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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 Children with primary immunodeficiencies, sickle cell disease and cystic fibrosis are at risk to develop invasive bacterial infections caused by respiratory tract pathogens, in particular Streptococcus pneumoniae, Haemophilus influenzae and Staphylococcus aureus. This review article evaluates the role of nasopharyngeal colonization by these pathogens in the high prevalence of respiratory and invasive infections in children with inherited disorders affecting the immune system or the respiratory tract. We conclude that respiratory and invasive diseases that occur in children with primary immunodeficiencies or sickle cell disease are probably a result of increased nasopharyngeal colonization rates compared with healthy children. However, when the inherited disorder is characterized by local airway abnormalities such as in cystic fibrosis, enhanced nasopharyngeal colonization does not seem to play a major role in invasive disease risk. As the evidence for the role of nasopharyngeal colonization in disease risk in these specific patient groups partly comes from experimental studies and animal models, longitudinal studies in children are needed. Detailed understanding of the effect of colonization on the development of respiratory and invasive infections in children with primary immunodeficiencies, sickle cell disease or cystic fibrosis provides a justification for the selective introduction of vaccination and prophylactic antibiotic treatment. Recommendations for the use of (preventive) therapeutic strategies in these patient groups taking into account disease-specific immunologic mechanisms underlying colonization and disease are described.

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 Immunodeficiency with centromeric instability and facial anomalies (ICF) syndrome is a primary immunodeficiency, predominantly characterized by agammaglobulinemia or hypoimmunoglobulinemia, centromere instability and facial anomalies. Mutations in two genes have been discovered to cause ICF syndrome: DNMT3B and ZBTB24. To characterize the clinical features of this syndrome, as well as genotype-phenotype correlations, we compared clinical and genetic data of 44 ICF patients. Of them, 23 had mutations in DNMT3B (ICF1), 13 patients had mutations in ZBTB24 (ICF2), whereas for 8 patients, the gene defect has not yet been identified (ICFX). While at first sight these patients share the same immunological, morphological and epigenetic hallmarks of the disease, systematic evaluation of all reported informative cases shows that: (1) the humoral immunodeficiency is generally more pronounced in ICF1 patients, (2) B- and T-cell compartments are both involved in ICF1 and ICF2, (3) ICF2 patients have a significantly higher incidence of intellectual disability and (4) congenital malformations can be observed in some ICF1 and ICF2 cases. It is expected that these observations on prevalence and clinical presentation will facilitate mutation-screening strategies and help in diagnostic counseling. 01 november 2013

