tbuckley/cabot-search huggingface dataset:
Taci Is a Traf-Interacting Receptor for Tall-1, a Tumor Necrosis Factor Family Member Involved in B Cell Regulation
Authors: Xing-Zhong Xia, James Treanor, Giorgio Senaldi, Sanjay D. Khare, Tom Boone, Michael Kelley, Lars E. Theill, Anne Colombero, Irina Solovyev, Frances Lee, Susan McCabe, Robin Elliott, Kent Miner, Nessa Hawkins, Jane Guo, Marina Stolina, Gang Yu, Judy Wang, John Delaney, Shi-Yuan Meng, William J. Boyle, Hailing Hsu
Journal: The Journal of Experimental Medicine (2000)

We and others recently reported tumor necrosis factor (TNF) and apoptosis ligand-related leukocyte-expressed ligand 1 (TALL-1) as a novel member of the TNF ligand family that is functionally involved in B cell proliferation. Transgenic mice overexpressing TALL-1 have severe B cell hyperplasia and lupus-like autoimmune disease. Here, we describe expression cloning of a cell surface receptor for TALL-1 from a human Burkitt's lymphoma RAJI cell library. The cloned receptor is identical to the previously reported TNF receptor (TNFR) homologue transmembrane activator and calcium modulator and cyclophilin ligand (CAML) interactor (TACI). Murine TACI was subsequently isolated from the mouse B lymphoma A20 cells. Human and murine TACI share 54% identity overall. Human TACI exhibits high binding affinities to both human and murine TALL-1. Soluble TACI extracellular domain protein specifically blocks TALL-1-mediated B cell proliferation without affecting CD40- or lipopolysaccharide-mediated B cell proliferation in vitro. In addition, when injected into mice, soluble TACI inhibits antibody production to both T cell-dependent and -independent antigens. By yeast two-hybrid screening of a B cell library with TACI intracellular domain, we identified that, like many other TNFR family members, TACI intracellular domain interacts with TNFR-associated factor (TRAF)2, 5, and 6. Correspondingly, TACI activation in a B cell line results in nuclear factor kappaB and c-Jun NH(2)-terminal kinase activation. The identification and characterization of the receptor for TALL-1 provides useful information for the development of a treatment for B cell-mediated autoimmune diseases such as systemic lupus erythematosus.
Gain-of-function mutations in signal transducer and activator of transcription 1 (STAT1): Chronic mucocutaneous candidiasis accompanied by enamel defects and delayed dental shedding
Authors: Glynis Frans, Leen Moens, Heidi Schaballie, Lien Van Eyck, Heleen Borgers, Margareta Wuyts, Doreen Dillaerts, Edith Vermeulen, James Dooley, Bodo Grimbacher, Andrew Cant, Dominique Declerck, Marleen Peumans, Marleen Renard, Kris De Boeck, Ilse Hoffman, Inge François, Adrian Liston, Frank Claessens, Xavier Bossuyt, Isabelle Meyts
Journal: Journal of Allergy and Clinical Immunology (2014)

The classical complement pathway is activated by allergenspecific pre-existing antibodies, and complement alternative pathway activation can be initiated directly by allergen polysaccharide structures.In addition, proteases directly activated by mite or mast cell tryptase or released by mucosal epithelial cells can generate complement split-product proteins during allergic reaction. 3 Bowser et al 8 first demonstrated that complement split products correlate with asthma severity and that changes in C3a and C5a levels reflect cutaneous allergic responses from dust mites after immunotherapy.Downregulation of the effector T-cell response through development of a T-cell lineage with suppressive properties might be a novel role for complement in the contraction of an immune response. 4 The complement regulatory protein CD46 can induce the development of a distinct immunomodulatory T-cell population similar to adaptive IL-10producing T R 1 cells. [5]6][7] Further understanding how CD46 activates IL-10-producing T R 1 cells during D pteronyssinus SIT and the dose of mite allergens might be important.The total dust mite SIT dosage has been reported to be associated with changes in C5a and C3a levels, and this might be due to activation of the complement activation by D pteronyssinus proteases, endotoxin, or both in multiple allergen extracts. 8 CD3/CD46-activated T R 1-like cells permit dendritic cell activation through their simultaneous secretion of GM-CSF and soluble CD40, which could be desirable in mucosal tolerance. 9 In the airway the cytokine profile of complement-activated Treg cells might ensure unresponsiveness to allergen-mediated complement activation by suppressing an unwanted T-cell response through IL-10 while maintaining reactivity to invading pathogens. 6 In summary, we have provided evidence that D pteronyssinus SIT can enhance the suppressive function of IL-10/IFN-g in CD3/CD46-activated T R 1-like cells from asthmatic patients, and this might explain the dysfunctional ability of Treg cells to suppress mite-induced airway epithelial cell inflammation.On the basis of these results, it might be possible to design therapeutic strategies to manipulate the complement-activated Treg cells to achieve allergen tolerance and suppress airway inflammation in patients with allergic asthma.
The antidiabetic gutsy role of metformin uncovered?
Authors: Rémy Burcelin
Journal: Gut (2013)

