Effectiveness of Immunoglobulin Replacement Therapy on Clinical Outcome in Patients with Primary Antibody Deficiencies: Results from a Multicenter Prospective Cohort Study

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Pulmonary Vaccination as a Novel Treatment for Lung Fibrosis

Pulmonary fibrosis is an untreatable, uniformly fatal disease of unclear etiology that is the result of unremitting chronic inflammation. Recent studies have implicated bone marrow derived fibrocytes and M2 macrophages as playing key roles in propagating fibrosis. While the disease process is characterized by the accumulation of lymphocytes in the lung parenchyma and alveolar space, their role remains unclear. In this report we definitively demonstrate the ability of T cells to regulate lung inflammation leading to fibrosis. Specifically we demonstrate the ability of intranasal vaccinia vaccination to inhibit M2 macrophage generation and fibrocyte recruitment and hence the accumulation of collagen and death due to pulmonary failure. Mechanistically, we demonstrate the ability of lung Th1 cells to prevent fibrosis as vaccinia failed to prevent disease in Rag−/− mice or in mice in which the T cells lacked IFN-γ. Furthermore, vaccination 3 months prior to the initiation of fibrosis was able to mitigate the disease. Our findings clearly demonstrate the role of T cells in regulating pulmonary fibrosis as well as suggest that vaccinia-induced immunotherapy in the lung may prove to be a novel treatment approach to this otherwise fatal disease

Peripheral anti-nociceptive effect of nociceptin/orphanin FQ in inflammation and stress-induced colonic hyperalgesia in rats

Nociceptin/orphanin FQ (N/OFQ) and its NOP receptors are present in the central nervous system and in the periphery playing important roles in the modulation of gastrointestinal functions and pain. The aim of this study was to investigate the role of central and peripheral N/OFQ-NOP receptor system in the nociceptive response to colorectal distension (CRD) in basal condition and in two models of gut hypersensitivity triggered by both inflammation and stress. Male Wistar rats were tested in basal and in post-inflammatory conditions, i.e., 5 days after IC TNBS instillation (80 mg/Kg) and received N/OFQ (2 nmol/Kg IP), UFP-101 (a selective NOP receptor antagonist, 10 nmol/Kg IP), N/OFQ+UFP-101, N/OFQ (0.5 nmol/rat ICV) or vehicle. Female rats were tested in basal and after partial restraint stress receiving the same pharmacological treatment. CRD was performed using barostat and abdominal contractions were recorded by electromyography. In basal condition, N/OFQ, ICV and IP injected, did not modify basal visceral sensitivity. Both in TNBS arid stress-induced hyperalgesia, IP but not ICV injection of N/OFQ significantly decreased the number of abdominal contractions. Peripheral injection of UFP-101 antagonized N/OFQ effect. Moreover, in post-inflammatory colitis, UFP-101, injected alone, exacerbated visceral hyperalgesia to CRD compared with vehicle. These findings indicate that in rats, N/OFQ, only peripherally injected, reduces visceral hypersensitivity triggered by inflammation or stress Without affecting basal sensitivity. N/OFQ visceral anti-hyperalgesic effect involves peripheral NOP receptors. In a post-inflammatory, but not in an acute stress colitis model, N/OFQergic system is endogenously activated. (C) 2008 International Association for the Study of Pain. Published by Elsevier B.V. All rights reserved

Evidence of Central and Peripheral Sensitization in a Rat Model of Narcotic Bowel-Like Syndrome

