Freedom of Information

OBJECTIVE: It has previously been shown that a combination of inhaled nitric oxide (iNO) and intravenous (IV) steroid attenuates endotoxin-induced organ damage in a 6-hour porcine endotoxemia model. We aimed to further explore these effects in a 30-hour model with attention to clinically important variables. DESIGN: Randomized controlled trial. SETTING: University animal laboratory. SUBJECTS: Domestic piglets (n = 30). INTERVENTIONS: Animals were randomized into 5 groups (n = 6 each): 1) Controls, 2) LPS-only (endotoxin/lipopolysaccharide (LPS) infusion), 3) LPS + iNO, 4) LPS + IV steroid, 5) LPS + iNO + IV steroid. MEASUREMENTS AND MAIN RESULTS: Exposure to LPS temporarily increased pulmonary artery mean pressure and impeded renal function with elevated serum creatinine and acidosis compared to a control group over the 30-hour study period. Double treatment with both iNO and IV steroid tended to blunt the deterioration in renal function, although the only significant effect was on Base Excess (p = 0.045). None of the LPS + iNO + IV steroid treated animals died during the study period, whereas one animal died in each of the other LPS-infused groups. CONCLUSIONS: This study suggests that combined early therapy with iNO and IV steroid is associated with partial protection of kidney function after 30 hours of experimental LPS infusion

Calcitonin gene-related peptide stimulates proliferation of alveolar epithelial cells

<p>Abstract</p> <p>Background</p> <p>Alveolar epithelial cells are known as progenitor cells for the restoration from the damage in the lung. Calcitonin gene-related peptide (CGRP) has been reported to play an important role in the proliferation of various types of epithelial and endothelial cells. We investigated the effects of CGRP on the proliferation of alveolar epithelial cells <it>in vitro </it>and <it>in vivo</it>.</p> <p>Methods</p> <p>A549 cells were cultured in Dulbecco Modified Eagle Medium with 5% fatal bovin serum for 24 hours, then CGRP was added <it>in vitro</it>. The proliferation of DNA synthesis was measured using 5-bromo-2-deoxyuridine, an analog of thymidine, by enzyme-linked immunosorbent assay.</p> <p>As one intracellular response to CGRP, we examined activation of p44/42- extracellular signal-regulated kinase (ERK) pathway by adding CGRP, using western blotting method.</p> <p>Recombinant adenovirus encoding nuclear-targeted-human β-CGRP (rhCGRP) was administered into Male Wister rat (n = 5, 10 weeks old) lungs by intratracheal instillation <it>in vivo</it>. 7 days after the administration of CGRP, rat lungs were harvested and histological findings and immunohistochemical staining of proliferating cell nuclear antigen (PCNA) were evaluated to examine cell proliferation.</p> <p>Results</p> <p><it>In vitro </it>study, CGRP increased the proliferation of A549 cells in a dose and time dependent manner. CGRP8-37 (inhibitor of CGRP receptor) decreased CGRP induced proliferation of DNA synthesis. Phosphorylation of ERK pathway was observed within 15 minutes and peaked in one hour. U0126 (inhibitor of ERK pathway) decreased CGRP induced proliferation of DNA synthesis.<it>In vivo </it>study, histological examination of the lung indicated proliferation of alveolar epithelial cells in the rhCGRP-treated group and the nuclei of alveolar epithelial cells were positive for PCNA immunostaining.</p> <p>Conclusion</p> <p>In this study, we conclude that CGRP stimulates proliferation of human alveolar epithelial cells <it>in vivo </it>and <it>in vitro</it>.</p

Role of Calcitonin Gene-Related Peptide in Bone Repair after Cyclic Fatigue Loading

