tbuckley/cabot-search huggingface dataset:
Mechanisms of Disease of Eosinophilic Esophagitis
Authors: Benjamin P. Davis, Marc E. Rothenberg
Journal: Annual Review of Pathology Mechanisms of Disease (2016)

Eosinophilic esophagitis (EoE) is a recently recognized inflammatory disease of the esophagus with clinical symptoms derived from esophageal dysfunction. The etiology of EoE is now being elucidated, and food hypersensitivity is emerging as the central cornerstone of disease pathogenesis. Herein, we present a thorough picture of the current clinical, pathologic, and molecular understanding of the disease with a focus on disease mechanisms.
Absolute lymphocyte count predicts therapeutic efficacy and survival at the time of radioimmunotherapy in patients with relapsed follicular lymphomas
Authors: L F Porrata, K Ristow, T E Witzig, N Tuinistra, T M Habermann, D J Inwards, S M Ansell, I N Micallef, P B Johnston, S N Markovic
Journal: Leukemia (2007)
Effect of breathing techniques on blood pressure response to resistance exercise.
Authors: S T Linsenbardt, T R Thomas, R W Madsen
Journal: British Journal of Sports Medicine (1992)

Twenty novice male weight lifters performed resistance exercises using three different breathing techniques to determine the effects on blood pressure. Systolic and diastolic blood pressures were measured by an automated non-invasive method while subjects performed the single arm curl and double knee extension using the different breathing techniques. Performing the Valsalva manoeuvre (breath-holding) during either the single arm curl or double knee extension produced the highest blood pressure responses. Inhaling during the concentric phase of the exercise was associated with blood pressure elevations that were similar to the elevations observed with exhaling during the concentric phase. The heart rate response was slightly higher with inhalation. These results suggest that performing the Valsalva manoeuvre exaggerates the blood pressure response to resistance exercise. In addition, coupling inhalation with the concentric phase of the lift offers no cardiovascular advantage over coupling exhalation with the concentric phase of the lift.
Differences in microsatellite DNA level between asthma and chronic obstructive pulmonary disease
Authors: M. I. Zervou, E. G. Tzortzaki, D. Makris, M. Gaga, E. Zervas, E. Economidou, M. Tsoumakidou, N. Tzanakis, J. Milic-Emili, N. M. Siafakas
Journal: European Respiratory Journal (2006)

Previous studies have shown that microsatellite (MS) DNA instability (MSI) is detectable in sputum cells in chronic obstructive pulmonary disease (COPD) and asthma. The aim of the present study was to investigate whether asthma and COPD could be distinguished at the MS DNA level. DNA was extracted from sputum cells and white blood cells from 63 COPD patients, 60 non-COPD smokers, 36 asthmatics and 30 healthy nonsmokers. Ten MS markers located on chromosomes 2p, 5q, 6p, 10q, 13q, 14q and 17q were analysed. No MSI was detected in non-COPD smokers or healthy nonsmokers. A significantly higher proportion of COPD patients exhibited MSI (49.2%) compared to asthmatics (22.2%). MSI was detected even in the mild stages of COPD (33.3%) and asthma (22.2%). No relationship was found between MSI and COPD severity. The most frequently affected marker was D14S588 (17.5% in COPD and 2.7% in asthma). The markers D6S344, G29802 and D13S71 showed alterations only in COPD, and G29802 was associated with a significantly decreased forced expiratory volume in one second FEV 1 (% predicted), whereas MSI in D6S344 was associated with a significantly higher FEV 1 (% pred). The frequency of microsatellite instability was higher in chronic obstructive pulmonary disease than in asthma, and microsatellite instability in three workers showed chronic obstructive pulmonary disease specificity. However, further studies are needed to verify the differences between chronic obstructive pulmonary disease and asthma at the microsatellite level.
Dissociation of FKBP12.6 from ryanodine receptor type 2 is regulated by cyclic ADP-ribose but not β-adrenergic stimulation in mouse cardiomyocytes
Authors: Xu Zhang, Yvonne N. Tallini, Zheng Chen, Lu Gan, Bin Wei, Robert Doran, Lin Miao, Hong-Bo Xin, Michael I. Kotlikoff, Guangju Ji
Journal: Cardiovascular Research (2009)

