Stromal cell-derived factor 1 (SDF-1) and antenatal human B cell lymphopoiesis: Expression of SDF-1 by mesothelial cells and biliary ductal plate epithelial cells

The chemokine stromal cell-derived factor 1 (SDF-1) stimulates the growth of pre-B cells in vitro, and mice with a disrupted SDF-1 gene have abnormal fetal liver B cell lymphopoiesis. The origin of SDF-1 production has not been determined yet. Using an anti-SDF-1 mAb, we performed immunohistochemical studies in four human embryos and five fetuses to define which cells express the SDF-1 protein at sites of antenatal B cell lymphopoiesis. All mesothelial cells contained SDF-1 at all stages of development, including in the intraembryonic splanchnopleuric mesoderm early into gestation. In fetal lungs and kidneys, SDF-1 was expressed by epithelial cells, and a few B lymphoid precursors, expressing V pre-B chains, were also detected. In the fetal liver, in addition to mesothelial cells, biliary epithelial cells were the only cells to contain SDF-1. Pre-B cells expressing V chains were abundant and exclusively located around the edge of portal spaces, in close contact with biliary ductal plate epithelial cells. They did not colocalize with biliary collecting ducts. Biliary ductal plate epithelial cells and liver B cell lymphopoiesis display a parallel development and disappearance during fetal life. These results indicate that early B cell lymphopoiesis in the splanchnopleura may be triggered by mesothelial cells producing SDF-1. Later into gestation, biliary ductal plate epithelial cells may support B cell lymphopoiesis, thus playing a role similar to that of epithelial cells in the avian bursa of Fabricius, and of thymic epithelial cells for T cell lymphopoiesis

A Genome-Wide Association Study of the Protein C Anticoagulant Pathway

The Protein C anticoagulant pathway regulates blood coagulation by preventing the inadequate formation of thrombi. It has two main plasma components: protein C and protein S. Individuals with protein C or protein S deficiency present a dramatically increased incidence of thromboembolic disorders. Here, we present the results of a genome-wide association study (GWAS) for protein C and protein S plasma levels in a set of extended pedigrees from the Genetic Analysis of Idiopathic Thrombophilia (GAIT) Project. A total number of 397 individuals from 21 families were typed for 307,984 SNPs using the Infinium® 317 k Beadchip (Illumina). Protein C and protein S (free, functional and total) plasma levels were determined with biochemical assays for all participants. Association with phenotypes was investigated through variance component analysis. After correcting for multiple testing, two SNPs for protein C plasma levels (rs867186 and rs8119351) and another two for free protein S plasma levels (rs1413885 and rs1570868) remained significant on a genome-wide level, located in and around the PROCR and the DNAJC6 genomic regions respectively. No SNPs were significantly associated with functional or total protein S plasma levels, although rs1413885 from DNAJC6 showed suggestive association with the functional protein S phenotype, possibly indicating that this locus plays an important role in protein S metabolism. Our results provide evidence that PROCR and DNAJC6 might play a role in protein C and free protein S plasma levels in the population studied, warranting further investigation on the role of these loci in the etiology of venous thromboembolism and other thrombotic diseases

Risk of Parkinson's disease after tamoxifen treatment

<p>Abstract</p> <p>Background</p> <p>Women have a reduced risk of developing Parkinson's disease (PD) compared with age-matched men. Neuro-protective effects of estrogen potentially explain this difference. Tamoxifen, commonly used in breast cancer treatment, may interfere with the protective effects of estrogen and increase risk of PD. We compared the rate of PD in Danish breast cancer patients treated with tamoxifen to the rate among those not treated with tamoxifen.</p> <p>Methods</p> <p>A cohort of 15,419 breast cancer patients identified from the Danish Breast Cancer Collaborative Group database was linked to the National Registry of Patients to identify PD diagnoses. Overall risk and rate of PD following identification into the study was compared between patients treated with tamoxifen as adjuvant hormonal therapy and patients not receiving tamoxifen. Time-dependent effects of tamoxifen treatment on PD rate were examined to estimate the likely induction period for tamoxifen.</p> <p>Results</p> <p>In total, 35 cases of PD were identified among the 15,419 breast cancer patients. No overall effect of tamoxifen on rate of PD was observed (HR = 1.3, 95% CI: 0.64-2.5), but a PD hazard ratio of 5.1 (95% CI: 1.0-25) was seen four to six years following initiation of tamoxifen treatment.</p> <p>Conclusions</p> <p>These results provide evidence that the neuro-protective properties of estrogen against PD occurrence may be disrupted by tamoxifen therapy. Tamoxifen treatments may be associated with an increased rate of PD; however these effects act after four years, are of limited duration, and the adverse effect is overwhelmed by the protection against breast recurrence conferred by tamoxifen therapy.</p

