bluuebunny/crossref_metadata_2025_split huggingface dataset:
S-Nitrosoglutathione reduces oxidative injury and promotes mechanisms of neurorepair following traumatic brain injury in rats
Authors: Khan Mushfiquddin , Sakakima Harutoshi , Dhammu Tajinder S , Shunmugavel Anandakumar , Im Yeong-Bin , Gilg Anne G , Singh Avtar K , Singh Inderjit 
Published: July 2011

Abstract

Background
Traumatic brain injury (TBI) induces primary and secondary damage in both the endothelium and the brain parenchyma, collectively termed the neurovascular unit. While neurons die quickly by necrosis, a vicious cycle of secondary injury in endothelial cells exacerbates the initial injury in the neurovascular unit following TBI. In activated endothelial cells, excessive superoxide reacts with nitric oxide (NO) to form peroxynitrite. Peroxynitrite has been implicated in blood brain barrier (BBB) leakage, altered metabolic function, and neurobehavioral impairment. S-nitrosoglutathione (GSNO), a nitrosylation-based signaling molecule, was reported not only to reduce brain levels of peroxynitrite and oxidative metabolites but also to improve neurological function in TBI, stroke, and spinal cord injury. Therefore, we investigated whether GSNO promotes the neurorepair process by reducing the levels of peroxynitrite and the degree of oxidative injury.

Methods
TBI was induced by controlled cortical impact (CCI) in adult male rats. GSNO or 3-Morpholino-sydnonimine (SIN-1) (50 μg/kg body weight) was administered orally two hours following CCI. The same dose was repeated daily until endpoints. GSNO-treated (GSNO group) or SIN-1-treated (SIN-1 group) injured animals were compared with vehicle-treated injured animals (TBI group) and vehicle-treated sham-operated animals (Sham group) in terms of peroxynitrite, NO, glutathione (GSH), lipid peroxidation, blood brain barrier (BBB) leakage, edema, inflammation, tissue structure, axon/myelin integrity, and neurotrophic factors.

Results
SIN-1 treatment of TBI increased whereas GSNO treatment decreased peroxynitrite, lipid peroxides/aldehydes, BBB leakage, inflammation and edema in a short-term treatment (4-48 hours). GSNO also reduced brain infarctions and enhanced the levels of NO and GSH. In a long-term treatment (14 days), GSNO protected axonal integrity, maintained myelin levels, promoted synaptic plasticity, and enhanced the expression of neurotrophic factors.

Conclusion
Our findings indicate the participation of peroxynitrite in the pathobiology of TBI. GSNO treatment of TBI not only reduces peroxynitrite but also protects the integrity of the neurovascular unit, indicating that GSNO blunts the deleterious effects of peroxynitrite. A long-term treatment of TBI with the same low dose of GSNO promotes synaptic plasticity and enhances the expression of neurotrophic factors. These results support that GSNO reduces the levels of oxidative metabolites, protects the neurovascular unit, and promotes neurorepair mechanisms in TBI.
Microglial p38α MAPK is a key regulator of proinflammatory cytokine up-regulation induced by toll-like receptor (TLR) ligands or beta-amyloid (Aβ)
Authors: Bachstetter Adam D , Xing Bin , de Almeida Lucia , Dimayuga Edgardo R , Watterson D Martin , Van Eldik Linda J 
Published: July 2011

