tbuckley/cabot-search huggingface dataset:
Ferret tracheal mucus rheology, clearability and volume following administration of substance P or methacholine
Authors: GT De Sanctis, BK Rubin, O Ramirez, M King
Journal: European Respiratory Journal (1993)

We studied the effects of substances P administration on tracheal mucus viscoelasticity, water content, clearability and secretion rate. Six neutered adult male ferrets (weight 1.1-1.5 kg) were studied, on four occasions each. They were anaesthetized with ketamine and xylazine, and intubated shallowly. Control mucus (pre- and post-Ringer instillation) was compared with the mucus obtained following instillation of 200 microliters of 10(-6), 10(-5), and 10(-4) M substance P (SP), and 10(-4) M methacholine chloride as a reference. Tracheal mucus was collected by inserting a soft-bristled cytology brush to the level of the carina, and leaving it in contact with the mucosa for 30 min. After withdrawing the brush, the adherent mucus was quickly scraped off and layered with paraffin oil to prevent evaporation. The mucus was analysed for viscoelasticity by magnetic rheometry and solids content by evaporation to dryness. Mucus transportability was assessed by comparison with model gels, and also by means of the frog palate assay, which indicates how well mucus is cleared by normal ciliary action. There was a dose-related increase in mucus volume, and a dose-related decrease in mucus viscosity and elasticity, with substance P administration. Mucus transportability increased with both substance P and methacholine. The effects of 10(-4) SP and methacholine were comparable in terms of viscoelasticity and volume; with both methacholine and SP, there appeared to be an additive effect. The mucus solids content did not correlate with the viscoelastic changes for SP administration, whereas it did for methacholine. These observations suggest that the hypersecretion induced by these two agents might involve different pathways.
T-Bet Polymorphisms Are Associated with Asthma and Airway Hyperresponsiveness
Authors: Benjamin A. Raby, Eun-Sook Hwang, Kristel Van Steen, Kelan Tantisira, Stanford Peng, Augusto Litonjua, Ross Lazarus, Cosmas Giallourakis, John D. Rioux, David Sparrow, Edwin K. Silverman, Laurie H. Glimcher, Scott T. Weiss
Journal: American Journal of Respiratory and Critical Care Medicine (2005)

T-bet (TBX21 or T-box 21) is a critical regulator of T-helper 1 lineage commitment and IFN-gamma production. Knockout mice lacking T-bet develop airway hyperresponsiveness (AHR) to methacholine, peribronchial eosinophilic and lymphocytic inflammation, and increased type III collagen deposition below the bronchial epithelium basement membrane, reminiscent of both acute and chronic asthma histopathology. Little is known regarding the role of genetic variation surrounding T-bet in the development of human AHR.
Exposure to hazardous substances and male reproductive health: a research framework.
Authors: J M Moline, A L Golden, N Bar-Chama, E Smith, M E Rauch, R E Chapin, S D Perreault, S M Schrader, W A Suk, P J Landrigan
Journal: Environmental Health Perspectives (2000)

The discovery in the mid-1970s that occupational exposures to pesticides could diminish or destroy the fertility of workers sparked concern about the effects of hazardous substances on male reproductive health. More recently, there is evidence that sperm quantity and quality may have declined worldwide, that the incidence of testicular cancer has progressively increased in many countries, and that other disorders of the male reproductive tract such as hypospadias and cryptorchidism may have also increased. There is growing concern that occupational factors and environmental chemical exposures, including in utero and childhood exposures to compounds with estrogenic activity, may be correlated with these observed changes in male reproductive health and fertility. We review the evidence and methodologies that have contributed to our current understanding of environmental effects on male reproductive health and fertility and discuss the methodologic issues which confront investigators in this area. One of the greatest challenges confronting researchers in this area is assessing and comparing results from existing studies. We elaborate recommendations for future research. Researchers in the field of male reproductive health should continue working to prioritize hazardous substances; elucidate the magnitude of male reproductive health effects, particularly in the areas of testicular cancer, hypospadias, and cryptorchidism; develop biomarkers of exposure to reproductive toxins and of reproductive health effects for research and clinical use; foster collaborative interdisciplinary research; and recognize the importance of standardized laboratory methods and sample archiving.
Comparison of the Action of Ouabain on the Heart in Hypothyroid, Euthyroid and Hyperthyroid Dogs
Authors: ANDERS ROSEN, NEIL C. MORAN
Journal: Circulation Research (1963)

