tbuckley/cabot-search huggingface dataset:
Shortened Outflow Tract Leads to Altered Cardiac Looping After Neural Crest Ablation
Authors: T. Mesud Yelbuz, Karen L. Waldo, Donna H. Kumiski, Harriett A. Stadt, Raymond R. Wolfe, Linda Leatherbury, Margaret L. Kirby
Journal: Circulation (2002)

Background — Congenital conotruncal malformations frequently involve dextroposed aorta. The pathogenesis of dextroposed aorta is not known but is thought to be due to abnormal looping and/or wedging of the outflow tract during early heart development. We examined the stage of cardiac looping in an experimental model of dextroposed aorta to determine the embryogenesis of this conotruncal malformation. Methods and Results — Hearts were examined from neural crest–ablated embryos by using videocinephotography, scanning electron microscopy, and histological sections. The inflow and outflow limbs of the looped cardiac tube were malpositioned with respect to each other, the inner curvature was diminished, and the outflow limb was straighter and displaced cranially in a manner consistent with diminished length. The altered length could be explained by a significant reduction in the number of cells added to the myocardium of the distal outflow tract from the secondary heart field. Conclusions — The data are consistent with research showing that normal looping and wedging are essential for normal alignment of the aorta with the left ventricle. These processes are abnormal in neural crest–ablated embryos because of a failure of the outflow tract to lengthen by the addition of myocardial cells from the secondary heart field.
Sports prehospital-immediate care and spinal injury: not a car crash in sight
Authors: Jonathan R Hanson, Brian Carlin
Journal: British Journal of Sports Medicine (2012)

The prehospital management of serious injury is a key skill required of pitch-side medical staff. Previously, specific training in sports prehospital-immediate care was lacking or not of a comparable standard to other aspects of emergency care. Many principles have been drawn from general prehospital care or in-hospital training courses. This article discusses sports prehospital-immediate care as a niche of general prehospital care, using spinal injury management as an illustration of the major differences. It highlights the need to develop the sport-specific prehospital evidence base, rather than relying exclusively on considerations relevant to prolonged immobilisation of multiply injured casualties from motor vehicle accidents, falls from height or burns.
Risk factors and prognostic influence of infection in a single cohort of 87 adults with systemic lupus erythematosus
Authors: V Noel
Journal: Annals of the Rheumatic Diseases (2001)

<h3>OBJECTIVES</h3> To describe infectious complications and analyse their risk factors and prognostic role in adults with systemic lupus erythematosus (SLE). <h3>METHODS</h3> A monocentric cohort of 87 adults with SLE (1960–1997) was studied to determine the risk factors for infection (disease activity evaluated by SLAM and SLEDAI scores, type of organ(s) involved or any biological abnormality, specific treatments) by comparing patients who had suffered at least one infectious episode (n=35; 40%) with non-infected patients (n=52; 60%). Prognostic indicators were assessed by comparing survivors at 10 years with non-survivors. <h3>RESULTS</h3> Of the 57 infectious episodes, 47 (82%) were of bacterial origin, 16 (28%) were pneumonia, and 46 (81%) were community acquired. According to univariate analysis, significant risk factors for infection were: severe flares, lupus glomerulonephritis, oral or intravenous corticosteroids, pulse cyclophosphamide, and/or plasmapheresis. No predictors were identified at the time of SLE diagnosis. Multivariate analyses retained intravenous corticosteroids (p&lt;0.001) and/or immunosuppressants (p&lt;0.01) as independent risk factors for infection, which was the only factor for death after 10 years of evolution (p&lt;0.001). <h3>CONCLUSION</h3> In adults with SLE, infections are common and most often caused by community acquired bacteria. Intravenous corticosteroids and immunosuppressants are independent risk factors for infection, which is the only independent risk factor for death after 10 years of SLE evolution.
Infliximab improves vascular stiffness in patients with rheumatoid arthritis
Authors: M Wong, S P Oakley, L Young, B Y Jiang, A Wierzbicki, G Panayi, P Chowienczyk, B Kirkham
Journal: Annals of the Rheumatic Diseases (2008)

