tbuckley/cabot-search huggingface dataset:
Inhibiting Mitochondrial Fission Protects the Heart Against Ischemia/Reperfusion Injury
Authors: Sang-Bing Ong, Sapna Subrayan, Shiang Y. Lim, Derek M. Yellon, Sean M. Davidson, Derek J. Hausenloy
Journal: Circulation (2010)

Background— Whether alterations in mitochondrial morphology affect the susceptibility of the heart to ischemia/reperfusion injury is unknown. We hypothesized that modulating mitochondrial morphology protects the heart against ischemia/reperfusion injury. Methods and Results— In response to ischemia, mitochondria in HL-1 cells (a cardiac-derived cell line) undergo fragmentation, a process that is dependent on the mitochondrial fission protein dynamin-related protein 1 (Drp1). Transfection of HL-1 cells with the mitochondrial fusion proteins mitofusin 1 or 2 or with Drp1 K38A , a dominant-negative mutant form of Drp1, increased the percentage of cells containing elongated mitochondria (65±4%, 69±5%, and 63±6%, respectively, versus 46±6% in control: n=80 cells per group; P &lt;0.05), decreased mitochondrial permeability transition pore sensitivity (by 2.4±0.5-, 2.3±0.7-, and 2.4±0.3-fold, respectively; n=80 cells per group; P &lt;0.05), and reduced cell death after simulated ischemia/reperfusion injury (11.6±3.9%, 16.2±3.9%, and 12.1±2.9%, respectively, versus 41.8±4.1% in control: n=320 cells per group; P &lt;0.05). Treatment of HL-1 cells with mitochondrial division inhibitor-1, a pharmacological inhibitor of Drp1, replicated these beneficial effects. Interestingly, elongated interfibrillar mitochondria were identified in the adult rodent heart with confocal and electron microscopy, and in vivo treatment with mitochondrial division inhibitor-1 increased the percentage of elongated mitochondria from 3.6±0.5% to 14.5±2.8% ( P =0.023). Finally, treatment of adult murine cardiomyocytes with mitochondrial division inhibitor-1 reduced cell death and inhibited mitochondrial permeability transition pore opening after simulated ischemia/reperfusion injury, and in vivo treatment with mitochondrial division inhibitor-1 reduced myocardial infarct size in mice subject to coronary artery occlusion and reperfusion (21.0±2.2% with mitochondrial division inhibitor-1 versus 48.0±4.5% in control; n=6 animals per group; P &lt;0.05). Conclusion— Inhibiting mitochondrial fission protects the heart against ischemia/reperfusion injury, suggesting a novel pharmacological strategy for cardioprotection.
RHEUMATISM, AND ITS TREATMENT BY TURKISH BATHS.Read in the Section of Practice of Medicine, Materia Medica and Physiology at the Forty-first Annual Meeting of the American Medical Association, at Nashville, Tenn., May, 1890.
Authors: CHAS. H. SHEPARD
Journal: JAMA (1890)

At what time the disease called rheumatism first made its appearance is not known. The name was first applied in 1642, in a treatise on the subject by one of the most celebrated physicians of his time, M. Guillaume de Baillou, who was an author of several medical works of great merit. No disease has proved more perplexing. Its uncertain course at times seems to baffle the physician at every point. Volumes have been written concerning its character, and other volumes still have been devoted to the various systems of treatment, which from time to time have held the favor of the medical world. Nor is the subject exhausted. While much is unsatisfacto, and many new facts are continually discovered, opportunity yet remains for the investigator to discover more. Every new thought advances the welfare of mankind. It is the purpose of this paper to suggest some conclusions on the
Pharmacogenetic Explanation for Excessive β-Blockade Following Timolol Eye Drops
Authors: Tim I. Edeki
Journal: JAMA (1995)

