tbuckley/cabot-search huggingface dataset:
Toward More Uniform Conflict Disclosures — The Updated ICMJE Conflict of Interest Reporting Form
Authors: Jeffrey M. Drazen, Peter W. de Leeuw, Christine Laine, Cynthia Mulrow, Catherine D. DeAngelis, Frank A. Frizelle, Fiona Godlee, Charlotte Haug, Paul C. Hébert, Astrid James, Sheldon Kotzin, Ana Marusic, Humberto Reyes, Jacob Rosenberg, Peush Sahni, Martin B. Van Der Weyden, Getu Zhaori
Journal: New England Journal of Medicine (2010)

The great variability in the processes that different journals use to ask about and report authors' potential conflicts of interest creates confusion for authors, readers, and the public. To help lessen this confusion, the International Committee of Medical Journal Editors (ICMJE) developed an electronic uniform disclosure form and placed it in the public domain in October 2009. The ICMJE member journals piloted the form, encouraged other journals to use it, and invited feedback. We recognized that the reporting of competing interests is complex and nuanced and sometimes contentious and thus anticipated modifying the form on the basis of feedback received. . . .
The p110δ of PI3K plays a critical role in NK cell terminal maturation and cytokine/chemokine generation
Authors: Hailong Guo, Asanga Samarakoon, Bart Vanhaesebroeck, Subramaniam Malarkannan
Journal: The Journal of Experimental Medicine (2008)

Phosphatidylinositol 3-kinases (PI3Ks) play a critical role in regulating B cell receptor– and T cell receptor–mediated signaling. However, their role in natural killer (NK) cell development and functions is not well understood. Using mice expressing p110δD910A, a catalytically inactive p110δ, we show that these mice had reduced NK cellularity, defective Ly49C and Ly49I NK subset maturation, and decreased CD27High NK numbers. p110δ inactivation marginally impaired NK-mediated cytotoxicity against tumor cells in vitro and in vivo. However, NKG2D, Ly49D, and NK1.1 receptor–mediated cytokine and chemokine generation by NK cells was severely affected in these mice. Further, p110δD910A/D910A NK cell–mediated antiviral responses through natural cytotoxicity receptor 1 were reduced. Analysis of signaling events demonstrates that p110δD910A/D910A NK cells had a reduced c-Jun N-terminal kinase 1/2 phosphorylation in response to NKG2D-mediated activation. These results reveal a previously unrecognized role of PI3K-p110δ in NK cell development and effector functions.
METABOLISM IN INFECTION: STUDY ON THE ENZYMATIC DAMAGE IN KIDNEY OF GUINEA PIG INFECTED WITH MYCOBACTERIUM TUBERCULOSIS
Authors: S. N. Chaudhuri, Elsi Suter, N. S. Shah, S. P. Martin
Journal: The Journal of Experimental Medicine (1963)

Malic dehydrogenase activity of the kidney homogenate from the normal and the tuberculous guinea pigs has been estimated. A defect in the electron transport chain has been detected at the level of flavoprotein-diaphorase system. A significantly high DPNase activity of kidney homogenate has also been found in the infected group. Niacin and phenazine methochloride could correct both the defects and improve the tetrazolium reduction of the homogenate in the infected group to the level of the normal activity. Oxidative phosphorylation by the kidney mitochondria from the tuberculous guinea pigs was found to be low and could not be improved by niacin and phenazine methochloride, unlike their effects on the reduction of tetrazolium. Results have been discussed in the light of the over-all intercellular economy and its relation to the symptom complexes in tuberculosis.
Outpatient management of pulmonary embolism
Authors: Sheena Barnett
Journal: Thorax (2011)

This multi-national, randomised trial compared outpatient versus inpatient care in patients with acute pulmonary embolism with a low risk of death (severity index category of I or II). Both groups were treated with enoxaparin (≥5 days) and oral anticoagulation (≥90 days).

