tbuckley/cabot-search huggingface dataset:
Medullary thymic epithelial cell depletion leads to autoimmune hepatitis
Authors: Anthony J. Bonito, Costica Aloman, M. Isabel Fiel, Nichole M. Danzl, Sungwon Cha, Erica G. Weinstein, Seihwan Jeong, Yongwon Choi, Matthew C. Walsh, Konstantina Alexandropoulos
Journal: Journal of Clinical Investigation (2013)

TRAF6, an E3 ubiquitin protein ligase, plays a critical role in T cell tolerance by regulating medullary thymic epithelial cell (mTEC) development. mTECs regulate T cell tolerance by ectopically expressing self-antigens and eliminating autoreactive T cells in the thymus. Here we show that mice with mTEC depletion due to conditional deletion of Traf6 expression in murine thymic epithelial cells (Traf6ΔTEC mice) showed a surprisingly narrow spectrum of autoimmunity affecting the liver. The liver inflammation in Traf6ΔTEC mice exhibited all the histological and immunological characteristics of human autoimmune hepatitis (AIH). The role of T cells in AIH establishment was supported by intrahepatic T cell population changes and AIH development after transfer of liver T cells into immunodeficient mice. Despite a 50% reduction in natural Treg thymic output, peripheral tolerance in Traf6ΔTEC mice was normal, whereas compensatory T regulatory mechanisms were evident in the liver of these animals. These data indicate that mTECs exert a cell-autonomous role in central T cell tolerance and organ-specific autoimmunity, but play a redundant role in peripheral tolerance. These findings also demonstrate that Traf6ΔTEC mice are a relevant model with which to study the pathophysiology of AIH, as well as autoantigen-specific T cell responses and regulatory mechanisms underlying this disease.
Sulphated glycosaminoglycan synthesis in normal and osteoarthrotic hip cartilage.
Authors: L.S McKenzie, B.A Horsburgh, P Ghosh, T.K Taylor
Journal: Annals of the Rheumatic Diseases (1977)

The in vitro sulphated glycosaminoglycan metabolism and uronate content of human aged and osteoarthrotic hip articular cartilages have been examined. Cartilages were sampled from nonfibrillated weight-bearing areas and cultured in Dulbecco Modified Eagle's medium with 35SO4. Uptake of 35SO4 was corrected for total sulphate concentration and related to uronate levels after papain digestion and dialysis. The levels of uronate in these tissues varied between 0 - 96% and 2 - 26% dry weight and did not correlate with either osteoarthrotic grading or sulphated glycosaminoglycan metabolism, irrespective of the source. Glycosaminoglycan metabolism of intact hip articular cartilage from clinically defined osteoarthrotics appears, from these results, to be comparable to that derived from nonsymptomatic hip joints from individuals of similar age. Sodium salicylate was found to depress sulphated glycosaminoglycan metabolism in osteoarthrotic cartilage.
Paradoxical Effect of Sibutramine on Autonomic Cardiovascular Regulation
Authors: Andreas L. Birkenfeld, Christoph Schroeder, Michael Boschmann, Jens Tank, Gabi Franke, Friedrich C. Luft, Italo Biaggioni, Arya M. Sharma, Jens Jordan
Journal: Circulation (2002)

Background— Sibutramine, a serotonin and norepinephrine transporter blocker, is widely used as an adjunctive obesity treatment. Norepinephrine reuptake inhibition with sibutramine conceivably could exacerbate arterial hypertension and promote cardiovascular disease. Methods and Results— In 11 healthy subjects (7 men, age 27±2 years, body mass index 23.1±0.7 kg/m 2 ), we compared the effect of sibutramine or matching placebo (ingested 26, 14, and 2 hours before testing) on cardiovascular responses to autonomic reflex tests and to a graded head-up tilt test. In addition, we tested sibutramine in combination with metoprolol. Testing was conducted in a double-blind and crossover fashion. Supine systolic blood pressure was 113±3 mm Hg with placebo, 121±3 mm Hg with sibutramine ( P &lt;0.001 versus placebo), and 111±2 mm Hg with the combination of sibutramine and metoprolol. Similarly, sibutramine increased upright blood pressure. Sibutramine substantially increased upright heart rate. This effect was abolished with metoprolol. The blood pressure response to cold pressor and handgrip testing was attenuated with sibutramine compared with placebo. Furthermore, sibutramine decreased low-frequency oscillations of blood pressure and plasma norepinephrine concentrations in the supine position. Conclusions— The cardiovascular effect of the antiobesity drug sibutramine results from a complex interaction of peripheral and central nervous system effects. The inhibitory clonidine-like action of sibutramine on the central nervous system attenuates the peripheral stimulatory effect. Our findings strongly suggest that current concepts regarding the action of sibutramine on the sympathetic nervous system should be reconsidered.
Structure and functional expression of the human macrophage inflammatory protein 1 alpha/RANTES receptor.
Authors: J L Gao, D B Kuhns, H L Tiffany, D McDermott, X Li, U Francke, P M Murphy
Journal: The Journal of Experimental Medicine (1993)

