Clcn7F318L/+ as a new mouse model of Albers-Schönberg disease

Dominant negative mutations in CLCN7, which encodes a homodimeric chloride channel needed for matrix acidification by osteoclasts, cause Albers-Schönberg disease (also known as autosomal dominant osteopetrosis type 2). More than 25 different CLCN7 mutations have been identified in patients affected with Albers-Schönberg disease, but only one mutation (Clcn7G213R) has been introduced in mice to create an animal model of this disease. Here we describe a mouse with a different osteopetrosis-causing mutation (Clcn7F318L). Compared to Clcn7+/+ mice, 12-week-old Clcn7F318L/+ mice have significantly increased trabecular bone volume, consistent with Clcn7F318L acting as a dominant negative mutation. Clcn7F318L/F318L and Clcn7F318L/G213R mice die by 1 month of age and resemble Clcn7 knockout mice, which indicate that p.F318L mutant protein is non-functional and p.F318L and p.G213R mutant proteins do not complement one another. Since it has been reported that treatment with interferon gamma (IFN-G) improves bone properties in Clcn7G213R/+ mice, we treated Clcn7F318L/+ mice with IFN-G and observed a decrease in osteoclast number and mineral apposition rate, but no overall improvement in bone properties. Our results suggest that the benefits of IFN-G therapy in patients with Albers-Schönberg disease may be mutation-specific

Early changes within the lymphocyte population are associated with the development of multiple organ dysfunction syndrome in trauma patients

2016 The Author(s). Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.JM was funded, in part, by the Royal College of Surgeons of England, The Phillip King Charitable Trust Research Fellowship and The National Institute of Health Research (NIHR)

The Third Fermi Large Area Telescope Catalog of Gamma-ray Pulsars

We present 294 pulsars found in GeV data from the Large Area Telescope (LAT) on the Fermi Gamma-ray Space Telescope. Another 33 millisecond pulsars (MSPs) discovered in deep radio searches of LAT sources will likely reveal pulsations once phase-connected rotation ephemerides are achieved. A further dozen optical and/or X-ray binary systems co-located with LAT sources also likely harbor gamma-ray MSPs. This catalog thus reports roughly 340 gamma-ray pulsars and candidates, 10% of all known pulsars, compared to $\leq 11$ known before Fermi. Half of the gamma-ray pulsars are young. Of these, the half that are undetected in radio have a broader Galactic latitude distribution than the young radio-loud pulsars. The others are MSPs, with 6 undetected in radio. Overall, >235 are bright enough above 50 MeV to fit the pulse profile, the energy spectrum, or both. For the common two-peaked profiles, the gamma-ray peak closest to the magnetic pole crossing generally has a softer spectrum. The spectral energy distributions tend to narrow as the spindown power $\dot E$ decreases to its observed minimum near $10^{33}$ erg s$^{-1}$, approaching the shape for synchrotron radiation from monoenergetic electrons. We calculate gamma-ray luminosities when distances are available. Our all-sky gamma-ray sensitivity map is useful for population syntheses. The electronic catalog version provides gamma-ray pulsar ephemerides, properties and fit results to guide and be compared with modeling results.Comment: 142 pages. Accepted by the Astrophysical Journal Supplemen

Basic science232. Certolizumab pegol prevents pro-inflammatory alterations in endothelial cell function

Background: Cardiovascular disease is a major comorbidity of rheumatoid arthritis (RA) and a leading cause of death. Chronic systemic inflammation involving tumour necrosis factor alpha (TNF) could contribute to endothelial activation and atherogenesis. A number of anti-TNF therapies are in current use for the treatment of RA, including certolizumab pegol (CZP), (Cimzia ®; UCB, Belgium). Anti-TNF therapy has been associated with reduced clinical cardiovascular disease risk and ameliorated vascular function in RA patients. However, the specific effects of TNF inhibitors on endothelial cell function are largely unknown. Our aim was to investigate the mechanisms underpinning CZP effects on TNF-activated human endothelial cells. Methods: Human aortic endothelial cells (HAoECs) were cultured in vitro and exposed to a) TNF alone, b) TNF plus CZP, or c) neither agent. Microarray analysis was used to examine the transcriptional profile of cells treated for 6 hrs and quantitative polymerase chain reaction (qPCR) analysed gene expression at 1, 3, 6 and 24 hrs. NF-κB localization and IκB degradation were investigated using immunocytochemistry, high content analysis and western blotting. Flow cytometry was conducted to detect microparticle release from HAoECs. Results: Transcriptional profiling revealed that while TNF alone had strong effects on endothelial gene expression, TNF and CZP in combination produced a global gene expression pattern similar to untreated control. The two most highly up-regulated genes in response to TNF treatment were adhesion molecules E-selectin and VCAM-1 (q 0.2 compared to control; p > 0.05 compared to TNF alone). The NF-κB pathway was confirmed as a downstream target of TNF-induced HAoEC activation, via nuclear translocation of NF-κB and degradation of IκB, effects which were abolished by treatment with CZP. In addition, flow cytometry detected an increased production of endothelial microparticles in TNF-activated HAoECs, which was prevented by treatment with CZP. Conclusions: We have found at a cellular level that a clinically available TNF inhibitor, CZP reduces the expression of adhesion molecule expression, and prevents TNF-induced activation of the NF-κB pathway. Furthermore, CZP prevents the production of microparticles by activated endothelial cells. This could be central to the prevention of inflammatory environments underlying these conditions and measurement of microparticles has potential as a novel prognostic marker for future cardiovascular events in this patient group. Disclosure statement: Y.A. received a research grant from UCB. I.B. received a research grant from UCB. S.H. received a research grant from UCB. All other authors have declared no conflicts of interes