Item does not contain fulltext INTRODUCTION: In the European Union (EU), notification of product information by industry to poisons centres and/or competent authorities is a legal obligation for mixtures classified as hazardous. However, EU legislation does not specify the precise information needed for this product notification. As a consequence, varying requirements have been developed in different EU Member States. The European Commission (EC) carried out an assessment of whether harmonisation of product notification can be achieved. This manuscript provides an overview of the most important (discussion) points to reach harmonisation. COMPOSITION AND CONCENTRATION OF INGREDIENTS: Discussions have focused mainly on whether non-classified ingredients should be notified only above a concentration threshold and on the use of defined, narrow concentration ranges instead of exact concentrations for hazardous ingredients. ELECTRONIC DATA EXCHANGE FORMAT: All stakeholders agree to the development of an electronic data exchange format for product notification and identify the eXtensible Markup Language (XML) as the most appropriate format. EUROPEAN PRODUCT DATABASE: Instead of multiple notifications to national databases, the EC will analyse the benefits, feasibility and costs of a European product database to provide a centralised portal for companies to upload their product information. Poisons centres and competent authorities need to have access to this information. UNIQUE PRODUCT IDENTIFIER: A Unique Product Identifier (UPI) on the product label can unambiguously identify the product and its formula and links it to the corresponding notified product information. A procedure for the creation of a UPI by companies has already been proposed. PRODUCT CATEGORY SYSTEM: There is broad support for the development of a hierarchical product category system to facilitate statistical analyses and comparability of poisoning incidents in EU Member States. OUTLOOK: Following a 3-year assessment period, the EC concluded that harmonisation of product notification is an achievable goal. In order to draft an Annex to the CLP Regulation concerning this topic, a new working group with representatives of EU Member States, European Association of Poisons Centres and Clinical Toxicologists (EAPCCT) and other stakeholders will attempt to find consensus on harmonisation of product notification. 01 februari 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 Background Patients and the course of treatment in daily practice are different from randomized controlled trials (RCTs). Objectives Primary objective: to analyse the percentage of patients achieving PASI 75. Secondary objectives: PASI 50, PASI 90, PASI 100 responses, the percentage of patients experiencing at least one serious adverse event (SAE) and the response in biologic-naive vs. non-naive patients. Methods Prospectively collected efficacy and safety data of a cohort of psoriasis patients treated with adalimumab in daily practice between May 2007 and July 2011 were analyzed. Efficacy was determined using an intention-to-treat analysis and an as treated analysis, in comparison with the course baseline PASI before the start of adalimumab and the original baseline PASI before the start of any biologic therapy. Results Eighty-five patients received adalimumab therapy with a mean treatment duration of 1.4 (range 0.02-3.1) years. Compared with the original baseline PASI, PASI 75 response rates at week 12 and 24 were 34% and 38% (ITT). PASI 75 responses were well maintained until week 132. Only the PASI 75 response rate at week 12 differed significantly between biologic-naive (56%) and non-naive patients (29%). Sixteen patients (19%) experienced 28 SAEs. Seven patients (8%) experienced SAEs considered possibly or probably related to adalimumab. Conclusions In this cohort, PASI75 responses were substantial but lower than in RCTs and other daily practice studies. Efficacy was well maintained during more than 2 years of follow-up and differed only between biologic-naive and non-naive patients at week 12. The incidence of SAEs was low but seems higher than observed in RCTs.

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 Summary Background Infantile haemangioma (IH) is a benign, common and self-limiting tumour of infancy; only a minority of cases need active treatment. Currently, propranolol appears superior to classic treatments. Objectives To document in a prospective study indications and side-effects of propranolol for complicated IH in a large patient group. Methods Analysis of prospectively collected data was performed on 174 patients with IH treated with propranolol in a tertiary referral centre from September 2008 to January 2012. Results The group consisted of children with a potentially threatening and/or complicated IH; the girl/boy ratio was 123/51, and the mean age at the start of treatment was 4.8 months. In 173 cases (99.4%), treatment was successful, as assessed nonquantitatively by clinical observation. This striking effect was characterized by immediate cessation of growth, softening, fading of the erythema and rapid induction of regression. The mean duration of treatment was 10.7 months. The most important adverse effects were hypotension (3.4%), wheezing (9.2%), nocturnal restlessness (22.4%) and cold extremities (36.2%). In one patient, propranolol was stopped. In 15 patients it was necessary to reduce the dose, although the lower dose was still effective. Conclusions In this study, propranolol was effective and safe in almost all patients with complex IH. Administration of systemic medication to an infant with a benign condition requires careful consideration, as only a minority of patients with IH require an active medical intervention. A shift of the indication of propranolol for IH is evident, expanding its application for life-threatening situations or severe functional impairment to early prevention of disfigurement or cosmetically permanent sequelae. However, the indication for such an active approach should be determined by experienced physicians.

Item does not contain fulltext The combination of ribavirin and peginterferon is the current standard of anti-viral treatment for chronic HCV patients. However, little is known on the mode of action of ribavirin in the anti-viral treatment of HCV patients. To investigate the immunomodulatory mechanism of ribavirin, we studied peginterferon alone versus peginterferon and ribavirin in chronic HBV patients. The addition of ribavirin did not affect the number of myeloid dendritic cells (mDC) or plasmacytoid dendritic cells (pDC), nor did it enhance T-helper-1 cell activity or T-cell proliferation. In contrast, it increased upregulation of activation markers on mDC and pDC, which was sustained throughout treatment. However, the addition of ribavirin had no effect on IFNalpha production by pDC. Our findings demonstrate that, although ribavirin does not lead to a viral load decline, in vivo treatment with ribavirin affects the activation of pDC and mDC in chronic HBV patients.

