tbuckley/cabot-search huggingface dataset:
One-year Expression From High-capacity Adenoviral Vectors in the Brains of Animals With Pre-existing Anti-adenoviral Immunity: Clinical Implications
Authors: Carlos Barcia, Maximiliano Jimenez-Dalmaroni, Kurt M Kroeger, Mariana Puntel, Alison J Rapaport, Daniel Larocque, Gwendalyn D King, Stephen A Johnson, Chunyan Liu, Weidong Xiong, Marianela Candolfi, Sonali Mondkar, Philip Ng, Donna Palmer, Maria G Castro, Pedro R Lowenstein
Journal: Molecular Therapy (2007)

The main challenge of gene therapy is to provide long-term, efficient transgene expression. Long-term transgene expression from first generation adenoviral vectors (Advs) delivered to the central nervous system (CNS) is elicited in animals not previously exposed to adenovirus (Ad). However, upon systemic immunization against Ad, transgene expression from a first generation Adv is abolished. High-capacity Advs (HC-Advs) provide sustained very long-term transgene expression in the brain, even in animals pre-immunized against Ad. In this study, we tested the hypothesis that a HC-Adv in the brain would allow for long-term transgene expression, for up to 1 year, in the brain of mice immunized against Ad prior to delivery of the vector to the striatum. In naïve animals, the expression of β-galactosidase from Adv or HC-Adv was sustained for 1 year. In animals immunized prior to vector delivery, expression from a first generation Adv was abolished. These results point to a very long-term HC-Adv-mediated transgene expression in the brain, even in animals that had been immunized systemically against Ad before the delivery of HC-Adv into the brain. This study therefore indicates the utility of HC-Adv as a powerful gene therapy vector for chronic neurological disorders, even in patients who had been pre-exposed to Ad prior to gene therapy. The main challenge of gene therapy is to provide long-term, efficient transgene expression. Long-term transgene expression from first generation adenoviral vectors (Advs) delivered to the central nervous system (CNS) is elicited in animals not previously exposed to adenovirus (Ad). However, upon systemic immunization against Ad, transgene expression from a first generation Adv is abolished. High-capacity Advs (HC-Advs) provide sustained very long-term transgene expression in the brain, even in animals pre-immunized against Ad. In this study, we tested the hypothesis that a HC-Adv in the brain would allow for long-term transgene expression, for up to 1 year, in the brain of mice immunized against Ad prior to delivery of the vector to the striatum. In naïve animals, the expression of β-galactosidase from Adv or HC-Adv was sustained for 1 year. In animals immunized prior to vector delivery, expression from a first generation Adv was abolished. These results point to a very long-term HC-Adv-mediated transgene expression in the brain, even in animals that had been immunized systemically against Ad before the delivery of HC-Adv into the brain. This study therefore indicates the utility of HC-Adv as a powerful gene therapy vector for chronic neurological disorders, even in patients who had been pre-exposed to Ad prior to gene therapy.
The response of rat liver perisinusoidal lipocytes to polypeptide growth regulator changes with their transdifferentiation into myofibroblast-like cells in culture
Authors: Max G. Bachem, Dieter Meyer, Wolfgang Schäfer, Uwe Riess, Ralph Melchior, Klaus-Martin Sell, Axel M. Gressner
Journal: Journal of Hepatology (1993)
Indian courts rule against criminal liability in cases of error
Authors: Sanjay Kumar
Journal: BMJ (2004)

A doctor should not be held criminally liable when a patient's death results from a physician's error of judgment, according to a new controversial judgment from the Supreme Court of India last week.

The judgment pleased the medical community, which has been bitterly resisting the prosecution of doctors in criminal and consumer courts by aggrieved patients.

The ruling came in the case pertaining to the death of Siavash Karim Arbab, who was operated on by plastic surgeon Dr Suresh Gupta for removal of a nasal deformity in April 1994 at the Delhi Plastic Surgery Clinic.

