tbuckley/cabot-search huggingface dataset:
Biochemical basis of synergy between antigen and T-helper (Th) cell-mediated activation of resting human B cells.
Authors: E K Chartash, M K Crow, S M Friedman
Journal: Journal of Clinical Investigation (1989)

We have utilized CD23 expression as a marker for B cell activation in order to investigate the biochemical basis for synergy between antigen and T helper (Th) cells in the activation of resting human B cells. Our results confirm that while ligation of surface immunoglobulin (sIg) receptors by antigen analogues (e.g., F(ab')2 goat anti-human IgM) does not lead to CD23 expression, this stimulus markedly enhances CD23 expression induced during antigen specific Th-B cell interaction or by rIL-4. Utilizing a panel of monoclonal anti-human IgM antibodies, we observed a positive correlation between the capacity of a particular antibody to synergize with rIL-4 in CD23 expression and with B cell growth factor in B cell proliferation; suggesting that synergy in CD23 expression reflects the transduction of a functionally important signal via the sIg receptor. We next assayed analogues of the "second messenger" molecules, released during inositol lipid hydrolysis, for their capacity to amplify CD23 expression. These studies showed that protein kinase C (PKC) activating phorbol esters and the synthetic diacylgylcerol analogue, DiC8, synergize with either Th cells or rIL-4 in CD23 expression, while under no experimental condition does increasing B cell [Ca2+]i with ionomycin enhance CD23 expression. Taken together, these data suggest that activation of B cell PKC is the crucial biochemical event that primes antigen-activated B cells to respond more vigorously to interaction with Th cells and/or their soluble products.
The management of the allergic child at school: EAACI/GA<sup>2</sup>LEN Task Force on the allergic child at school
Authors: A. Muraro, A. Clark, K. Beyer, L. M. Borrego, M. Borres, K. C. Lødrup Carlsen, P. Carrer, A. Mazon, F. Rancè, E. Valovirta, M. Wickman, M. Zanchetti
Journal: Allergy (2010)

Allergy affects at least one-quarter of European schoolchildren, it reduces quality of life and may impair school performance; there is a risk of severe reactions and, in rare cases, death. Allergy is a multi-system disorder, and children often have several co-existing diseases, i.e. allergic rhinitis, asthma, eczema and food allergy. Severe food allergy reactions may occur for the first time at school, and overall 20% of food allergy reactions occur in schools. Up to two-thirds of schools have at least one child at risk of anaphylaxis but many are poorly prepared. A cooperative partnership between doctors, community and school nurses, school staff, parents and the child is necessary to ensure allergic children are protected. Schools and doctors should adopt a comprehensive approach to allergy training, ensuring that all staff can prevent, recognize and initiate treatment of allergic reactions.
Intrathoracic Impedance Monitoring, Audible Patient Alerts, and Outcome in Patients With Heart Failure
Authors: Dirk J. van Veldhuisen, Frieder Braunschweig, Viviane Conraads, Ian Ford, Martin R. Cowie, Guillaume Jondeau, Josef Kautzner, Roberto Muñoz Aguilera, Maurizio Lunati, Cheuk Man Yu, Bart Gerritse, Martin Borggrefe
Journal: Circulation (2011)

Heart failure is associated with frequent hospitalizations, often resulting from volume overload. Measurement of intrathoracic impedance with an implanted device with an audible patient alert may detect increases in pulmonary fluid retention early. We hypothesized that early intervention could prevent hospitalizations and affect outcome.We studied 335 patients with chronic heart failure who had undergone implantation of an implantable cardioverter-defibrillator alone (18%) or with cardiac resynchronization therapy (82%). All devices featured a monitoring tool to track changes in intrathoracic impedance (OptiVol) and other diagnostic parameters. Patients were randomized to have information available to physicians and patients as an audible alert in case of preset threshold crossings (access arm) or not (control arm). The primary end point was a composite of all-cause mortality and heart failure hospitalizations. During 14.9±5.4 months, this occurred in 48 patients (29%) in the access arm and in 33 patients (20%) in the control arm (P=0.063; hazard ratio, 1.52; 95% confidence interval, 0.97-2.37). This was due mainly to more heart failure hospitalizations (hazard ratio, 1.79; 95% confidence interval, 1.08-2.95; P=0.022), whereas the number of deaths was comparable (19 versus 15; P=0.54). The number of outpatient visits was higher in the access arm (250 versus 84; P<0.0001), with relatively more signs of heart failure among control patients during outpatient visits. Although the trial was terminated as a result of slow enrollment, a post hoc futility analysis indicated that a positive result would have been unlikely.Use of an implantable diagnostic tool to measure intrathoracic impedance with an audible patient alert did not improve outcome and increased heart failure hospitalizations and outpatient visits in heart failure patients. Clinical Trial Registration-URL: http://www.clinicaltrials.gov. Unique identifier: NCT 00480077.
Does the site of magnetic resonance imaging abnormalities match the site of recent-onset inflammatory back pain? The DESIR cohort
Authors: Martin Blachier, Bertrand Coutanceau, Maxime Dougados, Alain Saraux, Sylvie Bastuji-Garin, Salah Ferkal, Philippe Le Corvoisier, Valérie Farrenq, Cécile Poulain, Bijan Ghaleh, Florence Canouï-Poitrine, Pascal Claudepierre
Journal: Annals of the Rheumatic Diseases (2012)