Ouabain-induced changes in cardiac contractile force and differences in the amount of ouabain required to induce arrhythmias and to produce death were evaluated in normal, thyroidectomized and thyroxine-treated dogs. It was found, that ouabain, following alterations in thyroid function, still substantially augmented cardiac contractile force in anesthetized open-chest dogs. In both the hypothyroid and the hyperthyroid animals a moderate dose of ouabain produced an increase in contractile force of approximately the same extent as in the euthyroid animals, although of slower onset in the hypothyroid dogs. Larger doses of ouabain caused a smaller positive inotropic response. in hyperthyroid dogs than in euthyroid and hypothyroid animals. Changes in thyroid function increased the arrhythmia-producing and the lethal dose of ouabain, which in the hyperthyroid dogs may have been due to the markedly elevated heart rate.
A multistage genome-wide association study in breast cancer identifies two new risk alleles at 1p11.2 and 14q24.1 (RAD51L1)
Authors: Gilles Thomas, Kevin B Jacobs, Peter Kraft, Meredith Yeager, Sholom Wacholder, David G Cox, Susan E Hankinson, Amy Hutchinson, Zhaoming Wang, Kai Yu, Nilanjan Chatterjee, Montserrat Garcia-Closas, Jesus Gonzalez-Bosquet, Ludmila Prokunina-Olsson, Nick Orr, Walter C Willett, Graham A Colditz, Regina G Ziegler, Christine D Berg, Saundra S Buys, Catherine A McCarty, Heather Spencer Feigelson, Eugenia E Calle, Michael J Thun, Ryan Diver, Ross Prentice, Rebecca Jackson, Charles Kooperberg, Rowan Chlebowski, Jolanta Lissowska, Beata Peplonska, Louise A Brinton, Alice Sigurdson, Michele Doody, Parveen Bhatti, Bruce H Alexander, Julie Buring, I-Min Lee, Lars J Vatten, Kristian Hveem, Merethe Kumle, Richard B Hayes, Margaret Tucker, Daniela S Gerhard, Joseph F Fraumeni, Robert N Hoover, Stephen J Chanock, David J Hunter
Journal: Nature Genetics (2009)
Injury risk of playing football in Futsal World Cups
Authors: Astrid Junge, Jiri Dvorak
Journal: British Journal of Sports Medicine (2010)

While injuries in football (soccer) have been the subject of numerous publications, little information is available about the injury risk in futsal.Analysis of the incidence and characteristics of injury in futsal players during top-level international tournaments.Prospective survey.Player injuries during three consecutive Futsal World Cups were analysed using an established injury report system. The physicians of all participating teams reported all injuries after each match on a standardised injury report form. The average response rate was 93%.A total of 165 injuries were reported from 127 matches, which is equivalent to an incidence of 195.6 injuries per 1000 player hours (95% CI 165.8 to 225.6) or 130.4 injuries per 1000 player matches (95% CI 110.5 to 150.3). The majority of injuries were caused by contact with another player, and 36% of the injuries occurred during non-contact activities. Most injuries affected the lower extremity (70%), followed by head and neck (13%), upper extremity (10%) and trunk (7%). The most frequent diagnoses were contusion of the lower leg (11%), ankle sprain (10%) and groin strain (8%). On average, one time-loss injury in every two matches was reported.While the location and diagnosis of injuries were similar in the two types of football, fewer injuries in futsal than in football were caused by contact with another player and by foul play. More information on injury mechanisms in futsal is needed to develop specific injury preventive interventions.
GP shortage could mean “untrained” doctors being employed, doctors’ leaders fear
Authors: Tom Moberly
Journal: BMJ (2015)

A plan to use government money intended to expand access to primary care to employ doctors who aren’t trained as GPs to provide primary care medical services has been criticised by the BMA and the Royal College of General Practitioners.

The Shropshire Doctors Co-operative is recruiting a “community physician” to work in several practices across Shropshire and Staffordshire. The advertisement for the role does not require applicants to have completed GP training. It stated that the post was “an exciting opportunity for fully registered medical practitioners, having completed at least foundation year 2.” 