Calcitonin gene related peptide (CGRP) is a neuropeptide that is abundant in the sensory neurons which innervate bone. The effects of CGRP on isolated bone cells have been widely studied, and CGRP is currently considered to be an osteoanabolic peptide that has effects on both osteoclasts and osteoblasts. However, relatively little is known about the physiological role of CGRP in-vivo in the skeletal responses to bone loading, particularly fatigue loading.We used the rat ulna end-loading model to induce fatigue damage in the ulna unilaterally during cyclic loading. We postulated that CGRP would influence skeletal responses to cyclic fatigue loading. Rats were fatigue loaded and groups of rats were infused systemically with 0.9% saline, CGRP, or the receptor antagonist, CGRP(8-37), for a 10 day study period. Ten days after fatigue loading, bone and serum CGRP concentrations, serum tartrate-resistant acid phosphatase 5b (TRAP5b) concentrations, and fatigue-induced skeletal responses were quantified. We found that cyclic fatigue loading led to increased CGRP concentrations in both loaded and contralateral ulnae. Administration of CGRP(8-37) was associated with increased targeted remodeling in the fatigue-loaded ulna. Administration of CGRP or CGRP(8-37) both increased reparative bone formation over the study period. Plasma concentration of TRAP5b was not significantly influenced by either CGRP or CGRP(8-37) administration.CGRP signaling modulates targeted remodeling of microdamage and reparative new bone formation after bone fatigue, and may be part of a neuronal signaling pathway which has regulatory effects on load-induced repair responses within the skeleton

The Adult Human Brain Harbors Multipotent Perivascular Mesenchymal Stem Cells

Blood vessels and adjacent cells form perivascular stem cell niches in adult tissues. In this perivascular niche, a stem cell with mesenchymal characteristics was recently identified in some adult somatic tissues. These cells are pericytes that line the microvasculature, express mesenchymal markers and differentiate into mesodermal lineages but might even have the capacity to generate tissue-specific cell types. Here, we isolated, purified and characterized a previously unrecognized progenitor population from two different regions in the adult human brain, the ventricular wall and the neocortex. We show that these cells co-express markers for mesenchymal stem cells and pericytes in vivo and in vitro, but do not express glial, neuronal progenitor, hematopoietic, endothelial or microglial markers in their native state. Furthermore, we demonstrate at a clonal level that these progenitors have true multilineage potential towards both, the mesodermal and neuroectodermal phenotype. They can be epigenetically induced in vitro into adipocytes, chondroblasts and osteoblasts but also into glial cells and immature neurons. This progenitor population exhibits long-term proliferation, karyotype stability and retention of phenotype and multipotency following extensive propagation. Thus, we provide evidence that the vascular niche in the adult human brain harbors a novel progenitor with multilineage capacity that appears to represent mesenchymal stem cells and is different from any previously described human neural stem cell. Future studies will elucidate whether these cells may play a role for disease or may represent a reservoir that can be exploited in efforts to repair the diseased human brain

Disease-specific U1 spliceosomal RNA mutations in mature B-cell neoplasms

Recurrent mutations in the third base of U1 spliceosomal RNA responsible for marked splicing and expression abnormalities have been described in chronic lymphocytic leukemia (CLL) and some solid tumors. However, the clinical significance of these mutations in large and independent CLL cohorts as well as their presence in other B-cell neoplasms is unknown. Here we characterized U1 mutations in 1670 CLL and 363 mature B-cell lymphomas. We confirmed that the g.3A&gt;C U1 mutation is found in 3.5% of CLL, which conferred rapid disease progression independently of the main biological and clinical prognostic markers of the disease. Additionally, a recurrent g.9C&gt;T mutation was found in 1.5% of CLL causing downstream splicing alterations and associated with adverse prognosis. We also identified a g.4C&gt;T mutation in 10% of diffuse large B-cell lymphomas of the germinal center subtype and a g.7A&gt;G mutation in 30% of EBV-negative Burkitt lymphomas, both of which altered the splicing pattern of multiple genes. This study reveals novel, recurrent, and tumor-specific U1 mutations in mature B-cell neoplasms with biological and prognostic implications, thus establishing U1 as a novel pan-B-cell malignancy driver gene

