tbuckley/cabot-search huggingface dataset:
Polymorphism within the Interferon-γ/Receptor Complex Is Associated with Pulmonary Tuberculosis
Authors: Graham S. Cooke, Sarah J. Campbell, Jackson Sillah, Per Gustafson, Boubacar Bah, Georgio Sirugo, Steve Bennett, Keith P. W. J. McAdam, Oumou Sow, Christian Lienhardt, Adrian V. S. Hill
Journal: American Journal of Respiratory and Critical Care Medicine (2006)

Interferon-gamma (IFN-gamma) is of central interest in the study of tuberculosis. A number of single-gene mutations have been identified in the IFN-gamma signaling pathway that predispose to severe mycobacterial disease, but the relevance of polymorphism within these genes to the common phenotype of tuberculosis remains unclear.A total of 1,301 individuals were included in a large, detailed study of West African populations with pulmonary tuberculosis. We investigated disease association with the genes encoding IFN-gamma and its receptor subunits (IFNG, IFNGR1, and IFNGR2).Within the IFNG gene, two promoter variants showed evidence of novel disease association: -1616GG (odds ratio [OR], 1.49; 95% confidence interval [CI], 1.11-2.00; p = 0.008) and +3234TT (OR, 1.40; 95% CI, 1.09-1.80; p = 0.009). The +874AA genotype was not significantly more frequent among cases over control subjects (OR, 1.16; 95%CI, 0.89-1.51; p = 0.25). In addition, novel disease association was also found with the -56CC genotype of the IFNGR1 promoter (OR, 0.75; 95% CI, 0.57-0.99; p = 0.041). No disease association was seen with the IFNGR2 locus.These results provide evidence of a significant role for genetic variation at the IFNG locus and provide detailed understanding of the genetic mechanisms underlying this association. The disease association with IFNGR1 is novel, and together these findings support the hypothesis that genetically determined variation in both IFN-gamma production and responsiveness influences the risk of developing tuberculosis.
Synergic in-vitro activity of imipenem and sulbactam against Acinetobacter baumannii
Authors: J.Y. Choi, Y. Soo Park, C.H. Cho, Y. Seon Park, S.Y. Shin, Y.G. Song, D. Yong, K. Lee, J.M. Kim
Journal: Clinical Microbiology and Infection (2004)
(NZW x BXSB)F1 mouse. A new animal model of idiopathic thrombocytopenic purpura.
Authors: N Oyaizu, R Yasumizu, M Miyama-Inaba, S Nomura, H Yoshida, S Miyawaki, Y Shibata, S Mitsuoka, K Yasunaga, S Morii
Journal: The Journal of Experimental Medicine (1988)

A decrease in thrombocyte count was observed in (NZW x BXSB)F1 (W/B F1) mice at the age of greater than 5 mo, whereas megakaryocyte counts were found to increase in such mice. FACS analyses revealed the presence of both platelet-associated antibodies (PAA) and circulating antiplatelet antibodies. There is a correlation between the presence of these antibodies and the degree of thrombocytopenia. The transplantation of normal bone marrow cells from BALB/c nu/nu mice to W/B F1 mice was found to have preventative and curative effects on thrombocytopenia; the mice showed normal platelet counts and no evidence of circulating antiplatelet antibodies. These results indicate that thrombocytopenia in W/B F1 mice is due to the presence of antibodies to platelets. We therefore think that W/B F1 mice serve as a useful animal model of idiopathic thrombocytopenic purpura (ITP) not only for elucidating the mechanism of the development of antiplatelet antibodies, but also for characterizing autoantibodies to platelets.
Child Molestation and Pedophilia
Authors: A. Kenneth Fuller
Journal: JAMA (1989)

Child sexual abuse is a serious, pervasive problem with clinical, social, moral, and legal implications. Between 100 000 and 500 000 children in the United States are thought to be sexually molested annually. Physicians in all specialties may detect sexual exploitation of youngsters and are mandated to report such cases. Failure to diagnose child molestation and pedophilia and to treat their cause can have serious, long-lasting consequences for innocent victims and continued distress for the perpetrator and for the professional who missed the diagnosis. A single child molester may commit hundreds of sexual acts on hundreds of children. The etiology of paraphilic syndromes is multifactorial. There are substantial differences among sexual abusers of children in their personalities and psychopathologies. Although available interventions are symptomatically palliative rather than curative, many pedophiles can benefit from appropriate treatment. Primary prevention may be the key to reducing the frequency of child sexual abuse. (<i>JAMA</i>1989;261:602-606)
Anthrax Vaccine–Induced Antibodies Provide Cross-Species Prediction of Survival to Aerosol Challenge
Authors: Michael P. Fay, Dean A. Follmann, Freyja Lynn, Jarad M. Schiffer, Gregory V. Stark, Robert Kohberger, Conrad P. Quinn, Edwin O. Nuzum
Journal: Science Translational Medicine (2012)