One of the 171 outpatients and none of the 168 inpatients had recurrence of venous …
312-nanometer Ultraviolet B Light (Narrow-Band UVB) Induces Apoptosis of T Cells within Psoriatic Lesions
Authors: Maki Ozawa, Katalin Ferenczi, Toyoko Kikuchi, Irma Cardinale, Lisa M. Austin, Todd R. Coven, Lauren H. Burack, James G. Krueger
Journal: The Journal of Experimental Medicine (1999)

Narrow-band (312 nm) ultraviolet B light (UVB) is a new form of therapy for psoriasis, but its mechanism of action is unknown. In a bilateral comparison clinical study, daily exposure of psoriatic plaques to broad-band UVB (290–320 nm) or 312-nm UVB depleted T cells from the epidermis and dermis of psoriatic lesions. However, 312-nm UVB was significantly more depleting in both tissue compartments. To characterize the mechanism of T cell depletion, assays for T cell apoptosis were performed on T cells derived from UVB-irradiated skin in vivo and on T cells irradiated in vitro with 312-nm UVB. Apoptosis was induced in T cells exposed to 50–100 mJ/cm2 of 312-nm UVB in vitro, as measured by increased binding of fluorescein isothiocyanate (FITC)–Annexin V to CD3+ cells and by characteristic cell size/granularity changes measured by cytometry. In vivo exposure of psoriatic skin lesions to 312-nm UVB for 1–2 wk also induced apoptosis in T cells as assessed by the terminal deoxynucleotidyl transferase–mediated dUTP-biotin nick end labeling (TUNEL) reaction in tissue sections, by binding of FITC–Annexin V to CD3+ T cells contained in epidermal cell suspensions, and by detection of apoptosis-related size shifts of CD3+ cells. Induction of T cell apoptosis could be the main mechanism by which 312-nm UVB resolves psoriasis skin lesions.
Tumor-Targeted Enzyme/Prodrug Therapy Mediates Long-term Disease-Free Survival of Mice Bearing Disseminated Neuroblastoma
Authors: Mary K. Danks, K. Jin Yoon, Rebecca A. Bush, Joanna S. Remack, Monika Wierdl, Lyudmila Tsurkan, Seung U. Kim, Elizabeth Garcia, Marianne Z. Metz, Joseph Najbauer, Philip M. Potter, Karen S. Aboody
Journal: Cancer Research (2007)

Abstract Neural stem cells and progenitor cells migrate selectively to tumor loci in vivo. We exploited the tumor-tropic properties of HB1.F3.C1 cells, an immortalized cell line derived from human fetal telencephalon, to deliver the cDNA encoding a secreted form of rabbit carboxylesterase (rCE) to disseminated neuroblastoma tumors in mice. This enzyme activates the prodrug CPT-11 more efficiently than do human enzymes. Mice bearing multiple tumors were treated with rCE-expressing HB1.F3.C1 cells and schedules of administration of CPT-11 that produced levels of active drug (SN-38) tolerated by patients. Both HB1.F3.C1 cells and CPT-11 were given i.v. None of the untreated mice and 30% of mice that received only CPT-11 survived long term. In contrast, 90% of mice treated with rCE-expressing HB1.F3.C1 cells and 15 mg/kg CPT-11 survived for 1 year without detectable tumors. Plasma carboxylesterase activity and SN-38 levels in mice receiving both rCE-expressing HB1.F3.C1 cells (HB1.F3.C1/AdCMVrCE) and CPT-11 were comparable with those in mice receiving CPT-11 only. These data support the hypothesis that the antitumor effect of the described neural stem/progenitor cell–directed enzyme prodrug therapy (NDEPT) is mediated by production of high concentrations of active drug selectively at tumor sites, thereby maximizing the antitumor effect of CPT-11. NDEPT approaches merit further investigation as effective, targeted therapy for metastatic tumors. We propose that the described approach may have greatest use for eradicating minimum residual disease. [Cancer Res 2007;67(1):22–5]
Changes in the enterocyte cytoskeleton in newborn rats exposed to ethanol in utero.
Authors: J F Montes, G Estrada, M D Lopez-Tejero, J Garcia-Valero
Journal: Gut (1996)

