tbuckley/cabot-search huggingface dataset:
Peroxisome Proliferator-Activated Receptor Gamma (PPARγ) Expression Is Decreased in Pulmonary Hypertension and Affects Endothelial Cell Growth
Authors: Shingo Ameshima, Heiko Golpon, Carlyne D. Cool, Daniel Chan, R. William Vandivier, Shyra J. Gardai, Marilee Wick, Raphael A. Nemenoff, Mark W. Geraci, Norbert F. Voelkel
Journal: Circulation Research (2003)

PPARgamma is a member of a family of nuclear receptors/ligand-dependent transcription factors, which bind to hormone response elements on target gene promoters. An antiproliferative and proapoptotic action profile of PPARgamma has been described and PPARgamma may function as a tumor suppressor gene, but little is known about the role of PPARgamma in vascular remodeling. One group of human diseases that shows impressive vascular remodeling exclusively in the lungs is the group of severe pulmonary hypertensive disorders, which is characterized by complex, endothelial cell-proliferative lesions of lung precapillary arterioles composed of clusters of phenotypically altered endothelial cells that occlude the vessel lumen and contribute to the elevation of the pulmonary arterial pressure and reduce local lung tissue blood flow. In the present study, we report the ubiquitous PPARgamma expression in normal lungs, and in contrast, a reduced lung tissue PPARgamma gene and protein expression in the lungs from patients with severe PH and loss of PPARgamma expression in their complex vascular lesions. We show that fluid shear stress reduces PPARgamma expression in ECV304 endothelial cells, that ECV304 cells that stably express dominant-negative PPARgamma (DN-PPARgamma ECV304) form sprouts when placed in matrigel and that DN-PPARgamma ECV304 cells, after tail vein injection in nude mice, form lumen-obliterating lung vascular lesions. We conclude that fluid shear stress decreases the expression of PPARgamma in endothelial cells and that loss of PPARgamma expression characterizes an abnormal, proliferating, apoptosis-resistant endothelial cell phenotype.
Tumor-Selective Gene Expression in a Hepatic Metastasis Model after Locoregional Delivery of a Replication-Competent Retrovirus Vector
Authors: Kei Hiraoka, Takahiro Kimura, Christopher R. Logg, Noriyuki Kasahara
Journal: Clinical Cancer Research (2006)

Replication-competent retrovirus (RCR) vectors have been shown to achieve highly efficient and tumor-restricted replicative spread and gene transfer in vivo after direct intratumoral injection in a variety of primary cancer models. In this setting, the intrinsic inability of retroviruses to infect postmitotic normal cells, combined with their unique ability to persist through stable integration, allow further transduction of ectopic tumor foci as the infected cancer cells migrate. However, i.v. delivery of RCR vectors has never been tested previously, particularly in an immunocompetent tumor model.We combined optical imaging, flow cytometry, and molecular analysis to monitor RCR vector spread after administration via locoregional infusion in a hepatic metastasis model of colorectal cancer.Robust RCR replication was first confirmed in both human WiDr and murine CT26 colorectal cancer cells in vitro, with transduction levels reaching >90% in <12 days after virus inoculation at multiplicities of infection of 0.01 to 0.1. In vivo, infusion of RCR supernatant into the portal circulation resulted in progressive and significant transduction of multifocal intrahepatic CT26 tumors in syngeneic mice, averaging about 30% but with up to 60% transduction in some tumors within 4 weeks. However, immunohistochemistry and quantitative PCR analysis showed no evidence of RCR spread to adjacent normal liver or to any other normal tissues.Our results thus show that locoregional infusion of RCR vectors can be used to deliver therapeutic genes selectively to tumor cells in the liver while sparing normal hepatocytes and without dissemination to extrahepatic normal tissues.
IMPACT REGISTRY: FIRST REVIEW OF COMMUNITY PRACTICE WITH RESPECT TO AORTIC AND PULMONARY ARTERY STENTING
Authors: John W.M. Moore, Robert Vincent, Robert Beekman, Lisa Bergersen, Lee Benson, Ralf Holzer, Kathy Jenkins, Richard Ringel, Jonathan Rome, Traci Connolly, Gerard Martin
Journal: Journal of the American College of Cardiology (2013)
Respiratory syncytial virus and asthma: still no final answer
Authors: R. T. Stein, F. D. Martinez
Journal: Thorax (2010)

During the past two decades, a large number of studies have addressed the association of viral respiratory events in early life and the subsequent development of recurrent wheezing and asthma later in life.1–4 Investigations performed both in animal models and in humans have provided new insights into potential pathogenetic mechanisms discernible during acute and convalescent stages of viral events and their potential association with the long-term consequences of these events.5 6 Retrospective analysis of clinical trials has suggested that the use of anti-respiratory syncytial virus (RSV) antibodies may decrease the incidence of subsequent asthma-like symptoms,7 but prospective data are lacking.