<h3>Objective.</h3> —To determine whether the effects of topically administered timolol in an individual would be dependent on the presence or absence in that individual of the P-450 enzyme CYP2D6 and whether the effects of topically administered timolol would be increased and its metabolism decreased by the oral administration of quinidine, a known inhibitor of CYP2D6. <h3>Design.</h3> —Single-blind randomized crossover comparison of topical timolol, placebo, and the effects of inhibition of timolol metabolism by oral quinidine. <h3>Setting.</h3> —Clinical research center of an academic medical center. <h3>Participants.</h3> —Eight male extensive metabolizers (EMs) and five male poor metabolizers (PMs) of debrisoquin. <h3>Intervention.</h3> —Two drops of 0.5% timolol or artificial tears were administered into each nostril in random order, and placebo or 50 mg of quinidine was administered orally to the EMs in random order, followed 30 minutes later by either the timolol or placebo drops. <h3>Main Outcome Measurement.</h3> —Plasma timolol concentrations were measured by high-pressure liquid chromatography, while the extent of β-blockade was determined by the suppression of exercise-induced rise in heart rate. <h3>Results.</h3> —The exercise heart rate was reduced following timolol eye drops compared with placebo in both EMs (<i>P</i>&lt;.001) and PMs (<i>P</i>&lt;.001) with significantly greater heart rate reduction (<i>P</i>=.01) higher plasma timolol concentration in PMs compared with EMs (<i>P</i>=.03). Administration of quinidine with timolol eye drops to EMs resulted in a further significant reduction in heart rate (<i>P</i>=.02) and increase in plasma timolol concentration (<i>P</i>=.04). <h3>Conclusions.</h3> —An individual's debrisoquin phenotype is an important determinant of β-blockade following timolol eye drops, and metabolism of timolol is inhibited and β-blockade increased by coadministration of oral quinidine. Clinicians should be aware of the potential for drug interactions that occur when orally administered drugs inhibit the metabolism of a topically administered drug. (<i>JAMA</i>. 1995;274:1611-1613)
Drug Spotlight Program
Authors: JAMES C. MELBY
Journal: Annals of Internal Medicine (1974)

The biochemical and metabolic effects of the corticosteroids cannot be easily related to their desired anti-inflammatory and antiallergic therapeutic actions. Ordinarily, the corticosteroids have no place in the treatment of uncomplicated rheumatoid arthritis. Corticosteroid therapy is most important in those disorders requiring prolonged, high-dose and short-term intensive therapy. The complications of corticosteroid therapy can be largely reduced if the underlying disease permits alternate-day therapy. Suppression of the hypothalamic-pituitary-adrenal system is potentially the most hazardous complication of high-dose, prolonged corticosteroid therapy. This complication can be avoided by the institution of alternate-day therapy but it can become manifest up to 6 months after cessation of therapy.
Thrombolytic and pharmacokinetic properties of chimeric tissue-type and urokinase-type plasminogen activators.
Authors: D Collen, H R Lu, H R Lijnen, L Nelles, J M Stassen
Journal: Circulation (1991)

Chimeric molecules comprising the A-chain of tissue-type plasminogen activator (t-PA) and the catalytic domain of urokinase-type plasminogen activator (u-PA) have intact enzymatic characteristics of u-PA, partial fibrin-binding properties of t-PA, and thrombolytic properties in animal models comparable with but not superior to those of single-chain u-PA (scu-PA). Deletion of the finger and growth factor domains (t-PA-delta FE/scu-PA-e) in such chimeras further reduces their affinity for fibrin.A detailed investigation of the thrombolytic potency and the pharmacokinetics of t-PA and u-PA chimeras was performed in quantitative animal models for thrombolysis. In hamsters with pulmonary embolism, in rabbits with jugular vein thrombosis, and in baboons with femoral vein thrombosis, the thrombolytic potency (percent lysis per milligram of compound administered per kilogram of body weight) of t-PA-delta FE/scu-PA-e was significantly higher than that of recombinant scu-PA (rscu-PA, Saruplase) as shown by a maximal rate of 720 +/- 170% versus 45 +/- 5% lysis per milligram of compound per kilogram of body weight (mean +/- SEM, p less than 0.01) in hamsters, 210 +/- 18% versus 49 +/- 3% lysis per milligram of compound per kilogram of body weight (mean +/- SEM, p less than 0.01) in rabbits, and 310 +/- 73% versus 90 +/- 0.3% lysis per milligram of compound per kilogram of body weight (p less than 0.01) in baboons. However, the specific thrombolytic activity (percent lysis per microgram per milliliter steady-state plasma antigen level) of t-PA-delta FE/scu-PA-e was not significantly different from that of rscu-PA in hamsters (210 +/- 57% versus 160 +/- 27% lysis per microgram per milliliter antigen level) and was lower than that of rscu-PA in rabbits (37 +/- 4% versus 130 +/- 5% lysis per microgram per milliliter antigen level; p less than 0.01). In dogs with a combined femoral vein blood clot and a platelet-rich femoral arterial eversion graft thrombosis, 0.25 mg/kg body wt bolus injections of t-PA-delta FE/scu-PA-e produced significantly more venous clot lysis (90 +/- 5%, n = 10) than 0.25 mg/kg rscu-PA (26 +/- 3%, n = 10) (p less than 0.001) and, at the arterial side, more frequent (10 of 10 dogs versus three of 10 dogs) and more persistent (six of 10 dogs versus none of 10 dogs) recanalization (p = 0.002). After bolus injection in hamsters, rabbits, or baboons, t-PA-delta FE/scu-PA-e had a fourfold to sixfold longer initial half-life than rscu-PA and a slower plasma clearance of sixfold in hamsters, 10-fold in rabbits, and more than 10-fold in baboons.These results indicate that t-PA-delta FE/scu-PA-e has a markedly enhanced thrombolytic potency toward venous and arterial thrombi caused by a delayed in vivo clearance with relatively maintained specific thrombolytic activity. These properties suggest that the chimera may be clinically useful for thrombolytic therapy by bolus administration in patients with thromboembolic disease.
A Test of Clinical Learning by Medical Students
Authors: ROBERT J. THURNBLAD, HYMAN MUSLIN, JOHN LOESCH
Journal: American Journal of Psychiatry (1973)

