tbuckley/cabot-search huggingface dataset:
Inhaled antihistamines--bronchodilatation and effects on histamine- and methacholine-induced bronchoconstriction.
Authors: S G Nogrady, C Bevan
Journal: Thorax (1978)

<h3>Objective</h3> To determine the clinical and prognostic value of identifying metabolic abnormalities of myocardial fatty acid metabolism in idiopathic dilated cardiomyopathy using iodine-123 β-methyl-iodophenyl pentadecanoic acid (<sup>123</sup>I BMIPP). <h3>Setting</h3> Cardiac care division in national hospital. <h3>Patients</h3> 32 consecutive patients with idiopathic dilated cardiomyopathy in whom both <sup>123</sup>I BMIPP and thallium-201 myocardial single photon emission computed tomography were performed. <h3>Methods</h3> The uptake of each tracer was scored visually from 0 (normal) to 3 (defect) in 17 segments (eight basal, eight midventricular, and one apical). A total score for all 17 segments was compared with clinicopathological variables. Prognostic value of mismatches between the two tracers were also evaluated. <h3>Results</h3> The<sup>123</sup>I BMIPP total score was correlated with pulmonary capillary wedge pressure (<i>r</i> = 0.68, p &lt; 0.001), left ventricular end diastolic pressure (<i>r</i> = 0.65, p &lt; 0.001), percentage fractional shortening at six months’ follow up (<i>r</i> = -0.58, p = 0.001), myocyte diameter (<i>r</i> = 0.66, p &lt; 0.001), and percentage area of interstitial fibrosis (<i>r</i> = 0.69, p &lt; 0.001) measured by morphometry in the biopsy specimens. During a mean (SD) follow up of 20 (11) months, deterioration of the New York Heart Association functional class was observed in 11 of the 32 patients; four of these died. Segments with a greater decrease in<sup>123</sup>I BMIPP than thallium-201 uptake (type B mismatching) were often observed in patients with deterioration (88/187, 29%<i>v</i> 58/357, 16%; p &lt; 0.001). <h3>Conclusions</h3> The extent of the abnormality of myocardial fatty acid metabolism in idiopathic dilated cardiomyopathy reflects the severity of haemodynamic deterioration and histopathological changes. Type B mismatching is one of the important prognostic indicators in idiopathic dilated cardiomyopathy.
Use of Pharmacologic Interventions for Breast Cancer Risk Reduction: American Society of Clinical Oncology Clinical Practice Guideline
Authors: Kala Visvanathan, Patricia Hurley, Elissa Bantug, Powel Brown, Nananda F. Col, Jack Cuzick, Nancy E. Davidson, Andrea DeCensi, Carol Fabian, Leslie Ford, Judy Garber, Maria Katapodi, Barnett Kramer, Monica Morrow, Barbara Parker, Carolyn Runowicz, Victor G. Vogel, James L. Wade, Scott M. Lippman
Journal: Journal of Clinical Oncology (2013)

To update the 2009 American Society of Clinical Oncology guideline on pharmacologic interventions for breast cancer (BC) risk reduction.A systematic review of randomized controlled trials and meta-analyses published from June 2007 through June 2012 was completed using MEDLINE and Cochrane Collaboration Library. Primary outcome of interest was BC incidence (invasive and noninvasive). Secondary outcomes included BC mortality, adverse events, and net health benefits. Guideline recommendations were revised based on an Update Committee's review of the literature.Nineteen articles met the selection criteria. Six chemoprevention agents were identified: tamoxifen, raloxifene, arzoxifene, lasofoxifene, exemestane, and anastrozole.In women at increased risk of BC age ≥ 35 years, tamoxifen (20 mg per day for 5 years) should be discussed as an option to reduce the risk of estrogen receptor (ER) -positive BC. In postmenopausal women, raloxifene (60 mg per day for 5 years) and exemestane (25 mg per day for 5 years) should also be discussed as options for BC risk reduction. Those at increased BC risk are defined as individuals with a 5-year projected absolute risk of BC ≥ 1.66% (based on the National Cancer Institute BC Risk Assessment Tool or an equivalent measure) or women diagnosed with lobular carcinoma in situ. Use of other selective ER modulators or other aromatase inhibitors to lower BC risk is not recommended outside of a clinical trial. Health care providers are encouraged to discuss the option of chemoprevention among women at increased BC risk. The discussion should include the specific risks and benefits associated with each chemopreventive agent.
Pulmonary Capillary Flow Pulse and the Site of Pulmonary Vasoconstriction in the Dog
Authors: EUGENE MORKIN, O. ROBERT LEVINE, ALFRED P. FISHMAN
Journal: Circulation Research (1964)

