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- 32D progenitor cells (1)
- Devic disease (1)
- Devic syndrome (1)
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Protocol TOP-Study (tacrolimus organ perfusion): a prospective randomized multicenter trial to reduce ischemia reperfusion injury in transplantation of marginal liver grafts with an ex vivo tacrolimus perfusion
(2013)
- Background: Critical organ shortage results in the utilization of extended donor criteria (EDC) liver grafts. These marginal liver grafts are prone to increased ischemia reperfusion injury (IRI) which may contribute to deteriorated graft function and survival. Experimental data have shown that the calcineurin inhibitor tacrolimus exerts protective effects on hepatic IRI when applied intravenously or directly as a hepatic rinse. Therefore, the aim of the present study is to examine the effects of an ex vivo tacrolimus perfusion on IRI in transplantation of EDC liver grafts. Methods/Design: The TOP-Study (tacrolimus organ perfusion) is a randomized multicenter trial comparing the ex vivo tacrolimus perfusion of marginal liver grafts with placebo. We hypothesize that a tacrolimus rinse reduces IRI, potentially improving organ survival following transplantation of EDC livers. The study includes livers with two or more EDC, according to Eurotransplant International Foundation’s definition of EDC livers. Prior to implantation, livers randomized to the treatment group are rinsed with tacrolimus at a concentration of 20 ng/ml in 1000 ml Custodiol solution and in the placebo group with Custodiol alone. The primary endpoint is the maximum serum alanine transamninase (ALT) level within the first 48 hours after surgery; however, the study design also includes a 1-year observation period following transplantation. The TOP-Study is an investigator-initiated trial sponsored by the University of Munich Hospital. Seven other German transplant centers are participating (Berlin, Frankfurt, Heidelberg, Mainz, Münster, Regensburg, Tübingen) and aim to include a total of 86 patients. Discussion: Tacrolimus organ perfusion represents a promising strategy to reduce hepatic IRI following the transplantation of marginal liver grafts. This treatment may help to improve the function of EDC grafts and therefore safely expand the donor pool in light of critical organ shortage. Trial register: EudraCT number: 2010-021333-31, ClinicalTrials.gov identifier: NCT01564095
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Novel Role of Ras-GTPase Activating Protein SH3 Domain-Binding Protein G3BP in Adhesion and Migration of 32D Myeloid Progenitor Cells
(2012)
- Rho GTPases are involved in homing and mobilization of hematopoietic stem and progenitor cells due to their impact on cytoskeleton remodeling. We have previously shown that inhibition of Rho, Rac and Cdc42 clearly impairs adhesion of normal and leukemic hematopoietic progenitor cells (HPC) to fibronectin and migration in a three-dimensional stromal cell model. Here, we identified the Ras GTPase-Activating Protein SH3 Domain-Binding Protein (G3BP) as a target gene of Rho GTPases and analysed its role in regulating HPC motility. Overexpression of G3BP significantly enhanced adhesion of murine 32D HPC to fibronectin and human umbilical vein endothelial cells, increased the proportion of adherent cells in a flow chamber assay and promoted cell migration in a transwell assay and a three-dimensional stromal cell model suggesting a strong impact on the cytoskeleton. Immunofluorescent staining of G3BP-overexpressing fibroblasts revealed a Rho-like phenotype characterized by formation of actin stress fibers in contrast to the Rac-like phenotype of control fibroblasts. This is the first report implicating a role for G3BP in Rho GTPase-mediated signalling towards adhesion and migration of HPC. Our results may be of clinical importance, since G3BP was found overexpressed in human cancers.