Risk Factors for Acute Graft-Versus-Host Disease After Human Leukocyte Antigen–Identical Sibling Transplants for Adults With Leukemia

International audiencePURPOSE: Acute graft-versus-host disease (GVHD) causes substantial morbidity and mortality after human leukocyte antigen (HLA)-identical sibling transplants. No large registry studies of acute GVHD risk factors have been reported in two decades. Risk factors may have changed in this interval as transplant-related techniques have evolved. PATIENTS AND METHODS: Acute GVHD risk factors were analyzed in 1,960 adults after HLA-identical sibling myeloablative transplant for acute myeloid leukemia (AML), acute lymphocytic leukemia (ALL), or chronic myeloid leukemia (CML) reported by 226 centers worldwide to the Center for International Blood and Marrow Transplant Research from 1995 to 2002. Outcome was measured as time from transplant to onset of grade 2 to 4 acute GVHD, with death without acute GVHD as a competing risk. RESULTS: Cumulative incidence of grade 2 to 4 acute GVHD was 35% (95% CI, 33% to 37%). In multivariable analyses, factors significantly associated with grade 2 to 4 acute GVHD were cyclophosphamide + total-body irradiation versus busulfan + cyclophosphamide (relative risk [RR] = 1.4; P < .0001), blood cell versus bone marrow grafts in patients age 18 to 39 years (RR = 1.43; P = .0023), recipient age 40 and older versus age 18 to 39 years receiving bone marrow grafts (RR = 1.44; P = .0005), CML versus AML/ALL (RR = 1.35; P = .0003), white/Black versus Asian/Hispanic race (RR = 1.54; P = .0003), Karnofsky performance score less than 90 versus 90 to 100 (RR = 1.27; P = .014), and recipient/donor cytomegalovirus-seronegative versus either positive (RR = 1.20; P = .04). Stratification by disease showed the same significant predictors of grade 2 to 4 acute GVHD for CML; however, KPS and cytomegalovirus serostatus were not significant predictors for AML/ALL. CONCLUSION: This analysis confirmed several previously reported risk factors for grade 2 to 4 acute GVHD. However, several new factors were identified whereas others are no longer significant. These new data may facilitate individualized risk estimates and raise several interesting biologic questions

Value of soluble TREM-1, procalcitonin, and C-reactive protein serum levels as biomarkers for detecting bacteremia among sepsis patients with new fever in intensive care units: a prospective cohort study

<p>Abstract</p> <p>Background</p> <p>The purpose of this study was to explore the diagnostic value of soluble triggering receptor expressed on myeloid cells 1 (sTREM-1), procalcitonin (PCT), and C-reactive protein (CRP) serum levels for differentiating sepsis from SIRS, identifying new fever caused by bacteremia, and assessing prognosis when new fever occurred.</p> <p>Methods</p> <p>We enrolled 144 intensive care unit (ICU) patients: 60 with systemic inflammatory response syndrome (SIRS) and 84 with sepsis complicated by new fever at more than 48 h after ICU admission. Serum sTREM-1, PCT, and CRP levels were measured on the day of admission and at the occurrence of new fever (>38.3°C) during hospitalization. Based on the blood culture results, the patients were divided into a blood culture-positive bacteremia group (33 patients) and blood culture-negative group (51 patients). Based on 28-day survival, all patients, both blood culture-positive and -negative, were further divided into survivor and nonsurvivor groups.</p> <p>Results</p> <p>On ICU day 1, the sepsis group had higher serum sTREM-1, PCT, and CRP levels compared with the SIRS group (<it>P</it> <0.05). The areas under the curve (AUC) for these indicators were 0.868 (95% CI, 0.798–0.938), 0.729 (95% CI, 0.637–0.821), and 0.679 (95% CI, 0.578–0.771), respectively. With 108.9 pg/ml as the cut-off point for serum sTREM-1, sensitivity was 0.83 and specificity was 0.81. There was no statistically significant difference in serum sTREM-1 or PCT levels between the blood culture-positive and -negative bacteremia groups with ICU-acquired new fever. However, the nonsurvivors in the blood culture-positive bacteremia group had higher levels of serum sTREM-1 and PCT (<it>P</it> <0.05), with a prognostic AUC for serum sTREM-1 of 0.868 (95% CI, 0.740–0.997).</p> <p>Conclusions</p> <p>Serum sTREM-1, PCT, and CRP levels each have a role in the early diagnosis of sepsis. Serum sTREM-1, with the highest sensitivity and specificity of all indicators studied, is especially notable. sTREM-1, PCT, and CRP levels are of no use in determining new fever caused by bacteremia in ICU patients, but sTREM-1 levels reflect the prognosis of bacteremia.</p> <p>Trial registration</p> <p>ClinicalTrial.gov identifier NCT01410578</p