Cytoskeletal changes after longterm exposure to ethanol have been described in a number of cell types in adult rat and humans. These changes can play a key part in the impairment of nutrient assimilation and postnatal growth retardation after prenatal damage of the intestinal epithelium produced by ethanol intake.To determine, in the newborn rat, which cytoskeletal proteins are affected by longterm ethanol exposure in utero and to what extent.The offspring of two experimental groups of female Wistar rats: ethanol treated group receiving up to 25% (w/v) of ethanol in the drinking fluid and control group receiving water as drinking fluid.Single and double electron microscopy immunolocalisation and label density estimation of cytoskeletal proteins on sections of proximal small intestine incubated with monoclonal antibodies against actin, alpha-tubulin, cytokeratin (polypeptides 1, 5, 6, 7, 8, 10, 11, and 18), and with a polyclonal antibody anti-beta 1,4-galactosyl transferase as trans golgi (TG) or trans golgi network (TGN) marker, or both. SDS-PAGE technique was also performed on cytoskeletal enriched fractions from small intestine. Western blotting analysis was carried out by incubation with the same antibodies used for immunolocalisation.Intestinal epithelium of newborn rats from the ethanol treated group showed an overexpression of cytoskeletal polypeptides ranging from 39 to 54 kDa, affecting actin and some cytokeratins, but not tubulin. Furthermore, a cytokeratin related polypeptide of 28-29 kDa was identified together with an increase in free ubiquitin in the same group. It was noteworthy that actin and cytokeratin were abnormally located in the TG or the TGN, or both.Longterm exposure to ethanol in utero causes severe dysfunction in the cytoskeleton of the developing intestinal epithelium. Actin and cytokeratins, which are involved in cytoskeleton anchoring to plasma membrane and cell adhesion, are particularly affected, showing overexpression, impaired proteolysis, and mislocalisation.
Validity of a three-variable Juvenile Arthritis Disease Activity Score in children with new-onset juvenile idiopathic arthritis
Authors: Flora Mcerlane, Michael W Beresford, Eileen M Baildam, S E Alice Chieng, Joyce E Davidson, Helen E Foster, Janet Gardner-Medwin, Mark Lunt, Lucy R Wedderburn, Wendy Thomson, Kimme L Hyrich
Journal: Annals of the Rheumatic Diseases (2012)

Objectives To investigate the validity and feasibility of the Juvenile Arthritis Disease Activity Score (JADAS) in the routine clinical setting for all juvenile idiopathic arthritis (JIA) disease categories and explore whether exclusion of the erythrocyte sedimentation rate (ESR) from JADAS (the ‘JADAS3’) influences correlation with single markers of disease activity. Methods JADAS-71, JADAS-27 and JADAS-10 were determined at baseline for an inception cohort of children with JIA in the Childhood Arthritis Prospective Study. JADAS3-71, JADAS3-27 and JADAS3-10 were determined using an identical formula but with exclusion of ESR. Correlation of JADAS with JADAS3 and single measures of disease activity/severity were determined by category. Results Of 956 eligible children, sufficient data were available to calculate JADAS-71, JADAS-27 and JADAS-10 at baseline in 352 (37%) and JADAS3 in 551 (58%). The median (IQR) JADAS-71, JADAS-27 and JADAS-10 for all 352 children was 11 (5.9–18), 10.4 (5.7–17) and 11 (5.9–17.3), respectively. Median JADAS and JADAS3 varied significantly with the category (Kruskal–Wallis p=0.0001), with the highest values in children with polyarticular disease patterns. Correlation of JADAS and JADAS3 across all categories was excellent. Correlation of JADAS71 with single markers of disease activity/severity was good to moderate, with some variation across the categories. With the exception of ESR, correlation of JADAS3-71 was similar to correlation of JADAS-71 with the same indices. Conclusions This study is the first to apply JADAS to all categories of JIA in a routine clinical setting in the UK, adding further information about the feasibility and construct validity of JADAS. For the majority of categories, clinical applicability would be improved by exclusion of the ESR.
Mitochondrial adaptations and dysfunctions in nonalcoholic fatty liver disease
Authors: Karima Begriche, Julie Massart, Marie-Anne Robin, Fabrice Bonnet, Bernard Fromenty
Journal: Hepatology (2013)

