Building silent compartments at the nuclear periphery: a recurrent theme.

In eukaryotes, the genetic material is stored in the nucleus, which is enclosed in a double lipid bilayer, the nuclear envelope (NE). It protects the genome from physical stress and separates it from the rest of the cell. On top of this physical function, growing evidence shows that the nuclear periphery contributes to the 3D organization of the genome. In turn, tridimensional organization of chromatin in the nuclear space influences genome expression. Here we review recent findings on the function of this physical barrier in gene repression and latest models on how silent subnuclear compartments at the NE are built in yeast as well as in the nematode C. elegans and mammalian cells; trying to draw parallels between the three systems.

European guidelines for sclerotherapy in chronic venous disorders.

AIM: Sclerotherapy is the targeted chemical ablation of varicose veins by intravenous injection of a liquid or foamed sclerosing drug. The treated veins may be intradermal, subcutaneous, and/or transfascial as well as superficial and deep in venous malformations. The aim of this guideline is to give evidence-based recommendations for liquid and foam sclerotherapy. METHODS: This guideline was drafted on behalf of 23 European Phlebological Societies during a Guideline Conference on 7-10 May 2012 in Mainz. The conference was organized by the German Society of Phlebology. These guidelines review the present state of knowledge as reflected in published medical literature. The regulatory situation of sclerosant drugs differs from country to country but this has not been considered in this document. The recommendations of this guideline are graded according to the American College of Chest Physicians Task Force recommendations on Grading Strength of Recommendations and Quality of Evidence in Clinical Guidelines. RESULTS: This guideline focuses on the two sclerosing drugs which are licensed in the majority of the European countries, polidocanol and sodium tetradecyl sulphate. Other sclerosants are not discussed in detail. The guideline gives recommendations concerning indications, contraindications, side-effects, concentrations, volumes, technique and efficacy of liquid and foam sclerotherapy of varicose veins and venous malformations.

Treatment of chronic venous disease with flavonoids: recommendations for treatment and further studies.

OBJECTIVES A variety of studies have suggested that flavonoids are effective for the treatment of CVD. However, many questions remain about their mechanism of action and when, how, and for what signs and symptoms they should be used. METHOD A panel of experts in CVD met in Budapest, Hungary in December 2011 to discuss the current state of knowledge of CVD and the role of flavonoids in its treatment. The discussion was based on a literature search in the current databases. The goals of this paper are recommendations for further studies on the use of flavonoids in the treatment of CVD. RESULTS There is good evidence to recommend the use of flavonoids in the treatment of CVD. However, because of the poor quality of some older clinical trials, inadequate reporting, and insufficient information, much work is still needed to firmly establish their clinical efficacy and to determine when and how they should be employed. In particular, long-term randomized, placebo-controlled, double-blind studies are needed to establish the efficacy and safety of flavonoids. Additional studies are also needed to establish their mechanism of action, pharmacokinetics, toxicity, and cost-effectiveness. CONCLUSIONS Aside from good evidence for the use of flavonoids in CVD further studies are indicated to establish long term treatment in this indication.

Loss of TRAIL-receptors is a recurrent feature in pancreatic cancer and determines the prognosis of patients with no nodal metastasis after surgery