To assess whether the site of axial pain (thoracic spine, lumbar spine or buttock(s)) was associated with the site of MRI lesions in patients with recent inflammatory back pain (IBP) suggesting spondyloarthritis.We conducted a cross-sectional study of baseline data in 708 patients with recent IBP from the DESIR cohort. Radiographs of the sacroiliac joints (SIJs) and MRI scans of the SIJs and thoracic and lumbar spine were obtained routinely. Associations between pain sites and sites of inflammatory and structural MRI changes were evaluated using separate multivariate logistic regressions.Of the 648 patients with complete data, 61% had thoracic pain, 91.6% lumbar pain and 79.2% buttock pain. MRI inflammation was seen in 19%, 21% and 46% of patients at the thoracic, lumbar and SIJ sites, respectively. By multivariate analysis, pain was significantly associated with MRI inflammation only at the same site (adjusted OR (aOR)thoracic pain 1.71; 95% CI 1.09 to 2.67; p=0.02; aORlumbar pain 2.53; 95% CI 1.03 to 6.20; p=0.04; aORbuttock pain 2.86; 95% CI 1.84 to 4.46; p<0.0001). Pain site was not significantly associated with the site of structural MRI changes, except for buttock pain and SIJ structural MRI changes (aORbuttock pain 1.89; 95% CI 1.22 to 2.90; p=0.004). The association between pain site and site of MRI inflammation persisted in the subgroups with normal or doubtful SIJ radiographs or with Assessment of SpondyloArthritis international Society criteria for axial spondyloarthritis.The site of pain (thoracic spine, lumbar spine or buttock(s)) is associated with MRI inflammation at the same site in patients with recent IBP.
2,3,7,8-Tetrachlorodibenzo-<i>p</i>-Dioxin and Related Halogenated Aromatic Hydrocarbons: Examination of the Mechanism of Toxicity
Authors: Alan Poland, Joyce C. Knutson
Journal: The Annual Review of Pharmacology and Toxicology (1982)

In this review, we have examined the biochemical and toxic responses produced by halogenated aromatic hydrocarbons and have tried to develop a model for their mechanism of action. These compounds bind to a cellular receptor and evoke a sustained pleiotropic response. In many tissues this response consists of the expression of a battery of enzymes which are, for the most part, involved in drug metabolism, but in other tissues, those which develop toxicity, an additional set of genes is expressed which effects cellular involution, division, and/or differentiation. The toxicity of these compounds appears to be due to the sustained expression of a normal cellular regulatory system, of which we were previously unaware. In future investigations it is hoped that we will learn the nature and physiologic role of this regulatory system. Only then can we hope to understand the mechanism of toxicity of these compounds.
A Novel, Macrophage Migration Inhibitory Factor Suicide Substrate Inhibits Motility and Growth of Lung Cancer Cells
Authors: Millicent Winner, Jason Meier, Swen Zierow, Beatriz E. Rendon, Gregg V. Crichlow, Randall Riggs, Richard Bucala, Lin Leng, Ned Smith, Elias Lolis, John O. Trent, Robert A. Mitchell
Journal: Cancer Research (2008)

Although chemokine and growth factor receptors are attractive and popular targets for cancer therapeutic intervention, structure-based targeting of the ligands themselves is generally not considered practical. New evidence indicates that a notable exception to this is macrophage migration inhibitory factor (MIF). MIF, an autocrine- and paracrine-acting cytokine/growth factor, plays a pivotal role in both the initiation and maintenance of neoplastic diseases. MIF possesses a nonphysiologic enzymatic activity that is evolutionarily well-conserved. Although small molecule antagonists of MIFs enzymatic active site have been reported to inhibit biological activities of MIF, universally high IC(50)s have limited their clinical appeal. Using a computational virtual screening strategy, we have identified a unique small molecule inhibitor that serves as a suicide substrate for MIF, resulting in the covalent modification of the catalytically active NH(2)-terminal proline. Our studies further reveal that this compound, 4-iodo-6-phenylpyrimidine (4-IPP), is approximately 5x to 10x times more potent in blocking MIF-dependent catalysis and lung adenocarcinoma cell migration and anchorage-independent growth than the prototypical MIF inhibitor, ISO-1. Finally, using an in silico combinatorial optimization strategy, we have identified four unique congeners of 4-IPP that exhibit MIF inhibitory activity at concentrations 10x to 20x lower than that of parental 4-IPP.
Stress fractures in rheumatoid arthritis: a case series and case-control study
Authors: L J Kay
Journal: Annals of the Rheumatic Diseases (2004)

