Deregulation of apoptosis mediators' p53 and bcl2 in lung tissue of COPD patients

Abnormal apoptotic events in chronic obstructive pulmonary disease (COPD) subvert cellular homeostasis and may play a primary role in its pathogenesis. However, studies in human subjects are limited

A Phase 3 Trial of Luspatercept in Patients with Transfusion-Dependent β-Thalassemia

BACKGROUND: Patients with transfusion-dependent β-thalassemia need regular red-cell transfusions. Luspatercept, a recombinant fusion protein that binds to select transforming growth factor β superfamily ligands, may enhance erythroid maturation and reduce the transfusion burden (the total number of red-cell units transfused) in such patients. METHODS: In this randomized, double-blind, phase 3 trial, we assigned, in a 2:1 ratio, adults with transfusion-dependent β-thalassemia to receive best supportive care plus luspatercept (at a dose of 1.00 to 1.25 mg per kilogram of body weight) or placebo for at least 48 weeks. The primary end point was the percentage of patients who had a reduction in the transfusion burden of at least 33% from baseline during weeks 13 through 24 plus a reduction of at least 2 red-cell units over this 12-week interval. Other efficacy end points included reductions in the transfusion burden during any 12-week interval and results of iron studies. RESULTS: A total of 224 patients were assigned to the luspatercept group and 112 to the placebo group. Luspatercept or placebo was administered for a median of approximately 64 weeks in both groups. The percentage of patients who had a reduction in the transfusion burden of at least 33% from baseline during weeks 13 through 24 plus a reduction of at least 2 red-cell units over this 12-week interval was significantly greater in the luspatercept group than in the placebo group (21.4% vs. 4.5%, P<0.001). During any 12-week interval, the percentage of patients who had a reduction in transfusion burden of at least 33% was greater in the luspatercept group than in the placebo group (70.5% vs. 29.5%), as was the percentage of those who had a reduction of at least 50% (40.2% vs. 6.3%). The least-squares mean difference between the groups in serum ferritin levels at week 48 was -348 μg per liter (95% confidence interval, -517 to -179) in favor of luspatercept. Adverse events of transient bone pain, arthralgia, dizziness, hypertension, and hyperuricemia were more common with luspatercept than placebo. CONCLUSIONS: The percentage of patients with transfusion-dependent β-thalassemia who had a reduction in transfusion burden was significantly greater in the luspatercept group than in the placebo group, and few adverse events led to the discontinuation of treatment. (Funded by Celgene and Acceleron Pharma; BELIEVE ClinicalTrials.gov number, NCT02604433; EudraCT number, 2015-003224-31.)

Basal fatty acid oxidation increases after recurrent low glucose in human primary astrocytes

YesAims/hypothesis Hypoglycaemia is a major barrier to good glucose control in type 1 diabetes. Frequent hypoglycaemic episodes impair awareness of subsequent hypoglycaemic bouts. Neural changes underpinning awareness of hypoglycaemia are poorly defined and molecular mechanisms by which glial cells contribute to hypoglycaemia sensing and glucose counterregulation require further investigation. The aim of the current study was to examine whether, and by what mechanism, human primary astrocyte (HPA) function was altered by acute and recurrent low glucose (RLG). Methods To test whether glia, specifically astrocytes, could detect changes in glucose, we utilised HPA and U373 astrocytoma cells and exposed them to RLG in vitro. This allowed measurement, with high specificity and sensitivity, of RLG-associated changes in cellular metabolism. We examined changes in protein phosphorylation/expression using western blotting. Metabolic function was assessed using a Seahorse extracellular flux analyser. Immunofluorescent imaging was used to examine cell morphology and enzymatic assays were used to measure lactate release, glycogen content, intracellular ATP and nucleotide ratios. Results AMP-activated protein kinase (AMPK) was activated over a pathophysiologically relevant glucose concentration range. RLG produced an increased dependency on fatty acid oxidation for basal mitochondrial metabolism and exhibited hallmarks of mitochondrial stress, including increased proton leak and reduced coupling efficiency. Relative to glucose availability, lactate release increased during low glucose but this was not modified by RLG. Basal glucose uptake was not modified by RLG and glycogen levels were similar in control and RLG-treated cells. Mitochondrial adaptations to RLG were partially recovered by maintaining euglycaemic levels of glucose following RLG exposure. Conclusions/interpretation Taken together, these data indicate that HPA mitochondria are altered following RLG, with a metabolic switch towards increased fatty acid oxidation, suggesting glial adaptations to RLG involve altered mitochondrial metabolism that could contribute to defective glucose counterregulation to hypoglycaemia in diabetes.Diabetes UK (RD Lawrence Fellowship to CB; 13/0004647); the Medical Research Council (MR/N012763/1) to KLJE, ADR and CB; and a Mary Kinross Charitable Trust PhD studentship to CB, ADR and RW to support PGWP. Additional support for this work came from awards from the British Society for Neuroendocrinology (to CB and KLJE), the Society for Endocrinology (CB), Tenovus Scotland (CB) and the University of Exeter Medical School (CB and KLJE). AR was also supported by a Royal Society Industry Fellowship

