tbuckley/cabot-search huggingface dataset:
Connexin45 Provides Optimal Atrioventricular Nodal Conduction in the Adult Mouse Heart
Authors: Marina Frank, Angela Wirth, René P. Andrié, Maria M. Kreuzberg, Radoslaw Dobrowolski, Gerald Seifert, Stefan Offermanns, Georg Nickenig, Klaus Willecke, Jan W. Schrickel
Journal: Circulation Research (2012)

The gap junctional protein connexin (Cx) 45 is strongly expressed in the early embryonic myocardium. In the adult hearts of mice and humans, the expression mainly is restricted to the cardiac conduction system. Cx45 plays an essential role for development and function of the embryonic heart because general and cardiomyocyte-directed deficiencies of Cx45 in mice lead to embryonic lethality attributable to morphological and functional cardiovascular defects. The function of Cx45 in the adult mouse has not yet been cleared.To clarify the function of Cx45 in the adult mouse heart.To circumvent the embryonic lethality resulting from Cx45 deficiency, mice were generated in which deletion of Cx45 specifically was induced in cardiomyocytes of adult mice. These Cx45-deficient mice were viable but showed a decrease in atrioventricular nodal conductivity. In addition, the Cx30.2 protein that is coexpressed with Cx45 in the cardiac conduction system was posttranscriptionally reduced by 70% in mutant hearts. Furthermore, deletion of both Cx45 and Cx30.2 resulted in viable mice that, however, showed stronger impairment of atrioventricular nodal conduction than the single Cx45-deficient mice.Cx45 is required for optimal impulse propagation in the atrioventricular node and stabilizes the level of the coexpressed Cx30.2 protein in the adult mouse heart. In contrast to the embryo, Cx45 is not essential for the viability of adult mice.
Placental Growth Factor-1 Attenuates Vascular Endothelial Growth Factor-A–Dependent Tumor Angiogenesis during β Cell Carcinogenesis
Authors: Tibor Schomber, Lucie Kopfstein, Valentin Djonov, Imke Albrecht, Vanessa Baeriswyl, Karin Strittmatter, Gerhard Christofori
Journal: Cancer Research (2007)

Abstract Members of the vascular endothelial growth factor (VEGF) family are critical players in angiogenesis and lymphangiogenesis. Although VEGF-A has been shown to exert fundamental functions in physiologic and pathologic angiogenesis, the exact role of the VEGF family member placental growth factor (PlGF) in tumor angiogenesis has remained controversial. To gain insight into PlGF function during tumor angiogenesis, we have generated transgenic mouse lines expressing human PlGF-1 in the β cells of the pancreatic islets of Langerhans (Rip1PlGF-1). In single-transgenic Rip1PlGF-1 mice, intra-insular blood vessels are found highly dilated, whereas islet physiology is unaffected. Upon crossing of these mice with the Rip1Tag2 transgenic mouse model of pancreatic β cell carcinogenesis, tumors of double-transgenic Rip1Tag2;Rip1PlGF-1 mice display reduced growth due to attenuated tumor angiogenesis. The coexpression of transgenic PlGF-1 and endogenous VEGF-A in the β tumor cells of double-transgenic animals causes the formation of low-angiogenic hPlGF-1/mVEGF-A heterodimers at the expense of highly angiogenic mVEGF-A homodimers resulting in diminished tumor angiogenesis and reduced tumor infiltration by neutrophils, known to contribute to the angiogenic switch in Rip1Tag2 mice. The results indicate that the ratio between the expression levels of two members of the VEGF family of angiogenic factors, PlGF-1 and VEGF-A, determines the overall angiogenic activity and, thus, the extent of tumor angiogenesis and tumor growth. [Cancer Res 2007;67(22):10840–8]
Exercise for lower limb osteoarthritis: systematic review incorporating trial sequential analysis and network meta-analysis
Authors: O. A. Uthman, D. A. van der Windt, J. L. Jordan, K. S. Dziedzic, E. L. Healey, G. M. Peat, N. E. Foster
Journal: BMJ (2013)

