tbuckley/cabot-search huggingface dataset:
P187Short term fenofibrate treatment increases nitric oxide production in cardiac endothelial cells through a nitric oxide synthase-independent mechanism
Authors: C Westcott, A Genis, M Mthethwa, H Strijdom
Journal: Cardiovascular Research (2014)

Purpose: The hypolipidaemic agent, fenofibrate, has been shown to exert pleiotropic (lipid-independent) effects, of which the stimulation of the cardioprotective vasodilator, nitric oxide (NO), is particularly relevant. In this study, the NO generating properties of fenofibrate were investigated in cardiac microvascular endothelial cells (CMECs), with particular focus on the underlying role of NO synthase (NOS) isoforms. Methods: CMECs were treated with 50μM fenofibrate for 1 and 24h. Intracellular NO levels were measured by mean diaminofluorescein diacetate (DAF-2/DA) fluorescence intensity (FACS analysis) and nitrite levels by the Griess-method (platereader analysis). The putative involvement of NOS isoforms was investigated by administering the pharmacological inhibitors, L-NMMA (100μM; selective for eNOS/nNOS) or 1400W (80μM; selective for iNOS). Relevant signalling proteins were investigated by means of Western blotting. Results: DAF-2/DA measurements showed that fenofibrate increased NO-production significantly after 1 hour (Control 100%: Feno: 174.7%±11.03;p<0.05), but not after 24 hours. Similarly, nitrite levels were increased after 1h (Control: 2.1μM±0.32; Feno: 3.4μM±0.39;p<0.05), but not at 24h. Surprisingly, western blot data showed that 1h fenofibrate treatment did not affect the phospho/total eNOS ratio of either the Ser 1177 or Thr 495 residues. iNOS expression was not detected in fenofibrate-treated cells, as shown by qPCR and western blotting, and nNOS phosphorylation Ser 1417 remained unchanged. Although pharmacological inhibition of NOS decreased baseline NO-production at 1h (DAF-2/DA fluorescence control: 100% vs. L-NMMA: 85.9%±4.53; p<0.05, and control: 100% vs. 1400W: 85.49%±4.5; p<0.05), the inhibitors had no effect on fenofibrate-induced increases in NO-production. Conclusion: Fenofibrate showed short-term NO generating properties, as demonstrated by two independent NO-measurement techniques. This effect was not sustained and disappeared at 24h. Previous studies (on different endothelial cell lines) showed involvement of eNOS Ser1177 phosphorylation. However, in our hands, involvement of this phosphorylation site could not be demonstrated. Furthermore, neither iNOS nor nNOS seemed to be affected by fenofibrate treatment. Our data suggest that short-term fenofibrate-induced NO-production in CMECs was NOS-independent, which is a novel finding.
Psychodrama Group Therapy for Patients with Functional Gastrointestinal Disorders – a Controlled Long-Term Follow-Up Study
Authors: Ingemar Arn, Töres Theorell, Kerstin Uvnäs-Moberg, Carl-Otto Jonsson
Journal: Psychotherapy and Psychosomatics (1989)

Patients with gastric dyspepsia and irritable bowel syndrome at a primary health care centre were offered a special form of group psychotherapy once a week during a 3-month period. The therapy included psychodrama and relaxation training. Results were evaluated by means of self-administered questionnaires on symptoms and anxiety, comparing pre-therapy levels with levels 6 months after the start of the therapy as well as 3 years later. In the studied treatment group – as well as in a control group selected in the same way but not undergoing the special treatment – the symptom levels decreased 3 months after therapy. In both groups, however, they tended to increase again after 3 years. Anxiety, on the other hand, decreased 6 months after the start of therapy in the specially treated group and no similar tendency was observed in the control group. In the treatment group subjects who reported immediately after treatment that they had learned 'a new behaviour' were more likely to report fewer symptoms of the irritable bowel syndrome 3 years later than other subjects.
Swiss voters reject plan to switch from private to public health system
Authors: N. Stafford
Journal: BMJ (2014)

Voters in Switzerland have rejected a proposed plan to dismantle the nation’s private health insurance system and replace it with a new state operated system.

In a nationwide referendum held on 28 September, 62% of voters opposed the establishment of a single state run entity providing basic health insurance, preferring instead to keep the private system, which currently has 61 private companies.

