tbuckley/cabot-search huggingface dataset:
A Randomized Clinical Trial of Peak Flow versus Symptom Monitoring in Older Adults with Asthma
Authors: A. Sonia Buist, William M. Vollmer, Sandra R. Wilson, E. Ann Frazier, Arthur D. Hayward
Journal: American Journal of Respiratory and Critical Care Medicine (2006)

To determine whether peak flow monitoring has value above and beyond symptom monitoring when used as part of an asthma management plan.From a large managed-care organization, 296 adults, aged 50-92 yr, were recruited and randomly assigned in equal numbers to either use of symptoms or peak flow rate (twice daily or "as needed") for asthma monitoring, and monitored every 6 mo for 2 yr. Interventions were delivered in four 90-min small-group classes and included a personalized action plan and coaching in proper use of asthma inhalers.We found no significant differences between peak flow rate and symptom monitoring, or between twice-daily and as-needed peak flow monitoring in the primary or secondary study outcomes: health care utilization (acute, nonacute, or total asthma visits), Asthma Quality-of-Life Questionnaire (AQLQ) scores, and lung function. AQLQ scores and prebronchodilator FEV1 increased significantly for both groups between baseline and 6 mo (AQLQ: mean, 0.4 units; 95% confidence interval, 0.3, 0.5; p < 0.0001; FEV1% predicted: mean, 4%). Inhaler technique improved substantially in both groups.Peak flow monitoring has no advantage over symptom monitoring as an asthma management strategy for older adults with moderate-severe asthma when used in a comprehensive asthma management program. Improved outcomes in both groups suggest that understanding proper medication use, regular monitoring of asthma status, and understanding how to respond to changes are of primary importance.
Staffing of a combined general medical service and gastroenterology unit in a district general hospital. A report prepared for the Royal College of Physicians (London). Gastroenterology Committee and the Clinical Services Committee of the British Society of Gastroenterology.
Authors: W R Burnham, J E Lennard-Jones, G E Sladen
Journal: Gut (1989)

Committee of the British Society of GastroenterologyThis paper describes the roles of a consultant general physician with a special interest in gastroenterology and associated staff working in a district general hospital.Its aim is to define the needs for staff in both the general medical and gastroenterological aspects of the service.Generalisations are based on data and comments received from 130 physicians.It is recognised that the staffing needs of University affiliated hospitals, or certain hospitals which provide a special service for patients outside their own district, differ from that presented here for hospitals which serve a local community. Work of the district hospital physician with a special interest in gastroenterologyThe physician/gastroenterologist, in a district general hospital fulfils a number of important functions.He/she shares with his colleagues in the rota for acute medical admissions, holds regular out-patient clinics and performs a substantial part of the diagnostic and therapeutic gastrointestinal endoscopy service.The staffing required to provide this service must be seen in relation to the volume and complexity of the work. INPATIENTS -GENERAL MEDICINEThe number of patients admitted and the frequency of emergency duties vary according to the size of the hospital, its catchment area and the morbidity of the local population.According to a recent College survey' of district hospital physicians, the average frequency of emergency duties was one in 4 7 days with approximately 700 acute admissions each year.In the North East Thames Region, five district hospital physicians with a special interest in gastroenterology reported more than 900 admissions per year.2In East Anglia, six single handed physicians/gastroenterologists reported 750- 1130 admissions annually.3These include admissions from outpatients, domiciliary consultations and personal referrals from general practitioners.The physician is also asked to advise on patients under the care of other consultants as well as supervising the care of his/her own patients.There is a regular commitment to administration and teaching.
Phase I Trial of a Combination of the Multikinase Inhibitor Sorafenib and the Farnesyltransferase Inhibitor Tipifarnib in Advanced Malignancies
Authors: David S. Hong, Said M. Sebti, Robert A. Newman, Michelle A. Blaskovich, Lei Ye, Robert F. Gagel, Stacy Moulder, Jennifer J. Wheler, Aung Naing, Nizar M. Tannir, Chaan S. Ng, Steven I. Sherman, Adel K. El Naggar, Rabia Khan, Jon Trent, John J. Wright, Razelle Kurzrock
Journal: Clinical Cancer Research (2009)

