tbuckley/cabot-search huggingface dataset:
Heart rate reduction with ivabradine improves energy metabolism and mechanical function of isolated ischaemic rabbit heart
Authors: Claudio Ceconi, Anna Cargnoni, Gloria Francolini, Giovanni Parinello, Roberto Ferrari
Journal: Cardiovascular Research (2009)

The anti-anginal agent ivabradine slows heart rate (HR) by selectively inhibiting the If current in the sinus node. We report an ex vivo study to evaluate the anti-ischaemic effect of ivabradine in terms of modulation of cardiac energy metabolism. A Langendorff-perfused rabbit heart model was subjected to low-flow ischaemia and reperfusion. Cardiac metabolism was studied by measuring cardiac high-energy phosphate contents via HPLC, mitochondrial respiration was analysed polarographically, and cardiac redox potentials by HPLC. Cardiac function was determined in terms of the recovery of developed pressure during reperfusion and release of creatine kinase (CK) (spectrophotometrically) and noradrenaline (HPLC) after reperfusion. Four concentrations of ivabradine (0.3, 1, 3, and 6 µM) were tested on aerobically perfused hearts to select the most effective without causing changes in mechanical parameters. This proved to be 3 µM, which was therefore the concentration selected for the ischaemia-reperfusion experiments. Ivabradine concentration-dependently reduced HR with a maximal effect of 41 ± 4% at 3 µM (P < 0.001 vs. vehicle), without a negative inotropic effect. This concentration protected the heart against ischaemia-reperfusion damage by reducing the rise in diastolic pressure (from 66 ± 3 with vehicle to 39 ± 4 mmHg, P < 0.01) and improving developed pressure after 30 min reperfusion (39 ± 3 vs. 18 ± 3 mmHg with vehicle, P < 0.01). Ivabradine reduced both CK and noradrenaline release by 47% (both P < 0.05 vs. vehicle) and improved mitochondrial respiratory control index (from 6.9 ± 0.3 to 11.9 ± 1.3, P < 0.001). It preserved cardiac energy metabolism (ATP, from 3.7 ± 0.3 to 11.0 ± 0.6 µM/g dry weight, P < 0.001) and redox state (NADPH/NADP+, from 2.5 ± 0.5 to 4.2 ± 0.5, P < 0.001). There was a significant correlation between HR reduction in the ivabradine-treated hearts and cardiac creatine phosphate (r = 0.574, P = 0.02) and ATP levels (ATP, r = 0.674, P = 0.0042) at the end of ischaemia. These benefits were no longer detectable during pacing. HR reduction by ivabradine confers a marked anti-ischaemic benefit. It significantly reduces cardiac energy consumption, preserves redox potentials during ischaemia, and enhances recovery at reperfusion.
Role of hydrogen peroxide in neutrophil-mediated destruction of cultured endothelial cells.
Authors: S J Weiss, J Young, A F LoBuglio, A Slivka, N F Nimeh
Journal: Journal of Clinical Investigation (1981)

Human neutrophils stimulated with phorbol myristate acetate were able to destroy suspensions or monolayers of cultured human endothelial cells. Neutrophil-mediated cytotoxicity was related to phorbol myristate acetate concentration, time of incubation and neutrophil number. Cytolysis was prevented by the addition of catalase, while superoxide dismutase had no effect on cytotoxicity. The addition of the heme-enzyme inhibitors, azide or cyanide, markedly stimulated neutrophil-mediated damage while exogenous myeloperoxidase failed to stimulate cytolysis. Neutrophils isolated from patients with chronic granulomatous disease did not destroy the endothelial cell targets while myeloperoxidase-deficient neutrophils successfully mediated cytotoxicity. Endothelial cell damage mediated by the myeloperoxidase deficient cells was also inhibited by catalase but not superoxide dismutase. The addition of purified myeloperoxidase to the deficient cells did not stimulate cytotoxicity. Glucose-glucose oxidase, an enzyme system capable of generating hydrogen peroxide, could replace the neutrophil as the cytotoxic mediator. The addition of myeloperoxidase at low concentrations of glucose oxidase did not increase cytolysis, but at the higher concentrations of glucose oxidase it stimulated cytotoxicity. The destruction of endothelial cells by the glucose oxidase-myeloperoxidase system was inhibited by the addition of hypochlorous acid scavengers. In contrast, neutrophil-mediated cytolysis was not effectively inhibited by the hypochlorous acid scavengers. Based on these observations, we propose that human neutrophils can destroy cultured human endothelial cells by generating cytotoxic quantities of hydrogen peroxide.
If Rabbits Can Regenerate the Eye's Lens, Will Science Find a Way for Humans to Do It?
Authors: None Carin M.
Journal: JAMA (1989)