Which types of exercise intervention are most effective in relieving pain and improving function in people with lower limb osteoarthritis?As of 2002 sufficient evidence had accumulated to show significant benefit of exercise over no exercise. An approach combining exercises to increase strength, flexibility, and aerobic capacity is most likely to be effective for relieving pain and improving function.Current international guidelines recommend therapeutic exercise (land or water based) as "core" and effective management of osteoarthritis. Evidence from this first network meta-analysis, largely based on studies in knee osteoarthritis, indicates that an intervention combining strengthening exercises with flexibility and aerobic exercise is most likely to improve outcomes of pain and function. Further trials of exercise versus no exercise are unlikely to overturn this positive result.
Telenzepine is at least 25 times more potent than pirenzepine--a dose response and comparative secretory study in man.
Authors: W Londong, V Londong, A Meierl, U Voderholzer
Journal: Gut (1987)

Telenzepine is an analogue of pirenzepine with a higher potency and similar selectivity for M1-receptors in animals. In this placebo controlled, double blind, randomised study mean peptone stimulated gastric acid secretion (mean +/- SEM) of 10 male healthy subjects (58 +/- 6 mmol H+/3 h for placebo) was significantly and dose dependently inhibited by oral telenzepine (2 mg: 31 +/- 5, 3 mg: 23 +/- 5, 5 mg: 21 +/- 4 mmol H+/3 h). Telenzepine 3 and 5 mg were significantly stronger than pirenzepine 50 mg orally (37 +/- 8 mmol H+/3 h). Mean percentage acid inhibition was 37% for pirenzepine, and 48, 61, and 64% for 2, 3, and 5 mg telenzepine, respectively. Basal and peptone stimulated gastrin release was unaffected. Mean salivary output per three hours declined moderately from 156 +/- 45 g (placebo) to 136 +/- 45 g with pirenzepine and significantly to 88 +/- 28 g, 95 +/- 39 g and 39 +/- 13 g with telenzepine 2, 3, and 5 mg, respectively. There was a parallel effect on Na+, K+, Ca++ and amylase output in saliva. Near point vision was not altered by either drug. Pulse rates were lowered by both substances. Complaints of dry mouth were more frequent with telenzepine 5 mg. On a molar basis telenzepine proved to be a 25 and 50 times more potent inhibitor of gastric and salivary secretion, respectively.
Exhaled nitric oxide and asthma: complex interactions between atopy, airway responsiveness, and symptoms in a community population of children
Authors: P J Franklin
Journal: Thorax (2003)

<b>Background:</b> Exhaled nitric oxide (FE<sub>NO</sub>) is raised in asthmatic children, but there are inconsistencies in the relationship between FE<sub>NO</sub> and characteristics of asthma, including atopy, increased airway responsiveness (AR), and airway inflammation. The aim of this study was to investigate the relationship between FE<sub>NO</sub> and asthma, atopy, and increased AR in children. <b>Methods:</b> One hundred and fifty five children (79 boys) of mean age 11.5 years underwent an assessment that included FE<sub>NO</sub> measurements, spirometric tests, inhaled histamine challenge, and a skin prick test. Blood was collected for eosinophil count. Current and past asthma like symptoms were determined by questionnaire. <b>Results:</b> In multiple linear regression analyses FE<sub>NO</sub> was associated with atopy (p&lt;0.001), level of AR (p = 0.005), blood eosinophil count (p = 0.007), and height (p = 0.002) but not with physician diagnosed asthma (p = 0.1) or reported wheeze in the last 12 months (p = 0.5). Separate regression models were conducted for atopic and non-atopic children and associations between FE<sub>NO</sub> and AR, blood eosinophils and height were only evident in atopic children. Exhaled NO was raised in children with a combination of atopy and increased AR independent of symptoms. <b>Conclusion:</b> Raised FE<sub>NO</sub> seems to be associated with an underlying mechanism linking atopy and AR but not necessarily respiratory symptoms.
Right vocal cord paralysis and mediastinal lymphadenopathy
Authors: M. Boyd, S. Malaisamy, S. Ie, E. Rubio
Journal: Thorax (2010)

