Helios Klinikum Krefeld

Therapy options at the time of recurrence of glioblastoma multiforme are often limited. We investigated whether treatment with a new intratumoral thermotherapy procedure using magnetic nanoparticles improves survival outcome. In a single-arm study in two centers, 66 patients (59 with recurrent glioblastoma) received neuronavigationally controlled intratumoral instillation of an aqueous dispersion of iron-oxide (magnetite) nanoparticles and subsequent heating of the particles in an alternating magnetic field. Treatment was combined with fractionated stereotactic radiotherapy. A median dose of 30 Gy using a fractionation of 5 × 2 Gy/week was applied. The primary study endpoint was overall survival following diagnosis of first tumor recurrence (OS-2), while the secondary endpoint was overall survival after primary tumor diagnosis (OS-1). Survival times were calculated using the Kaplan-Meier method. Analyses were by intention to treat. The median overall survival from diagnosis of the first tumor recurrence among the 59 patients with recurrent glioblastoma was 13.4 months (95% CI: 10.6-16.2 months). Median OS-1 was 23.2 months while the median time interval between primary diagnosis and first tumor recurrence was 8.0 months. Only tumor volume at study entry was significantly correlated with ensuing survival (P < 0.01). No other variables predicting longer survival could be determined. The side effects of the new therapeutic approach were moderate, and no serious complications were observed. Thermotherapy using magnetic nanoparticles in conjunction with a reduced radiation dose is safe and effective and leads to longer OS-2 compared to conventional therapies in the treatment of recurrent glioblastoma.

Kinase inhibitors are important cancer therapeutics. Polypharmacology is commonly observed, requiring thorough target deconvolution to understand drug mechanism of action. Using chemical proteomics, we analyzed the target spectrum of 243 clinically evaluated kinase drugs. The data revealed previously unknown targets for established drugs, offered a perspective on the "druggable" kinome, highlighted (non)kinase off-targets, and suggested potential therapeutic applications. Integration of phosphoproteomic data refined drug-affected pathways, identified response markers, and strengthened rationale for combination treatments. We exemplify translational value by discovering SIK2 (salt-inducible kinase 2) inhibitors that modulate cytokine production in primary cells, by identifying drugs against the lung cancer survival marker MELK (maternal embryonic leucine zipper kinase), and by repurposing cabozantinib to treat FLT3-ITD-positive acute myeloid leukemia. This resource, available via the ProteomicsDB database, should facilitate basic, clinical, and drug discovery research and aid clinical decision-making.

The objective of this article is to provide evidence-based recommendations for the management of patients with herpes zoster (HZ) that take into account clinical efficacy, adverse effects, impact on quality of life, and costs of treatment. Systematic literature reviews, published randomized clinical trials, existing guidelines, and the authors' clinical and research experience relevant to the management of patients with HZ were reviewed at a consensus meeting. The results of controlled trials and the clinical experience of the authors support the use of acyclovir, brivudin (where available), famciclovir, and valacyclovir as first-line antiviral therapy for the treatment of patients with HZ. Specific recommendations for the use of these medications are provided. In addition, suggestions are made for treatments that, when used in combination with antiviral therapy, may further reduce pain and other complications of HZ.

Medical laser applications require knowledge about the optical properties of target tissue. In this study, the optical properties of selected native and coagulated human brain structures were determined in vitro in the spectral range between 360 and 1100 nm. The tissues investigated included white brain matter, grey brain matter, cerebellum and brainstem tissues (pons, thalamus). In addition, the optical properties of two human tumours (meningioma, astrocytoma WHO grade II) were determined. Diffuse reflectance, total transmittance and collimated transmittance of the samples were measured using an integrating-sphere technique. From these experimental data, the absorption coefficients, the scattering coefficients and the anisotropy factors of the samples were determined employing an inverse Monte Carlo technique. The tissues investigated differed from each other predominantly in their scattering properties. Thermal coagulation reduced the optical penetration depth substantially. The highest penetration depths for all tissues investigated were found in the wavelength range between 1000 and 1100 nm. A comparison with data from the literature revealed the importance of the employed tissue preparation technique and the impact of the theoretical model used to extract the optical coefficients from the measured quantities.