INTRODUCTION Agonistic antibodies targeting TRAIL-receptors 1 and 2 (TRAIL-R1 and TRAIL-R2) are being developed as a novel therapeutic approach in cancer therapy including pancreatic cancer. However, the cellular distribution of these receptors in primary pancreatic cancer samples has not been sufficiently investigated and no study has yet addressed the issue of their prognostic significance in this tumor entity. AIMS AND METHODS Applying tissue microarray (TMA) analysis, we performed an immunohistochemical assessment of TRAIL-receptors in surgical samples from 84 consecutive patients affected by pancreatic adenocarcinoma and in 26 additional selected specimens from patients with no lymph nodes metastasis at the time of surgery. The prognostic significance of membrane staining and staining intensity for TRAIL-receptors was evaluated. RESULTS The fraction of pancreatic cancer samples with positive membrane staining for TRAIL-R1 and TRAIL-R2 was lower than that of cells from surrounding non-tumor tissues (TRAIL-R1: p<0.001, TRAIL-R2: p = 0.006). In addition, subgroup analyses showed that loss of membrane staining for TRAIL-R2 was associated with poorer prognosis in patients without nodal metastases (multivariate Cox regression analysis, Hazard Ratio: 0.44 [95% confidence interval: 0.22-0.87]; p = 0.019). In contrast, analysis of decoy receptors TRAIL-R3 and -R4 in tumor samples showed an exclusively cytoplasmatic staining pattern and no prognostic relevance. CONCLUSION This is a first report on the prognostic significance of TRAIL-receptors expression in pancreatic cancer showing that TRAIL-R2 might represent a prognostic marker for patients with early stage disease. In addition, our data suggest that loss of membrane-bound TRAIL-receptors could represent a molecular mechanism for therapeutic failure upon administration of TRAIL-receptors-targeting antibodies in pancreatic cancer. This hypothesis should be evaluated in future clinical trials.

Safety and Feasibility of a Diagnostic Algorithm Combining Clinical Probability, d-Dimer Testing, and Ultrasonography for Suspected Upper Extremity Deep Venous Thrombosis: A Prospective Management Study.

BACKGROUND Although well-established for suspected lower limb deep venous thrombosis, an algorithm combining a clinical decision score, d-dimer testing, and ultrasonography has not been evaluated for suspected upper extremity deep venous thrombosis (UEDVT). OBJECTIVE To assess the safety and feasibility of a new diagnostic algorithm in patients with clinically suspected UEDVT. DESIGN Diagnostic management study. (ClinicalTrials.gov: NCT01324037) SETTING: 16 hospitals in Europe and the United States. PATIENTS 406 inpatients and outpatients with suspected UEDVT. MEASUREMENTS The algorithm consisted of the sequential application of a clinical decision score, d-dimer testing, and ultrasonography. Patients were first categorized as likely or unlikely to have UEDVT; in those with an unlikely score and normal d-dimer levels, UEDVT was excluded. All other patients had (repeated) compression ultrasonography. The primary outcome was the 3-month incidence of symptomatic UEDVT and pulmonary embolism in patients with a normal diagnostic work-up. RESULTS The algorithm was feasible and completed in 390 of the 406 patients (96%). In 87 patients (21%), an unlikely score combined with normal d-dimer levels excluded UEDVT. Superficial venous thrombosis and UEDVT were diagnosed in 54 (13%) and 103 (25%) patients, respectively. All 249 patients with a normal diagnostic work-up, including those with protocol violations (n = 16), were followed for 3 months. One patient developed UEDVT during follow-up, for an overall failure rate of 0.4% (95% CI, 0.0% to 2.2%). LIMITATIONS This study was not powered to show the safety of the substrategies. d-Dimer testing was done locally. CONCLUSION The combination of a clinical decision score, d-dimer testing, and ultrasonography can safely and effectively exclude UEDVT. If confirmed by other studies, this algorithm has potential as a standard approach to suspected UEDVT. PRIMARY FUNDING SOURCE None.

Diagnosis and Treatment of Venous Malformations Consensus Document of the International Union of Phlebology (IUP): updated 2013