A nitrous oxide-plethysmographic method was used to measure simultaneously the instantaneous pulmonary capillary blood flow and the pressure gradient across the pulmonary vascular bed. The method entailed the use of lightly anesthetized, curarized dogs for the moment-to-moment measurement of nitrous oxide uptake and the corresponding pulmonary arterial and wedge pressures. After establishing the usual patterns of pulmonary capillary blood flow, the flow patterns were modified by atropine, norepinephrine, and acute hypoxia. Before the exhibition of these agents, pulmonary capillary flow was pulsatile, with peak rates of flow of approximately twice the mean. After atropine, the amplitude of the flow pulse decreased passively as stroke volume and the pulmonary arterial pulse pressure decreased. In contrast to atropine, acute hypoxia elicited precapillary vasoconstriction as manifested by an increase in pulmonary arterial pressure and an unchanged pulmonary arterial wedge pressure in conjunction with an unchanged, or diminished and blunted, pulmonary capillary flow pulse. The predominant effect of norepinephrine appeared to be exerted distal to the pulmonary capillary bed since pulmonary arterial and wedge pressures increased in parallel while the capillary flow pulse changed passively according to changes in stroke volume.
Regulation of large coronary arteries by beta-adrenergic mechanisms in the conscious dog.
Authors: S F Vatner, T H Hintze, P Macho
Journal: Circulation Research (1982)

We examined, in conscious dogs, the effects of beta-adrenergic stimulation on measurements of left circumflex coronary arterial diameter and blood flow and on calculations of late diastolic coronary resistance (LDCR) and left circumflex coronary internal cross-sectional area (CSA). Isoproterenol (0.1 microgram/kg) initially decreased mean arterial pressure by 25 +/- 2% (mean +/- SEM), and LDCR by 62 +/- 4%, and increased heart rate by 82 +/- 10%, left ventricular (LV) dP/dt by 79 +/- 12%, and mean coronary blood flow by 85 +/- 5%, while CSA rose slightly. The peak effects on CSA (24 +/- 2%) occurred later, along with decreases in mean arterial pressure (7.4 +/- 1.0%) and LDCR (25 +/-5.3%) and increases in coronary blood flow (14 +/- 2%), LV dP/dt (12 +/- 3%), and heart rate (24 +/- 4%). Pirbuterol (1.0 microgram/kg) induced changes that were qualitatively similar to those induced by isoproterenol. Prenalterol (20 micrograms/kg), a cardioselective beta 1-adrenergic receptor agonist, did not affect mean arterial pressure, but increased heart rate by 40 +/- 5%, LV dP/dt by 72 +/- 10%, mean coronary blood flow by 34 +/- 11%, and CSA by 26 +/- 3%, and decreased LDCR by 29 +/- 5+. Isoproterenol and pirbuterol, but not prenalterol, increased coronary sinus O2 content and decreased A-VO2 difference. After beta 1-adrenergic receptor blockade with atenolol (1 mg/kg), prenalterol no longer induced significant effects, whereas isoproterenol and pirbuterol decreased mean arterial pressure similarly to what was observed prior to blockade, but did not increase LV dP/dt, and induced attenuated increases in mean coronary blood flow, CSA, and decreases in LDCR. Thus, in the intact, conscious animal, large coronary arteries are regulated by beta-adrenergic mechanisms. Surprisingly, a major fraction of large coronary arterial dilation appeared to be either directly or indirectly due to beta 1-adrenergic receptor mechanisms, although beta 2-adrenergic effects were also significant.
Comprehensive Analysis of Missense Variations in the BRCT Domain of BRCA1 by Structural and Functional Assays
Authors: Megan S. Lee, Ruth Green, Sylvia M. Marsillac, Nicolas Coquelle, R. Scott Williams, Telford Yeung, Desmond Foo, D. Duong Hau, Ben Hui, Alvaro N.A. Monteiro, J.N. Mark Glover
Journal: Cancer Research (2010)