<h3>Objectives:</h3> Patients with rheumatoid arthritis (RA) have increased cardiovascular mortality. Tumour necrosis factor α (TNFα)-blocking therapy has been shown to reduce RA disease activity measures and joint damage progression. Some observational studies suggest that TNFα blockade reduces mortality and incidence of first cardiovascular events. The mechanisms contributing to these outcomes are unclear. This study assessed the effects of infliximab treatment on vascular stiffness and structure in patients with RA. <h3>Methods:</h3> A post hoc analysis of longitudinal data from a randomised placebo controlled study evaluated the effect of infliximab on vascular assessments. 26 patients received intravenous infliximab (3 mg/kg) at weeks 0, 2, 6 and every 8 weeks thereafter to week 54. Patients were followed up to 56 weeks of infliximab therapy with assessments of RA disease activity, cardiovascular risk factors, vascular stiffness (pulse wave velocity (PWV)), carotid intima media thickness (CIMT) and carotid artery plaque (CAP). Univariate analyses of changes over time by repeated measures analysis of variance (ANOVA) were followed by multivariate time-series regression analysis (TSRA) if changes were seen. <h3>Results:</h3> PWV was significantly lower (better) after 56 weeks of treatment with infliximab (ANOVA p&lt;0.01, TSRA p&lt;0.01). However, CIMT (ANOVA p = 0.50) and CAP (χ<sup>2</sup> = 4.13, p = 0.88) did not change over the study period. Multiple cardiovascular risk measures did not change with treatment and did not correlate with changes in measures of vascular structure. <h3>Conclusions:</h3> Arterial stiffness improves with infliximab treatment in RA. This change may help explain the improved cardiovascular disease survival in patients with RA receiving TNFα-blocking therapy.
Tumor Suppressor Alterations Cooperate to Drive Aggressive Mesotheliomas with Enriched Cancer Stem Cells via a p53–miR-34a–c-Met Axis
Authors: Craig W. Menges, Yuwaraj Kadariya, Deborah Altomare, Jacqueline Talarchek, Erin Neumann-Domer, Yue Wu, Guang-Hui Xiao, Irina M. Shapiro, Vihren N. Kolev, Jonathan A. Pachter, Andres J. Klein-Szanto, Joseph R. Testa
Journal: Cancer Research (2013)

Malignant mesothelioma is a highly aggressive, asbestos-related cancer frequently marked by mutations of both NF2 and CDKN2A. We demonstrate that germline knockout of one allele of each of these genes causes accelerated onset and progression of asbestos-induced malignant mesothelioma compared with asbestos-exposed Nf2(+/-) or wild-type mice. Ascites from some Nf2(+/-);Cdkn2a(+/-) mice exhibited large tumor spheroids, and tail vein injections of malignant mesothelioma cells established from these mice, but not from Nf2(+/-) or wild-type mice, produced numerous tumors in the lung, suggesting increased metastatic potential of tumor cells from Nf2(+/-);Cdkn2a(+/-) mice. Intraperitoneal injections of malignant mesothelioma cells derived from Nf2(+/-);Cdkn2a(+/-) mice into severe combined immunodeficient mice produced tumors that penetrated the diaphragm and pleural cavity and harbored increased cancer stem cells (CSC). Malignant mesothelioma cells from Nf2(+/-);Cdkn2a(+/-) mice stained positively for CSC markers and formed CSC spheroids in vitro more efficiently than counterparts from wild-type mice. Moreover, tumor cells from Nf2(+/-);Cdkn2a(+/-) mice showed elevated c-Met expression/activation, which was partly dependent on p53-mediated regulation of miR-34a and required for tumor migration/invasiveness and maintenance of the CSC population. Collectively, these studies demonstrate in vivo that inactivation of Nf2 and Cdkn2a cooperate to drive the development of highly aggressive malignant mesotheliomas characterized by enhanced tumor spreading capability and the presence of a CSC population associated with p53/miR-34a-dependent activation of c-Met. These findings suggest that cooperativity between losses of Nf2 and Cdkn2a plays a fundamental role in driving the highly aggressive tumorigenic phenotype considered to be a hallmark of malignant mesothelioma.
How to build a brain: Multiple memory systems have evolved and only some of them are constructivist
Authors: James E. Black, William T. Greenough
Journal: Behavioral and Brain Sciences (1997)