Immunomodulating regulatory T-cell (Treg) therapy is a promising strategy in autoimmunity and transplantation. However, to achieve full clinical efficacy, better understanding of in vivo human Treg biology is warranted. Here, we demonstrate that in contrast to blood and bone marrow Tregs, which showed a resting phenotype, the majority of CD4(pos)CD25(pos)CD127(neg)FoxP3(pos) Tregs in secondary lymphoid organs were proliferating activated CD69(pos)CD45RA(neg) cells with a hyperdemethylated FOXP3 gene and a broad T-cell receptor-V beta repertoire, implying polyclonal activation. Activated CD69(pos) Tregs were distributed over both T-cell and B-cell areas, distant from Aire(pos) and CD11c(pos) cells. In contrast to the anergic peripheral blood Tregs, lymphoid organ Tregs had significant ex vivo proliferative capacity and produced cytokines like interleukin-2, while revealing similar suppressive potential. Also, next to Treg-expressing chemokine receptors important for a prolonged stay in lymphoid organs, a significant part of the cells expressed peripheral tissue-associated, functional homing markers. In conclusion, our data suggest that human secondary lymphoid organs aid in the maintenance and regulation of Treg function and homeostasis. This knowledge may be exploited for further optimization of Treg immunotherapy, for example, by ex vivo selection of Tregs with capacity to migrate to lymphoid organs providing an in vivo platform for further Treg expansion.

Item does not contain fulltext Background Basal cell carcinoma (BCC) is the most frequently occurring cancer in humans. Worldwide incidences rise about 10% each year, increasing the burden on dermatologists, general practitioners and pathologists as well as increasing costs for the health care system. Increasingly non-surgical treatment options are used in the treatment of BCC, without histological confirmation of BCC subtype, potentially resulting in under-treatment. Objective We evaluated the diagnostic accuracy of a punch biopsy for the BCC histological subytpe in a primary BCC and the prevalence of biopsy-based under-diagnosis of aggressive subtypes. Accuracy of a punch biopsy was defined as concordance of the diagnosis of subtype of BCC at punch biopsy and excision. Methods A retrospective chart-review was performed of primary BCC, which were proven by punch biopsy and subsequently treated by excision. The first 100 consecutive BCCs per year during the years 2004-2009 were included, yielding a total of 500 evaluated BCCs. Results The overall accuracy of punch biopsy for BCC subtype at excision was 69%, in single-type BCC 83% (n = 343) and in mixed-type BCC 37% (n = 157). Accuracy varied substantially according to BCC subtype, being highest in the superficial subtype (84%) and subsequently in infiltrative (69%), nodular (63%) and micronodular subtype (38%). In 11% of all cases, an unsuspected more aggressive subtype was present. Conclusion Punch biopsy has a high accuracy in single-type BCCs and a considerably lower accuracy in mixed-type BCCs for establishing BCC subtype compared to excision. The presence of an unsuspected aggressive subtype could explain therapy failure of non-surgical treatments like imiquimod or photodynamic therapy.

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.

Contains fulltext : 118364.pdf (Publisher’s version ) (Closed access) Background Most psoriasis patients suffering from mild to moderate disease are treated with first-line topical treatments, including corticosteroids, vitamin D analogues, topical retinoids and calcineurin inhibitors. Although evidence-based guidelines on combinations are lacking, the majority of patients will be treated with combinations of these popular topicals at some point during their life-long treatment. Objectives We intended to systematically review all available literature on the efficacy and safety of combinations of first-line topicals in chronic plaque psoriasis, and ultimately, to propose recommendations for combined regimens concerning first-line treatments. Methods Databases used as data sources were PubMed, EMBASE and the Cochrane Controlled Clinical Trial Register. According to standardized procedures, literature searches were performed and a level of evidence was determined. Results In total, 2918 publications on topical combination therapy were revealed, of which 45 articles on first-line combinations were included. The combination of potent and superpotent corticosteroids with vitamin D analogues provides an improvement of psoriasis within 2 weeks, reaching a maximal improvement after 4 weeks in the majority of patients. The two-compound product permits once-daily treatment and therefore is a good solution for chronic plaque psoriasis including scalp psoriasis. Combinations of corticosteroids, with tazarotene or with calcineurin inhibitors do not provide an advantage above corticosteroid monotherapy. Conclusion The combination of potent corticosteroids with calcipotriol has been studied most extensively and should be regarded as an efficacious and safe treatment option with the two-compound products as the most practical solution.