The Green Party of Switzerland issued a press statement after …
Lymphocyte subpopulations of intestinal mucosa in inflammatory bowel disease.
Authors: O E Eade, S S Andre-Ukena, C Moulton, B MacPherson, W L Beeken
Journal: Gut (1980)

Lymphocyte subpopulations in peripheral blood (PBL) and intestinal mucosa (IML) of 10 patients with inflammatory bowel disease (IBD) were compared with those of 11 non-IBD controls. PBL were separated on Ficoll/hypaque gradients, and IML were isolated by incubation in dithiothreitol, EDTA, and collagenase. These methods yielded cells of good viability and with intact HLA A and B-antigens. T-cells, identified by neuraminidase-treated sheep RBC rosettes and non-specific esterase staining, comprised approximately 91% of the IML from normal mucosa of all groups. B-cells, identified by erythrocyte-antibody-complement rosettes and surface immunoglobulins, were only 7% of these IML populations. Cell yields were two-fold or more greater from abnormal IBD mucosa, with T-cells ranging from 55 to 95% and B-cells from 2 to 36%. The percentage of Fc receptor bearing cells was low in all specimens. By these methods, T-lymphocytes predominated in intestinal mucosa of both IBD and non-IBD patients, but there is marked increase in the percentage of B-cells isolated from abnormal mucosa in IBD.
Refined Carbohydrates, Dietary Fiber, and Gastrointestinal Abnormality
Authors: K. K. Kimura
Journal: JAMA (1976)

<h3>To the Editor.—</h3> The Life Sciences Research Office of the Federation of American Societies for Experimental Biology is conducting a study for the Bureau of Foods, Food and Drug Administration on the "Nutritional Significance of Refined Carbohydrates and Dietary Fiber and Their Role in the Prevention or Induction of Gastrointestinal Pathology." Attention will be given to effects on the gastrointestinal tract and to cardiovasculorenal and oncologic considerations, as well as to hypersensitivity to dietary carbohydrates and fiber in children and adults. In connection with this study, we would like to learn the incidence of sensitivity to refined carbohydrates and dietary fiber. Preclinical scientists and clinicians who have an interest in refined carbohydrates and dietary fiber are requested to correspond with me.
Rapid detection of the common mediterranean α-globin deletions/rearrangements using PCR
Authors: Varda Oron-Karni, Dvora Filon, Ariella Oppenheim, Deborah Rund
Journal: American Journal of Hematology (1998)

The most frequent molecular lesions causing α-thalassemia are deletions of one or more α-globin genes. Detection of these deletions generally requires genomic Southern analysis, which is cumbersome and time consuming. We have designed new sets of primers for PCR identification of the common Mediterranean α-globin gene rearrangements, including the -α3.7 deletion and the αααanti3.7 triplication, the -α4.2 deletion, and the --Med allele. We have established reaction conditions that provide easily interpretable, unambiguous diagnoses. Some of the PCR reactions are multiplex, simultaneously identifying several genotypes, thus reducing the time and cost of screening and prenatal testing. The use of these methods should facilitate carrier screening and identification of couples at risk for α-thalassemia. Am. J. Hematol. 58:306–310, 1998. © 1998 Wiley-Liss, Inc.
Tween 80 containing lipid nanoemulsions for delivery of indinavir to brain
Authors: Kandadi Prabhakar, Syed Muzammil Afzal, Goparaboina Surender, Veerabrahma Kishan
Journal: Acta Pharmaceutica Sinica B (2013)

Indinavir is a protease inhibitor used in the treatment of HIV infection. However, it has limited efficacy in eradicating the virus in the brain due to efflux by P-glycoprotein (P-gp) expressed at the blood–brain barrier (BBB). The objective of this work was to develop an o/w lipid nanoemulsion (LNE) of indinavir using Tween 80 as co-emulsifier to improve its brain specific delivery. LNEs were prepared with different compositions and were characterized for globule size, polydispersity index, zeta potential and in vitro drug release. Five formulations were then evaluated for drug content, entrapment efficiency and stability after which brain uptake studies were carried out using fluorescent labeled LNEs and pharmacokinetic (PK) and tissue distribution studies were conducted after intravenous administration in mice. Brain uptake of indinavir was shown to be improved for a 1% Tween 80 containing formulation (F5) compared to a formulation containing 0.3% cholesterol (F2). In PK studies, the brain level of indinavir subsequent to administration of F5 was significantly (P<0.05) higher than produced by administration of a drug solution (2.44-fold) or a control nanoemulsion (F1) (1.48-fold) or formulation F2 (1.6-fold). The increased brain specific accumulation of indinavir from F5 is probably due to enhanced low density lipoprotein-mediated endocytosis and P-gp inhibition by Tween 80 at the BBB. These results suggest Tween 80 containing LNEs could provide a simple but effective means of delivering indinavir to brain.
Sudden and Unexpected Deaths in Infants: Histology and Virology
Authors: J. A. J. Ferris, W. A. Aherne, W. S. Locke, J. M. Quillin, P. S. Gardner
Journal: BMJ (1973)