Primary versus early secondary referral to a specialized neurotrauma center in patients with moderate/severe traumatic brain injury: a CENTER TBI study.

BackgroundPrehospital care for patients with traumatic brain injury (TBI) varies with some emergency medical systems recommending direct transport of patients with moderate to severe TBI to hospitals with specialist neurotrauma care (SNCs). The aim of this study is to assess variation in levels of early secondary referral within European SNCs and to compare the outcomes of directly admitted and secondarily transferred patients.MethodsPatients with moderate and severe TBI (Glasgow Coma Scale ResultsA total of 1347 moderate/severe TBI patients from 53 SNCs in 18 European countries were included. Of these 1347 patients, 195 (14.5%) were admitted after early secondary referral. Secondarily referred moderate/severe TBI patients presented more often with a CT abnormality: mass lesion (52% vs. 34%), midline shift (54% vs. 36%) and acute subdural hematoma (77% vs. 65%). After adjusting for case-mix, there was a large European variation in early secondary referral, with a median OR of 1.69 between countries. Early secondary referral was not associated with functional outcome (adjusted OR 1.07, 95% CI 0.78-1.69), nor with survival at discharge (1.05, 0.58-1.90).ConclusionsAcross Europe, substantial practice variation exists in the proportion of secondarily referred TBI patients at SNCs that is not explained by case mix. Within SNCs early secondary referral does not seem to impact functional outcome and survival after stabilisation in a non-specialised hospital. Future research should identify which patients with TBI truly benefit from direct transportation

The Anticoagulation of Calf Thrombosis (ACT) project: study protocol for a randomized controlled trial

<p>Abstract</p> <p>Background</p> <p>Half of all lower limb deep vein thrombi (DVT) in symptomatic ambulatory patients are located in the distal (calf) veins. While proximal disease warrants therapeutic anticoagulation to reduce the associated risks, distal DVT often goes untreated. However, a proportion of untreated distal disease will undoubtedly propagate or embolize. Concern also exists that untreated disease could lead to long-term post thrombotic changes. Currently, it is not possible to predict which distal thrombi will develop such complications. Whether these potential risks outweigh those associated with unrestricted anticoagulation remains unclear. The Anticoagulation of Calf Thrombosis (ACT) trial aims to compare therapeutic anticoagulation against conservative management for patients with acute symptomatic distal deep vein thrombosis.</p> <p>Methods</p> <p>ACT is a pragmatic, open-label, randomized controlled trial. Adult patients diagnosed with acute distal DVT will be allocated to either therapeutic anticoagulation or conservative management. All patients will undergo 3 months of clinical and assessor blinded sonographic follow-up, followed by 2-year final review. The project will commence initially as an external pilot study, recruiting over a 16-month period at a single center to assess feasibility measures and clinical event rates. Primary outcome measures will assess feasibility endpoints. Secondary clinical outcomes will be collected to gather accurate data for the design of a definitive clinical trial and will include: (1) a composite endpoint combining thrombus propagation to the popliteal vein or above, development of symptomatic pulmonary embolism or sudden death attributable to venous thromboembolic disease; (2) the incidence of major and minor bleeding episodes; (3) the incidence of post-thrombotic leg syndrome at 2 years using a validated screening tool; and (4) the incidence of venous thromboembolism (VTE) recurrence at 2 years.</p> <p>Discussion</p> <p>The ACT trial will explore the feasibility of comparing therapeutic anticoagulation to conservative management in acute distal DVT, within a modern cohort. We also aim to provide contemporary data on clot propagation, bleeding rates and long-term outcomes within both groups. These results will inform the conduct of a definitive study if feasibility is established.</p> <p>Trial registration</p> <p>Current Controlled Trials <a href="http://www.controlled-trials.com/ISRCTN75175695">ISRCTN75175695</a></p