The BMA said that only GPs could provide certain primary care services and that the provision of such roles could be misleading. The Royal College of General Practitioners has asked Health Education England for “urgent clarification” about …
Does PEEP facilitate the resolution of extravascular lung water after experimental hydrostatic pulmonary oedema?
Authors: H Blomqvist, CJ Wickerts, B Berg, C Frostell, A Jolin, G Hedenstierna
Journal: European Respiratory Journal (1991)

The effect of mechanical ventilation with positive end-expiratory pressure on the resolution of hydrostatic pulmonary oedema created by temporary left atrial balloon inflation was studied in mechanically ventilated dogs. Immediately after the hydrostatic process was terminated, by deflating the left atrial balloon, the animals were ventilated for 4 h with zero end-expiratory pressure (ZEEP, n = 6) or with a positive end-expiratory pressure (PEEP, n = 6) of 1.0 kPa (10 cmH2O). Gas exchange and extravascular lung water content (EVLW) with the double indicator dilution technique (dye/cold) were studied and gravimetric determination of lung water was made postmortem. EVLW decreased from 31.6 +/- 7.3 mean +/- SD ml.kg.1 during maximal oedema to 14.5 +/- 2.1 ml.kg.1 (p less than 0.001) 4 h after deflation of the left atrial balloon in dogs ventilated with ZEEP. The corresponding values in dogs ventilated with PEEP were a reduction in EVLW from 28.0 +/- 4.1 to 20.7 +/- 4.0 ml.kg.1 (p less than 0.01) (mean decrease 7.3 +/- 4.0 ml.kg.1). EVLW was significantly higher after 4 h on PEEP than after ZEEP (p less than 0.01). Gravimetric values at the end of the experiment were 12.4 +/- 2.8 ml.kg.1 (ZEEP) and 14.7 +/- 4.5 ml.kg.1 (PEEP) (NS). Oxygenation improved in both groups during the resolution of oedema with a more evident and early effect in the PEEP group. It is concluded that mechanical ventilation with PEEP of 1.0 kPa (10 cmH2O) in the resolution phase after experimental hydrostatic oedema improves oxygenation but retards the resolution of oedema.
David Weatherall wins the 2010 Lasker~Koshland Special Achievement Award in Medical Research for advances in thalassemia
Authors: Kathryn Claiborn
Journal: Journal of Clinical Investigation (2010)

In 1958, David J. Weatherall was a newly qualified physician preparing to enter the British Army for two years of compulsory service; terrified of flying and intimidated by the risks of violent combat and biting snakes, he hoped to serve his term in a hospital on UK soil. Two weeks later, though, he was on a ship bound for Sing­apore. Despite his trepidation, his experiences there launched not only a remarkable and distinguished research career, but also a new scientific field — molecular medicine. On September 21, Weatherall (Figure ​(Figure1)1) will receive the 2010 Lasker~Koshland Special Achievement Award in Medical Research, honoring his 50 years of dedication to the research and treatment of hereditary blood disorders. 



Figure 1

David Weatherall is the recipient of the 2010 Lasker~Koshland Special Achievement Award in Medical Research in recognition of his contributions to the molecular understanding and treatment of thalassemia.
Endothelin B Receptor, a New Target in Cancer Immune Therapy
Authors: Lana E. Kandalaft, Andrea Facciabene, Ron J. Buckanovich, George Coukos
Journal: Clinical Cancer Research (2009)

The endothelins and their G protein-coupled receptors A and B have been implicated in numerous diseases and have recently emerged as pivotal players in a variety of malignancies. Tumors overexpress the endothelin 1 (ET-1) ligand and the endothelin-A-receptor (ET(A)R). Their interaction induces tumor growth and metastasis by promoting tumor cell survival and proliferation, angiogenesis, and tissue remodeling. On the basis of results from xenograft models, drug development efforts have focused on antagonizing the autocrine-paracrine effects mediated by ET-1/ET(A)R. In this review, we discuss a novel role of the endothelin-B-receptor (ET(B)R) in tumorigenesis and the effect of its blockade during cancer immune therapy. We highlight key characteristics of the B receptor such as its specific overexpression in the tumor compartment; and specifically, in the tumor endothelium, where its activation by ET-1 suppresses T-cell adhesion and homing to tumors. We also review our recent findings on the effects of ET(B)R-specific blockade in increasing T-cell homing to tumors and enhancing the efficacy of otherwise ineffective immunotherapy.
Overnight prescription of oxygen in long term oxygen therapy: time to reconsider the guidelines?
Authors: M Nisbet, T Eaton, C Lewis, W Fergusson, J Kolbe
Journal: Thorax (2006)

