tbuckley/cabot-search huggingface dataset:
Pharmacological Treatment of Coronary Artery Disease With Recombinant Fibroblast Growth Factor-2
Authors: Michael Simons, Brian H. Annex, Roger J. Laham, Neal Kleiman, Timothy Henry, Harold Dauerman, James E. Udelson, Ernesto V. Gervino, Marilyn Pike, M.J. Whitehouse, Thomas Moon, Nicolas A. Chronos
Journal: Circulation (2002)

Background— Single-bolus intracoronary administration of fibroblast growth factor-2 (FGF2) improved symptoms and myocardial function in a phase I, open-label trial in patients with coronary artery disease. We conducted the FGF Initiating RevaScularization Trial (FIRST) to evaluate further the efficacy and safety of recombinant FGF2 (rFGF2). Methods and Results— FIRST is a multicenter, randomized, double-blind, placebo-controlled trial of a single intracoronary infusion of rFGF2 at 0, 0.3, 3, or 30 μg/kg (n=337 patients). Efficacy was evaluated at 90 and 180 days by exercise tolerance test, myocardial nuclear perfusion imaging, Seattle Angina Questionnaire, and Short-Form 36 questionnaire. Exercise tolerance was increased at 90 days in all groups and was not significantly different between placebo and FGF-treated groups. rFGF2 reduced angina symptoms as measured by the angina frequency score of the Seattle Angina Questionnaire (overall P =0.035) and the physical component summary scale of the Short-Form 36 (pairwise P =0.033, all FGF groups versus placebo). These differences were more pronounced in highly symptomatic patients (baseline angina frequency score ≤40 or Canadian Cardiovascular Society score of III or IV). None of the differences were significant at 180 days because of continued improvement in the placebo group. Adverse events were similar across all groups, except for hypotension, which occurred with higher frequency in the 30-μg/kg rFGF2 group. Conclusions— A single intracoronary infusion of rFGF2 does not improve exercise tolerance or myocardial perfusion but does show trends toward symptomatic improvement at 90 (but not 180) days.
A Network of Genetic Events Sufficient to Convert Normal Human Cells to a Tumorigenic State
Authors: S. DiSean Kendall, Corinne M. Linardic, Stacey J. Adam, Christopher M. Counter
Journal: Cancer Research (2005)

Although great progress has been made at identifying and characterizing individual genes involved in cancer, less is known about how the combination of such genes collaborate to form tumors in humans. To this end, we sought to genetically recreate tumorigenesis in normal human cells using genes altered in human cancer. We now show that expression of mammalian proteins that inactivate the tumor suppressors Rb and p53 in conjunction with the oncoproteins Ras and Myc and the telomerase subunit hTERT is sufficient to drive a number of normal human somatic cells to a tumorigenic fate. This provides a blueprint of the events that lead to human cancer, allowing different cancers to be genetically modeled from normal human cells.
Is there a familial link between Down's syndrome and neural tube defects? Population and familial survey
Authors: M. R Amorim
Journal: BMJ (2004)

<h3>Abstract</h3> <b>Objective</b> To verify whether Down9s syndrome and neural tube defects arise more often in the same family than expected by chance. <b>Design</b> Population and familial survey. <b>Setting</b> Network of maternity hospitals in the Latin American collaborative study of congenital malformations (ECLAMC) in Argentina, Bolivia, Brazil, Chile, Colombia, Ecuador, Paraguay, Peru, Uruguay, and Venezuela between 1982 and 2000. <b>Probands</b> 2421 cases of neural tube defects, 952 of hydrocephalus, and 3095 of Down9s syndrome registered from a total of 1 583 838 live births and stillbirths. <b>Main outcome measures</b> Observed number of cases of Down9s syndrome among siblings of probands with a neural tube defect or hydrocephalus and number expected on the basis of maternal age; observed number of cases of neural tube defects or hydrocephalus among siblings of probands with Down9s syndrome and number expected according to the prevalence in the same population. <b>Results</b> Five cases of Down9s syndrome occurred among 5404 pregnancies previous to a case of neural tube defect or hydrocephalus, compared with 5.13 expected after adjustment by maternal age. Twelve cases of neural tube defect or hydrocephalus occurred among 8066 pregnancies previous to a case of Down9s syndrome, compared with 17.18 expected on the basis of the birth prevalence for neural tube defects plus hydrocephalus in the same population. <b>Conclusion</b> No association occurred between families at risk of neural tube defects and those at risk of Down9s syndrome.
Reduced production, absorption, and elimination of erythropoietin in uremia compared with healthy volunteers.
Authors: J D Jensen, J K Madsen, L W Jensen, E B Pedersen
Journal: Journal of the American Society of Nephrology (1994)

