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ObjectiveSeveral cross-sectional studies on populations with iodine deficiency showed that TSH-levels are negatively associated with age, while in populations with high iodine intake TSH is positively associated with age. The question is whether such an age-thyroid function relation is an ongoing process apparent also in longitudinal studies and whether it reflects an actual iodine deficiency or an iodine insufficiency in the past.MethodsIn an area with a borderline iodine status in the past, we studied 980 participants of the Nijmegen Biomedical Study. We measured serum TSH, free thyroxine (FT4), total triiodothyronine (T3), peroxidase antibodies, and the urine iodine and creatinine concentration 4 years after our initial survey of thyroid function, in which we reported a negative association between TSH and age.ResultsWithin 4 years, TSH decreased by 5.4% (95% CI 2.5–8.3%) and FT4increased by 3.7% (95% CI 2.9–4.6%). Median urinary iodine concentration was 130 μg/l. Estimated 24-h iodine excretion was not associated with TSH, T3, change of TSH, or FT4over time or with the presence of antibodies against thyroid peroxidase. Only FT4appeared to be somewhat higher at lower urine iodine levels: a 1.01% (95% CI 0.17–1.84%) higher FT4for each lower iodine quintile.ConclusionsIn this longitudinal study, we found an ongoing decrease in TSH and increase in FT4in a previously iodine insufficient population, despite the adequate iodine status at present. This suggests that low iodine intake at young age leads to thyroid autonomy (and a tendency to hyperthyroidism) that persists despite normal iodine intake later in life.

Item does not contain fulltext OBJECTIVES: Reducing the incidence of delayed graft function after transplant with donation after cardiac death donor renal allografts would facilitate managing recipients during their first weeks after a transplant. To reduce this incidence, in most studies, induction therapy with depleting anti-T-lymphocyte antibodies is coupled with a reduction of the dosage of the calcineurin inhibitor. The separate effect of anti-T-cell therapy on the incidence and duration of delayed graft function is therefore difficult to assess. PATIENTS AND METHODS: We performed a randomized study to evaluate the effect of a single intraoperative high-dose of anti-T-lymphocyte immunoglobulin (ATG)-Fresenius (9 mg/kg body weight) on the incidence of delayed graft function. Eligible adult recipients of a first donation after cardiac death donor renal allograft were randomly assigned to ATG-Fresenius or no induction therapy. Maintenance immunosuppression consisted of tacrolimus, in an unadjusted dose, mycophenolate mofetil, and steroids. RESULTS: The study was prematurely terminated because of a lower-than-anticipated inclusion rate. Baseline characteristics were comparable in the ATG-Fresenius group (n=28) and the control group (n=24). Twenty-two patients in the ATG-Fresenius group (79%) had delayed graft function, compared with 13 in the control group (54%; P = .06). Allograft and patient survival were comparable in both groups. Serious adverse events occurred more frequently in the ATG-Fresenius group than they did in the control group (57% vs 29%; P < .05). CONCLUSIONS: Intraoperative administration of a single high-dose of ATG-Fresenius in donation after cardiac death donor renal allograft recipients, followed by triple immunosuppression with an unadjusted tacrolimus dose, seems ineffective to reduce the incidence of delayed graft function. Moreover, this was associated with a higher rate of serious adverse events (EudraCT-number, 2007-000210-36.).

Item does not contain fulltext Objective. Because TNF inhibitors are not approved for persistent oligoarticular JIA (oJIA), although they are used off-label, we evaluated their effectiveness in patients in this category. Methods. Persistent oJIA patients were selected from the Dutch Arthritis and Biologicals in Children (ABC) register, an ongoing multicentre prospective study that aims to include all Dutch children with JIA using biologic agents. Response was assessed by the JIA core-set disease activity variables and modified Wallace criteria for inactive disease. Results. Until February 2011, 16 persistent oJIA patients (68.8% females) had been included in the register. Median age of onset was 8.4 years [interquartile range (IQR) 2.1-13.5 years]; history of uveitis in 18.8%; ANA-positive 56.3%. All had previously used MTX, and 81.3% had used IA CSs. Median follow-up after the introduction of biologic treatment was 13.7 months (IQR 8.3-16.7 months). Fourteen patients started etanercept and two patients who had active arthritis as well as uveitis started adalimumab. Although patients with persistent oJIA had few affected joints [median of two active joints at the start of biologic (IQR 1-3)], the patient/parent assessments of pain [median visual analogue score (VAS) 51 (IQR 1-64)] and well-being [median VAS 44 (IQR 6-66)] were high. Additionally, their physician evaluated the disease activity as moderately high [median VAS 36 (IQR 4-65)]. After 3 months this decreased to 0 (IQR 0-30) and 63% achieved inactive disease. After 15 months the disease was inactive in 9/10 observed patients. TNF inhibitors were tolerated well. Conclusion. TNF blocking agents seem an effective and justifiable option in persistent oJIA when treatment with IA CS injections and MTX has failed. 01 april 2013

Item does not contain fulltext BACKGROUND: 'Covering your cough' reduces droplet number, but its effect on airborne pathogen transmission is less clear. The World Health Organization specifically recommends cough etiquette to prevent the spread of Mycobacterium tuberculosis, but implementation is generally poor and evidence supporting its value is lacking. METHODS: We constructed a model to assess 'real life' transmission risk by counting viable pathogens from aerosols produced by coughing patients, thus allowing the assessment of outward protection measures in a standardised fashion. During the validation process, we focused on rod-shaped bacteria as surrogates for M. tuberculosis. RESULTS: The Cough Cylinder enabled us to sample Pseudomonas aeruginosa, Escherichia coli and mycobacteria from aerosols produced by patients with cystic fibrosis, primary ciliary dyskinesia and tuberculosis. Pathogens in droplets and in airborne particles could be sampled. Delayed air sampling allowed specific measurement of persistent airborne particles. CONCLUSION: This novel experimental system allows measurement of aerosol pathogen spread in a highly standardised fashion. It also offers the possibility to assess the impact of different interventions to limit aerosol transmission. 01 januari 2013 8 p.

Item does not contain fulltext BACKGROUND: The development of atherosclerosis may be enhanced by iron accumulation in macrophages. Hepcidin-25 is a key regulator of iron homeostasis, which downregulates the cellular iron exporter ferroportin. In haemodialysis (HD) patients, hepcidin-25 levels are increased. Therefore, it is conceivable that hepcidin-25 is associated with all-cause mortality and/or fatal and non-fatal cardiovascular (CV) events in this patient group. The aim of the current analysis was to study the relationship between hepcidin-25 and all-cause mortality and both fatal and non-fatal CV events in chronic HD patients. METHODS: Data from 405 chronic HD patients included in the CONvective TRAnsport STudy (NCT00205556) were studied (62% men, age 63.7 +/- 13.9 years [mean +/- SD]). The median (range) follow-up was 3.0 (0.8-6.6) years. Hepcidin-25 was measured with mass spectrometry. The relationship between hepcidin-25 and all-cause mortality or fatal and non-fatal CV events was investigated with multivariate Cox proportional hazard models. RESULTS: Median (interquartile range) hepcidin-25 level was 13.8 (6.6-22.5) nmol/L. During follow-up, 158 (39%) patients died from any cause and 131 (32%) had a CV event. Hepcidin-25 was associated with all-cause mortality in an unadjusted model [hazard ratio (HR) 1.14 per 10 nmol/L, 95% CI 1.03-1.26; P = 0.01], but not after adjustment for all confounders including high-sensitive C-reactive protein (HR 1.02 per 10 nmol/L, 95% CI 0.87-1.20; P = 0.80). At the same time, hepcidin-25 was significantly related to fatal and non-fatal CV events in a fully adjusted model (HR 1.24 per 10 nmol/L, 95% CI 1.05-1.46, P = 0.01). CONCLUSION: Hepcidin-25 was associated with fatal and non-fatal CV events, even after adjustment for inflammation. Furthermore, inflammation appears to be a significant confounder in the relation between hepcidin-25 and all-cause mortality. These findings suggest that hepcidin-25 might be a novel determinant of CV disease in chronic HD patients.

Item does not contain fulltext Background: To increase effectiveness of standard adalimumab treatment 40 mg every other week (EOW) for patients with psoriasis, dose escalation to 40 mg every week or addition of methotrexate (MTX) are possible strategies. Methods: Daily practice data about adalimumab treatment were extracted from a prospective observational cohort. We analyzed all patients with insufficient efficacy of adalimumab EOW who received 1) adalimumab dose escalation, 2) addition of MTX to adalimumab EOW, or 3) both. Effectiveness was analyzed after 12 and 24 weeks using PASI50, PASI75, and mean differences in PASI. Results: Forty-seven treatment episodes (TE) of adalimumab dose escalations, 11 of MTX addition and six combinations were analyzed. After a first episode of adalimumab dose escalation, 25% and 35% achieved PASI50 after 12 and 24 weeks, respectively. After MTX introduction to adalimumab EOW, 9% and 18% achieved PASI50 after 12 and 24 weeks, respectively. No related serious adverse events were reported. Conclusions:Twenty-five percent of first TE with adalimumab dose escalation induced a PASI50 response after 12 weeks and 35% after 24 weeks. Addition of MTX to adalimumab EOW resulted in PASI50 in 9% after 12 weeks and 18% after 24 weeks. Defining patient-groups that will benefit from these interventions is important.

