tbuckley/cabot-search huggingface dataset:
Circulating Endothelial Microparticles Are Associated with Vascular Dysfunction in Patients with End-Stage Renal Failure
Authors: Nicolas Amabile, Alain P. Guérin, Aurélie Leroyer, Ziad Mallat, Clément Nguyen, Jacques Boddaert, Gérard M. London, Alain Tedgui, Chantal M. Boulanger
Journal: Journal of the American Society of Nephrology (2005)

Endothelial dysfunction and arterial stiffness are major determinants of cardiovascular risk in patients with end-stage renal failure (ESRF). Microparticles are membrane fragments shed from damaged or activated cells. Because microparticles can affect endothelial cells, this study investigated the relationship between circulating microparticles and arterial dysfunction in patients with ESRF and identified the cellular origin of microparticles associated with these alterations. Flow cytometry analysis of platelet-free plasma from 44 patients with ESRF indicated that circulating levels of Annexin V+ microparticles were increased compared with 32 healthy subjects, as were levels of microparticles derived from endothelial cells (three-fold), platelets (16.5-fold), and erythrocytes (1.6-fold). However, when arterial function was evaluated noninvasively in patients with ESRF, only endothelial microparticle levels correlated highly with loss of flow-mediated dilation (r = -0.543; P = 0.004), increased aortic pulse wave velocity (r = 0.642, P < 0.0001), and increased common carotid artery augmentation index (r = 0.463, P = 0.0017), whereas platelet-derived, erythrocyte-derived, and Annexin V+ microparticle levels did not. In vitro, microparticles from patients with ESRF impaired endothelium-dependent relaxations and cyclic guanosine monophosphate generation, whereas microparticles from healthy subjects did not. Moreover, in vitro endothelial dysfunction correlated with endothelial-derived (r = 0.891; P = 0.003) but not platelet-derived microparticle concentrations. In fact, endothelial microparticles alone decreased endothelial nitric oxide release by 59 +/- 7% (P = 0.025). This study suggests that circulating microparticles of endothelial origin are tightly associated with endothelial dysfunction and arterial dysfunction in ESRF.
Effects of Digitalis Upon Body Electrolytes
Authors: BERNARD LOWN, GERALD H. WHIPPLE, GEORGE MCLEMORE, SAMUEL A. LEVINE
Journal: Circulation Research (1961)

Studies of the electrolyte alterations in 54 dogs during 165 discrete digitalizations with acetyl strophantbidin to an endpoint of ventricular tachycardia are reported. In 94 per cent of digitalizatious, increase in arterial potassium concentration occurred. This was noted as early as five niinutes after drug administration. At the time of ventricular tachycardia, the increase was 0.67 mEq./L. When digitalization was carried to ventricular fibrillation, the increase was 3.1 mEq./L. In 75.5 per cent of the digitalizations, arterial sodium concentration decreased; average de crease was 2.6 mEq./L. At ventricular fibril lation, the decrease amounted to 11.0 mEq./L. Arterial calcium concentration and oxygen saturation were not altered. There was a modest decrease in CO 2 content and an increase in arterial pH and hcmatoerit. Peaking of the late portion of the T wave was common during acute digitalization and correlated with the increase in extracellular potassium concentration. The relationship of the electrolyte changes to the process of digitalization is discussed.
Superoxide dismutase downregulation in osteoarthritis progression and end-stage disease
Authors: J. L. Scott, C. Gabrielides, R. K. Davidson, T. E. Swingler, I. M. Clark, G. A. Wallis, R. P. Boot-Handford, T. B. L. Kirkwood, R. W. Talyor, D. A. Young
Journal: Annals of the Rheumatic Diseases (2010)