Much of our work with enriched experience and training in animals supports the Quartz &amp; Sejnowski (Q&amp;S) thesis that environmental information can interact with pre-existing neural structures to produce new synapses and neural structure. However, substantial data as well as an evolutionary perspective indicate that multiple information-capture systems exist: some are constructivist, some are selectionist, and some may be tightly constrained.
Long-term efficacy and safety of alemtuzumab in advanced primary cutaneous T-cell lymphomas
Authors: A. de Masson, P. Guitera, P. Brice, I. Moulonguet, F. Mouly, J.-D. Bouaziz, M. Battistella, I. Madelaine, J. Roux, C. Ram-Wolff, J.-M. Cayuela, H. Bachelez, A. Bensussan, L. Michel, M. Bagot
Journal: British Journal of Dermatology (2014)

Background Alemtuzumab has been proposed as salvage therapy for refractory cutaneous T-cell lymphomas (CTCLs). Long-term follow-up data are scarce. Objectives To assess the efficacy and safety of alemtuzumab in the treatment of advanced CTCL. Methods A multicentre retrospective analysis was carried out of 39 patients with advanced CTCL treated with alemtuzumab between 2003 and 2013. Results Thirty-nine patients (median age 62 years, range 20–83) with Sézary syndrome (SS, n = 23) or advanced mycosis fungoides (MF, n = 16) received alemtuzumab 30 mg two to three times per week for a median duration of 12 weeks (range 1–35). Fifteen patients received maintenance therapy for a median duration of 24 weeks (range 6–277). Eleven patients (28%) had transformed disease (MF, n = 10; SS, n = 1). After a median follow-up of 24 months (range 0·3–124), eight patients (21%) were still alive. The overall response rate was 51% in the whole study group (partial response, n = 13; complete response, n = 7); 70% in patients with SS and 25% in patients with MF (P = 0·009). The median time to progression was 3·4 months (range 0·4–42). Six patients (15%; SS, n = 5; MF, n = 1) remained progression free for > 2 years (median 56 months, range 28–117). Five patients experienced cutaneous large T-cell transformation during alemtuzumab treatment and one patient developed primary cutaneous large B-cell lymphoma. Twenty-four patients (62%) had a grade three or higher infectious adverse event and 10 (26%) a haematological toxicity, which led to treatment discontinuation in 17 cases (44%) and death in two (5%). Conclusions Alemtuzumab may induce long-term remission in SS but seems ineffective in MF and transformed CTCL.
Effect of two gold compounds on lysosomes.
Authors: P M Graabaek, S M Pedersen
Journal: Annals of the Rheumatic Diseases (1988)