THE ABILITY of rabbits to regenerate the lens of the eye was observed and described by French investigators in 1824. Now, Arlene Gwon, MD, Department of Ophthalmology, University of California, Irvine, and colleagues have used that model in developing techniques to induce lens regeneration. The investigators use ultrasound to break up the material within the rabbit lens capsule (phacoemulsification). The cȯntents are aspirated, and fetal cells are placed within the lens capsule. <h3>Regrowth Pattern</h3> The pattern of regrowth follows that of embryonic development. The crystallin proteins that develop are the same as in the adult lens, but in proportions similar to those found in fetal lenses, the researchers explained at the recent Research to Prevent Blindness science writers' conference in Arlington, Va. They add that this model can be used to study the influence of growth factors, either to promote or inhibit growth. Presently, 1 million Americans have cataract surgery
Predicting asthma in preschool children with asthma-like symptoms: Validating and updating the PIAMA risk score
Authors: Esther Hafkamp-de Groen, Hester F. Lingsma, Daan Caudri, Deborah Levie, Alet Wijga, Gerard H. Koppelman, Liesbeth Duijts, Vincent W.V. Jaddoe, Henriëtte A. Smit, Marjan Kerkhof, Henriëtte A. Moll, Albert Hofman, Ewout W. Steyerberg, Johan C. de Jongste, Hein Raat
Journal: Journal of Allergy and Clinical Immunology (2013)
Prenatal Exposure to Maternal Cigarette Smoking, Amygdala Volume, and Fat Intake in Adolescence
Authors: Amirreza Haghighi, Deborah H. Schwartz, Michal Abrahamowicz, Gabriel T. Leonard, Michel Perron, Louis Richer, Suzanne Veillette, Daniel Gaudet, Tomáš Paus, Zdenka Pausova
Journal: JAMA Psychiatry (2012)

<h3>Context</h3>Prenatal exposure to maternal cigarette smoking is a well-established risk factor for obesity, but the underlying mechanisms are not known. Preference for fatty foods, regulated in part by the brain reward system, may contribute to the development of obesity.<h3>Objective</h3>To examine whether prenatal exposure to maternal cigarette smoking is associated with enhanced fat intake and risk for obesity, and whether these associations may be related to subtle structural variations in brain regions involved in reward processing.<h3>Design</h3>Cross-sectional study of a population-based cohort.<h3>Setting</h3>The Saguenay Youth Study, Quebec, Canada.<h3>Participants</h3>A total of 378 adolescents (aged 13 to 19 years; Tanner stage 4 and 5 of sexual maturation), half of whom were exposed prenatally to maternal cigarette smoking (mean [SD], 11.1 [6.8] cigarettes/d).<h3>Main Outcome Measures</h3>Fat intake was assessed with a 24-hour food recall (percentage of energy intake consumed as fat). Body adiposity was measured with anthropometry and multifrequency bioimpedance. Volumes of key brain structures involved in reward processing, namely the amygdala, nucleus accumbens, and orbitofrontal cortex, were measured with magnetic resonance imaging.<h3>Results</h3>Exposed vs nonexposed subjects exhibited a higher total body fat (by approximately 1.7 kg; P = .009) and fat intake (by 2.7%; P = .001). They also exhibited a lower volume of the amygdala (by 95 mm<sup>3</sup>; P &lt; .001) but not of the other 2 brain structures. Consistent with its possible role in limiting fat intake, amygdala volume correlated inversely with fat intake (r = −0.15; P = .006).<h3>Conclusions</h3>Prenatal exposure to maternal cigarette smoking may promote obesity by enhancing dietary preference for fat, and this effect may be mediated in part through subtle structural variations in the amygdala.
Underdiagnosis of Peripheral Neuropathy in Type 2 Diabetes
Authors: William H. Herman, Laurence Kennedy
Journal: Diabetes Care (2005)