Contains fulltext : 127297.pdf (Publisher’s version ) (Closed access) Context: Heterozygous mutations or deletions of the transcription factor hepatocyte nuclear factor 1beta (HNF1beta) result in a heterogeneous syndrome characterized by renal cysts and diabetes, together with a variety of other extrarenal and renal manifestations. Interestingly, in several patients with HNF1beta abnormalities, we observed early hyperparathyroidism and PTH levels that we judged inappropriately high compared with the degree of renal function decline. Objective: Based on the above clinical observations, we tested the hypothesis of a direct role of HNF1beta in the transcriptional regulation of the human PTH gene in the parathyroid gland. Design, Setting, and Patients: Immunostaining of human parathyroid sections, RT-PCR, chromatin immunoprecipitation (ChIP), and luciferase reporter assays in human embryonic kidney cells (HEK293) were performed. We eventually report clinical data from all 11 HNF1beta patients known at our institute, 9 with heterozygous HNF1beta whole-gene deletions and 2 with heterozygous HNF1beta mutations. Results: PTH levels were high in 8 patients. In 2 of these patients, the hyperparathyroidism was clearly appropriate for the level of kidney function, whereas PTH might be discrepant in the others. We demonstrated HNF1beta expression in PTH-positive cells of human parathyroid gland. Chromatin immunoprecipitation analysis showed that HNF1beta directly binds responsive elements within the human PTH promoter. Cotransfection of a PTH promoter- luciferase construct with a wild-type HNF1beta construct resulted in a maximal reduction of 30% of PTH promoter activity. Importantly, HNF1beta mutants lacked this inhibitory property. Serial deletions in the PTH promoter construct revealed that the inhibitory effect of HNF1beta resides between -200 and -70 bp from the transcription initiation site. Conclusions: Our data demonstrate that HNF1beta is a novel repressor of human PTH gene transcription, which could contribute to the development of hyperparathyroidism in patients with HNF1beta mutations or deletions. 01 oktober 2013

Item does not contain fulltext BACKGROUND: Excess risks for death/opportunistic disease in adults randomized to CD4-driven planned treatment interruption (PTI) in the Strategies for Management of Antiretroviral Therapy (SMART) trial remained after antiretroviral therapy (ART) re-initiation. Risks for children following PTI were evaluated in long-term follow-up of children in the PENTA 11 trial. METHODS: Children with HIV RNA below 50 copies/ml and CD4 at least 30% (2-6 years) or at least 500 cells/mul (7-15 years) were randomized to continuous ART (cART) or PTI in PENTA 11 (ISRCTN 36694210). After the end of the trial, all were recommended to resume ART. Data were collected annually and analysed up to the second year of visit. RESULTS: One hundred and one (51 cART, 50 PTI; median baseline age 9.2 years) children had median overall follow-up 4.6 (range 3.7-5.0) years. During 2-year post-trial period, there were no deaths or new Centers for Disease Control and Prevention (CDC) stage B/C events. Rate of clinical grade of at least two events was similar between PTI and cART [relative risk (RR) 1.03; 95% confidence interval (CI) 0.43, 2.50; P = 0.94]. At 2 years, difference in absolute CD4% between PTI and cART was -1.6% (-4.5%; 1.3%; P = 0.27), and proportions with HIV RNA below 50 copies/ml were 82 versus 86% (P = 0.57), respectively; no differences in growth or fasting lipids were observed. Key predictors of greater CD4% recovery after re-initiating ART were higher CD4% at baseline (P < 0.001) and longer time since ART re-initiation (P < 0.001). During overall follow-up, 4 (8%) PTI versus 5 (10%) CT children switched ART for failure (P = 0.75) and 9 (18%) versus 1 (2%) (P = 0.008) substituted ART for simplification. CONCLUSIONS: No adverse clinical, immunological or virological consequences of PTI were observed 2 years after the end of PENTA 11 trial. Although ART interruption is not generally recommended, it may be an acceptable option for children, particularly when there is high risk of unplanned treatment interruptions.

Item does not contain fulltext BACKGROUND: Expanding the use of elderly live donors may help meet the demand for kidney transplants. The aim of this study was to quantify the effect of the surgical procedure on the quality of life (QOL) of elderly donors compared with younger donors. METHODS: Alongside three prospective studies (two randomized) running between May 2001 and October 2010, we asked 501 live donors to fill out the Short Form-36 questionnaire preoperatively and at 1, 3, 6, and 12 months postoperatively. We defined live donors 60 years or older as elderly. Between-group analyses regarding QOL were adjusted for baseline values and gender. RESULTS: One hundred thirty-five donors were older and 366 donors were younger than 60 years. The response rate was high, with 87% at 12 months postoperatively. Elderly donors less often scored as American Society of Anaesthesiology classification 1 (60% vs. 81%; P

Item does not contain fulltext Objectives. To evaluate differences in baseline characteristics between etanercept- and adalimumab-treated JIA patients and to reveal factors that influence the choice between these TNF inhibitors, which are considered equally effective in the recent ACR recommendations for JIA treatment. Methods. Biologic-naive JIA patients with active arthritis who started treatment with adalimumab or etanercept between March 2008 and December 2011 were selected from the Dutch Arthritis and Biologicals in Children register. Baseline characteristics were compared. Focus group interviews with paediatric rheumatologists were performed to evaluate factors determining treatment choices. Results. A total of 193 patients started treatment with etanercept and 21 with adalimumab. Adalimumab-treated patients had longer disease duration prior to the start of biologics (median 5.7 vs 2.0 years) and more often a history of uveitis (71% vs 4%). Etanercept-treated patients had more disability at baseline (median Childhood Health Assessment Questionnaire score 1.1 vs 0.4) and more active arthritis (median number of active joints 6 vs 4). The presence of uveitis was the most important factor directing the choice towards adalimumab. Factors specific for the paediatric population-such as painful adalimumab injections-as well as the physician's familiarity with the drug accounted for the preference for etanercept. Conclusion. Although the two TNF inhibitors are considered equally effective, in daily practice etanercept is most often prescribed; adalimumab is mainly preferred when uveitis is present. In choosing the most suitable biologic treatment, paediatric rheumatologists take into account drug and patient factors, considering newly published data and cautiously implementing this into daily care. 01 september 2013

Item does not contain fulltext OBJECTIVES: Infantile hemangiomas (IHs) in the airway may be potentially life-threatening during the proliferative phase. Available treatments like oral corticosteroids (OCS) and chemotherapeutic agents usually showed variable responses and serious side effects. Propranolol is a new and promising treatment option. METHODS: A case series of five IH patients with airway involvement is presented, supplemented with a review of literature. Propranolol treatment (2.0-3.0mg/kg/day) was initiated between 3 weeks and 6 months of age. Three cases were treated with propranolol monotherapy, 2 cases with OCS primarily and propranolol secondarily, in which treatment with OCS could be reduced rapidly. RESULTS: In our case series a dramatic, fast response was observed in all cases, with a permanent effect after discontinuation in four cases. In one patient a relapse of airway problems occurred two months after discontinuation of propranolol at 16 months of age; this resolved after re-start of propranolol. Review of literature together with these five cases showed 81 patients with airway IHs treated with propranolol. Propranolol was effective in 90% of the cases and seven patients were classified as non-responders. Eight IHs relapsed while weaning of propranolol or after discontinuation; dose adjustment or restart was effective in most cases but one patient appeared resistant to therapy. CONCLUSIONS: Propranolol seems to be a rapidly effective and safe treatment strategy for most IHs obstructing the airway. Because of the fast and important effects of propranolol, randomized controlled trials are hardly justifiable for this specific, relatively rare but, acute treatment indication. Despite the efficacy of propranolol, close monitoring of the patients with an airway IH is required, considering the risk of relapse of symptoms during or after treatment and the reported resistance to propranolol in at least 9% of the published cases. The dose and duration of treatment should be high and long enough to prevent relapse. Further research should focus on the optimal treatment protocol; the actual percentage of non-responders and also the mechanism of resistance to propranolol is unknown and needs to be illuminated.

