tbuckley/cabot-search huggingface dataset:
Understanding Consequences of Concurrent Therapies
Authors: Carl C. Peck
Journal: JAMA (1993)

In 1989, the occurrence of a rare, life-threatening ventricular arrhythmia (torsades de pointes) in an otherwise healthy young woman led alert clinicians at the Naval Hospital in Bethesda, Md, to consider the possibility that the patient's near-fatal arrhythmia was triggered by a drug-drug interaction involving her antihistamine (terfenadine) and her antifungal (ketoconazole) medications.<sup>1</sup>Consulting clinical pharmacologists from the Uniformed Services University of the Health Sciences and the US Food and Drug Administration (FDA) suggested that ketoconazole inhibited the oxidative metabolism of terfenadine. Analysis of blood samples revealed that the patient had high levels of unmetabolized terfenadine, a compound not usually detectable in blood because it is metabolized so quickly. Review of reports to the FDA's spontaneous reporting system revealed that among additional cases of torsades de pointes in patients receiving terfenadine, many were also receiving ketoconazole. This evidence led the FDA to ask Marion Merrill Dow, Kansas City, Mo,
The Lipids in Xanthomata *
Authors: Ronald F. Fletcher, Josephine Gloster
Journal: Journal of Clinical Investigation (1964)

Since the original description (1) in 1850 of "vitiligoidea" in association with chronic jaundice and diabetes, it has become apparent that lipid containing fibrous masses, now called xanthomata, may appear in the skin and occasionally other tis- sues in many disorders of lipid metabolism (2).The commonest form, xanthoma of the eyelids (xanthelasma), and some of the rarer dissemi- nated types may occur in patients with normal serum lipids (2, 3).However, the larger xanthomata (tuberous on pressure areas such as el- bows, knees, and buttocks, and tendinous in the tendons) are almost always associated with an increase in the patient's total serum lipids.Xanthomata from different sites are similar histologically (2).There is much fibrous and connective tissue with conglomerations of sudanophilic material mostly in foam cells; giant cells may be present.In older lesions nests of cholesterol crystals may be seen.Xanthomata may wax and wane with rise and fall in the serum lipids (4), and it has long been supposed that the lipids in the lesions may be derived from the serum (5).Credence would be given to this hypothesis if the lipids in the xanthomata were the same as in the serum lipids, but published data are sparse and were mostly ac- cumulated before satisfactory methods of separating small amounts of the lipid classes and fatty acids became available.Because of the continuing interest in the interrelationships of tissue and se- rum lipids, we thought the problem worth re- examining. MethodsSeven patients with elevated serum lipids and xantho- mata or xanthelasmata were studied (Table I).In ad-
283. DNA Vaccination with Genes Encoding an Antigenic Protein and Fas Ligand Increased Antigen-Specific Humoral Responses
Authors: Osamu Shimozato, Ayako Sato, Kiyoko Kawamura, Quanhai Li, Guangyu Ma, Masatoshi Tagawa
Journal: Molecular Therapy (2006)

Fas ligand (FasL) is a member of the TNF ligand superfamily and induces apoptotic cell death through Fas-mediated pathways. Our previous studies demonstrated that transduction of FasL in tumors produced anti-tumor effects, when they were inoculated into mice and that expressed FasL on tumor cells enhanced antigen acquisition of Fas-positive dendritic cells to elicit tumor-specific immune responses. We here examined the effectiveness of DNA vaccine, which included FasL as an adjuvant and β-galastosidase (β-gal) as an antigen, by measuring the β-gal-specific immune responses. The pcDNA3-based β-gal-expressing vector (β-gal DNA), the pCAGGS- based FasL-expressing vector (FasL DNA) or both vectors (β- gal+FasL DNA) were administrated into quadriceps of DBA/2 mice and subsequently the mice were inoculated with the β-gal-expressing P815 (P815 β) cells. The growth of P815β tumors was retarded in the mice immunized with β-gal+FasL DNA but not β-gal DNA or FasL DNA alone. The mice administrated with the β-gal+FasL DNA produced greater amounts of anti- β-gal antibody than those injected with β-gal DNA alone. In particular, production of IgG2a subclass of anti- β-gal antibody was increased in the mice immunized with β- gal+FasL DNA, when compared with mice administered with β-gal DNA alone. These results revealed that administration of DNA encoding the FasL gene combined with DNA of the β-gal gene could successfully immunized mice and enhanced humoral immunity against β-gal protein; consequently, growth of β-gal-expressing tumors was retarded. Administration of DNA encoding the FasL gene can be an adjuvant and injection together with DNA of an antigenic protein could be applicable as a method of DNA vaccination.
Estrogen monotherapy and combined estrogen-progestogen replacement therapy attenuate aortic accumulation of cholesterol in ovariectomized cholesterol-fed rabbits.
Authors: J Haarbo, P Leth-Espensen, S Stender, C Christiansen
Journal: Journal of Clinical Investigation (1991)