The authors compared the performance of different classes of medical students on an examination using videotaped clinical material. Although the examination was designed to test some aspects of clinical learning, the principal finding was that students achieved high scores at the end of two years of preclinical work; after that no further increment was found. This points up the need to evaluate test instruments carefully and especially to continue direct assessment of students doing clinical work.
Crossroads or threshold? Sport and exercise medicine as a specialty in the UK
Authors: Michael Cullen
Journal: British Journal of Sports Medicine (2009)

How successful have we been in developing the specialty of sport and exercise medicine? Dr Pigozzi’s article on the development of Sports Medicine in Europe caused me to sit back and examine how Sport and Exercise Medicine (SEM) has progressed in the United Kingdom since first being declared a medical specialty in 2005.1 (see page 1085) At that time Mark Batt and I described the path to specialty recognition and concluded that there was considerable work to be done to ensure that SEM became an integral and essential component of the National Health Service.2

Following recognition as a specialty and the subsequent creation of a Faculty of Sport and Exercise Medicine (FSEM UK), there has been considerable time and energy expended to create the infrastructure to develop and promote SEM. The original specialty training curriculum was approved in 2007 and sets out the knowledge, skills and experiences expected of a doctor completing specialty training (www.jrcptb.org.uk/Specialty/Pages/SportandExerciseMedicine.aspx). It has recently been rewritten (along with all other medical specialties) to conform to the revised standards of training and assessments set out by the Postgraduate Medical Education and Training Board and will become operative in 2010.

Training posts in SEM commenced in 2007 and at present there are approximately 30 doctors undergoing higher specialty training; recent …
204 Impaired toll-like receptor expression in chronic hepatitis B
Authors: K VISVANATHAN, N SKINNER, S LOCARMINI, R WILLIAMS, S RIORDAN
Journal: Hepatology (2003)

Dendritic cells (DCs) play a critical role in activation of T cells as well as shaping immune responses. DCs express a pattern of Toll-like receptors (TLRs) to recognize invading pathogens and to initiate specific immune responses. In this study, we investigated the effect of Porphyromonas gingivalis fimbriae on the phenotype and function of human peripheral blood DCs (PBDCs) in comparison to TLR2 and TLR4 ligand, peptidoglycan (PGN) from Staphylococcus aureus and Escherichia coli O55:B5 LPS, respectively. P. gingivalis fimbriae and PGN preferentially upregulated CD14 and CD16 expression on immature PBDCs (CD14−CD16−), although E. coli LPS did not alter the expression of these molecules. Fimbriae-stimulated DCs also exhibited a different profile of cytokine production and surface molecule expression as compared with E. coli LPS-stimulated DCs. Pretreatment of PBDCs with anti-TLR2 monoclonal antibody (mAb), but not with anti-TLR4 mAb, abrogated the upregulation of CD14 and CD16 on fimbriae and PGN-treated DCs. These results indicate that different TLR signaling affects the mature DC phenotype and function and is thus crucial to the regulation of immunity to the pathogen.
Are combined orthopaedic and rheumatology clinics worth while?
Authors: R J Newman, J Belch, I G Kelly, R D Sturrock
Journal: BMJ (1987)