The purpose of this study was to investigate the metabolism of erythropoietin (EPO) in uremia compared with healthy subjects. Twenty-one patients (nine men and 12 women) with end-stage renal failure and anemia and 12 healthy volunteers (3 women and nine men) were studied. The pharmacokinetic parameters were calculated after an i.v. and a femoral sc injection of 100 U/kg of recombinant human EPO. The serum EPO (s-EPO) was measured by radio-immunoassay at regular intervals until 48 h (i.v.) and 120 h (sc). In uremia, the median terminal elimination half-life was significantly longer (8.31 versus 4.92 h; P < 0.001) and the clearance was reduced (5.00 versus 7.88 mL/min per 1.73 m2; P < 0.01). The volume of distribution was (3.70 versus 3.31 L/1.73 m2) not significant. The estimated endogenous EPO production was significantly lower in uremia (146 versus 290 U/day per 1.73 m2; P < 0.001). After sc administration, the bioavailability was significantly lower in the patients (23.7 versus 38.5%; P < 0.01), and the maximal s-EPO was lower (113 versus 153 U/L; P < 0.05) and delayed (15.4 versus 11.0 h; P < 0.02), but the mean input time (sc) was not significantly different (23.3 versus 27.8 h). The basal s-EPO was lower in the uremic patients (20.0 versus 26.3 U/L; P < 0.05). There was no difference between patients treated with hemodialysis and peritoneal dialysis or between uremic men and women. There was no correlation between the pharmacokinetic parameters and age.(ABSTRACT TRUNCATED AT 250 WORDS)
Comparison of 2 Interventions for Liquid Aspiration on Pneumonia Incidence
Authors: JoAnne Robbins
Journal: Annals of Internal Medicine (2008)

Background: Aspiration pneumonia is common among frail elderly persons with dysphagia. Although interventions to prevent aspiration are routinely used in these patients, little is known about the effectiveness of those interventions. Objective: To compare the effectiveness of chin-down posture and 2 consistencies (nectar or honey) of thickened liquids on the 3-month cumulative incidence of pneumonia in patients with dementia or Parkinson disease. Design: Randomized, controlled, parallel-design trial in which patients were enrolled for 3-month periods from 9 June 1998 to 19 September 2005. Setting: 47 hospitals and 79 subacute care facilities. Patients: 515 patients age 50 years or older with dementia or Parkinson disease who aspirated thin liquids (demonstrated videofluoroscopically). Of these, 504 were followed until death or for 3 months. Intervention: Participants were randomly assigned to drink all liquids in a chin-down posture (n = 259) or to drink nectar-thick (n = 133) or honey-thick (n = 123) liquids in a head-neutral position. Measurements: The primary outcome was pneumonia diagnosed by chest radiography or by the presence of 3 respiratory indicators. Results: 52 participants had pneumonia, yielding an overall estimated 3-month cumulative incidence of 11%. The 3-month cumulative incidence of pneumonia was 0.098 and 0.116 in the chin-down posture and thickened-liquid groups, respectively (hazard ratio, 0.84 [95% CI, 0.49 to 1.45]; P = 0.53). The 3-month cumulative incidence of pneumonia was 0.084 in the nectar-thick liquid group compared with 0.150 in the honey-thick liquid group (hazard ratio, 0.50 [CI, 0.23 to 1.09]; P = 0.083). More patients assigned to thickened liquids than those assigned to the chin-down posture intervention had dehydration (6% vs. 2%), urinary tract infection (6% vs. 3%), and fever (4% vs. 2%). Limitations: A no-treatment control group was not included. Follow-up was limited to 3 months. Care providers were not blinded, and differences in cumulative pneumonia incidence between interventions had wide CIs. Conclusion: No definitive conclusions about the superiority of any of the tested interventions can be made. The 3-month cumulative incidence of pneumonia was much lower than expected in this frail elderly population. Future investigation of chin-down posture combined with nectar-thick liquid may be warranted to determine whether this combination better prevents pneumonia than either intervention independently.
Expression and Role of Myeloid-related Protein-14 in Clinical and Experimental Sepsis
Authors: Marieke A. D. van Zoelen, Thomas Vogl, Dirk Foell, Suzanne Q. Van Veen, Jan W. O. van Till, Sandrine Florquin, Michael W. Tanck, Xavier Wittebole, Pierre-François Laterre, Marja A. Boermeester, Johannes Roth, Tom van der Poll
Journal: American Journal of Respiratory and Critical Care Medicine (2009)