Lethal toxin–neutralizing activity in serum after vaccination can provide cross-species predictions of survival against inhalation anthrax.
Regulatory B cells in ANCA-associated vasculitis
Authors: B Wilde, M Thewissen, J Damoiseaux, S Knippenberg, M Hilhorst, P van Paassen, O Witzke, J W Cohen Tervaert
Journal: Annals of the Rheumatic Diseases (2013)

B cells have immunoregulatory function acting as antigen-presenting cells. A separate subset of interleukin (IL)-10 producing B cells (Breg) regulating T cell mediated immunity has been identified. In the present study, we investigated the role of Breg in antineutrophil cytoplasmic antibodies-associated vasculitis (AAV).17 healthy controls (HCs) and 41 patients with AAV were enrolled. 30 patients with AAV were in remission. Furthermore, 11 patients with AAV with active disease were studied. Breg were defined as IL-10(+)CD19(+) B cells upon culture with cytosine-phosphate-guanosine oligodeoxynucleotide (CpG ODN) 2006. Next to Breg, CD4(+)CD127(low)CD25(hi)CD39(neg)/CD39(+) regulatory T-cells (Treg), interferon (IFN)γ(+), IL-4(+) and Il-17A(+)T helper cell subsets were determined via flow cytometry.Patients with active or quiescent disease showed a diminished fraction of Breg as compared with HCs. The frequency of IFNγ(+) T helper cells was negatively associated with Breg in untreated AAV in remission but not in active vasculitis or in HCs. Interestingly, the total Treg population and the CD39(+) Treg subpopulation correlated positively with Breg in inactive patients with AAV.IL-10 producing B cells are diminished in AAV. Furthermore, Breg might regulate Th1 cells and are associated with Treg in quiescent AAV. Suppression of Th1 cells by Breg may be insufficient in active AAV.
Cytotoxic T cells recognize a peptide from the circumsporozoite protein on malaria-infected hepatocytes.
Authors: W R Weiss, S Mellouk, R A Houghten, M Sedegah, S Kumar, M F Good, J A Berzofsky, L H Miller, S L Hoffman
Journal: The Journal of Experimental Medicine (1990)

Irradiated malaria sporozoites can induce CD8+ T cells that are required for protection against infection. However, the parasite antigens targeted by this immune response are unknown. We have discovered a 16-amino acid epitope from the Plasmodium yoelii circumsporozoite (CS) protein that is recognized by cytotoxic T cells from immune mice. Lymphocytes stimulated with this peptide can kill P. yoelii liver stage parasites in vitro in an MHC-restricted, antigen-specific manner. Thus, epitopes from the CS protein are presented on the surface of infected hepatocytes and can be targets for T cells, even though intact CS protein has not been detected on the surface of the infected hepatocyte. A vaccine that induced CTL to parasite antigens might protect humans against malaria by eliminating liver stage parasites.
RET-Familial Medullary Thyroid Carcinoma Mutants Y791F and S891A Activate a Src/JAK/STAT3 Pathway, Independent of Glial Cell Line–Derived Neurotrophic Factor
Authors: Ivan Plaza Menacho, Roelof Koster, Almer M. van der Sloot, Wim J. Quax, Jan Osinga, Tineke van der Sluis, Harry Hollema, Grzegorz M. Burzynski, Oliver Gimm, Charles H.C.M. Buys, Bart J.L. Eggen, Robert M.W. Hofstra
Journal: Cancer Research (2005)