Aims: The clinical value of percutaneous coronary intervention (PCI) for chronic coronary total occlusions (CTOs) is not established by randomized trials. This study should compare the benefit of PCI vs. optimal medical therapy (OMT) on the health status in patients with at least one CTO. Method and results: Three hundred and ninety-six patients were enrolled in a prospective randomized, multicentre, open-label, and controlled clinical trial to compare the treatment by PCI with OMT with a 2:1 randomization ratio. The primary endpoint was the change in health status assessed by the Seattle angina questionnaire (SAQ) between baseline and 12 months follow-up. Fifty-two percent of patients have multi-vessel disease in whom all significant non-occlusive lesions were treated before randomization. An intention-to-treat analysis was performed including 13.4% failed procedures in the PCI group and 7.3% cross-overs in the OMT group. At 12 months, a greater improvement of SAQ subscales was observed with PCI as compared with OMT for angina frequency [5.23, 95% confidence interval (CI) 1.75; 8.71; P = 0.003], and quality of life (6.62, 95% CI 1.78-11.46; P = 0.007), reaching the prespecified significance level of 0.01 for the primary endpoint. Physical limitation (P = 0.02) was also improved in the PCI group. Complete freedom from angina was more frequent with PCI 71.6% than OMT 57.8% (P = 0.008). There was no periprocedural death or myocardial infarction. At 12 months, major adverse cardiac events were comparable between the two groups. Conclusion: Percutaneous coronary intervention leads to a significant improvement of the health status in patients with stable angina and a CTO as compared with OMT alone. Trial registration: NCT01760083.

BACKGROUND: Central venous catheters (CVCs) can help with diagnosis and treatment of the critically ill. The catheter may be placed in a large vein in the neck (internal jugular vein), upper chest (subclavian vein) or groin (femoral vein). Whilst this is beneficial overall, inserting the catheter risks arterial puncture and other complications and should be performed with as few attempts as possible. Traditionally, anatomical 'landmarks' on the body surface were used to find the correct place in which to insert catheters, but ultrasound imaging is now available. A Doppler mode is sometimes used to supplement plain 'two-dimensional' ultrasound. OBJECTIVES: The primary objective of this review was to evaluate the effectiveness and safety of two-dimensional (imaging ultrasound (US) or ultrasound Doppler (USD)) guided puncture techniques for insertion of central venous catheters via the internal jugular vein in adults and children. We assessed whether there was a difference in complication rates between traditional landmark-guided and any ultrasound-guided central vein puncture.Our secondary objectives were to assess whether the effect differs between US and USD; whether the effect differs between ultrasound used throughout the puncture ('direct') and ultrasound used only to identify and mark the vein before the start of the puncture procedure (indirect'); and whether the effect differs between different groups of patients or between different levels of experience among those inserting the catheters. SEARCH METHODS: We searched the Central Register of Controlled Trials (CENTRAL) (2013, Issue 1), MEDLINE (1966 to 15 January 2013), EMBASE (1966 to 15 January 2013), the Cumulative Index to Nursing and Allied Health Literature (CINAHL) (1982 to 15 January 2013 ), reference lists of articles, 'grey literature' and dissertations. An additional handsearch focused on intensive care and anaesthesia journals and abstracts and proceedings of scientific meetings. We attempted to identify unpublished or ongoing studies by contacting companies and experts in the field, and we searched trial registers. We reran the search in August 2014. We will deal with identified studies of interest when we update the review. SELECTION CRITERIA: We included randomized and quasi-randomized controlled trials comparing two-dimensional ultrasound or Doppler ultrasound with an anatomical 'landmark' technique during insertion of internal jugular venous catheters in both adults and children. DATA COLLECTION AND ANALYSIS: Three review authors independently extracted data on methodological quality, participants, interventions and outcomes of interest using a standardized form. A priori, we aimed to perform subgroup analyses, when possible, for adults and children, and for experienced operators and inexperienced operators. MAIN RESULTS: Of 735 identified citations, 35 studies enrolling 5108 participants fulfilled the inclusion criteria. The quality of evidence was very low for most of the outcomes and was moderate at best for four of the outcomes. Most trials had an unclear risk of bias across the six domains, and heterogeneity among the studies was significant.Use of two-dimensional ultrasound reduced the rate of total complications overall by 71% (14 trials, 2406 participants, risk ratio (RR) 0.29, 95% confidence interval (CI) 0.17 to 0.52; P value < 0.0001, I² = 57%), and the number of participants with an inadvertent arterial puncture by 72% (22 trials, 4388 participants, RR 0.28, 95% CI 0.18 to 0.44; P value < 0.00001, I² = 35%). Overall success rates were modestly increased in all groups combined at 12% (23 trials, 4340 participants, RR 1.12, 95% CI 1.08 to 1.17; P value < 0.00001, I² = 85%), and similar benefit was noted across all subgroups. The number of attempts needed for successful cannulation was decreased overall (16 trials, 3302 participants, mean difference (MD) -1.19 attempts, 95% CI -1.45 to -0.92; P value < 0.00001, I² = 96%) and in all subgroups. Use of two-dimensional ultrasound increased the chance of success at the first attempt by 57% (18 trials, 2681 participants, RR 1.57, 95% CI 1.36 to 1.82; P value < 0.00001, I² = 82%) and reduced the chance of haematoma formation (overall reduction 73%, 13 trials, 3233 participants, RR 0.27, 95% CI 0.13 to 0.55; P value 0.0004, I² = 54%). Use of two-dimensional ultrasound decreased the time to successful cannulation by 30.52 seconds (MD -30.52 seconds, 95% CI -55.21 to -5.82; P value 0.02, I² = 97%). Additional data are available to support use of ultrasound during, not simply before, line insertion.Use of Doppler ultrasound increased the chance of success at the first attempt by 58% (four trials, 199 participants, RR 1.58, 95% CI 1.02 to 2.43; P value 0.04, I² = 57%). No evidence showed a difference for the total numbers of perioperative and postoperative complications/adverse events (three trials, 93 participants, RR 0.52, 95% CI 0.16 to 1.71; P value 0.28), the overall success rate (seven trials, 289 participants, RR 1.09, 95% CI 0.95 to 1.25; P value 0.20), the total number of attempts until success (two trials, 69 participants, MD -0.63, 95% CI -1.92 to 0.66; P value 0.34), the overall number of participants with an arterial puncture (six trials, 213 participants, RR 0.61, 95% CI 0.21 to 1.73; P value 0.35) and time to successful cannulation (five trials, 214 participants, each using a different definition for this outcome; MD 62.04 seconds, 95% CI -13.47 to 137.55; P value 0.11) when Doppler ultrasound was used. It was not possible to perform analyses for the other outcomes because they were reported in only one trial. AUTHORS' CONCLUSIONS: Based on available data, we conclude that two-dimensional ultrasound offers gains in safety and quality when compared with an anatomical landmark technique. Because of missing data, we did not compare effects with experienced versus inexperienced operators for all outcomes (arterial puncture, haematoma formation, other complications, success with attempt number one), and so the relative utility of ultrasound in these groups remains unclear and no data are available on use of this technique in patients at high risk of complications. The results for Doppler ultrasound techniques versus anatomical landmark techniques are also uncertain.