Myeloid-related protein-8 (MRP8) and MRP14 can form heterodimers that elicit a variety of inflammatory responses. We showed that MRP8/14 is a ligand for Toll-like receptor-4, and that mice deficient in MRP8/14 are protected against endotoxic shock-induced lethality.To determine (1) the extent of MRP8/14 release in patients with sepsis and/or peritonitis and in healthy humans exposed to LPS and (2) the contribution of MRP8/14 to the host response in murine abdominal sepsis.MRP8/14 was measured in 51 patients with severe sepsis, 8 subjects after intravenous injection of LPS, and 17 patients with peritonitis. Host responses to sepsis were compared in mrp14 gene-deficient (and thereby MRP8/14-deficient) and wild-type mice intraperitoneally injected with Escherichia coli.Patients with sepsis displayed elevated circulating MRP8/14 concentrations on both Days 0 and 3, and LPS injection resulted in systemic MRP8/14 release in healthy humans. In patients with peritonitis, MRP8/14 levels in abdominal fluid were more than 15-fold higher than in plasma. MRP14-deficient mice displayed improved defense against E. coli abdominal sepsis in an early phase, as indicated by diminished dissemination of the bacteria at 6 hours. In addition, MRP14-deficient mice demonstrated decreased systemic inflammation, as reflected by lower cytokine plasma concentrations, and less severe liver damage.Human sepsis and endotoxemia are associated with enhanced release of MRP8/14. In abdominal sepsis, MRP8/14 likely occurs primarily at the site of the infection, facilitating bacterial dissemination at an early phase and liver injury.
Apoptosis of T cells and the control of inflammatory bowel disease: therapeutic implications
Authors: J Mudter, M F Neurath
Journal: Gut (2006)

Inflammatory bowel diseases (IBDs) such as Crohn's disease and ulcerative colitis are the result of an imbalanced mucosal T cell response.Despite the identification of a genetic susceptibility region in the NOD2/CARD15 (nucleotide-binding oligomerisation domain 2/caspase recruitment domain 15) gene, the aetiology is still unclear.Thus, the hunt for disease-initiating factors such as defects in the mucosal barrier or pathogenic microorganisms is ongoing.By contrast, the immunopathogenesis in IBDs is better understood.The identification of cytokines that are involved in T cell and monocyte signalling led to specific therapeutic concepts.Recent data have clearly shown that the most powerful therapeutic approaches inhibit T cell survival by inducing apoptosis.The efficacy of anti-tumour necrosis factor (TNF) strategies was proved to be at least partially due to its ability to induce apoptosis in T cells and monocytes.Furthermore, other powerful anticytokine strategies-namely, anti-interleukin (IL)12 and anti-IL6 antibodies, which are currently tested in clinical trials-also inhibit antiapoptotic pathways in T cells.Recently, the well-established immunosuppressive drug azathioprine was identified as blocking antiapoptotic pathways in T cells.Data from these studies underline the pivotal role of lymphocyte apoptosis in the regulation of mucosal immune balance.
Fascin, a Novel Target of β-Catenin-TCF Signaling, Is Expressed at the Invasive Front of Human Colon Cancer
Authors: Danijela Vignjevic, Marie Schoumacher, Nancy Gavert, Klaus-Peter Janssen, Gloria Jih, Marick Laé, Daniel Louvard, Avri Ben-Ze'ev, Sylvie Robine
Journal: Cancer Research (2007)