Cardiovascular disease is currently the leading cause of death among women in the United States. To investigate the effect of postmenopausal hormone therapy on atherogenesis, we studied 75 cholesterol-fed female rabbits for 19 wk. The rabbits were randomly assigned to five groups. Four groups underwent bilateral ovariectomy followed by treatment with either 17 beta-estradiol, 17 beta-estradiol plus norethisterone acetate, 17 beta-estradiol plus levonorgestrel, or placebo. The fifth group had a sham operation and received placebo. The hormone groups had only one-third of the aortic accumulation of cholesterol found in the placebo groups, a difference that was highly statistically significant (P less than 0.0001). No significant differences in aortic accumulation of cholesterol were found in the hormone groups. This indicates that estrogen attenuates atherogenesis in cholesterol-fed ovariectomized rabbits and that two commonly prescribed progestogens do not counteract the effect. The beneficial effect of estradiol could only partly be explained by its lowering effects on serum total cholesterol or VLDL cholesterol, which implies that estradiol possesses additional beneficial effects, possibly a direct action on the arterial wall.
Hypokalaemic alkalosis and hyperplasia of the juxtaglomerular apparatus without hypertension or oedema.
Authors: L J Beilin, N Schiffman, M Crane, D H Nelson
Journal: BMJ (1967)

Burkit's Lymphoaorrow et al. Ma3Z7dsurvival rate is approximately 1 in 5.This rate is-markedly dependent on the extent of natomical involvement of the lymphoma at presentation in this series, but in the previously reported series of Clifford (1966) this is not so.A possible reason for this discrepancy is sought in the different dosages of drugs used in the two centres.This investigation represents a continuation and extension of the work initiated by Mr. D. Burkitt.We are grateful to Mr. Burkitt and Mr. S. Kyalwazi, who between them treated nearly all the cases reported in this series, for permission to follow up their patients.Special acknowledgement is due to both the past and the present pathologists at Makerere Medical School, and in par- ticular to Dr. D. H. Wright, for carrying out the microscopy of the cases considered in this paper.We would like to thank Mrs.
In vitro immunotoxicological assays for detection of compounds requiring metabolic activation.
Authors: A N Tucker, V M Sanders, P Hallett, B M Kauffmann, A E Munson
Journal: Environmental Health Perspectives (1982)

A system for metabolic activation of cyclophosphamide (CP), consisting of a crude microsomal fraction of mouse liver and necessary cofactors (S9 mix), was interfaced with three murine cell culture assays for immunotoxicity. These assays were: the Mishell-Dutton assay for in vitro antibody formation, splenic lymphocyte responsiveness to mitogens and bone marrow cell cultures. There was no effect of CP at doses up to 261 microgram/ml (lmM) on any of the parameters measured unless S9 mix was included. Much greater potency was achieved if the S9 mix was prepared from livers of mice pretreated with phenobarbital. Under these conditions and dose-related inhibition of plaque-forming cells (PFC) in the Mishell-Dutton assay was observed, yielding an ED50 of 6.3 microgram/ml. When splenic lymphocytes were exposed to CP in the presence of induced S9 mix, a dose related inhibition of the response to the B-cell mitogen, lipopolysaccharide (LPS), and to the T-cell mitogen, concanavalin A (Con A), was observed. For the optimum LPS concentration, the ED50 for CP was 8.1 microgram/ml; for the optimum concentration of Con A, the ED50 was 6.7 microgram/ml. DNA synthesis was not inhibited by the doses used. When bone marrow cells were exposed to CP in the presence of induced S9 mix, the stem cell population, enumerated by colonization in semisolid medium, was reduced in a dose-dependent manner, with an ED50 of 5.2 microgram/ml. Again, DNA synthesis was not affected unless higher doses of CP were used.
Electrocardiographic screening in athletes: the time is now for universal screening
Authors: M Papadakis, S Sharma
Journal: British Journal of Sports Medicine (2009)