The practice of holding combined orthopaedic and rheumatology clinics is widespread, but no attempt has been made to assess their usefulness. In a one year prospective study patients were randomised either to a combined clinic with a rheumatologist and an orthopaedic surgeon or to a clinic with an orthopaedic surgeon alone. The details of the patients' disease, the interview, the surgeons' and rheumatologists' responses, and the patients' opinions were recorded on questionnaires. Interviews were appreciably longer in the combined clinic, and more referrals for surgery were made. The rheumatologist correctly predicted the need for surgery in 95% of cases, and his presence in the clinic was considered desirable by the surgeon, principally when the referral letter was inadequate. It is concluded that most patients with rheumatic diseases can be seen more efficiently in routine orthopaedic clinics provided a good quality letter of referral is sent.
A novel CXCR4 antagonist derived from human SDF-1β enhances angiogenesis in ischaemic mice
Authors: Yi Tan, Yan Li, Jian Xiao, Hongwei Shao, Chuanlin Ding, Gavin E. Arteel, Keith A. Webster, Jun Yan, Hong Yu, Lu Cai, Xiaokun Li
Journal: Cardiovascular Research (2009)

AimsThe effects on angiogenesis of a novel CXC chemokine receptor 4 (CXCR4) antagonist, SDF-1βP2G, derived from human stromal cell-derived factor-1β (SDF-1β), were examined in a model of hind limb ischaemia in mice.
Smallpox Vaccination for Chronic Herpetic Ulcers
Authors: Harvey J. Cohen
Journal: JAMA (1970)

To the Editor.—  Neff and Lane state that smallpox vaccination as a treatment for herpes simplex may result in dire consequences. Of the nine cases cited, however, all had underlying diseases of the reticuloendothelial system or were receiving immunosuppressive therapy. Smallpox vaccinations as a treatment for herpes simplex in a patient without immunologic malfunction would not be expected to cause such complications. Immunologically impoverished patients suffer these sorts of complications from smallpox vaccination regardless of the reason for performing the procedure. This aspect should be emphasized. We do agree that smallpox vaccination has not been established as effective therapy for herpes simplex.
Impact of rhinitis on asthma severity in school-age children
Authors: M. Deliu, D. Belgrave, A. Simpson, C. S. Murray, G. Kerry, A. Custovic
Journal: Allergy (2014)

Background In a population-based sample of school-age children, we investigated factors associated with rhinitis, and differences between allergic and nonallergic rhinitis. Amongst children with asthma, we explored the association between rhinitis and asthma severity. Methods Children participating in a birth cohort study (n = 906) were reviewed at age 8 years. Asthma was defined as at least two of the following three features: physician-diagnosed asthma, currently using asthma medication and current wheeze. We measured lung function (plethysmography and spirometry) and airway hyper-reactivity (AHR; methacholine challenge). Results In the analysis adjusted for the presence of asthma, children with rhinitis had significantly higher AHR (P = 0.001). Maternal smoking and absence of breastfeeding were stronger predictors of nonallergic rhinitis, whereas current wheeze and eczema were stronger predictors of allergic rhinitis. Amongst asthmatics (n = 159), when compared to 76 children without rhinitis, those with rhinitis (n = 83) were 2.89-fold (95% CI 1.41–5.91) more likely to experience frequent attacks of wheezing, 3.44-fold (1.19–9.94) more likely to experience severe attacks of wheezing limiting speech, 10.14-fold (1.27–81.21) more likely to have frequent visits to their doctor because of asthma and nine-fold (1.11–72.83) more likely to miss school. Reported use of intranasal corticosteroids resulted in a numerically small, but consistent reduction in risk, rendering the associations between rhinitis and asthma severity nonsignificant. Conclusion We observed differences in risk factors and severity between allergic and nonallergic rhinitis. In children with asthma, rhinitis had adverse impact on asthma severity. The use of intranasal corticosteroids resulted in a small, but consistent reduction in the risk.
High dose chemotherapy offers little benefit in breast cancer
Authors: A. Berger
Journal: BMJ (1999)

The use of high dose chemotherapy with bone marrow rescue for women with breast cancer seems to offer little improvement in outcome compared with standard chemotherapy.