Why are grams of metformin recommended to lower hyperglycaemia in type 2 diabetic patients whereas the dose ranges from micrograms to milligrams for all other antidiabetic agents? Why is that 50% of the patients should discontinue or reduce the daily therapeutic doses to avoid diarrhoea? Why has the previously established mode of action of metformin been continuously disputed and re-evaluated by the scientific community? To these questions, Shin et al 1 shifted again the paradigm related to numerous modes of action of metformin described so far to show that the drug lowers glycaemia by targeting gut microbiota. The gutsy role of metformin might have been uncovered.

For the last 50 years, ever since the biosynthesis of metformin by Emil Werner and James Bell in 1922, the scientific community has been revisiting the mode of action of the …
Local Innervation and Atrial Fibrillation
Authors: S. Rasika Wickramasinghe, Vickas V. Patel
Journal: Circulation (2013)

A trial fibrillation (AF) is the most common human arrhythmia in the world and, depending on individual demographics, afflicts from 0.1% to 4% of the general population. 1 With the steady rise of cardiovascular disease in the industrialized world, it is no surprise that the incidence of AF is also increasing. 2,3However, despite its ubiquitous presence in adult medicine, AF remains an enigmatic disease whose pathophysiology is very complex and incompletely understood.Unlike traditional macroreentrant arrhythmias that arise from better understood electrophysiological substrates, AF is a more complex disease arising from multiple, mutually interacting mechanisms.In part, because of our incomplete understanding of the mechanisms underlying AF, therapeutic success rates in patients treated with either antiarrhythmic drug therapy, catheter-based ablation, or both remain highly variable. 4merging data from the basic science laboratory is starting to shed some light on the mechanistic basis of this disease, which may lead to the development of long-term therapies for patients with AF.One of the ideas that has persisted for several decades about AF, and is fast gaining traction, is that there may be a strong contribution from the autonomic nervous system in both the initiation and maintenance of this disease. 5he structural basis for this theory stems from the discovery of rich autonomic innervation and ganglionated plexi (GP) associated with the pulmonary veins and sites in the atria from which AF triggers often originate. 6Although the exact causal relationship between these autonomic connections and the initiation of AF is not well understood, anecdotal clinical and laboratory findings suggest that such a link is plausible.In this review, we will explore our current understanding of the cardiac nervous system and its role in the pathogenesis of AF, with an eye toward future therapeutic strategies that could exploit this relationship.
Photosensitizer-conjugated magnetic nanoparticles for in vivo simultaneous magnetofluorescent imaging and targeting therapy
Authors: Peng Huang, Zhiming Li, Jing Lin, Dapeng Yang, Guo Gao, Cheng Xu, Le Bao, Chunlei Zhang, Kan Wang, Hua Song, Hengyao Hu, Daxiang Cui
Journal: Biomaterials (2011)
Exercise Oscillatory Ventilation in Systolic Heart Failure
Authors: Ryan M. Murphy, Ravi V. Shah, Rajeev Malhotra, Paul P. Pappagianopoulos, Stacyann S. Hough, David M. Systrom, Marc J. Semigran, Gregory D. Lewis
Journal: Circulation (2011)