Diabetic peripheral neuropathy and its late sequelae cost >$4 billion annually in the U.S. (1). Improved glycemic control, early detection, and preventive care can prevent or delay adverse outcomes (2–4). An annual foot exam, which may include monofilament testing, is recommended by the American Diabetes Association (5). Unfortunately, neuropathy screening is underutilized in primary care practice (6,7). The GOAL A1C (Glycemic Optimization with Algorithms and Labs At Po1nt of Care) study assessed methods of A1C testing and insulin titration monitoring strategies in a large nationwide sample of predominantly primary care patients with type 2 diabetes. At baseline, physician perception of the presence of neuropathy was assessed via a survey before monofilament testing. A comparison between physician perception and monofilament testing is reported.

GOAL A1C was a randomized, open-label, parallel, four-arm study that compared the impact of point of care versus laboratory A1C testing and weekly versus less frequent insulin titration monitoring on glycemic control in patients with type 2 diabetes adding insulin glargine to existing oral antidiabetic therapy. Eligible patients were aged ≥18 years, inadequately controlled on oral antidiabetic agents (A1C >7.0%), and candidates for insulin. All signed informed consent …
Efficacy and safety of tanezumab monotherapy or combined with non-steroidal anti-inflammatory drugs in the treatment of knee or hip osteoarthritis pain
Authors: Thomas J Schnitzer, Evan F Ekman, Egilius L H Spierings, H Scott Greenberg, Michael D Smith, Mark T Brown, Christine R West, Kenneth M Verburg
Journal: Annals of the Rheumatic Diseases (2014)

Objective To evaluate whether subjects with knee or hip osteoarthritis (OA) pain on non-steroidal anti-inflammatory drugs (NSAIDs) received greater benefit when tanezumab monotherapy replaced or was coadministered with NSAIDs. Methods Subjects (N=2700) received intravenous tanezumab (5 or 10 mg) or placebo every 8 weeks with or without oral naproxen 500 mg twice daily or celecoxib 100 mg twice daily. Efficacy was assessed as change from baseline to week 16 in three co-primary endpoints: Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) Pain, WOMAC Physical Function and Patient's Global Assessment (PGA) of OA. Safety assessments included adverse events, physical and neurological examinations, laboratory tests and vital signs. Results Although all tanezumab treatments provided significant improvements in WOMAC Pain and Physical Function over either NSAID alone, only tanezumab+NSAIDs were significant versus NSAIDs with PGA and met the prespecified definition of superiority. Combination treatment did not substantially improve pain or function over tanezumab monotherapy. Adverse event frequency was higher with tanezumab than with NSAIDs and highest with combination therapy. Higher incidence of all-cause total joint replacements occurred with tanezumab+NSAID versus tanezumab monotherapy or NSAIDs. Rapidly progressive OA incidence was significantly greater versus NSAID in all tanezumab groups except tanezumab 5 mg monotherapy. Conclusions Subjects receiving partial symptomatic relief of OA pain with NSAIDs may receive greater benefit with tanezumab monotherapy. While only coadministration of tanezumab with NSAIDs met the definition of superiority, combination treatment did not provide important benefits over tanezumab monotherapy; small differences in efficacy were negated by treatment-limiting or irreversible safety outcomes. Trial registration number NCT00809354
Childhood Pulmonary Tuberculosis
Authors: Ben J. Marais, Robert P. Gie, H. Simon Schaaf, Nulda Beyers, Peter R. Donald, Jeff R. Starke
Journal: American Journal of Respiratory and Critical Care Medicine (2006)

Section:ChooseTop of pageAbstract <<CONTENTSCONCEPTS FROM THE NATURAL...DIAGNOSISTREATMENTCONCLUSIONSReferencesCITING ARTICLES
Treatment of unresectable stage IV metastatic melanoma with aviscumine after anti-neoplastic treatment failure: a phase II, multi-centre study
Authors: Uwe Trefzer, Ralf Gutzmer, Tabea Wilhelm, Florian Schenck, Katharina C Kähler, Volkmar Jacobi, Klaus Witthohn, Hans Lentzen, Peter Mohr
Journal: Journal for ImmunoTherapy of Cancer (2014)