Abstract The RET proto-oncogene encodes a receptor tyrosine kinase whose dysfunction plays a crucial role in the development of several neural crest disorders. Distinct activating RET mutations cause multiple endocrine neoplasia type 2A (MEN2A), type 2B (MEN2B), and familial medullary thyroid carcinoma (FMTC). Despite clear correlations between the mutations found in these cancer syndromes and their phenotypes, the molecular mechanisms connecting the mutated receptor to the different disease phenotypes are far from completely understood. Luciferase reporter assays in combination with immunoprecipitations, and Western and immunohistochemistry analyses were done in order to characterize the signaling properties of two FMTC-associated RET mutations, Y791F and S891A, respectively, both affecting the tyrosine kinase domain of the receptor. We show that these RET-FMTC mutants are monomeric receptors which are autophosphorylated and activated independently of glial cell line–derived neurotrophic factor. Moreover, we show that the dysfunctional signaling properties of these mutants, when compared with wild-type RET, involve constitutive activation of signal transducers and activators of transcription 3 (STAT3). Furthermore, we show that STAT3 activation is mediated by a signaling pathway involving Src, JAK1, and JAK2, differing from STAT3 activation promoted by RETC634R which was previously found to be independent of Src and JAKs. Three-dimensional modeling of the RET catalytic domain suggested that the structural changes promoted by the respective amino acids substitutions lead to a more accessible substrate and ATP-binding monomeric conformation. Finally, immunohistochemical analysis of FMTC tumor samples support the in vitro data, because nuclear localized, Y705-phosphorylated STAT3, as well as a high degree of RET expression at the plasma membrane was observed.
Turnover of Cholesterol in the Artery Walls of Normal Chickens
Authors: SEYMOUR DAYTON
Journal: Circulation Research (1959)

Studies of cholesterol metabolism in the walls of arteries of normal intact cockerels indicate that plasma cholesterol is the major precursor of the cholesterol in the artery wall, but that local synthesis may contribute a significant fraction. The fractional turnover of cholesterol in the wall of the abdominal aorta is faster than in either the thoracic aorta or the brachiocephalic arteries. However, considered in relation to endothelial surface area, the rate of cholesterol transfer from plasma is smallest in the abdominal aorta. The abdominal aorta also has a lower cholesterol concentration in this species than do the other large arteries.
Recommendations on Disease Management for Patients With Advanced Human Epidermal Growth Factor Receptor 2–Positive Breast Cancer and Brain Metastases: American Society of Clinical Oncology Clinical Practice Guideline
Authors: Naren Ramakrishna, Sarah Temin, Sarat Chandarlapaty, Jennie R. Crews, Nancy E. Davidson, Francisco J. Esteva, Sharon H. Giordano, Ana M. Gonzalez-Angulo, Jeffrey J. Kirshner, Ian Krop, Jennifer Levinson, Shanu Modi, Debra A. Patt, Edith A. Perez, Jane Perlmutter, Eric P. Winer, Nancy U. Lin
Journal: Journal of Clinical Oncology (2014)

To provide formal expert consensus-based recommendations to practicing oncologists and others on the management of brain metastases for patients with human epidermal growth factor receptor 2 (HER2) -positive advanced breast cancer.The American Society of Clinical Oncology (ASCO) convened a panel of medical oncology, radiation oncology, guideline implementation, and advocacy experts and conducted a systematic review of the literature. When that failed to yield sufficiently strong quality evidence, the Expert Panel undertook a formal expert consensus-based process to produce these recommendations. ASCO used a modified Delphi process. The panel members drafted recommendations, and a group of other experts joined them for two rounds of formal ratings of the recommendations.No studies or existing guidelines met the systematic review criteria; therefore, ASCO conducted a formal expert consensus-based process.Patients with brain metastases should receive appropriate local therapy and systemic therapy, if indicated. Local therapies include surgery, whole-brain radiotherapy, and stereotactic radiosurgery. Treatments depend on factors such as patient prognosis, presence of symptoms, resectability, number and size of metastases, prior therapy, and whether metastases are diffuse. Other options include systemic therapy, best supportive care, enrollment onto a clinical trial, and/or palliative care. Clinicians should not perform routine magnetic resonance imaging (MRI) to screen for brain metastases, but rather should have a low threshold for MRI of the brain because of the high incidence of brain metastases among patients with HER2-positive advanced breast cancer.
Intercellular Transfer and Supramolecular Organization of Human Leukocyte Antigen C at Inhibitory Natural Killer Cell Immune Synapses
Authors: Leo M. Carlin, Konstantina Eleme, Fiona E. McCann, Daniel M. Davis
Journal: The Journal of Experimental Medicine (2001)

