tbuckley/cabot-search huggingface dataset:
Efficacy and Safety of Long-term Prophylaxis in Severe Hemophilia A Dogs Following Liver Gene Therapy Using AAV Vectors
Authors: Denise E Sabatino, Amy M Lange, Ekaterina S Altynova, Rita Sarkar, Shangzhen Zhou, Elizabeth P Merricks, Helen G Franck, Timothy C Nichols, Valder R Arruda, Haig H Kazazian Jr
Journal: Molecular Therapy (2010)

Developing adeno-associated viral (AAV)-mediated gene therapy for hemophilia A (HA) has been challenging due to the large size of the factor VIII (FVIII) complementary DNA and the concern for the development of inhibitory antibodies to FVIII in HA patients. Here, we perform a systematic study in HA dogs by delivering a canine FVIII (cFVIII) transgene either as a single chain or two chains in an AAV vector. An optimized cFVIII single chain delivered using AAV serotype 8 (AAV8) by peripheral vein injection resulted in a dose-response with sustained expression of FVIII up to 7% (n = 4). Five HA dogs administered two-chain delivery using either AAV8 or AAV9 via the portal vein expressed long-term, vector dose-dependent levels of FVIII activity (up to 10%). In the two-chain approach, circulating cFVIII antigen levels were more than fivefold higher than activity. Notably, no long-term immune response to FVIII was observed in any of the dogs (1/9 dogs had a transient inhibitor). Long-term follow-up of the dogs showed a remarkable reduction (>90%) of bleeding episodes in a combined total of 24 years of observation. These data demonstrate that both approaches are safe and achieve dose-dependent therapeutic levels of FVIII expression, which supports translational studies of AAV-mediated delivery for HA.
William Harvey and the Circulation
Authors: Lester S. King
Journal: JAMA (1967)

The discovery of the circulation marked a turning point in the history of thought, and consequently, William Harvey will always hold a dominant place among the immortals of medical science. Yet, when we compare him with many figures of lesser prominence, biographical data are quite sparse and primary documents, on which all biography must ultimately rest, relatively scanty. A biographer, therefore, in portraying Harvey, must emphasize the relationships into which he entered, the people with whom he came in contact, and the events in which he participated. Sir Geoffrey Keynes, the outstanding authority on Sir Thomas Browne as well as on Harvey, has just published the<i>Life of William Harvey</i>,<sup>1</sup>which will long stand as the definitive biography. Perhaps a more appropriate title might have been "The Life and Times" of William Harvey. Keynes depicts Harvey in relation to his friends, professional colleagues, and patients; to his sovereigns James
NOTE ON THE USE OF ORTHO-IODOXYBENZOIC ACID
Authors: A. G. Young
Journal: JAMA (1926)

To the Editor:  —The Journalof September 4 published the work of Young and Youmans on the treatment of infectious arthritis by the use of ortho-iodoxybenzoic acid. Through some error, a note of recognition at the end of the paper in which we thank Dr. A. S. Loevenhart of the University of Wisconsin for his personal interest in our work and also for a personal communication from him in which he stated that in 1910 he had treated a number of cases of arthritis in Cook County Hospital with this compound with apparently beneficial results was omitted. However, this note appears in the reprints and was probably omitted fromThe Journalfor the sake of brevity. The authors regret very much that this occurred and they are pleased to make formal correction of this omission.
Erythema Nodosum and Pustular Ringworm
Authors: C. J. La Touche
Journal: BMJ (1963)