Item does not contain fulltext BACKGROUND: Skin manifestations are the most characteristic finding of psoriasis. However, nail involvement is also a clinical feature of disease although it is often overlooked. The documented prevalence of nail psoriasis varies between 10.0% and 81.1%. OBJECTIVES: The aim of this investigation is to gain knowledge about the prevalence and clinical manifestations of nail psoriasis and patient experiences of treatment of nail psoriasis. METHODS: A structured, self-administered questionnaire was distributed to all members (n = 5400) of the Dutch Psoriasis Association. The questionnaire enquired about sociodemographic patient characteristics, disease-related data and treatment of nail psoriasis. Patients reported their nail manifestations with photographs after instruction. Patients with nail psoriasis were compared with patients without nail psoriasis. RESULTS: A response rate of 27% was achieved. The prevalence of nail psoriasis was 66.0%. The most frequently observed psoriatic nail manifestation was pitting (65.4%), whereas red spots in the lunula were infrequently seen (6.5%). Patients with nail psoriasis more frequently stated psoriasis capitis (75.8% vs. 65.7%), genital psoriasis (32.7% vs. 20.3%) and psoriatic arthritis (46.4% vs. 30.6%) compared with patients with psoriasis without nail involvement. Only 16.0% of patients received treatment for nail psoriasis. Systemic therapies were most frequently stated as being effective for nail lesions. CONCLUSIONS: Nail manifestations seem to be more prevalent in patients with psoriasis than previously thought. In addition, nail psoriasis is shown to be associated with widespread and more severe forms of psoriasis, and different treatment options are experienced as being effective for nail psoriasis. Notwithstanding, nail psoriasis is still an often overlooked feature of the disease.

Objective: To assess the effect of graduated compression stockings (GCS) on lower leg volume and leg complaints in runners during and after exercise. Design: Cross-sectional study. Setting: Radboud University Nijmegen Medical Centre and an outdoor running track in Nijmegen, The Netherlands. Patients or Other Participants: Thirteen Dutch trained recreational runners. Intervention(s): Participants used a GCS on 1 leg during running. Main Outcome Measures: (1) Lower leg volume of both legs was measured at baseline, directly after running, and at 5 minutes and 30 minutes after running using a validated perometer. (2) Leg complaints were reported on questionnaires at set intervals. Results: (1) In both experiments, the legs with GCS showed a reduction in mean (± SEM) leg volume directly after running, as compared with the leg without GCS: −14.1 ± 7.6 mL (P = .04) for the 10-km running track and −53.5 ± 17.8 mL (P = .03) for the maximum exercise test. This effect was not observed at 5 and 30 minutes after running. (2) No differences in leg complaints were reported in either experiment. Conclusions: The GCS prevented an increase in leg volume just after the running exercise. However, this result was not accompanied by a reduction in subjective questionnaire-reported leg complaints. The practical consequences of the present findings need further study.

Contains fulltext : 125312.pdf (Publisher’s version ) (Closed access) Binding of vasopressin to its type 2 receptor in renal collecting ducts induces cAMP signaling, transcription and translocation of aquaporin (AQP)2 water channels to the plasma membrane, and water reabsorption from the prourine. Demeclocycline is currently used to treat hyponatremia in patients with the syndrome of inappropriate antidiuretic hormone secretion (SIADH). Demeclocycline's mechanism of action, which is poorly understood, is studied here. In mouse cortical collecting duct (mpkCCD) cells, which exhibit deamino-8-d-arginine vasopressin (dDAVP)-dependent expression of endogenous AQP2, demeclocycline decreased AQP2 abundance and gene transcription but not its protein stability. Demeclocycline did not affect vasopressin type 2 receptor localization but decreased dDAVP-induced cAMP generation and the abundance of adenylate cyclase 3 and 5/6. The addition of exogenous cAMP partially corrected the demeclocycline effect. As in patients, demeclocycline increased urine volume, decreased urine osmolality, and reverted hyponatremia in an SIADH rat model. AQP2 and adenylate cyclase 5/6 abundances were reduced in the inner medulla but increased in the cortex and outer medulla, in the absence of any sign of toxicity. In conclusion, our in vitro and in vivo data indicate that demeclocycline mainly attenuates hyponatremia in SIADH by reducing adenylate cyclase 5/6 expression and, consequently, cAMP generation, AQP2 gene transcription, and AQP2 abundance in the renal inner medulla, coinciding with a reduced vasopressin escape response in other collecting duct segments.

Item does not contain fulltext Fusion of the sagittal suture is the most prevalent form of craniosynostosis. Due to the variety of deformities of scaphocephaly depending on the location of the fused sagittal suture, the surgical procedure has to be adjusted to the individual case. In this study, 38 patients with a predominantly posterior sagittal suture closure were treated with a modified technique of the pi-procedure and the surgical outcome has been evaluated with respect to complications, morphological and aesthetic outcome. The improvement of the cephalic index in our series in the follow-up examination (mean 60.1 months) after surgery was significant (p

Item does not contain fulltext This review article gives a state-of-the-art synopsis of current pathophysiological concepts in Sjogren-Larsson syndrome (SLS) mainly based upon original research data of the authors in one of the world's largest clinical SLS study cohorts. Clinical features are discussed in order of appearance, and diagnostic tests are set out to guide the clinician toward the diagnosis SLS. Furthermore, current and future treatment strategies are discussed to render a comprehensive review of the topic.

Item does not contain fulltext OBJECTIVE: To evaluate the effectiveness and safety of switching to a second or third biological agent in juvenile idiopathic arthritis (JIA) after etanercept failure. METHODS: The Arthritis and Biologicals in Children Register aims to include all Dutch JIA patients who have used biological agents. Data on the disease course were used to estimate drug survival with Kaplan-Meier and calculate adverse event (AE) rates. RESULTS: Of 307 biologically naive JIA patients who started etanercept, 80 (26%) switched to a second and 22 (7%) to a third biological agent. During 1030 patient-years of follow-up after the introduction of etanercept, 49 switches to adalimumab, 28 infliximab, 17 anakinra, four abatacept and four trial drugs were evaluated. 84% (95% CI 80% to 88%) of patients who started etanercept as a first biological agent were, after 12 months, still on the drug, compared with 47% (95% CI 35% to 60%) who started a second and 51% (95% CI 26% to 76%) who started a third biological agent. Patients who switched because of primary ineffectiveness continued the second agent less often (32%, 95% CI 12% to 53%). After etanercept failure, drug continuation of adalimumab was similar to infliximab for patients with non-systemic JIA; anakinra was superior to a second TNF-blocker for systemic JIA. AE rates within first 12 months after initiation were comparable for each course and each biological agent. CONCLUSIONS: Switching to another biological agent is common, especially for systemic JIA patients. A second (and third) agent was less effective than the first. The choice of second biological agent by the physician mainly depends on availability and JIA category. 01 mei 2013

Item does not contain fulltext We report here on a European cohort of 27 kidney transplant recipients displaying operational tolerance, compared to two cohorts of matched kidney transplant recipients under immunosuppression and patients who stopped immunosuppressive drugs and presented with rejection. We report that a lower proportion of operationally tolerant patients received induction therapy (52% without induction therapy vs. 78.3%[p = 0.0455] and 96.7%[p = 0.0001], respectively), a difference likely due to the higher proportion (18.5%) of HLA matched recipients in the tolerant cohort. These patients were also significantly older at the time of transplantation (p = 0.0211) and immunosuppression withdrawal (p = 0.0002) than recipients who rejected their graft after weaning. Finally, these patients were at lower risk of infectious disease. Among the 27 patients defined as operationally tolerant at the time of inclusion, 19 still display stable graft function (mean 9 +/- 4 years after transplantation) whereas 30% presented slow deterioration of graft function. Six of these patients tested positive for pre-graft anti-HLA antibodies. Biopsy histology studies revealed an active immunologically driven mechanism for half of them, associated with DSA in the absence of C4d. This study suggests that operational tolerance can persist as a robust phenomenon, although eventual graft loss does occur in some patients, particularly in the setting of donor-specific alloantibody.

Item does not contain fulltext The Ehlers-Danlos syndrome (EDS) is a clinically and genetically heterogeneous group of inherited connective tissue disorders. The six major, well-defined, subtypes are classified according to diagnostic criteria, formalized in the Villefranche revised nosology. Shortly after the publication of these criteria in 1998, a further distinct type of EDS, the tenascin-X (TNX)-deficient type EDS, was reported. The phenotype of this largely unknown type of EDS resembles the phenotype of the classical type of EDS, but its inheritance is autosomal recessive and wound healing is normal; hence, no atrophic scars are present. The clinical diagnosis can be confirmed by the absence of TNX in the serum and by mutation analysis of the TNXB gene. Because the TNX-deficient type EDS is rare and not included in the current diagnostic criteria, this diagnosis is often delayed or even overlooked. Here, we describe four cases which improve the clinical recognition of this type of EDS. 01 januari 2012

