Flow Cytometric Analysis of Hematopoietic Populations in Rat Bone Marrow. Impact of Trauma and Hemorrhagic Shock

Severe injury and hemorrhagic shock (HS) result in multiple changes to hematopoietic differentiation, which contribute to the development of immunosuppression and multiple organ failure (MOF). Understanding the changes that take place during the acute injury phase may help predict which patients will develop MOF and provide potential targets for therapy. Obtaining bone marrow from humans during the acute injury phase is difficult so published data is largely derived from peripheral blood samples, which infer bone marrow changes that reflect the sustained inflammatory response. This preliminary and opportunistic study investigated leucopoietic changes in rat bone marrow 6 hours following traumatic injury and HS. Terminally anesthetized male Porton Wistar rats were allocated randomly to receive a sham operation (cannulation with no injury) or femoral fracture and HS. Bone marrow cells were flushed from rat femurs and immunophenotypically stained with specific antibody panels for lymphoid (CD45R, CD127, CD90, IgM) or myeloid (CD11b, CD45, RP-1) lineages. Subsequently, cell populations were fluorescence activated cell sorted for morphological assessment. Stage-specific cell populations were identified using a limited number of antibodies and leucopoietic changes were determined 6 hours following trauma and HS. Myeloid sub-populations could be identified by varying levels CD11b expression, CD45 and RP-1. Trauma and HS resulted in a significant reduction in total CD11b+ myeloid cells including both immature (RP-1(-)) and mature (RP-1+) granulocytes. Multiple B-cell lymphoid subsets were identified. The total % of CD90+ subsets remained unchanged following trauma and HS, but there was a reduction in the numbers of maturing CD90(-) cells suggesting movement into the periphery

A randomized multi-center phase II trial of the angiogenesis inhibitor Cilengitide (EMD 121974) and gemcitabine compared with gemcitabine alone in advanced unresectable pancreatic cancer

BACKGROUND: Anti-angiogenic treatment is believed to have at least cystostatic effects in highly vascularized tumours like pancreatic cancer. In this study, the treatment effects of the angiogenesis inhibitor Cilengitide and gemcitabine were compared with gemcitabine alone in patients with advanced unresectable pancreatic cancer. METHODS: A multi-national, open-label, controlled, randomized, parallel-group, phase II pilot study was conducted in 20 centers in 7 countries. Cilengitide was administered at 600 mg/m(2 )twice weekly for 4 weeks per cycle and gemcitabine at 1000 mg/m(2 )for 3 weeks followed by a week of rest per cycle. The planned treatment period was 6 four-week cycles. The primary endpoint of the study was overall survival and the secondary endpoints were progression-free survival (PFS), response rate, quality of life (QoL), effects on biological markers of disease (CA 19.9) and angiogenesis (vascular endothelial growth factor and basic fibroblast growth factor), and safety. An ancillary study investigated the pharmacokinetics of both drugs in a subset of patients. RESULTS: Eighty-nine patients were randomized. The median overall survival was 6.7 months for Cilengitide and gemcitabine and 7.7 months for gemcitabine alone. The median PFS times were 3.6 months and 3.8 months, respectively. The overall response rates were 17% and 14%, and the tumor growth control rates were 54% and 56%, respectively. Changes in the levels of CA 19.9 went in line with the clinical course of the disease, but no apparent relationships were seen with the biological markers of angiogenesis. QoL and safety evaluations were comparable between treatment groups. Pharmacokinetic studies showed no influence of gemcitabine on the pharmacokinetic parameters of Cilengitide and vice versa. CONCLUSION: There were no clinically important differences observed regarding efficacy, safety and QoL between the groups. The observations lay in the range of other clinical studies in this setting. The combination regimen was well tolerated with no adverse effects on the safety, tolerability and pharmacokinetics of either agent

A topological Dirac insulator in a quantum spin Hall phase : Experimental observation of first strong topological insulator

When electrons are subject to a large external magnetic field, the conventional charge quantum Hall effect \cite{Klitzing,Tsui} dictates that an electronic excitation gap is generated in the sample bulk, but metallic conduction is permitted at the boundary. Recent theoretical models suggest that certain bulk insulators with large spin-orbit interactions may also naturally support conducting topological boundary states in the extreme quantum limit, which opens up the possibility for studying unusual quantum Hall-like phenomena in zero external magnetic field. Bulk Bi$_{1-x}$Sb$_x$ single crystals are expected to be prime candidates for one such unusual Hall phase of matter known as the topological insulator. The hallmark of a topological insulator is the existence of metallic surface states that are higher dimensional analogues of the edge states that characterize a spin Hall insulator. In addition to its interesting boundary states, the bulk of Bi$_{1-x}$Sb$_x$ is predicted to exhibit three-dimensional Dirac particles, another topic of heightened current interest. Here, using incident-photon-energy-modulated (IPEM-ARPES), we report the first direct observation of massive Dirac particles in the bulk of Bi$_{0.9}$Sb$_{0.1}$, locate the Kramers' points at the sample's boundary and provide a comprehensive mapping of the topological Dirac insulator's gapless surface modes. These findings taken together suggest that the observed surface state on the boundary of the bulk insulator is a realization of the much sought exotic "topological metal". They also suggest that this material has potential application in developing next-generation quantum computing devices.Comment: 16 pages, 3 Figures. Submitted to NATURE on 25th November(2007