To review cases of stress fracture in patients with rheumatoid arthritis (RA) presenting to our service over a 10 year period; to identify possible risk factors and test these in a case-control study.A retrospective case note review of all patients with a final diagnosis of stress fracture, presenting between 1990 and 1999 was performed. A case-control study of consecutive patients with RA, matched for age, sex and duration of disease, attending the same clinics.24 stress fractures were identified in 18 patients, representing 0.8% of the RA clinic population; all were women, median age 69.5 years (range 47-79). Bone mineral densitometry showed median T scores of -3.06 and -2.27 SD at the hip and lumbar spine, respectively. Case-control study: In the stress fractures group, past steroid doses were higher (p = 0.003). No significant differences in the bone mineral density (BMD) T score at the hip or lumbar spine were found (p = 0.59, p = 0.77).Stress fractures are a significant cause of morbidity in RA. Diagnosis is often delayed and presentation can be misleading. Past steroid use, particularly at higher doses, confers an increased risk of stress fracture, but the increased risk is not attributable to osteoporosis as assessed by BMD.
ICOS maintains the T follicular helper cell phenotype by down-regulating Krüppel-like factor 2
Authors: Jan P. Weber, Franziska Fuhrmann, Randi K. Feist, Annette Lahmann, Maysun S. Al Baz, Lea-Jean Gentz, Dana Vu Van, Hans W. Mages, Claudia Haftmann, René Riedel, Joachim R. Grün, Wolfgang Schuh, Richard A. Kroczek, Andreas Radbruch, Mir-Farzin Mashreghi, Andreas Hutloff
Journal: The Journal of Experimental Medicine (2015)

The co-stimulators ICOS (inducible T cell co-stimulator) and CD28 are both important for T follicular helper (TFH) cells, yet their individual contributions are unclear. Here, we show that each molecule plays an exclusive role at different stages of TFH cell development. While CD28 regulated early expression of the master transcription factor Bcl-6, ICOS co-stimulation was essential to maintain the phenotype by regulating the novel TFH transcription factor Klf2 via Foxo1. Klf2 directly binds to Cxcr5, Ccr7, Psgl-1, and S1pr1, and low levels of Klf2 were essential to maintain this typical TFH homing receptor pattern. Blocking ICOS resulted in relocation of fully developed TFH cells back to the T cell zone and reversion of their phenotype to non-TFH effector cells, which ultimately resulted in breakdown of the germinal center response. Our study describes for the first time the exclusive role of ICOS and its downstream signaling in the maintenance of TFH cells by controlling their anatomical localization in the B cell follicle.
Ozone-induced respiratory symptoms: exposure-response models and association with lung function
Authors: W.F. McDonnell, P.W. Stewart, M.v Smith, W.k Pan, J Pan
Journal: European Respiratory Journal (1999)

Ozone-induced respiratory symptoms are known to be functions of concentration, minute ventilation, and duration of exposure. The purposes of this study were to identify an exposure-response model for symptoms, to determine whether response was related to age, and to assess the relationships between symptom and lung function responses to ozone. Four hundred and eighty-five healthy male volunteers (ages 18-35 yrs) were exposed to one of six ozone concentrations at one of three activity levels for 2 h. Symptoms and forced expiratory volume in one second (FEV1) were assessed at the end of 1 and 2 h. The exposure and response data were fitted by a nonlinear exposure-response model previously found to describe FEV1 response. The proportion of individuals experiencing moderate or severe cough, shortness of breath, and pain on deep inspiration were accurately described as functions of concentration, minute ventilation, and time. Response was inversely related to age for shortness of breath (p=0.0001), pain on deep inspiration (p=0.0002), and cough (p=0.0013). Controlling for exposure differences, symptom responses were significantly but weakly (correlation coefficient 0.30-0.41) related to the FEV1 response. In conclusion, the exposure-response model did accurately predict symptoms, response was inversely related to age.
Reforming Care for Persons Near the End of Life: The Promise of Quality Improvement
Authors: Joanne Lynn, Kevin Nolan, Andrea Kabcenell, David Weissman, Casey Milne, Donald M. Berwick
Journal: Annals of Internal Medicine (2002)