Somatostatin Inhibits Cell Migration and Reduces Cell Counts of Human Keratinocytes and Delays Epidermal Wound Healing in an Ex Vivo Wound Model

The peptide hormone somatostatin (SST) and its five G protein-coupled receptors (SSTR1-5) were described to be present in the skin, but their cutaneous function(s) and skin-specific signalling mechanisms are widely unknown. By using receptor specific agonists we show here that the SSTRs expressed in keratinocytes are functionally coupled to the inhibition of adenylate cyclase. In addition, treatment with SSTR4 and SSTR5/1 specific agonists significantly influences the MAP kinase signalling pathway. As epidermal hormone receptors in general are known to regulate re-epithelialization following skin injury, we investigated the effect of SST on cell counts and migration of human keratinocytes. Our results demonstrate a significant inhibition of cell migration and reduction of cell counts by SST. We do not observe an effect on apoptosis and necrosis. Analysis of signalling pathways showed that somatostatin inhibits cell migration independent of its effect on cAMP. Migrating keratinocytes treated with SST show altered cytoskeleton dynamics with delayed lamellipodia formation. Furthermore, the activity of the small GTPase Rac1 is diminished, providing evidence for the control of the actin cytoskeleton by somatostatin receptors in keratinocytes. While activation of all receptors leads to redundant effects on cell migration, only treatment with a SSTR5/1 specific agonist resulted in decreased cell counts. In accordance with reduced cell counts and impaired migration we observe delayed re-epithelialization in an ex vivo wound healing model. Consequently, our experiments suggest SST as a negative regulator of epidermal wound healing

Platelet Rich Plasma: Quantification of growth factor levels and the effect on growth and differentiation of rat bone marrow cells.

Contains fulltext : 49701.pdf (publisher's version ) (Open Access

New Therapeutic Strategies in Retinal Vascular Diseases: A Lipid Target, Phosphatidylserine, and Annexin A5&mdash;A Future Theranostic Pairing in Ophthalmology

Despite progress in the management of patients with retinal vascular and degenerative diseases, there is still an unmet clinical need for safe and effective therapeutic options with novel mechanisms of action. Recent mechanistic insights into the pathogenesis of retinal diseases with a prominent vascular component, such as retinal vein occlusion (RVO), diabetic retinopathy (DR) and wet age-related macular degeneration (AMD), may open up new treatment paradigms that reach beyond the inhibition of vascular endothelial growth factor (VEGF). Phosphatidylserine (PS) is a novel lipid target that is linked to the pathophysiology of several human diseases, including retinal diseases. PS acts upstream of VEGF and complement signaling pathways. Annexin A5 is a protein that targets PS and inhibits PS signaling. This review explores the current understanding of the potential roles of PS as a target and Annexin A5 as a therapeutic. The clinical development status of Annexin A5 as a therapeutic and the potential utility of PS-Annexin A5 as a theranostic pairing in retinal vascular conditions in particular is described

Den attraktiva arbetsplatsen : Möter platskontoren de anställdas behov?