Aviscumine, a recombinant plant protein, is an immune modulator that induces ribotoxic stress at the 28S ribosomal RNA subunit. In this way cytokine release and T-cell responses are enhanced. This phase II trial was conducted to test the efficacy and safety of aviscumine in patients with systemically pre-treated metastatic melanoma stage IV.A total of 32 patients with progressive stage IV melanoma after failure of standard therapy were enrolled onto a single-arm, multi-centre, open-label, phase II trial. All patients had an ECOG performance status of 0 or 1. Patients received 350 ng aviscumine twice weekly by subcutaneous injection until progression. The primary end points were progression-free survival (PFS) and overall survival (OS). Safety was assessed as adverse events (AEs). Tumor response was assessed every eight weeks and survival of patients was followed up to one year after the end of therapy. Thirty one patients (intent-to-treat population (ITT)) were assessed for efficacy; safety was assessed in the whole population.One patient achieved a partial response (PR) and 10 patients showed stable disease/no change (SD). The median progression-free survival (mPFS) was 63 days (95% CI 57-85) and median overall survival (mOS) was 335 days (95% CI 210-604). In total 210 treatment-emergent adverse events were recorded. Grade 1 or 2 AEs occurred in 72% of patients and were mostly application-site effects such as pruritus Grade 3-4 treatment-emergent drug-related adverse events occurred in 9% of patients.These results suggest that aviscumine may have a clinical impact in patients with previously treated metastatic melanoma and provide rationale for further clinical evaluation of this agent. In the light of effective new immune checkpoint blockers it might be a candidate for combinations with these agents.ClinicalTrials.gov: NCT00658437.
Change in smoking status after low-dose spiral chest CT screening for lung cancer: opportunity for smoking intervention
Authors: M. M Clark, J. R Jett
Journal: Thorax (2009)

an extension of the original finding, which needs further replication itself to increase the likelihood that the reported association is real.Nevertheless, these studies, as well as failures to replicate, should be published to evolve a full picture of a gene's possible effects.Much can be learned from these findings and, in the end, they may be even more important for our understanding of genetics and disease mechanisms in complex diseases than straightforward replication.Blakey et al studied five positionally cloned genes, initially found in linkage and association studies in children.They now aimed to replicate associations with asthma, wheezing and IgE in their large British population sample.They found small but significant effects for polymorphisms in DPP10 and ADAM33 (and borderline for GPR154), with odds ratios of around 1.1 per allele.Is this the final verdict on the role of these genes in asthma?Rather not.Although this is a large and well phenotyped cross-sectional and probably unbiased population sample, it is a snapshot in time.The individuals studied were born in 1 week of 1958 in Britain.It may be assumed that environmental factors were very different at the time these individuals developed their asthma compared with children growing up nowadays.Looking back on the second half of the 20th century we have witnessed rising prevalence rates for asthma, and fundamental changes in lifestyle, diet, and personal and meta-environments.It could very well be that asthma of today's children and youth is the result of mechanisms different from those relevant for asthma development 50 years ago.However, when associations are found consistently across time, this could point to very basic and timeless asthma mechanisms.This is nothing but a hypothesis-but one to consider when indulging in replication studies such as this that look simple at first glance but may hold more food for thought than expected.
Host Antitumor Immunity Plays a Role in the Survival of Patients With Newly Diagnosed Triple-Negative Breast Cancer
Authors: Sherene Loi
Journal: Journal of Clinical Oncology (2014)

In the article that accompanies this editorial, Adams et al report on the prognostic value of the presence of tumor-infiltrating lymphocytes (TILs) evaluated on samples from 481 patients with triplenegative breast cancer (TNBC) who were enrolled onto two prospective Eastern Cooperative Oncology Group (ECOG) adjuvant clinical trials (E2197 and E1199). This prospectively defined, retrospective analysis was powered to replicate findings from previous reports, by using the same method of quantification, to confirm that TILs are positively associated with prognosis in primary TNBC. Despite the independent nature of this validation study, the point estimates for the adjusted hazard ratios for disease-free and overall survival were remarkably similar to those previously reported (Table 1). Given that the multitude of biomarker findings are never further validated, the authors should be commended for attempting to
A phase I study of the humanized monoclonal anti-epidermal growth factor receptor (EGFR) antibody EMD 72000 (matuzumab) in combination with paclitaxel in patients with EGFR-positive advanced non-small-cell lung cancer (NSCLC)
Authors: C. Kollmannsberger, M. Schittenhelm, F. Honecker, J. Tillner, D. Weber, K. Oechsle, L. Kanz, C. Bokemeyer
Journal: Annals of Oncology (2006)
Bone protection by estrens occurs through non–tissue-selective activation of the androgen receptor
Authors: Sara H. Windahl, René Galien, Riccardo Chiusaroli, Philippe Clément-Lacroix, Frederic Morvan, Liên Lepescheux, François Nique, William C. Horne, Michèle Resche-Rigon, Roland Baron
Journal: Journal of Clinical Investigation (2006)