Importance: Case series suggest favorable results of peroral endoscopic myotomy (POEM) for treatment of patients with achalasia. Data comparing POEM with pneumatic dilation, the standard treatment for patients with achalasia, are lacking. Objective: To compare the effects of POEM vs pneumatic dilation as initial treatment of treatment-naive patients with achalasia. Design, Setting, and Participants: This randomized multicenter clinical trial was conducted at 6 hospitals in the Netherlands, Germany, Italy, Hong Kong, and the United States. Adult patients with newly diagnosed achalasia and an Eckardt score greater than 3 who had not undergone previous treatment were included. The study was conducted between September 2012 and July 2015, the duration of follow-up was 2 years after the initial treatment, and the final date of follow-up was November 22, 2017. Interventions: Randomization to receive POEM (n = 67) or pneumatic dilation with a 30-mm and a 35-mm balloon (n = 66), with stratification according to hospital. Main Outcomes and Measures: The primary outcome was treatment success (defined as an Eckardt score ≤3 and the absence of severe complications or re-treatment) at the 2-year follow-up. A total of 14 secondary end points were examined among patients without treatment failure, including integrated relaxation pressure of the lower esophageal sphincter via high-resolution manometry, barium column height on timed barium esophagogram, and presence of reflux esophagitis. Results: Of the 133 randomized patients, 130 (mean age, 48.6 years; 73 [56%] men) underwent treatment (64 in the POEM group and 66 in the pneumatic dilation group) and 126 (95%) completed the study. The primary outcome of treatment success occurred in 58 of 63 patients (92%) in the POEM group vs 34 of 63 (54%) in the pneumatic dilation group, a difference of 38% ([95% CI, 22%-52%]; P < .001). Of the 14 prespecified secondary end points, no significant difference between groups was demonstrated in 10 end points. There was no significant between-group difference in median integrated relaxation pressure (9.9 mm Hg in the POEM group vs 12.6 mm Hg in the pneumatic dilation group; difference, 2.7 mm Hg [95% CI, -2.1 to 7.5]; P = .07) or median barium column height (2.3 cm in the POEM group vs 0 cm in the pneumatic dilation group; difference, 2.3 cm [95% CI, 1.0-3.6]; P = .05). Reflux esophagitis occurred more often in the POEM group than in the pneumatic dilation group (22 of 54 [41%] vs 2 of 29 [7%]; difference, 34% [95% CI, 12%-49%]; P = .002). Two serious adverse events, including 1 perforation, occurred after pneumatic dilation, while no serious adverse events occurred after POEM. Conclusions and Relevance: Among treatment-naive patients with achalasia, treatment with POEM compared with pneumatic dilation resulted in a significantly higher treatment success rate at 2 years. These findings support consideration of POEM as an initial treatment option for patients with achalasia. Trial Registration: Netherlands Trial Register number: NTR3593.