Previous research have shown a possible relationship between the indoor work environmentand the impact it has on the employees’ performance. Different factors can affect theperformance; physical parameters, such as ventilation and air quality, noise levels, thermalclimate, lighting and access to daylight, as well as the level of flexibility of the work, furnitureetc. Therefore, this study aims to investigate the quality of the indoor work environment at siteoffices within Company AB in Sweden. Further, how the physical and the psychologicalenvironment play an important role regarding the attractiveness of the workspace. The studywill only focus on four physical parameters affecting the physical functionality of an office; airquality, noise, temperature and lighting. The following research questions were asked: 1) Whatdifferent types of site offices can be identified in Sweden and what are the commonly usedoffice layouts? 2) How well does the actual indoor work environment at site offices align withthe restrictions by the Swedish Work Environment Authority? 3) How is the indoorenvironment of the site offices perceived by the people utilizing the workspace? 4) Which arethe most important parts to look at to improve the attractiveness of the site offices at CompanyAB? The study is both qualitative and quantitative including measurements, interviews,meetings, and a questionnaire as the main sources of information used to answer the researchquestions.According to the results, the two most commonly used site offices are construction trailers andrented premises. The visited offices had varied layouts since they are designed to fit the needsof the specific project organizations. Out of the four parameters, noise was the only one thatentirely fulfilled the requirements in the six site offices visited.The employees perceived the physical parameters in the site offices differently. The air qualitywas generally perceived to be sufficient in the office spaces but quite bad in the meeting rooms.Multiple employees thought noise was one of the most problematic parameters and it wasshown to possibly depend on work role or task. Employees expressed the need of a versatileoffice layout, with both open office areas and smaller secluded rooms combined, which couldincrease their concentration level and decrease disturbance. Another problematic parameterwas the temperature and generally, the need was to stabilize it throughout the year. Regardingthe lighting, many expressed the desire to be able to adjust it on their own.People perceive things differently which is why a more varied and flexible office might fulfillmore people’s needs. If these needs are fulfilled, it could improve not only the physical workenvironment but also the psychological work environment and therefore increase theattractiveness and job satisfaction of the employees.Tidigare forskning har visat en möjlig koppling mellan inomhusklimat och dess påverkan påden anställdas prestation. Olika faktorer kan påverka prestationen; fysiska parametrar; såsomventilation och luftkvalitet, ljudnivå, termiskt klimat, ljus och tillgång till dagsljus samt nivånav flexibilitet på jobbet, möbler och andra faktorer. Därför syftar denna studie till att undersökakvalitén av arbetsmiljön inomhus på platskontor hos Company AB i Sverige. Vidare, hur denfysiska och psykiska miljön spelar en stor roll gällande hur attraktiv en arbetsplats är. Dennastudie kommer bara fokusera på fyra fysiska parametrar som påverkar den fysiskafunktionaliteten av ett kontor; luftkvalitet, ljud, temperatur och ljus. Följande forskningsfrågorhar ställts: 1) Vilka olika typer av platskontor kan identifieras i Sverige och vilka olikautformningar används vanligast? 2) Hur väl uppfyller den faktiska inomhusmiljön påplatskontoren kraven från Arbetsmiljöverket? 3) Hur upplevs inomhusmiljön på platskontorenav människorna som jobbar i dem? 4) Vilka är de viktigaste aspekterna för att ökaattraktiviteten av platskontoren på Company AB? Studien är både kvalitativ och kvantitativoch inkluderar både mätningar, intervjuer, möten och en enkät som de främstainformationskällorna för att svara på forskningsfrågorna.Resultaten visar på att de vanligaste platskontoren är byggbodar och inhyrda lokaler. Debesökta kontoren hade olika uppbyggnad eftersom de var utformade för att passa de specifikaprojektorganisationerna. Utav de fyra parametrarna var ljudet det enda som uppfyllde kraven ide sex besökta platskontoren.De anställda upplevde de fysiska parametrarna på olika sätt. Luftkvaliteten upplevdes generelltsom tillräcklig bland kontorsplatserna men ganska dålig i mötesrummen. Flera anställda tyckteatt ljudet var en av de mest problematiska parametrarna och det visade sig möjligtvis bero påarbetsroll eller uppgift. De anställda uttryckte ett behov av en varierad utformning av kontorenmed en kombination av både öppna kontorslandskap och mindre avskilda rum vilket skullekunna öka koncentrationsförmågan och minska störande ljud. En annan problematiskparameter var temperaturen och generellt var behovet att få en mer stabil temperatur över året.Vad gäller ljussättningen så uttryckte många att de ville kunna reglera den själva.Människor upplever saker olika vilket gör att ett mer varierat och flexibelt kontor kan uppfyllafler människors behov. Om dessa behov uppfylls kan detta förbättra inte bara den fysiskaarbetsmiljön utan också den psykiska arbetsmiljön och kan därigenom öka attraktiviteten samtarbetsnöjdheten hos de anställda