After accumulation of target cell human leukocyte antigen (HLA)-C at inhibitory natural killer (NK) cell immune synapses, some HLA-C transfers from target cells to NK cell plasma membranes and cytoplasm. This unexpected intercellular transfer of HLA-C is dependent on NK receptor recognition, since HLA-Cw6 or -Cw4 but not -Cw3 transfer to an NK transfectant expressing killer Ig-like receptor (KIR)2DL1. Strikingly, live-cell time-lapse laser scanning confocal microscopy shows vesicles containing target cell green fluorescent protein–tagged HLA-C migrating away from immune synapses into NK cells. Unlike clustering of HLA-C at the immune synapse, intercellular transfer of HLA-C is dependent on NK cell ATP, but not target cell ATP. However, the intercellular transfer of HLA-C is not dependent on active polymerization of the actin cytoskeleton. In addition, different arrangements of HLA-C are seen at inhibitory NK immune synapses, and these alter as NK synapses mature, but in a fashion distinct from that seen upon T cell activation.
Altered Peptide Ligand–Induced Partial T Cell Activation: Molecular Mechanisms and Role in T Cell Biology
Authors: Joanne Sloan-Lancaster, Paul M. Allen
Journal: Annual Review of Immunology (1996)

The elucidation of the phenomena of T cell antagonism and partial activation by altered peptide ligands has necessitated a revision in the traditional concepts of TCR recognition of antigen and subsequent signal transduction. Whereas previous models supported a single ligand specificity for any particular T cell, many studies using analogs of immunogenic peptides have now demonstrated a flexibility in this recognition. Moreover, interaction with such altered peptide ligands can result in dramatically different phenotypes of the T cells, ranging from inducing selective stimulatory functions to completely turning off their functional capacity. Investigations of the biochemical basis leading to these phenotypes have shown that altered peptide ligands can induce a qualitatively different pattern of signal transduction events than does any concentration of the native ligand. Such observations imply that several signaling modules are directly linked to the TCR/CD3 complex and that they can be dissociated from each other as a direct result of the nature of the ligand bound. Interestingly, many in vivo models of T cell activation are compatible with a selective signaling model, and several studies have shown that peptide analogs can play a role in various T cell biologic phenomena. These data strongly suggest that naturally occurring altered peptide ligands for any TCR exist in the repertoire of self-peptides or, in nature, derived from pathogens, and recent reports provide compelling evidence that this is indeed the case. The concept of altered peptide ligands, their effects on T cell signaling, the hypothesized mechanisms by which they exert their effects, and their possible roles in shaping the T cell immune response are the scope of this review.
Long-Term Follow-Up of Patients With Newly Diagnosed Follicular Lymphoma in the Prerituximab Era: Effect of Response Quality on Survival—A Study From the Groupe d'Etude des Lymphomes de l'Adulte
Authors: Emmanuel Bachy, Pauline Brice, Richard Delarue, Nicole Brousse, Corinne Haioun, Steven Le Gouill, Alain Delmer, Dominique Bordessoule, Hervé Tilly, Bernadette Corront, Christian Allard, Charles Foussard, André Bosly, Bertrand Coiffier, Christian Gisselbrecht, Philippe Solal-Celigny, Gilles Salles
Journal: Journal of Clinical Oncology (2009)

PURPOSE First-line treatment for patients with newly diagnosed follicular lymphoma (FL) still remains debated, even in the rituximab-based combination therapy era. Few studies have addressed the question whether complete remission (CR) translates into better survival. The aim of this study was to assess the long-term follow-up of prospectively treated patients with FL and the potential correlation between response quality to first-line treatment and overall survival (OS). PATIENTS AND METHODS Data from 536 patients with FL with low (n = 193) or high (n = 343) tumor burden enrolled from October 1986 to May 1995 in the French and Belgian GELF86 studies were analyzed. Data from these trials have been previously reported for low-tumor burden and high-tumor burden patients. Results Median follow-up was 14.9 years, and median OS was 9.8 years. Treated patients who achieved a complete response (CR; n = 194; 45%) had a significant longer OS than those only reaching a partial response (PR; n = 168; 39%) throughout treatment (hazard ratio [HR], 0.55; 95% CI, 0.42 to 0.72; P < .001) in an univariate time-dependent Cox model. Similar findings were found when response to treatment (CR v PR) was adjusted for potentially confounding factors in a multivariate model (HR, 0.53; 95% CI, 0.38 to 0.73; P < .001). CONCLUSION These data provide a long follow-up of these patients' cohorts and indicate that a better response to first-line treatment translates into an improved survival for patients with FL. Therefore, response-adapted therapy aiming to achieve a CR should be considered as first-line treatment.
A Critical Analysis of RBRVS
Authors: C. Franklin Church
Journal: JAMA (1992)