We evaluated the safety, maximum tolerated dose, pharmacokinetics, and biological effects of the combination of the Raf-1, RET, KIT, platelet-derived growth factor receptor, and vascular endothelial growth factor receptor 2 kinase inhibitor sorafenib and the farnesyltransferase inhibitor tipifarnib.A standard 3 + 3 phase I dose-escalation design was used with a 28-day cycle (sorafenib daily and tipifarnib for 21 days, by mouth).Fifty patients were treated; 43 reached restaging evaluation after cycle 2. The most common side effects were grade 1 to 2 rash, hyperglycemia, and diarrhea. Dose-limiting toxicity was rash, and the recommended phase II dose is sorafenib 400 mg p.o. qam/200 mg p.o. qpm and tipifarnib p.o. 100 mg bd. Despite the low doses of tipifarnib, one quarter of patients had > or =50% reduction in farnesyltransferase levels. Interestingly, six of eight patients with medullary thyroid cancer had durable stable disease (n = 3) or partial remissions (n = 3), lasting 12 to 26+ months. Five of the six responders had available tissue, and RET gene mutations were identified in them. Prolonged (> or =6 months) stable disease was also seen in nine patients as follows: papillary thyroid cancer (n = 4; 18+ to 27+ months), adrenocortical cancer (n = 2; 7 and 11 months), and one each of melanoma (platelet-derived growth factor receptor mutation positive; 14 months), renal (6 months), and pancreatic cancer (6 months).Our study shows that the combination of tipifarnib and sorafenib is well tolerated. Activity was seen, especially in patients with medullary thyroid cancer, a tumor characterized by RET mutations.
Absence of Respiratory Burst in X-linked Chronic Granulomatous Disease Mice Leads to Abnormalities in Both Host Defense and Inflammatory Response to <i>Aspergillus fumigatus</i>
Authors: David E. Morgenstern, Mary A.C. Gifford, Ling Lin Li, Claire M. Doerschuk, Mary C. Dinauer
Journal: The Journal of Experimental Medicine (1997)

Mice with X-linked chronic granulomatous disease (CGD) generated by targeted disruption of the gp91phox subunit of the NADPH–oxidase complex (X-CGD mice) were examined for their response to respiratory challenge with Aspergillus fumigatus. This opportunistic fungal pathogen causes infection in CGD patients due to the deficient generation of neutrophil respiratory burst oxidants important for damaging A. fumigatus hyphae. Alveolar macrophages from X-CGD mice were found to kill A. fumigatus conidia in vitro as effectively as alveolar macrophages from wild-type mice. Pulmonary disease in X-CGD mice was observed after administration of doses ranging from 105 to 48 spores, none of which produced disease in wild-type mice. Higher doses produced a rapidly fatal bronchopneumonia in X-CGD mice, whereas progression of disease was slower at lower doses, with development of chronic inflammatory lesions. Marked differences were also observed in the response of X-CGD mice to the administration of sterilized Aspergillus hyphae into the lung. Within 24 hours of administration, X-CGD mice had significantly higher numbers of alveolar neutrophils and increased expression of the proinflammatory cytokines IL-1β and TNF-α relative to the responses seen in wild-type mice. By one week after administration, pulmonary inflammation was resolving in wild-type mice, whereas X-CGD mice developed chronic granulomatous lesions that persisted for at least six weeks. This is the first experimental evidence that chronic inflammation in CGD does not always result from persistent infection, and suggests that the clinical manifestations of this disorder reflect both impaired microbial killing as well as other abnormalities in the inflammatory response in the absence of a respiratory burst.
Diagnostic Usefulness of a Peribulbar Eosinophilic Infiltrate in Alopecia Areata
Authors: Tae Young Yoon, Dong Yoon Lee, Young Jin Kim, Ji Yeoun Lee, Mi Kyeong Kim
Journal: JAMA Dermatology (2014)