Background— Exercise oscillatory ventilation (EOV) is a noninvasive parameter that potently predicts outcomes in systolic heart failure (HF). However, mechanistic insights into EOV have been limited by the absence of studies relating EOV to invasive hemodynamic measurements and blood gases performed during exercise. Methods and Results— Fifty-six patients with systolic HF (mean±SEM age, 59±2 years; left ventricular ejection fraction, 30±1%) and 19 age-matched control subjects were studied with incremental cardiopulmonary exercise testing. Fick cardiac outputs, filling pressures, and arterial blood gases were measured at 1-minute intervals during exercise. We detected EOV in 45% of HF (HF+EOV) patients and in none of the control subjects. The HF+EOV group did not differ from the HF patients without EOV (HF−EOV) in age, sex, body mass index, left ventricular ejection fraction, or origin of HF. Univariate predictors of the presence of EOV in HF, among measurements performed during exercise, included higher right atrial pressure and pulmonary capillary wedge pressure and lower cardiac index (CI) but not Pa co 2 or Pa o 2 . Multivariate logistic regression identified that low exercise CI is the strongest predictor of EOV (odds ratio, 1.39 for each 1.0-L · min −1 · m −2 decrement in CI; 95% confidence interval, 1.14–1.70; P =0.001). Among HF patients with EOV, exercise CI was inversely related to EOV cycle length ( R =−0.71) and amplitude ( R =−0.60; both P &lt;0.001). In 11 HF+EOV subjects treated with 12 weeks of sildenafil, EOV cycle length and amplitude decreased proportionately to increases in CI. Conclusion— Exercise oscillatory ventilation is closely related to reduced CI and elevated filling pressures during exercise and may be an important surrogate for exercise-induced hemodynamic impairment in HF patients. Clinical Trial Registration— URL: http://www.clinicaltrials.gov . Unique identifier: NCT00309790.
Dendritic Cells Induce Autoimmune Diabetes and Maintain Disease via De Novo Formation of Local Lymphoid Tissue
Authors: Burkhard Ludewig, Bernhard Odermatt, Salome Landmann, Hans Hengartner, Rolf M. Zinkernagel
Journal: The Journal of Experimental Medicine (1998)

Activation of autoreactive T cells can lead to autoimmune diseases such as insulin-dependent diabetes mellitus (IDDM). The initiation and maintenance of IDDM by dendritic cells (DC), the most potent professional antigen-presenting cells, were investigated in transgenic mice expressing the lymphocytic choriomeningitis virus glycoprotein (LCMV-GP) under the control of the rat insulin promoter (RIP-GP mice). We show that after adoptive transfer of DC constitutively expressing the immunodominant cytotoxic T lymphocyte (CTL) epitope of the LCMV-GP, RIP-GP mice developed autoimmune diabetes. Kinetic and functional studies of DC-activated CTL revealed that development of IDDM was dependent on dose and timing of antigenic stimulation. Strikingly, repeated CTL activation by DC led to severe destructive mononuclear infiltration of the pancreatic islets but also to de novo formation of islet-associated organized lymphoid structures in the pancreatic parenchyma. In addition, repetitive DC immunization induced IDDM with lymphoid neogenesis also in perforin-deficient RIP-GP mice, illustrating that CD8+ T cell–dependent inflammatory mechanisms independent of perforin could induce IDDM. Thus, DC presenting self-antigens not only are potent inducers of autoreactive T cells, but also help to maintain a peripheral immune response locally; therefore, the induction of autoimmunity against previously ignored autoantigens represents a potential hazard, particularly in DC-based antitumor therapies.
Simultaneous rupture of the quadriceps tendon with contralateral rupture of the patellar tendon in an otherwise healthy athlete.
Authors: N I Munshi, C E Mbubaegbu
Journal: British Journal of Sports Medicine (1996)

A case of a healthy athlete with simultaneous rupture of quadriceps tendon and rupture of the contralateral patella tendon is reported. Both tendons rupturing in the same patient is rare and this is the first reported case in a previously healthy person. Different mechanisms are implicated in the different ruptures. The rarity is because the simultaneous presence of contributory factors for either injury in the same person is uncommon.
Needlestick Injuries among Surgeons in Training
Authors: Martin A. Makary, Ali Al-Attar, Christine G. Holzmueller, J. Bryan Sexton, Dora Syin, Marta M. Gilson, Mark S. Sulkowski, Peter J. Pronovost
Journal: New England Journal of Medicine (2007)

