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101.
102.
Fibroblast growth factor 2 decreases bleomycin‐induced pulmonary fibrosis and inhibits fibroblast collagen production and myofibroblast differentiation 下载免费PDF全文
Hyun Young Koo Lamis MF El‐Baz StaceyL House Sarah N Cilvik Samuel J Dorry Nahla M Shoukry Mohamed L Salem Hani S Hafez Nickolai O Dulin David M Ornitz Robert D Guzy 《The Journal of pathology》2018,246(1):54-66
Fibroblast growth factor (FGF) signaling has been implicated in the pathogenesis of pulmonary fibrosis. Mice lacking FGF2 have increased mortality and impaired epithelial recovery after bleomycin exposure, supporting a protective or reparative function following lung injury. To determine whether FGF2 overexpression reduces bleomycin‐induced injury, we developed an inducible genetic system to express FGF2 in type II pneumocytes. Double‐transgenic (DTG) mice with doxycycline‐inducible overexpression of human FGF2 (SPC‐rtTA;TRE‐hFGF2) or single‐transgenic controls were administered intratracheal bleomycin and fed doxycycline chow, starting at either day 0 or day 7. In addition, wild‐type mice received intratracheal or intravenous recombinant FGF2, starting at the time of bleomycin treatment. Compared to controls, doxycycline‐induced DTG mice had decreased pulmonary fibrosis 21 days after bleomycin, as assessed by gene expression and histology. This beneficial effect was seen when FGF2 overexpression was induced at day 0 or day 7 after bleomycin. FGF2 overexpression did not alter epithelial gene expression, bronchoalveolar lavage cellularity or total protein. In vitro studies using primary mouse and human lung fibroblasts showed that FGF2 strongly inhibited baseline and TGFβ1‐induced expression of alpha smooth muscle actin (αSMA), collagen, and connective tissue growth factor. While FGF2 did not suppress phosphorylation of Smad2 or Smad‐dependent gene expression, FGF2 inhibited TGFβ1‐induced stress fiber formation and serum response factor‐dependent gene expression. FGF2 inhibition of stress fiber formation and αSMA requires FGF receptor 1 (FGFR1) and downstream MEK/ERK, but not AKT signaling. In summary, overexpression of FGF2 protects against bleomycin‐induced pulmonary fibrosis in vivo and reverses TGFβ1‐induced collagen and αSMA expression and stress fiber formation in lung fibroblasts in vitro, without affecting either inflammation or epithelial gene expression. Our results suggest that in the lung, FGF2 is antifibrotic in part through decreased collagen expression and fibroblast to myofibroblast differentiation. Copyright © 2018 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd. 相似文献
103.
Aim
The purpose of this study was to report surgical management and outcome of corrosive-induced gastric injuries in children at our institute over the last decade.Patients & method
Medical records of patients admitted for corrosive-induced gastric injury at the Pediatric Surgery Department of Ain Shams University between January 2007 and January 2017 were retrospectively reviewed.Results
Twenty six cases (17 boys and 9 girls) were enrolled. Mean age was 3.61 ± 1.29. Ingested agent was acid in all the patients. Main presenting symptom was gastric output obstruction in 22 cases. The interval between corrosive ingestion and presentation ranged from one to 135 days (mean = 43.9 ± 34). Surgical procedure included total gastrectomy (n = 2), partial gastrectomy (n = 2), augmentation gastroplasty (n = 1), Billroth I (n = 2), antrectomy (n = 2), antroplasty (n = 3), gastrojejunostomy (n = 2), Heineke–Mikulicz pyloroplasty (n = 9), Finney pyloroplasty (n = 5), and feeding jejunostomy (n = 4). Anastomotic stricture requiring a second operation developed in one patient. There were three mortalities related to the associated esophageal strictures. The mean follow-up period is 3.5 years. All patients are free of symptoms and gained adequate weight.Conclusion
Surgery is the mainstay of management for corrosive-induced gastric injuries with good long-term results. Surgical procedure should be tailored according to the patient's general condition and extent of gastric injury.Level of evidence
This is a case series with no comparison group (level IV). 相似文献104.
105.