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Contrasting disease patterns in seropositive and seronegative neuromyelitis optica: A multicentre study of 175 patients
(2012)
- BACKGROUND: The diagnostic and pathophysiological relevance of antibodies to aquaporin-4 (AQP4-Ab) in patients with neuromyelitis optica spectrum disorders (NMOSD) has been intensively studied. However, little is known so far about the clinical impact of AQP4-Ab seropositivity. OBJECTIVE: To analyse systematically the clinical and paraclinical features associated with NMO spectrum disorders in Caucasians in a stratified fashion according to the patients' AQP4-Ab serostatus. METHODS: Retrospective study of 175 Caucasian patients (AQP4-Ab positive in 78.3%). RESULTS: Seropositive patients were found to be predominantly female (p < 0.0003), to more often have signs of co-existing autoimmunity (p < 0.00001), and to experience more severe clinical attacks. A visual acuity of ≤ 0.1 during acute optic neuritis (ON) attacks was more frequent among seropositives (p < 0.002). Similarly, motor symptoms were more common in seropositive patients, the median Medical Research Council scale (MRC) grade worse, and MRC grades ≤ 2 more frequent, in particular if patients met the 2006 revised criteria (p < 0.005, p < 0.006 and p < 0.01, respectively), the total spinal cord lesion load was higher (p < 0.006), and lesions ≥ 6 vertebral segments as well as entire spinal cord involvement more frequent (p < 0.003 and p < 0.043). By contrast, bilateral ON at onset was more common in seronegatives (p < 0.007), as was simultaneous ON and myelitis (p < 0.001); accordingly, the time to diagnosis of NMO was shorter in the seronegative group (p < 0.029). The course of disease was more often monophasic in seronegatives (p < 0.008). Seropositives and seronegatives did not differ significantly with regard to age at onset, time to relapse, annualized relapse rates, outcome from relapse (complete, partial, no recovery), annualized EDSS increase, mortality rate, supratentorial brain lesions, brainstem lesions, history of carcinoma, frequency of preceding infections, oligoclonal bands, or CSF pleocytosis. Both the time to relapse and the time to diagnosis was longer if the disease started with ON (p < 0.002 and p < 0.013). Motor symptoms or tetraparesis at first myelitis and > 1 myelitis attacks in the first year were identified as possible predictors of a worse outcome. CONCLUSION: This study provides an overview of the clinical and paraclinical features of NMOSD in Caucasians and demonstrates a number of distinct disease characteristics in seropositive and seronegative patients
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Evolution of particle composition in CLOUD nucleation experiments
(2012)
- Sulphuric acid, ammonia, amines, and oxidised organics play a crucial role in nanoparticle formation in the atmosphere. In this study, we investigate the composition of nucleated nanoparticles formed from these compounds in the CLOUD chamber experiments at CERN. The investigation is carried out via analysis of the particle hygroscopicity, ethanol affinity, oxidation state, and ion composition. Hygroscopicity was studied by a hygroscopic tandem differential mobility analyser and a cloud condensation nuclei counter, ethanol affinity by an organic differential mobility analyser and particle oxidation level by a high-resolution time-of-flight aerosol mass spectrometer. The ion composition was studied by an atmospheric pressure interface time-of-flight mass spectrometer. The volume fraction of the organics in the particles during their growth from sizes of a few nanometers to tens of nanometers was derived from measured hygroscopicity assuming the Zdanovski-Stokes-Robinson relationship, and compared to values gained from the spectrometers. The ZSR-relationship was also applied to obtain the measured ethanol affinities during the particle growth, which were used to derive the volume fractions of sulphuric acid and the other inorganics (e.g. ammonium salts). In the presence of sulphuric acid and ammonia, particles with a mobility diameter of 150 nm were chemically neutralised to ammonium sulphate. In the presence of oxidation products of pinanediol, the organic volume fraction of freshly nucleated particles increased from 0.4 to ∼0.9, with an increase in diameter from 2 to 63 nm. Conversely, the sulphuric acid volume fraction decreased from 0.6 to 0.1 when the particle diameter increased from 2 to 50 nm. The results provide information on the composition of nucleated aerosol particles during their growth in the presence of various combinations of sulphuric acid, ammonia, dimethylamine and organic oxidation products.
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Long term outcome of high-risk neuroblastoma patients after immunotherapy with antibody ch14.18 or oral metronomic chemotherapy
(2011)
- Background: The treatment of high-risk neuroblastoma patients consists of multimodal induction therapy to achieve remission followed by consolidation therapy to prevent relapses. However, the type of consolidation therapy is still discussed controversial. We applied metronomic chemotherapy in the prospective NB90 trial and monoclonal anti-GD2-antibody (MAB) ch14.18 in the NB97 trial. Here, we present the long term outcome data of the patient cohort. Methods: A total of 334 stage 4 neuroblastoma patients one year or older were included. All patients successfully completed the induction therapy. In the NB90 trial, 99 patients received at least one cycle of the oral maintenance chemotherapy (NB90 MT, 12 alternating cycles of oral melphalan/etoposide and vincristine/cyclophosphamide). In the NB97 trial, 166 patients commenced the MAB ch14.18 consolidation therapy (six cycles over 12 months). Patients who received no maintenance therapy according to the NB90 protocol or by refusal in NB97 (n = 69) served as controls. Results: The median observation time was 11.11 years. The nine-year event-free survival rates were 41 ± 4%, 31 ± 5%, and 32 ± 6% for MAB ch14.18, NB90 MT, and no consolidation, respectively (p = 0.098). In contrast to earlier reports, MAB ch14.18 treatment improved the long-term outcome compared to no additional therapy (p = 0.038). The overall survival was better in the MAB ch14.18-treated group (9-y-OS 46 ± 4%) compared to NB90 MT (34 ± 5%, p = 0.026) and to no consolidation (35 ± 6%, p = 0.019). Multivariable Cox regression analysis revealed ch14.18 consolidation to improve outcome compared to no consolidation, however, no difference between NB90 MT and MAB ch14.18-treated patients was found. Conclusions: Follow-up analysis of the patient cohort indicated that immunotherapy with MAB ch14.18 may prevent late relapses. Finally, metronomic oral maintenance chemotherapy also appeared effective.