AbstractBackgroundOverproduction of proinflammatory cytokines from activated microglia has been implicated as an important contributor to pathophysiology progression in both acute and chronic neurodegenerative diseases. Therefore, it is critical to elucidate intracellular signaling pathways that are significant contributors to cytokine overproduction in microglia exposed to specific stressors, especially pathways amenable to drug interventions. The serine/threonine protein kinase p38α MAPK is a key enzyme in the parallel and convergent intracellular signaling pathways involved in stressor-induced production of IL-1β and TNFα in peripheral tissues, and is a drug development target for peripheral inflammatory diseases. However, much less is known about the quantitative importance of microglial p38α MAPK in stressor-induced cytokine overproduction, or the potential of microglial p38α MAPK to be a druggable target for CNS disorders. Therefore, we examined the contribution of microglial p38αMAPK to cytokine up-regulation, with a focus on the potential to suppress the cytokine increase by inhibition of the kinase with pharmacological or genetic approaches.MethodsThe microglial cytokine response to TLR ligands 2/3/4/7/8/9 or to Aβ1-42was tested in the presence of a CNS-penetrant p38α MAPK inhibitor, MW01-2-069A-SRM. Primary microglia from mice genetically deficient in p38α MAPK were used to further establish a linkage between microglia p38α MAPK and cytokine overproduction. Thein vivosignificance was determined by p38α MAPK inhibitor treatment in a LPS-induced model of acute neuroinflammation.ResultsIncreased IL-1β and TNFα production by the BV-2 microglial cell line and by primary microglia cultures was inhibited in a concentration-dependent manner by the p38α MAPK-targeted inhibitor. Cellular target engagement was demonstrated by the accompanying decrease in the phosphorylation state of two p38α MAPK protein substrates, MK2 and MSK1. Consistent with the pharmacological findings, microglia from p38α-deficient mice showed a diminished cytokine response to LPS. Further, oral administration of the inhibitor blocked the increase of IL-1β in the cerebral cortex of mice stressed by intraperitoneal injection of LPS.ConclusionThe p38α MAPK pathway is an important contributor to the increased microglial production of proinflammatory cytokines induced by diverse stressors. The results also indicate the feasibility of targeting p38α MAPK to modulate CNS proinflammatory cytokine overproduction.
Increased local concentration of complement C5a contributes to incisional pain in mice
Authors: Jang Jun H , Liang Deyong , Kido Kanta , Sun Yuan , Clark David J , Brennan Timothy J 
Published: July 2011

Abstract

Background
In our previous study, we demonstrated that local injection of complement C5a and C3a produce mechanical and heat hyperalgesia, and that C5a and C3a activate and sensitize cutaneous nociceptors in normal skin, suggesting a contribution of complement fragments to acute pain. Other studies also have shown that the complement system can be activated by surgical incision, and the systemic blockade of C5a receptor (C5aR) reduces incision-induced pain and inflammation. In this study, we further examined the possible contribution of wound area C5a to incisional pain.

Methods
Using of a hind paw incisional model, the effects of a selective C5aR antagonist, PMX53, on nociceptive behaviors were measured after incision in vivo. mRNA levels of C5 and C5aR in skin, dorsal root ganglia (DRG) and spinal cord, and C5a protein levels in the skin were quantified after incision. The responses of nociceptors to C5a were also evaluated using the in vitro skin-nerve preparation.

Results
Local administration of PMX53 suppressed heat hyperalgesia and mechanical allodynia induced by C5a injection or after hind paw incision in vivo. mRNA levels of C5 and C5aR in the skin, but not DRG and spinal cord, were dramatically increased after incision. C5a protein in the skin was also increased after incision. In vitro C5a did not increase the prevalence of fibers with ongoing activity in afferents from incised versus control, unincised skin. C5a sensitized C-fiber afferent responses to heat; however, this was less evident in afferents adjacent to the incision. PMX53 blocked sensitization of C-fiber afferents to heat by C5a but did not by itself influence ongoing activity or heat sensitivity in afferents innervating control or incised skin. The magnitude of mechanical responses was also not affected by C5a in any nociceptive fibers innervating incised or unincised skin.

Conclusions
This study demonstrates that high locally generated C5a levels are present in wounds for at least 72 hours after incision. In skin, C5a contributes to hypersensitivity after incision, but increased responsiveness of cutaneous nociceptors to C5a was not evident in incised skin. Thus, high local concentrations of C5a produced in wounds likely contribute to postoperative pain.
INVESTIGATE-I (INVasive Evaluation before Surgical Treatment of Incontinence Gives Added Therapeutic Effect?): study protocol for a mixed methods study to assess the feasibility of a future randomised controlled trial of the clinical utility of invasive urodynamic testing
Authors: Murdoch Megan , McColl Elaine , Howel Denise , Deverill Mark , Buckley Brian S , Lucas Malcolm , Chapple Christopher R , Tincello Douglas G , Armstrong Natalie , Brennand Cath , Shen Jing , Vale Luke , Hilton Paul 
Published: July 2011

Abstract

Background
Urinary incontinence is an important health problem to the individual sufferer and to health services. Stress and stress predominant mixed urinary incontinence are increasingly managed by surgery due to advances in surgical techniques. Despite the lack of evidence for its clinical utility, most clinicians undertake invasive urodynamic testing (IUT) to confirm a functional diagnosis of urodynamic stress incontinence before offering surgery for this condition. IUT is expensive, embarrassing and uncomfortable for women and carries a small risk. Recent systematic reviews have confirmed the lack of high quality evidence of effectiveness.
The aim of this pilot study is to test the feasibility of a future definitive randomised control trial that would address whether IUT alters treatment decisions and treatment outcome in these women and would test its clinical and cost effectiveness.