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 Infantile haemangiomas (IHs) are common, benign vascular tumours in children that appear soon after birth and regress before the age of 12 years. Physicians have always been concerned about the considerable psychosocial impact these lesions might have on children and their parents. This is the first critical review of studies on the psychosocial impact of IHs on children and their families. Future directions for research are suggested. As propranolol is becoming the most common first choice treatment for IHs, this article discusses its use in the light of this review.

Item does not contain fulltext Ataxia-telangiectasia (A-T) is classically characterized by progressive neurodegeneration, oculocutaneous telangiectasia, immunodeficiency and elevated alpha-fetoprotein levels. Some patients, classified as variant A-T, exhibit a milder clinical course. In the latter patients extrapyramidal symptoms, instead of cerebellar ataxia, tend to be the dominating feature and other classical disease hallmarks, like telangiectasia, appear later or even may be absent. Some patients with variant disease have clinically pronounced anterior horn cell degeneration. Neuropathological studies of genetically proven A-T patients are lacking. The aims of our study were to describe the neuropathology of three A-T patients; in two of them the diagnosis was genetically confirmed. The neuropathological findings were compared with those of all known published autopsy findings in A-T patients up to now. Two classical A-T patients aged 19 and 22 and a 33-year-old patient with variant disease were autopsied. In line with previous reports, our patients had severe cerebellar atrophy, less pronounced degeneration of the dentate nucleus and inferior olive, degeneration of the posterior columns and neurogenic muscular atrophy. In addition, all three had anterior horn cell degeneration, which was most prominent at the lumbar level. Compared to the literature, the degenerative changes in the brain stem of the variant A-T patient were somewhat less than anticipated for his age. Degenerative changes in the cerebellum and spinal cord were comparable with those in the literature. Progeric changes were lacking. In conclusion, compared to classical A-T, the variant A-T patient showed essentially the same, only slightly milder neuropathological abnormalities, except for anterior horn degeneration. 01 juni 2012

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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.

The immune regulatory mechanisms involved in the acquisition of Mycobacterium tuberculosis infection in children are largely unknown. We investigated the influence of parasitic infections, malnutrition and plasma cytokine profiles on tuberculin skin test (TST) positivity in Warao Amerindians in Venezuela. Pediatric household contacts of sputum smear-positive tuberculosis (TB) cases were enrolled for TST, chest radiograph, plasma cytokine analyses, QuantiFERON-TB Gold In-Tube (QFT-GIT) testing and stool examinations. Factors associated with TST positivity were studied using generalized estimation equations logistic regression models. Of the 141 asymptomatic contacts, 39% was TST-positive. After adjusting for age, gender and nutritional status, TST positivity was associated with Trichuris trichiura infections (OR 3.5, 95% CI 1.1-11.6) and low circulating levels of T helper 1 (Th1) cytokines (OR 0.51, 95% CI 0.33-0.79). Ascaris lumbricoides infections in interaction with Th2- and interleukin (IL)-10-dominated cytokine profiles were positively associated with TST positivity (OR 3.1, 95% CI 1.1-8.9 and OR 2.4,95% CI 1.04-5.7, respectively). A negative correlation of QFT-GIT mitogen responses with Th1 and Th2 levels and a positive correlation with age were observed (all p