The effect of two gold(I) compounds on stability of lysosomes in vitro was studied. Lysosomes from homogenates of rat kidney cortex were isolated by differential centrifugation. These lysosomes were incubated at 37 degrees C with widely varied concentrations of sodium aurothiomalate and sodium aurothiosulphate for 5, 35, and 65 minutes. Acid phosphatase activities were measured and used as an indication of lysosomal membrane stability in the presence and absence of drugs. The enhanced release of acid phosphatase from lysosomes by aurothiomalate and aurothiosulphate was related to dose, but the drugs differed substantially in their potencies. The disruptive effect on lysosomes was more marked for aurothiosulphate than for aurothiomalate. In addition, both drugs inhibited acid phosphatase activities at relatively high gold concentrations. Aurothiomalate had a moderate and aurothiosulphate a weaker inhibitory effect on the enzyme. Our results indicate that aurothiomalate and aurothiosulphate exert their beneficial effect in the treatment of rheumatoid arthritis through mechanism(s) other than lysosomal membrane stabilisation.
CD137 Accurately Identifies and Enriches for Naturally Occurring Tumor-Reactive T Cells in Tumor
Authors: Qunrui Ye, De-Gang Song, Mathilde Poussin, Tori Yamamoto, Andrew Best, Chunsheng Li, George Coukos, Daniel J. Powell
Journal: Clinical Cancer Research (2013)

Upregulation of CD137 (4-1BB) on recently activated CD8(+) T cells has been used to identify rare viral or tumor antigen-specific T cells from peripheral blood. Here, we evaluated the immunobiology of CD137 in human cancer and the utility of a CD137-positive separation methodology for the identification and enrichment of fresh tumor-reactive tumor-infiltrating lymphocytes (TIL) or tumor-associated lymphocytes (TAL) from ascites for use in adoptive immunotherapy.TILs from resected ovarian cancer or melanoma were measured for surface CD137 expression directly or after overnight incubation in the presence of tumor cells and homeostatic cytokines. CD137(pos) TILs were sorted and evaluated for antitumor activity in vitro and in vivo.Fresh ovarian TILs and TALs naturally expressed higher levels of CD137 than circulating T cells. An HLA-dependent increase in CD137 expression was observed following incubation of fresh enzyme-digested tumor or ascites in IL-7 and IL-15 cytokines, but not IL-2. Enriched CD137(pos) TILs, but not PD-1(pos) or PD-1(neg) CD137(neg) cells, possessed autologous tumor reactivity in vitro and in vivo. In melanoma studies, all MART-1-specific CD8(+) TILs upregulated CD137 expression after incubation with HLA-matched, MART-expressing cancer cells and antigen-specific effector function was restricted to the CD137(pos) subset in vitro. CD137(pos) TILs also mediated superior antitumor effects in vivo, compared with CD137(neg) TILs.Our findings reveal a role for the TNFR-family member CD137 in the immunobiology of human cancer where it is preferentially expressed on tumor-reactive subset of TILs, thus rationalizing its agonistic engagement in vivo and its use in TIL selection for adoptive immunotherapy trials.
VEGF-C and VEGF-D Blockade Inhibits Inflammatory Skin Carcinogenesis
Authors: Annamari K. Alitalo, Steven T. Proulx, Sinem Karaman, David Aebischer, Stefania Martino, Manuela Jost, Nicole Schneider, Maija Bry, Michael Detmar
Journal: Cancer Research (2013)

Abstract VEGF-C and VEGF-D were identified as lymphangiogenic growth factors and later shown to promote tumor metastasis, but their effects on carcinogenesis are poorly understood. Here, we have studied the effects of VEGF-C and VEGF-D on tumor development in the murine multistep chemical carcinogenesis model of squamous cell carcinoma by using a soluble VEGF-C/VEGF-D inhibitor. After topical treatment with a tumor initiator and repeated tumor promoter applications, transgenic mice expressing a soluble VEGF-C/VEGF-D receptor (sVEGFR-3) in the skin developed significantly fewer squamous cell tumors with a delayed onset when compared with wild-type mice or mice expressing sVEGFR-3 lacking the ligand-binding site. Epidermal proliferation was reduced in the carcinogen-treated transgenic skin, whereas epidermal keratinocyte proliferation in vitro was not affected by VEGF-C or VEGF-D, indicating indirect effects of sVEGFR-3 expression. Importantly, transgenic mouse skin was less sensitive to tumor promoter–induced inflammation, with reduced angiogenesis and blood vessel leakage. Cutaneous leukocytes, especially macrophages, were reduced in transgenic skin without major changes in macrophage polarization or blood monocyte numbers. Several macrophage-associated cytokines were also reduced in transgenic papillomas, although the dermal macrophages themselves did not express VEGFR-3. These findings indicate that VEGF-C/VEGF-D are involved in shaping the inflammatory tumor microenvironment that regulates early tumor progression. Our results support the use of VEGF-C/VEGF-D–blocking agents not only to inhibit metastatic progression, but also during the early stages of tumor growth. Cancer Res; 73(14); 4212–21. ©2013 AACR.
Changes in atrial and ventricular refractoriness and in atrioventricular nodal conduction produced by combinations of vagal and sympathetic stimulation that result in a constant spontaneous sinus cycle length.
Authors: H Inoue, D P Zipes
Journal: Circulation Research (1987)