Barranco Quintana JL Allam MF Serrano Del Castillo A Fernández-Crehuet Navajas R 《Neurological research》2007,29(1):91-95
PURPOSE: To estimate the pooled risk of coffee consumption for Alzheimer's disease (AD). MATERIAL AND METHODS: We have reviewed all observational studies that evaluated the association between AD risk and coffee consumption. Four studies were identified: two case-control studies and two cohorts. These studies were carried out between 1990 and 2002. RESULTS: There was an obvious protective effect of coffee consumption in the pooled estimate [risk estimate: 0.73 (95% confidence interval: 0.58-0.92)]. However, the homogeneity test was highly significant (p<0.01), indicating heterogeneity across the pooled studies. Pooled analysis applying the random effect model was 0.79 with 95% confidence interval overlapping unity (95% confidence interval: 0.46-1.36). Three studies assessed coffee consumption by interview questionnaire. The risk of AD in coffee consumers versus non-consumers in studies that used interview questionnaire had a pooled risk estimate of 0.70 with 95% confidence interval 0.55-0.90. CONCLUSION: Although our pooled estimates show that coffee consumption is inversely associated with the risk of AD, the four studies had heterogeneous methodologies and results. Further prospective studies evaluating the association between coffee consumption and AD are strongly needed. 相似文献
106.
Efficacy of adaptive servoventilation in treatment of complex and central sleep apnea syndromes 总被引:2,自引:0,他引:2
BACKGROUND: Complex sleep apnea syndrome (CompSAS) is recognized by the concurrence of mixed or obstructive events with central apneas, the latter predominating on exposure to continuous positive airway pressure (CPAP). Treatment of CompSAS or central sleep apnea (CSA) syndrome with adaptive servoventilation (ASV) is now an option, but no large series exist describing the application and effectiveness of ASV. METHODS: Retrospective chart review of the first 100 patients who underwent polysomnography using ASV at Mayo Clinic Sleep Center. RESULTS: ASV titration was performed for CompSAS (63%), CSA (22%), or CSA/Cheyne Stokes breathing patterns (15%). The median diagnostic sleep apnea hypopnea index (AHI) was 48 events per hour (range, 24 to 62). With CPAP, obstructive apneas decreased, but the appearance of central apneas maintained the AHI at 31 events per hour (range, 17 to 47) [p = 0.02]. With bilevel positive airway pressure (BPAP) in spontaneous mode, AHI trended toward worsening vs baseline, with a median of 75 events per hour (range, 46 to 111) [p = 0.055]. BPAP with a backup rate improved the AHI to 15 events per hour (range, 11 to 31) [p = 0.002]. Use of ASV dramatically improved the AHI to a mean of 5 events per hour (range, 1 to 11) vs baseline and vs CPAP (p < 0.0001). ASV also resulted in an increase in rapid eye movement sleep vs baseline and CPAP (18% vs 12% and 10%, respectively; p < 0.0001). Overall, 64 patients responded to the ASV treatment with a mean AHI < 10 events per hour. Of the 44 successful survey follow-up patients contacted, 32 patients reported some improvement in sleep quality. CONCLUSION: The ASV device appears to be an effective treatment of both CompSAS and CSA syndromes that are resistant to CPAP. 相似文献
107.
Katharina Flür Ramanjaneyulu Allam Daniel Zecher Onkar P. Kulkarni Julia Lichtnekert Martin Schwarz Bruce Beutler Volker Vielhauer Hans-Joachim Anders 《The American journal of pathology》2009,175(5):2014-2022
Viral RNA can trigger interferon signaling in dendritic cells via the innate recognition receptors melanoma-differentiation-associated gene (MDA)-5 and retinod-inducible gene (RIG)-I in the cytosol or via Toll-like receptors (TLRs) in intracellular endosomes. We hypothesized that viral RNA would also activate glomerular mesangial cells to produce type I interferon (IFN) via TLR-dependent and TLR-independent pathways. To test this hypothesis, we examined Toll/Interleukin-1 receptor domain-containing adaptor-inducing interferon-β (TRIF)-deficient mice, which lack a key adaptor for TLR3 signaling. In primary mesangial cells, poly I:C RNA-mediated IFN-β induction was partially TRIF dependent; however, when poly I:C RNA was complexed with cationic lipids to enhance cytosolic uptake, mesangial cells produced large amounts of IFN-α and IFN-β independent of TRIF. Mesangial cells expressed RIG-I and MDA-5 and their mitochondrial adaptor IFN-β promoter stimulator-1 as well, and small interfering RNA studies revealed that MDA5 but not RIG-I was required for cytosolic poly I:C RNA signaling. In addition, mesangial cells produced Il-6 on stimulation with IFN-α and IFN-β, suggesting an autocrine proinflammatory effect. Indeed, blockade of IFN-αβ or lack of the IFNA receptor reduced viral RNA-induced Il-6 production and apoptotic