<h3>Background</h3> Oxidative stress is proposed as an important factor in osteoarthritis (OA). <h3>Objective</h3> To investigate the expression of the three superoxide dismutase (SOD) antioxidant enzymes in OA. <h3>Methods</h3> SOD expression was determined by real-time PCR and immunohistochemistry using human femoral head cartilage. SOD2 expression in Dunkin–Hartley guinea pig knee articular cartilage was determined by immunohistochemistry. The DNA methylation status of the SOD2 promoter was determined using bisulphite sequencing. RNA interference was used to determine the consequence of SOD2 depletion on the levels of reactive oxygen species (ROS) using MitoSOX and collagenases, matrix metalloproteinase 1 (MMP-1) and MMP-13, gene expression. <h3>Results</h3> All three SOD were abundantly expressed in human cartilage but were markedly downregulated in end-stage OA cartilage, especially SOD2. In the Dunkin–Hartley guinea pig spontaneous OA model, SOD2 expression was decreased in the medial tibial condyle cartilage before, and after, the development of OA-like lesions. The SOD2 promoter had significant DNA methylation alterations in OA cartilage. Depletion of SOD2 in chondrocytes increased ROS but decreased collagenase expression. <h3>Conclusion</h3> This is the first comprehensive expression profile of all SOD genes in cartilage and, importantly, using an animal model, it has been shown that a reduction in SOD2 is associated with the earliest stages of OA. A decrease in SOD2 was found to be associated with an increase in ROS but a reduction of collagenase gene expression, demonstrating the complexities of ROS function.
Exercise therapy for the conservative management of full thickness tears of the rotator cuff: a systematic review
Authors: Roberta Ainsworth, Jeremy S Lewis
Journal: British Journal of Sports Medicine (2007)

Purpose: To review the evidence for the effectiveness of therapeutic exercise for the treatment of full thickness (including massive and inoperable) tears of the rotator cuff. Relevance: There is little consensus as to the most effective treatment of full thickness and massive tears of the rotator cuff. There is consensus that the outcome of rotator cuff tendon surgery in the elderly is generally very poor. As such, exercise therapy is usually recommended for this patient group. Although commonly prescribed, the evidence to support this approach is equivocal. The aim of this study was to conduct a systematic review of the literature to determine the efficacy of exercise therapy for the management of full thickness rotator cuff tears. Methods: A systematic review was conducted to synthesise the available research literature on the effectiveness of exercise therapy for full thickness tears of the rotator cuff. Data source: Reports up to and including September 2006 were located from MEDLINE, the Cumulative Index to Nursing &amp; Allied Health Literature (CINAHL), AMED, EMBASE, the Cochrane Database of Systematic Reviews and the Physiotherapy Evidence Database (PEDro) using the terms “rotator cuff” and “tear/s” and “exercise” or “physiotherapy” or “physical therapy” or “rehabilitation”. Study selection: Studies were included if they related to full thickness rotator cuff tears and exercise. Data extraction: Two independent reviewers assessed the methodological quality of the studies. Differences were resolved by consensus. Analysis/Data synthesis: Ten studies met the inclusion criteria: eight were observational case series and two were single case studies. There were no randomised clinical trials. Results: Four studies were specific to massive rotator cuff tears. One study had a sub-group with massive cuff tears and five studies were not specific as to the size of the full thickness tear. Due to the heterogeneity of outcome measures used, it was not possible to combine results. In all studies an improvement in outcome scores was reported. Exercise programmes were well documented in five studies. Conclusions: No randomised controlled trials met the inclusion criteria and the evaluation has been based on observational studies of lower scientific merit. The findings suggest that some evidence exists to support the use of exercise in the management of full thickness rotator cuff tears. There is a definite need for well-planned randomised controlled trials investigating the efficacy of exercise in the management of full thickness and massive rotator cuff tears.
Improved Potency and Selectivity of an Oncolytic E1ACR2 and E1B19K Deleted Adenoviral Mutant in Prostate and Pancreatic Cancers
Authors: Daniel Öberg, Eva Yanover, Virginie Adam, Katrina Sweeney, Celina Costas, Nick R. Lemoine, Gunnel Halldén
Journal: Clinical Cancer Research (2010)