OBJECTIVE: Glucagon-like peptide (GLP)-1 lowers postprandial glycemia primarily through inhibition of gastric emptying. We addressed whether the GLP-1-induced deceleration of gastric emptying is subject to rapid tachyphylaxis and if so, how this would alter postprandial glucose control. RESEARCH DESIGN AND METHODS: Nine healthy volunteers (25 ± 4 years old, BMI: 24.6 ± 4.7 kg/m(2)) were examined with intravenous infusion of GLP-1 (0.8 pmol · kg(-1) · min(-1)) or placebo over 8.5 h. Two liquid mixed meals were administered at a 4-h interval. Gastric emptying was determined, and blood samples were drawn frequently. RESULTS: GLP-1 decelerated gastric emptying significantly more after the first meal compared with the second meal (P = 0.01). This was associated with reductions in pancreatic polypeptide levels (marker of vagal activation) after the first but not the second meal (P < 0.05). With GLP-1, glucose concentrations declined after the first meal but increased after the second meal (P < 0.05). The GLP-1-induced reductions in postprandial insulin and C-peptide levels were stronger during the first meal course (P < 0.05). Likewise, glucagon levels were lowered by GLP-1 after the first meal but increased after the second test meal (P < 0.05). CONCLUSIONS: The GLP-1-induced delay in gastric emptying is subject to rapid tachyphylaxis at the level of vagal nervous activation. As a consequence, postprandial glucose control by GLP-1 is attenuated after its chronic administration.

Aims: The aim of this study was to investigate the effect of contact-to-balloon time on mortality in ST-segment elevation myocardial infarction (STEMI) patients with and without haemodynamic instability. Methods and results: Using data from the prospective, multicentre Feedback Intervention and Treatment Times in ST-Elevation Myocardial Infarction (FITT-STEMI) trial, we assessed the prognostic relevance of first medical contact-to-balloon time in n = 12 675 STEMI patients who used emergency medical service transportation and were treated with primary percutaneous coronary intervention (PCI). Patients were stratified by cardiogenic shock (CS) and out-of-hospital cardiac arrest (OHCA). For patients treated within 60 to 180 min from the first medical contact, we found a nearly linear relationship between contact-to-balloon times and mortality in all four STEMI groups. In CS patients with no OHCA, every 10-min treatment delay resulted in 3.31 additional deaths in 100 PCI-treated patients. This treatment delay-related increase in mortality was significantly higher as compared to the two groups of OHCA patients with shock (2.09) and without shock (1.34), as well as to haemodynamically stable patients (0.34, P < 0.0001). Conclusions: In patients with CS, the time elapsing from the first medical contact to primary PCI is a strong predictor of an adverse outcome. This patient group benefitted most from immediate PCI treatment, hence special efforts to shorten contact-to-balloon time should be applied in particular to these high-risk STEMI patients. Clinical Trial Registration: NCT00794001.