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The L76V mutation in HIV-1 protease is potentially associated with hypersusceptibility to protease inhibitors Atazanavir and Saquinavir: is there a clinical advantage?
(2011)
- Background: Although being considered as a rarely observed HIV-1 protease mutation in clinical isolates, the L76V-prevalence increased 1998-2008 in some European countries most likely due to the approval of Lopinavir, Amprenavir and Darunavir which can select L76V. Beside an enhancement of resistance, L76V is also discussed to confer hypersusceptibility to the drugs Atazanavir and Saquinavir which might enable new treatment strategies by trying to take advantage of particular mutations. Results: Based on a cohort of 47 L76V-positive patients, we examined if there might exist a clinical advantage for L76V-positive patients concerning long-term success of PI-containing regimens in patients with limited therapy options. Genotypic- and phenotypic HIV-resistance tests from 47 mostly multi-resistant, L76V-positive patients throughout Germany were accomplished retrospectively 1999-2009. Five genotype-based drug-susceptibility predictions received from online interpretation-tools for Atazanavir, Saquinavir, Amprenavir and Lopinavir, were compared to phenotype-based predictions that were determined by using a recombinant virus assay along with a Virtual Phenotype™(Virco). The clinical outcome of the L76V-adapted follow-up therapy was determined by monitoring viral load for 96 weeks. Conclusions: In this analysis, the mostly used interpretation systems overestimated the L76V-mutation concerning Atazanavir- and SQV resistance. In fact, a clear benefit in drug susceptibility for these drugs was observed in phenotype analysis after establishment of L76V. More importantly, long-term therapy success was significantly higher in patients receiving Atazanavir and/or Saquinavir plus one L76V-selecting drug compared to patients without L76V-selecting agents (p = 0.002). In case of L76V-occurrence ATV and/or SQV may represent encouraging options for patients in deep salvage situations.
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Primary care practice-based care management for chronically ill patients (PraCMan): study protocol for a cluster randomized controlled trial [ISRCTN56104508]
(2011)
- Background: Care management programmes are an effective approach to care for high risk patients with complex care needs resulting from multiple co-occurring medical and non-medical conditions. These patients are likely to be hospitalized for a potentially "avoidable" cause. Nurse-led care management programmes for high risk elderly patients showed promising results. Care management programmes based on health care assistants (HCAs) targeting adult patients with a high risk of hospitalisation may be an innovative approach to deliver cost-efficient intensified care to patients most in need. Methods: PraCMan is a cluster randomized controlled trial with primary care practices as unit of randomisation. The study evaluates a complex primary care practice-based care management of patients at high risk for future hospitalizations. Eligible patients either suffer from type 2 diabetes mellitus, chronic obstructive pulmonary disease, chronic heart failure or any combination. Patients with a high likelihood of hospitalization within the following 12 months (based on insurance data) will be included in the trial. During 12 months of intervention patients of the care management group receive comprehensive assessment of medical and non-medical needs and resources as well as regular structured monitoring of symptoms. Assessment and monitoring will be performed by trained HCAs from the participating practices. Additionally, patients will receive written information, symptom diaries, action plans and a medication plan to improve self-management capabilities. This intervention is addition to usual care. Patients from the control group receive usual care. Primary outcome is the number of all-cause hospitalizations at 12 months follow-up, assessed by insurance claims data. Secondary outcomes are health-related quality of life (SF12, EQ5D), quality of chronic illness care (PACIC), health care utilisation and costs, medication adherence (MARS), depression status and severity (PHQ-9), self-management capabilities and clinical parameters. Data collection will be performed at baseline, 12 and 24 months (12 months post-intervention). Discussion: Practice-based care management for high risk individuals involving trained HCAs appears to be a promising approach to face the needs of an aging population with increasing care demands. Trial registration: Current Controlled Trials ISRCTN56104508
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Safety and clinical outcomes of rituximab therapy in patients with different autoimmune diseases: experience from a national registry (GRAID)
(2011)