The strongest data for the association between early RSV events and asthma comes from longitudinal studies. The Tucson Children's Respiratory Study was based on a healthy and representative population, and its results, if not automatically applicable to all communities given the peculiarities of the Arizona desert, have been replicated in other population-based studies. The main findings from the Tucson study indicated that RSV, independent of other known risk factors for asthma, was significantly associated with recurrent wheeze in the first decade of life.1 The results of a larger birth cohort, also population based, the ALSPAC study from Bristol points in the same direction as the Tucson study: children with a RSV bronchiolitis admission in the first year of life were more likely to have asthma at age 7 years, compared with controls and there was no relation with RSV infection and the development of atopy at this age.8 The issue of a possible relation between early life RSV bronchiolitis and the later development of atopy has been entertained by a series of studies, and the disparities of findings seem to be …
TWO CASES OF POSTURAL HYPOTENSION SHOWING A DEFICIENCY IN RELEASE OF NOR-EPINEPHRINE AND EPINEPHRINE
Authors: Rolf Luft, Ulf S. Von Euler
Journal: Journal of Clinical Investigation (1953)

Of the two forms of orthostatic hypotension, one, the arterial orthostatic anemia or hypotonic regulatory disturbance (1), is characterized by an increase in the pulse rate and a fall of the systolic blood pressure, with or without a rise in the diastolic pressure, upon change from the recumbent to the erect posture. These circulatory reactions are due to an increased activity of the sympathetic nervous system, which normally compensates for the hydrostatic displacement of blood due to the changes in position. In the second form, the postural hypotension or hypodynamic regulatory disturbance, this reaction of the sympathetic system to changes in posture is absent. The result is a momentary fall of the systolic as well as the diastolic blood pressure during a change from the recumbent to the erect posture, the pulse rate being maintained at a constant level (Figure 1). Postural hypotension was described for the first time in 1925 by Bradbury and Eggleston (2). It is a rather rare condition, of which Springarn and Hitzig (3), in 1942, found only 50 cases described in the literature. It is supposed to be due to organic lesions in the brain stem or spinal cord, following encephalitis, encephalomalacia and tumors,
Efficacy and safety of perhexiline maleate in refractory angina. A double-blind placebo-controlled clinical trial of a novel antianginal agent.
Authors: P L Cole, A D Beamer, N McGowan, C O Cantillon, K Benfell, R A Kelly, L H Hartley, T W Smith, E M Antman
Journal: Circulation (1990)

Despite large gains in the medical and surgical treatment of angina pectoris in the past two decades, many patients are refractory to conventional medical therapy and are unsuitable for a first or, more commonly, repeat coronary revascularization procedure. We evaluated the efficacy of perhexiline maleate, a drug with an antianginal mechanism of action in humans that is as yet unknown, by using a randomized double-blind placebo-controlled crossover design in 17 patients with refractory angina who continued to receive maximal antianginal therapy, typically including nitrates, a beta-blocker, and a calcium channel antagonist. In view of perhexiline's potential for hepatic and neurological toxicity, plasma drug levels were monitored and maintained in the 150-600 ng/ml range. Sixty-three percent of patients were judged perhexiline responders by objective exercise testing criteria, as compared with 18% of patients on placebo (p less than 0.05). By blinded review of subjective measures of anginal frequency and severity, 65% of patients noted an improvement while on perhexiline, whereas no patient identified the placebo phase with improvement. Side effects observed in 29% of patients were minor and related to transient elevations of blood levels of more than 600 ng/ml; no patient suffered hemodynamic or cardiac conduction abnormalities attributable to perhexiline. With attention to the pharmacokinetics of perhexiline's elimination in individual patients, this novel antianginal agent seems to be safe and effective and deserves further evaluation in patients already receiving maximal antianginal therapy who are not candidates for revascularization procedures.
Sequential chemoradiotherapy (SCRT) for larynx preservation (LP): Preliminary results of the randomized phase II TREMPLIN study
Authors: J. Lefebvre, Y. Pointreau, F. Rolland, M. Alfonsi, A. Baudoux, C. Sire, D. de Raucourt, E. Bardet, C. Tuchais, G. Calais
Journal: Journal of Clinical Oncology (2009)