BACKGROUND: Central venous catheters can help with diagnosis and treatment of the critically ill. The catheter may be placed in a large vein in the neck (internal jugular vein), upper chest (subclavian vein) or groin (femoral vein). Whilst this is beneficial overall, inserting the catheter risks arterial puncture and other complications and should be performed in as few attempts as possible.In the past, anatomical 'landmarks' on the body surface were used to find the correct place to insert these catheters, but ultrasound imaging is now available. A Doppler mode is sometimes used to supplement plain 'two-dimensional' ultrasound. OBJECTIVES: The primary objective of this review was to evaluate the effectiveness and safety of two-dimensional ultrasound (US)- or Doppler ultrasound (USD)-guided puncture techniques for subclavian vein, axillary vein and femoral vein puncture during central venous catheter insertion in adults and children. We assessed whether there was a difference in complication rates between traditional landmark-guided and any ultrasound-guided central vein puncture.When possible, we also assessed the following secondary objectives: whether a possible difference could be verified with use of the US technique versus the USD technique; whether there was a difference between using ultrasound throughout the puncture ('direct') and using it only to identify and mark the vein before starting the puncture procedure ('indirect'); and whether these possible differences might be evident in different groups of patients or with different levels of experience among those inserting the catheters. SEARCH METHODS: We searched the Cochrane Central Register of Controlled Trials (CENTRAL) (2013, Issue 1), MEDLINE (1966 to 15 January 2013), EMBASE (1966 to 15 January 2013), the Cumulative Index to Nursing and Allied Health Literature (CINAHL) (1982 to 15 January 2013), reference lists of articles, 'grey literature' and dissertations. An additional handsearch focused on intensive care and anaesthesia journals and abstracts and proceedings of scientific meetings. We attempted to identify unpublished or ongoing studies by contacting companies and experts in the field, and we searched trial registers. We reran the search in August 2014. We will deal with any studies of interest when we update the review. SELECTION CRITERIA: Randomized and quasi-randomized controlled trials comparing two-dimensional ultrasound or Doppler ultrasound versus an anatomical 'landmark' technique during insertion of subclavian or femoral venous catheters in both adults and children. DATA COLLECTION AND ANALYSIS: Three review authors independently extracted data on methodological quality, participants, interventions and outcomes of interest using a standardized form. We performed a priori subgroup analyses. MAIN RESULTS: Altogether 13 studies enrolling 2341 participants (and involving 2360 procedures) fulfilled the inclusion criteria. The quality of evidence was very low (subclavian vein N = 3) or low (subclavian vein N = 4, femoral vein N = 2) for most outcomes, moderate for one outcome (femoral vein) and high at best for two outcomes (subclavian vein N = 1, femoral vein N = 1). Most of the trials had unclear risk of bias across the six domains, and heterogeneity among the studies was significant.For the subclavian vein (nine studies, 2030 participants, 2049 procedures), two-dimensional ultrasound reduced the risk of inadvertent arterial puncture (three trials, 498 participants, risk ratio (RR) 0.21, 95% confidence interval (CI) 0.06 to 0.82; P value 0.02, I² = 0%) and haematoma formation (three trials, 498 participants, RR 0.26, 95% CI 0.09 to 0.76; P value 0.01, I² = 0%). No evidence was found of a difference in total or other complications (together, US, USD), overall (together, US, USD), number of attempts until success (US) or first-time (US) success rates or time taken to insert the catheter (US).For the femoral vein, fewer data were available for analysis (four studies, 311 participants, 311 procedures). No evidence was found of a difference in inadvertent arterial puncture or other complications. However, success on the first attempt was more likely with ultrasound (three trials, 224 participants, RR 1.73, 95% CI 1.34 to 2.22; P value < 0.0001, I² = 31%), and a small increase in the overall success rate was noted (RR 1.11, 95% CI 1.00 to 1.23; P value 0.06, I² = 50%). No data on mortality or participant-reported outcomes were provided. AUTHORS' CONCLUSIONS: On the basis of available data, we conclude that two-dimensional ultrasound offers small gains in safety and quality when compared with an anatomical landmark technique for subclavian (arterial puncture, haematoma formation) or femoral vein (success on the first attempt) cannulation for central vein catheterization. Data on insertion by inexperienced or experienced users, or on patients at high risk for complications, are lacking. The results for Doppler ultrasound techniques versus anatomical landmark techniques are uncertain.