Methods/design
This is a mixed methods pragmatic multicentre feasibility pilot study with four components:-
(a) A multicentre, external pilot randomised trial comparing basic clinical assessment with non-invasive tests and IUT. The outcome measures are rates of recruitment, randomisation and data completion. Data will be used to estimate sample size necessary for the definitive trial.
(b) Qualitative interviews of a purposively sampled sub-set of women eligible for the pilot trial will explore willingness to participate, be randomised and their overall trial experience.
(c) A national survey of clinicians to determine their views of IUT in this context, the main outcome being their willingness to randomise patients into the definitive trial.
(d) Qualitative interviews of a purposively sampled group of these clinicians will explore whether and how they use IUT to inform their decisions.

Discussion
The pilot trial will provide evidence of feasibility and acceptability and therefore inform the decision whether to proceed to the definitive trial. Results will inform the design and conduct of the definitive trial and ensure its effectiveness in achieving its research aim.

Trial registration number
Current Controlled Trials ISRCTN71327395 assigned 7th June 2010.
Ectopic cervical thymoma in a patient with Myasthenia gravis
Authors: Wu Ti Hei , Jin Jong Shiaw , Huang Tsai Wang , Chang Hung , Lee Shih Chun 
Published: July 2011

Abstract
Ectopic cervical thymoma is rare and is often misdiagnosed as a thyroid tumor or other malignancy. Ectopic thymic tissue can be found along the entire thymic descent path during embryogenesis. However, a thymoma arising from such ectopic thymic tissue is extremely rare. Herein we report a patient with ectopic cervical thymoma and myasthenia gravis (MG) and discuss the management.
An organogenesis network-based comparative transcriptome analysis for understanding early human development in vivo and in vitro
Authors: Fang Hai , Jin Wen , Yang Ying , Jin Ying , Zhang Ji , Wang Kankan 
Published: July 2011

Abstract

Background
Integrated networks hold great promise in a variety of contexts. In a recent study, we have combined expression and interaction data to identify a putative network underlying early human organogenesis that contains two modules, the stemness-relevant module (hStemModule) and the differentiation-relevant module (hDiffModule). However, owing to its hypothetical nature, it remains unclear whether this network allows for comparative transcriptome analysis to advance our understanding of early human development, both in vivo and in vitro.

Results
Based on this integrated network, we here report comparisons with the context-dependent transcriptome data from a variety of sources. By viewing the network and its two modules as gene sets and conducting gene set enrichment analysis, we demonstrate the network's utility as a quantitative monitor of the stem potential versus the differentiation potential. During early human organogenesis, the hStemModule reflects the generality of a gradual loss of the stem potential. The hDiffModule indicates the stage-specific differentiation potential and is therefore not suitable for depicting an extended developmental window. Processing of cultured cells of different types further revealed that the hStemModule is a general indicator that distinguishes different cell types in terms of their stem potential. In contrast, the hDiffModule cannot distinguish between differentiated cells of different types but is able to predict differences in the differentiation potential of pluripotent cells of different origins. We also observed a significant positive correlation between each of these two modules and early embryoid bodies (EBs), which are used as in vitro differentiation models. Despite this, the network-oriented comparisons showed considerable differences between the developing embryos and the EBs that were cultured in vitro over time to try to mimic in vivo processes.

Conclusions
We strongly recommend the use of these two modules either when pluripotent cell types of different origins are involved or when the comparisons made are constrained to the in vivo embryos during early human organogenesis (and an equivalent in vitro differentiation models). Network-based comparative transcriptome analysis will contribute to an increase in knowledge about human embryogenesis, particularly when only transcriptome data are currently available. These advances will add an extra dimension to network applications.
Spontaneous traumatic macular hole closure in a 50-year-old woman: a case report
Authors: Nasr Mayssa B , Symeonidis Chrysanthos , Tsinopoulos Ioannis , Androudi Sofia , Rotsos Tryfon , Dimitrakos Stavros A 
Published: July 2011

Abstract

Introduction
Traumatic macular holes (TMH) are well-known complications of ocular contusion injury. Spontaneous closure occurs in approximately 50% of cases, but rarely after the age of thirty. We report a case of spontaneous closure of a full thickness macular hole due to a blunt trauma and we suggest possible mechanisms for this closure.

Case presentation
A 50-year-old Greek woman was referred with a history of reduced best-corrected visual acuity after blunt trauma to her right eye. Diagnosis was based on fundoscopic, optical coherence tomography as well as fluorescein angiography findings with follow-up visits at two days, 20 days and five months. Fundoscopy revealed a full-thickness TMH with a minor sub-retinal hemorrhage and posterior vitreous detachment. The presence of a coagulum in the TMH base was observed. Subsequently, TMH closure was observed.