Regular physical exercise reduces cardiovascular morbidity and mortality. A small proportion of athletes, however, are at increased risk of exercise-related sudden cardiac death (SCD) as a result of quiescent cardiac anomalies. The preventable nature of such deaths has prompted the medical and sporting governing bodies to recommend preparticipation cardiovascular screening (PPS) in young athletes (⩽35 years) to permit the identification of potentially fatal disorders. Although evidence from the Italian experience suggests that electrocardiographic screening of young athletes has led to a significant reduction in SCD from cardiomyopathies, considerable controversy relating to the efficacy, cost-effectiveness and the impact of false-positive results of PPS still exists. This review presents an appraisal of all the available scientific evidence, attempting to resolve the concerns of the antagonists and examine how PPS compares with the World Health Organization screening criteria, providing compelling justifications for the implementation of universal PPS in young, competitive athletes.
1049-117 B-type natriuretic peptide is a biochemical predictor of myocardial contractile reserve during dobutamine stress echocardiogram
Authors: Ann Tong, Daniel Lenihan, Vivjay Divakaran, Jessica M Tristan, Mona Nemer, Joseph Swafford, Gregory Geisler, Mary Vooletich, Beverly Handy, Jean-Bernard Durand
Journal: Journal of the American College of Cardiology (2004)
Abundant expression of parathyroid hormone-related protein in primary rat aortic smooth muscle cells accompanies serum-induced proliferation.
Authors: T Hongo, J Kupfer, H Enomoto, B Sharifi, D Giannella-Neto, J S Forrester, F R Singer, D Goltzman, G N Hendy, C Pirola
Journal: Journal of Clinical Investigation (1991)

Parathyroid hormone-related protein (PTHrP), which is responsible for producing hypercalcemia in patients with humoral hypercalcemia of malignancy, has recently been identified in several normal tissues. Because PTHrP, like parathyroid hormone (PTH), is known to exhibit vasodilatory properties, we investigated the expression and regulation of PTHrP mRNA in cultured rat aortic smooth muscle cells (SMC). We report here that PTHrP mRNA is expressed in SMC and is markedly induced by serum in a time- and concentration-dependent fashion. Addition of 10% fetal calf serum to serum-deprived, confluent cells, resulted in a marked induction of PTHrP mRNA by 2 h with a peak at 4-6 h. PTHrP was detected in SMC by immunocytochemistry and radioimmunoassay of conditioned medium, and was shown to be up-regulated within 24 h after the addition of serum. The serum induction of PTHrP mRNA was blocked by actinomycin D and by cycloheximide indicating the need for protein synthesis to evoke the serum effect on PTHrP gene transcription. In addition, treatment with dexamethasone, which has been previously shown to reduce the constitutive expression of PTHrP in human cancer cells, also blunted the serum induction of PTHrP mRNA in SMC. Treatment of quiescent cells with the serum mitogens platelet-derived growth factor or insulin-like growth factor-I had no effect on PTHrP, whereas the vasoactive peptides endothelin, norepinephrine and thrombin stimulated PTHrP expression. Exogenous addition of recombinant PTHrP-(1-141) had no significant effect on SMC DNA synthesis as measured by [3H]thymidine incorporation. In summary, the abundance of PTHrP mRNA and the characteristics of its regulation in SMC suggest a major role for PTHrP as a local modulator in vascular smooth muscle.
Irish government backpedals on decision to reduce entitlement to free health care
Authors: M. Houston
Journal: BMJ (2009)

Older people in Ireland have lost their automatic entitlement to free primary care in a move that has provoked street protests and a partial retreat by the government.

Last year a 2009 budgetary measure was announced that abolished the automatic entitlement of all people aged 70 and over to a medical card regardless of income. This has been changed to reduce the number of people affected.