Surgeons in training are at high risk for needlestick injuries. The reporting of such injuries is a critical step in initiating early prophylaxis or treatment.We surveyed surgeons in training at 17 medical centers about previous needlestick injuries. Survey items inquired about whether the most recent injury was reported to an employee health service or involved a "high-risk" patient (i.e., one with a history of infection with human immunodeficiency virus, hepatitis B or hepatitis C, or injection-drug use); we also asked about the perceived cause of the injury and the surrounding circumstances.The overall response rate was 95%. Of 699 respondents, 582 (83%) had had a needlestick injury during training; the mean number of needlestick injuries during residency increased according to the postgraduate year (PGY): PGY-1, 1.5 injuries; PGY-2, 3.7; PGY-3, 4.1; PGY-4, 5.3; and PGY-5, 7.7. By their final year of training, 99% of residents had had a needlestick injury; for 53%, the injury had involved a high-risk patient. Of the most recent injuries, 297 of 578 (51%) were not reported to an employee health service, and 15 of 91 of those involving high-risk patients (16%) were not reported. Lack of time was the most common reason given for not reporting such injuries among 126 of 297 respondents (42%). If someone other than the respondent knew about an unreported injury, that person was most frequently the attending physician (51%) and least frequently a "significant other" (13%).Needlestick injuries are common among surgeons in training and are often not reported. Improved prevention and reporting strategies are needed to increase occupational safety for surgical providers.
Predictive value of BAL cell differentials in the diagnosis of interstitial lung diseases
Authors: L. Welker, R.A. Jörres, U. Costabel, H. Magnussen
Journal: European Respiratory Journal (2004)

The current authors aimed to quantify how the likelihood for a given diagnosis changes with the knowledge of bronchoalveolar lavage (BAL) cell differentials. As an initial estimate (a priori probability), frequencies of final diagnoses were taken. Using categorisations for cell differentials, a posteriori probabilities were then derived for each disease, according to Bayes. The analysis was performed in three of five groups of diagnoses suspected prior to BAL: interstitial lung disease (ILD; n=710), inflammatory disease (n=583), or lung tumour mimicking ILD (n=455). Overall, out of 1,971 patients, 18.3% had sarcoidosis, 7.7% usual interstitial pneumonia (UIP), 4.4% extrinsic allergic alveolitis (EAA), and 19.0% tumours. In the group with suspected ILD, the likelihood for sarcoidosis increased from 33.7 to 68.1% when lymphocyte numbers were 30-50% and granulocyte numbers were low; the likelihood for UIP increased from 15.8 to 33.3% when lymphocyte numbers were <30% with granulocytes elevated. CD4/CD8 was informative, especially in sarcoidosis and EAA. Despite considerable increases, the likelihood of rare diseases rarely reached appreciable values. Similar results were obtained in the other two groups of suspected diagnoses. In conclusion, these data suggest that bronchoalveolar lavage cell counts per se provide substantial diagnostic information only in relatively frequent diseases, such as sarcoidosis and usual interstitial pneumonia, and are less helpful in infrequent diseases.
Evolution of Dopamine Receptor Genes of the D1 Class in Vertebrates
Authors: Kei Yamamoto, Olivier Mirabeau, Charlotte Bureau, Maryline Blin, Sophie Michon-Coudouel, Michaël Demarque, Philippe Vernier
Journal: Molecular Biology and Evolution (2012)

The receptors of the dopamine neurotransmitter belong to two unrelated classes named D1 and D2. For the D1 receptor class, only two subtypes are found in mammals, the D1A and D1B, receptors, whereas additional subtypes, named D1C, D1D, and D1X, have been found in other vertebrate species. Here, we analyzed molecular phylogeny, gene synteny, and gene expression pattern of the D1 receptor subtypes in a large range of vertebrate species, which leads us to propose a new view of the evolution of D1 dopamine receptor genes. First, we show that D1C and D1D receptor sequences are encoded by orthologous genes. Second, the previously identified Cypriniform D1X sequence is a teleost-specific paralog of the D1B sequences found in all groups of jawed vertebrates. Third, zebrafish and several sauropsid species possess an additional D1-like gene, which is likely to form another orthology group of vertebrate ancestral genes, which we propose to name D1E. Ancestral jawed vertebrates are thus likely to have possessed four classes of D1 receptor genes-D1A, D1B(X), D1C(D), and D1E-which arose from large-scale gene duplications. The D1C receptor gene would have been secondarily lost in the mammalian lineage, whereas the D1E receptor gene would have been lost independently in several lineages of modern vertebrates. The D1A receptors are well conserved throughout jawed vertebrates, whereas sauropsid D1C receptors have rapidly diverged, to the point that they were misidentified as D1D. The functional significance of the D1C receptor loss is not known. It is possible that the function may have been substituted with D1A or D1B receptors in mammals, following the disappearance of D1C receptors in these species.
Collaborative genome-wide association analysis supports a role for ANK3 and CACNA1C in bipolar disorder
Authors: Manuel A R Ferreira, Michael C O'Donovan, Yan A Meng, Ian R Jones, Douglas M Ruderfer, Lisa Jones, Jinbo Fan, George Kirov, Roy H Perlis, Elaine K Green, Jordan W Smoller, Detelina Grozeva, Jennifer Stone, Ivan Nikolov, Kimberly Chambert, Marian L Hamshere, Vishwajit L Nimgaonkar, Valentina Moskvina, Michael E Thase, Sian Caesar, Gary S Sachs, Jennifer Franklin, Katherine Gordon-Smith, Kristin G Ardlie, Stacey B Gabriel, Christine Fraser, Brendan Blumenstiel, Matthew Defelice, Gerome Breen, Michael Gill, Derek W Morris, Amanda Elkin, Walter J Muir, Kevin A McGhee, Richard Williamson, Donald J MacIntyre, Alan W MacLean, David St Clair, Michelle Robinson, Margaret Van Beck, Ana C P Pereira, Radhika Kandaswamy, Andrew McQuillin, David A Collier, Nicholas J Bass, Allan H Young, Jacob Lawrence, I Nicol Ferrier, Adebayo Anjorin, Anne Farmer, David Curtis, Edward M Scolnick, Peter McGuffin, Mark J Daly, Aiden P Corvin, Peter A Holmans, Douglas H Blackwood, Hugh M Gurling, Michael J Owen, Shaun M Purcell, Pamela Sklar, Nick Craddock
Journal: Nature Genetics (2008)
The Structure of the Depressive Response to Stress
Authors: RONALD F. BENTON
Journal: American Journal of Psychiatry (1972)