The cause of …
Studies of the In Vivo Metabolism of Mevalonic Acid in the Normal Rat
Authors: Kjell H. Hellstrom, Marvin D. Siperstein, Lee A. Bricker, Lynne J. Luby
Journal: Journal of Clinical Investigation (1973)

Studies were performed to examine synthesis, tissue localization, and metabolism of mevalonic acid in normal rats. Circulating mevalonate was found to have a rapid turnover phase of 5 min and a slower phase of 40-50 min. Under in vitro conditions the synthesis of mevalonate is carried out most actively by the liver and only to a minor extent by the other tissues studied. The most unexpected finding of this study was that both in vivo and in vitro the kidneys rather than the liver are the primary site of the metabolism of circulating mevalonate. Whereas mevalonate in the liver is rapidly transformed to cholesterol, the major products of mevalonate metabolism in the renal tissues during the same time period are squalene and lanosterol. Exogenous in contrast to circulating mevalonate is metabolized primarily in the intestine.
Discrimination between Crigler-Najjar type I and II by expression of mutant bilirubin uridine diphosphateglucuronosyltransferase Seppen J, Bosma PJ, Goldhoorn BG, Bakker CTM, Roy Chowdhury J, Roy Chowdhury N, Jansen PLM. J Clin Invest 1994; 94: 2385?2391
Authors: C BERG
Journal: Hepatology (1995)
Assessing the Value of Treatments to Increase Height
Authors: Leona Cuttler, Robert L. Rosenfield
Journal: New England Journal of Medicine (2011)

The use of growth hormone and estrogen has a long and often controversial history in the manipulation of growth. Pharmacologic interventions to increase growth in short children are increasingly common. We believe that the usefulness of growth-promoting treatments depends on well-designed studies that assess both the effect on height and the functional benefit of height gained.In this issue of the Journal, Ross et al. report the results of a unique, placebo-controlled trial of growth hormone treatment, with or without early low-dose ethinyl estradiol, on adult height in Turner's syndrome, which is characterized by short stature and hypogonadism.1 This randomized . . .
Analysis of the Orthogonal Electrocardiogram and Vectorcardiogram in Ventricular Conduction Defects With and Without Myocardial Infarction
Authors: MERVIN J. GOLDMAN, HUBERT V. PIPBERGER
Journal: Circulation (1969)

Correlations were computed for 320 electrocardiographic measurements and variables of ventricular conduction defects in 452 unselected patients. The variables consisted of right and left ventricular conduction defects with and without myocardial infarction. Quantitative criteria were established which led to the identification of infarction in the presence of a ventricular conduction defect. The data were analyzed by two methods: (1) using four independent measurements, and (2) discriminant function analysis in conjunction with a likelihood ratio test using 9 or 10 measurements. Both techniques yielded similar results. In the presence of left ventricular conduction defects 52% of the cases of infarction were identified with a 14% false positive diagnosis of infarction. In the cases of right ventricular conduction defects the results were 54% and 11%, respectively. In both, the sensitivity could be increased at the expense of an increase in the false positive frequency. This study confirms the difficulties in the electrocardiographic diagnosis of infarction in the presence of left ventricular conduction defects. In addition, it emphasizes that a simlar problem exists with right ventricular conduction defects, a finding which has not been adequately appreciated to date.
Role of family history in patients with myocardial infarction. An Italian case-control study. GISSI-EFRIM Investigators.
Authors: M C Roncaglioni, L Santoro, B D'Avanzo, E Negri, A Nobili, A Ledda, F Pietropaolo, M G Franzosi, C La Vecchia, G A Feruglio
Journal: Circulation (1992)

BACKGROUND A family history of heart disease has been reported to increase the risk of coronary heart disease. We examined the relation between family history of myocardial infarction (MI) and risk of acute MI to establish the independency of this association, the degree of risk in relation to the number and age of relatives affected, and the possible interaction between family history and other major risk factors for MI. METHODS AND RESULTS In a case-control study conducted in Italy within the framework of the GISSI-2 Trial, 916 cases of newly diagnosed MI and 1,106 hospital controls were identified. Using a structured questionnaire, data were collected on the history of MI in first-degree relatives and the age at which the event occurred. Compared with subjects without family history of MI in first-degree relatives, the relative risk (RR) of MI was 2.0 (95% confidence interval, CI, 1.6-2.5) in those with one and 3.0 (95% CI, 2.0-4.4) in those with two or more relatives affected (chi 2(1) test for trend, 54.1; p less than 0.001). Such an increase was not substantially affected by allowance for recognized risk factors. The risk related to family history involving at least two relatives was higher for early MI (less than 55 years) (RR, 20.0; 95% CI, 3.3-121.2) compared with later MI (less than or equal to 65 years) (RR, 3.5; 95% CI, 1.8-6.6). When known risk factors were considered for their interaction with family history, the effect on RR was approximately multiplicative for several variables, including smoking, serum cholesterol, hypertension, and hyperlipidemia but not for diabetes and body mass index. Thus, the presence of both family history and smoking and cholesterol levels greater than or equal to 226 mg/dl led to an RR of 14 (95% CI, 3.7-50.0) and 8.3 (95% CI, 1.8-38.7), respectively. CONCLUSIONS This study indicates that a family history of MI is an independent risk factor for MI, and that the number of relatives and the age at which they were affected is related to the strength of the association. There is a multiplicative effect on RR between family history and several major risk factors for MI.
GP struck off for fraud in drug trials
Authors: O. Dyer
Journal: BMJ (1996)