Guidelines for long term oxygen therapy (LTOT) recommend increasing oxygen flow by 1 l/min overnight. A study was undertaken in patients with COPD on LTOT to determine the prevalence of overnight desaturation if the usual oxygen flow rate is not increased at night, whether resting oxygen saturation predicts overnight desaturation, and whether overnight desaturation correlates with health related quality of life (HRQL) and sleep quality.A cross sectional prospective study was performed on consecutive patients with COPD on LTOT attending our regional outpatient oxygen service. All patients fulfilled standard criteria for LTOT, had been established on LTOT at a flow to achieve resting oxygen saturations >90%, but had not been instructed to increase oxygen flow overnight. Overnight desaturation was defined as <90% for > or =30% of the night on either of two consecutive nights. HRQL was evaluated with the SF-36 Health Survey Questionnaire, Chronic Respiratory Questionnaire, and the Pittsburgh Sleep Quality Index.Thirty eight patients (63% men) of mean (SD) age 73.5 (8.04) years and mean (SD) forced expiratory volume in 1 second 0.77 (0.35) l were evaluated. Overnight desaturation occurred in six (16%; 95% CI 4 to 27). Desaturators had mean (SD) resting oxygen saturation on room air of 88 (4.2)% compared with 90 (4.1)% in non-desaturators (p = 0.15), and corrected saturations of 93 (2.0)% versus 94 (2.0)% (p = 0.18). HRQL and sleep quality were poor but did not differ between desaturators and non-desaturators.Most patients did not exhibit overnight desaturation despite not increasing their LTOT prescription overnight. These results challenge the recommendation of routinely increasing overnight oxygen flow in patients receiving LTOT.
Combined use of anti-ErbB monoclonal antibodies and erlotinib enhances antibody-dependent cellular cytotoxicity of wild-type erlotinib-sensitive NSCLC cell lines
Authors: Andrea Cavazzoni, Roberta R Alfieri, Daniele Cretella, Francesca Saccani, Luca Ampollini, Maricla Galetti, Federico Quaini, Gallia Graiani, Denise Madeddu, Paola Mozzoni, Elena Galvani, Silvia La Monica, Mara Bonelli, Claudia Fumarola, Antonio Mutti, Paolo Carbognani, Marcello Tiseo, Elisabetta Barocelli, Pier Giorgio Petronini, Andrea Ardizzoni
Journal: Molecular Cancer (2012)

Abstract Background The epidermal growth factor receptor (EGFR) is an established target for anti-cancer treatment in different tumour types. Two different strategies have been explored to inhibit this pivotal molecule in epithelial cancer development: small molecules TKIs and monoclonal antibodies. ErbB/HER-targeting by monoclonal antibodies such as cetuximab and trastuzumab or tyrosine-kinase inhibitors as gefitinib or erlotinib has been proven effective in the treatment of advanced NSCLC. Results In this study we explored the potential of combining either erlotinib with cetuximab or trastuzumab to improve the efficacy of EGFR targeted therapy in EGFR wild-type NSCLC cell lines. Erlotinib treatment was observed to increase EGFR and/or HER2 expression at the plasma membrane level only in NSCLC cell lines sensitive to the drug inducing protein stabilization. The combined treatment had marginal effect on cell proliferation but markedly increased antibody-dependent, NK mediated, cytotoxicity in vitro . Moreover, in the Calu-3 xenograft model, the combination significantly inhibited tumour growth when compared with erlotinib and cetuximab alone. Conclusion Our results indicate that erlotinib increases surface expression of EGFR and/or HER2 only in EGFR-TKI sensitive NSCLC cell lines and, in turns, leads to increased susceptibility to ADCC both in vitro and in a xenograft models. The combination of erlotinib with monoclonal antibodies represents a potential strategy to improve the treatment of wild-type EGFR NSCLC patients sensitive to erlotinib.
Human Platelets Stimulate Mesangial Cells to Produce Monocyte Chemoattractant Protein-1 via the CD40/CD40 Ligand Pathway and May Amplify Glomerular Injury
Authors: Takaharu Tanaka, Takashi Kuroiwa, Hidekazu Ikeuchi, Fumie Ota, Yoriaki Kaneko, Kazue Ueki, Yoshito Tsukada, Iain B. McInnes, Dimitrios T. Boumpas, Yoshihisa Nojima
Journal: Journal of the American Society of Nephrology (2002)

ABSTRACT. Platelets are thought to play an important role in the initiation and the progression of a variety of glomerulonephritides. This study examined whether platelets induce production of monocyte chemoattractant protein-1 (MCP-1), a chemokine involved in leukocyte recruitment and glomerular injury, by cultured human mesangial cells (MC). To this end, platelets isolated from normal human donors were cocultured with MC at various ratios. MCP-1 synthesis was evaluated by quantitative real-time PCR and enzyme-linked immunosorbent assay. Platelets at 1:100 ratio (MC to platelets) induced an approximately 20-fold increase in mesangial MCP-1 mRNA and protein expression through an obligatory cell-to-cell contact–dependent mechanism. Importantly, blockade of the CD40/CD40 ligand (CD40L) pathway with neutralizing antibodies decreased MCP-1 production by approximately 60%. It was confirmed that CD40 was functionally expressed on MC. Gel-shift assays and inhibitors of phosphorylation were used to demonstrate that activation of p38 mitogen-activated protein kinase, protein tyrosine kinases, and nuclear factor–κB activation were essential for MCP-1 production. These data indicate that platelet/MC contact stimulates the production of MCP-1 and may contribute to glomerular inflammatory responses by recruiting leukocytes from the peripheral blood. E-mail: [email protected]
Vestibular System: The Many Facets of a Multimodal Sense
Authors: Dora E. Angelaki, Kathleen E. Cullen
Journal: Annual Review of Neuroscience (2008)