Malformations of cortical development are a group of rare disorders commonly manifesting with developmental delay, cerebral palsy or seizures. The neurological outcome is extremely variable depending on the type, extent and severity of the malformation and the involved genetic pathways of brain development. Neuroimaging plays an essential role in the diagnosis of these malformations, but several issues regarding malformations of cortical development definitions and classification remain unclear. The purpose of this consensus statement is to provide standardized malformations of cortical development terminology and classification for neuroradiological pattern interpretation. A committee of international experts in paediatric neuroradiology prepared systematic literature reviews and formulated neuroimaging recommendations in collaboration with geneticists, paediatric neurologists and pathologists during consensus meetings in the context of the European Network Neuro-MIG initiative on Brain Malformations (https://www.neuro-mig.org/). Malformations of cortical development neuroimaging features and practical recommendations are provided to aid both expert and non-expert radiologists and neurologists who may encounter patients with malformations of cortical development in their practice, with the aim of improving malformations of cortical development diagnosis and imaging interpretation worldwide.

OBJECTIVE: Endoscopic full-thickness resection (EFTR) is a novel treatment of colorectal lesions not amenable to conventional endoscopic resection. The aim of this prospective multicentre study was to assess the efficacy and safety of the full-thickness resection device. DESIGN: 181 patients were recruited in 9 centres with the indication of difficult adenomas (non-lifting and/or at difficult locations), early cancers and subepithelial tumours (SET). Primary endpoint was complete en bloc and R0 resection. RESULTS: EFTR was technically successful in 89.5%, R0 resection rate was 76.9%. In 127 patients with difficult adenomas and benign histology, R0 resection rate was 77.7%. In 14 cases, lesions harboured unsuspected cancer, another 15 lesions were primarily known as cancers. Of these 29 cases, R0 resection was achieved in 72.4%; 8 further cases had deep submucosal infiltration >1000 µm. Therefore, curative resection could only be achieved in 13/29 (44.8%). In the subgroup with SET (n=23), R0 resection rate was 87.0%. In general, R0 resection rate was higher with lesions ≤2 cm vs >2 cm (81.2% vs 58.1%, p=0.0038). Adverse event rate was 9.9% with a 2.2% rate of emergency surgery. Three-month follow-up was available from 154 cases and recurrent/residual tumour was evident in 15.3%. CONCLUSION: EFTR has a reasonable technical efficacy especially in lesions ≤2 cm with acceptable complication rates. Curative resection rate for early cancers was too low to recommend its primary use in this indication. Further comparative studies have to show the clinical value and long-term outcome of EFTR in benign colorectal lesions. TRIAL REGISTRATION NUMBER: NCT02362126; Results.

The fatal immune dysregulation that sometimes follows EBV infection in boys has been linked to mutations in two X chromosome-encoded genes, SLAM-associated protein (SAP) and X-linked inhibitor of apoptosis (XIAP). In this study we describe 2 girls from a consanguineous Turkish family who died after developing severe immune dysregulation and therapy-resistant EBV-positive B cell proliferation following EBV infection. SNP array-based genome-wide linkage analysis revealed IL-2-inducible T cell kinase (ITK) as a candidate gene for this immunodeficiency syndrome. Both girls harbored a homozygous missense mutation that led to substitution of a highly conserved residue (R335W) in the SH2 domain of ITK. Characteristics of ITK deficiency in mouse models, such as absence of NKT cells and high levels of eomesodermin in CD8+ cells, were seen in either one or both of the girls. Two lines of evidence suggested that R335W caused instability of the ITK protein. First, in silico modeling of the mutant protein predicted destabilization of the SH2 domain. Additionally, Western blot analysis revealed that, unlike wild-type ITK, the R335W mutant was nearly undetectable when expressed in 293 T cells. Our results suggest that ITK deficiency causes what we believe to be a novel immunodeficiency syndrome that leads to a fatal inadequate immune response to EBV. Because ITK deficiency resembles EBV-associated lymphoproliferative disorders in boys, we suggest that this molecular cause should be considered during diagnosis and treatment.

Abstract Irritable bowel syndrome (IBS) results from disordered brain–gut interactions. Identifying susceptibility genes could highlight the underlying pathophysiological mechanisms. We designed a digestive health questionnaire for UK Biobank and combined identified cases with IBS with independent cohorts. We conducted a genome-wide association study with 53,400 cases and 433,201 controls and replicated significant associations in a 23andMe panel (205,252 cases and 1,384,055 controls). Our study identified and confirmed six genetic susceptibility loci for IBS. Implicated genes included NCAM1 , CADM2 , PHF2/FAM120A , DOCK9 , CKAP2/TPTE2P3 and BAG6 . The first four are associated with mood and anxiety disorders, expressed in the nervous system, or both. Mirroring this, we also found strong genome-wide correlation between the risk of IBS and anxiety, neuroticism and depression ( r g &gt; 0.5). Additional analyses suggested this arises due to shared pathogenic pathways rather than, for example, anxiety causing abdominal symptoms. Implicated mechanisms require further exploration to help understand the altered brain–gut interactions underlying IBS.