A medical card gives the holder the right to free drugs and primary care as well as access to social and …
Value of an Electrode Catheter in Diagnosis of Ebstein's Disease
Authors: BERNARD J. B. YIM, PAUL N. YU
Journal: Circulation (1958)

Various features of Ebstein's disease, an unusual congenital malformation of the tricuspid valve, are discussed briefly. Cardiac catheterization with the use of an electrode catheter in such a case is described. The pathophysiologic changes as illustrated by simultaneous intracardiac potentials and pressures are discussed.
Infection with <i>Cysticercus cellulosae</i>
Authors: Gilbert Greenspan, Lehrue Stevens
Journal: New England Journal of Medicine (1961)

CYSTICERCUS cellulosae, the systemic form of infection with the larvae of the pork tapeworm, is rarely diagnosed in this country.1 There are only sporadic reports of native-born persons who contracted the disease without having traveled abroad.2,3 However, with increasing world travel, the disease will be encountered with greater frequency.The following case illustrates the neurologic manifestations of C. cellulosae in a young Mexican immigrant, and the value of at least one course of treatment with a vermifuge despite persistently negative stool examinations.Case ReportE.M. (H.H. 163–265), a 28-year-old Mexican immigrant, was admitted to the Harbor General Hospital because . . .
Endogenous Excitatory Drive Modulating Respiratory Muscle Activity across Sleep–Wake States
Authors: Erin Chan, Hendrik W. Steenland, Hattie Liu, Richard L. Horner
Journal: American Journal of Respiratory and Critical Care Medicine (2006)

Rationale: The concept of a tonic drive activating respiratory muscle in wakefulness but not sleep has been an important and enduring notion in respiratory medicine, not least because it is useful in modeling sleep effects on breathing and understanding the pathogenesis of sleep-related breathing disorders such as obstructive sleep apnea. However, a neurotransmitter substrate mediating respiratory muscle activation across sleep–wake states has not been identified.Objectives: We determined if α1 receptor antagonism at the hypoglossal motor nucleus (HMN) decreases genioglossus (GG) activity consistent with a role for an endogenous noradrenergic drive contributing to GG activation across sleep–wake states. We also determined if α1 receptor stimulation could counteract reduced endogenous noradrenergic drive and increase sleeping GG activity.Methods: Thirty-five rats were implanted with electroencephalogram and neck electrodes to record sleep–wake states and GG and diaphragm electrodes for respiratory muscle recordings. Microdialysis probes were inserted into the HMN.Measurements and Main Results: Microdialysis perfusion of the α1 receptor antagonist terazosin into the HMN significantly decreased GG activity in wakefulness and nonrapid eye movement (non-REM) sleep but not REM sleep. The α1 receptor agonist phenylephrine increased GG activity in wakefulness and sleep, but periods of motor inactivity persisted in REM sleep; there was no potentiating effect of combined α1 and 5-HT2 receptor stimulation.Conclusions: Identification of an endogenous noradrenergic drive contributing to GG activation in wakefulness and non-REM sleep, but not REM sleep, is important given the prevalence and clinical significance of sleep-induced hypoventilation and obstructive sleep apnea in humans and the potential for pharmacologic treatment.
Pertussis toxin-sensitive G proteins influence nitric oxide synthase III activity and protein levels in rat heart.
Authors: J M Hare, B Kim, N A Flavahan, K M Ricker, X Peng, L Colman, R G Weiss, D A Kass
Journal: Journal of Clinical Investigation (1998)

Inhibitory G protein activity (Gi) and nitric oxide (NO) modulate muscarinic-cholinergic (MC) inhibition of cardiac beta-adrenergic inotropic responses. We hypothesized that Gi mediates MC-NO synthase (NOS) signal transduction. Isoproterenol (0.2-0.8 microg/min) and acetylcholine (1 microM) were administered to isolated perfused rat hearts pretreated with saline (controls; n = 8) or pertussis toxin (PT; 30 microg/kg intraperitoneally 3 d before study; n = 20). PT abrogated in vitro ADP-ribosylation of Gi protein alpha subunit(s) indicating near-total decrease in Gi protein function. Isoproterenol increased peak +dP/dt in both control (peak isoproterenol effect: +2, 589+/-293 mmHg/s, P < 0.0001) and PT hearts (+3,879+/-474 mmHg/s, P < 0.0001). Acetylcholine reversed isoproterenol inotropy in controls (108+/-21% reduction of +dP/dt response, P = 0.001), but had no effect in PT hearts. In controls, NG-monomethyl-L-arginine (100 microM) reduced basal +dP/dt, augmented isoproterenol +dP/dt (peak effect: +4,634+/-690 mmHg/s, P < 0.0001), and reduced the MC inhibitory effect to 69+/-8% (P < 0.03 vs. baseline). L-arginine (100 M) had no effect in controls but in PT hearts decreased basal +dP/dt by 1, 426+/-456 mmHg/s (P < 0.005), downward-shifted the isoproterenol concentration-effect curve, and produced a small MC inhibitory effect (27+/-4% reduction, P < 0.05). This enhanced response to NO substrate was associated with increased NOS III protein abundance, and a three- to fivefold increase in in vitro calcium-dependent NOS activity. Neomycin (1 microM) inhibition of phospholipase C did not reverse L-arginine enhancement of MC inhibitory effects. These data support a primary role for Gi in MC receptor signal transduction with NOS in rat heart, and demonstrate regulatory linkage between Gi and NOS III protein levels.
The subject of continuous vigilance
Authors: Arthur M. Langer
Journal: Environmental Health Perspectives (1974)