The histological appearance of lungs of children whose death had been sudden and unexpected has been studied in relation with the viruses found at necropsy. Fifty-one children were investigated and in 33 the lungs had the histological appearance widely accepted as characteristic of the condition previously termed “cot death.” Sixteen had the histological appearance of lymphocytic bronchiolitis, and it was from this group only that viruses were isolated. The viruses isolated were those associated with respiratory infections. Two patients showed the histological appearance of bacterial bronchopneumonia. Viruses are probably responsible for a substantial proportion of unexpected sudden deaths in infancy.
Using controlled clinical trials to learn more about acute drug-induced liver injury
Authors: Paul B. Watkins, Paul J. Seligman, John S. Pears, Mark I. Avigan, John R. Senior
Journal: Hepatology (2008)

Drug-induced liver injury (DILI) is of major interest to hepatologists and clinicians in general, patients, government regulators, and the pharmaceutical industry. Understanding why this form of injury occurs only in certain individuals has major implications for the development and availability of drug therapies and in the prevention of these events. A single controlled clinical trial may be unlikely to show cases of such rare events, but in the aggregate, clinical trials offer a unique resource for learning more about individual susceptibility and developing truly predictive new biomarkers for DILI. We pose the question as to whether clinical trials could be modified or improved to provide data that would better answer some of the outstanding issues. At a recent (March 2008) public meeting, experts from academia, industry, and regulatory bodies discussed several major issues regarding liver safety in clinical trials including: what signals of liver injury should justify stopping administration of study drug or allowing it to continue; if deliberate rechallenge should be done and under what circumstances; whether patients with liver disease should be included in clinical trials; and what kinds of new biomarkers will be needed to answer these questions more clearly. Past clinical trials have not provided data to settle those issues, and reliance has defaulted to consensus of expert opinions. Modified and better clinical trials with standardized collection of data and biospecimens are probably the best source of new and potentially valuable information to supplant current rules based on consensus of expert opinions and to understand by what mechanisms and how to distinguish those individuals who are susceptible to severe DILI.
Mechanism of hypoxic K loss in rabbit ventricle.
Authors: K Shivkumar, N A Deutsch, S T Lamp, K Khuu, J I Goldhaber, J N Weiss
Journal: Journal of Clinical Investigation (1997)

Although a critical factor causing lethal ischemic ventricular arrhythmias, net cellular K loss during myocardial ischemia and hypoxia is poorly understood. We investigated whether selective activation of ATP-sensitive K (KATP) channels causes net cellular K loss by examining the effects of the KATP channel agonist cromakalim on unidirectional K efflux, total tissue K content, and action potential duration (APD) in isolated arterially perfused rabbit interventricular septa. Despite increasing unidirectional K efflux and shortening APD to a comparable degree as hypoxia, cromakalim failed to induce net tissue K loss, ruling out activation of KATP channels as the primary cause of hypoxic K loss. Next, we evaluated a novel hypothesis about the mechanism of hypoxic K loss, namely that net K loss is a passive reflection of intracellular Na gain during hypoxia or ischemia. When the major pathways promoting Na influx were inhibited, net K loss during hypoxia was almost completely eliminated. These findings show that altered Na fluxes are the primary cause of net K loss during hypoxia, and presumably also in ischemia. Given its previously defined role during hypoxia and ischemia in promoting intracellular Ca overload and reperfusion injury, this newly defined role of intracellular Na accumulation as a primary cause of cellular K loss identifies it as a central pathogenetic factor in these settings.
701 HEPATIC STEATOSIS AND BACTERIAL TRANSLOCATION MODULATES PROGRESSION OF HEPATIC FIBROSIS DURING CHRONIC LIVER INJURY
Authors: S. De Minicis, C. Rychlicki, L. Trozzi, S. Saccomanno, C. Candelaresi, L. Agostinelli, F. Orlando, M. Marzioni, A. Benedetti, G. Svegliati-Baroni
Journal: Journal of Hepatology (2009)
Pancreatic Inflammatory Disease:A Physiologic Approach
Authors: Gordon McHardy
Journal: JAMA (1965)