BACKGROUND: Continuous venovenous haemofiltration (CVVH) in the intensive care setting requires anticoagulation to prevent clotting of the extracorporeal circuit. Several protocols avoiding heparin and using regional citrate anticoagulation have been developed to diminish bleeding risks. However, data from randomized trials comparing citrate anticoagulation with systemic heparinization are very limited. METHODS: One hundred and seventy-four patients on mechanical ventilation, requiring renal replacement therapy for acute renal failure, were included in this prospective randomized multicentre trial comparing regional citrate with systemic heparin. The study was performed at nine different intensive care units at university or academic teaching hospitals. The participants were randomized to either CVVH using regional citrate anticoagulation or CVVH using systemic anticoagulation with unfractionated heparin. The primary outcome was to compare treatment efficacy represented by the patients' acid base status on Day 3 and on each consecutive day. Several parameters of safety and efficacy were analysed as secondary outcomes. RESULTS: Comparison of standard bicarbonate from Day 3 to Day 11 revealed no difference between both treatment modalities. Use of citrate resulted in less systemic anticoagulation, a lower risk of bleeding and a longer haemofilter patency. Episodes of hypercalcaemia, hypocalcaemia and the need for additional bicarbonate infusions occurred more often under citrate. The patients' high mortality was not influenced by the mode of anticoagulation. CONCLUSIONS: Citrate may be used as a regional anticoagulant and the only buffering agent in CVVH with adequate treatment efficacy and safety. However, neither citrate nor heparin anticoagulation should be regarded as a therapeutic standard, since there is no advantage of one of these substances with regard to patient mortality.

Bordetella pertussis-specific antibodies can be detected by enzyme-linked immunosorbent assays (ELISAs) or multiplex immunoassays. Assays use purified or mixed antigens, and only pertussis toxin (PT) is specific for B. pertussis. The interpretation of results can be based on dual-sample or single-sample serology using one or two cut-offs. The EU Pertstrain group recommends that: (i) ELISAs and multiplex immunoassays should use purified non-detoxified PT as an antigen, that they should have a broad linear range and that they should express results quantitatively in International Units per millilitre (IU/ml); (ii) a single or dual diagnostic cut-off for single-serum serology using IgG-anti-PT between 50 and 120 IU/ml should be used, and diagnostic serology cannot be validly interpreted for one year after vaccination with acellular pertussis (aP) vaccines; (iii) IgA-anti-PT should only be used with indeterminate IgG-anti-PT levels or when a second sample cannot be obtained. This group discourages using: (i) other antigens in routine diagnostics, as they are not specific; (ii) micro-agglutination, due to its lack of sensitivity; (iii) immunoblots for pertussis serodiagnosis, as results cannot be quantified; (iv) other methods, such as complement fixation or indirect immunofluorescence, due to their low sensitivity and/or specificity.

Pertussis has reemerged as a problem across the world. To better understand the nature of the resurgence, we reviewed recent epidemiologic data and we report disease trends from across the world. Published epidemiologic data from January 2000 to July 2013 were obtained via PubMed searches and open-access websites. Data on vaccine coverage and reported pertussis cases from 2000 through 2012 from the 6 World Health Organization regions were also reviewed. Findings are confounded not only by the lack of systematic and comparable observations in many areas of the world but also by the cyclic nature of pertussis with peaks occurring every 3-5 years. It appears that pertussis incidence has increased in school-age children in North America and western Europe, where acellular pertussis vaccines are used, but an increase has also occurred in some countries that use whole-cell vaccines. Worldwide, pertussis remains a serious health concern, especially for infants, who bear the greatest disease burden. Factors that may contribute to the resurgence include lack of booster immunizations, low vaccine coverage, improved diagnostic methods, and genetic changes in the organism. To better understand the epidemiology of pertussis and optimize disease control, it is important to improve surveillance worldwide, irrespective of pertussis vaccine types and schedules used in each country.