Conclusion
The clot in the TMH base, potentially a hemorrhage by-product containing a significant quantity of platelets, may have simulated the clot observed after autologous serum use, thus facilitating a similar effect. This may have stimulated glial cell migration and proliferation, thus contributing to spontaneous hole closure.
Multiple-center evaluation of mortality associated with acute kidney injury in critically ill patients: a competing risks analysis
Authors: Clec'h Christophe , Gonzalez Frédéric , Lautrette Alexandre , Nguile-Makao Molière , Garrouste-Orgeas Maïté , Jamali Samir , Golgran-Toledano Dany , Descorps-Declere Adrien , Chemouni Frank , Hamidfar-Roy Rebecca , Azoulay Elie , Timsit Jean-François 
Published: July 2011

Abstract
Introduction
In this study, we aimed to assess the association between acute kidney injury (AKI) and mortality in critically ill patients using an original competing risks approach.

Methods
Unselected patients admitted between 1997 and 2009 to 13 French medical or surgical intensive care units were included in this observational cohort study. AKI was defined according to the RIFLE criteria. The following data were recorded: baseline characteristics, daily serum creatinine level, daily Sequential Organ Failure Assessment (SOFA) score, vital status at hospital discharge and length of hospital stay. Patients were classified according to the maximum RIFLE class reached during their ICU stay. The association of AKI with hospital mortality with "discharge alive" considered as a competing event was assessed according to the Fine and Gray model.

Results
Of the 8,639 study patients, 32.9% had AKI, of whom 19.1% received renal replacement therapy. Patients with AKI had higher crude mortality rates and longer lengths of hospital stay than patients without AKI. In the Fine and Gray model, independent risk factors for hospital mortality were the RIFLE classes Risk (sub-hazard ratio (SHR) 1.58 and 95% confidence interval (95% CI) 1.32 to 1.88; P < 0.0001), Injury (SHR 3.99 and 95% CI 3.43 to 4.65; P < 0.0001) and Failure (SHR 4.12 and 95% CI 3.55 to 4.79; P < 0.0001); nonrenal SOFA score (SHR 1.19 per point and 95% CI 1.18 to 1.21; P < 0.0001); McCabe class 3 (SHR 2.71 and 95% CI 2.34 to 3.15; P < 0.0001); and respiratory failure (SHR 3.08 and 95% CI 1.36 to 7.01; P < 0.01).

Conclusions
By using a competing risks approach, we confirm in this study that AKI affecting critically ill patients is associated with increased in-hospital mortality.
Phase I/II Study of Trastuzumab in Combination With Everolimus (RAD001) in Patients With HER2-Overexpressing Metastatic Breast Cancer Who Progressed on Trastuzumab-Based Therapy
Authors: Morrow Phuong K. , Wulf Gerburg M. , Ensor Joe , Booser Daniel J. , Moore Julia A. , Flores Peter R. , Xiong Yan , Zhang Siyuan , Krop Ian E. , Winer Eric P. , Kindelberger David W. , Coviello Jeanna , Sahin Aysegul A. , Nuñez Rodolfo , Hortobagyi Gabriel N. , Yu Dihua , Esteva Francisco J. 
Published: July 2011

Purpose Trastuzumab resistance has been linked to activation of the phosphoinositol 3-kinase (PI3K) pathway. Phosphatase and tensin homolog (PTEN) is a dual phosphatase that counteracts the PI3K function; PTEN loss leads to activation of the Akt cascade and the downstream mammalian target of rapamycin (mTOR). Preclinical studies demonstrated that mTOR inhibition sensitized the response to trastuzumab in mice with HER2 overexpressing and PTEN-deficient breast xenografts. Our trial evaluated the safety and efficacy of the combination of everolimus and trastuzumab in women with HER2-overexpressing metastatic breast cancer (MBC) that progressed on trastuzumab-based therapy. Patients and Methods This represents a pooled analysis (n = 47), stemming from two trials that occurred concurrently in The University of Texas MD Anderson Cancer Center, Beth Israel Deaconess Medical Center, and Dana-Farber Cancer Institute. Patients with HER2-overexpressing MBC who had progressed on trastuzumab-based therapy received trastuzumab every 3 weeks in combination with daily everolimus. Results Among 47 patients, the combination of everolimus and trastuzumab provided partial responses in seven patients (15%) and persistent stable disease (lasting 6 months or longer) in nine patients (19%), resulting in a clinical benefit rate of 34%. The median progression-free survival (PFS) was 4.1 month. Fatigue, infection, and mucositis were the predominant nonhematologic toxicities. Trastuzumab did not have significant influence on the pharmacokinetic profile of everolimus. Patients with PTEN loss demonstrated decreased overall survival (P = .048). However, PFS was not affected by PTEN loss. Conclusion Inhibition of mTOR results in clinical benefit and disease response in patients with trastuzumab-resistant HER2-overexpressing MBC.
Tandem Autologous/Reduced-Intensity Conditioning Allogeneic Stem-Cell Transplantation Versus Autologous Transplantation in Myeloma: Long-Term Follow-Up
Authors: Björkstrand Bo , Iacobelli Simona , Hegenbart Ute , Gruber Astrid , Greinix Hildegard , Volin Liisa , Narni Franco , Musto Pellegrino , Beksac Meral , Bosi Alberto , Milone Giuseppe , Corradini Paolo , Goldschmidt Hartmut , de Witte Theo , Morris Curly , Niederwieser Dietger , Gahrton Gösta 
Published: July 2011