Beta-adrenergic augmentation of Ca(2+) sparks and cardiac contractility has been functionally linked to phosphorylation-dependent dissociation of FK506 binding protein 12.6 (FKBP12.6) regulatory proteins from ryanodine receptors subtype 2 (RYR2). We used FKBP12.6 null mice to test the extent to which the dissociation of FKBP12.6 affects Ca(2+) sparks and mediates the inotropic action of isoproterenol (ISO), and to investigate the underlying mechanisms of cyclic ADP-ribose (cADPR) regulation of Ca(2+) sparks.Ca(2+) sparks and contractility were measured in cardiomyocytes and papillary muscle segments from FKBP12.6 null mice, and western blot analysis was carried out on sarcoplasmic reticulum microsomes prepared from mouse heart. Exposure to ISO resulted in a three- and two-fold increase in Ca(2+) spark frequency in wild-type (WT) and FKBP12.6 knockout (KO) myocytes, respectively, and Ca(2+) spark kinetics were also significantly altered in both types of cells. The effects of ISO on Ca(2+) spark properties in KO cells were inhibited by pre-treatment with thapsigargin or phospholamban inhibitory antibody, 2D12. Moreover, twitch force magnitude and the rate of force development were not significantly different in papillary muscles from WT and KO mice. Unlike beta-adrenergic stimulation, cADPR stimulation increased Ca(2+) spark frequency (2.8-fold) and altered spark kinetics only in WT but not in KO mice. The effect of cADPR on spark properties was not entirely blocked by pre-treatment with thapsigargin or 2D12. In voltage-clamped cells, cADPR increased the peak Ca(2+) of the spark without altering the decay time. We also noticed that basal Ca(2+) spark properties in KO mice were markedly altered compared with those in WT mice.Our data demonstrate that dissociation of FKBP12.6 from the RYR2 complex does not play a significant role in beta-adrenergic-stimulated Ca(2+) release in heart cells, whereas this mechanism does underlie the action of cADPR.
CDw60: a marker for human CD8+ T helper cells.
Authors: E P Rieber, G Rank
Journal: The Journal of Experimental Medicine (1994)

The existence of helper cells among the CD8+ T cell subset has been recognized for a long time. However, the phenotype of these cells has remained elusive. In this study, we provide evidence that the expression of the CDw60 antigen on human CD8+ T cell allows one to distinguish between CD8+ T helper cells and CD8+ T cells with cytotoxic and suppressor capacity. CDw60 monoclonal antibodies (mAb) recognize the 9-O-acetylated disialosyl group on ganglioside GD3 expressed on 20-40% of CD8+ cells. By use of the direct and indirect mAb-rosetting technique, we were able to isolate the CDw60+CD8+ and CDw60-CD8+ cells at high purity. The alloantigen-specific cytotoxic activity of CD8+ cells resided entirely in the CDw60- population. Helper and suppressor capacity of both CD8 subsets was assayed by the pokeweed mitogen-induced differentiation of B cells into immunoglobulin-secreting cells. These studies clearly indicate that the CDw60+CD8+ subset provided substantial help to B lymphocytes, whereas the CD8+ cells with the CDw60- phenotype were suppressing B cell differentiation. Both subsets produced similar amounts of interleukin 2 (IL-2) after stimulation with phytohemagglutinin. Activation with phorbol myristate acetate in combination with Ca-ionophore induced IL-4 secretion in both populations, but preferentially in the CDw60+ subset, whereas the vast majority of interferon gamma was produced by the CDw60-CD8+ cells. When used in combination with other markers, CDw60 may prove to be useful in defining CD8+ subsets with reciprocal functional activities.
Soluble NKG2D ligand promotes MDSC expansion and skews macrophage to the alternatively activated phenotype
Authors: Gang Xiao, Xuanjun Wang, Jun Sheng, Shengjun Lu, Xuezhong Yu, Jennifer D Wu
Journal: Journal of Hematology & Oncology (2015)

Expression of surface NKG2D ligand MIC on tumor cells is deemed to stimulate NK and co-stimulate CD8 T cell anti-tumor immunity. Human cancer cells however frequently adopt a proteinase-mediated shedding strategy to generate soluble MIC (sMIC) to circumvent host immunity. High levels of sMIC have been shown to correlate with advanced disease stages in cancer patients. The underlying mechanism is currently understood as systemic downregulation of NKG2D expression on CD8 T and NK cells and perturbing NK cell periphery maintenance. Herein we report a novel mechanism by which sMIC poses immune suppressive effect on host immunity and tumor microenvironment. We demonstrate that sMIC facilitates expansion of myeloid-derived suppressor cells (MDSCs) and skews macrophages to the more immune suppressive alternative phenotype through activation of STAT3. These findings further endorse that sMIC is an important therapeutic target for cancer immunotherapy.
Tumor cells convert immature myeloid dendritic cells into TGF-β–secreting cells inducing CD4<b>+</b>CD25<b>+</b> regulatory T cell proliferation
Authors: François Ghiringhelli, Pierre E. Puig, Stephan Roux, Arnaud Parcellier, Elise Schmitt, Eric Solary, Guido Kroemer, François Martin, Bruno Chauffert, Laurence Zitvogel
Journal: The Journal of Experimental Medicine (2005)