Genetic screening of the breast and ovarian cancer susceptibility gene BRCA1 has uncovered a large number of variants of uncertain clinical significance. Here, we use biochemical and cell-based transcriptional assays to assess the structural and functional defects associated with a large set of 117 distinct BRCA1 missense variants within the essential BRCT domain of the BRCA1 protein that have been documented in individuals with a family history of breast or ovarian cancer. In the first method, we used limited proteolysis to assess the protein folding stability of each of the mutants compared with the wild-type. In the second method, we used a phosphopeptide pull-down assay to assess the ability of each of the variants to specifically interact with a peptide containing a pSer-X-X-Phe motif, a known functional target of the BRCA1 BRCT domain. Finally, we used transcriptional assays to assess the ability of each BRCT variant to act as a transcriptional activation domain in human cells. Through a correlation of the assay results with available family history and clinical data, we define limits to predict the disease risk associated with each variant. Forty-two of the variants show little effect on function and are likely to represent variants with little or no clinical significance; 50 display a clear functional effect and are likely to represent pathogenic variants; and the remaining 25 variants display intermediate activities. The excellent agreement between the structure/function effects of these mutations and available clinical data supports the notion that functional and structure information can be useful in the development of models to assess cancer risk.
Incidence of Falls, Risk Factors for Falls, and Fall-Related Fractures in Individuals With Diabetes and a Prior Foot Ulcer
Authors: Carolyn Wallace, Gayle E. Reiber, Joseph LeMaster, Douglas G. Smith, Katrina Sullivan, Shane Hayes, Christy Vath
Journal: Diabetes Care (2002)

OBJECTIVE—To describe the incidence of falls, risk factors for falls, and the frequency of fall-related fractures in a cohort of individuals with diabetes and a prior foot ulcer. RESEARCH DESIGN AND METHODS—A total of 400 individuals with diabetes and a prior foot ulcer were recruited from two western Washington State health care organizations and followed prospectively for 2 years. Diabetes, demographic, and health information was collected at baseline, 1 year, and 2 years. Data on falls were collected at baseline, 4 weeks, and every 17 weeks thereafter. Medical records were abstracted to confirm fall-related morbidity. RESULTS—The average age of the study population was 62 years, with 77% male and 23% female. Approximately 32% had fixed foot deformities, 58% had insensate feet, and 76% had comorbid conditions. Of the participants, 252 (64%) reported at least one fall during the 2-year study period. The overall incidence of falls in this cohort was 1.25 falls/person-year (95% CI 1.17–1.33). For the 164 participants (41%) who reported two or more falls, a BMI ≥30 kg/m2, the presence of one or more comorbid conditions, and insensate feet increased the risk. Two or more falls of any type were associated with a higher fracture risk. Although women were not at significantly greater risk for falls than men, their fracture incidence was 3.6 times higher. CONCLUSIONS—Falls are very common in individuals with diabetes and prior foot ulcers. A small percentage of falls resulted in fractures. The risk of a fall-related fracture was significantly higher in women than in men. Increased attention to falls and fall prevention is indicated for diabetes care providers.
Dynamic Regulation of Phosphoinositide 3-Kinase-γ Activity and β-Adrenergic Receptor Trafficking in End-Stage Human Heart Failure
Authors: Cinzia Perrino, Jacob N. Schroder, Brian Lima, Nestor Villamizar, Jeffrey J. Nienaber, Carmelo A. Milano, Sathyamangla V. Naga Prasad
Journal: Circulation (2007)

Downregulation of beta-adrenergic receptors (betaARs) under conditions of heart failure requires receptor targeting of phosphoinositide 3-kinase (PI3K)-gamma and redistribution of betaARs into endosomal compartments. Because support with a left ventricular assist device (LVAD) results in significant improvement of cardiac function in humans, we investigated the effects of mechanical unloading on regulation of PI3Kgamma activity and intracellular distribution of betaARs. Additionally, we tested whether displacement of PI3Kgamma from activated betaARs would restore agonist responsiveness in failing human cardiomyocytes.To test the role of PI3K on betaAR endocytosis in failing human hearts, we assayed for PI3K activity in human left ventricular samples before and after mechanical unloading (LVAD). Before LVAD, failing human hearts displayed a marked increase in betaAR kinase 1 (betaARK1)-associated PI3K activity that was attributed exclusively to enhanced activity of the PI3Kgamma isoform. Increased betaARK1-coupled PI3K activity in the failing hearts was associated with downregulation of betaARs from the plasma membrane and enhanced sequestration into early and late endosomes compared with unmatched nonfailing controls. Importantly, LVAD support reversed PI3Kgamma activation, normalized the levels of agonist-responsive betaARs at the plasma membrane, and depleted the betaARs from the endosomal compartments without changing the total number of receptors (sum of plasma membrane and early and late endosome receptors). To test whether the competitive displacement of PI3K from the betaAR complex restored receptor responsiveness, we overexpressed the phosphoinositide kinase domain of PI3K (which disrupts betaARK1/PI3K interaction) in primary cultures of failing human cardiomyocytes. Adenoviral-mediated phosphoinositide kinase overexpression significantly increased basal contractility and rapidly reconstituted responsiveness to beta-agonist.These results suggest a novel paradigm in which human betaARs undergo a process of intracellular sequestration that is dynamically reversed after LVAD support. Importantly, mechanical unloading leads to complete reversal in PI3Kgamma and betaARK1-associated PI3K activation. Furthermore, displacement of active PI3K from betaARK1 restores betaAR responsiveness in failing myocytes.
Dendritic Cell Vaccination Combined with CTLA4 Blockade in Patients with Metastatic Melanoma
Authors: Antoni Ribas, Begoña Comin-Anduix, Bartosz Chmielowski, Jason Jalil, Pilar de la Rocha, Tara A. McCannel, Maria Teresa Ochoa, Elizabeth Seja, Arturo Villanueva, Denise K. Oseguera, Bradley R. Straatsma, Alistair J. Cochran, John A. Glaspy, Liu Hui, Francesco M. Marincola, Ena Wang, James S. Economou, Jesus Gomez-Navarro
Journal: Clinical Cancer Research (2009)