This is a timely, well-written easily readable, adequately illustrated coverage of pancreatic inflammatory disease by well-qualified authors. It is a remarkable achievement to have condensed so much knowledge of pancreatitis into 182 pages. The breadth of bibliographic research is indicated in the listing of 930 references, which carry through to publications of 1962.  The book is divided into four sections. The first covers the regulation of pancreatic secretion by hormonal and neurogenic factors. The mechanism and control of the exocrine component, fluid and electrolytes, and enzymes, is a composite physiological study. The pancreatic outflow tract, its anomalies, pressure relationship in the biliary-pancreatic ductal system and the potential to disease states therefrom, are depicted.  The second part describes etiological and pathogenetic factors, including infectious, mechanical, metabolic and nutritional, vascular, toxic, allergic, and traumatic. Pathogenesis and the mechanism of symptom manifestation lead in nicely to the following sections, which consider diagnosis and
Involvement of p53 and Raf/MEK/ERK pathways in hematopoietic drug resistance
Authors: J A McCubrey, S L Abrams, G Ligresti, N Misaghian, E W T Wong, L S Steelman, J Bäsecke, J Troppmair, M Libra, F Nicoletti, S Molton, M McMahon, C Evangelisti, A M Martelli
Journal: Leukemia (2008)
The Practice of Hospital Psychiatry: A Formulation
Authors: GARY J. TUCKER, JERROLD S. MAXMEN
Journal: American Journal of Psychiatry (1973)

Most psychiatric hospital treatment in this country has been based on the theories and techniques of the office practice of individual psychotherapy. As a result, if a patient requires hospitalization he is apt to automatically get "more of the same" type of therapy he received on the outside. Although it may be useful, this approach fails to distinguish between the goals and practices of outpatient versus inpatient treatment. The authors attempt to spell out a more rational basis for the use of psychiatric hospitalization.
THE RIGHTS AND DUTIES OF MEDICAL WITNESSES.
Authors: W. S. KERR
Journal: JAMA (1895)

The scope of this paper carries us to the gate of medical jurisprudence, and a little beyond, but I do not enter far its inviting domain. I deal largely with the rights of physicians and surgeons when subpœnaed as expert witnesses, and with the duties incumbent upon them as members of a learned and honored profession when they are called upon to testify as medical experts. Medical witnesses have been extravagantly eulogized and unmeasurably condemned by courts and law writers. They merit both the eulogium and the condemnation. When they traffic in their evidence and appear as hired advocates the condemnation is just; when they appear as members of a great and enlightened profession, to aid in the administration of the law, and testify conscientiously, no tribute is undeserved. The weight of medical expert evidence depends upon two qualities: 1, the skill, learning and experience of the witness; and 2,
Motion perception during selfmotion: The direct versus inferential controversy revisited
Authors: Alexander H. Wertheim
Journal: Behavioral and Brain Sciences (1994)

Abstract According to the traditional inferential theory of perception, percepts of object motion or stationarity stem from an evaluation of afferent retinal signals (which encode image motion) with the help of extraretinal signals (which encode eye movements). According to direct perception theory, on the other hand, the percepts derive from retinally conveyed information only. Neither view is compatible with a perceptual phenomenon that occurs during visually induced sensations of ego motion (vection). A modified version of inferential theory yields a model in which the concept of extraretinal signals is replaced by that of reference signals, which do not encode how the eyes move in their orbits but how they move in space. Hence reference signals are produced not only during eye movements but also during ego motion (i.e., in response to vestibular stimulation and to retinal image flow, which may induce vection). The present theory describes the interface between self-motion and object-motion percepts. An experimental paradigm that allows quantitative measurement of the magnitude and gain of reference signals and the size of the just noticeable difference (JND) between retinal and reference signals reveals that the distinction between direct and inferential theories largely depends on: (1) a mistaken belief that perceptual veridicality is evidence that extraretinal information is not involved, and (2) a failure to distinguish between (the perception of) absolute object motion in space and relative motion of objects with respect to each other. The model corrects these errors, and provides a new, unified framework for interpreting many phenomena in the field of motion perception.
Abstract 3514: A dose-escalation study of anastrozole and everolimus in patients with advanced gynecologic and breast malignancies: tolerance, biological activity, and molecular alterations in the PI3K/AKT/mTOR pathway.
Authors: Jennifer J. Wheler, Stacey L. Moulder, Aung Naing, Filip Janku, Sarina A. Piha-Paul, Gerald S. Falchook, Ralph Zinner, Apostolia M. Tsimberidou, Siqing Fu, David S. Hong, Johnique T. Atkins, Maureen Cronin, Roman Yelensky, Phil Stephens
Journal: Cancer Research (2013)