Asbestos disease in the occupational setting has been documented since the beginning of this century. Modern usage of asbestos fiber has brought with it concomitant and widespread contamination of the environment. The need to control asbestos is required in the forms of legislation and surveillance, to prevent the spread of asbestos disease into the general population.
A Phase I/II Study of GTI-2040 Plus Docetaxel as Second-Line Treatment in Advanced Non-small Cell Lung Cancer: A Study of the PMH Phase II Consortium
Authors: Natasha B. Leighl, Scott A. Laurie, Xueyu E. Chen, Peter Ellis, Frances A. Shepherd, Jennifer J. Knox, Glenwood Goss, Ronald L. Burkes, Gregory R. Pond, Christopher Dick, Yun Yen, James A. Zwiebel, Malcolm J. Moore
Journal: Journal of Thoracic Oncology (2009)
Irruption of genomics in the search for disease related genes
Authors: G Thomas
Journal: Gut (2003)

Genomics was initiated when robotics made possible the characterisation of large numbers of DNA fragments and when ever improving computers with dedicated software were applied to the localisation in the genome of these sequences and to the analysis of their content. By enabling the generation and management of large amounts of DNA based sequences these tools have changed our perception of the genomes of living organisms. These data, as applied to humans, are contributing to the understanding of gene function, disease processes, and evolution of our species. Presently they are changing the research strategies for identifying genetic variations influencing disease susceptibility and response to treatment. These advances will have a profound impact in biomedicine.
Learning from Failure in Health Care Reform
Authors: Jonathan Oberlander
Journal: New England Journal of Medicine (2007)

Jonathan Oberlander writes that just a year after its introduction in September 1993, the Clinton Health Security Act was dead in Congress. What happened to the Clinton plan, and what lessons can today's reformers learn from its failure? Jonathan Oberlander discusses the pitfalls of the Clinton health care plan of 1993, the obstacles to reforming the U.S. health care system, and the outlook for the future. Dr. Oberlander is an associate professor of social medicine and of health policy and administration at the University of North Carolina, Chapel Hill.
DARPins: An Efficient Targeting Domain for Lentiviral Vectors
Authors: Robert C Münch, Michael D Mühlebach, Thomas Schaser, Sabrina Kneissl, Christian Jost, Andreas Plückthun, Klaus Cichutek, Christian J Buchholz
Journal: Molecular Therapy (2011)

We have recently developed a retargeting system for lentiviral vectors (LVs) that relies on the pseudotyping of LVs with engineered measles virus (MV) glycoproteins (hemagglutinin (H) and fusion protein (F)). Specificity is provided through display of a single-chain antibody (scFv) as targeting domain by fusion to the MV-H protein. As an alternative to scFv, designed ankyrin repeat proteins (DARPins) can be selected to become high-affinity binders to any kind of target molecule. In this study six HER2/neu-specific DARPins exhibiting different affinities and binding to different HER2/neu epitopes were applied as targeting domains. All H-DARPin fusion proteins were efficiently expressed on the cell surface. Upon coexpression with F, syncytia formation was observed in HER2/neu positive cells only and correlated directly with the HER2/neu receptor density. All H-DARPin proteins incorporated into LVs, albeit at different levels. The vectors only transduced HER2/neu-positive cells, while HER2/neu-negative cells remained untransduced. Highest titers were observed with one particular DARPin binding to the membrane distal domain of HER2/neu with medium affinity. When applied in vivo systemically, HER2/neu-targeted LVs showed exclusive gene expression in HER2/neu positive tumor tissue, while vesicular stomatitis virus-glycoprotein (VSV-G) pseudotyped vectors mainly transduced cells in spleen and liver. Thus, DARPins are a promising alternative to scFvs for retargeting of LVs.