Abstract Purpose: Tumor antigen–loaded dendritic cells (DC) are believed to activate antitumor immunity by stimulating T cells, and CTL-associated antigen 4 (CTLA4)–blocking antibodies should release a key negative regulatory pathway on T cells. The combination was tested in a phase I clinical trial in patients with advanced melanoma. Experimental Design: Autologous DC were pulsed with MART-126-35 peptide and administered with a dose escalation of the CTLA4-blocking antibody tremelimumab. Sixteen patients were accrued to five dose levels. Primary end points were safety and immune effects; clinical efficacy was a secondary end point. Results: Dose-limiting toxicities of grade 3 diarrhea and grade 2 hypophysitis developed in two of three patients receiving tremelimumab at 10 mg/kg monthly. Four patients had an objective tumor response, two partial responses and two complete responses, all melanoma free between 2 and 4 years after study initiation. There was no difference in immune monitoring results between patients with an objective tumor response and those without a response. Exploratory gene expression analysis suggested that immune-related gene signatures, in particular for B-cell function, may be important in predicting response. Conclusion: The combination of MART-1 peptide–pulsed DC and tremelimumab results in objective and durable tumor responses at the higher range of the expected response rate with either agent alone. (Clin Cancer Res 2009;15(19):6267–76)
425 FOUR-WEEK TREATMENT WITH GS-9256 AND TEGOBUVIR (GS-9190), ± RBV ± PEG, RESULTS IN ENHANCED VIRAL SUPPRESSION ON FOLLOW-UP PEG/RBV THERAPY, IN GENOTYPI 1A/1B HCV PATIENTS
Authors: G.R. Foster, P. Buggisch, P. Marcellin, S. Zeuzem, K. Agarwal, M. Manns, D. Sereni, H. Klinker, C. Moreno, J.P. Zarski, Y. Horsmans, M. Shelton, S. Arterburn, W. Lee, J. McHutchison, W. Delaney, D. Oldach
Journal: Journal of Hepatology (2011)
Evolution and Development of the Chordates: Collagen and Pharyngeal Cartilage
Authors: Amanda L. Rychel, Shannon E. Smith, Heather T. Shimamoto, Billie J. Swalla
Journal: Molecular Biology and Evolution (2005)

Chordates evolved a unique body plan within deuterostomes and are considered to share five morphological characters, a muscular postanal tail, a notochord, a dorsal neural tube, an endostyle, and pharyngeal gill slits. The phylum Chordata typically includes three subphyla, Cephalochordata, Vertebrata, and Tunicata, the last showing a chordate body plan only as a larva. Hemichordates, in contrast, have pharyngeal gill slits, an endostyle, and a postanal tail but appear to lack a notochord and dorsal neural tube. Because hemichordates are the sister group of echinoderms, the morphological features shared with the chordates must have been present in the deuterostome ancestor. No extant echinoderms share any of the chordate features, so presumably they have lost these structures evolutionarily. We review the development of chordate characters in hemichordates and present new data characterizing the pharyngeal gill slits and their cartilaginous gill bars. We show that hemichordate gill bars contain collagen and proteoglycans but are acellular. Hemichordates and cephalochordates, or lancelets, show strong similarities in their gill bars, suggesting that an acellular cartilage may have preceded cellular cartilage in deuterostomes. Our evidence suggests that the deuterostome ancestor was a benthic worm with gill slits and acellular gill cartilages.
Factors Affecting Workload of Cancer Clinical Trials: Results of a Multicenter Study of the National Cancer Institute of Canada Clinical Trials Group
Authors: Kathyrn Roche, Nancy Paul, Bobbi Smuck, Marlo Whitehead, Benny Zee, Joseph Pater, Mary Anne Hiatt, Hugh Walker
Journal: Journal of Clinical Oncology (2002)