<h3>Objective:</h3> Evaluate PK and generate preliminary safety and efficacy data for perampanel oral suspension given as adjunctive therapy in pediatric patients (aged ≥1 to &lt;24 months) with epilepsy in Study 238 (NCT02914314). <h3>Background:</h3> Perampanel is a once-daily oral antiepileptic drug (AED) for partial-onset seizures and primary generalized tonic-clonic seizures. <h3>Design/Methods:</h3> Study 238 is a multicenter, open-label Phase II study comprising the Pretreatment and Treatment Phases (Core Study), and the Extension Phase. Planned enrollment is ≥16 patients with evaluable PK data. The primary endpoint is perampanel PK during the Maintenance Period of the Core Study. Secondary (safety) endpoints include incidence rate of treatment-emergent adverse events (TEAEs) and clinical laboratory parameters. Perampanel is initiated at 0.5 mg/day and titrated to a maximum dose of 12 mg/day (patients taking non–enzyme-inducing AEDs [EIAEDs]) or 16 mg/day (patients taking EIAEDs) based on clinical response and tolerability. <h3>Results:</h3> As of July 26, 2018, 11 patients were enrolled and 9 (2 aged &gt;6 to ≤12 months and 7 aged &gt;12 to &lt;24 months) entered into the Core Study. Of these, 7 have completed the Core Study, 1 is ongoing, and 1 discontinued due to inadequate therapeutic effect. Limited PK data, based on dose-normalized plasma concentrations, from 7 patients (aged &gt;6 to &lt;24 months; 1 taking EIAEDs) suggested that perampanel exposure was within the range of patients aged ≥2 years. TEAEs were experienced by 8 (88.9%) patients, and treatment-related TEAEs occurred in 5 (55.6%) patients. The most common TEAEs were upper respiratory tract infection (55.6%), pyrexia (44.4%), nasopharyngitis (33.3%), and somnolence (33.3%). <h3>Conclusions:</h3> Preliminary data suggest that perampanel is safe and well tolerated in pediatric patients with epilepsy aged &gt;6 to &lt;24 months and perampanel exposure is comparable with patients aged ≥2 years. The safety profile is consistent with prior clinical studies. Enrollment is ongoing. <b>Funding:</b> Eisai Inc. <b>Disclosure:</b> Dr. Renfroe has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Eisai, Livanova, Ipsen. Dr. Rozentals has nothing to disclose. Dr. Aluri has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Eisai. Dr. Umetsu has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Eisai. Dr. Ma has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Eisai. Dr. Laurenza has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Eisai and Takeda. Dr. Ngo has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Eisai.
Abstract 2456: Mechanism of pancreatic cancer induction by smoking
Authors: ChangHwan Park, In Seok Lee, Amro M. Abdulsattar, Paul J. Grippo, Stephen J. Pandol, Anna S. Gukovskaya, Mouad Edderkaoui
Journal: Cancer Research (2010)

Abstract Background &amp; Aims: Cigarette smoking is a major risk factor for pancreatic cancer. However, the molecular signaling mechanisms of cigarette smoking remain poorly understood. We studied the effects of the cigarette smoking extract (CSE) and the tobacco-specific nitrosamine 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) on apoptosis, proliferation and autophagy and underlying signaling mechanisms both in vitro in human pancreatic ductal cells and in vivo in mouse pancreas. We also studied the effect of K-ras mutation on the smoking-induced cell survival and proliferation. Methods: Immortalized human ductal cells HPDE6 were cultured for up to 1 week in the presence or absence of CSE (0.04-4µg/ml) or NNK (1nM-1µM). Pancreas-specific K-ras transgenic mice EL-K-ras were used as a cancer model. Wild type and EL-K-ras mice were injected with NNK (100mg/Kg) once weekly for 4 weeks and animals sacrificed 72h after the last injection. Apoptosis was assessed by measuring DNA fragmentation with Cell death ELISA or TUNEL and proliferation by 3H-thymidine incorporation into DNA or BrdUrd labeling. Autophagy was measured with its marker LC3 using immunofluorescence staining. Molecular signaling mechanisms were evaluated with Western. Results: Exposure of human ductal cells to CSE and NNK for 24h to 1 week time-dependently decreased apoptosis and autophagy and increased proliferation. Exposure to CSE and NNK decreased AMPK phosphorylation and increased Akt phosphorylation. Akt activation occurred at the times of AMPK inhibition. Pharmacological Akt inactivation reversed the inhibition of AMPK phosphorylation by CSE and NNK and prevented the effects of CSE and NNK on apoptosis and autophagy, indicating a central role of Akt in the prosurvival effects of tobacco compounds. In K-ras mice model of pancreatic cancer NNK injections induced increase in Akt kinase and decrease in AMPK phosphorylation. NNK decreased autophagy and apoptosis and stimulated proliferation in the pancreas. The NNK inhibitory effect on apoptosis and autophagy and the stimulation of proliferation were more pronounced in K-ras mice compared to wild type mice. Conclusion: Our in vitro and in vivo data indicate that smoking compounds create conditions favorable for cancer promotion through activating survival pathways including activation of Akt kinase and inhibition of AMPK activities; this leads to a decrease in apoptosis and autophagy and stimulation of proliferation. Our data suggest that smoking works in concert with K-ras mutation to induce adenocarcinoma. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 2456.
Arnold Philip Bentley
Authors: P J D Heaf
Journal: BMJ (2002)

Former consultant chest physician Royal British Legion Village Maidstone and Maidstone Chest Clinic (b 1922; q London 1944; MBE), d 19 April 2002.