Geo-environmental mapping using physiographic analysis: constraints on the evaluation of land instability and groundwater pollution hazards in the Metropolitan District of Campinas, Brazil

Geo-environmental terrain assessments and territorial zoning are useful tools for the formulation and implementation of environmental management instruments (including policy-making, planning, and enforcement of statutory regulations). They usually involve a set of procedures and techniques for delimitation, characterisation and classification of terrain units. However, terrain assessments and zoning exercises are often costly and time-consuming, particularly when encompassing large areas, which in many cases prevent local agencies in developing countries from properly benefiting from such assessments. In the present paper, a low-cost technique based on the analysis of texture of satellite imagery was used for delimitation of terrain units. The delimited units were further analysed in two test areas situated in Southeast Brazil to provide estimates of land instability and the vulnerability of groundwater to pollution hazards. The implementation incorporated procedures for inferring the influences and potential implications of tectonic fractures and other discontinuities on ground behaviour and local groundwater flow. Terrain attributes such as degree of fracturing, bedrock lithology and weathered materials were explored as indicators of ground properties. The paper also discusses constraints on- and limitations of- the approaches taken

Constraints on chiral operators in N=2 SCFTs

Open Access, © The Authors. Article funded by SCOAP3. This article is distributed under the terms of the Creative Commons Attribution License ( CC-BY 4.0 ), which permits any use, distribution and reproduction in any medium, provided the original author(s) and source are credited

Ferritins: furnishing proteins with iron

Ferritins are a superfamily of iron oxidation, storage and mineralization proteins found throughout the animal, plant, and microbial kingdoms. The majority of ferritins consist of 24 subunits that individually fold into 4-α-helix bundles and assemble in a highly symmetric manner to form an approximately spherical protein coat around a central cavity into which an iron-containing mineral can be formed. Channels through the coat at inter-subunit contact points facilitate passage of iron ions to and from the central cavity, and intrasubunit catalytic sites, called ferroxidase centers, drive Fe2+ oxidation and O2 reduction. Though the different members of the superfamily share a common structure, there is often little amino acid sequence identity between them. Even where there is a high degree of sequence identity between two ferritins there can be major differences in how the proteins handle iron. In this review we describe some of the important structural features of ferritins and their mineralized iron cores and examine in detail how three selected ferritins oxidise Fe2+ in order to explore the mechanistic variations that exist amongst ferritins. We suggest that the mechanistic differences reflect differing evolutionary pressures on amino acid sequences, and that these differing pressures are a consequence of different primary functions for different ferritins

Human Mas-related G protein-coupled receptors-X1 induce chemokine receptor 2 expression in rat dorsal root ganglia neurons and release of chemokine ligand 2 from the human LAD-2 mast cell line

Primate-specific Mas-related G protein-coupled receptors-X1 (MRGPR-X1) are highly enriched in dorsal root ganglia (DRG) neurons and induce acute pain. Herein, we analyzed effects of MRGPR-X1 on serum response factors (SRF) or nuclear factors of activated T cells (NFAT), which control expression of various markers of chronic pain. Using HEK293, DRG neuron-derived F11 cells and cultured rat DRG neurons recombinantly expressing human MRGPR-X1, we found activation of a SRF reporter gene construct and induction of the early growth response protein-1 via extracellular signal-regulated kinases-1/2 known to play a significant role in the development of inflammatory pain. Furthermore, we observed MRGPR-X1-induced up-regulation of the chemokine receptor 2 (CCR2) via NFAT, which is considered as a key event in the onset of neuropathic pain and, so far, has not yet been described for any endogenous neuropeptide. Up-regulation of CCR2 is often associated with increased release of its endogenous agonist chemokine ligand 2 (CCL2). We also found MRGPR-X1-promoted release of CCL2 in a human connective tissue mast cell line endogenously expressing MRGPR-X1. Thus, we provide first evidence to suggest that MRGPR-X1 induce expression of chronic pain markers in DRG neurons and propose a so far unidentified signaling circuit that enhances chemokine signaling by acting on two distinct yet functionally co-operating cell types. Given the important role of chemokine signaling in pain chronification, we propose that interruption of this signaling circuit might be a promising new strategy to alleviate chemokine-promoted pain

Lower extremity compartment syndrome in the acute care surgery paradigm: safety lessons learned

This is an Open Access article distributed under the terms of the Creative Commons Attribution Licens