Abstract Cancer cells become metastatic by acquiring a motile and invasive phenotype. This step requires remodeling of the actin cytoskeleton and the expression of exploratory, sensory organelles known as filopodia. Aberrant β-catenin-TCF target gene activation plays a major role in colorectal cancer development. We identified fascin1, a key component of filopodia, as a target of β-catenin-TCF signaling in colorectal cancer cells. Fascin1 mRNA and protein expression were increased in primary cancers in a stage-dependent manner. Fascin1 was exclusively localized at the invasive front of tumors also displaying nuclear β-catenin. Forced expression of fascin1 in colorectal cancer cells increased their migration and invasion in cell cultures and caused cell dissemination and metastasis in vivo, whereas suppression of fascin1 expression by small interfering RNA reduces cell invasion. Although expression of fascin1 in primary tumors correlated with the presence of metastases, fascin1 was not expressed in metastases. Our studies show that fascin1 expression is tightly regulated during development of colon cancer metastases and is a novel target of β-catenin-TCF signaling. We propose that transient up-regulation of fascin1 in colorectal cancer promotes the acquisition of migratory and invasive phenotypes that lead to metastasis. Moreover, the expression of fascin1 is down-regulated when tumor cells reach their metastatic destination where migration ceases and proliferation is enhanced. Although metastasis to vital organs is often the cause of mortality, only limited success has been attained in developing effective therapeutics against metastatic disease. We propose that genes involved in cell migration and invasion, such as fascin1, could serve as novel targets for metastasis prevention. [Cancer Res 2007;67(14):6844–53]
Postoperative Course and Hemodynamic Profile After the Arterial Switch Operation in Neonates and Infants
Authors: Gil Wernovsky, David Wypij, Richard A. Jonas, John E. Mayer, Frank L. Hanley, Paul R. Hickey, Amy Z. Walsh, Anthony C. Chang, Aldo R. Castañeda, Jane W. Newburger, David L. Wessel
Journal: Circulation (1995)

Background The neurological morbidity associated with prolonged periods of circulatory arrest has led some cardiac surgical teams to promote continuous low-flow cardiopulmonary bypass as an alternative strategy. The nonneurological postoperative effects of both techniques have been previously studied only in a limited fashion. Methods and Results We compared the hemodynamic profile (cardiac index and systemic and pulmonary vascular resistances), intraoperative and postoperative fluid balance, and perioperative course after deep hypothermia and support consisting predominantly of total circulatory arrest or low-flow cardiopulmonary bypass in a randomized, single-center trial. Eligibility criteria included a diagnosis of transposition of the great arteries and a planned arterial switch operation before the age of 3 months. Of the 171 patients, 129 (66 assigned to circulatory arrest and 63 to low-flow bypass) had an intact ventricular septum and 42 (21 assigned to circulatory arrest and 21 to low-flow bypass) had an associated ventricular septal defect. There were 3 (1.8%) hospital deaths. Patients assigned to low-flow bypass had significantly greater weight gain and positive fluid balance compared with patients assigned to circulatory arrest. Despite the increased weight gain in the infants assigned to low-flow bypass, the duration of mechanical ventilation, stay in the intensive care unit, and hospital stay were similar in both groups. Hemodynamic measurements were made in 122 patients. During the first postoperative night, the cardiac index decreased (32.1±15.4%, mean±SD), while pulmonary and systemic vascular resistance increased. The measured cardiac index was &lt;2.0 L · min −1 · m −2 in 23.8% of the patients, with the lowest measurement typically occurring 9 to 12 hours after surgery. Perfusion strategy assignment was not associated with postoperative hemodynamics or other nonneurological postoperative events. Conclusions After heart surgery in neonates and infants, both low-flow bypass and circulatory arrest perfusion strategies have comparable effects on the nonneurological postoperative course and hemodynamic profile.
Raising the Bar of Efficacy for Drug Approval Requires an Understanding of Patient Diversity
Authors: Marc L. Berger, Stephen Eck, Stephen J. Ruberg
Journal: Journal of Clinical Oncology (2010)

We agree with the authors 1 that expensive new oncology treatments that deliver only incremental benefits over existing therapies may not be valued by payors, physicians, and patients.The authors propose to eliminate this potential problem by making a criterion for drug approval demonstrating improved clinical outcomes that are "paradigm changing."For new oncology treatments that only demonstrate incremental improvement (so-called limbolevel compounds), the authors propose a variation on the theme of conditional regulatory approval.Although we understand and appreciate the motivation behind the authors' proposal, we believe that these recommendations may be imprudent for a number of reasons.We note that regulatory approval does not directly translate into uptake and use of new biopharmaceuticals.The decision to reimburse and provide access is a separate process involving analyses of the comparative clinical and economic value of a new treatment as well as its budget impact.These considerations are appropriately separated from the initial regulatory approval, given that the two reviews have different mandates as well as tolerance for uncertainty.While the authors suggest that "the approval process, and the time from approval to market … [are] beyond the scope" of their report, adoption of their proposals could have profound negative impacts on the regulatory process, actual uptake, and use of new oncology treatments, as well as investment in future research and development; therefore, it is necessary to raise these issues in the context of this report.Regulatory bodies are well aware that their approvals have been frequently interpreted by purchasers and users of newly marketed treatments as definitive evidence of their safety and efficacy, even though the full risk-benefit profile will not emerge for years.
Fibrinolytic and inflammatory processes in pleural effusions
Authors: F Philip-Joet, MC Alessi, C Philip-Joet, M Aillaud, None Barriere, A Arnaud, I Juhan-Vague
Journal: European Respiratory Journal (1995)