Purpose Results of allogeneic stem-cell transplantation (allo) in myeloma are controversial. In this trial autologous stem-cell transplantation (auto) followed by reduced-intensity conditioning matched sibling donor allo (auto-allo) was compared with auto only in previously untreated multiple myeloma. Patients and Methods In all, 357 patients with myeloma up to age 69 years were enrolled from 2001 to 2005. Patients with an HLA-identical sibling donor were allocated to the auto-allo arm (n = 108) and patients without a matched sibling donor were allocated to the auto arm (n = 249). Single (n = 145) or tandem (n = 104) auto was optional. Conditioning for the auto arm was melphalan 200 mg/m2; conditioning for the allo arm was total-body irradiation 2 Gy plus fludarabine 30 mg/m2/d for 3 days. Median follow-up time was 61 months. Primary end point was progression-free survival. Results Progression-free survival at 60 months was significantly better with auto-allo than with allo alone (35% v 18%; P = .001), as was the risk of death and of relapse in the long term (P = .047 and P = .003, respectively). Overall survival at 60 months was 65% versus 58%, and relapse incidence was 49% versus 78%. Complete remission rates were 51% and 41%, respectively (P = .020). Nonrelapse mortality at 24 months was 12% after auto-allo compared with 3% in the auto group (P < .001). The incidence of grade 2 to 4 acute graft-versus-host disease (GvHD) was 20%, and the incidence of limited and extensive chronic GvHD was 31% and 23%. Conclusion In patients with previously untreated multiple myeloma, long-term outcome with respect to progression-free survival, overall survival, and relapse rate is superior after auto-allo compared with auto only. Nonrelapse mortality is at a reasonable level in both groups.
Variability of Lung Tumor Measurements on Repeat Computed Tomography Scans Taken Within 15 Minutes
Authors: Oxnard Geoffrey R. , Zhao Binsheng , Sima Camelia S. , Ginsberg Michelle S. , James Leonard P. , Lefkowitz Robert A. , Guo Pingzhen , Kris Mark G. , Schwartz Lawrence H. , Riely Gregory J. 
Published: July 2011

Purpose We use changes in tumor measurements to assess response and progression, both in routine care and as the primary objective of clinical trials. However, the variability of computed tomography (CT) –based tumor measurement has not been comprehensively evaluated. In this study, we assess the variability of lung tumor measurement using repeat CT scans performed within 15 minutes of each other and discuss the implications of this variability in a clinical context. Patients and Methods Patients with non–small-cell lung cancer and a target lung lesion ≥ 1 cm consented to undergo two CT scans within a period of minutes. Three experienced radiologists measured the diameter of the target lesion on the two scans in a side-by-side fashion, and differences were compared. Results Fifty-seven percent of changes exceeded 1 mm in magnitude, and 33% of changes exceeded 2 mm. Median increase and decrease in tumor measurements were +4.3% and −4.2%, respectively, and ranged from 23% shrinkage to 31% growth. Measurement changes were within ± 10% for 84% of measurements, whereas 3% met criteria for progression according to Response Evaluation Criteria in Solid Tumors (RECIST; ≥ 20% increase). Smaller lesions had greater variability of percent measurement change (P = .005). Conclusion Apparent changes in tumor diameter exceeding 1 to 2 mm are common on immediate reimaging. Increases and decreases less than 10% can be a result of the inherent variability of reimaging. Caution should be exercised in interpreting the significance of small changes in lesion size in the care of individual patients and in the interpretation of clinical trial results.