6010 Background: Induction chemotherapy (ICT) followed by irradiation (RT) and concurrent chemoradiotherapy (CRT) are validated options for LP. Docetaxel-based ICT, concurrent cetuximab and RT are new options and SCRT (ICT followed by CRT) has been reported as a potential new approach. However, to date there are no data assessing SCRT specifically for LP. Methods: Previously untreated patients (pts) with larynx or hypopharynx squamous cell carcinoma and candidates for a total laryngectomy were eligible for this randomized phase II study. Eligible pts received 3 cycles of ICT (docetaxel and cisplatin both 75 mg/m 2 on day 1 and 5-FU 750 mg/m 2 /day on days 1–5). In case of response ≥ 50 % pts were randomized to receive either in arm A: RT (70 Gy) with cisplatin (100 mg/m 2 on days 1, 22 and 43 of RT) or in arm B: Cetuximab (400 mg/m 2 loading dose before RT and 250 mg/m 2 on the first day of the 7 weeks of RT. Pts with response &lt; 50% had salvage surgery. Primary endpoint was LP 3 months after treatment, secondary endpoints were larynx function preservation at 18 months, quality of function and tolerance to treatment. Results: From March 2006 to April 2008 (end of accrual), 153 pts with stage III-IV larynx/hypopharynx cancer were enrolled in the study and could start ICT. Of them 74 % could receive the planned ICT while the others had either reduced dosages or less than 3 cycles. Toxic deaths occurred in 3 pts (2%). Of the 147 evaluable pts after ICT, 22 were non-responders (15%), 4 pts were withdrawn from the study, 6 responding pts with ICT-related toxicity precluding any further cisplatin could not be randomized and finally 115 pts could be randomized (59 in arm A and 56 in arm B). 3 months after treatment there was no significant difference in LP (93% in arm A and 96% in arm B). In arm A, 45 % of pts could receive the full CRT protocol vs 71 % in arm B. In arm A 50% of pts had cisplatin-related toxicity (definitive in 52% the cases) while in arm B 26 % of patients had cetuximab-related toxicity (definitive in only 1 case). There was no CRT treatment-related death. Conclusions: SCRT is considered for LP. ICT followed by RT with concurrent cetuximab appeared better tolerated than with concurrent cisplatin with the same LP rate 3 months after treatment. [Table: see text]
Renal Effects of Glibenclamide in Cystic Fibrosis Mice
Authors: JONATHAN KIBBLE, ANDREW NEAL, STANLEY WHITE, ROGER GREEN, STEVE EVANS, CHRISTOPHER TAYLOR
Journal: Journal of the American Society of Nephrology (2001)

In vitro studies have shown that glibenclamide sensitivity is conferred upon Kir 1.1 K+ channels when they are co-expressed with the cystic fibrosis transmembrane conductance regulator (CFTR). In rats, glibenclamide acts as a K+-sparing diuretic by a mechanism that involves blockade of Kir 1.1 channels in the distal nephron. To test whether interaction between Kir 1.1 and CFTR is required to mediate the renal effects of glibenclamide (15 mg/kg), clearance experiments were performed comparing wild type (WT) and Cftrtm2cam ▵F508 cystic fibrosis (CF) mice. Glibenclamide treatment was associated with an equivalent diuresis in both WT and CF mice. Glibenclamide was K+-sparing in both genotypes with no significant change in urinary K+ excretion observed. That glibenclamide was an effective K+-sparing diuretic in CF animals suggests that CFTR expression is not a requirement to mediate its renal actions in mice.
Statistics Notes: Concealing treatment allocation in randomised trials
Authors: D. G Altman, K. F Schulz
Journal: BMJ (2001)

their feet.There are even more fundamental reasons why depending on the rationality of the market will never work well for quality of care (box).Sensible policy for providing nursing home care requires a larger welfare state, a larger regulatory state, and encouragement of public, non-profit providers.Australia's recent experience shows that to head in the opposite direction is medically, economically, and politically irrational.
Botulinum Toxin as a Biological Weapon
Authors: Stephen S. Arnon, Robert Schechter, Thomas V. Inglesby, Donald A. Henderson, John G. Bartlett, Michael S. Ascher, Edward Eitzen, Anne D. Fine, Jerome Hauer, Marcelle Layton, Scott Lillibridge, Michael T. Osterholm, Tara O'Toole, Gerald Parker, Trish M. Perl, Philip K. Russell, David L. Swerdlow, Kevin Tonat, None for the Working Group on Civilian Biodefense
Journal: JAMA (2001)