After qualification and a junior post at Preston Hall Hospital, Maidstone, Arnold Bentley served in the Royal Army Medical Corps. He was posted to the army tuberculosis unit 



in Hindhead, which established his path in chest medicine. On demobilisation, he returned to Preston Hall, a Royal British Legion hospital for the treatment of former servicemen and women with tuberculosis. With the decline of tuberculosis, Preston Hall increased its rehabilitation function. The British Legion Industries catered for all types of disability in former servicemen and Arnold played an essential role in the success of this venture, for which he was awarded his MBE. He leaves a wife, Jennie; and two daughters.
Fever of Prolonged Duration Due to Chronic Otitis Media
Authors: Clifford F. Lake
Journal: JAMA (1965)

IN RECENT YEARS there has been some confusion in the minds of many physicians regarding the use of local and systemic antibiotic therapy in the treatment of chronic otitis media. Any cessation or reduction of otorrhea in any ear in which long-standing chronic otitis media is present is only transient. When cholesteatoma and granulations are present in the middle ear and the mastoid process, the cessation of otorrhea after antibiotic therapy may well lull both the physician and the patient into a state of false security. The activity of the cholesteatoma and granulations continues, and the risk of complications remains.  We are presenting a case in which the patient's chief complaints and symptoms were related to a prolonged febrile state and were not singly or collectively otogenic in nature.  A comprehensive review of the literature of these more-enlightened postantibiotic years fails to reveal any report of a similar problem. A
As Nation's Long, Hot Summer Drags On, So Does War Against Forms of Air Pollution
Authors: Charles Marwick
Journal: JAMA (1988)

THE AIR POLLUTION WAR could be going better than it is. But at the moment the battle is being more successfully fought against carbon monoxide than it is against ozone. The Environmental Protection Agency says that the number of areas having levels of ozone higher than the allowed minimum has increased since the last estimate was made. However, the agency says, the number of areas with excessive amounts of carbon monoxide has decreased. Still, Environmental Protection Agency officials say, 44 states and the District of Columbia have places where ozone and carbon monoxide levels are in excess of those laid down by the Clean Air Act. <h3>Physicians' Role</h3> As to what physicians can do to help patients exposed to such levels of pollution, Samuel V. Spagnolo, MD, director, Division of Pulmonary Diseases and Allergy, George Washington University School of Medicine, Washington, DC, said: "Pollution at these levels irritates the trachea
Experience with irinotecan for the treatment of malignant glioma
Authors: James J. Vredenburgh, Annick Desjardins, David A. Reardon, Henry S. Friedman
Journal: Neuro-Oncology (2008)

Malignant glioma is the most commonly occurring primary malignant brain tumor. It is difficult to treat and is usually associated with an inexorable, rapidly fatal clinical course. Chemotherapy, radiotherapy, and surgical excision are core components in the management of malignant glioma. However, chemotherapy, even with the most active regimens currently available, achieves only modest improvement in overall survival. Novel agents and new approaches to therapy are required to improve clinical outcomes. Irinotecan, a first-line treatment for metastatic colorectal cancer and an agent with high activity against solid tumors of the gastrointestinal tract, is an inhibitor of topoisomerase I, a critical enzyme needed for DNA transcription. Irinotecan crosses the blood-brain barrier and, in preclinical investigations, has demonstrated cytotoxic activity against central nervous system tumor xenografts. Its antitumor activity has also been demonstrated against glioblastoma cells with multidrug resistance. Studies in adult and pediatric patients with recurrent, intractable malignant glioma have evaluated irinotecan as monotherapy and in combination with other agents, including temozolomide, carmustine, thalidomide, and bevacizumab. Studies of irinotecan in combination with other medications, particularly temozolomide and bevacizumab, have yielded promising results. Irinotecan monotherapy has demonstrated efficacy; however, its efficacy appears to be enhanced when used in combination with other chemotherapeutic agents. When administered concurrently with enzyme-inducing antiepileptic drugs, the dosage must be increased to compensate for enhanced cytochrome CY3A4/5 enzyme activity. Toxicities associated with irinotecan have been manageable; the most important dose-limiting toxicities are neutropenia and diarrhea. Irinotecan-based chemotherapy of malignant glioma merits further study.
Day 15 bone marrow driven double induction in young adult patients with acute myeloid leukemia: Feasibility, toxicity, and therapeutic results
Authors: Felicetto Ferrara, Tiziana Izzo, Clelia Criscuolo, Cira Riccardi, Maria Celentano, Giuseppina Mele
Journal: American Journal of Hematology (2010)