The use of estrogens and androgens to prevent bone loss is limited by their unwanted side effects, especially in reproductive organs and breast. Selective estrogen receptor modulators (SERMs) partially avoid such unwanted effects, but their efficacy on bone is only moderate compared with that of estradiol or androgens. Estrens have been suggested to not only prevent bone loss but also exert anabolic effects on bone while avoiding unwanted effects on reproductive organs. In this study, we compared the effects of a SERM (PSK3471) and 2 estrens (estren-α and estren-β) on bone and reproductive organs to determine whether estrens are safe and act via the estrogen receptors and/or the androgen receptor (AR). Estrens and PSK3471 prevented gonadectomy-induced bone loss in male and female mice, but none showed true anabolic effects. Unlike SERMs, the estrens induced reproductive organ hypertrophy in both male and female mice and enhanced MCF-7 cell proliferation in vitro. Estrens directly activated transcription in several cell lines, albeit at much higher concentrations than estradiol or the SERM, and acted for the most part through the AR. We conclude that the estrens act mostly through the AR and, in mice, do not fulfill the preclinical efficacy or safety criteria required for the treatment or prevention of osteoporosis.
Patterns of Cortical Synchronization in Isolated Dystonia Compared With Parkinson Disease
Authors: Svjetlana Miocinovic, Coralie de Hemptinne, Salman Qasim, Jill L. Ostrem, Philip A. Starr
Journal: JAMA Neurology (2015)

<h3>Importance</h3> Isolated dystonia and Parkinson disease (PD) are disorders of the basal gangliothalamocortical network. They have largely distinct clinical profiles, but both disorders respond to deep brain stimulation (DBS) in the same subcortical targets using similar stimulation paradigms, suggesting pathophysiologic overlap. We hypothesized that, similar to PD, isolated dystonia is associated with elevated cortical neuronal synchronization. <h3>Objective</h3> To investigate the electrophysiologic characteristics of the sensorimotor cortex arm-related area using a temporary subdural electrode strip in patients with isolated dystonia and PD undergoing DBS implantation in the awake state. <h3>Design, Setting, and Participants</h3> An observational study recruited patients scheduled for DBS at the University of California, San Francisco and the San Francisco Veterans Affairs Medical Center. Data were collected from May 1, 2008, through April 1, 2015. Findings are reported for 22 patients with isolated cervical or segmental dystonia (8 with [DYST-ARM] and 14 without [DYST] arm symptoms) and 14 patients with akinetic rigid PD. Data were analyzed from November 1, 2014, through May 1, 2015. <h3>Main Outcomes and Measures</h3> Cortical local field potentials, power spectral density, and phase-amplitude coupling (PAC). <h3>Results</h3> Among our 3 groups that together included 36 patients, cortical PAC was present in primary motor and premotor arm-related areas for all groups, but the DYST group was less likely to exhibit increased PAC (<i>P</i>= .008). Similar to what has been shown for patients with PD, subthalamic DBS reversibly decreased PAC in a subset of patients with dystonia who were studied before and during intraoperative test stimulation (n = 4). At rest, broadband gamma (50-200 Hz) power in the primary motor cortex was greater in the DYST-ARM and PD groups compared with the DYST group, whereas alpha (8-13 Hz) and beta (13-30 Hz) power was comparable in all 3 groups. During movement, the DYST-ARM group had impaired beta and low gamma desynchronization in the primary motor cortex. <h3>Conclusions and Relevance</h3> Isolated dystonia and PD have physiologic overlap with respect to high levels of motor cortex synchronization and reduction of cortical synchronization by subthalamic DBS, providing an explanation for their similar therapeutic response to basal ganglia stimulation.