Inflammation plays a key role in the pathogenesis of a number of chronic inflammatory systemic diseases (CISDs), including psoriasis, rheumatoid arthritis, systemic lupus erythematosus and Crohn's disease, and also in the pathogenesis of atherosclerosis. CISDs and cardiovascular diseases, such as atherosclerosis, share common pathogenic features, and cardiovascular disease is an important cause of morbidity and mortality in patients with CISDs. Activated inflammatory cells and pro-inflammatory cytokines contribute to the development of psoriatic lesions and play an important role in the breakdown of atherosclerotic plaques. Psoriasis and atherosclerosis also have similar histological characteristics involving T cells, macrophages and monocytes. In particular, the extravasation of T cells through the epithelium is characteristic of both psoriatic and atherosclerotic plaques. Cardiovascular disease is an important cause of morbidity and mortality in patients with psoriasis, which is associated with an increased cardiovascular risk profile compared with the general population. Patients with psoriasis are at increased risk of arterial hypertension, coronary heart disease, hyperlipidaemia, obesity and type II diabetes, which are more prevalent than in control patients. This increased risk could be due to the effects of chronic inflammatory changes, particularly the infiltration of T cells and subsequent secretion of pro-inflammatory cytokines. Some drugs used in the treatment of cardiovascular disease, such as 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors (statins) and angiotensin-converting enzyme inhibitors have anti-inflammatory activity. In addition, systemic treatments for psoriasis may, by decreasing inflammation, reduce the risk of cardiovascular disease. It is suggested, therefore, that an integrated approach to the treatment of the inflammatory processes underlying both psoriasis and atherosclerosis may be beneficial in reducing cardiovascular risk in patients with psoriasis. The newer targeted biological therapies, such as efalizumab and infliximab, which offer the potential for long-term disease control in psoriasis, may be of particular use in this setting.

BACKGROUND: After the first investigational study on the use of extracorporeal photopheresis for the treatment of cutaneous T-cell lymphoma was published in 1983 with its subsequent recognition by the FDA for its refractory forms, the technology has shown significant promise in the treatment of other severe and refractory conditions in a multi-disciplinary setting. Among the major studied conditions are graft versus host disease after allogeneic bone marrow transplantation, systemic sclerosis, solid organ transplant rejection and inflammatory bowel disease. MATERIALS AND METHODS: In order to provide recognized expert practical guidelines for the use of this technology for all indications the European Dermatology Forum (EDF) proceeded to address these questions in the hands of the recognized experts within and outside the field of dermatology. This was done using the recognized and approved guidelines of EDF for this task. RESULTS AND CONCLUSION: These guidelines provide at present the most comprehensive available expert recommendations for the use of extracorporeal photopheresis based on the available published literature and expert consensus opinion.

Autosomal dominant spinocerebellar ataxias (SCA) form a group of clinically and genetically heterogeneous neurodegenerative disorders. The defect responsible for SCA3/Machado-Joseph disease (MJD) has been identified as an unstable and expanded (CAG)n trinucleotide repeat in the coding region of a novel gene of unknown function. The MJD1 gene product, ataxin-3, exists in several isoforms. We generated polyclonal antisera against an alternate carboxy terminus of ataxin-3. This isoform, ataxin-3c, is expressed as a protein of approximately 42 kDa in normal individuals but is significantly enlarged in affected patients confirming that the CAG repeat is part of the ataxin-3c isoform and is translated into a polyglutamine stretch, a feature common to all known CAG repeat disorders. Ataxin-3 like immunoreactivity was observed in all human brain regions and peripheral organs studied. In neuronal cells of control individuals, ataxin-3c was expressed cytoplasmatically and had a somatodendritic and axonal distribution. In SCA3 patients, however, C-terminal ataxin-3c antibodies as well as anti-ataxin-3 monoclonal antibodies (1 H9) and anti-ubiquitin antibodies detected intranuclear inclusions (NIs) in neuronal cells of affected brain regions. A monoclonal antibody, 2B6, directed against an internal part of the protein, barely detected these NIs implying proteolytic cleavage of ataxin-3 prior to its transport into the nucleus. These findings provide evidence that the alternate isoform of ataxin-3 is involved in the pathogenesis of SCA3/MJD. Intranuclear protein aggregates appear as a common feature of neurodegenerative polyglutamine disorders.