The worldwide epidemic of obesity and insulin resistance favors nonalcoholic fatty liver disease (NAFLD). Insulin resistance (IR) in the adipose tissue increases lipolysis and the entry of nonesterified fatty acids (NEFAs) in the liver, whereas IR-associated hyperinsulinemia promotes hepatic de novo lipogenesis. However, several hormonal and metabolic adaptations are set up in order to restrain hepatic fat accumulation, such as increased mitochondrial fatty acid oxidation (mtFAO). Unfortunately, these adaptations are usually not sufficient to reduce fat accumulation in liver. Furthermore, enhanced mtFAO without concomitant up-regulation of the mitochondrial respiratory chain (MRC) activity induces reactive oxygen species (ROS) overproduction within different MRC components upstream of cytochrome c oxidase. This event seems to play a significant role in the initiation of oxidative stress and subsequent development of nonalcoholic steatohepatitis (NASH) in some individuals. Experimental investigations also pointed to a progressive reduction of MRC activity during NAFLD, which could impair energy output and aggravate ROS overproduction by the damaged MRC. Hence, developing drugs that further increase mtFAO and restore MRC activity in a coordinated manner could ameliorate steatosis, but also necroinflammation and fibrosis by reducing oxidative stress. In contrast, physicians should be aware that numerous drugs in the current pharmacopoeia are able to induce mitochondrial dysfunction, which could aggravate NAFLD in some patients. (Hepatology 2013;58:1497–1507)
Schwann Cell Contact Guidance versus Boundary ­Interaction in Functional Wound Healing along Nano and Microstructured Membranes
Authors: Ilaria Tonazzini, Emanuela Jacchetti, Sandro Meucci, Fabio Beltram, Marco Cecchini
Journal: Advanced Healthcare Materials (2015)

Peripheral nerve transection is often encountered after trauma and can lead to long‐term/permanent loss of sensor/motor functionality. Here, the effect of pure contact interaction of nano/microgrooved substrates on Schwann cells (SCs) is studied in view of their possible use for nerve‐repair applications. Elastomeric gratings (GRs; i.e., alternating lines of ridges and grooves) are developed with different lateral periods (1–20 μm) and depths (0.3–2.5 μm), leading to two distinct cell–material interaction regimes: contact guidance (grating period &lt; cell body diameter) and boundary guidance (grating period ≥ cell body diameter). Here, it is shown that boundary guidance leads to the best single‐cell polarization, actin organization, and single‐cell directional migration. Remarkably, contact guidance is instead more effective in driving collective SC migration and improves functional wound healing. It is also demonstrated that this behavior is linked to the properties of the SC monolayers on different GRs. SCs on large‐period GRs are characterized by N‐Cadherin downregulation and enhanced single‐cell scattering into the wound with respect to SCs on small‐period GRs, indicating a less compact monolayer characterized by looser cell–cell junctions in the boundary guidance regime. The present results provide information on the impact of specific sub­micrometer topographical elements on SC functional response, which can be exploited for nerve‐regeneration applications.
Delayed Treatment with Lithospermate B Attenuates Experimental Diabetic Renal Injury
Authors: GEUN TAEK Lee, Hunjoo Ha, Mankil Jung, Hari Li, Soon Won Hong, Bong Soo Cha, Hyun Chul Lee, and Young Dong Cho
Journal: Journal of the American Society of Nephrology (2003)