Objective: to examine the impact of delirium during intensive care unit stay on long-term health-related quality of life and cognitive function in intensive care unit survivors. Design: prospective 18-month follow-up study. Setting: four intensive care units of a university hospital. Patients: a median of 18 months after intensive care discharge, questionnaires were sent to 1,292 intensive care survivors with (n = 272) and without (n = 1020) delirium during their intensive care stay. Measurements and Main Results: the Short Form-36v1, checklist individual strength-fatigue, and cognitive failure questionnaire were used. Covariance analysis was performed to adjust for relevant covariates. Of the 915 responders, 171 patients were delirious during their intensive care stay (median age 65 [interquartile range 58–85], Acute Physiology and Chronic Health Evaluation II score 17 [interquartile range 14–20]), and 745 patients were not (median age 65 [interquartile range 57–72], Acute Physiology and Chronic Health Evaluation II score 13 [interquartile range 10–16]). After adjusting for covariates, no differences were found between delirium and nondelirium survivors on the Short Form-36 and checklist individual strength-fatigue. However, survivors who had suffered from delirium reported that they made significantly more social blunders, and their total cognitive failure questionnaire score was significantly higher, compared to survivors who had not been delirious. Survivors of a hypoactive delirium subtype performed significantly better on the domain mental health than mixed and hyperactive delirium patients. Duration of delirium was significantly correlated to problems with memory and names. Conclusions: intensive care survivors with delirium during their intensive care unit stay had a similar adjusted health-related quality of life evaluation, but significantly more cognitive problems than those who did not suffer from delirium, even after adjusting for relevant covariates. In addition, the duration of delirium was related to long-term cognitive problems

Background. FTY720 (fingolimod), a novel immunomodulator, has demonstrated potential for prevention of acute rejection in combination with cyclosporine.Methods. This study evaluated FTY720 2.5 mg versus mycophenolate mofetil (MMF) in a combination regimen with standard tacrolimus and corticosteroids in de novo renal transplant recipients for the composite efficacy within 6 months of transplantation.Results. Incidence of treated biopsy-proven acute rejection was 22.9% with FTY720 and 18.5% with MMF. Increased incidence of macular oedema, transient decrease in heart rate and low rate of infections were seen in the FTY720 arm.Conclusion. FTY720 combined with tacrolimus and steroids did not show a significant therapeutic advantage over MMF for the prevention of acute rejection in de novo renal transplant recipients. © The Author 2011. Published by Oxford University Press on behalf of ERA-EDTA. All rights reserved.

Contains fulltext : 97089.pdf (Publisher’s version ) (Closed access) BACKGROUND: Immunodeficiency in ataxia telangiectasia (A-T) is less severe in patients expressing some mutant or normal ATM kinase activity. We, therefore, determined whether expression of residual ATM kinase activity also protected against tumour development in A-T. METHODS: From a total of 296 consecutive genetically confirmed A-T patients from the British Isles and the Netherlands, we identified 66 patients who developed a malignant tumour; 47 lymphoid tumours and 19 non-lymphoid tumours were diagnosed. We determined their ATM mutations, and whether cells from these patients expressed any ATM with residual ATM kinase activity. RESULTS: In childhood, total absence of ATM kinase activity was associated, almost exclusively, with development of lymphoid tumours. There was an overwhelming preponderance of tumours in patients

Objective: To describe cognitive and speech-language functioning of patients with ataxia-telangiectasia (A-T) in relation to their deteriorating (oculo)motor function.Design: Observational case series.Methods: Cognitive functioning, language, speech and oral-motor functioning were examined in eight individuals with A-T (six boys, two girls), taking into account the confounding effects of motor functioning on test performance.Results: All patients, except the youngest one, suffered from mild-to-moderate/severe intellectual impairment. Compared to developmental age, patients showed cognitive deficits in attention, (non) verbal memory and verbal fluency. Furthermore, dysarthria and weak oral-motor performance was found. Language was one of the patients' assets.Conclusion: In contrast to the severe deterioration of motor functioning in A-T, cognitive and language functioning appeared to level off with a typical profile of neuropsychological strengths and weaknesses. Based on our experiences with A-T, suggestions are made to determine a valid assessment of the cognitive and speech-language manifestations.

Contains fulltext : 98411.pdf (Publisher’s version ) (Closed access) OBJECTIVE: Rituximab has been shown to be successful in the treatment of rheumatoid arthritis (RA), and this unexpected finding indicates that B cells have an important role in this disease. The present study was undertaken to investigate the mechanism of action of rituximab in RA. METHODS: Twelve patients with active RA were treated with rituximab. Disease activity was evaluated using the 28-joint Disease Activity Score. Synovial biopsy samples obtained at baseline and 12 weeks after treatment initiation were analyzed by microarray, quantitative polymerase chain reaction, and immunohistochemistry. Peripheral blood mononuclear cells (PBMCs) from healthy volunteers and from 4 patients with X-linked agammaglobulinemia were stimulated with the Th17-inducing stimulus Candida albicans, and the response in the presence and absence of rituximab was examined. RESULTS: In RA patients, rituximab reduced expression of retinoic acid-related orphan receptor gammat and interleukin-22 (IL-22) and numbers of Th17-positive cells in synovial tissue, and this correlated with better clinical outcome. Rituximab did not affect tumor necrosis factor alpha (TNFalpha), Th1 cell, or Treg cell responses. Rituximab strongly reduced in vitro IL-17 and IL-22 production induced by C albicans. This effect was not observed in PBMCs from patients with X-linked agammaglobulinemia. CONCLUSION: Rituximab reduced the local Th17 response in RA patients, whereas it did not influence Th1 cell, Treg cell, or TNFalpha responses. The decreased Th17 response was associated with reduced inflammation and better clinical outcome. Moreover, inhibition of the Th17 response by rituximab was lost in the absence of B cells, providing evidence that the effects of rituximab are due to B cell depletion. These data demonstrate an unexpected role of B cells in the development of Th17 responses, which could possibly lead to B cell-based strategies for the treatment of Th17-related autoimmune diseases.

Item does not contain fulltext BACKGROUND: Perioperative cardiovascular events in renal transplantation are common and non-invasive cardiac stress tests are recommended in high-risk renal transplant candidates. In 2004, we introduced a standardized preoperative cardiac risk assessment programme with the aim of reducing perioperative cardiac events. METHODS: Since 2004, all asymptomatic high-risk renal transplant candidates had to undergo non-invasive cardiac stress testing. Patients with a positive stress test went for a coronary angiography and if indicated for revascularization. The incidence of perioperative cardiac events (

Contains fulltext : 98068.pdf (Publisher’s version ) (Closed access) BACKGROUND: Early diagnosis of HIV-1 infection will probably beneficially impact onward transmission and life expectancy. We compared mortality rates and CD4 cell counts at start of combination antiretroviral therapy (cART) in patients with different frequencies of diagnostic testing for HIV. METHODS: Patients infected with HIV-1 through sexual contact and in follow-up anytime from 2004 through 2008 were selected from the AIDS Therapy Evaluation in the Netherlands national observational HIV cohort and stratified into three groups: patients without a prior negative HIV antibody test (i.e., with a positive first-test result); patients with 1-2 years between the last negative and first positive test; and patients with less than 1 year between tests. Outcome measures were mortality from 2004 through 2008 and CD4 cell count at cART initiation. RESULTS: Of 5494 patients, the mortality rate was highest among the 4067 patients with a positive first test (1.33/100 person-years) and the adjusted relative risk of mortality was 0.50 in 561 patients with tests 1-2 years apart (P = 0.04 compared to patients with a positive first test) and 0.49 (P = 0.02) when tests were less than 1 year apart (n = 866). In patients with a positive first test, 48% had CD4 cell counts less than 200 cells/mul at cART initiation; this proportion was 23-26% in the two groups of repeatedly tested patients (adjusted odds ratio compared to patients with a positive first test 0.43 and 0.37, respectively; both P < 0.0001). CONCLUSION: Frequent repeated testing for HIV may improve the rate of timely diagnosis and treatment, thereby preventing disease progression.

Contains fulltext : 96418.pdf (Publisher’s version ) (Closed access) BACKGROUND: In the Netherlands, a non-selective opt-out instead of a selective opt-in antenatal HIV screening strategy was implemented in 2004. In case of infection, screening was followed by prevention of mother-to-child-transmission (PMTCT). We compared the performance of the two strategies in terms of detection of new cases of HIV and vertical transmission. METHODS: HIV-infected pregnant women were identified retrospectively from the Dutch HIV cohort ATHENA January 2000 to January 2008. Apart from demographic, virological and immunological data, the date of HIV infection in relation to the index pregnancy was established. Separately, all infants diagnosed with HIV born following implementation of the screening program were identified by a questionnaire via the paediatric HIV centres. RESULTS: 162/481 (33.7%) HIV-positive pregnant women were diagnosed with HIV before 2004 and 172/214 (80.3%) after January 2004. Multivariate analysis showed an 8-fold (95% confidence interval 5.47-11.87) increase in the odds of HIV detection during pregnancy after the national introduction of the opt-out strategy. Still, three children born during a 5-year period after July 2004 were infected due to de novo infection in pregnancy. CONCLUSIONS: Implementation of a nation-wide screening strategy based upon non-selective opt-out screening followed by effective PMTCT appeared to detect more HIV-infected women for the first time in pregnancy and to reduce vertical transmission of HIV substantially. Nonetheless, still few children are infected because of maternal infection after the first trimester. We propose the introduction of partner screening on HIV as part of the antenatal screening strategy.