Abstract Background Combining aromatase inhibitors with PI3K/AKT/mTOR inhibitors is synergistic and may overcome hormone resistance. Patients and Methods We evaluated anastrozole and everolimus in patients with metastatic estrogen receptor (ER) and/or progesterone receptor (PR)-positive breast and gynecologic tumors. Endpoints were safety, antitumor activity and molecular correlates. Results Fifty-five patients were enrolled. Full doses of anastrozole (1 mg PO daily) and everolimus (10 mg PO daily) were well tolerated. Fifty patients were evaluable for response with a median age of 57 (range: 24-82) and a median number of prior therapies of 3 (range: 0-13). Twelve of 50 patients (24%) achieved stable disease (SD) ≥ 6 months/partial response (PR)/complete response (CR), including 9 of 32 patients (28%) with breast cancer, 2 of 9 patients (22%) with ovarian cancer and 1 of 6 patients (17%) with uterine cancer. Six of 8 patients (75%) with SD ≥ 6 months/PR/CR with molecular testing demonstrated at least one alteration in the PI3K/AKT/mTOR pathway including mutations in PIK3CA (n=3) and AKT1 (n=1) or PTEN loss (n=3). All 3 patients who had next generation sequencing demonstrated additional alterations: amplifications in CCNE1, IRS2, MCL1, CCND1, FGFR1 and MYC and a rearrangement in PRKDC. Six of 22 patients (27%) with molecular alterations in the PI3K/AKT/mTOR pathway achieved SD ≥ 6 months/PR/CR. Conclusion Combination anastrozole and everolimus is well tolerated at full approved doses and active in heavily pretreated patients with ER and/or PR-positive breast, ovarian and endometrial cancers. Patients with SD ≥ 6 months/PR/CR frequently had alterations in the PI3K/AKT/mTOR pathway. Citation Format: Jennifer J. Wheler, Stacey L. Moulder, Aung Naing, Filip Janku, Sarina A. Piha-Paul, Gerald S. Falchook, Ralph Zinner, Apostolia M. Tsimberidou, Siqing Fu, David S. Hong, Johnique T. Atkins, Maureen Cronin, Roman Yelensky, Phil Stephens. A dose-escalation study of anastrozole and everolimus in patients with advanced gynecologic and breast malignancies: tolerance, biological activity, and molecular alterations in the PI3K/AKT/mTOR pathway. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 3514. doi:10.1158/1538-7445.AM2013-3514
Precursors to Malignant Melanoma-Reply
Authors: Henry T. Lynch
Journal: JAMA (1985)

<h3>In Reply.—</h3> Dr Jacoby states that our "rebuttal" lacked comprehension of the conference objectives. We participated in the conference, have published our data on the FAMMM syndrome widely,<sup>1,2</sup>and followed actively all of the research and issues discussed at the conference. We did<i>not</i>object to the theme of the conference; rather, we disagreed strongly with the conclusions. We must reject Dr Jacoby's statement that our rebuttal was misleading and that it was not in accord with the intent of the conference. Furthermore, Dr Jacoby's statement indicates that<i>he</i>did not comprehend the issues and the conclusions of the conference, which he was coordinating as acting director of the Office of Medical Applications of Research, NIH. We are deeply concerned about Dr Jacoby's confrontational letter, which is very defensive in character and implies a sacrosanct nature in the published conclusions of the expert panelists. Are we to believe that
Monitoring Temperature During Anesthesia
Authors: Gary L. Fanning
Journal: JAMA (1976)

<h3>To the Editor.—</h3> In regard to Dr Flewellen's letter about temperature monitoring during anesthesia (235: 1967,1976), I wish to make a few comments. First of all, although temperature monitoring is a relatively benign procedure, nothing we do is completely free of hazards, and personal injuries have occurred because of temperature monitoring devices. Secondly, it makes no sense to me to mandate a monitoring procedure for<i>every</i>patient to pick up a phenomenon so rare as malignant hyperpyrexia. We are physicians and ought to use clinical judgement based on training and experience when deciding which monitoring devices to apply to our patients. There is no monitoring device as effective as a well-trained physician who cares about his patient and pays attention to his patient constantly during the procedure. Thirdly, while I am certainly not against the use of temperaturemonitoring devices when they are indicated, I am vehemently opposed to blanket statements