ObjectiveThe Working Group on Civilian Biodefense has developed consensus-based recommendations for measures to be taken by medical and public health professionals if botulinum toxin is used as a biological weapon against a civilian population.ParticipantsThe working group included 23 representatives from academic, government, and private institutions with expertise in public health, emergency management, and clinical medicine.EvidenceThe primary authors (S.S.A. and R.S.) searched OLDMEDLINE and MEDLINE (1960–March 1999) and their professional collections for literature concerning use of botulinum toxin as a bioweapon. The literature was reviewed, and opinions were sought from the working group and other experts on diagnosis and management of botulism. Additional MEDLINE searches were conducted through April 2000 during the review and revisions of the consensus statement.Consensus ProcessThe first draft of the working group's consensus statement was a synthesis of information obtained in the formal evidence-gathering process. The working group convened to review the first draft in May 1999. Working group members reviewed subsequent drafts and suggested additional revisions. The final statement incorporates all relevant evidence obtained in the literature search in conjunction with final consensus recommendations supported by all working group members.ConclusionsAn aerosolized or foodborne botulinum toxin weapon would cause acute symmetric, descending flaccid paralysis with prominent bulbar palsies such as diplopia, dysarthria, dysphonia, and dysphagia that would typically present 12 to 72 hours after exposure. Effective response to a deliberate release of botulinum toxin will depend on timely clinical diagnosis, case reporting, and epidemiological investigation. Persons potentially exposed to botulinum toxin should be closely observed, and those with signs of botulism require prompt treatment with antitoxin and supportive care that may include assisted ventilation for weeks or months. Treatment with antitoxin should not be delayed for microbiological testing.
Sputum eosinophilia and the short term response to inhaled mometasone in chronic obstructive pulmonary disease
Authors: C E Brightling
Journal: Thorax (2005)

<b>Background:</b> An association between the sputum eosinophil count and the response to a 2 week course of prednisolone has previously been reported in patients with chronic obstructive pulmonary disease (COPD). Whether the response to inhaled corticosteroids is related to the presence of eosinophilic inflammation is unclear. <b>Methods:</b> A randomised, double blind, crossover trial of placebo and mometasone furoate (800 μg/day), each given for 6 weeks with a 4 week washout period, was performed in subjects with COPD treated with bronchodilator therapy only. Spirometric tests, symptom scores, chronic respiratory disease questionnaire (CRQ), and induced sputum were performed before and after each treatment phase. <b>Results:</b> Ninety five patients were recruited of which 60 were randomised. Overall there were no treatment associated changes in forced expiratory volume in 1 second (FEV<sub>1</sub>), total CRQ, or sputum characteristics. After stratification into tertiles by baseline eosinophil count, the net improvement in post-bronchodilator FEV<sub>1</sub> increased with mometasone compared with placebo progressively from the least to the most eosinophilic tertile. The mean change in post-bronchodilator FEV<sub>1</sub> with mometasone compared with placebo in the highest tertile was 0.11 l (95% CI 0.03 to 0.19). This improvement was not associated with a fall in the sputum eosinophil count. <b>Conclusions:</b> An increased sputum eosinophil count is related to an improvement in post-bronchodilator FEV<sub>1</sub> following treatment with inhaled mometasone in COPD, but the improvement is not associated with a reduction in the sputum eosinophil count.
Addressing Dual Agency: Getting Specific About the Expectations of Professionalism
Authors: Jon C. Tilburt
Journal: The American Journal of Bioethics (2014)