PURPOSE: Increasingly, cancer treatment centers need to be able to estimate specific costs and resources associated with clinical trials. Because the time requirements of trial coordination and data collection are not well known, the Clinical Research Associates (CRA) Committee of the National Cancer Institute of Canada Clinical Trials Group carried out a multicenter study to measure trials' task times and evaluate the effects of certain factors. METHODS: A data collection instrument was designed and validated before its implementation in the study. Eighty-three CRAs from 24 cancer treatment institutions across Canada collected timing observations of 41 tasks (156 subtasks). Information from all stages of trials activity (protocol management, eligibility and entry, treatment, and follow-up and final stage) was obtained, from initial negotiations to follow-up after study closure. RESULTS: After controlling for stage, phase and sponsor were found to be significant independent factors. Analysis within the stages showed similar patterns. New drug inclusion as a factor was confounded with phase. Industry-sponsored studies had significantly higher overall mean times than did local and cooperative group studies. Early-phase studies required more time than did phase III trials. External sponsorship of any kind increased CRA time more than that necessary for locally coordinated studies, except during the protocol management stage. The burden of a phase I study increased to greater than average once underway and accruing patients. CONCLUSION: Our data demonstrated that sponsor and study phase are important factors to be taken into consideration when estimating clinical trial costs and resource use.
Lost in translation
Authors: Matthias G. von Herrath, Gerald T. Nepom
Journal: The Journal of Experimental Medicine (2005)

Induction of selective, autoantigen-specific tolerance is the "holy grail" for the treatment and prevention of autoimmune diseases. Despite successes in many differential murine models, rational and efficient translation to the clinic has been difficult. During the 5th Annual Federation of Clinical Immunological Societies (FOCIS) Meeting, May 12-16, 2005, in Boston, MA, a Kirin-sponsored "Ideashop" was convened to discuss this theme amongst scientists, clinicians, industry partners, and funding agencies.
CIRCULATORY DISEASES OF THE EXTREMITIES
Authors: J. Fraser
Journal: BMJ (1935)

It is only within recent years that the group of conditions collectively described as circulatory diseases of the ex- tlremities has come within the sphere of surgical interest and attention.Hitherto they have been regarded as matters of medical significance; in fact, the surgical text- books of a decade ago made little or no reference to the subject except in so far as gangrene and its treatment was concerned.It is interesting to recall how the wider question has come to attract the notice of the surgeon.As long ago as 189 Alexander of Liverpool performed bilateral extirpa- tion of the superior cervical sympathctic ganglion in a
Prospective study of serum cysteine levels and oesophageal and gastric cancers in China
Authors: G. Murphy, J.-H. Fan, S. D. Mark, S. M. Dawsey, J. Selhub, J. Wang, P. R. Taylor, Y.-L. Qiao, C. C. Abnet
Journal: Gut (2011)

<h3>Background</h3> Cancers of the upper gastrointestinal tract remain a significant cause of morbidity and mortality. Cysteine, known to be involved in a myriad of immuno-modulatory, anti-oxidant, and anti-carcinogenic pathways, has not been investigated in the aetiology of oesophageal or gastric cancers. To examine the relationship between serum cysteine concentration and risk of these cancers we conducted a nested case–cohort study within the General Population Nutrition Intervention Trial in Linxian, China. <h3>Methods</h3> 498 oesophageal squamous cell carcinomas (OSCCs) and 255 gastric cardia adenocarcinomas (GCAs) were matched by age and sex to 947 individuals from the wider cohort. We calculated HRs and 95% CIs using the case–cohort estimator for the Cox proportional hazards models, stratified on age and sex, with adjustment for potential confounders. <h3>Results</h3> Higher concentrations of serum cysteine were significantly associated with a lower risk of both OSCC and GCA. For those in the highest quartile of serum cysteine, compared to those in the lowest, the multivariate HRs were 0.70 for OSCC (95% CI 0.51 to 0.98) and 0.59 for GCA (95% CI 0.38 to 0.91). These associations were dose dependent (p for trend=0.006 and 0.008, respectively). These inverse associations were not significantly modified by other risk factors, with the exception of age, where a stronger association was noted among persons in the older age strata. <h3>Conclusion</h3> Higher serum concentrations of cysteine were associated with a significantly reduced risk of OSCC and GCA. Cysteine should be further investigated for its potential as a chemopreventive agent for upper gastrointestinal cancers.