Right vocal cord paralysis and mediastinal lymphadenopathy CASE PRESENTATIONA non-smoking 45-year-old white man presented with a globus sensation worsened by lying down, with no complaints of hoarseness or dysphonia.He denied fever, fatigue, cough, chest pain, sweats, weight loss, reflux, arthralgias, myalgias and rash.He also denied exposure to asbestosis, beryllium, silica, HIV or tuberculosis, but he reported a recent cat bite.Physical examination revealed normal vital signs, no cervical or supraclavicular lympadenopathy and a normal cardiorespiratory system.He was referred to the otolaryngology department.Laryngoscopy revealed right vocal cord paralysis.A CT scan of the neck/chest identified diffuse mediastinal lymphadenopathy without parenchymal changes (figures 1 and 2).
Basophil Response To Storage Proteins and Oleosins From Sunflower Seed
Authors: Maria Luisa Macias, Francisca Gómez, Araceli Diaz, Cristobalina Mayorga, Ana Aranda, Miguel González, Natalia Blanca-López, Gabriela Canto, Miriam Osorio, Maria Garrido, Maria J. Torres, Miguel Blanca
Journal: Journal of Allergy and Clinical Immunology (2014)
THE EFFECT OF ANTI-LYMPHOCYTE GLOBULIN ON CELL-MEDIATED RESISTANCE TO INFECTION
Authors: G. B. Mackaness, William C. Hill
Journal: The Journal of Experimental Medicine (1969)

The specificity of anti-lymphocyte globulin (ALG) has been used to analyze an immune mechanism which is mediated by immunologically committed lymphoid cells to the apparent exclusion of humoral antibody. Rabbit antimouse lymphocyte globulin completely suppressed the immunity which can be passively transferred with Listeria-immune lymphoid cells from actively infected donors. When prospective donors were given a single dose of 1.0 mg of ALG, it remained active against immune lymphoid cells transferred 24 hr later; yet immune cells in the spleens of donors could not be inactivated in situ by even larger doses of ALG given 24 hr prior to cell harvest. In keeping with this finding, the immunity to reinfection with Listeria was not suppressed by a single dose of ALG, indicating that the immunologically active cells in the spleen are not accessible to intravenously administered ALG. On the other hand, protracted treatment with ALG did abolish most of the memory of a previous infection in intact animals. From this and other evidence, it was concluded that immunologically committed cells are vulnerable to attack by ALG only if they circulate. While in circulation, they make contact both with ALG and the phagocytic elements of the reticuloendothelial system which appear to be responsible for their destruction. Four lines of evidence indicated that the suppression of anti-Listeria resistance with ALG depends upon destruction of immune lymphoid cells and not to any action it has on host macrophages. It is possible to infer from this that immunity to L. monocytogenes depends upon a two cell system in which the donor lymphoid cells provide the immunological reactivity to the organism and recipient macrophages provide the mechanism through which resistance is expressed. Accompanying papers provide additional support for this view, and reasons for believing that delayed-type hypersensitivity and acquired cellular resistance are mediated by the same population of immunologically committed lymphoid cells.
Much doth it profit a subtle doc
Authors: L. Farrell
Journal: BMJ (2003)

My native village of Rostrevor dates to pre-Christian times, and the Farrell clan have been here all along, a savage race as ancient and atavistic as the peat; to us the good old days means hunter-gathering, not poncing about in fake Victorian costumes. The ancestral Farrells used to own all the land, until the Druids stole it from us.