- Introduction Evidence from a number of open-label, uncontrolled studies has suggested that rituximab may benefit patients with autoimmune diseases who are refractory to standard of care. The objective of this study was to evaluate the safety and clinical outcomes of rituximab in several standard of care-refractory autoimmune diseases (within rheumatology, nephrology, dermatology and neurology) other than rheumatoid arthritis or non-Hodgkin's lymphoma in a real-life clinical setting. Methods Patients who received rituximab having shown an inadequate response to standard of care had their safety and clinical outcomes data retrospectively analysed as part of the German Registry of Autoimmune Diseases. The main outcome measures were safety and clinical response, as judged at the discretion of the investigators. Results A total of 370 patients (299 patient-years) with various autoimmune diseases (23.0% with systemic lupus erythematosus, 15.7% antineutrophil cytoplasmic antibody-associated vasculitides, 15.1% multiple sclerosis and 10.0% pemphigus) from 42 centres received a mean dose of 2440 mg of rituximab over a median (range) of 194 (180 to 1407) days. The overall rate of serious infections was 5.3 per 100 patient-years during rituximab therapy. Opportunistic infections were infrequent across the whole study population, and mostly occurred in patients with systemic lupus erythematosus. There were 11 deaths (3.0% of patients) after rituximab treatment (mean 11.6 months after first infusion, range 0.8 to 31.3 months), with most of the deaths caused by infections. Overall (n = 293), 13.3% of patients showed no response, 45.1% showed a partial response and 41.6% showed a complete response. Responses were also reflected by reduced use of glucocorticoids and various immunosuppressives during rituximab therapy and follow-up compared with before rituximab. Rituximab generally had a positive effect on patient well-being (physician's visual analogue scale; mean improvement from baseline of 12.1 mm). Conclusions Data from this registry indicate that rituximab is a commonly employed, well-tolerated therapy with potential beneficial effects in standard of care-refractory autoimmune diseases, and support the results from other open-label, uncontrolled studies. Additional file 1: Supplemental tables. Table A1. Duration of follow-up from first rituximab infusion to last control visit by diagnosis. Table A2. Number of rituximab infusions by diagnosis.
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Genome sequence of the necrotrophic plant pathogen Pythium ultimum reveals original pathogenicity mechanisms and effector repertoire
(2010)
- Background: Pythium ultimum (P. ultimum) is a ubiquitous oomycete plant pathogen responsible for a variety of diseases on a broad range of crop and ornamental species. Results: The P. ultimum genome (42.8 Mb) encodes 15,290 genes and has extensive sequence similarity and synteny with related Phytophthora species, including the potato blight pathogen Phytophthora infestans. Whole transcriptome sequencing revealed expression of 86% of genes, with detectable differential expression of suites of genes under abiotic stress and in the presence of a host. The predicted proteome includes a large repertoire of proteins involved in plant pathogen interactions although surprisingly, the P. ultimum genome does not encode any classical RXLR effectors and relatively few Crinkler genes in comparison to related phytopathogenic oomycetes. A lower number of enzymes involved in carbohydrate metabolism were present compared to Phytophthora species, with the notable absence of cutinases, suggesting a significant difference in virulence mechanisms between P. ultimum and more host specific oomycete species. Although we observed a high degree of orthology with Phytophthora genomes, there were novel features of the P. ultimum proteome including an expansion of genes involved in proteolysis and genes unique to Pythium. We identified a small gene family of cadherins, proteins involved in cell adhesion, the first report in a genome outside the metazoans. Conclusions: Access to the P. ultimum genome has revealed not only core pathogenic mechanisms within the oomycetes but also lineage specific genes associated with the alternative virulence and lifestyles found within the pythiaceous lineages compared to the Peronosporaceae.
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Development of a primary care-based complex care management intervention for chronically ill patients at high risk for hospitalization: a study protocol
(2010)
- Background: Complex care management is seen as an approach to face the challenges of an ageing society with increasing numbers of patients with complex care needs. The Medical Research Council in the United Kingdom has proposed a framework for the development and evaluation of complex interventions that will be used to develop and evaluate a primary care-based complex care management program for chronically ill patients at high risk for future hospitalization in Germany. Methods and design: We present a multi-method procedure to develop a complex care management program to implement interventions aimed at reducing potentially avoidable hospitalizations for primary care patients with type 2 diabetes mellitus, chronic obstructive pulmonary disease, or chronic heart failure and a high likelihood of hospitalization. The procedure will start with reflection about underlying precipitating factors of hospitalizations and how they may be targeted by the planned intervention (pre-clinical phase). An intervention model will then be developed (phase I) based on theory, literature, and exploratory studies (phase II). Exploratory studies are planned that entail the recruitment of 200 patients from 10 general practices. Eligible patients will be identified using two ways of 'case finding': software based predictive modelling and physicians' proposal of patients based on clinical experience. The resulting subpopulations will be compared regarding healthcare utilization, care needs and resources using insurance claims data, a patient survey, and chart review. Qualitative studies with healthcare professionals and patients will be undertaken to identify potential barriers and enablers for optimal performance of the complex care management program. Discussion: This multi-method procedure will support the development of a primary care-based care management program enabling the implementation of interventions that will potentially reduce avoidable hospitalizations.