The mechanisms through which regulatory T cells accumulate in lymphoid organs of tumor-bearing hosts remain elusive. Our experiments indicate that the accumulation of CD4+CD25+ regulatory T cells (T reg cells) expressing FoxP3 and exhibiting immunosuppressive function originates from the proliferation of naturally occurring CD25+ T cells and requires signaling through transforming growth factor (TGF)–β receptor II. During tumor progression, a subset of dendritic cells (DCs) exhibiting a myeloid immature phenotype is recruited to draining lymph nodes. This DC subset selectively promotes the proliferation of T reg cells in a TGF-β–dependent manner in mice and rats. Tumor cells are necessary and sufficient to convert DCs into regulatory cells that secrete bioactive TGF-β and stimulate T reg cell proliferation. In conclusion, tumor expansion can stimulate T reg cells via a specific DC subset.
Professionalism and injuries in rugby union
Authors: J R Silver
Journal: British Journal of Sports Medicine (2001)

Editor,—Garraway et al 1 are to be congratulated on their meticulous investigation of the incidence of rugby injuries.

Rugby has a very high incidence of injuries. Garraway et al state: “An injury episode occurred in a professional team for every 59 minutes of competitive play”—that is, one serious injury among 30 professional players every 59 minutes. Of greater concern is the fact that Garraway et al reported two neck dislocations, one of which resulted in permanent neurological damage, in this recent paper compared with nil in the earlier one.2

The question of …
Inhibitors of the Proteasome Suppress Homologous DNA Recombination in Mammalian Cells
Authors: Yasuhiro Murakawa, Eiichiro Sonoda, Louise J. Barber, Weihua Zeng, Kyoko Yokomori, Hiroshi Kimura, Atsuko Niimi, Alan Lehmann, Guang Yu Zhao, Helfrid Hochegger, Simon J. Boulton, Shunichi Takeda
Journal: Cancer Research (2007)

Abstract Proteasome inhibitors are novel antitumor agents against multiple myeloma and other malignancies. Despite the increasing clinical application, the molecular basis of their antitumor effect has been poorly understood due to the involvement of the ubiquitin-proteasome pathway in multiple cellular metabolisms. Here, we show that treatment of cells with proteasome inhibitors has no significant effect on nonhomologous end joining but suppresses homologous recombination (HR), which plays a key role in DNA double-strand break (DSB) repair. In this study, we treat human cells with proteasome inhibitors and show that the inhibition of the proteasome reduces the efficiency of HR-dependent repair of an artificial HR substrate. We further show that inhibition of the proteasome interferes with the activation of Rad51, a key factor for HR, although it does not affect the activation of ATM, γH2AX, or Mre11. These data show that the proteasome-mediated destruction is required for the promotion of HR at an early step. We suggest that the defect in HR-mediated DNA repair caused by proteasome inhibitors contributes to antitumor effect, as HR plays an essential role in cellular proliferation. Moreover, because HR plays key roles in the repair of DSBs caused by chemotherapeutic agents such as cisplatin and by radiotherapy, proteasome inhibitors may enhance the efficacy of these treatments through the suppression of HR-mediated DNA repair pathways. [Cancer Res 2007;67(18):8536–43]
What Is Existential Psychiatry?
Authors: CLEMENS E. BENDA
Journal: American Journal of Psychiatry (1966)

Existentialism, as it has evolved over the past 50 years, contains much that is relevant for contemporary psychiatry. It offers a new orientation toward man in health and disease, focusing on the central problems of modern man-the relationship between the self and its body, the realm of emotions as the attunement of the personality to the world of encounter, and language as the mold of the experienced world.
Inspiratory muscle maximum relaxation rate measured from submaximal sniff nasal pressure in patients with severe COPD
Authors: D Kyroussis
Journal: Thorax (2002)