Abstract Purpose: Replication-selective oncolytic adenoviruses are a promising class of tumor-targeting agents with proven safety in hundreds of patients. However, clinical responses have been limited and viral mutants with higher potency are needed. Here, we report on the generation of a novel set of mutants with improved efficacy in prostate and pancreatic carcinoma models. Currently, no curative treatments are available for late-stage metastatic prostate or rapidly progressing pancreatic cancers. Experimental Design: Adenovirus type 5 mutants were created with deletions in the E1ACR2 region for tumor selectivity and/or the E1B19K gene for attenuated replication in vivo; all constructs retain the E3 genes intact. Cell-killing efficacy, replication, and cytotoxicity in combination with chemotherapeutics were investigated in normal cells (PrEC and NHBE), seven carcinoma cell lines, and human (PC3 and DU145) and murine (TRAMPC, CMT-64, and CMT-93) tumor models in vivo. Results: The double-deleted AdΔΔ (ΔE1ACR2 and ΔE1B19K) mutant had high cell-killing activity in prostate, pancreatic, and lung carcinomas. Replication was similar to wild-type in all tumor cells and was attenuated in normal cells to levels less than the single-deleted AdΔCR2 mutant. AdΔΔ combined with the chemotherapeutics docetaxel and mitoxantrone resulted in synergistically enhanced cell killing and greatly improved antitumor efficacy in prostate xenografts in vivo. In murine immunocompetent in vivo models efficacy was greater for mutants with the E3B genes intact even in the absence of viral replication, indicating attenuated macrophage-dependent clearance. Conclusions: These data suggest that the novel oncolytic mutant AdΔΔ is a promising candidate for targeting of solid tumors specifically in combination with chemotherapeutics. Clin Cancer Res; 16(2); 541–53
Recent Advancements in the Treatment of Chronic Myelogenous Leukemia
Authors: Michael E. O'Dwyer, Michael J. Mauro, Brian J. Druker
Journal: Annual Review of Medicine (2002)

▪ Abstract Chronic myelogenous leukemia (CML) is a clonal hematopoetic stem cell disorder characterized by the Philadelphia chromosome and resultant production of the constitutively activated Bcr-Abl tyrosine kinase. Characterized clinically by marked myeloid proliferation, it invariably terminates in an acute leukemia. Conventional therapeutic options include interferon-based regimens and stem cell transplantation, with stem cell transplantation being the only curative therapy. Through rational drug development, STI571, a Bcr-Abl tyrosine kinase inhibitor, has emerged as a paradigm for gene product targeted therapy, offering new hope for expanded treatment options for patients with CML.
A trick presentation
Authors: Hema Bashyam
Journal: The Journal of Experimental Medicine (2008)

On page 1201, Huang et al. find that an antigen-presenting protein suffers from an identity crisis: it looks like MHC class I but behaves like MHC class II.

This molecule, MR1, is recognized by a subset of gut-roving T cells. When MR1 carries the right antigen, these T cells suppress gut inflammation, but the identity of that antigen is a mystery. Because MR1 is structurally similar to MHC class I molecules, which usually pick up proteasome-processed peptides in the ER, MR1 was thought to do the same.

This notion is now disproved by Huang et al., who show that MR1-expressing cells treated with proteasome inhibitors or lacking ER peptide–loading chaperones can still activate these T cells. Instead, they found, MR1 picked up its antigens in endosomes, where MHC class II molecules get theirs.

MR1 bound to a chaperone called the invariant chain, which ferries MHC class II molecules from the ER into endosomes. There, it bound another chaperone, called DM, which loads them up with peptides. MR1-expressing cells that lacked the invariant chain were unable to activate gut T cells, whereas high levels of this protein increased their activation.

The immune-suppressing ability of MR1-activated T cells suggests that they might prevent the gut from attacking its helpful resident flora. The authors therefore speculate that the MR1 ligand might be derived from one or more of these residents.
Occupational asthma to solder wire containing an adipic acid flux
Authors: V.C. Moore, P.S. Burge
Journal: European Respiratory Journal (2010)

Occupational asthma to solder wire containing an adipic acid fluxTo the Editors:We present the first case of occupational asthma to colophonyfree solder wire containing an adipic acid flux, previously only reported in a pharmaceutical factory worker who was in contact with spiramycin powder [1].The 43-yr-old female presented with rhinitic symptoms in 1992.She had worked as a solderer and desolderer of alternator parts since June 1989.The process used a colophony-free solder wire containing an adipic acid flux from 1996, but, when desoldering, colophony fluxes may still have been present.
Cerebral Blood Flow Regulation by Nitric Oxide: Recent Advances
Authors: Noboru Toda, Kazuhide Ayajiki, Tomio Okamura
Journal: Pharmacological Reviews (2009)