The chemokine beta family is comprised of at least six distinct cytokines that regulate trafficking of phagocytes and lymphocytes in mammalian species; at least one of these, macrophage inflammatory protein 1 alpha (MIP-1 alpha), also regulates the growth of hematopoietic stem cells. We now show that MIP-1 alpha and the related beta chemokine, RANTES, induce transient alterations in intracellular Ca2+ concentration in polymorphonuclear leukocytes that can be reciprocally and specifically desensitized, suggesting a common receptor. Moreover, we have now cloned both the cDNA and the gene for this receptor, functionally expressed the receptor in Xenopus oocytes, and mapped the gene to human chromosome 3p21. Transcripts for the receptor were found in mature and immature myeloid cells as well as B cells. The receptor is a member of the G protein-coupled receptor superfamily. It has approximately 33% amino acid identity with receptors for the alpha chemokine, interleukin 8, and may be the human homologue of the product of US28, an open reading frame of human cytomegalovirus.
Non-Eosinophilic Nasal Polyps In Second-Generation Asian Patients In The U.S. With Chronic Rhinosinusitis; Evidence For Genetic Influence On Eosinophilia
Authors: Mahboobeh Mahdavinia, Lydia Suh, James Norton, Roderick Carter, Atsushi Kato, Anju T. Peters, Rakesh Chandra, Bruce K. Tan, David Conley, Robert C. Kern, Leslie C. Grammer, Robert P. Schleimer
Journal: Journal of Allergy and Clinical Immunology (2014)
Persistence of Reduction in Blood Pressure and Mortality of Participants in the Hypertension Detection and Follow-up Program
Authors: Neil Shulman
Journal: JAMA (1988)

The Hypertension Detection and Follow-up Program (HDFP) previously described a significant reduction in five-year, all-cause mortality in its intensively treated stepped care (SC) group relative to its referred care (RC) control group. At the time this finding was described, a proportion of the SC cohort had been treated for periods as long as 6.7 years, but comparable RC and SC mortality data beyond five years were not available. These data, which are described herein, indicate that the 6.7-year life-table mortality rates were 95.1/1000 participants for SC vs 116.3/1000 participants for RC, a larger mortality difference than was observed at five years. This favorable finding for SC extended to all major subgroups, including white women and those aged 30 to 49 years at trial entry. Six months after the close of the treatment trial, a two-year posttrial surveillance study, which extended mortality follow-up to 8.3 years, was conducted. The posttrial use of antihypertensive medication declined in SC and increased in RC participants so that by the end of the posttrial period, there was little difference in the percentages of SC and RC participants taking medication. Control of blood pressure, indicated by mean diastolic blood pressure and by percent of participants with a pressure of 90 mm Hg or less, was slightly better for SC than for RC participants (SC group, 86.5 mm Hg and 68% controlled; RC group, 87.8 mm Hg and 62% controlled). The absolute mortality advantage found at 6.7 years persisted and increased throughout the posttrial period of follow-up despite discontinuation of the formal SC therapy program. It is postulated that regression of hypertensive end-organ changes brought about by the more effective SC treatment caused this favorable outcome. (<i>JAMA</i>1988;259:2113-2122)
MiR-106a is an independent prognostic marker in patients with glioblastoma
Authors: Shiguang Zhao, Guang Yang, Yulong Mu, Dayong Han, Chen Shi, Xin Chen, Yifan Deng, Daming Zhang, Lu Wang, Yaohua Liu, Xu Hou, Chunlei Wang, Jianing Wu, Huailei Liu, Ligang Wang, Guang Zhang, Jiping Qi, Xiang Fang, Changbin Shi, Jing Ai
Journal: Neuro-Oncology (2013)