To  Editor  —As my grandfather used to say, liars figure and figures lie. Though I wish to impune neither JAMA nor Dr Maloney, I question his analytic assumptions and conclusions 1 based on data reported in Medical Economics . 2 Although Maloney himself equivocates regarding the small sample size, incomplete coverage of specialties and  use of external data sources, his conclusions fail to reflect  issues of most concern to those who have considered both  problem and  solution.  Crane's data 3 concerning work hours are simply not credible. An example: a family physician in 10 minutes of careful history-taking and examination makes  diagnosis of acute appendicitis. This encounter is reimbursed at  rate of $50. This physician's overhead is 50%. The patient is then referred to a general surgeon who removes  appendix and is paid $500 with no overhead. Therefore,  family physician would have
Cushing Syndrome From Low Doses of Dexamethasone
Authors: A. Wayne Meikle
Journal: JAMA (1976)

DEXAMETHASONE, a potent synthetic analog of hydrocortisone, was introduced in 1958 for treatment of rheumatoid arthritis. A satisfactory antirheumatic response usually requires treatment with a dose that is commonly associated with side effects.<sup>1</sup>We recently observed a patient with rheumatoid arthritis in whom 0.75 mg of dexamethasone daily for two months resulted in Cushing syndrome. We thought that this dose was approximately equal in glucocorticoid potency to the amount of cortisol secreted daily by the adrenal cortex. Endogenous Cushing syndrome was considered initially but was excluded. We studied the patient's metabolism of dexamethasone in an attempt to explain the phenomenon. <h3>Methods</h3> All studies were performed in the Clinical Research Center. Written consent was obtained from the patient after the nature of the procedure was explained. Our normal values and methods for measuring plasma cortisol, plasma 11-deoxycortisol, and dexamethasone have been described in detail previously.<sup>2-4</sup>The coefficient of variation
Fourier analysis of arterial pulse in patients with advanced cirrhosis indicates reduced wave reflections that may protect against manifest cardiac dysfunction
Authors: Jens H Henriksen, Stefan Fuglsang, Flemming Bendtsen
Journal: Gut (2011)

Several recent articles in Gut have dealt with different aspects of the systemic circulation in liver disease.1–4 Patients with advanced cirrhosis have cardiovascular dysfunction and altered mechanics of large and small arteries.5 ,6 The configuration of the arterial pressure curve from these patients may disclose a flatter profile with fewer peaks.7 However, systematic investigations have not been performed. We applied the fast Fourier analysis to quantify the components of the arterial pressure curve …
Myocardial fibrin deposition in experimental viral myocarditis that progresses to dilated cardiomyopathy.
Authors: S J Schnitt, I E Stillman, D V Owings, C Kishimoto, H F Dvorak, W H Abelmann
Journal: Circulation Research (1993)

Myocardial fibrosis is a characteristic late feature in cases of viral myocarditis that progress to dilated cardiomyopathy. However, the pathogenesis of the myocardial fibrosis in such cases is unknown. Prior studies have shown that in healing wounds and tumor stroma generation, interstitial fibrin deposition precedes the development of fibrosis. Therefore, interstitial fibrin deposition in the myocardium was investigated in a murine model of myocarditis in which dilated cardiomyopathy develops. Inbred male C3H/He mice inoculated with coxsackievirus B3 were killed 0, 3, 7, 14, 21, 30, and 60 days after infection. Paraffin sections of hearts were stained with hematoxylin-eosin, Masson's trichrome stain, and antibodies to fibrinogen/fibrin by use of an immunoperoxidase technique. Pretreatment of all mice with anticoagulants and antifibrinolytics 5 minutes before death was used to prevent artifactual fibrin deposition and fibrinolysis during tissue manipulation. Tissue fixation in formalin supplemented with acetic acid served to extract non-cross-linked fibrin, fibrinogen, and fibrinogen and fibrin degradation products, thus ensuring that clotted and cross-linked fibrin was the major immunoreactant. Myocardial fibrin deposition and fibrosis were each quantitated by computer-assisted image analysis. Myocardial fibrin deposition first appeared on day 3, was maximal on day 14, and disappeared by day 30. Conversely, myocardial fibrosis was not detectable until day 14 and was maximal at day 60. Thus, as in healing wounds and developing tumor stroma, fibrin deposition preceded fibrosis in this murine model of myocarditis that progresses to dilated cardiomyopathy.