Nitric oxide (NO) is undoubtedly quite an important intercellular messenger in cerebral and peripheral hemodynamics. This molecule, formed by constitutive isomers of NO synthase, endothelial nitric-oxide synthase, and neuronal nitric-oxide synthase, plays pivotal roles in the regulation of cerebral blood flow and cell viability and in the protection of nerve cells or fibers against pathogenic factors associated with cerebral ischemia, trauma, and hemorrhage. Cerebral blood flow is increased and cerebral vascular resistance is decreased by NO derived from endothelial cells, autonomic nitrergic nerves, or brain neurons under resting and stimulated conditions. Somatosensory stimulation also evokes cerebral vasodilatation mediated by neurogenic NO. Oxygen and carbon dioxide alter cerebral blood flow and vascular tone mainly via constitutively formed NO. Endothelial dysfunction impairs cerebral hemodynamics by reducing the bioavailability of NO and increasing the production of reactive oxygen species (ROS). The NO-ROS interaction is an important issue in discussing blood flow and cell viability in the brain. Recent studies on brain circulation provide quite useful information concerning the physiological roles of NO produced by constitutive isoforms of nitric-oxide synthase and how NO may promote cerebral pathogenesis under certain conditions, including cerebral ischemia/stroke, cerebral vasospasm after subarachnoid hemorrhage, and brain injury. This information would contribute to better understanding of cerebral hemodynamic regulation and its dysfunction and to development of novel therapeutic measures to treat diseases of the central nervous system.
Do asbestos-related pleural plaques on HRCT scans cause restrictive impairment in the absence of pulmonary fibrosis?
Authors: B. Clin, C. Paris, J. Ameille, P. Brochard, F. Conso, A. Gislard, F. Laurent, M. Letourneux, A. Luc, E. Schorle, J.-C. Pairon
Journal: Thorax (2011)

<h3>Background</h3> It is uncertain whether isolated pleural plaques cause functional impairment. <h3>Objective</h3> To analyse the relationship between isolated pleural plaques confirmed by CT scanning and lung function in subjects with occupational exposure to asbestos. <h3>Methods</h3> The study population consisted of 2743 subjects presenting with no parenchymal interstitial abnormalities on the high-resolution CT (HRCT) scan. Asbestos exposure was evaluated by calculation of an individual cumulative exposure index (CEI). Each subject underwent pulmonary function tests (PFTs) and HRCT scanning. Variables were adjusted for age, smoking status, body mass index, CEI to asbestos and the centres in which the pulmonary function tests were conducted. <h3>Results</h3> All functional parameters studied were within normal limits for subjects presenting with isolated pleural plaques and for those presenting with no pleuropulmonary abnormalities. However, isolated parietal and/or diaphragmatic pleural plaques were associated with a significant decrease in total lung capacity (TLC) (98.1% predicted in subjects with pleural plaques vs 101.2% in subjects free of plaques, p=0.0494), forced vital capacity (FVC) (96.6% vs 100.4%, p&lt;0.001) and forced expiratory volume in 1 s (FEV<sub>1</sub>) (97.9% vs 101.9%, p=0.0032). In contrast, no significant relationship was observed between pleural plaques and FEV<sub>1</sub>/FVC ratio, forced expiratory flow at 25–75% FVC and residual volume. A significant correlation was found between the extent of pleural plaques and the reduction in FVC and TLC, whereas plaque thickness was not related to functional impairment. <h3>Conclusions</h3> The results show a relationship between isolated parietal and/or diaphragmatic pleural plaques and a trend towards a restrictive pattern, although the observed decrease in FVC and TLC is unlikely to be of real clinical relevance for the majority of subjects in this series.
Functional Neuroimaging Studies of Depression: The Anatomy of Melancholia
Authors: Wayne C. Drevets
Journal: Annual Review of Medicine (1998)

Functional brain imaging techniques, which permit noninvasive measures of neurophysiology and neuroreceptor binding, are powerful and sensitive tools for research aimed at elucidating the pathophysiology of major depression. The application of these technologies in depression research has produced several studies of resting cerebral blood flow (BF) and glucose metabolism in subjects imaged during various phases of illness and treatment. This review examines these data and the principles relevant to their interpretation and discusses the insights they provide into the anatomical correlates of depression. Within the anatomical networks implicated in emotional processing by other types of evidence, these BF and metabolic data demonstrate that major depression is associated with reversible, mood state–dependent, neurophysiological abnormalities in some structures and irreversible, trait-like abnormalities in other structures. In some of the regions in which trait-like abnormalities appear, abnormal metabolic activity appears at least partly related to the anatomical abnormalities identified in magnetic resonance imaging (MRI) studies of depression.
Surgical treatment of primary malignancies of trachea
Authors: Igor Mosin, Nina Mosina, Olga Lukina, Yana Dorofeeva
Journal: European Respiratory Journal (2011)

The main treatment of patients with primary malignant tumors of the trachea is endoscopic recanalization of the trachea lumen with stenting and radiotherapy. Radical surgery of the trachea primary malignancies is single-step circular resection with end-to-end anastomosis.