Elegant sensory structures in the inner ear have evolved to measure head motion. These vestibular receptors consist of highly conserved semicircular canals and otolith organs. Unlike other senses, vestibular information in the central nervous system becomes immediately multisensory and multimodal. There is no overt, readily recognizable conscious sensation from these organs, yet vestibular signals contribute to a surprising range of brain functions, from the most automatic reflexes to spatial perception and motor coordination. Critical to these diverse, multimodal functions are multiple computationally intriguing levels of processing. For example, the need for multisensory integration necessitates vestibular representations in multiple reference frames. Proprioceptive-vestibular interactions, coupled with corollary discharge of a motor plan, allow the brain to distinguish actively generated from passive head movements. Finally, nonlinear interactions between otolith and canal signals allow the vestibular system to function as an inertial sensor and contribute critically to both navigation and spatial orientation.
Validity and reliability of three definitions of hip osteoarthritis: cross sectional and longitudinal approach
Authors: M Reijman
Journal: Annals of the Rheumatic Diseases (2004)

<b>Objectives:</b> To compare the reliability and validity in a large open population of three frequently used radiological definitions of hip osteoarthritis (OA): Kellgren and Lawrence grade, minimal joint space (MJS), and Croft grade; and to investigate whether the validity of the three definitions of hip OA is sex dependent. <b>Methods:</b> Subjects from the Rotterdam study (aged ⩾55 years, n = 3585) were evaluated. The inter-rater reliability was tested in a random set of 148 <i>x</i> rays. The validity was expressed as the ability to identify patients who show clinical symptoms of hip OA (construct validity) and as the ability to predict total hip replacement (THR) at follow up (predictive validity). <b>Results:</b> Inter-rater reliability was similar for the Kellgren and Lawrence grade and MJS (κ statistics 0.68 and 0.62, respectively) but lower for Croft's grade (κ statistic, 0.51). The Kellgren and Lawrence grade and MJS showed the strongest associations with clinical symptoms of hip OA. Sex appeared to be an effect modifier for Kellgren and Lawrence and MJS definitions, women showing a stronger association between grading and symptoms than men. However, the sex dependency was attributed to differences in height between women and men. The Kellgren and Lawrence grade showed the highest predictive value for THR at follow up. <b>Conclusions:</b> Based on these findings, Kellgren and Lawrence still appears to be a useful OA definition for epidemiological studies focusing on the presence of hip OA.
Oct2 enhances antibody-secreting cell differentiation through regulation of IL-5 receptor α chain expression on activated B cells
Authors: Dianne Emslie, Kathy D'Costa, Jhagvaral Hasbold, Donald Metcalf, Kiyoshi Takatsu, Philip O. Hodgkin, Lynn M. Corcoran
Journal: The Journal of Experimental Medicine (2008)

Mice lacking a functional gene for the Oct2 transcriptional activator display several developmental and functional deficiencies in the B lymphocyte lineage. These include defective B cell receptor (BCR) and Toll-like receptor 4 signaling, an absence of B-1 and marginal zone populations, and globally reduced levels of serum immunoglobulin (Ig) in naive and immunized animals. Oct2 was originally identified through its ability to bind to regulatory regions in the Ig loci, but genetic evidence has not supported an essential role for Oct2 in the expression of Ig genes. We describe a new Oct2-mediated role in B cells. Oct2 augments the ability of activated B cells to differentiate to antibody-secreting plasma cells (ASCs) under T cell-dependent conditions through direct regulation of the gene encoding the alpha chain of the interleukin (IL) 5 receptor. Ectopic expression of IL-5Ralpha in oct2-deficient B cells largely restores their ability to differentiate to functional ASCs in vitro but does not correct other phenotypic defects in the mutants, such as the maturation and specialization of peripheral B cells, which must therefore rely on distinct Oct2 target genes. IL-5 augments ASC differentiation in vitro, and we show that IL-5 directly activates the plasma cell differentiation program by enhancing blimp1 expression.