The histopathologic diagnosis of alopecia areata (AA) may be difficult in the chronic stage in which the presence of a peribulbar lymphocytic infiltrate is not definite. An eosinophilic infiltrate has been reported as a relatively common histopathologic finding and a helpful diagnostic feature in AA.To investigate the frequency and diagnostic usefulness of an eosinophilic infiltrate around the hair bulbs or within the fibrous tracts during the chronic stage of AA.A retrospective review was conducted at Chungbuk National University Hospital. A total of 162 scalp biopsy specimens of AA were analyzed.The frequency of a peribulbar eosinophilic infiltrate in AA.In 30 of 162 specimens (18.5%) of AA in all stages, eosinophils were found around the hair bulbs with variable density but were not identified in the fibrous tracts of any specimen. Eosinophils around the hair bulbs were detected in 24 of 78 specimens (30.8%) of the acute stage of AA in which a peribulbar lymphocytic infiltrate was present, and eosinophils were densely infiltrated in 6 of these specimens (7.7%). In contrast, in the chronic stage of AA in which a peribulbar lymphocytic infiltrate was sparse or absent, eosinophils around the hair bulbs were found in only 6 of 84 specimens (7.1%); furthermore, eosinophils were sparsely present in all specimens. Pigmentary incontinence around the hair follicles was found in 58 of 84 specimens (69.0%), follicular miniaturization in 52 (61.9%), and shift to the catagen or telogen phase in 46 (54.8%).An eosinophilic infiltrate around the hair bulbs or within the fibrous tracts is not a common finding in the histopathologic characteristics of AA, especially in the chronic stage of the disease. Thus, the diagnostic usefulness of the eosinophilic infiltrate is limited to few cases of AA in the chronic stage. Other histopathologic findings, such as pigmentary incontinence around the hair follicles, follicular miniaturization, and shift to the catagen or telogen phase, are more useful diagnostic features in the cases of AA not showing a definite peribulbar lymphocytic infiltrate.
Cell-Mediated Immunity and Specific Serum Factors in Human Cancer: The Leukocyte Adherence Inhibition Test2
Authors: Annette Maluish, W. J. Halliday
Journal: JNCI Journal of the National Cancer Institute (1974)

Journal Article Cell-Mediated Immunity and Specific Serum Factors in Human Cancer: The Leukocyte Adherence Inhibition Test Get access Annette Maluish, Annette Maluish Search for other works by this author on: Oxford Academic PubMed Google Scholar W. J. Halliday W. J. Halliday Department of Microbiology, University of Queensland, St. Lucia, Brisbane, Australia Search for other works by this author on: Oxford Academic PubMed Google Scholar JNCI: Journal of the National Cancer Institute, Volume 52, Issue 5, May 1974, Pages 1415–1420, https://doi.org/10.1093/jnci/52.5.1415 Published: 01 May 1974 Article history Received: 16 October 1973 Accepted: 28 January 1974 Published: 01 May 1974
Abstract 3239: The Notch pathway as a new target in gastrointestinal stromal tumors
Authors: Amaury G. Dumont, Dennis P. Hughes, Jonathan Trent
Journal: Cancer Research (2012)

Abstract Small molecule kinase inhibitors have dramatically improved the survival of patients with Gastrointestinal Stromal Tumors (GIST), yet most patients develop resistance, urging us to understand better the molecular mechanisms underlying this disease and identify new therapeutic strategies. Notch signaling is a conserved developmental pathway known to play a critical role in the development of several cancers, functioning as a tumor promoter or a tumor suppressor. Given that the normal progenitor cell for GIST, the Interstitial Cell of Cajal, has characteristics similar to those of cells of neuroendocrine origin, we hypothesized that Notch pathway impacts the biology of GIST cells. In a previous study, we demonstrated that constitutively active intracellular domain of Notch1 (ICN-1) induced growth arrest in GIST cell lines. Here we report that ICN-1 downregulated KIT protein by a flow cytometric analysis in the three cell lines analyzed (GIST-T1, GIST882, GIST48IM). In parallel, inhibitions of Hes1, a major target gene of ICN-1, with a dominant negative construct, upregulated KIT protein expression in vitro (60% increase on western blot). This anti-tumor effect of Notch1 in GIST leads to a therapeutic opportunity as we showed in the present study that treatment with the histone deacetylase inhibitor, SAHA, caused a dose-dependent upregulation of Notch1 (6 fold increase of the mRNA with SAHA 2 µm/L on GIST-T1, P&amp;lt;0.05), downregulation of KIT and pKIT (9 fold decrease of pKIT on western blot with SAHA 2 µm/L on GIST-T1), increase in apoptosis (25-fold increase in the sub-G1 population with SAHA 2 µmol/L on GIST-T1, P&amp;lt;0.05), decrease in viability of the GIST cells (IC50 = 2 µmol/L on GIST-T1).To confirm the clinical relevance of the Notch pathway on GIST, we performed a retrospective analysis on 15 pre-treated patient tumors and showed that GIST patients with high Hes1 mRNA levels have a significantly longer relapse-free survival than the one with low Hes1 mRNA levels (median of 37 months for the low group versus median not reached at &amp;gt;80 months for the high group; P=0.005). These results identify a novel anti-tumor effect of Notch1 via a crosstalk between the Notch1 and KIT pathways in GIST cells. This finding may lead to new therapeutic strategies for GIST patients, in particular after failure of tyrosine kinase inhibitors. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 3239. doi:1538-7445.AM2012-3239
Naive tumor-specific CD4+ T cells differentiated in vivo eradicate established melanoma
Authors: Ying Xie, Akgül Akpinarli, Charles Maris, Edward L. Hipkiss, Malcolm Lane, Eun-Kyung M. Kwon, Pawel Muranski, Nicholas P. Restifo, Paul Andrew Antony
Journal: The Journal of Experimental Medicine (2010)