Venous malformations (VMs) are the most common vascular developmental anomalies (birth defects) . These defects are caused by developmental arrest of the venous system during various stages of embryogenesis. VMs remain a difficult diagnostic and therapeutic challenge due to the wide range of clinical presentations, unpredictable clinical course, erratic response to the treatment with high recurrence/persistence rates, high morbidity following non-specific conventional treatment, and confusing terminology. The Consensus Panel reviewed the recent scientific literature up to the year 2013 to update a previous IUP Consensus (2009) on the same subject. ISSVA Classification with special merits for the differentiation between the congenital vascular malformation (CVM) and vascular tumors was reinforced with an additional review on syndrome-based classification. A "modified" Hamburg classification was adopted to emphasize the importance of extratruncular vs. truncular sub-types of VMs. This incorporated the embryological origin, morphological differences, unique characteristics, prognosis and recurrence rates of VMs based on this embryological classification. The definition and classification of VMs were strengthened with the addition of angiographic data that determines the hemodynamic characteristics, the anatomical pattern of draining veins and hence the risk of complication following sclerotherapy. The hemolymphatic malformations, a combined condition incorporating LMs and other CVMs, were illustrated as a separate topic to differentiate from isolated VMs and to rectify the existing confusion with name-based eponyms such as Klippel-Trenaunay syndrome. Contemporary concepts on VMs were updated with new data including genetic findings linked to the etiology of CVMs and chronic cerebrospinal venous insufficiency. Besides, newly established information on coagulopathy including the role of D-Dimer was thoroughly reviewed to provide guidelines on investigations and anticoagulation therapy in the management of VMs. Congenital vascular bone syndrome resulting in angio-osteo-hyper/hypotrophy and (lateral) marginal vein was separately reviewed. Background data on arterio-venous malformations was included to differentiate this anomaly from syndrome-based VMs. For the treatment, a new section on laser therapy and also a practical guideline for follow up assessment were added to strengthen the management principle of the multidisciplinary approach. All other therapeutic modalities were thoroughly updated to accommodate a changing concept through the years.

The equine DNAH3 gene: SNP discovery and exclusion of an involvement in recurrent airway obstruction (RAO) in European Warmblood horses

Recurrent airway obstruction is one of the most common airway diseases affecting mature horses. Increased bronchoalveolar mucus, neutrophil accumulation in airways, and airway obstruction are the main features of this disease. Mucociliary clearance is a key component of pulmonary defense mechanisms. Cilia are the motile part of this system and a complex linear array of dynein motors is responsible for their motility by moving along the microtubules in the axonemes of cilia and flagella. We previously detected a QTL for RAO on ECA 13 in a half-sib family of European Warmblood horses. The gene encoding DNAH3 is located in the peak of the detected QTL and encodes a dynein subunit. Therefore, we analysed this gene as a positional and functional candidate gene for RAO. In a mutation analysis of all 62 exons we detected 53 new polymorphisms including 7 non-synonymous variants. We performed an association study using 38 polymorphisms in a cohort of 422 animals. However, after correction for multiple testing we did not detect a significant association of any of these polymorphisms with RAO (P>0.05). Therefore, it seems unlikely that variants at the DNAH3 gene are responsible for the RAO QTL in European Warmblood horses.

Anatomic pathways of peripancreatic fluid draining to mediastinum in recurrent acute pancreatitis: visible human project and CT study

BACKGROUND In past reports, researchers have seldom attached importance to achievements in transforming digital anatomy to radiological diagnosis. However, investigators have been able to illustrate communication relationships in the retroperitoneal space by drawing potential routes in computerized tomography (CT) images or a virtual anatomical atlas. We established a new imaging anatomy research method for comparisons of the communication relationships of the retroperitoneal space in combination with the Visible Human Project and CT images. Specifically, the anatomic pathways of peripancreatic fluid extension to the mediastinum that may potentially transform into fistulas were studied. METHODS We explored potential pathways to the mediastinum based on American and Chinese Visible Human Project datasets. These drainage pathways to the mediastinum were confirmed or corrected in CT images of 51 patients with recurrent acute pancreatitis in 2011. We also investigated whether additional routes to the mediastinum were displayed in CT images that were not in Visible Human Project images. PRINCIPAL FINDINGS All hypothesized routes to the mediastinum displayed in Visible Human Project images, except for routes from the retromesenteric plane to the bilateral retrorenal plane across the bilateral fascial trifurcation and further to the retrocrural space via the aortic hiatus, were confirmed in CT images. In addition, route 13 via the narrow space between the left costal and crural diaphragm into the retrocrural space was demonstrated for the first time in CT images. CONCLUSION This type of exploration model related to imaging anatomy may be used to support research on the communication relationships of abdominal spaces, mediastinal spaces, cervical fascial spaces and other areas of the body.