The vagal nerves modulate adrenergic effects on sinus cycle length, atrioventricular (AV) nodal conduction, and refractoriness of atria and ventricles. We tested whether varying levels of vagal-sympathetic input could yield the same spontaneous sinus cycle length but also alter effective refractory periods of the right atrium, right ventricle, and left ventricle and AV nodal conduction times. Dogs anesthetized by alpha-chloralose were studied in the open-chest, neurally decentralized state. In 10 dogs, sinus cycle length was maintained constant during 3 levels of bilateral ansae subclaviae stimulation (4 msec, 3 mA at 1, 2, and 4 Hz) by titrating simultaneous bilateral vagal stimulation (varying pulse width and frequency). Each combination of ansae subclaviae-vagal stimulation yielded the same sinus cycle length as the control value, but refractory periods of right atrium and right and left ventricles shortened progressively as the frequency of ansae subclaviae stimulation increased. Atrioventricular nodal conduction time (AH interval) shortened in 2 dogs and lengthened in 3 dogs. His-Purkinje conduction time (HV interval) was unchanged. In 9 dogs, the effect of simultaneous unilateral ansae subclaviae stimulation at 2 Hz and ipsilateral vagal stimulation that yielded the same sinus cycle length were determined. Right-sided ansae subclaviae-vagal stimulation shortened refractoriness of right atrium and anterior left ventricle significantly. The AH interval lengthened in 1 dog. Left ansae subclaviae-vagal stimulation shortened the refractory periods of anterior and posterior left ventricle significantly and reduced the AH interval in 3 dogs. In 8 dogs, the effects of bilateral ansae subclaviae stimulation alone at 2 Hz, vagal stimulation alone at an intensity required to keep the sinus cycle length constant during ansae subclaviae stimulation, and simultaneous bilateral ansae subclaviae and vagal stimulation were tested. The right atrial refractory period was shortened significantly by ansae subclaviae stimulation alone and by vagal stimulation alone and was shortened further by simultaneous stimulation of both autonomic limbs. The right and left ventricular refractory periods were shortened by ansae subclaviae stimulation alone and by simultaneous stimulation of both limbs but tended to be prolonged by vagal stimulation alone and when added to ansae subclaviae stimulation. In 7 dogs, the effects of simultaneous stimulation of bilateral ansae subclaviae at 2 Hz and vagi at intensities that maintained the AH interval constant at an atrial pacing cycle length of 300 msec were determined.(ABSTRACT TRUNCATED AT 400 WORDS)
Enalapril and Losartan Reduce Sympathetic Hyperactivity in Patients with Chronic Renal Failure
Authors: Inge H H T Klein, Gerry Ligtenberg, P Liam Oey, Hein A Koomans, Peter J Blankestijn
Journal: Journal of the American Society of Nephrology (2003)