The strategy named double induction (DI) in acute myeloid leukemia (AML) consists of two courses of chemotherapy irrespective of the degree of cytoreduction in the bone marrow (BM) after the first course, unless severe complications prohibit its application. We describe treatment results from a series of 33 patients in whom DI was adopted only after demonstration of persistence of more than 10% blast cells at day 15 (D15) examination of BM. All patients received as induction idarubicin, cytarabine, and etoposide. As second induction, we administered the combination of fludarabine, intermediate dose cytarabine, and Granulocyte colony stimulating factor (G-CSF). The median blast count at D15 was 30 (15-90). Overall, 30 of 33 patients were judged as eligible to receive DI, reasons for exclusion being in all cases active infection in the context of severe pancytopenia. Nineteen patients (63%) had unfavorable karyotype and 11 (37%) normal karyotype; seven of these had Fms-like tyrosine kinase gene internal tandem duplication (FLT3/ITD) mutation. Overall, complete remission (CR) was achieved in 20/30 patients (67%), while eight patients (27%) were refractory and two died of infectious complications. All refractory patients had unfavorable cytogenetics. All patients achieving CR were programmed to receive allogeneic stem cell transplantation (allo-SCT), which was actually performed in 11 patients. Our study suggest that D15 driven DI represents a feasible and effective therapeutic strategy in young adult AML patients, improving therapeutic results and not compromising feasibility of allo-SCT. When compared with conventional DI, it offers the potential to avoid unnecessary toxicity in a consistent proportion of patients.
Ciguatera Fish Poisoning in Miami
Authors: Dale N. Lawrence
Journal: JAMA (1980)

Ciguatoxic fish constitute a continuing foodborne disease problem in Miami. Information from 129 cases of ciguatera fish poisoning reported to the Dade County (Miami) department of Public Health during 1974 to 1976 was used for epidemiologic study of the syndrome. The case definition required that both gastrointestinal and paresthetic neurological symptoms be experienced within 36 hours after eating fish. Grouper and snapper were the fish most frequently implicated. Neither methods of storage nor means of preparation seemed to affect fish toxicity. A predominantly late spring and summer seasonality was noted. The true annual incidence of this syndrome in Miami may be ten times the number reported to the health department, suggesting an average annual incidence of at least five cases per 10,000 resident population. Recent advances in ciguatoxin research may lead to much needed assays for toxin detection.
Public Health Lessons From the Bhopal Chemical Disaster
Authors: Jeffrey P. Koplan
Journal: JAMA (1990)

THE 1984 CHEMICAL disaster in Bhopal, India, was first and foremost a terrible human tragedy. For those who were there and even for those at considerable distances who read about it, the reality of 2000 or more persons dead and many tens of thousands poisoned by a toxic cloud is horrifying. However, in its particulars and complexities, Bhopal's chemical disaster can also serve as a case example for almost any discipline taught in a school of public health. The disaster has elements of acute and chronic epidemiology, industrial hygiene, toxicology, environmental pollution and planning, disaster preparedness and management, health economics, medical ethics, and environmental protection law, to name a few. Mehta et al<sup>1</sup>review the literature on the Bhopal disaster and its aftermath and focus on the long-term health effects. They recognize the incomplete nature of much of the data and the serious methodologic limitations for study that the
p46, a Novel Natural Killer Cell–specific Surface Molecule That Mediates Cell Activation
Authors: Simona Sivori, Massimo Vitale, Luigia Morelli, Lorenza Sanseverino, Raffaella Augugliaro, Cristina Bottino, Lorenzo Moretta, Alessandro Moretta
Journal: The Journal of Experimental Medicine (1997)