Item does not contain fulltext INTRODUCTION: Malignancy is a well-known complication after renal transplantation. We studied the influence of cancer on patient survival in the Dutch renal transplant population in a nested case-controlled analysis. METHODS: Between March 1966 and May 2008, 15,227 renal transplantations in 12,805 recipients were registered in the Netherlands Organ Transplant Registry database. Total follow-up was 89,651 person years. We performed an analysis of patient and graft survival both from the day of transplantation and the diagnosis of cancer in recipients with invasive cancer. Recipients without invasive cancer, matched for gender, age, and year of transplantation, served as a control group. For the survival analysis after the diagnosis of cancer, the matched control group consisted of patients with a functioning graft at the moment the index patient was diagnosed with cancer. RESULTS: Cancer had been registered in 908 (7.1%) patients, 630 (69%) of them died with functioning kidney, 510 (81%) because of their malignancy (at 8.2 years after transplantation, median). The median patient survival after transplantation was 11.9 vs. 16.8 years in the study and control group, respectively (P

12 páginas, 11 figuras., α-Keto acids (α-KAs) are not just metabolic intermediates but are also powerful modulators of different cellular pathways. Here, we tested the hypothesis that α-KA concentrations are regulated by complex II (succinate dehydrogenase = SDH), which represents an intersection between the mitochondrial respiratory chain for which an important function in cardiopulmonary oxygen sensing has been demonstrated, and the Krebs cycle, a central element of α-KA metabolism. SDH subunit D heterozygous (SDHD+/−) and wild-type (WT) mice were housed at normoxia or hypoxia (10% O2) for 4 days or 3 weeks, and right ventricular pressure, right ventricle/(left ventricle + septum) ratio, cardiomyocyte ultrastructure, pulmonary vascular remodelling, ventricular complex II subunit expression, SDH activity and α-KA concentrations were analysed. In both strains, hypoxia induced increases in right ventricular pressure and enhanced muscularization of distal pulmonary arteries. Right ventricular hypertrophy was less severe in SDHD+/− mice although the cardiomyocyte ultrastructure and mitochondrial morphometric parameters were unchanged. Protein amounts of SDHA, SDHB and SDHC, and SDH activity were distinctly reduced in SDHD+/− mice. In normoxic SDHD+/− mice, α-ketoisocaproate concentration was lowered to 50% as compared to WT animals. Right/left ventricular concentration differences and the hypoxia-induced decline in individual α-KAs were less pronounced in SDHD+/− animals indicating that mitochondrial complex II participates in the adjustment of cardiac α-KA concentrations both under normoxic and hypoxic conditions. These characteristics are not related to the hemodynamic consequences of hypoxia-induced pulmonary vascular remodelling, since its extent and right ventricular pressure were not affected in SDHD+/− mice albeit right ventricular hypertrophy was attenuated., This work was supported by the Deutsche Forschungsgemeinschaft (Sonderforschungsbereich 547, project C1) and the Excellence Cluster Cardio-Pulmonary System. Dres. J. I. Piruat and J. López-Barneo are members of the “Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas (CIBERNED)”.

Contains fulltext : 88713.pdf (Publisher’s version ) (Closed access) OBJECTIVE: To evaluate the efficacy of the Nijmegen Falls Prevention Program (NFPP) for persons with osteoporosis and a fall history in a randomized controlled trial. Persons with osteoporosis are at risk for fall-related fractures because of decreased bone strength. A decrease in the number of falls therefore is expected to be particularly beneficial for these persons. DESIGN: Randomized controlled trial. SETTING: Hospital. PARTICIPANTS: Persons with osteoporosis and a fall history (N=96; mean +/- SD age, 71.0+/-4.7y; 90 women). INTERVENTION: After baseline assessment, participants were randomly assigned to the exercise (n=50; participated in the NFPP for persons with osteoporosis [5.5wk]) or control group (n=46; usual care). MAIN OUTCOME MEASURES: Primary outcome measure was fall rate, measured by using monthly fall calendars for 1 year. Secondary outcomes were balance confidence (Activity-specific Balance Confidence Scale), quality of life (QOL; Quality of Life Questionnaire of the European Foundation for Osteoporosis), and activity level (LASA Physical Activity Questionnaire, pedometer), assessed posttreatment subsequent to the program and after 1 year of follow-up. RESULTS: The fall rate in the exercise group was 39% lower than for the control group (.72 vs 1.18 falls/person-year; risk ratio, .61; 95% confidence interval, .40-.94). Balance confidence in the exercise group increased by 13.9% (P=.001). No group differences were observed in QOL and activity levels. CONCLUSION: The NFPP for persons with osteoporosis was effective in decreasing the number of falls and improving balance confidence. Therefore, it is a valuable new tool to improve mobility and independence of persons with osteoporosis. 01 november 2010

Contains fulltext : 89628.pdf (Publisher’s version ) (Open Access) Treatment-failure gout (TFG) affects approximately 50,000 patients or about 1% of the overall population of patients with gout in the United States of America. The severity of TFG is manifested by frequent acute attacks of disabling arthritis, chronic deforming joint disease, destructive masses of urate crystals (tophi), progressive physical disability, and poor health-related quality of life. Pegloticase (Krystexxa((R)); Savient Pharmaceuticals, Inc), a novel PEGylated urate oxidase (uricase) enzyme, has been resubmitted for US Food and Drug Administration approval. In a 6-month, placebo-controlled clinical trial, 8 mg of pegloticase for every 2 weeks induced a lytic decrease of serum urate (sUr) concentrations, leading to dissolution of tophi in 40% of patients at final visit. However, 58% were nonresponders to the defined target sUr of 0.36 mmol/L (80% were nonresponders during months 3 and 6), possibly due to anti-body formation. Also, 26%-31% experienced infusion reactions (IRs) and 77% suffered from gout flares. Although long-term data are awaited, an anti-inflammatory strategy, eg, based on glucocorticosteroids, is needed to prevent pegloticase antibody formation leading to IRs and diminished or shortened efficacy, and might also prevent gout flares. According to the current clinical data, pegloticase might have an important role as a (bridging) treatment in sUr-responsive patients for tophi clearance in severe chronic refractory gout.

Contains fulltext : 89691.pdf (Publisher’s version ) (Closed access) A rat model of osteoarthritis was used to investigate the effect of pre-treatment with capsaicin on the symptoms of osteoarthritis induced by the injection of monosodium iodoacetate. This model mimics both histopathology and symptoms associated of human osteoarthritis. Injection of monosodium iodoacetate, an inhibitor of glycolysis, into the femorotibial joints of rodents promotes loss of articular trabecular bone and invokes pain symptoms similar to those noted in human osteoarthritis. Twenty rats were divided in two groups either receiving placebo or monosodium iodoacetate. Each group was subdivided in two groups either receiving pre-treatment with capsaicin two weeks before monosodium iodoacetate injection or not, resulting in four groups of five rats each. The impact of a single intra-articular administration of capsaicin (0.5%) on the generation of evoked mechanical pain (hind limb weight bearing, automated von Frey monofilament and RotaRod tests) and bone lesions (micro-CT scan radiographic analyses of bone structure) following monosodium iodoacetate-induced osteoarthritis in rats was determined. Evoked mechanical pain as monitored over a period of 4 weeks after monosodium iodoacetate injection was abolished in capsaicin pre-treated animals and pain values are comparable to those of capsaicin controls. Chronic joint pathological changes such as bone erosion and trabecular damage were significantly reduced by pre-treatment with a single administration of capsaicin. Decrease of bone volume was considerably ameliorated and trabecular connectivity was substantially better in capsaicin pre-treated animals. Capsaicin, an agonist activator of the vanilloid nociceptors (TRPV1), appears to be effective in protecting bone from arthritic damage. The present results support the hypothesis that capsaicin-sensitive sensory neurons contribute to bone lesions in the monosodium iodoacetate-induced osteoarthritis rat model.