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

Item does not contain fulltext Background In vivo reflectance confocal microscopy (RCM) is a novel, noninvasive imaging technique which enables imaging of skin at a cellular resolution comparable to conventional microscopy. Objectives We performed a pilot study to evaluate RCM as a noninvasive tool for monitoring ultraviolet (UV) B phototherapy in psoriasis. Methods In six patients with psoriasis, lesional and nonlesional skin was selected for RCM imaging using a standardized protocol. Well-known histological features of psoriasis were visualized: parakeratosis, acanthosis, agranulosis, papillomatosis, presence of epidermal inflammatory cells, increased number of papillary capillaries and increased capillary blood flow. RCM imaging was performed before the first irradiation with UVB phototherapy, after nine irradiations, at clearance and 12 weeks after clearance. In four patients, 4-mm punch biopsies were obtained and stained with haematoxylin-eosin. Additionally, immunohistochemical staining was performed with monoclonal antibodies specific for CD31, CD3, filaggrin, K16, Ki67 and CD1a for correlation to RCM images. Results There was a high correlation between clinical, RCM and histological features. Normalization of RCM and histological features corresponded highly to clinical improvement of psoriasis. Conclusions This study is the first to establish the use of RCM as an effective tool for noninvasive monitoring of UVB phototherapy in patients with psoriasis. Potentially, RCM could be used in many other skin diseases for monitoring therapeutic response on a cellular level in a clinical or research setting. 01 augustus 2012

Item does not contain fulltext INTRODUCTION: Given the central role of T cells in the alloimmune response, anti-T-cell antibodies retain a prominent place in the treatment of renal allograft rejection. During the past decades, many anti-T-cell antibodies have emerged and subsequently left the field of solid organ transplantation, but rabbit-antithymocyte globulin (ATG) and the humanized anti-CD52 monoclonal rat antibody alemtuzumab have remained. AREAS COVERED: This article reviews the literature about the use of ATG and alemtuzumab for the treatment of acute rejection after renal transplantation. Furthermore, it discusses possible side effects, including infusion reactions. A literature search using PubMed and Embase databases was undertaken using search words alemtuzumab, antithymocyte globulin, rejection, kidney and renal transplantation. EXPERT OPINION: Treatment of severe or steroid-resistant renal allograft rejections with ATG is very effective, but is also associated with frequent infusion reactions and an increased incidence of infections and posttransplant lymphoproliferative disease. Alemtuzumab may prove to be an attractive alternative. It can be administered easily, is relatively cheap and nearly devoid of acute side effects, but the long-term efficacy and safety as anti-rejection treatment are currently difficult to judge. The increasing knowledge about lymphocyte subsets and their plasticity will drive the development of new, specific immunosuppression that lacks side effects of ATG and alemtuzumab. TOL101, a monoclonal antibody specifically directed against the human alphabeta T cell receptor, might be of potential value. 01 augustus 2012

von Willebrand factor (VWF) is a large adhesive glycoprotein with established functions in hemostasis. It serves as a carrier for factor VIII and acts as a vascular damage sensor by attracting platelets to sites of vessel injury. VWF size is important for this latter function, with larger multimers being more hemostatically active. Functional imbalance in multimer size can variously cause microvascular thrombosis or bleeding. The regulation of VWF multimeric size and platelet-tethering function is carried out by ADAMTS13, a plasma metalloprotease that is constitutively active. Unusually, protease activity of ADAMTS13 is controlled not by natural inhibitors but by conformational changes in its substrate, which are induced when VWF is subject to elevated rheologic shear forces. This transforms VWF from a globular to an elongated protein. This conformational transformation unfolds the VWF A2 domain and reveals cryptic exosites as well as the scissile bond. To enable VWF proteolysis, ADAMTS13 makes multiple interactions that bring the protease to the substrate and position it to engage with the cleavage site as this becomes exposed by shear. This article reviews recent literature on the interaction between these 2 multidomain proteins and provides a summary model to explain proteolytic regulation of VWF by ADAMTS13.

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.