Multiproject–multicenter evaluation of automatic brain tumor classification by magnetic resonance spectroscopy

Contains fulltext : 75361.pdf (publisher's version ) (Open Access)14 p

Progressive dementia associated with ataxia or obesity in patients with Tropheryma whipplei encephalitis

<p>Abstract</p> <p>Background</p> <p><it>Tropheryma whipplei</it>, the agent of Whipple's disease, causes localised infections in the absence of histological digestive involvement. Our objective is to describe <it>T. whipplei </it>encephalitis.</p> <p>Methods</p> <p>We first diagnosed a patient presenting dementia and obesity whose brain biopsy and cerebrospinal fluid specimens contained <it>T. whipplei </it>DNA and who responded dramatically to antibiotic treatment. We subsequently tested cerebrospinal fluid specimens and brain biopsies sent to our laboratory using <it>T. whipplei </it>PCR assays. PAS-staining and <it>T. whipplei </it>immunohistochemistry were also performed on brain biopsies. Analysis was conducted for 824 cerebrospinal fluid specimens and 16 brain biopsies.</p> <p>Results</p> <p>We diagnosed seven patients with <it>T. whipplei </it>encephalitis who demonstrated no digestive involvement. Detailed clinical histories were available for 5 of them. Regular PCR that targeted a monocopy sequence, PAS-staining and immunohistochemistry were negative; however, several highly sensitive and specific PCR assays targeting a repeated sequence were positive. Cognitive impairments and ataxia were the most common neurologic manifestations. Weight gain was paradoxically observed for 2 patients. The patients' responses to the antibiotic treatment were dramatic and included weight loss in the obese patients.</p> <p>Conclusions</p> <p>We describe a new clinical condition in patients with dementia and obesity or ataxia linked to <it>T. whipplei </it>that may be cured with antibiotics.</p

Collaborative European NeuroTrauma Effectiveness Research in Traumatic Brain Injury (CENTER-TBI): A Prospective Longitudinal Observational Study

BACKGROUND: Current classification of traumatic brain injury (TBI) is suboptimal, and management is based on weak evidence, with little attempt to personalize treatment. A need exists for new precision medicine and stratified management approaches that incorporate emerging technologies. OBJECTIVE: To improve characterization and classification of TBI and to identify best clinical care, using comparative effectiveness research approaches. METHODS: This multicenter, longitudinal, prospective, observational study in 22 countries across Europe and Israel will collect detailed data from 5400 consenting patients, presenting within 24 hours of injury, with a clinical diagnosis of TBI and an indication for computed tomography. Broader registry-level data collection in approximately 20 000 patients will assess generalizability. Cross sectional comprehensive outcome assessments, including quality of life and neuropsychological testing, will be performed at 6 months. Longitudinal assessments will continue up to 24 months post TBI in patient subsets. Advanced neuroimaging and genomic and biomarker data will be used to improve characterization, and analyses will include neuroinformatics approaches to address variations in process and clinical care. Results will be integrated with living systematic reviews in a process of knowledge transfer. The study initiation was from October to December 2014, and the recruitment period was for 18 to 24 months. EXPECTED OUTCOMES: Collaborative European NeuroTrauma Effectiveness Research in TBI should provide novel multidimensional approaches to TBI characterization and classification, evidence to support treatment recommendations, and benchmarks for quality of care. Data and sample repositories will ensure opportunities for legacy research. DISCUSSION: Comparative effectiveness research provides an alternative to reductionistic clinical trials in restricted patient populations by exploiting differences in biology, care, and outcome to support optimal personalized patient management