Contains fulltext : 87712.pdf (Publisher’s version ) (Closed access) OBJECTIVES: Tight control studies including regular assessments of disease activity have shown that this approach has beneficial effects on disease activity, disability and joint damage in treating RA patients. Some of these studies included tight control with protocolized treatment, while others applied tight control without protocolized treatment. The aim of this study was to compare the effects of tight control with usual care and to compare the effects of tight control studies with and without protocolized treatment adjustments. METHODS: A systematic literature search was performed to identify clinical trials in RA that evaluated tight control strategies in comparison with usual care. Two types of study were compared: (i) those using disease activity monitoring with protocolized treatment adjustments, and (ii) those using disease activity monitoring without protocolized treatment adjustments. The databases PubMed and Cochrane were searched from 1995 up to 2009. Primary outcome measure was the mean change in the 28-joint DAS (DAS-28), which was used in a random-effects meta-analysis. RESULTS: Six controlled trials regarding tight control in RA patients were included in the meta-analysis. In all trials, patients treated in the tight control arms had significantly higher DAS-28 responses than patients treated according to usual care [weighted mean difference (WMD) = 0.59, P < 0.001]. Moreover, tight control was significantly more effective (P < 0.001) by means of protocolized treatment adjustments (WMD = 0.97) compared with non-protocolized monitoring of disease activity (WMD = 0.25). CONCLUSION: Tight control in RA resulted in significantly better clinical outcomes than usual care. It is suggested but not proved that tight control with protocolized treatment adjustments is more beneficial than if no such protocol is used. 01 november 2010

Contains fulltext : 87756.pdf (Publisher’s version ) (Closed access) BACKGROUND: Response shift theory suggests that improvements in health lead patients to change their internal standards and re-assess former health states as worse than initially rated when using retrospective ratings via the then-test. The predictions of response shift theory can be illustrated using prospect theory, whereby a change in current health causes a change in reference frame. Therefore, if health deteriorates, the former health state will receive a better rating, whereas if it improves, the former health state will receive a worse rating. OBJECTIVE: To explore the predictions of response shift and prospect theory by relating subjective change to objective change. METHODS: Baseline and 3-month follow-up data from a cohort of rheumatoid arthritis patients (N = 197) starting on TNFalpha-blocking agents were used. Objective disease change was classified according to a disease-specific clinical outcome measure (DAS28). Visual analogue scales (VAS) for general health (GH) and pain were used as self-reported measures. Three months after starting on anti-TNFalpha, patients used the then-test to re-rate their baseline health with regard to general health and pain. Differences between then-test value and baseline values were calculated and tested between improved, non-improved and deteriorated patients by the Student t-test. RESULTS: At 3 months, 51 (25.9%) patients had good improvement in health, 83 (42.1%) had moderate improvement, and 63 (32.0%) had no improvement or deteriorated in health. All patients no matter whether they improved, did not improve, or even became worse rated their health as worse retrospectively. The difference between the then-test rating and the baseline value was similarly sized in all groups. CONCLUSION: More positive ratings of retrospective health are independent of disease change. This suggests that patients do not necessarily change their standards in line with their disease change, and therefore it is inappropriate to use the then-test to correct for such a change. If a then-test is used to correct for shifts in internal standards, it might lead to the paradoxical result that patients who do not improve or even deteriorate increase significantly on self-reported health and pain. An alternative explanation for differences in retrospective and prospective ratings of health is the implicit theory of change which is more successful in explaining our results than prospect theory. 01 september 2010

Contains fulltext : 88603.pdf (Publisher’s version ) (Closed access) OBJECTIVE: To describe the frequency and effectiveness of dose increase of adalimumab, etanercept, and infliximab in the treatment of rheumatoid arthritis (RA) in daily clinical practice. METHODS: All RA patients with a dose increase of tumor necrosis factor (TNF)-blocking therapy between January 1997 and January 2008 were selected from a register including data from RA patients starting a first TNF-blocking agent (the Dutch Rheumatoid Arthritis Monitoring registry). The primary outcome was change in Disease Activity Score in 28 joints (DAS28) at 3 months after dose increase. Secondary outcomes were the change in DAS28 at 6 months after dose increase, the European League Against Rheumatism response rates, and the percentages of patients reaching a DAS28 of

Contains fulltext : 89217.pdf (Publisher’s version ) (Closed access) SUMMARY: Immunosuppressive therapy in renal transplant recipients (RTRs) is associated with an increased risk for the development of (pre)malignancies involving the skin and the female lower genital tract. We assessed whether yearly cervical screening was performed and evaluated the development of skin cancer and gynaecological (pre)malignancies in RTRs. Female RTRs (n = 224), transplanted between 1991 and 1995, were analysed retrospectively. Sociodemographic patient characteristics, frequency and results of cervical smears and prevalence of cutaneous, cervical, vaginal or vulvar (pre)malignancies were investigated and compared with that in the general population. A mean of 0.2 cervical smears per patient per year was found to have been performed in RTRs, which is significantly less than the recommended screening ratio of 1.0 for female RTRs (P < 0.001). The risk for RTRs to develop malignancies of the female lower genital tract was increased: twofold to sixfold for cervical intraepithelial neoplasia, threefold for cervical carcinoma and 50-fold for vulvar carcinoma. Cervical screening is not performed in accordance with the advised yearly intervals, and the risk for RTRs to develop vulvar and cervical (pre)malignancies is increased. More attention should be paid to the vulvar and cervical surveillance of RTRs by both medical specialists and general physicians. 01 februari 2010

Contains fulltext : 89257.pdf (Publisher’s version ) (Closed access) BACKGROUND: Most cases of acute gouty arthritis are diagnosed in primary care and without joint fluid analysis in many instances. Our objectives were to estimate the validity of this diagnosis by family physicians and to develop a diagnostic rule. METHODS: Patients with monoarthritis recruited in an open Dutch population with gout by family physician diagnosis were enrolled in a diagnostic study (March 24, 2004, through July 14, 2007). Validity variables were estimated using 2 x 2 tables, with the presence of synovial monosodium urate crystals as the reference test. For development of the diagnostic rule, clinical variables (including the presence of synovial monosodium urate crystals) were collected within 24 hours. Statistically significant variables and predefined variables were separately entered in multivariate logistic regression models to predict the presence of synovial monosodium urate crystals. Diagnostic performance of the models was tested by receiver operating characteristic curve analysis. The most appropriate model was transformed to a clinically useful diagnostic rule. RESULTS: Three hundred twenty-eight patients were included in the study. The positive and negative predictive values of family physician diagnosis of gout were 0.64 and 0.87, respectively. The most appropriate model contained the following predefined variables: male sex, previous patient-reported arthritis attack, onset within 1 day, joint redness, first metatarsophalangeal joint (MTP1) involvement, hypertension or 1 or more cardiovascular diseases, and serum uric acid level exceeding 5.88 mg/dL (to convert serum uric acid level to micromoles per liter, multiply by 59.485). The area under the receiver operating characteristic curve for this model was 0.85 (95% confidence interval, 0.81-0.90). Performance did not change after transforming the regression coefficients to easy-to-use scores and was almost equal to that of the statistically optimal model (area under the receiver operating characteristic curve, 0.87; 95% confidence interval, 0.83-0.91). CONCLUSIONS: The validity of family physician diagnosis of acute gouty arthritis was moderate in this study. An easy-to-use diagnostic rule without joint fluid analysis was developed for their use.

Contains fulltext : 87620.pdf (Publisher’s version ) (Open Access) Renal involvement in systemic lupus erythematosus patients is a severe disease manifestation characterized by various clinical and histopathological alterations. The revised International Society of Nephrology/Renal Pathology Society 2003 classification defines the subclasses of lupus nephritis (LN) according to their pathological glomerular patterns, which has a crucial impact on the prognosis and treatment options for LN patients. There are widely accepted therapeutic agents available, such as cyclophosphamide, mycophenolate mofetil, azathioprine and corticosteroids. Several trials have tried to determine a gold standard for induction and maintenance therapy in LN, and the place of newer drugs, biologicals, has been investigated. We review recently reported data on current treatment regimens in LN, in particular in the context of the International Society of Nephrology/Renal Pathology Society 2003 classification. 01 november 2010

Contains fulltext : 88471.pdf (Publisher’s version ) (Closed access) OBJECTIVE: To investigate the possible association of the BANK1 gene with genetic susceptibility to systemic sclerosis (SSc) and its subphenotypes. METHODS: A large multicentre case-control association study including 2380 patients with SSc and 3270 healthy controls from six independent case-control sets of Caucasian ancestry (American, Spanish, Dutch, German, Swedish and Italian) was conducted. Three putative functional BANK1 polymorphisms (rs17266594 T/C, rs10516487 G/A, rs3733197 G/A) were selected as genetic markers and genotyped by Taqman 5 allelic discrimination assay. RESULTS: A significant association of the rs10516487 G and rs17266594 T alleles with SSc susceptibility was observed (pooled OR=1.12, 95% CI 1.03 to 1.22; p=0.01 and pooled OR=1.14, 95% CI 1.05 to 1.25; p=0.003, respectively), whereas the rs3733197 genetic variant showed no statistically significant deviation. Stratification for cutaneous SSc phenotype showed that the BANK1 rs10516487 G, rs17266594 T and rs3733197 G alleles were strongly associated with susceptibility to diffuse SSc (dcSSc) (pooled OR=1.20, 95% CI 1.05 to 1.37, p=0.005; pooled OR=1.23, 95% CI 1.08 to 1.41, p=0.001; pooled OR=1.15, 95% CI 1.02 to 1.31, p=0.02, respectively). Similarly, stratification for specific SSc autoantibodies showed that the association of BANK1 rs10516487, rs17266594 and rs3733197 polymorphisms was restricted to the subgroup of patients carrying anti-topoisomerase I antibodies (pooled OR=1.20, 95% CI 1.02 to 1.41, p=0.03; pooled OR=1.24, 95% CI 1.05 to 1.46, p=0.01; pooled OR=1.26, 95% CI 1.07 to 1.47, p=0.004, respectively). CONCLUSION: The results suggest that the BANK1 gene confers susceptibility to SSc in general, and specifically to the dcSSc and anti-topoisomerase I antibody subsets. 01 april 2010