Background: Slowing of the inspiratory muscle maximum relaxation rate (MRR) is a useful index of severe inspiratory muscle loading and potential fatigue and has been measured from the oesophageal pressure during sniffs in patients with chronic obstructive pulmonary disease (COPD). The purpose of this study was to investigate whether it is possible to measure MRR and detect slowing using sniff nasal pressure in patients with COPD and to investigate the relationship between sniff oesophageal and sniff nasal MRR. Methods: Eight patients with severe COPD (mean FEV<sub>1</sub> 0.7 l; 26% predicted) were studied. Each subject performed submaximal sniff manoeuvres before and after walking to a state of severe dyspnoea on a treadmill. Oesophageal and gastric pressures were measured using balloon tipped catheters and nasal pressure was measured using an individually modelled nasal cast. MRR (% pressure fall/10 ms) was determined for each sniff and any change following exercise was reported as percentage of baseline to allow comparison of sniff nasal and oesophageal MRR. Results: At rest the mean (SE) sniff Poes MRR was 7.1 (0.3) and the mean Pnasal MRR was 8.6 (0.1). At 1 minute following exercise there was a mean decrease in sniff Poes MRR of 33.7% (range 20.7–53.4%) and a mean decrease in sniff Pnasal MRR of 28.2% (range 8.1–52.8%). The degree of slowing and time course of recovery was similar, with both returning to baseline values within 5–10 minutes. A separate analysis of the sniff pressures using only the nasal pressure traces demonstrated a similar pattern of slowing and recovery. Conclusions: It is possible to detect slowing of the inspiratory muscles non-invasively using sniff nasal pressures in patients with COPD. This could be a useful technique with which to measure severe and potentially fatiguing inspiratory muscle loading, both in clinical settings and during exercise studies.
Immune and Inflammatory Mechanisms of Atherosclerosis
Authors: Elena Galkina, Klaus Ley
Journal: Annual Review of Immunology (2009)

Atherosclerosis is an inflammatory disease of the wall of large- and medium-sized arteries that is precipitated by elevated levels of low-density lipoprotein (LDL) cholesterol in the blood. Although dendritic cells (DCs) and lymphocytes are found in the adventitia of normal arteries, their number is greatly expanded and their distribution changed in human and mouse atherosclerotic arteries. Macrophages, DCs, foam cells, lymphocytes, and other inflammatory cells are found in the intimal atherosclerotic lesions. Beneath these lesions, adventitial leukocytes organize in clusters that resemble tertiary lymphoid tissues. Experimental interventions can reduce the number of available blood monocytes, from which macrophages and most DCs and foam cells are derived, and reduce atherosclerotic lesion burden without altering blood lipids. Under proatherogenic conditions, nitric oxide production from endothelial cells is reduced and the burden of reactive oxygen species (ROS) and advanced glycation end products (AGE) is increased. Incapacitating ROS-generating NADPH oxidase or the receptor for AGE (RAGE) has beneficial effects. Targeting inflammatory adhesion molecules also reduces atherosclerosis. Conversely, removing or blocking IL-10 or TGF-β accelerates atherosclerosis. Regulatory T cells and B1 cells secreting natural antibodies are atheroprotective. This review summarizes our current understanding of inflammatory and immune mechanisms in atherosclerosis.
7 Liver transplantation after non heart beating multi-organ donation, first results of a new technique in the Netherlands
Authors: J. Dubbeld, B. Hoek, R.J. Porte, M.J. Slooff, J.N.M. Ijjermans, H.W. Tilanus, A.F.M. Schaapherder, A. Baranski, J. Ringers
Journal: Journal of Hepatology (2004)
Molecular markers for colorectal cancer screening
Authors: Brandon T Dickinson, John Kisiel, David A Ahlquist, William M Grady
Journal: Gut (2015)

Colorectal cancer (CRC), although a significant cause of morbidity and mortality worldwide, has seen a declining incidence and mortality in countries with programmatic screening. Faecal occult blood testing and endoscopic approaches are the predominant screening methods currently. The discovery of the adenoma–carcinoma sequence and a greater understanding of the genetic and epigenetic changes that drive the formation of CRC have contributed to innovative research to identify molecular markers for highly accurate, non-invasive screening tests for CRC. DNA, proteins, messenger RNA and micro-RNA have all been evaluated. The observation of tumour cell exfoliation into the mucocellular layer of the colonic epithelium and proven stability of DNA in a harsh stool environment make stool DNA a particularly promising marker. The development of a clinically useful stool DNA test has required numerous technical advances, including optimisation in DNA stabilisation, the development of assays with high analytical sensitivity, and the identification of specific and broadly informative molecular markers. A multitarget stool DNA test, which combines mutant and methylated DNA markers and a faecal immunochemical test, recently performed favourably in a large cross-sectional validation study and has been approved by the US Food and Drug Administration for the screening of asymptomatic, average-risk individuals. The ultimate way in which molecular marker screening assays will be used in clinical practice will require additional studies to determine optimal screening intervals, factors affecting compliance, management of false-positive results, and the use of these assays in high-risk populations, as well as other considerations.
Romosozumab in Postmenopausal Women with Low Bone Mineral Density
Authors: Michael R. McClung, Andreas Grauer, Steven Boonen, Michael A. Bolognese, Jacques P. Brown, Adolfo Diez-Perez, Bente L. Langdahl, Jean-Yves Reginster, Jose R. Zanchetta, Scott M. Wasserman, Leonid Katz, Judy Maddox, Yu-Ching Yang, Cesar Libanati, Henry G. Bone
Journal: New England Journal of Medicine (2014)