Gaelic football is our passion; my son Jack now wears the same red and black worn by his father …
Pathological Neovascularization Is Reduced by Inactivation of ADAM17 in Endothelial Cells but Not in Pericytes
Authors: Gisela Weskamp, Karen Mendelson, Steve Swendeman, Sylvain Le Gall, Yan Ma, Stephen Lyman, Akinari Hinoki, Satoru Eguchi, Victor Guaiquil, Keisuke Horiuchi, Carl P. Blobel
Journal: Circulation Research (2010)

Pathological neovascularization is a critical component of diseases such as proliferative retinopathies, cancer and rheumatoid arthritis, yet much remains to be learned about the underlying causes. Previous studies showed that vascular endothelial growth factor (VEGF)-A activates the membrane-anchored metalloproteinase ADAM17 (a disintegrin and metalloproteinase 17) in endothelial cells, thereby stimulating crosstalk between VEGF receptor 2 and extracellular signal-regulated kinase. These findings raised interesting questions about the role of ADAM17 in angiogenesis and neovascularization in vivo.The objective of this study was to inactivate ADAM17 in endothelial cells or in pericytes to determine how this affects developmental angiogenesis, pathological retinal neovascularization and heterotopic tumor growth.We generated animals in which floxed ADAM17 was removed by Tie2-Cre in endothelial cells, or by smooth muscle (sm) Cre in smooth muscle cells and pericytes. There were no evident developmental defects in either conditional knockout strain, but pathological retinal neovascularization and growth of heterotopically injected tumor cells was reduced in Adam17flox/flox/Tie2-Cre mice, although not in Adam17flox/flox/sm-Cre mice. Moreover, lack of ADAM17 in endothelial cells decreased ex vivo chord formation, and this could be largely restored by addition of the ADAM17 substrate HB-EGF (heparin-binding epidermal growth factor-like growth factor). Finally we found that ADAM17 is important for the VEGF receptor 2 stimulated processing of several receptors with known functions in endothelial cell biology.These results provide the first evidence for a role for ADAM17 in pathological neovascularization in vivo. Because ADAM17 does not appear to be required for normal developmental angiogenesis or vascular homeostasis, it could emerge as a good target for treatment of pathological neovascularization.
Poly I:C treatment causes fatal AHR in sensitized mice
Authors: M. Starkhammar, S. Georen-Kumlien, S.-E. Dahlén, M. Adner, L.-O. Cardell
Journal: European Respiratory Journal (2011)

Respiratory infections are known to promote airway hyperresponsiveness (AHR) in asthmatic patients. Toll-like receptors (TLRs) are parts of the innate immune system that recognize viral and bacterial components. This  in vivo  study explores the relation between TLR activation and AHR in a model of allergic airway inflammation.  Female BALB/c mice where sensitized on day 1 and 8, then challenged with either ovalbumin (OVA) or PBS on day 15-17. PolyI:C activating TLR3, LPS triggering TLR4 or PBS were then given i.n. during 4 consecutive days. On day 22 the outcome of metacholine (Mch) induced airway resistance was investigated with  flexi Vent® technique. Cells and inflammatory mediators were analysed in bronchoalveolar fluid (BALF).  PolyI:C and LPS treated mice developed a marked AHR not seen among control mice. The airway resistance reached critically high levels in mice concomitantly challenged with OVA (Rmax at 1mgMch/kg: PBS: 2.1±0.1, PBS-LPS: 2.9±0.3, PBS-polyI:C: 3.6±0.2, OVA:5.6±0.2, OVA-LPS: 9.3±0.6 and OVA-polyI:C: 7.3±0.5 cmH 2 O s ml -1 ). The OVA-polyI:C mice also displayed circulatory collapse (p  Costimulation with PolyI:C and LPS, representing viral and bacterial activation, respectively, caused AHR above the effect of OVA which in by polyI:C caused fatal circulatory responses. It is therefore tempting to suggest that TLRs might play a vital role in virus-induced exacerbation of allergic asthma.
Nodal dissection for patients with gastric cancer: a randomised controlled trial
Authors: Chew-Wun Wu, Chao A Hsiung, Su-Shun Lo, Mao-Chin Hsieh, Jen-Hao Chen, Anna Fen-Yau Li, Wing-Yiu Lui, Jacqueline Whang-Peng
Journal: The Lancet Oncology (2006)
Cost-effective undergraduate medical education?
Authors: Melanie J Calvert, Nick Freemantle
Journal: Journal of the Royal Society of Medicine (2009)