Translesion DNA synthesis, a process orchestrated by monoubiquitinated PCNA, is critical for DNA damage tolerance. While the ubiquitin-conjugating enzyme RAD6 and ubiquitin ligase RAD18 are known to monoubiquitinate PCNA, how they are regulated by DNA damage is not fully understood. We show that NBS1 (mutated in Nijmegen breakage syndrome) binds to RAD18 after UV irradiation and mediates the recruitment of RAD18 to sites of DNA damage. Disruption of NBS1 abolished RAD18-dependent PCNA ubiquitination and Polη focus formation, leading to elevated UV sensitivity and mutation. Unexpectedly, the RAD18-interacting domain of NBS1, which was mapped to its C terminus, shares structural and functional similarity with the RAD18-interacting domain of RAD6. These domains of NBS1 and RAD6 allow the two proteins to interact with RAD18 homodimers simultaneously and are crucial for Polη-dependent UV tolerance. Thus, in addition to chromosomal break repair, NBS1 plays a key role in translesion DNA synthesis., 放射線の修復蛋白NBS1放によるRAD18を介した損傷乗り越えDNA合成の開始. 京都大学プレスリリース. 2011-09-02.

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

The platelet-tethering function of von Willebrand factor (VWF) is proteolytically regulated by ADAMTS13 (a disintegrin and metalloproteinase with a thrombospondin type 1 motif, member 13), which cleaves the Tyr1605-Met1606 (P1-P1′) bond in the VWF A2 domain. To date, most of the functional interactions between ADAMTS13 and VWF that have been characterized involve VWF residues that are C terminal to the scissile bond. We now demonstrate that the substrate P3 position in VWF, Leu1603, is a critical determinant of VWF proteolysis. When VWF Leu1603 was substituted with Ser, Ala, Asn, or Lys in a short VWF substrate, VWF115, proteolysis was either greatly reduced or ablated (up to 400-fold reduction in k cat /K m ). As Leu1603 must interact with residues proximate to the Zn 2+ ion coordinated in the active center of ADAMTS13, we sought the corresponding S3 interacting residues. Substitution of 10 candidate residues in the metalloprotease domain of ADAMTS13 identified two spatially separated clusters centered on Leu198 or Val195 (acting with Leu232 and Leu274, or with Leu151, respectively), as possible subsites interacting with VWF. These experimental findings using the short VWF115 substrate were replicated using full-length VWF. It is hypothesized that VWF Leu1603 interacts with ADAMTS13 Leu198/Leu232/Leu274 and that Val195/Leu151 may form part of a S1 subsite. The recognition of VWF Leu1603 by ADAMTS13, in conjunction with previously reported remote exosites C terminal of the cleavage site, suggests a mechanism whereby the VWF P1-P1′ scissile bond is brought into position over the active site for cleavage. Together with recently characterized remote exosite interactions, these findings provide a general framework for understanding the ADAMTS family substrate interactions.

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 : 97774.pdf (Publisher’s version ) (Closed access) Background: Non-infective cutaneous granulomas with unknown pathogenesis occur in various primary immunodeficiencies (PIDs) including ataxia telangiectasia (A-T). Objective: To find a common immunological denominator in these cutaneous granulomas. Methods: The dermatological and immunological features of 4 patients with A-T and cutaneous granulomas were described. The literature on skin granulomas in A-T and in other PIDs is reviewed. Results: All 4 A-T patients had progressive granulomas on their limbs and showed decreased IgG and IgA concentrations with normal IgM levels. They had a marked decrease in B cells and naive T cells coinciding with the appearance of the cutaneous granulomas. Similar B- and T-cell abnormalities were described in patients with other PIDs with skin granulomas. Conclusions: We hypothesize that the pathogenesis of these skin granulomas is related to immune dysregulation of macrophages due to the absence of naive T cells with an appropriate T-cell receptor repertoire and the unopposed activity of gammadelta T cells and/or natural killer cells.

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.