This study was designed to evaluate major fibrinolytic parameters in relation to parameters of inflammation associated with different kinds of pleural effusion. Sixty patients with pleural effusion were studied. The underlying aetiology was empyema in 10 cases, tuberculosis in 9, cancer in 31, cardiac failure in 7, and undetermined in 3. Plasminogen, plasminogen activator inhibitor 1 (PAI-1) and 2 (PAI-2), tissue type plasminogen activator (t-PA), urokinase (u-PA) and D-dimers (D-D) were quantified in plasma samples and pleural effusion specimens. These data were then correlated with inflammatory or infectious parameters, i.e. fibrinogen, von Willebrand factor (vWF), erythrocyte sedimentation rate (ESR), protein concentration, and white blood cell count. D-D levels were higher in pleural fluid than in plasma. D-D levels were not correlated with either plasminogen activator or plasminogen activator inhibitor levels, suggesting the presence of other fibrinolytic pathways. PAI levels (PAI activity, PAI-1 antigenicity, PAI-2 antigenicity) and vWF levels were significantly higher in patients with tuberculosis and empyema than in patients with cancer or cardiac failure. Regression analysis between inflammatory and fibrinolytic parameters showed that pleural PAI levels were significantly correlated with pleural neutrophil count, vWF levels, and plasma fibrinogen levels. D-D levels were correlated with blood ESR. No significant difference in pleural t-PA, u-PA and D-D levels was observed between aetiologies. The highest pleural t-PA and u-PA values were noted in patients with cancer, especially lymphoma. Plasma t-PA levels were higher inpatients with pleural effusion secondary to congestive heart failure, but this difference did not reach statistical significance.(ABSTRACT TRUNCATED AT 250 WORDS)
STUDIES OF THE RELATIONSHIP BETWEEN THE PRODUCTION OF BACTERIOCINES BY GROUP A STREPTOCOCCI AND ACUTE GLOMERULONEPHRITIS
Authors: Gary D. Overturf, Edward A. Mortimer
Journal: The Journal of Experimental Medicine (1970)

The previously reported relationship between nephritogenicity and bacteriocine production among Group A streptococci has been examined. Using techniques comparable to the earlier study, the present study did not reveal any such relationship. Among 73 strains tested, 53% produced bacteriocines; no significant difference was noted between bacteriocines from strains isolated from cases of nephritis and those from a group of strains recovered from patients with other conditions. In addition, no correlation between type and bacteriocine production was observed.
Lung perfusion and chest wall configuration is altered by glossopharyngeal breathing
Authors: L.M. Seccombe, S.C.S. Chung, C.R. Jenkins, C.J. Frater, D.W.J. Mackey, M.A. Pearson, L. Emmett, M.J. Peters
Journal: European Respiratory Journal (2009)

Glossopharyngeal insufflation is used by competitive breath-hold divers to increase lung gas content above baseline total lung capacity (TLC) in order improve performance. Whilst glossopharyngeal insufflation is known to induce hypotension and tachycardia, little is known about the effects on the pulmonary circulation and structural integrity of the thorax. Six male breath-hold divers were studied. Exhaled lung volumes were measured before and after glossopharyngeal insufflation. On two study days, subjects were studied in the supine position at baseline TLC and after maximal glossopharyngeal insufflation above TLC. Tc 99 m labelled macro-aggregated albumin was injected and a computed tomography (CT) scan of the thorax was performed during breath-hold. Single photon emission CT images determined flow and regional deposition. Registered CT images determined change in the volume of the thorax. CT and perfusion comparisons were possible in four subjects. Lung perfusion was markedly diminished in areas of expanded lung. 69% of the increase in expired lung volume was via thoracic expansion with a caudal displacement of the diaphragm. One subject who was not proficient at glossopharyngeal insufflation had no change in CT appearance or lung perfusion. We have demonstrated areas of hyperexpanded, under perfused lung created by glossopharyngeal insufflation above TLC.