Recurrent stroke predictors differ in medically treated patients with pathogenic vs other PFOs

OBJECTIVE: To examine predictors of stroke recurrence in patients with a high vs a low likelihood of having an incidental patent foramen ovale (PFO) as defined by the Risk of Paradoxical Embolism (RoPE) score.METHODS: Patients in the RoPE database with cryptogenic stroke (CS) and PFO were classified as having a probable PFO-related stroke (RoPE score of >6, n = 647) and others (RoPE score of

Characterization of the inflammatory infiltrate and cytokine expression in the skin of horses with recurrent urticaria.

BACKGROUND Recurrent urticaria (RU) is a common skin disease of horses, but little is known about its pathogenesis. HYPOTHESIS/OBJECTIVE The aim of this study was to characterize the inflammatory cell infiltrate and cytokine expression pattern in the skin of horses with RU. ANIMALS   Biopsies of lesional and nonlesional skin of horses with RU (n = 8) and of skin from healthy control horses (n = 8) were evaluated. METHODS The inflammatory cell infiltrate was analysed by routine histology. Immunohistochemistry was used to identify T cells (CD3), B  ells (CD79), macrophages (MAC387) and mast cells (tryptase). Expression of T-helper 2 cytokines (interleukins IL-4, IL-5 and IL-13), a T-helper 1 cytokine (interferon-γ), IL-4 receptor α and thymic stromal lymphopoietin was assessed by quantitative RT-PCR. Results -  In subepidermal lesional skin of RU-affected horses, increased numbers of eosinophils (P ≤ 0.01), CD79-positive (P ≤ 0.01), MAC387-positive (P ≤ 0.01) and tryptase-positive cells (P ≤ 0.05) were found compared with healthy horses. Subepidermal lesional skin of RU-affected horses contained more eosinophils (P ≤ 0.05) and tryptase-positive cells (P ≤ 0.05) compared with nonlesional skin. There was no significant difference in infiltrating cells between nonlesional skin and skin of healthy horses. Expression of IL-4 (P ≤ 0.01), IL-13 (P ≤ 0.05), thymic stromal lymphopoietin (P ≤ 0.05) and IL-4 receptor α (P ≤ 0.05) was increased in lesional skin of RU-affected horses compared with control horses. Expression of IL-4 was higher (P ≤ 0.05) in lesional compared with nonlesional RU skin. CONCLUSIONS AND CLINICAL IMPORTANCE Analysis of cytokine expression and inflammatory infiltrate suggests that T-helper 2 cytokines, eosinophils, mast cells and presumptive macrophages play a role in the pathogenesis of equine RU.

The ovine cerebral venous system: comparative anatomy, visualization, and implications for translational research.

Cerebrovascular diseases are significant causes of death and disability in humans. Improvements in diagnostic and therapeutic approaches strongly rely on adequate gyrencephalic, large animal models being demanded for translational research. Ovine stroke models may represent a promising approach but are currently limited by insufficient knowledge regarding the venous system of the cerebral angioarchitecture. The present study was intended to provide a comprehensive anatomical analysis of the intracranial venous system in sheep as a reliable basis for the interpretation of experimental results in such ovine models. We used corrosion casts as well as contrast-enhanced magnetic resonance venography to scrutinize blood drainage from the brain. This combined approach yielded detailed and, to some extent, novel findings. In particular, we provide evidence for chordae Willisii and lateral venous lacunae, and report on connections between the dorsal and ventral sinuses in this species. For the first time, we also describe venous confluences in the deep cerebral venous system and an 'anterior condylar confluent' as seen in humans. This report provides a detailed reference for the interpretation of venous diagnostic imaging findings in sheep, including an assessment of structure detectability by in vivo (imaging) versus ex vivo (corrosion cast) visualization methods. Moreover, it features a comprehensive interspecies-comparison of the venous cerebral angioarchitecture in man, rodents, canines and sheep as a relevant large animal model species, and describes possible implications for translational cerebrovascular research.