The undergraduate medical curriculum is in a labile state, with rapid developments in evidence-based interventions and a shift in emphasis ‘from gaining knowledge to a learning process that includes the ability to evaluate data as well as to develop skills to interact with patients and colleagues’.1 In addition Government-led initiatives to widen participation to medical schools and increasing student numbers2 mean that medical education programmes need to develop alternative learning and teaching resources and strategies to ensure that students from increasingly diverse backgrounds with different learning needs are able to achieve core outcomes. In this editorial we advocate evidence-based curriculum development that also addresses constraints on time and resources: cost-effective curriculum development.
Toxic epidermal necrolysis: Effector cells are drug-specific cytotoxic T cells
Authors: Amal Nassif, Armand Bensussan, Laurence Boumsell, Aurelien Deniaud, Homayoun Moslehi, Pierre Wolkenstein, Martine Bagot, Jean-Claude Roujeau
Journal: Journal of Allergy and Clinical Immunology (2004)
Altered Expression of Small-Conductance Ca <sup>2+</sup> -Activated K <sup>+</sup> (SK3) Channels Modulates Arterial Tone and Blood Pressure
Authors: Mark S. Taylor, Adrian D. Bonev, Tobias P. Gross, Delrae M. Eckman, Joseph E. Brayden, Chris T. Bond, John P. Adelman, Mark T. Nelson
Journal: Circulation Research (2003)

The endothelium is a critical regulator of vascular tone, and dysfunction of the endothelium contributes to numerous cardiovascular pathologies. Recent studies suggest that apamin-sensitive, small-conductance, Ca2+-activated K+ channels may play an important role in active endothelium-dependent vasodilations, and expression of these channels may be altered in disease states characterized by vascular dysfunction. Here, we used a transgenic mouse (SK3T/T) in which SK3 expression levels can be manipulated with dietary doxycycline (DOX) to test the hypothesis that the level of expression of the SK subunit, SK3, in endothelial cells alters arterial function and blood pressure. SK3 protein was elevated in small mesenteric arteries from SK3T/T mice compared with wild-type mice and was greatly suppressed by dietary DOX. SK3 was detected in the endothelium and not in the smooth muscle by immunohistochemistry. In whole-cell patch-clamp experiments, SK currents in endothelial cells from SK3T/T mice were almost completely suppressed by dietary DOX. In intact arteries, SK3 channels contributed to sustained hyperpolarization of the endothelial membrane potential, which was communicated to the arterial smooth muscle. Pressure- and phenylephrine-induced constrictions of SK3T/T arteries were substantially enhanced by treatment with apamin, suppression of SK3 expression with DOX, or removal of the endothelium. In addition, suppression of SK3 expression caused a pronounced and reversible elevation of blood pressure. These results indicate that endothelial SK3 channels exert a profound, tonic, hyperpolarizing influence in resistance arteries and suggest that the level of SK3 channel expression in endothelial cells is a fundamental determinant of vascular tone and blood pressure.
Ultraviolet mutagenesis in a plasmid vector replicated in lymphoid cells from patient with the melanoma-prone disorder dysplastic nevus syndrome.
Authors: Saraswathy Seetharam, Haywood L. Waters, Michael M. Seidman, Kenneth H. Kraemer
Journal: Cancer Research (1989)