Most people in developed countries will live with a serious, eventually fatal, chronic condition for months or years before dying; yet, the delivery of health care services has only just recently begun adapting to this reality. Quality improvement methods have been effective in helping clinical services to make substantial changes quickly. Quality improvement requires stating an aim, measuring success, and testing possible improvements. The testing of changes requires a clinical team to Plan, Do, Study, and Act on new insights (the "PDSA cycle"). Repeated PDSA cycles generate deep understanding of complex systems and make sustainable improvements rapidly. This paper discusses a composite case study in a nursing home setting, which builds on experience with multisite collaborative efforts and introduces quality improvement methods in the context of end-of-life care. *For members of the End-of-Life Care Consensus Panel, see the Appendix.
Androgens potentiate renal vascular responses to angiotensin II via amplification of the Rho kinase signaling pathway
Authors: J SONG, C KOSTJR, D MARTIN
Journal: Cardiovascular Research (2006)

This study assessed whether the Rho kinase signaling pathway contributes to androgenic amplification of angiotensin II (Ang II) induced pressor and renal constrictor responses.Mean arterial pressure (MAP) responses to angiotensin II receptor 1 (AT1) inhibition were measured in conscious male New Zealand genetically hypertensive rats (NZGH) subjected to sham operation, castration or castration+testosterone replacement. MAP and renal vascular resistance (RVR) responses to Ang II were recorded with and without a Rho kinase inhibitor, fasudil, in anesthetized NZGH. Western blot was used to analyze target protein expression in the kidney.MAP responses to AT1 receptor inhibition and exogenous Ang II were attenuated in castrated NZGH. The increase in RVR (mm Hg/ml/min/g kidney) at the maximum dose of Ang II was significantly lower in castrated NZGH than in sham operated NZGH. Testosterone replacement restored RVR responses to Ang II in castrated rats. Fasudil treatment reduced both MAP and RVR responses to Ang II in each group. In addition, the differential MAP and RVR responses to Ang II amongst the three groups were significantly attenuated by Rho kinase inhibition. Western blot showed that Rho kinase protein expression was reduced by castration, while testosterone replacement restored the Rho kinase protein levels in castrated rats. The phosphorylation of myosin phosphatase target subunit 1 (MYPT1), a downstream target of Rho kinase, was also increased by androgens.Collectively, these results indicate that androgens potentiate Ang II-induced renal vascular responses, an effect mediated at least partly via up-regulation of the Rho kinase signaling pathway.
PKCα Attenuates Jagged-1–Mediated Notch Signaling in ErbB-2–Positive Breast Cancer to Reverse Trastuzumab Resistance
Authors: Kinnari Pandya, Debra Wyatt, Brian Gallagher, Deep Shah, Andrew Baker, Jeffrey Bloodworth, Andrei Zlobin, Antonio Pannuti, Andrew Green, Ian O. Ellis, Aleksandra Filipovic, Jason Sagert, Ajay Rana, Kathy S. Albain, Lucio Miele, Mitchell F. Denning, Clodia Osipo
Journal: Clinical Cancer Research (2015)

Abstract Purpose: Breast cancer is the second leading cause of cancer mortality among women worldwide. The major problem with current treatments is tumor resistance, recurrence, and disease progression. ErbB-2–positive breast tumors are aggressive and frequently become resistant to trastuzumab or lapatinib. We showed previously that Notch-1 is required for trastuzumab resistance in ErbB-2–positive breast cancer. Experimental Design: Here, we sought to elucidate mechanisms by which ErbB-2 attenuates Notch signaling and how this is reversed by trastuzumab or lapatinib. Results: The current study elucidates a novel Notch inhibitory mechanism by which PKCα downstream of ErbB-2 (i) restricts the availability of Jagged-1 at the cell surface to transactivate Notch, (ii) restricts the critical interaction between Jagged-1 and Mindbomb-1, an E3 ligase that is required for Jagged-1 ubiquitinylation and subsequent Notch activation, (iii) reverses trastuzumab resistance in vivo, and (iv) predicts better outcome in women with ErbB-2–positive breast cancer. Conclusions: The clinical impact of these studies is PKCα is potentially a good prognostic marker for low Notch activity and increased trastuzumab sensitivity in ErbB-2–positive breast cancer. Moreover, women with ErbB-2–positive breast tumors expressing high Notch activation and low PKCα expression could be the best candidates for anti-Notch therapy. Clin Cancer Res; 22(1); 175–86. ©2015 AACR.
Systematic Review: The Effects of Growth Hormone on Athletic Performance
Authors: Hau Liu, Dena M. Bravata, Ingram Olkin, Anne Friedlander, Vincent Liu, Brian Roberts, Eran Bendavid, Olga Saynina, Shelley R. Salpeter, Alan M. Garber, Andrew R. Hoffman
Journal: Annals of Internal Medicine (2008)