Professionalism requires that physicians uphold the best interests of patients while simultaneously insuring just use of health care resources. Current articulations of these obligations like the American Board of Internal Medicine (ABIM) Foundation's Physician Charter do not reconcile how these obligations fit together when they conflict. This is the problem of dual agency. The most common ways of dealing with dual agency: "bunkering"--physicians act as though societal cost issues are not their problem; "bailing"--physicians assume that they are merely agents of society and deliver care typically based on a strongly consequentialist public health ethic; or "balancing"--a vaguely specified attempt to uphold both patient welfare and societal need for judicious resource use simultaneously--all fail. Here I propose how the problem of dual agency might begin to be addressed with rigor and consistency. Without dealing with the dual agency problem and getting more specific about how to reconcile its norms when they conflict, the expectations of professionalism risk being written off as cute, nonbinding aphorisms from the medical profession.
Esmolol tilt testing with esmolol withdrawal for the evaluation of syncope in the young.
Authors: M Ovadia, D Thoele
Journal: Circulation (1994)

Head-upright tilt (HUT) testing is valuable in evaluating syncope. Isoproterenol is used to increase sensitivity. However, isoproterenol is contraindicated or dangerous in undiagnosed heart disease and produces false-positives. We introduced esmolol withdrawal during esmolol HUT, hypothesizing that (1) acute withdrawal of the ultrashort-acting beta-blocker induces beta-adrenergic effects by unmasking endogenous catecholamines and may provoke syncope with fewer risks, and (2) response to esmolol/esmolol withdrawal may predict effective therapy.Thirty-six patients with unexplained recurrent syncope/presyncope (7 to 35 years old, known heart disease or arrhythmia in 14) underwent 2 to 4 HUT tests (60 degrees, 49 minutes): (1) baseline, (2) esmolol (500 micrograms/kg plus 50 micrograms.kg-1.min-1), (3) esmolol withdrawal (HUT continued after esmolol stopped), and (4) isoproterenol if tests 1 through 3 were negative and isoproterenol was not contraindicated. A positive test reproduced symptoms with hypotension or bradycardia, requiring recumbency for recovery. Twenty-five had positive tests, and 11 had negative tests. In 5, only the baseline test was positive; in 15, esmolol/esmolol withdrawal tests were also positive, with 3 in whom esmolol withdrawal was positive although negative at baseline. Two isoproterenol tilts were positive. Esmolol withdrawal and isoproterenol tilts had the highest initial heart rate and similar maximal heart rate increment. Only isoproterenol caused hypertension. One isoproterenol test was false-positive, with hypertension-induced arterial baroreflex. Treatment was beta-blockers (8), Na/fludrocortisone (9), both (6), and DDD pacemakers (2). Esmolol/esmolol withdrawal accurately predicted therapeutic response in 15; isoproterenol predicted therapeutic response in none.Esmolol withdrawal tilt testing is preferable to isoproterenol for provocative testing of syncope in the young, and it appears to be safer. Esmolol withdrawal testing has clinical utility before invasive testing as a first-line investigation for syncope in patients with or without heart disease.
Unexpected Severe Calcification After Transplantation of Bone Marrow Cells in Acute Myocardial Infarction
Authors: Young-Sup Yoon, Jong-Seon Park, Tengiz Tkebuchava, Corinne Luedeman, Douglas W. Losordo
Journal: Circulation (2004)

Background— There has been a rapid increase in the number of clinical trials using unselected bone marrow (BM) cells or the mononuclear fraction of BM cells for treating ischemic heart diseases. Thus far, no significant deleterious effects or complications have been reported in any studies using BM-derived cells for treatment of various cardiac diseases. Methods and Results— Seven-week-old female Fisher-344 rats underwent surgery to induce acute myocardial infarction and were randomized into 3 groups of 16 rats, each receiving intramyocardial injection of either 7×10 5 DiI-labeled total BM cells (TBMCs), the same number of DiI-labeled, clonally expanded BM multipotent stem cells, or the same volume of phosphate-buffered saline in the peri-infarct area. Echocardiography 2 weeks after cell transplantation indicated intramyocardial calcification in 4 of 14 surviving rats (28.5%) in the TBMC group. Histological examination with hematoxylin and eosin staining and von Kossa staining confirmed the presence of extensive intramyocardial calcification. Alkaline phosphatase staining revealed strong positivity surrounding the calcified area suggestive of ongoing osteogenic activity. Fluorescent microscopic examination revealed that acellular calcific areas were surrounded by DiI-labeled TBMCs, suggesting the direct involvement of transplanted TBMCs in myocardial calcification. In contrast, in hearts receiving equal volumes of saline or BM multipotent stem cells delivered in the same manner, there was no evidence of calcification. Conclusions— These results demonstrate that direct transplantation of unselected BM cells into the acutely infarcted myocardium may induce significant intramyocardial calcification.