A general practitioner in Britain has been struck off after the professional conduct committee of the General Medical Council decided that he had entered patients for paid drug trials without their consent (see p.789) Dr Geoffrey Fairhurst, 57, a former government health adviser, practised in St Helens, Merseyside. Sir Donald Irvine, president of the GMC, expressed particular concern that Dr Fairhurst had served on a research ethics committee.

Dr Fairhurst signed agreements to test various drugs including captopril, bumetanide, and lacidipine between 1988 and …
Pure red cell aplasia after chemotherapy for Hodgkin's lymphoma: In vitro evidence for t cell mediated suppression of erythropoiesis and response to sequential cyclosporin and erythropoietin
Authors: Thomas J. Reid, Mark Mullaney, Linda M. Burrell, John Redmond, Kenneth F. Mangan
Journal: American Journal of Hematology (1994)

Abstract Acquired pure red cell aplasia (PRCA) has been associated with various lymphoproliferative conditions but its occurrence with Hodgkin's disease is rare. We report a case of PRCA occurring immediately following the completion of induction chemotherapy in a patient with Stage IIIB nodular sclerosing Hodgkin's disease. In vitro erythroid colony studies documented evidence for T cell mediated suppression of erythropoiesis and lack of a serum inhibitor. Addition of cyclosporin to the in vitro cultures stimulated erythroid colony growth. Following in vivo treatment with cyclosporin peripheral blood CD4/CD8 ratios returned to normal. However, serum erythropoietin levels were inappropriately low. Subsequent treatment with erythropoietin induced a reticulocytosis and transfusion independence. Since discontinuing the erythropoietin, the patient has been able to maintain a hemoglobin of 100 g/L. This case illustrates that red cell aplasia occurring in the setting of Hodgkin's disease may be due to T cell mediated suppression of erythropoiesis. A response to cyclosporin may be masked by inappropriately low erythropoietin levels. © 1994 Wiley‐Liss, Inc.
Recombinant superoxide dismutase reduces oxygen free radical concentrations in reperfused myocardium.
Authors: J L Zweier, B K Rayburn, J T Flaherty, M L Weisfeldt
Journal: Journal of Clinical Investigation (1987)

It has been proposed that oxygen free radicals mediate damage that occurs during postischemic reperfusion. Recombinant human superoxide dismutase (r-h-SOD) has been shown to be effective at reducing reperfusion injury, but it is not known if this infused enzyme actually reduces oxygen free radical concentrations in the myocardial tissue. Electron paramagnetic resonance spectroscopy was used to directly measure the effect of r-h-SOD on free radical concentrations in the postischemic heart. Hearts were freeze clamped at 77 degrees K after 10 min of normothermic global ischemia followed by 10 s of reflow with control perfusate (n = 7) or perfusate containing 60,000 U r-h-SOD (n = 7). The spectra of these hearts exhibited three different signals: signal A isotropic, g = 2.004, identical to the carbon-centered ubiquinone free radical; signal B anisotropic with axial symmetry, g parallel = 2.033, g perpendicular = 2.005, identical to the oxygen-centered alkyl peroxyl free radical; and the signal C an isotropic triplet, g parallel = 2.000, an = 24 G, similar to a nitrogen-centered free radical such as a peroxyl amine. With r-h-SOD administration the concentration of the oxygen free radical, signal B, was reduced 49% from 6.8 +/- 0.3 microM to 3.5 +/- 0.3 microM (P less than 0.01) and the concentration of the nitrogen free radical, signal C, was reduced 38% from 3.4 +/- 0.3 to 2.1 +/- 0.3 microM (P less than 0.01). The concentration of the carbon-centered free radical, signal A, however, was increased 51% from 3.3 +/- 0.2 to 5.0 +/- 0.2 microM (P less than 0.01). Identical reperfusion with peroxide-inactivated r-h-SOD did not alter the concentrations of free radicals indicating that the specific enzymatic activity of r-h-SOD is required to decrease the concentrations of reactive oxygen free radicals. Additional measurements performed varying the duration of reflow demonstrate a burst of oxygen free radical generation peaking at 10 s of reperfusion. r-h-SOD entirely abolished this burst. These studies demonstrate that superoxide-derived free radicals are generated during postischemic reperfusion and suggest that the beneficial effect of r-h-SOD is due to its specific enzymatic scavenging of superoxide free radicals.
The Diagnosis and Treatment of Intestinal Obstruction
Authors: H. J. Benham
Journal: BMJ (1882)