Very little is known regarding correlation of micro RNA (miR)-106a with clinical outcomes of patients with glioblastoma multiforme (GBM). This study determined whether miR-106a could be used as an independent prognostic biomarker in those patients.A total of 156 GBM patients were divided into 2 cohorts. In the first cohort, matched fresh frozen and formalin-fixed paraffin-embedded (FFPE) samples were collected from 24 GBM patients, while in the second cohort, only FFPE samples were collected from 132 GBM patients. MiR-106a expression levels were examined by quantitative real-time PCR in the 2 cohorts and further validated by in situ hybridization assay in the second cohort. The correlation between miR-106a expression levels and overall survival was evaluated in the second cohort of 114 GBM patients available for follow-up by a log-rank test and a multivariate Cox proportional hazards model.Our data showed a very good correlation of miR-106a or U6 expression between fresh frozen and FFPE GBM specimens, with Pearson's correlation coefficients of 0.849 and 0.823, respectively (P < .001). Their expression levels in archival FFPE samples were quite stable for at least 7 years when stored at room temperature. Multivariate analysis revealed that the expression level of miR-106a was an independent and significant predictor of overall survival in GBM patients (P = .011).MiR-106a expression was relatively abundant and stable in a large cohort of archival FFPE GBM specimens and could be used as an independent prognostic biomarker in those patients. Thus, miR-106a can be used to predict prognosis and treatment response in individual GBM patients.
ΔF508 GENE DELETION IN CYSTIC FIBROSIS IN SOUTHERN EUROPE
Authors: X. Estivill, T. Casals, N. Morral, M. Chillon, A. Bosch, V. Nunes, P. Gasparini, A. Seia, P.F. Pignatti, G. Novelli, B. Dallapiccola, E. Fernandez, J. Benitez, R. Williamson
Journal: The Lancet (1989)
State of the art: Using natriuretic peptide levels in clinical practice
Authors: Alan Maisel, Christian Mueller, Kirkwood Adams, Stefan D. Anker, Nadia Aspromonte, John G.F. Cleland, Alain Cohen‐Solal, Ulf Dahlstrom, Anthony DeMaria, Salvatore Di Somma, Gerasimos S. Filippatos, Gregg C. Fonarow, Patrick Jourdain, Michel Komajda, Peter P. Liu, Theresa McDonagh, Kenneth McDonald, Alexandre Mebazaa, Markku S. Nieminen, W. Frank Peacock, Marco Tubaro, Roberto Valle, Marc Vanderhyden, Clyde W. Yancy, Faiez Zannad, Eugene Braunwald
Journal: European Journal of Heart Failure (2008)
Heart and Lungs as a Common Chamber during Extracorporeal Support of the Fibrillating Canine Heart
Authors: JOHN W. BELL, FRANCESCO F. BERETTA, WAYNE E. GARRETT
Journal: Circulation Research (1959)

Ventricular fibrillation was induced by electric shock in both closed- and open-chest animals. Total body perfusion was provided by extracorporeal circulation with a bubble oxygenator. The failure of left heart pressure to increase during prolonged observations indicates the probable competency of the aortic valve and retrograde flow of bronchial arterial blood to the right heart. Evidence for left-to-right flow is shown by reciprocal pressures in parallel chambers, by recovery of isotope in the pulmonary artery following left heart and aortic injection and by a cardiopneumonogram. The existence of a common mean pressure in the left heart, lungs and right heart during ventricular fibrillation confirms the hypothesis that the central circulation is in essence a, system of tubes permitting the passive transfer of blood with the prevailing gradient.
Tissue Distribution of Human Papillomavirus 16 DNA Integration in Patients with Tonsillar Carcinoma
Authors: Shahnaz Begum, Dengfeng Cao, Maura Gillison, Marianna Zahurak, William H. Westra
Journal: Clinical Cancer Research (2005)