Limited information is available on the surface molecules that are involved in natural killer (NK) cell triggering. In this study, we selected the BAB281 monoclonal antibody (mAb) on the basis of its ability to trigger NK-mediated target cell lysis. BAB281 identified a novel NK cell–specific surface molecule of 46 kD (p46) that is expressed by all resting or activated NK cells. Importantly, unlike the NK cell antigens identified so far, the expression of p46 was strictly confined to NK cells. Upon mAb-mediated cross-linking, p46 molecules induced strong cell triggering leading to [Ca2+]i increases, lymphokine production, and cytolytic activity both in resting NK cells and NK cell clones. The p46-mediated induction of Ca2+ increases or triggering of cytolytic activity was downregulated by the simultaneous engagement of inhibitory receptors including p58, p70, and CD94/NKG2A. Both the unique cellular distribution and functional capability of p46 molecules suggest a possible role in the mechanisms of non-major histocompatibility complex–restricted cytolysis mediated by human NK cells.
Effectiveness of seasonal influenza vaccination during pregnancy in preventing influenza infection in infants, England, 2013/14
Authors: G Dabrera, H Zhao, N Andrews, F Begum, H K Green, J Ellis, K Elias, M Donati, M Zambon, R Pebody
Journal: Eurosurveillance (2014)

In this study we used the screening method to estimate the effectiveness of seasonal influenza vaccination during pregnancy in preventing influenza virus infection and influenza-related hospitalisation in infants under six months, in England in the 2013/14 season. Seasonal influenza vaccination in pregnancy was 71% (95% CI: 24–89%) effective in preventing infant influenza virus infection and 64% (95% CI: 6–86%) effective in preventing infant influenza hospitalisation, and should be recommended in pregnancy.
Beyond MICRA: New Ideas for Liability Reform
Authors: Leo Uzych
Journal: Annals of Internal Medicine (1995)

Letters1 October 1995Beyond MICRA: New Ideas for Liability ReformLeo Uzych, JD, MPHLeo Uzych, JD, MPHWallingford, PA 19086Search for more papers by this authorAuthor, Article, and Disclosure Informationhttps://doi.org/10.7326/0003-4819-123-7-199510010-00020 SectionsAboutFull TextPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissions ShareFacebookTwitterLinkedInRedditEmail TO THE EDITOR:In its position paper, the American College of Physicians [1] identifies liability reforms emanating from the California Medical Injury Compensation Reform Act (MICRA), including caps on damages, limits on attorney contingency fees, and offsets of awards from collateral sources. These reform mechanisms, however, remain highly contentious and may adversely affect the public health.One major academic study found that 98% of all adverse events caused by negligence did not result in malpractice claims [2]. Indeed, the failure of most negligence cases to enter the system is probably the biggest problem plaguing the malpractice system. Contingency-fee caps will ...References1. American College of Physicians. Beyond MICRA: new ideas for liability reform. Ann Intern Med. 1995; 122:466-73. Google Scholar2. Localio AR, Lawthers AG, Brennan TA, Laird NM, Hebert LE, Peterson LM, et al. Relation between malpractice claims and adverse events due to negligence: results of the Harvard Medical Practice Study III. N Engl J Med. 1991; 325:245-51. Google Scholar3. Ominsky AJ. Health care reform and medical malpractice: health care reform does not require tort reform. The Legal Intelligencer/Pennsylvania Law Weekly Health Care Reform Supplement. 1994; August 15:S20-1. Google Scholar4. Freudenheim M. Dealing in myths on malpractice. New York Times. 1992. October 13:D2(col 1). Google Scholar5. Brennan TA, Leape LL, Laird NM, Hebert L, Localio AR, Lawthers AG, et al. Incidence of adverse events and negligence in hospitalized patients: results of the Harvard Medical Practice Study I. N Engl J Med. 1991; 324:370-6. Google Scholar Author, Article, and Disclosure InformationAffiliations: Wallingford, PA 19086 PreviousarticleNextarticle Advertisement FiguresReferencesRelatedDetails Metrics Cited byLetters 1 October 1995Volume 123, Issue 7Page: 554KeywordsAdverse eventsHealth careHealth insuranceInsurancePrevention, policy, and public health Issue Published: 1 October 1995 Copyright & PermissionsCopyright © 1995 by American College of Physicians. All Rights Reserved.PDF downloadLoading ...