Early, disappointing, results from international trials were presented at the 35th annual meeting of the American Society of Clinical Oncology in Atlanta, Georgia, last week. In the United States, high dose chemotherapy, followed by autologous bone marrow or stem cell rescue, has become almost standard treatment for women with high risk breast cancer. This approach has been adopted despite a lack of evidence showing that this more toxic procedure confers any significant benefit over the use of standard dose chemotherapy.

In the United Kingdom, the only centres offering women the opportunity to …
US fear of bioterrorism spreads as anthrax cases increase
Authors: D. Josefson
Journal: BMJ (2001)

Anxiety about anthrax was spreading in the United States this week after exposures to the bacterium in Florida, Nevada, Washington DC, and New York were confirmed.

On Monday a letter sent to US Senate majority leader Tom Daschle was found to contain anthrax, and a baby boy and a 73 year old man were diagnosed with the infection. The baby, the son of an ABC news producer, is thought to have been exposed to the bacterium in …
Remedial therapy after stroke: a randomised controlled trial.
Authors: D S Smith, E Goldenberg, A Ashburn, G Kinsella, K Sheikh, P J Brennan, T W Meade, D W Zutshi, J D Perry, J S Reeback
Journal: BMJ (1981)

Of 1094 patients with a confirmed stroke admitted to Northwick Park, a district general hospital, 364 (33%) died while in hospital, 215 (20%) were fully recovered when discharged, and 329 (30%) were too frail or too ill from diseases other than stroke to be considered for active rehabilitation. Only 121 (11%) were suitable for intensive treatment. They and 12 patients referred direct to outpatients were allocated at random to one of three different courses of rehabilitation. Intensive was compared with conventional rehabilitation and with a third regimen which included no routine rehabilitation, but under which patients were encouraged to continue with exercises taught while in hospital and were regularly seen at home by a health visitor. Progress at three months and 12 months was measured by an index of activities of daily living. Improvement was greatest in those receiving intensive treatment, intermediate in those receiving conventional treatment, and least in those receiving no routine treatment. Decreasing intensity of treatment was associated with a significant increase in the proportions of patients who deteriorated and in the extent to which they deteriorated. Probably only a few stroke patients, mostly men, are suitable for intensive outpatient rehabilitation, but for those patients the treatment is effective and realistic.
Abstract 704: Expression of FOXO1 is associated with GATA3 and Annexin-1 and predicts disease-free survival in breast cancer
Authors: Yan Yuan Wu, Yayha Elshimali, Marianna Sarkissyan, Hezla Mohamed, Sheila Clayton, Jay Vadgama
Journal: Cancer Research (2012)

Abstract Purpose: To determine the prognostic value of FOXO1, GATA3 and Annexin-1 expression in breast cancer. Methods: Tissue microarray and individual paraffin tissue slides from 131 patients were used for the study. The association of FOXO1, GATA3 and Annexin-1 expression with clinicopathological features of breast cancer and disease outcome was examined in retrospective samples. Kaplan-Meier survival curves and Cox regression with multivariate analysis were used for assessing the relative risk (RR) and disease-free survival (DFS). The expression of FOXO1, GATA3 and Annexin-1 were determined by immunohistochemistry and the association among the three proteins was analyzed by Logistic regression analysis. Results: The nuclear expression of FOXO1 was observed in most of the normal breast tissues and 51.3% of the malignant breast tissues. GATA3 and Annexin-1 were expressed at 73% and 24.6% respectively in breast cancer tissues. The expression of FOXO1, GATA3 and Annexin-1 were all inversely correlated with lymph node-positive tumors. Both FOXO1 and Annexin-1 expression were also inversely associated with HER2-overexpressing tumors. FOXO1 expression was significantly associated with both GATA3 and Annexin-1 expression. In addition, Multivariate analyses confirm that only FOXO1 levels independently predict DFS. Conclusion: FOXO1 expression in breast cancer is regulated by the PI3K/Akt pathway. The expression of FOXO1 is also associated with GATA3 and/or Annexin-1. Restoring or targeting FOXO1 to the cell nucleus in breast cancer tissues may improve response to therapy and disease outcome. Further clinical studies are warranted to test this hypothesis. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 704. doi:1538-7445.AM2012-704