Human papillomavirus 16 (HPV-16) has been implicated as a causative agent in a subset of head and neck squamous cell carcinomas (HNSCC). This study was undertaken to discern the distribution and timing of HPV viral integration during tumorigenesis of the upper respiratory tract.A tissue array was assembled from a consecutive group of 176 patients with HNSCCs. The array was evaluated by HPV-16 in situ hybridization and p16 immunohistochemistry. Patients with HPV-positive tonsillar cancers who had undergone bilateral tonsillectomies were selected for more complete mapping of viral integration.HPV-16 was detected in 38 of the 176 (22%) cases by in situ hybridization. When stratified by site of origin, HPV-16 was detected in 37 of 45 cancers arising from the oropharynx but in only 1 of 131 tumors arising from nonoropharyngeal sites (82% versus 0.8%, P < 0.00001). P16 expression was associated with the presence of HPV-16: 31 of 38 HPV-positive tumors exhibited p16 expression, whereas only 9 of the 138 HPV-negative tumors were p16-positive (82% versus 6%, P < 0.00001). In the bilateral tonsil sections, hybridization signals were strictly limited to the invasive cancers and associated dysplasias. P16 staining was widely distributed throughout the nonneoplastic crypt epithelium of individuals with and without tonsillar cancer.HPV-16 is strongly associated with carcinomas arising from the oropharynx, and integration is tightly coupled to the neoplastic process. Viral integration does not occur as a field alteration throughout normal tonsillar epithelium. P16 expression localizes to HPV-positive cancers, and is intrinsic to the specialized epithelium of the tonsillar crypts. For risk assessment, early cancer detection and disease surveillance, evidence of HPV-16 integration may represent a meaningful finding, whereas high p16 expression, by itself, may not.
Resuscitating Cancer Immunosurveillance: Selective Stimulation of DLL1-Notch Signaling in T cells Rescues T-cell Function and Inhibits Tumor Growth
Authors: Yuhui Huang, Luping Lin, Anil Shanker, Anshu Malhotra, Li Yang, Mikhail M. Dikov, David P. Carbone
Journal: Cancer Research (2011)

Deficiencies in immune function that accumulate during cancer immunoediting lead to a progressive escape from host immunosurveillance. Therapies that correct or overcome these defects could have a powerful impact on cancer management, but current knowledge of the types and mechanisms of immune escape is still incomplete. Here, we report a novel mechanism of escape from T-cell immunity that is caused by reduction in levels of the Delta family Notch ligands DLL1 and DLL4 in hematopoietic microenvironments. An important mediator of this effect was an elevation in the levels of circulating VEGF. Selective activation of the DLL1-Notch signaling pathway in bone marrow precursors enhanced T-cell activation and inhibited tumor growth. Conversely, tumor growth led to inhibition of Delta family ligand signaling through Notch in the hematopoietic environment, resulting in suppressed T-cell function. Overall, our findings uncover a novel mechanism of tumoral immune escape and suggest that a soluble multivalent form of DLL1 may offer a generalized therapeutic intervention to stimulate T-cell immunity and suppress tumor growth.
Joan Davies (nee Evans)
Authors: C. D. D. Howard
Journal: BMJ (2008)

Joan Davies was born in Llanelli, but after house appointments in Cardiff she moved to Edinburgh with her husband. There she obtained a DPH (with distinction) and then trained as a general practitioner. There were further moves to Sheffield, Toronto, and finally Bath. Joan had intended to become a GP, but a chance meeting between her husband and Dr Allan Dixon led to a research appointment in rheumatology, and later a clinical appointment with a special interest …
Identification of Differentially Expressed Long Noncoding RNAs in Bladder Cancer
Authors: Stefan Peter, Edyta Borkowska, Ross M. Drayton, Callum P. Rakhit, Aidan Noon, Wei Chen, James WF Catto
Journal: Clinical Cancer Research (2014)

Loss of epigenetic gene regulation through altered long noncoding RNA (lncRNA) expression seems important in human cancer. LncRNAs have diagnostic and therapeutic potential, and offer insights into the biology disease, but little is known of their expression in urothelial cancer. Here, we identify differentially expressed lncRNAs with potential regulatory functions in urothelial cancer.The expression of 17,112 lncRNAs and 22,074 mRNAs was determined using microarrays in 83 normal and malignant urothelial (discovery) samples and selected RNAs with qPCR in 138 samples for validation. Significantly differentially expressed RNAs were identified and stratified according to tumor phenotype. siRNA knockdown, functional assays, and whole-genome transcriptomic profiling were used to identify potential roles of selected lncRNAs.We observed upregulation of many lncRNAs in urothelial cancer that was distinct to corresponding, more balanced changes for mRNAs. In general, lncRNA expression reflected disease phenotype. We identified 32 lncRNAs with potential roles in disease progression. Focusing upon a promising candidate, we implicate upregulation of AB074278 in apoptosis avoidance and the maintenance of a proproliferative state in cancer through a potential interaction with EMP1, a tumor suppressor and a negative regulator of cell proliferation.We report differential expression profiles for numerous lncRNA in urothelial cancer. We identify phenotype-specific expression and a potential mechanistic target to explain this observation. Further studies are required to validate lncRNAs as prognostic biomarkers in this disease.
Steps Toward Percutaneous Aortic Valve Replacement
Authors: Younes Boudjemline, Philipp Bonhoeffer
Journal: Circulation (2002)