In vitro differentiated CD8(+) T cells have been the primary focus of immunotherapy of cancer with little focus on CD4(+) T cells. Immunotherapy involving in vitro differentiated T cells given after lymphodepleting regimens significantly augments antitumor immunity in animals and human patients with cancer. However, the mechanisms by which lymphopenia augments adoptive cell therapy and the means of properly differentiating T cells in vitro are still emerging. We demonstrate that naive tumor/self-specific CD4(+) T cells naturally differentiated into T helper type 1 cytotoxic T cells in vivo and caused the regression of established tumors and depigmentation in lymphopenic hosts. Therapy was independent of vaccination, exogenous cytokine support, CD8(+), B, natural killer (NK), and NKT cells. Proper activation of CD4(+) T cells in vivo was important for tumor clearance, as naive tumor-specific CD4(+) T cells could not completely treat tumor in lymphopenic common gamma chain (gamma(c))-deficient hosts. gamma(c) signaling in the tumor-bearing host was important for survival and proper differentiation of adoptively transferred tumor-specific CD4(+) T cells. Thus, these data provide a platform for designing immunotherapies that incorporate tumor/self-reactive CD4(+) T cells.
Structure-affinity relationships of adenosine A2B receptor ligands
Authors: Margot W. Beukers, Illiana Meurs, Adriaan P. IJzerman
Journal: Medicinal Research Reviews (2006)

Many selective and high affinity agonists and antagonists have been developed for the adenosine A1, A2A, and A3 receptors. Very recently such compounds have been identified for the adenosine A2B receptors. This review presents an overview of the structure-affinity relationships of antagonists and agonists for this receptor subtype as published in the scientific and patent literature. To date the most selective >370-fold, high affinity adenosine A2B receptor antagonist is the xanthine analog, compound 16 (8-(1-(3-phenyl-1,2,4-oxadiazol-5-yl)methyl)-1H-pyrazol-4-yl)-1,3-dipropyl-1H-purine-2,6(3H,7H)-dione). The pyrrolopyrimidine analog OSIP339391 (73) is slightly less selective, 70-fold, but has a higher affinity 0.41 nM compared to 1 nM for compound 16. Other promising classes of compounds with selectivities ranging from 10- to 160-fold and affinities ranging from 3 to 112 nM include triazolo, aminothiazole, quinazoline, and pyrimidin-2-amine analogs. Progress has also been achieved concerning the development of selective high affinity agonists for the adenosine A2B receptor. For years the most potent, albeit non-selective adenosine A2B receptor agonist was (S)PHPNECA (88). Last year, a new class of non-ribose ligands was reported. Several compounds displayed selectivity with respect to adenosine A2A and A3 receptors. In addition, full and partial agonists for the adenosine A2B receptor were identified with EC50 values of 10 nM (LUF5835, 103) and 9 nM (LUF5845, 105), respectively. © 2006 Wiley Periodicals, Inc. Med Res Rev, 26, No. 5, 667–698, 2006
Association of Blood Pressure With Genetic Variation in <i>WNK</i> Kinases in a White European Population
Authors: Haifeng Zhang, Jan A. Staessen
Journal: Circulation (2005)