Item does not contain fulltext van der Vliet JA, Warle MC, Cheung CLS, Teerenstra S, Hoitsma AJ. Influence of prolonged cold ischemia in renal transplantation. Clin Transplant 2011: 25: E612-E616. (c) 2011 John Wiley & Sons A/S. Abstract: Aim: To determine to what extent current cold ischemia times (CITs) affect the results of renal transplantation in the Netherlands. Methods: Retrospective survey of the Dutch Organ Transplant Registry concerning transplants from deceased donors between 1990 and 2007. Results: A total of 6322 recipients were identified, of whom 5306 received a kidney from deceased heartbeating (HBD) and 1016 from donors after cardiac death (DCD). Mean CIT was 24.0 +/- 7.9 h in HBD and 21.6 +/- 6.7 h in DCD. The percentage delayed graft function (DGF) was 12.3 and 50.4, respectively (p < 0.001). Primary non-function (PNF) occurred in, respectively, 1.7% and 5.0% (p < 0.001). Serum creatinine after three months was 166 muM in HBD and 213 muM in DCD (p < 0.001). Five-yr graft survival was 79.5% and 78.3%, respectively (p = ns). In multivariate analysis, CIT proved to be an independent risk factor for DGF and PNF. Shorter CIT was associated with better graft survival in both groups with a hazard ratio of 1.024 (1.011-1.037, 95% CI)/h. CIT

Artemis deficiency is known to result in classical T-B- severe combined immunodeficiency (SCID) in case of Artemis null mutations, or Omenn's syndrome in case of hypomorphic mutations in the Artemis gene. We describe two unrelated patients with a relatively mild clinical T-B- SCID phenotype, caused by different homozygous Artemis splice-site mutations. The splice-site mutations concern either dysfunction of a 5' splice-site or an intronic point mutation creating a novel 3' splice-site, resulting in mutated Artemis protein with residual activity or low levels of wild type (WT) Artemis transcripts. During the first 10 years of life, the patients suffered from recurrent infections necessitating antibiotic prophylaxis and intravenous immunoglobulins. Both mutations resulted in increased ionizing radiation sensitivity and insufficient variable, diversity and joining (V(D)J) recombination, causing B-lymphopenia and exhaustion of the naive T-cell compartment. The patient with the novel 30 splice-site had progressive granulomatous skin lesions, which disappeared after stem cell transplantation (SCT). We showed that an alternative approach to SCT can, in principle, be used in this case; an antisense oligonucleotide (AON) covering the intronic mutation restored WT Artemis transcript levels and non-homologous end-joining pathway activity in the patient fibroblasts. Genes and Immunity (2011) 12, 434-444; doi:10.1038/gene.2011.16; published online 10 March 2011

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 OBJECTIVE: Interleukin-22 (IL-22) is a mediator in antimicrobial responses and inflammatory autoimmune diseases. Although IL-22 and its receptor, IL-22R, have been identified in the synovium of rheumatoid arthritis patients, the source of IL-22 and its contribution to disease pathogenicity remain to be established. This study was undertaken to investigate the regulation of IL-22 by Th17 cells in vitro and to evaluate the potential for IL-22 depletion in an experimental arthritis model using mice deficient in the IL-1 receptor antagonist (IL-1Ra-/-). METHODS: Naive murine T cells were cultured under conditions leading to polarization of the cells into subsets of Th1, Th2, induced Treg, and Th17. Cytokines were measured in the culture supernatants, and the cells were analyzed by fluorescence-activated cell sorting. Tissue samples from the inflamed ankle synovium of IL-1Ra-/- mice were isolated, and messenger RNA levels of marker genes were quantified. IL-1Ra-/- mice were treated with neutralizing anti-IL-22 antibodies. Synovial cells were isolated from the inflamed tissue and sorted into fractions for analysis of cytokine production. RESULTS: In vitro tests showed that Th17 cells produced high levels of IL-22 after stimulation with IL-1 or IL-23. Interestingly, a synergistic increase in the production of IL-22 was observed after combining IL-1 and IL-23. In vivo, IL-1Ra-/- mice displayed a progressive erosive arthritis, characterized by up-regulation of IL-17 in mildly and severely inflamed tissue, whereas the levels of IL-22 and IL-22R were increased only in severely inflamed synovia. Anti-IL-22 treatment of IL-1Ra-/- mice significantly reduced the inflammation and bone erosion. Analysis of isolated single cells from the inflamed synovia revealed that IL-22 was mainly produced by IL-17-expressing T cells. CONCLUSION: These findings suggest that IL-22 plays an important role in IL-1-driven chronic joint destruction.

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