Mitochondrial physiology

As the knowledge base and importance of mitochondrial physiology to evolution, health and disease expands, the necessity for harmonizing the terminology concerning mitochondrial respiratory states and rates has become increasingly apparent. The chemiosmotic theory establishes the mechanism of energy transformation and coupling in oxidative phosphorylation. The unifying concept of the protonmotive force provides the framework for developing a consistent theoretical foundation of mitochondrial physiology and bioenergetics. We follow the latest SI guidelines and those of the International Union of Pure and Applied Chemistry (IUPAC) on terminology in physical chemistry, extended by considerations of open systems and thermodynamics of irreversible processes. The concept-driven constructive terminology incorporates the meaning of each quantity and aligns concepts and symbols with the nomenclature of classical bioenergetics. We endeavour to provide a balanced view of mitochondrial respiratory control and a critical discussion on reporting data of mitochondrial respiration in terms of metabolic flows and fluxes. Uniform standards for evaluation of respiratory states and rates will ultimately contribute to reproducibility between laboratories and thus support the development of data repositories of mitochondrial respiratory function in species, tissues, and cells. Clarity of concept and consistency of nomenclature facilitate effective transdisciplinary communication, education, and ultimately further discovery

3D RECORDING OF UNDERWATER ANTIQUITIES IN THE SOUTH EUBOEAN GULF

An underwater archaeological survey was initiated in 2006 by the Hellenic Institute of Marine Archaeology in collaboration with the Ephorate of Underwater Antiquities of Greece, in the South Euboean Gulf. The survey is being conducted under the direction of the archaeologist Dr G. Koutsouflakis and in the course of the project important shipwrecks of Classical, Roman, and Byzantine periods have been brought to light, adding tangible evidence on ancient seafaring and maritime trade. The South Euboean Gulf archaeological survey has presented many challenges to the documentation team of H.I.M.A, and has served as a case-study for 3D recording applied on ancient wrecks, found at medium depths (22-47m) and under the conditions that are imposed during an archaeological survey of a certain geographical region. This paper focuses on the implementation of photogrammetric and geodetic techniques used for acquisition and processing of collected data, in order to generate 3D models for six different wrecks, resulting in a fast, reliable and cost efficient method to record underwater archaeological sites

SURVEYING THE UNDERWATER ARCAHEOLOGICAL SITE OF CAPE GLAROS AT PAGASETIKOS GULF

The Hellenic Institute of Marine Archaeology (H.I.M.A.)1 has been conducting an underwater archaeological research in the west coast of southern Pagasetikos Gulf, since 2000. Every year the underwater research focuses on specific archaeological targets that have been recovered during previous field campaigns. The current publication elaborates on the comprehensive documentation of the underwater archaeological site at Cape Glaros, during the 2015 field season, under the direction of the archaeologist Elias Spondylis. The 2015 research campaign was conducted within the framework of the ITACA- Innovation Technologies and Applications for Coastal Archaeological sites European Project (FP7/2007-2013, GA No 606805), at two archaeological sites, namely the Cape Glaros and Metohi. It was among the most important challenges of the project to successfully produce the detailed and accurate 3D mapping of the Cape Glaros site that covers an extended area. Four large concentrations of pottery finds and numerous anchors of different typology have been recorded, that can be dated from the late Hellenistic to the Byzantine periods. This challenge was tackled through the simultaneous implementation of three recording methods; photogrammetry, geodesy and conventional architectural mapping. The workflow of the documentation process, including data acquisition, processing and graphic visualization, along with the derived results are presented below. 1The Hellenic Institute of Marine Archaeology (H.I.M.A.) is a private, non-profit organization, founded in 1973, which undertakes maritime archaeological research under the supervision or in collaboration with the Greek Ministry of Culture. It has over 100 members, with diverse academic credentials, all of whom work, mainly, on a voluntary basis. 3D recording of underwater archaeological sites has been applied to numerous projects that have been carried out by the multidisciplinary team of H.I.M.A. in locations of utmost archaeological importance and interest, such as Modi island (Poros) and numerous wreck sites in Pagasetikos and South Euboean (Diamanti, Vlachaki, 2015) Gulfs and others

Pure red cell aplasia in a Sjogren&apos;s syndrome/lupus erythematosus overlap patient

Hematological complications of systemic lupus erythematosus usually include anemia of chronic disease and peripheral destruction of blood cells. We describe the case of a Sjogren’s syndrome/lupus erythematosus overlap, mother of infant young woman with congenital heart block, complicated by pure red cell aplasia. The patient was asymptomatic until the onset of severe anemia. A serum inhibitor of erythropoiesis was detected before the onset of immunosuppression. Bone marrow examination showed a low CD4:CD8 ratio, an immune defect possibly linked with the unrestrained production of antibodies against erythroid progenitor cells. (C) 2003 Wiley-Liss, Inc