ABSTRACT. The aim of this study was to compare the effects on BP and sympathetic activity of chronic treatment with an angiotensin (Ang)-converting enzyme (ACE) inhibitor and an AngII receptor blocker in hypertensive patients with chronic renal failure (CRF). In ten stable hypertensive CRF patients (creatinine clearance, 46 ± 17 ml/min per 1.73 m<sup>2</sup>), muscle sympathetic nerve activity (MSNA), plasma renin activity (PRA), baroreceptor sensitivity, and 24-h ambulatory BP were measured in the absence of antihypertensive drugs (except diuretics) after 6 wk of enalapril (10 mg orally) and after 6 wk of losartan (100 mg orally). The order of the three phases was randomized. Normovolemia was controlled with diuretics and confirmed with extracellular fluid volume measurements throughout the study. Both enalapril and losartan reduced MSNA (from 33 ± 10 to 27 ± 13 and 27 ± 13 bursts/min, respectively; <i>P</i> &lt; 0.05) and average 24-h BP (from 141 ± 8/93 ± 8 to 124 ± 9/79 ± 8 and 127 ± 8/81 ± 9 mmHg; <i>P</i> &lt; 0.01). PRA was not different during the treatments. The change in BP and the change in MSNA during the treatments were correlated (<i>r</i> = 0.70 and <i>r</i> = 0.63, respectively; both <i>P</i> &lt; 0.05). Baroreceptor sensitivity was not affected by the treatments. This is the first study to compare the effects of ACE inhibition and AngII blockade on MSNA. In hypertensive CRF patients, enalapril and losartan equally reduced BP and MSNA. Differences in modes of action of the two drugs did not result in differences in effects on MSNA, supporting the view that AngII-mediated mechanisms contribute importantly in the pathogenesis of sympathetic hyperactivity in these patients. E-mail: p.j.blankestijn@azu.nl
Basal Insulin Peglispro Demonstrates Preferential Hepatic Versus Peripheral Action Relative to Insulin Glargine in Healthy Subjects
Authors: Robert R. Henry, Sunder Mudaliar, Theodore P. Ciaraldi, Debra A. Armstrong, Paivi Burke, Jeremy Pettus, Parag Garhyan, Siak Leng Choi, Scott J. Jacober, Mary Pat Knadler, Eric Chen Quin Lam, Melvin J. Prince, Namrata Bose, Niels Porksen, Vikram P. Sinha, Helle Linnebjerg
Journal: Diabetes Care (2014)

We evaluated the endogenous glucose production (EGP) and glucose disposal rate (GDR) over a range of doses of basal insulin peglispro (BIL) and insulin glargine in healthy subjects.This was a single-center, randomized, open-label, four-period, incomplete-block, crossover study conducted in eight healthy male subjects. Subjects had 8-h euglycemic clamps performed with primed, continuous infusions of BIL (5.1 to 74.1 mU/min) in three dosing periods and insulin glargine (20 or 30 mU/m(2)/min) in a fourth period, targeted to achieve 50-100% suppression of EGP. D-[3-(3)H] glucose was infused to assess rates of glucose appearance and disappearance.Mean BIL and insulin glargine concentrations (targeted to reflect the differences in intrinsic affinities of the two basal insulins) ranged from 824 to 11,400 and 212 to 290 pmol/L, respectively, and increased accordingly with increases in dose. Suppression of EGP and stimulation of GDR were observed with increasing concentrations of both insulins. At insulin concentrations where EGP was significantly suppressed, insulin glargine resulted in increased GDR. In contrast, at comparable suppression of EGP, BIL had minimal effect on GDR at lower doses and had substantially less effect on GDR than insulin glargine at higher doses.The novel basal insulin analog BIL has relative hepatopreferential action and decreased peripheral action, compared with insulin glargine, in healthy subjects.
Human mesenchymal stem cells derived from induced pluripotent stem cells down-regulate NK-cell cytolytic machinery
Authors: Massimo Giuliani, Noufissa Oudrhiri, Zaeem M. Noman, Amelia Vernochet, Salem Chouaib, Bruno Azzarone, Antoine Durrbach, Annelise Bennaceur-Griscelli
Journal: Blood (2011)