cell death in mesangial cells. Furthermore, viral RNA/cationic lipid complexes increased focal necrosis in murine nephrotoxic serum nephritis in association with increased renal mRNA expression of IFN-related genes. Thus, TLR-independent recognition of viral RNA is a potent inducer of type I interferon in mesangial cells, which can be an important mediator of virally induced glomerulonephritis.Chronic viral infections can trigger de novo immune complex glomerulonephritis, eg, hepatitis C virus-associated glomerulonephritis, but more frequently, acute viral infections trigger disease activity of pre-existing glomerulonephritis, like in IgA nephropathy, lupus nephritis, or renal vasculitis.1 Viral infections activate systemic antiviral immunity, which may contribute to disease flares of glomerulonephritis by enhancing autoantibody production, immune complex formation, or by systemic interferon (IFN) release.2 In fact, rapid production of type I IFN is a central element of antiviral immunity because type I IFNs inhibit viral replication in the infected cells and have pleiotrophic immunomodulatory effects on macrophages, T cells, and natural killer cells.2,3The main source of type I IFNs is plasmacytoid dendritic cells (pDCs) in the intravascular compartment.4 Several viral components can induce type I IFNs in pDCs. For example, viral proteins activate Toll-like receptor (TLR) 2 and 4 signaling at the cell surface.5 By contrast, different shapes of viral nucleic acids can activate TLRs in intracellular endosomes, ie, TLR3 (double-stranded (dsRNA)), TLR7/8 (single-stranded (ssRNA)), and TLR9 (CpG-DNA).5 Furthermore, viral RNA can also be detected in the intracellular cytosol, eg, via melanoma-differentiation-associated gene (MDA)-5 (dsRNA) and retinoic-acid-inducible protein (RIG) (dsRNA and 5′-triphosphate RNA).5,6,7,8 Ligation of any of these innate RNA recognition receptors rapidly triggers the production of type I IFN in pDCs.It is thought that most cells can produce type I IFNs when they are infected with a DNA or RNA virus. For example, TLR3-mediated recognition of viral dsRNA in pancreatic islet cells can trigger autoimmune pancreatic islet destruction via local production of IFN-α.9 But whether locally produced type I IFNs contribute to viral infection-induced glomerulonephritis is not known.10 In fact, to our best knowledge, IFN release by glomerular cells, including mesangial cells, has not been reported. The only nucleic acid-specific TLR expressed by mesangial cells is TLR3, and mesangial cells produce Il-6 and CCL2 on exposure to viral dsRNA.11 However, whether this effect is mediated via endosomal TLR3 or by cytosolic dsRNA receptors is not known. We hypothesized that viral RNA will trigger an innate antiviral response program in glomerular mesangial cells, including the release of type I IFN, and that this effect is mediated by TLR-dependent as well as TLR-independent RNA recognition. 相似文献
108.
109.
S Van der Borght V Janssens MF Schim van der Loeff A Kajemba H Rijckborst JMA Lange TF Rinke de Wit 《Bulletin of the World Health Organization》2009,87(10):794-798
Problem
A multinational company with operations in several African countries was committed to offer antiretroviral treatment to its employees and their dependants.Approach
The Accelerating Access Initiative (AAI), an initiative of six pharmaceutical companies and five United Nations’ agencies, offered the possibility of obtaining brand antiretroviral drugs (ARVs) at 10% of the commercial price. PharmAccess, a foundation aimed at removing barriers to AIDS treatment in Africa, helped to establish an HIV policy and treatment guidelines, and a workplace programme was rolled out from September 2001.Local setting
Private sector employers in Africa are keen to take more responsibility in HIV prevention and AIDS care. An important hurdle for African employers remains the price and availability of ARVs.Relevant changes
The programme encountered various hurdles, among them the need for multiple contracts with multiple companies, complex importation procedures, taxes levied on ARVs, lack of support from pharmaceutical companies in importation and transportation, slow delivery of the drugs, lack of institutional memory in pharmaceutical companies and government policies excluding the company from access to ARVs under the AAI.Lessons learned
The launch of the AAI enabled this multinational company to offer access to ARVs to its employees and dependants. The private sector should have access to these discounted drugs under the AAI. A network of local AAI offices should be created to assist in logistics of drugs ordering, purchase and clearance. No taxes should be levied on ARVs. 相似文献110.
Judith L Ngondi Blanche C Etoundi Christine B Nyangono Carl MF Mbofung Julius E Oben 《Lipids in health and disease》2009,8(1):7