utations in a recently discovered family of protein kinases are responsible for an autosomal-dominant form of inherited hypertension, known as Gordon's syndrome or pseudohypoaldosteronism type II (PHAII). 1 The phenotype also includes hyperkalemia and hyperchloremic metabolic acidosis. 1The name of this kinase family is WNK (with no lysine [K]) because of the absence of a lysine in subdomain II of the enzymes. 2 WNK1 and WNK4, located in human chromosomes 12 and 17, respectively, are predominantly expressed in the distal convoluted tubules and the collecting ducts of the kidney.
Significance of ventricular arrhythmias initiated by programmed ventricular stimulation: the importance of the type of ventricular arrhythmia induced and the number of premature stimuli required.
Authors: P Brugada, M Green, H Abdollah, H J Wellens
Journal: Circulation (1984)

An increasing number of premature ventricular stimuli are being used during programmed stimulation of the heart in the investigation of patients with documented or suspected ventricular arrhythmias. To analyze the significance of the different types of ventricular arrhythmias that are initiated, we evaluated in a prospective study the effect of from one to four ventricular premature stimuli in 52 patients without (non-VT group) and 50 patients with (prior-VT group) documented ventricular tachycardia or ventricular fibrillation. More than half of the patients in the prior-VT group had coronary heart disease. In the majority of patients of the non-VT group the heart was normal. In 44 of the 50 patients in the prior-VT group the clinically documented ventricular arrhythmia was initiated by programmed ventricular stimulation of the heart. In 88% of these 44 patients, one or two ventricular premature beats were required to initiate the clinical arrhythmia. A ventricular arrhythmia could be initiated in 31 of the 52 patients in the non-VT group. The ventricular arrhythmias included nonsustained monomorphic ventricular tachycardia (two patients), six to 25 complexes of sustained polymorphic ventricular tachycardia (24 patients), and ventricular fibrillation (five patients). In 70% of patients in the non-VT group three or four ventricular premature beats were required to initiate the ventricular arrhythmia. Our results indicate that not only the number of extrastimuli required to initiate ventricular arrhythmias but also the type of ventricular arrhythmia initiated differed between the two groups of patients. Nonsustained polymorphic ventricular tachycardia and ventricular fibrillation are nonspecific responses to aggressive stimulation protocols.
Effect of two different neuroprotection systems on microembolization during carotid artery stenting
Authors: Andrej Schmidt, Klaus-Werner Diederich, Susanne Scheinert, Sven Bräunlich, Tatjana Olenburger, Giancarlo Biamino, Gerhard Schuler, Dierk Scheinert
Journal: Journal of the American College of Cardiology (2004)
Transcriptome analysis of haploid male gametophyte development in Arabidopsis
Authors: David Honys, David Twell
Journal: Genome biology (2004)

Abstract Background The haploid male gametophyte generation of flowering plants consists of two- or three-celled pollen grains. This functional specialization is thought to be a key factor in the evolutionary success of flowering plants. Moreover, pollen ontogeny is also an attractive model in which to dissect cellular networks that control cell growth, asymmetric cell division and cellular differentiation. Our objective, and an essential step towards the detailed understanding of these processes, was to comprehensively define the male haploid transcriptome throughout development. Results We have developed staged spore isolation procedures for Arabidopsis and used Affymetrix ATH1 genome arrays to identify a total of 13,977 male gametophyte-expressed mRNAs, 9.7% of which were male-gametophyte-specific. The transition from bicellular to tricellular pollen was accompanied by a decline in the number of diverse mRNA species and an increase in the proportion of male gametophyte-specific transcripts. Expression profiles of regulatory proteins and distinct clusters of coexpressed genes were identified that could correspond to components of gametophytic regulatory networks. Moreover, integration of transcriptome and experimental data revealed the early synthesis of translation factors and their requirement to support pollen tube growth. Conclusions The progression from proliferating microspores to terminally differentiated pollen is characterized by large-scale repression of early program genes and the activation of a unique late gene-expression program in maturing pollen. These data provide a quantum increase in knowledge concerning gametophytic transcription and lay the foundations for new genomic-led studies of the regulatory networks and cellular functions that operate to specify male gametophyte development.