Item does not contain fulltext BACKGROUND AND OBJECTIVE: Mild therapeutic hypothermia (MTH) is used after out-of-hospital cardiac arrest (OHCA) to minimize cerebral damage. Induced hypothermia may further interfere with cardiac function and influence haemodynamics after OHCA. METHODS: This was a prospective study of haemodynamic variables in 50 consecutive patients with OHCA treated with MTH. Patients were cooled to a core body temperature of 32.5 degrees C for 24 h. Induction and maintenance of cooling was accomplished via infusion of 2 l of cold isotonic saline (4 degrees C) and a cooling blanket. Rewarming was performed to 36 degrees C at a rate of 0.3 degrees C per hour. Haemodynamic data were analysed and compared in individual patients during different temperature phases. RESULTS: Heart rate dropped from a mean of 85 to 60 beats per min (P=0.001) during hypothermia. Mean arterial pressure dropped from 79 to 72 mmHg, despite a rise in vasopressors and inotropes. Lactate levels were elevated throughout the induction (mean+/-SD) and maintenance phase (mean+/-SD); however, this did not correlate with a decrease in SVO2. Pulmonary artery pressures decreased during induction of hypothermia despite rapid infusion. CONCLUSION: MTH after OHCA lowered the heart rate. Despite induction of hypothermia with cold fluids, filling pressures decreased. Lower mean arterial pressure and cardiac output were observed during MTH, without deleterious effect on ScVO2. Lactate levels were elevated during MTH; however, levels did not correlate with outcome. Although the need for vasopressors and inotropes increases, this hypothermia-induced metabolic beta-blocker-like effect seems to have no negative effect on oxygen consumption and only temporarily affects anaerobic metabolism. No association of haemodynamic changes during MTH with outcome was found. 01 april 2010

BACKGROUND Hepcidin is an iron-regulatory peptide hormone that consists of 3 isoforms: bioactive hepcidin-25, and inactive hepcidin-22 and hepcidin-20. Hepcidin is instrumental in the diagnosis and monitoring of iron metabolism disorders, but reliable methods for its quantification in serum are sparse, as is knowledge of their relative analytical strengths and clinical utility. METHODS We developed a competitive (c)-ELISA and an immunocapture TOF mass-spectrometry (IC-TOF-MS) assay. Exploiting these 2 methods and our previously described weak cation exchange (WCX)-TOF-MS assay, we measured serum hepcidin concentrations in 186 patients with various disorders of iron metabolism and in 23 healthy controls. RESULTS We found that (a) the relative differences in median hepcidin concentrations in various diseases to be similar, although the absolute concentrations measured with c-ELISA and WCX-TOF-MS differed; (b) hepcidin isoforms contributed to differences in hepcidin concentrations between methods, which were most prominent in patients with chronic kidney disease; and (c) hepcidin concentrations measured by both the c-ELISA and IC-TOF-MS correlated with ferritin concentrations CONCLUSIONS c-ELISA is the method of choice for the large-scale quantification of serum hepcidin concentrations, because of its low limit of detection, low cost, and high-throughput. Because of its specificity for bioactive hepcidin-25, WCX-TOF-MS can be regarded as a valuable special-purpose assay for disorders with variable concentrations of hepcidin isoforms, such as chronic kidney disease.

Contains fulltext : 89015.pdf (Publisher’s version ) (Closed access) Carbon monoxide-releasing molecules can counteract inflammatory responses. The aim of this study was to investigate whether tricarbonylchloro(glycinate)ruthenium (II) (CORM-3) is able to control the effector phase of experimental arthritis. Arthritis was induced in C57Black-6 mice by an intraperitoneal injection of serum from arthritic K/BxN mice. CORM-3 was administered intraperitoneally at 10 mg/kg/day (5 mg/kg twice a day) from days 0 to 10 and animals were sacrificed on day 11. Serum levels of osteocalcin and prostanoids were measured by enzyme-linked immunosorbent assay and radioimmunoassay. Gene expression was determined by real-time PCR. Histological analysis was performed and protein expression was examined by immunohistochemistry. Treatment with CORM-3 reduced the macroscopic score in hind paws, the migration of inflammatory cells and erosion of cartilage and bone. CORM-3 increased the levels of osteocalcin in the serum and reduced PGD2 levels, whereas PGE2 and 6-ketoPGF1alpha were not affected. In synovial tissues, we also observed a significant reduction in gene expression of interleukin-1beta, receptor activator of nuclear factor kappaB ligand (RANKL), matrix metalloproteinase (MMP)-9 and MMP-13. CORM-3 induced HO-1 expression in joint tissues but inhibited high mobility group box 1 (HMGB1), hematopoietic-prostaglandin D2 synthase (H-PGDS) and lipocalin-type prostaglandin D2 synthase (L-PGDS), as well as RANKL and intercellular adhesion molecule-1. COX-2 expression was not affected by CORM-3 treatment. We have shown that CORM-3 decreases the inflammatory response and protects against the degradation of cartilage and bone in the arthritic mice. Pharmacological CO delivery represents a novel strategy to regulate the effector phase of arthritis.

Objective.C-C chemokine receptor 5 (CCR5) plays an important role in inflammation. A 32 base-pair (Δ32) deletion in the CCR5 gene leads to a nonfunctional receptor. This deletion has been reported to have a protective effect on the development and progression of several autoimmune diseases. We investigated whether the Δ32 deletion is associated with disease susceptibility in a population of patients with rheumatoid arthritis (RA), systemic lupus erythematosus (SLE), and lupus nephritis (LN); and whether it is associated with disease severity.MethodsDNA samples from 405 RA patients, 97 SLE patients, 113 LN patients, and 431 healthy controls were genotyped for the CCR5 Δ32 deletion. Differences in genotype frequencies were tested between patients and controls. Association of genotypes with disease severity was analyzed.ResultsGenotype frequencies of each group were in Hardy-Weinberg equilibrium. The genotype frequencies of patients did not differ significantly from controls (CCR5/Δ32, Δ32/Δ32: RA 18.3% and 1.2%, respectively; SLE 17.5% and 2.1%; LN 13.3% and 1.8%; controls 20.0% and 2.8%). However, there was a trend for lower Δ32 deletion allele frequency in LN patients compared to controls (p = 0.08). There was no significant association between the CCR5 status and disease severity in RA, SLE, or LN.Conclusion.Although an association with LN cannot be excluded, the CCR5 Δ32 deletion does not seem to be a disease susceptibility genotype for RA, SLE, or LN. No significant effect of the Δ32 deletion on disease severity was demonstrated.

Contains fulltext : 87344.pdf (Publisher’s version ) (Closed access) INTRODUCTION: Recruitment maneuvers (RMs) are advocated to prevent pulmonary collapse during low tidal volume ventilation and improve oxygenation. However, convincing clinical evidence for improved outcome is lacking. Recent experimental studies demonstrate that RMs translocate pulmonary inflammatory mediators into the circulation. To determine whether a single RM in ventilated children affects pulmonary and systemic cytokine levels, we performed a prospective intervention study. METHODS: Cardiorespiratory stable ventilated patients (0.5-45 months, n = 7) with acute lung injury were subjected to an RM determining opening and closing pressures (peak inspiratory pressure < or =45 cmH(2)O, positive end expiratory pressure (PEEP) < or =30 cmH(2)O). Before and after RM, cardiorespiratory parameters and ventilator settings were recorded, blood gas analysis performed, and bronchoalveolar lavage fluid and plasma TNF-alpha, IL-1beta, IL-6, IL-8, and IL-10 concentrations were determined. RESULTS: Fifteen minutes after the RM, an increase was observed in plasma tumor necrosis factor-alpha (400% +/- 390% of baseline, P = .04), IL-6 (120% +/- 35%, P = .08), and IL-1beta (520% +/- 535%, P = .04), which decreased at T = 60 minutes, hence indicative of translocation. Recruitment maneuver did not change the plasma levels of the anti-inflammatory IL-10 (105% +/- 12%, P = .5). Apart from a nonsignificant increase of IL-8 after 360 minutes (415% +/- 590%,P = .1), bronchoalveolar cytokine levels were not influenced by the RM. No increase in oxygenation or improvement of lung kinetics was observed. CONCLUSIONS: A single RM can translocate pro-inflammatory cytokines from the alveolar space into the systemic circulation in ventilated critically ill children. 01 maart 2010

