL, as compared to SRH, is attenuated by this dose of naloxone. In addition to previously obtained evidence of a genotype-dependent cholinergic mechanism in the mouse dorsal hippocampus controlling exploratory responses to novelty, these findings indicate that hippocampal opioid peptides are also involved in the genotype-dependent regulation of exploration.

IL-4 supplemented B-cell cultures of allergic children show reduced IgA and IgG production in response to additional stimulation with IL-10.

BACKGROUND: Cytokines play an important role in mediating immunoglobulin switch, the secretion of protective mucosal immunoglobulins, and the development of allergic diseases. This study investigates whether B cells from allergic and healthy children have different capacities to secrete immunoglobulins after stimulation with IL-4, IL-6, IL-10, IL-11, and IL13. METHODS: We analyzed the peripheral venous blood of 44 healthy probands and of 109 allergic patients with a mean age of 13 years, allergic to grass pollen, birch pollen, and house dust mites. Lymphocytes were isolated by a density gradient and B cells were enriched by using a Magnetic Activated Cell Separator (MACS) and anti-CD19 microbeads. B Cells were co-cultured with human CDw32 (Fc gammaRII) expressing mouse Ltk fibroblasts and mouse anti-human CD40 monoclonal antibodies (CD40 system). The interleukins IL-4, IL-6, IL-10, IL-11, and IL-13 were supplemented in various combinations. After 14 days, concentrations of IgE, IgG, IgA, and IgM were measured in the supernatants with ELISA. RESULTS: Suppression of IgA-, IgG, and IgM- synthesis was induced by stimulation of B cells with IL-4. After additional application of IL-10, IgA, IgG, and IgM synthesis was significantly increased. When cultures stimulated with IL-4 were additionally supplemented with IL-10, IgA, and IgG synthesis of B cells obtained from allergic individuals was significantly decreased compared to nonallergic individuals. IgE-secretion of B cells from allergic individuals was significantly increased compared to nonallergic individuals after stimulation with IL-4. CONCLUSION: Our results implicate that IL-4 is essential for the regulation of immunoglobulin class switch to IgE and that IL-4 is an important cytokine for the development of allergic diseases. The capacity of B cells in allergic children to produce less IgA and IgG in response to additional stimulation with IL-10 of cultures supplemented with IL-4 could play an important role in mediating a mucosal immune system vulnerable to allergens. This phenomenon could contribute to the pathogenesis of allergic diseases.

The haemodynamic effect of an intracranial arteriovenous anomaly. A Doppler-haematotachographic study.

Determination of the mean blood flow velocity by means of Doppler haematotachography is suggested as an aid in evaluating the haemodynamic changes associated with an intracranial arteriovenous anomaly. A Doppler haematotachogram (HTG) was obtained in 13 patients with a radiologically diagnosed arteriovenous anomaly, with marked interindividual variations in dimensions and blood supply; in 6 of these patients the Doppler HTG was obtained before and after total neurosurgical extirpation. The large majority of the patients showed a significant increase in diastolic, and to a lesser degree in systolic flow velocity at the level of the common carotid artery. In most cases the flow velocity curve of the ophthalmic artery showed a decrease in amplitude. These are the most useful parameters in evaluating the haemodynamic effect of an intracranial arteriovenous anomaly. After the surgical removal of the anomaly, the carotid flow velocity decreased significantly. In the internal and external jugular veins, Doppler-haematotachographic pulse waves were registered for the first time. These may have been conducted from the internal carotid artery to the jugular veins via the arteriovenous anomaly. The usefulness of this parameter is reduced because of the cumbersome calculations required to determine the time within which an arterial pulse wave conducted via the arteriovenous anomaly reaches the jugular vein. Registration of this unusual pulse wave is solely of theoretical value.

A comparison of the rates of methylation of mercury(II) species in aquatic media by various organotin and organosilicon moieties.

Metals can be methylated in environmental aqueous media by a variety of organotin and organosilicon compounds. Main group metals and metalloids were surveyed for the identification of species that can either donate or accept methyl groups. The methylation of mercury(II) by trimethyltin cation was found to be a bimolecular reaction, the reaction rate of which decreased with increasing chloride concentration. Kinetic investigations using NMR techniques showed that the most important pairs of reactants were (CH3)3Sn+ + HgCl2, (CH3)3SnCl + HgCl2, and (CH3)3SnCl + HgCl-3. Sodium 2,2,3,3-tetradeutero-3-(trimethylsilyl)propionate (TSP) and sodium 2,2-dimethyl-2-silapentane-5-sulfonate (DSS) were found to methylate mercury(II). Organylsilatranes were found to transfer their organic groups readily to mercury(II) to produce organomercury compounds.

From adverse drug event detection to prevention. A novel clinical decision support framework for medication safety.

BACKGROUND: Errors related to medication seriously affect patient safety and the quality of healthcare. It has been widely argued that various types of such errors may be prevented by introducing Clinical Decision Support Systems (CDSSs) at the point of care. OBJECTIVES: Although significant research has been conducted in the field, still medication safety is a crucial issue, while few research outcomes are mature enough to be considered for use in actual clinical settings. In this paper, we present a clinical decision support framework targeting medication safety with major focus on adverse drug event (ADE) prevention. METHODS: The novelty of the framework lies in its design that approaches the problem holistically, i.e., starting from knowledge discovery to provide reliable numbers about ADEs per hospital or medical unit to describe their consequences and probable causes, and next employing the acquired knowledge for decision support services development and deployment. Major design features of the framework's services are: a) their adaptation to the context of care (i.e. patient characteristics, place of care, and significance of ADEs), and b) their straightforward integration in the healthcare information technologies (IT) infrastructure thanks to the adoption of a service-oriented architecture (SOA) and relevant standards. RESULTS: Our results illustrate the successful interoperability of the framework with two commercially available IT products, i.e., a Computerized Physician Order Entry (CPOE) and an Electronic Health Record (EHR) system, respectively, along with a Web prototype that is independent of existing healthcare IT products. The conducted clinical validation with domain experts and test cases illustrates that the impact of the framework is expected to be major, with respect to patient safety, and towards introducing the CDSS functionality in practical use. CONCLUSIONS: This study illustrates an important potential for the applicability of the presented framework in delivering contextualized decision support services at the point of care and for making a substantial contribution towards ADE prevention. Nonetheless, further research is required in order to quantitatively and thoroughly assess its impact in medication safety.