Background — To date, the surgical approach is the only option to replace the aortic valve. Percutaneous pulmonary valve replacement has recently opened new perspectives on transcatheter replacement of cardiac valves. We report our experience of aortic valve replacement through a percutaneous technique in lambs. Methods and Results — A bovine jugular vein containing a valve was dissected and sutured into a stent. Twelve lambs were divided into 3 groups. In the first, a valved stent was implanted in the descending aorta after creation of an aortic insufficiency. In the second, the valve was implanted in the native position. In the third, we inserted a valved stent in the native position using an orientation mechanism. All valves were successfully delivered and functioned perfectly in short-term evaluation. All experiments in group 2 failed: 1 valve obstructed the coronary artery orifices, 1 stent was responsible for a major mitral valve insufficiency, and the third implant migrated prematurely. A paraprosthetic leak occurred in the last animal in this group. Animals in group 3 had successful implantation of the valved stent. The orientation mechanism allowed perfect alignment of the device without any damage to the coronary circulation or to mitral valve function. Conclusions — Nonsurgical implantation of an aortic valve is possible in lambs in the descending aorta and in the native position. An orientation mechanism is obviously needed to avoid obstruction of the coronary orifices. With further improvements, this technique should be feasible in humans.
Clinical evaluation of GPL core IgA antibodies for serodiagnosis of MAC pulmonary disease
Authors: Yoshihiro Kobashi, Masaki Ikeda, Keiji Mouri, Yasushi Obase, Mikio Oka
Journal: European Respiratory Journal (2012)

Objective: To evaluate the clinical usefulness of GPL core antibodies for diagnosing MAC-PD and distinguishing MAC-PD from other lung diseases.  Methods: GPL core antibody levels were measured in 57 patients with MAC-PD, 18 with clinically suspected MAC-PD but who did not satisfy the diagnostic criteria of MAC-PD proposed by ATS, 10 with MAC contamination, 18 with pulmonary tuberculosis (TB), 9 with other nontuberculous mycobacterial (NTM) disease, 18 with other lung diseases.  Results: The positive response rate for MAC-PD was 77%, that for suspected MAC-PD was 39%, and that for MAC contamination was 10%, and that for pulmonary TB, other NTM diseases, and other lung diseases was 0%, respectively. GPL core antibody levels were significantly higher in patients with MAC-PD, including patients with clinically suspected MAC-PD, than in those in the other groups (p  Conclusions: The EIA kit is a useful supportive method for the rapid and convenient diagnosis of MAC-PD using a small dose of serum, and for the differentiation od MAC-PD from other lung diseases.
Respiratory failure and sleep in neuromuscular disease.
Authors: P T Bye, E R Ellis, F G Issa, P M Donnelly, C E Sullivan
Journal: Thorax (1990)

Sleep hypoxaemia in non-rapid eye movement (non-REM) and rapid eye movement (REM) sleep was examined in 20 patients with various neuromuscular disorders with reference to the relation between oxygen desaturation during sleep and daytime lung and respiratory muscle function. All the patients had all night sleep studies performed and maximum inspiratory and expiratory mouth pressures (PI and Pemax), lung volumes, single breath transfer coefficient for carbon monoxide (KCO), and daytime arterial oxygen (PaO2) and carbon dioxide tensions (PaCO2) determined. Vital capacity in the erect and supine posture was measured in 14 patients. Mean (SD) PI max at RV was low at 33 (19) cm H2O (32% predicted). Mean PE max at TLC was also low at 53 (24) cm H2O (28% predicted). Mean daytime PaO2 was 67 (16) mm Hg and PaCO2 52 (13) mm Hg (8.9 (2.1) and 6.9 (1.7) kPa). The mean lowest arterial oxygen saturation (SaO2) was 83% (12%) during non-REM and 60% (23%) during REM sleep. Detailed electromyographic evidence in one patient with poliomyelitis showed that SaO2% during non-REM sleep was maintained by accessory respiratory muscle activity. There was a direct relation between the lowest SaO2 value during REM sleep and vital capacity, daytime PaO2, PaCO2, and percentage fall in vital capacity from the erect to the supine position (an index of diaphragm weakness). The simple measurement of vital capacity in the erect and supine positions and arterial blood gas tensions when the patient is awake provide a useful initial guide to the degree of respiratory failure occurring during sleep in patients with neuromuscular disorders. A sleep study is required to assess the extent of sleep induced respiratory failure accurately.