THE BRITISH MEDICAL 7OURNAL.i65 there, according to the plan sometimes adopted in cases of ovariotomy.As regards the operation itself, which has not hitherto been adopted in this country, it has now been performed on fifteen occasions by Billroth, Wolfier, and others with considerable success, five recoveries having taken place, and one patient was recently described as being alive and in good health-the digestive functions being in no way impaired-eight months after its performance.It is, I think, therefore well worthy of further trial ; but in order that it may be successful, it should only be performed in the early stage of the disease, when the pylorus alone is involved, and where the general condition of the patient is such, that he will be able to bear the severe shock which is necessarily attendant upon so serious an operation.
Multimodal Cancer Therapy for Breast Cancer in the First Trimester of Pregnancy
Authors: Charles L. Murray, John A. Reichert, Jo Anderson, Leo B. Twiggs
Journal: JAMA (1984)

OCCASIONALLY, because of clinical considerations, cytotoxic drug therapy is necessary during pregnancy, or unfortunately a patient conceives while under treatment. It is known that the human fetus is the most susceptible to teratogenic agents, such as x-radiation<sup>1</sup>and rubella virus,<sup>2</sup>during the first trimester, and it seems probable that this is also the case for cytotoxic chemotherapy.<sup>3</sup>It is important to assess the risks to which the fetus is subjected under these circumstances. The teratogenicity of antineoplastic agents has been proved in laboratory animals. Similar phenomena are seen in human fetal development when such drugs are administered during the first trimester of pregnancy. Aminopterin, which has been used in the past as an abortifacient, has been reported to cause profound abnormalities in a high percentage of fetuses.<sup>2</sup>Alkylating agents, especially cyclophosphamide, when administered during the first trimester, have been associated with major and minor abnormalities, including
Ethical commentaries must be based on sound science
Authors: J. J Pandit
Journal: BMJ (1998)

EDITOR—It is unfortunate that the scientific basis of Savulescu's commentary on the ethics of the study by Parkins et al, in which infants were exposed to 15% oxygen, is so weak.1 Savulescu states that evidence exists that exposure to hypoxia is related to sudden infant death; he refers to a study in piglets to support his assertion.2 In fact, this study he cites shows no such thing. Parkins et al cogently explain the scarcity of evidence on the effects of exposure to 15% …
Protective effects of nipradilol, isosorbide dinitrate, and bunazosin on coronary artery constriction induced by intracoronary injection of acetylcholine in pigs
Authors: A. Kawamura, H. Fujiwara, M. Ishida, G. Takemura, M. Kida, T. Uegaito, M. Tanaka, C. Kawai
Journal: Cardiovascular Research (1990)