ABSTRACT. Extracellular matrix (ECM) accumulation in the glomerular mesangium is a characteristic feature of diabetic nephropathy. While transforming growth factor-β1 (TGF-β1) is the final mediator of ECM accumulation, reactive oxygen species (ROS) and protein kinase C (PKC) are the upstream signaling molecules that mediate hyperglycemia-induced ECM expansion. Magnesium lithospermate B (LAB) is an active component isolated from Salvia miltiorrhizae with known renoprotective properties due to its antioxidative effects. Thus, the present study examined the effects of LAB on renal injury in streptozotocin-induced diabetic rats (STZR) and on the activation of mesangial cells cultured under high glucose conditions. Ten micrtograms of LAB/kg per day was started 8 wk after streptozotocin injection and continued for a period of 8 wk. It significantly suppressed renal malondialdehyde (MDA), microalbuminuria, glomerular hypertrophy, mesangial expansion, and the upregulation of renal TGF-β1, fibronectin, and collagen in STZR without significantly affecting plasma glucose. Both 30 mM of glucose and 100 uM of H2O2 significantly increased TGF-β1 and fibronectin protein secretion by mesangial cells. LAB at 10 μg/ml inhibited high glucose- and H2O2-induced TGF-β1 and fibronectin secretion. LAB also inhibited glucose-induced intracellular ROS generation and PKC activation in mesangial cells, but it did not directly inhibit PKC activity at dosages that inhibited ROS generation. The in vitro data of this study show that LAB inhibits ROS generation leading to PKC activation and TGF-β1 and fibronectin upregulation in mesangial cells cultured under high glucose conditions. Moreover, delayed treatment with LAB was found to significantly suppress the progression of renal injury in STZR. LAB may become a new therapeutic agent for the treatment of diabetic nephropathy. E-mail: [email protected]
Integrins αvβ5 and αvβ3 promote latent TGF-β1 activation by human cardiac fibroblast contraction
Authors: Vincent Sarrazy, Anne Koehler, Melissa L. Chow, Elena Zimina, Chen X. Li, Hideyuki Kato, Christopher A. Caldarone, Boris Hinz
Journal: Cardiovascular Research (2014)

Pathological tissue remodelling by myofibroblast contraction is a hallmark of cardiac fibrosis. Myofibroblasts differentiate from cardiac fibroblasts under the action of transforming growth factor-β1 (TGF-β1), which is secreted into the extracellular matrix as a large latent complex. Integrin-mediated traction forces activate TGF-β1 by inducing a conformational change in the latent complex. The mesenchymal integrins αvβ5 and αvβ3 are expressed in the heart, but their role in the activation of TGF-β1 remains elusive. Here, we test whether targeting αvβ5 and αvβ3 integrins reduces latent TGF-β1 activation by cardiac fibroblasts with the goal to prevent the formation of α-smooth muscle actin (α-SMA)-expressing cardiac myofibroblasts and their contribution to fibrosis.Using a porcine model of induced right ventricular fibrosis and pro-fibrotic culture conditions, we show that integrins αvβ5 and αvβ3 are up-regulated in myofibroblast-enriched fibrotic lesions and differentiated cultured human cardiac myofibroblasts. Both integrins autonomously contribute to latent TGF-β1 activation and myofibroblast differentiation, as demonstrated by function-blocking peptides and antibodies. Acute blocking of both integrins leads to significantly reduced TGF-β1 activation by cardiac fibroblast contraction and loss of α-SMA expression, which is restored by adding active TGF-β1. Manipulating integrin protein levels in overexpression and shRNA experiments reveals that both integrins can compensate for each other with respect to TGF-β1 activation and induction of α-SMA expression.Integrins αvβ5 and αvβ3 both control myofibroblast differentiation by activating latent TGF-β1. Pharmacological targeting of mesenchymal integrins is a possible strategy to selectively block TGF-β1 activation by cardiac myofibroblasts and progression of fibrosis in the heart.
When a “wheeze” is not a wheeze: acoustic analysis of breath sounds in infants
Authors: H.E. Elphick, S. Ritson, H Rodgers, M.L Everard
Journal: European Respiratory Journal (2000)