Contains fulltext : 80926.pdf (Publisher’s version ) (Closed access) OBJECTIVE: To evaluate the accuracy of right ventricular ejection fraction and right ventricular end-diastolic volume obtained by volumetric pulmonary artery catheter, using the conductance catheter as reference method. DESIGN: Prospective, comparative study. SETTING: Research laboratory of a university hospital. SUBJECTS: Seven young female German landrace pigs. INTERVENTIONS: Ligation of the distal right coronary artery to induce temporary acute ischemia. MEASUREMENTS AND MAIN RESULTS: Right ventricular ejection fraction and right ventricular end-diastolic volume were measured simultaneously with a volumetric pulmonary artery catheter and the conductance catheter technique (reference method), in an animal model of acute right ventricular ischemia. Measurements were performed at baseline, during ischemia, and during reperfusion. The methods were compared with Bland-Altman analyses and their diagnostic accuracy to detect ischemia was quantified by receiver operating characteristic curve analysis. For right ventricular ejection fraction measurements, Bland-Altman analysis indicated a bias of -9.9% indicating underestimation by pulmonary artery catheter with limits of agreement ranging from -26% to 6.1%. The data showed a trend for more underestimation at higher right ventricular ejection fraction values. For right ventricular end-diastolic volume, a bias of 31 mL, indicating overestimation by pulmonary artery catheter was found. Limits of agreement ranged from -25 mL to 88 mL. Ischemia induced a decrease in right ventricular ejection fraction and an increase in right ventricular end-diastolic volume, as expected, which was detected by conductance catheter with a significant higher diagnostic accuracy indicated by a receiver operating characteristic area under the curve of 0.98 (p < .001) and 0.92 (p < .001), respectively. Corresponding sensitivity and specificity were 100% and 86%, respectively, for right ventricular ejection fraction conductance catheter (cutoff value = 94 mL). However, diagnostic accuracy for right ventricular ejection fraction pulmonary artery catheter and end-diastolic volume pulmonary artery catheter to detect ischemia was limited with area under the curve 0.76 (p = .06) and 0.57 (p = .65), respectively. CONCLUSIONS: Accuracy of volumetric pulmonary artery catheter in conditions of right ventricular ischemia is low and inadequate for diagnosis of right ventricular ischemia and failure.

Contains fulltext : 81312.pdf (Publisher’s version ) (Closed access) OBJECTIVES: To investigate if the protective effects of xenon and isoflurane against myocardial ischemia-reperfusion damage would be additive. DESIGN: A prospective, randomized laboratory investigation. SETTING: An animal laboratory of a university hospital. PARTICIPANTS: Thirty-six pigs (female German landrace). INTERVENTIONS: In an open-chest preparation with thiopental anesthesia, the left anterior descending artery was occluded to produce ischemia for 60 minutes. One hour previously, ischemic preconditioning, isoflurane (0.55 minimum alveolar concentration [MAC]) alone, or isoflurane together with xenon (0.55 MAC each) were started in the respective groups. A fourth (control) group received no protective intervention. Myocardial ischemia was followed by 2 hours of reperfusion. MEASUREMENTS AND MAIN RESULTS: Hearts were excised and stained (Evans Blue/TTC) to measure infarct size as related to the area at risk. Myocardial infarct size was reduced (means +/- standard deviation) from 64% +/- 9% of the area at risk in the control group to 19% +/- 12% with ischemic preconditioning to 46% +/- 12% with isoflurane and to 39% +/- 13% with isoflurane and xenon. All intervention groups were significantly different from the control (p < 0.05), and both anesthetic groups were significantly different from ischemic preconditioning (p < 0.05). CONCLUSION: Combined isoflurane/xenon anesthesia reduced infarct size but not more than isoflurane alone. Ischemic preconditioning was more effective than the anesthetics.

Contains fulltext : 88616.pdf (Publisher’s version ) (Closed access) BACKGROUND: alpha-Dystroglycan (alpha-DG) is a negatively charged glycoprotein that covers the surface of podocytes. A decreased glomerular expression of alpha-DG has been described in minimal change nephropathy (MCN), but not in focal segmental glomerulosclerosis (FSGS). This was suggested as a tool to distinguish these diseases. Sialic acid is a negatively charged carbohydrate extensively present on both alpha-DG and podocalyxin, which is also expressed on podocytes. Intrarenal perfusion with bacterial sialidase leads to foot process effacement and proteinuria. This is the first study on the expression of endogenous glomerular sialidase; furthermore, the expression of dystroglycan was re-evaluated. METHODS: The expression of alpha-DG and sialidase was investigated by immunofluorescence in kidney biopsies of patients with MCN (n = 5), FSGS (n = 15), proliferative lupus nephritis (LN, n = 9), membranous glomerulopathy (MG, n = 10) and normal human kidneys (NHK, n = 4). The urinary sialic acid concentration was measured using a newly developed LC-tandem mass spectrometry method. RESULTS: A 3-fold increased glomerular expression of sialidase was found in MG, accompanied with an increased urinary sialic acid concentration in two MG patients. However, we did not observe major changes in the expression of alpha-DG in patients with the above-mentioned glomerular diseases compared to NHK, also not between MCN and FSGS. CONCLUSIONS: Endogenous glomerular sialidase expression is increased in MG, which might represent a novel mechanism for the loss of negative charge in the glomerular capillary filter. The expression of dystroglycan cannot be used as a diagnostic tool to differentiate between glomerular diseases. 01 februari 2010

Contains fulltext : 81723.pdf (Publisher’s version ) (Closed access) BACKGROUND: Inhibition of the renin-angiotensin-aldosterone system (RAAS) provides renoprotection in adriamycin nephropathy (AN), along with a decrease in overexpression of glomerular heparanase. Angiotensin II (AngII) and reactive oxygen species (ROS) are known to regulate heparanase expression in vivo. However, it is unknown whether this is also the case for aldosterone. Therefore, we further assessed the role of aldosterone, AngII and ROS in the regulation of glomerular heparanase expression. METHODS: Six weeks after the induction of AN, rats were treated with vehicle (n = 8), lisinopril (75 mg/L, n = 10), spironolactone (3.3 mg/day, n = 12) or the combination of lisinopril and spironolactone (n = 14) for 12 weeks. Age-matched healthy rats served as controls (n = 6). After 18 weeks, renal heparanase and heparan sulfate (HS) expression were examined by immunofluorescence staining. In addition, the effect of aldosterone, AngII and ROS on heparanase expression in cultured podocytes was determined. RESULTS: Treatment with lisinopril, spironolactone or their combination significantly blunted the increased glomerular heparanase expression and restored the decreased HS expression in the GBM. Addition of aldosterone to cultured podocytes resulted in a significantly increased heparanase mRNA and protein expression, which could be inhibited by spironolactone. Heparanase mRNA and protein expression in podocytes were also significantly increased after stimulation with AngII or ROS. CONCLUSIONS: Our in vivo and in vitro results show that not only AngII and ROS, but also aldosterone is involved in the regulation of glomerular heparanase expression.

Objective.Rheumatoid arthritis (RA) is an inflammatory joint disease with features of an autoimmune disease with female predominance. Candidate genes located on the X-chromosome were selected for a family trio-based association study.Methods.A total of 1452 individuals belonging to 3 different sample sets were genotyped for 16 single-nucleotide polymorphisms (SNP) in 7 genes. The first 2 sets consisted of 100 family trios, each of French Caucasian origin, and the third of 284 additional family trios of European Caucasian origin. Subgroups were analyzed according to sex of patient and presence of anti-cyclic citrullinated peptide (anti-CCP) autoantibodies.Results.Four SNP were associated with RA in the first sample set and were genotyped in the second set. In combined analysis of sets 1 and 2, evidence remained for association of 3 SNP in the genesUBA1, TIMP1,andIL9R.These were again genotyped in the third sample set. Two SNP were associated with RA in the joint analysis of all samples: rs6520278 (TIMP1) was associated with RA in general (p = 0.035) and rs3093457 (IL9R) with anti-CCP-positive RA patients (p = 0.037) and male RA patients (p = 0.010). A comparison of the results with data from whole-genome association studies further supports an association of RA withTIMPLThe sex-specific association of rs3093457 (IL9R) was supported by the observation that men homozygous for rs3093457-CC are at a significantly higher risk to develop RA than women (risk ratio male/female = 2.98; p = 0.048).Conclusion.We provide evidence for an association of at least 2 X-chromosomal genes with RA:TIMP1(rs6520278) andIL9R(rs3093457).

Contains fulltext : 80105.pdf (Publisher’s version ) (Closed access) OBJECTIVE: High-density lipoprotein (HDL) antiatherogenic functions seem to be diminished during inflammatory conditions such as rheumatoid arthritis (RA). The aim of this study was to investigate the effects of tumour necrosis factor (TNF) inhibition on the antioxidative capacity of HDL in RA. METHODS: Plasma lipids and paraoxonase (PON-1) activity were investigated in 45 RA patients, before and during 6 months of anti-TNF therapy. In addition, HDL was isolated and tested for its ability to inhibit copper-induced oxidation of low-density lipoprotein in vitro. RESULTS: Plasma HDL concentrations did not change considerably after 6 months of therapy. However, stable increases of PON-1 activities were observed throughout the same period (p