Study objective – Protective effects of nipradilol, a newly synthesised vasodilating β adrenoceptor antagonist, isosorbide dinitrate, and bunazosin on coronary artery constriction induced by intracoronary injection of acetylcholine were determined by coronary arteriography and compared in vivo in pigs. Design – Acetylcholine (12.5,25,50, 100 and 200 μg) was given into the right coronary artery under left ventricular pacing to maintain constant systemic haemodynamics. Percentage narrowing of the major epicardial coronary artery was used as an indicator of constriction of the large coronary arteries, and the time required for the contrast medium to reach the posterior descending coronary artery from the ostium of the right coronary artery (blood flow delay) was used as an indicator of constriction of the small coronary arteries. Subjects – 15 farm pigs weighing 80 to 90 kg were used. Measurements and main results – A marked blood flow delay of over 7.0 s (control: ≤1.8 s) with less than 34% narrowing of the epicardial major coronary artery was observed in 13 of 15 pigs with 12.5-50 μg of acetylcholine, and in the other two pigs with 100 μg of acetylcholine. When marked blood flow delay occurred, the perfused right ventricular myocardium became macroscopically anaemic (ischaemic). Over 75% narrowing of the major epicardial coronary artery was induced in six of the 15 pigs, and over 50% narrowing in 12, with marked blood flow delay with 100 to 200 μg of acetylcholine. However, after intracoronary infusion of 10 μg of nipradilol, acetylcholine induced narrowing in the epicardial major coronary artery was significantly reduced from 44- 79% in control to 19-37% despite 200 μg of acetylcholine, though the time delay in coronary blood flow did not change significantly. By pretreatment with intracoronary isosorbide dinitrate (2.5 mg), the percent narrowing of the large coronary artery and the time delay in coronary blood flow were signifcantly reduced (narrowing from 32-84% to 10.27%; time delay from 7.6-41.6 s to 2.7-22.7 s). Pretreatment with intracoronary bunazosin, an α 1 adrenoceptor antagonist (100 μg), showed no protective effect on narrowing of the epicardial major coronary artery or blood flow delay. Conclusions – Isosorbide dinitrate prevents coronary artery constriction induced by acetylcholine in swine. Nipradilol prevents large, but not small, coronary artery constriction, probably through a direct nitrate like vasodilating action.
Morphological and pharmacological studies of the parietal cells of the stomach in the dog during periods of maximal acid output and after the gastric secretory inhibitor UK-9040.
Authors: D B Hamer, A B Price, J H Baron
Journal: Gut (1977)

UK-9040, a derivative of the antihistamine triprolidine, is a potent gastric secretory inhibitor. Given orally to dogs it reduced gastric acid, pepsin and volume output in response to food, insulin, histamine, N-methyl histamine, and pentagastrin. Doses of 6-36 mg/kg administered orally four to five hours before the secretagogues produced a dose-dependant and up to 100% inhibition in the outputs of innervated gastric fistula and denervated Heidenhain pouch. Inhibition was still present 24 hours after administration of UK-9040 but was absent at 48 hours. Blood pressure and pulse rate were not affected. Studies with the electron microscope revealed that the normal ultrastructural responses to gastric secretory stimulation were arrested. UK-9040 showed no cumulative effect, tolerance did not occur, and after withdrawal of the drug the physiological and morphological gastric responses of the parietal cells rapidly returned to normal.
Goserelin for Ovarian Protection during Breast-Cancer Adjuvant Chemotherapy
Authors: Halle C.F. Moore, Joseph M. Unger, Kelly-Anne Phillips, Frances Boyle, Erika Hitre, David Porter, Prudence A. Francis, Lori J. Goldstein, Henry L. Gomez, Carlos S. Vallejos, Ann H. Partridge, Shaker R. Dakhil, Agustin A. Garcia, Julie Gralow, Janine M. Lombard, John F. Forbes, Silvana Martino, William E. Barlow, Carol J. Fabian, Lori Minasian, Frank L. Meyskens, Richard D. Gelber, Gabriel N. Hortobagyi, Kathy S. Albain
Journal: New England Journal of Medicine (2015)

Ovarian failure is a common toxic effect of chemotherapy. Studies of the use of gonadotropin-releasing hormone (GnRH) agonists to protect ovarian function have shown mixed results and lack data on pregnancy outcomes.
Reversal of Hypermetabolic Brown Adipose Tissuein F-18 FDG PET Imaging
Authors: Carl R. Christensen, Paige B. Clark, Kathryn A. Morton
Journal: Clinical Nuclear Medicine (2006)

With the increasing application of F-18-fluorodeoxyglucose (FDG) positron emission imaging, there has been an evolving appreciation for the range of normal variants and the realization that false-positives can lead to serious consequences.One of the most common causes of a false-positive study is the uptake of FDG in areas of hypermetabolic brown adipose tissue (HBAT). Areas of involvement are often spatially closely related to important lymph node groups in the neck, axilla, and upper mediastinum, making critical differentiation difficult, even with PET-CT.FDG uptake in HBAT has been noted to occur more frequently in cold months and benzodiazepines have been proposed for its prevention. The use of these drugs is, in our experience, of limited value and may complicate patient care in both inpatient and outpatient populations. In this report, we describe considerable success by completely reversing HBAT in 9 of 10 sequential patients with simple core warming maneuvers, which obviate the use of benzodiazepines.