Background: Human growth hormone is reportedly used to enhance athletic performance, although its safety and efficacy for this purpose are poorly understood. Purpose: To evaluate evidence about the effects of growth hormone on athletic performance in physically fit, young individuals. Data Sources: MEDLINE, EMBASE, SPORTDiscus, and Cochrane Collaboration databases were searched for English-language studies published between January 1966 and October 2007. Study Selection: Randomized, controlled trials that compared growth hormone treatment with no growth hormone treatment in community-dwelling healthy participants between 13 and 45 years of age. Data Extraction: 2 authors independently reviewed articles and abstracted data. Data Synthesis: 44 articles describing 27 study samples met inclusion criteria; 303 participants received growth hormone, representing 13.3 person-years of treatment. Participants were young (mean age, 27 years [SD, 3]), lean (mean body mass index, 24 kg/m2 [SD, 2]), and physically fit (mean maximum oxygen uptake, 51 mL/kg of body weight per minute [SD, 8]). Growth hormone dosage (mean, 36 µg/kg per day [SD, 21]) and treatment duration (mean, 20 days [SD, 18] for studies giving growth hormone for >1 day) varied. Lean body mass increased in growth hormone recipients compared with participants who did not receive growth hormone (increase, 2.1 kg [95% CI, 1.3 to 2.9 kg]), but strength and exercise capacity did not seem to improve. Lactate levels during exercise were statistically significantly higher in 2 of 3 studies that evaluated this outcome. Growth hormone–treated participants more frequently experienced soft tissue edema and fatigue than did those not treated with growth hormone. Limitations: Few studies evaluated athletic performance. Growth hormone protocols in the studies may not reflect real-world doses and regimens. Conclusion: Claims that growth hormone enhances physical performance are not supported by the scientific literature. Although the limited available evidence suggests that growth hormone increases lean body mass, it may not improve strength; in addition, it may worsen exercise capacity and increase adverse events. More research is needed to conclusively determine the effects of growth hormone on athletic performance.
Risk Factors for β-Amyloid Deposition in Healthy Aging
Authors: Karen M. Rodrigue, Jennifer R. Rieck, Kristen M. Kennedy, Michael D. Devous, Ramon Diaz-Arrastia, Denise C. Park
Journal: JAMA Neurology (2013)

<h3>Importance</h3>Identifying risk factors for increased β-amyloid (Aβ) deposition is important for targeting individuals most at risk for developing Alzheimer disease and informing clinical practice concerning prevention and early detection.<h3>Objective</h3>To investigate risk factors for Aβ deposition in cognitively healthy middle-aged and older adults. Specifically, we hypothesized that individuals with a vascular risk factor such as hypertension, in combination with a genetic risk factor for Alzheimer disease (apolipoprotein E ϵ4 allele), would show greater amyloid burden than those without such risk.<h3>Design</h3>Cross-sectional study.<h3>Setting</h3>General community.<h3>Participants</h3>One hundred eighteen well-screened and cognitively normal adults, aged 47 to 89 years. Participants were classified in the hypertension group if they reported a medical diagnosis of hypertension or if blood pressure exceeded 140 mm Hg systolic/90 mm Hg diastolic, as measured across 7 occasions at the time of study.<h3>Intervention</h3>Participants underwent Aβ positron emission tomography imaging with radiotracer fluorine 18–labeled florbetapir. Participants were genotyped for apolipoprotein E and were classified as ϵ4<sup>+</sup> or ϵ4<sup>−</sup>.<h3>Main Outcome Measure</h3>Amyloid burden.<h3>Results</h3>Participants in the hypertension group with at least 1 ϵ4 allele showed significantly greater amyloid burden than those with only 1 risk factor or no risk factors. Furthermore, increased pulse pressure was strongly associated with increased mean cortical amyloid level for subjects with at least 1 ϵ4 allele.<h3>Conclusions and Relevance</h3>Vascular disease is a prevalent age-related condition that is highly responsive to both behavioral modification and medical treatment. Proper control and prevention of risk factors such as hypertension earlier in the life span may be one potential mechanism to ameliorate or delay neuropathological brain changes with aging.