BACKGROUND & AIMS: Narcotic bowel syndrome (NBS) is a subset of opioid bowel dysfunctions that results from prolonged treatment with narcotics and is characterized by chronic abdominal pain. NBS is under-recognized and its molecular mechanisms are unknown. We aimed to (1) develop a rat model of NBS and (2) to investigate its peripheral and central neurobiological mechanisms. METHODS: Male Wistar rats were given a slow-release emulsion that did or did not contain morphine (10 mg/kg) for 8 days. Visceral sensitivity to colorectal distension (CRD) was evaluated during and after multiple administrations of morphine or vehicle (controls). The effects of minocycline (a microglia inhibitor), nor-binaltorphimine (a kappa-opioid antagonist), and doxantrazole (a mast-cell inhibitor) were observed on morphine-induced visceral hyperalgesia. Levels of OX-42, P-p38 mitogen-activated protein kinase, rat mast cell protease 11, and protein gene product 9.5 were assessed at different spinal segments (lumbar 6 to sacral 1) or colonic mucosa by immunohistochemistry. RESULTS: On day 8 of morphine administration, rats developed visceral hyperalgesia to CRD (incipient response) that lasted for 8 more days (delayed response). Minocycline reduced the incipient morphine-induced hypersensitivity response to CRD whereas nor-binaltorphimine and doxantrazole antagonized the delayed hyperalgesia. Levels of OX-42 and P-p38 increased in the spinal sections, whereas rat mast cell protease II and protein gene product 9.5 increased in the colonic mucosa of rats that were given morphine compared with controls. CONCLUSIONS: We developed a rat model of narcotic bowel-like syndrome and showed that spinal microglia activation mediates the development of morphine-induced visceral hyperalgesia; peripheral neuroimmune activation and spinal dynorphin release represent an important mechanism in the delayed and long-lasting morphine-induced colonic hypersensitivity response to CRD

Connectivity patterns of coastal fishes following different dispersal scenarios across a transboundary marine protected area (Bonifacio strait, NW Mediterranean)

The Strait of Bonifacio constitutes one of the rare transboundary Marine Protected Areas (MPA) of the Mediterranean Sea (between Sardinia, Italy and Corsica, France). Based on the hypothesis that no-take zones will produce more fish larvae, compared to adjacent fished areas, we modeled the outcome of larvae released by coastal fishes inside the no-take zones of the MPA in order to: (i) characterize the dispersal patterns across the Strait of Bonifacio; (ii) identify the main potential settlement areas; (iii) quantify the connectivity and the larval supply from the MPAs to the surrounding areas. A high resolution hydrodynamic model (MARS 3D, Corse 400m) combined to an individual based model (Ichthyop software) was used to model the larval dispersal of fish following various scenarios (Pelagic Larval Duration PLD and release depth) over the main spawning period (i.e. between April and September). Dispersal model outputs were then compared with those obtained from an ichthyoplankton sampling cruise performed in August 2012. There was a the significant influence of PLD to the connectivity between coastal areas. The synchronization between spawning and hydrodynamic conditions appeared to be determinant in the larval transport success. Biotic and abiotic parameters affecting the dispersal dynamic of fish larvae within the Strait of Bonifacio were identified and synthesis maps were established as a tool for conservation planning

Overview and guidelines of off-label use of methotrexate in ectopic ă pregnancy: report by CNGOF

International audienceOur objective is to describe off-label use of methotrexate in ectopic ă pregnancy treatment using evidence based medicine. The patient group ă includes all women with a pregnancy outside the usual endometrium, or of ă unknown location. ă Method used was a Medline search on ectopic pregnancy managed using ă methotrexate treatment; evidence synthesis was done based on this ă current literature analysis. ă Level of evidence (LE) were given according to the centre for evidence ă base medicine rules. Grade was proposed for guidelines but no ă recommendation was possible as misoprostol is off label use for all the ă indications studied. ă In the absence of any contraindication, the protocol recommended for ă medical treatment of ectopic pregnancy is a single intramuscular ă injection of methotrexate (MTX) at a dosage of 1 mg/kg or 50 mg/m(2) ă (Grade A). It can be repeated once at the same dose should the hCG ă concentration not fall sufficiently. Pretreatment laboratory results ă must include a complete blood count and kidney and liver function tests ă (in accordance with its marketing authorization). ă MTX is an alternative to conservative treatment such as laparoscopic ă salpingotomy for uncomplicated tubal pregnancy (Grade A) with ă pretreatment hCG levels 20001U/1, routine MTX treatment is an option. ă MTX is not indicated for combination with treatments such as ă mifepristone or potassium. (C) 2016 Published by Elsevier Ireland Ltd