The psychiatric literature dealing with the significance of stress in the causation of depression is reviewed. Definitive studies await the indispensable conceptual tools of a comprehensive theory. The author suggests criteria for distinguishing normal from abnormal despondency, pathogenic from nonpathogenic losses, and stress-induced lowering of self-esteem from stress-released despair of self. These criteria define a structure for coordinating and classifying despondent states in their relationship to stress. The clinical and research utility of the model are suggested.
Influence of inflammatory bowel disease on the ability of patients to tolerate systemic fluorouracil-based chemotherapy.
Authors: A Tiersten, L B Saltz
Journal: Journal of Clinical Oncology (1996)

PURPOSE To evaluate the safety of administering fluorouracil (5FU)-based chemotherapy to cancer patients with inflammatory bowel disease (IBD). PATIENTS AND METHODS We retrospectively reviewed all patients entered into the Memorial Sloan-Kettering Cancer Center clinical data base from 1985 through 1995 who had a diagnosis of IBD, had a gastrointestinal malignancy, and were treated with systemic 5FU-based chemotherapy. A total of 19 patient charts were identified and reviewed. RESULTS Fifty-three percent of patients reviewed experienced severe (grade III/IV) diarrhea on treatment. Sixty percent of patients with a history of active IBD and 40% of patients with a history of inactive IBD experienced severe diarrhea on treatment. The incidence of severe diarrhea did not appear to be substantially influenced by age, schedule of 5FU administration, concurrent radiation, or type of IBD. CONCLUSION While there does appear to be an increased risk of diarrhea exacerbation in IBD patients treated with 5FU, a substantial number of patients tolerate chemotherapy without increased difficulty. The degree of IBD activity or other clinical parameters can not be used to predict accurately the likelihood of toxicity.
Systemic sclerosis in Iceland. A nationwide epidemiological study.
Authors: A J Geirsson, K Steinsson, S Guthmundsson, V Sigurthsson
Journal: Annals of the Rheumatic Diseases (1994)

OBJECTIVES--To investigate the incidence, prevalence and clinical features of systemic sclerosis (SS) in Iceland. METHODS--All patients diagnosed with SS from 1975-90 were included. Retrieval for the study began in 1980 and was carried out by computerised search from registers of all hospitals and health care clinics and death registration files, and with personal communication with doctors in Iceland. RESULTS--Over a 16 year period from 1975-90, 15 new cases were found with an incidence of 0.7 and 0.05/100,000, for females and males at risk respectively, and 0.38 for both sexes. At the end of 1990 there were 18 patients alive with SS, 13 with limited and five with diffuse cutaneous involvement. The age standardised prevalence was 11.9 and 1.5/100,000 for females and males at risk respectively. The crude prevalence rate for both sexes was 7.1/100,000. There were five deaths, two patients died of SS related causes, one had SS renal disease. The relative risk of death was similar to that in the general population. The calculated five year survival rate was 100% and the 10 year survival rate 81%. No HLA antigen association was found. CONCLUSION--Compared with previous surveys this study shows a low incidence of systemic sclerosis and a high proportion of patients with limited cutaneous involvement.