Sclerostin is an osteocyte-derived inhibitor of osteoblast activity. The monoclonal antibody romosozumab binds to sclerostin and increases bone formation.In a phase 2, multicenter, international, randomized, placebo-controlled, parallel-group, eight-group study, we evaluated the efficacy and safety of romosozumab over a 12-month period in 419 postmenopausal women, 55 to 85 years of age, who had low bone mineral density (a T score of -2.0 or less at the lumbar spine, total hip, or femoral neck and -3.5 or more at each of the three sites). Participants were randomly assigned to receive subcutaneous romosozumab monthly (at a dose of 70 mg, 140 mg, or 210 mg) or every 3 months (140 mg or 210 mg), subcutaneous placebo, or an open-label active comparator--oral alendronate (70 mg weekly) or subcutaneous teriparatide (20 μg daily). The primary end point was the percentage change from baseline in bone mineral density at the lumbar spine at 12 months. Secondary end points included percentage changes in bone mineral density at other sites and in markers of bone turnover.All dose levels of romosozumab were associated with significant increases in bone mineral density at the lumbar spine, including an increase of 11.3% with the 210-mg monthly dose, as compared with a decrease of 0.1% with placebo and increases of 4.1% with alendronate and 7.1% with teriparatide. Romosozumab was also associated with large increases in bone mineral density at the total hip and femoral neck, as well as transitory increases in bone-formation markers and sustained decreases in a bone-resorption marker. Except for mild, generally nonrecurring injection-site reactions with romosozumab, adverse events were similar among groups.In postmenopausal women with low bone mass, romosozumab was associated with increased bone mineral density and bone formation and with decreased bone resorption. (Funded by Amgen and UCB Pharma; ClinicalTrials.gov number, NCT00896532.).
Methods of the international study on soccer at altitude 3600 m (ISA3600)
Authors: Christopher J Gore, Robert J Aughey, Pitre C Bourdon, Laura A Garvican-Lewis, Rudy Soria, Jesus C Jimenez Claros, Charli Sargent, Gregory D Roach, Martin Buchheit, Ben M Simpson, Kristal Hammond, Marlen Kley, Nadine Wachsmuth, Mark Pepper, Alistair Edwards, Douglas Cuenca, Tony Vidmar, Hilde Spielvogel, Walter F Schmidt
Journal: British Journal of Sports Medicine (2013)

Background We describe here the 3-year process underpinning a multinational collaboration to investigate soccer played at high altitude—La Paz, Bolivia (3600 m). There were two main aims: first, to quantify the extent to which running performance would be altered at 3600 m compared with near sea level; and second, to characterise the time course of acclimatisation of running performance and underlying physiology to training and playing at 3600 m. In addition, this project was able to measure the physiological changes and the effect on running performance of altitude-adapted soccer players from 3600 m playing at low altitude. Methods A U20 Bolivian team (‘The Strongest’ from La Paz, n=19) played a series of five games against a U17 team from sea level in Australia (The Joeys, n=20). 2 games were played near sea level (Santa Cruz 430 m) over 5 days and then three games were played in La Paz over the next 12 days. Measures were (1) game and training running performance—including global positioning system (GPS) data on distance travelled and velocity of movement; (2) blood—including haemoglobin mass, blood volume, blood gases and acid–base status; (3) acclimatisation—including resting heart rate variability, perceived altitude sickness, as well as heart rate and perceived exertion responses to a submaximal running test; and (4) sleep patterns. Conclusions Pivotal to the success of the project were the strong professional networks of the collaborators, with most exceeding 10 years, the links of several of the researchers to soccer federations, as well as the interest and support of the two head coaches.