Epidemiological studies indicate that the prevalence of "wheeze" is very high in early childhood. However, it is clear that parents and clinicians frequently use the term "wheeze" for a range of audible respiratory noises. The commonest audible sounds originating from the lower airways in infancy are ruttles, which differ from classical wheeze in that the sound is much lower in pitch, with a continuous rattling quality and lacking any musical features. The aim of this study was to clearly differentiate wheeze and ruttles objectively using acoustic analysis. Lung sounds were recorded in 15 infants, seven with wheeze and eight with ruttles, using a small sensitive piezoelectric accelerometer, and information relating to the respiratory cycle was obtained using inductive plethysmography. The acoustic signals were analysed using a fast fourier transformation technique (Respiratory Acoustics Laboratory Environment programme). The acoustic properties of the two noises were shown to be quite distinct, the classical wheeze being characterized by a sinusoidal waveform with one or more distinct peaks in the power spectrum display; the ruttle is represented by an irregular nonsinusoidal waveform with diffuse peaks in the power spectrum and with increased sound intensity at a frequency of <600 Hz. It is important for clinicians and epidemiologists to recognize that there are distinct types of audible respiratory noise in early life with characteristic acoustic properties.
Autosomal recessive phosphoglucomutase 3 (PGM3) mutations link glycosylation defects to atopy, immune deficiency, autoimmunity, and neurocognitive impairment
Authors: Yu Zhang, Xiaomin Yu, Mie Ichikawa, Jonathan J Lyons, Shrimati Datta, Ian T Lamborn, Huie Jing, Emily S Kim, Matthew Biancalana, Lynne A Wolfe, Thomas DiMaggio, Helen F Matthews, Sarah M Kranick, Kelly D Stone, Steven M Holland, Daniel S Reich, Jason D Hughes, Huseyin Mehmet, Joshua McElwee, Alexandra F Freeman, Hudson H Freeze, Helen C Su, Joshua D Milner
Journal: Journal of Allergy and Clinical Immunology (2014)
A novel potent Fas agonist for selective depletion of tumor cells in hematopoietic transplants
Authors: A Nahimana, D Aubry, L Lagopoulos, P Greaney, A Attinger, S Demotz, K M Dawson, M Schapira, J Tschopp, M Dupuis, M A Duchosal
Journal: Blood Cancer Journal (2011)

There remains a clear need for effective tumor cell purging in autologous stem cell transplantation (ASCT) where residual malignant cells within the autograft contribute to disease relapse. Here we propose the use of a novel Fas agonist with potent pro-apoptotic activity, termed MegaFasL, as an effective ex-vivo purging agent. MegaFasL selectively kills hematological cancer cells from lymphomas and leukemias and prevents tumor development at concentrations that do not reduce the functional capacity of human hematopoietic stem/progenitor cells both in in vitro and in in vivo transplantation models. These findings highlight the potential use of MegaFasL as an ex-vivo purging agent in ASCT.
Episodic Memory Performance Predicted by the 2bp Deletion in Exon 6 of the “Alpha 7-Like” Nicotinic Receptor Subunit Gene
Authors: Emma L. Dempster, Timothea Toulopoulou, Colm Mcdonald, Elvira Bramon, Muriel Walshe, Harvey Wickham, Pak C. Sham, Robin M. Murray, David A. Collier
Journal: American Journal of Psychiatry (2006)

Objective: There is evidence of linkage between chromosome 15q14 and the P50 auditory evoked response, a heritable neuropsychological marker associated with increased risk of schizophrenia. Chromosome 15q14 harbors the alpha-7 nicotinic receptor subunit gene (CHRNA7) and a hybrid gene of unknown function (CHRFAM7A). CHRNA7 is involved in memory formation, a core dysfunction in schizophrenia. The authors set out to determine if this locus is associated with memory dysfunction in schizophrenia. Method: A 2bp deletion in exon 6 of CHRFAM7A, which disrupts the hybrid gene and has previously been associated with P50 deficit, was genotyped in 251 individuals from the Maudsley Family Study of schizophrenia. Episodic memory function was assessed using the Wechsler Memory Scale. Results: Significant associations were identified with delayed recall and percentage retained, with the presence of the deletion predicting worse performance. Conclusions: These observations indicate that episodic memory function is a schizophrenia endophenotype and implicate the CHRFAM7A/CHRNA7 locus in modulating its function.