The hereditary dysplastic nevus syndrome (DNS) is an autosomal dominant disorder in which affected individuals have increased numbers of dysplastic (premalignant) nevi and a greater than 100-fold increased risk of developing cutaneous melanoma. Epstein-Barr virus-transformed lymphoblastoid cell lines from patients with hereditary DNS have been shown to be hypermutable to UV radiation (M.I.R. Perera et al., Cancer Res., 46: 1005-1009, 1986). To examine the mechanism involved in this UV hypermutability, we used a shuttle vector plasmid, pZ189, which carries a 160-base pair marker gene, supF, and can replicate in human cells. pZ189 was treated with UV radiation and transfected into DNS6BE, a lymphoblastoid cell line from a patient with hereditary DNS. Plasmid survival after UV was similar with the DNS6BE line and with a lymphoblastoid cell line from a normal donor. Plasmid mutation frequency was greater with the DNS line in accord with the DNS cellular hypermutability. Base sequence analysis was performed on 69 mutated plasmids recovered from the DNS line. There were significantly more plasmids with single base substitution mutations (P less than 0.01) in comparison to UV-treated plasmids passed through normal fibroblasts. pZ189 hypermutability and an increased frequency of single base substitutions was previously found with a cell line from a melanoma-prone xeroderma pigmentosum patient. These differences may be related to the increased melanoma susceptibility in both DNS and xeroderma pigmentosum.
Impaired serum cholesterol efflux capacity in rheumatoid arthritis and systemic lupus erythematosus
Authors: Nicoletta Ronda, Elda Favari, Maria Orietta Borghi, Francesca Ingegnoli, Maria Gerosa, Cecilia Chighizola, Francesca Zimetti, Maria Pia Adorni, Franco Bernini, Pier Luigi Meroni
Journal: Annals of the Rheumatic Diseases (2013)

Objectives The marked cardiovascular risk in autoimmune diseases is only partly explained. The capacity of high-density lipoproteins (HDL) to promote cell cholesterol efflux is a property with a well-known anti-atherogenic significance, but is also involved in functional modulation of endothelial and immune cells. The aim of this work was to evaluate HDL functionality with respect to cell cholesterol efflux in rheumatoid arthritis (RA) and systemic lupus erythemathosus (SLE) patients. Methods We evaluated serum cholesterol efflux capacity (CEC) of apoB-depleted serum, which mainly reflects HDL activity, from 30 RA and 30 SLE patients, and from 30 healthy controls by radioisotopic ex-vivo systems discriminating between the specific pathways of cholesterol efflux. Results RA patients presented impairment of ATP-binding cassette G1-mediated CEC that correlated with disease activity. SLE patients showed a more complex pattern of modifications unrelated to disease activity, with marked reduction of ATP-binding cassette G1-mediated CEC and impairment of ATP-binding cassette A1-mediated CEC. The relationship between specific pathways of CEC values and serum total HDL differed between groups and there was no relationship with autoantibody profile or current therapy. Conclusions CEC is impaired in RA and SLE, with a specific mechanism pattern in each disease not depending on serum HDL levels. These findings provide a new mechanism for the increased atherosclerotic risk in RA and SLE patients.
THE ROLE OF VESICULAR TRANSPORT PROTEINS IN SYNAPTIC TRANSMISSION AND NEURAL DEGENERATION
Authors: Yongjian Liu, Robert H. Edwards
Journal: Annual Review of Neuroscience (1997)

▪ Abstract Classical neurotransmitters are synthesized in the cytoplasm, so they require transport into secretory vesicles for regulated exocytotic release. Previous work has identified distinct vesicular transport activities for the different classical transmitters, and all depend on the H + -electrochemical gradient across the vesicle membrane but differ in the extent to which they rely on the chemical and electrical components of this gradient. Drugs that interfere with vesicular amine transport have implicated this activity in psychiatric disease. Selection for a cDNA encoding vesicular amine transport in the neurotoxin MPP + also implicates the activity in Parkinson's disease. Molecular cloning of vesicular monoamine transporters shows sequence similarity to bacterial antibiotic resistance proteins, supporting a role for transport in detoxification and defining a novel mammalian gene family that now also includes a transporter for acetylcholine. Current work focuses on the mechanism of transport and the role that regulation of activity and its subcellular localization have in transmitter release, behavior, and neural degeneration.