The aim was to demonstrate that a single-step circular resection is possible when tumor extension is 45% of the trachea length, with involvement of the epiglottis subfold portion.

18 single-step circular resections were performed in patients with primary tumor of the trachea. Adenocystic cancer of the trachea was diagnosed in 13 subjects, and typical carcinoid – in 5. Among them over 45% of trachea was resected in 10 patients. Localisation and extension of the tumor was established by fibrobronchoscopy, and MDCT. Tumor extension from 1.0 to 3.0sm was diagnosed in 8 patients, and from 3.0 to 6.0sm – in 10 patients. Single-step circular resections and tracheotracheal anastomosis were performed in 7 patients, laryngotracheal anastomosis - in 6, and a laryngotracheal resections were made in 5 patients. Immediate and prospective results of the treatment are considered to be sufficient in all patients. In Pearson-Grillo laryngotracheal resection the distance between the anastomosis and vocal cords varied from 1 sm to 3 sm.

Single-step circular resection is the only radical surgical treatment of primary trachea malignancies. Subfold portion involvement is not a contraindication to a single-step circular resection of the trachea and subfolder portion of the epiglottis. Postoperatively, a single-step circular resection for adenocystic cancer must be followed by radiotherapy.
Effective Immunotherapy against Murine Gliomas Using Type 1 Polarizing Dendritic Cells—Significant Roles of CXCL10
Authors: Mitsugu Fujita, Xinmei Zhu, Ryo Ueda, Kotaro Sasaki, Gary Kohanbash, Edward R. Kastenhuber, Heather A. McDonald, Gregory A. Gibson, Simon C. Watkins, Ravikumar Muthuswamy, Pawel Kalinski, Hideho Okada
Journal: Cancer Research (2009)

In an attempt to develop effective vaccines against central nervous system (CNS) tumors, we evaluated the ability of vaccines with standard dendritic cells (DC) versus type 1 polarizing DCs (DC1) to induce glioma-specific type 1 CTLs with CNS tumor-relevant homing properties and the mechanism of their action. C57BL/6 mouse-derived bone marrow cells were cultured with mouse granulocyte/macrophage colony-stimulating factor (GM-CSF) for 6 days, and CD11c(+) cells were subsequently cultured with GM-CSF, rmIFN-gamma, rmIFN-alpha, rmIL-4, and polyinosinic-polycytidylic acid stabilized by lysine and carboxymethylcellulose for 24 hours to generate DC1s. In analogy to their human counterparts, mouse DC1s exhibited surface marker profiles of mature DCs and produced high levels of IL-12 and CXCL10. Importantly for their application as cancer vaccines, such DC1s stably retained their type 1 phenotype even when exposed to type 2-promoting or regulatory T cell (Treg)-promoting environments. Consistently, mouse DC1s induced antigen-specific type 1 CTLs more efficiently than nonpolarized DCs in vitro. DC1s given s.c. migrated into draining lymph nodes, induced antigen-specific CTLs, and suppressed Treg accumulation. In addition, s.c. immunization with DC1s loaded with glioma-associated antigen (GAA)-derived CTL epitope peptides prolonged the survival of CNS GL261 glioma-bearing mice, which was associated with efficient CNS glioma homing of antigen-specific CTLs. Intratumoral injections of GAA peptide-loaded DC1s further enhanced the anti-CNS glioma effects of DC1-based s.c. immunization. Interestingly, the antitumor functions were abrogated with CXCL10(-/-) mouse-derived DC1s. Collectively, these findings show the anti-CNS glioma effects of DC1-based therapy and a novel role of CXCL10 in the immunologic and therapeutic activity of DC-based cancer vaccines.