tbuckley/cabot-search huggingface dataset:
The Scientific Mind at Work (and Play)
Authors: Harry S. Jacob, Dale E. Hammerschmidt
Journal: JAMA (1981)

<h3>The Thorndike Model</h3><h3>JAMA:</h3> Dr Jacob, what guidelines did you use to establish your clinical research program? <h3>Jacob:</h3> My own group has been presaged on the type of clinical investigation that culminated in the Thorndike Laboratory at the Boston City Hospital under William Castle, MD, with other greats, such as Maxwell Finland, MD, and Charles Davidson, MD. Within the hospital setting, physicians at the patient's bedside generated insights and trained their students to bring those insights back to the laboratory bench. This approach requires not only a strong subspecialty group, but also an environment in which there are many other subspecialists who have a similar interest in pathogenetic mechanisms of illness. One of the major problems in research training and clinical investigation is that they have become wildly superspecialized in that people believe that research in their own subspecialty can be done without knowledge of other subspecialties, and this leads
IMPACT OF LOADING- VERSUS MAINTENANCE-DOSE CLOPIDOGREL ON PLATELET AGGREGATION IN CHINESE WITH DIFFERENT CYP2C19 GENOTYPES: A PROSPECTIVE OBSERVATIONAL FACTORIAL TRIAL
Authors: Xiao-Xing Zhang, Li-Rong Yan, Dongxue Wang, Lulu Han, Yan Li, Lei Tian, Hong Liu, Yi-Shi Li
Journal: Journal of the American College of Cardiology (2014)
Pediatric HIV Disease, Zidovudine in Pregnancy, and Unblinding Heelstick Surveys
Authors: Howard Minkoff
Journal: JAMA (1995)

FEDERAL AND state legislatures have recently taken up the issue of identification of newborns exposed to the human immunodeficiency virus (HIV). Proposed legislation (eg, the Coburn/Waxman HIV testing amendment to the Ryan White CARE Act, the Ackerman Newborn HIV Notification Act [HR 1289], and NY A4413 and NY 52704) would include consideration of "unblinding" newborn heelstick surveys, which, until quite recently, were performed anonymously for surveillance purposes. These surveys, which relied on the detection of passively acquired maternal antibody to HIV, allowed health departments to track the course of the HIV epidemic among women of reproductive age. By unblinding these surveys, ie, ending the anonymity built into current protocols, health departments would identify exposed newborns, who could then be provided with appropriate therapeutic and prophylactic interventions. Since identification of exposed newborns relies on serological testing for passively acquired maternal antibody, such unblinding identifies infected women, and this discussion becomes, in
Characterization and pharmacological relevance of high affinity binding sites for [3H]LY186126, a cardiotonic phosphodiesterase inhibitor, in canine cardiac membranes.
Authors: R F Kauffman, B G Utterback, D W Robertson
Journal: Circulation Research (1989)

[3H]LY186126, an analogue of the cardiotonic agent indolidan, was shown to bind reversibly and with high affinity (Kd = 4 nM) to a single class of binding sites within canine myocardial vesicles. Binding site density measured in various cardiac membrane fractions correlated well with Ca2+-ATPase activity (r = 0.94; p less than 0.01), but not with Na+,K+-ATPase or azide sensitive ATPase, indicating a localization of these sites within sarcoplasmic reticulum membranes. Divalent cations were required for binding and displayed the following order of activation: Zn2+ greater than Mn2+ greater than Mg2+ greater than Ca2+. Differential activation of [3H]LY186126 binding by various divalent cations was due to alterations in binding site density, rather than affinity. cGMP and selective inhibitors of type IV membrane-bound phosphodiesterase (SR-PDE), for example, indolidan, milrinone, imazodan, and enoximone, selectively displaced bound [3H]LY186126 caffeine, theophylline, and rolipram were relatively impotent as inhibitors of radiolabel binding. Kd values from displacement curves were highly correlated with IC50 values for inhibition of SR-PDE (r = 0.92; p less than 0.001). In addition, Kd values correlated well with published ED50 values for increases in cardiac contractility in pentobarbital-anesthetized dogs (r = 0.94; p less than 0.001). The results support the hypothesis that [3H]LY186126 labels the pharmacological receptor for the class of positive inotropic agents characterized as isozyme-selective phosphodiesterase inhibitors. Furthermore, the data suggest that the identity of the site labeled by [3H]LY186126 is SR-PDE, the type IV isozyme of cardiac phosphodiesterase located in the sarcoplasmic reticulum.
Developing Britain's police surgeon service
Authors: G. Moon, K. Kelly, S. P Savage, Y. Bradshaw
Journal: BMJ (1995)

Needs better legal and forensic training

Police surgeons, also known as forensic medical examiners, are doctors who have agreed to make themselves readily available to respond to calls by the police.1 Their work entails examining detainees and police officers who have sustained injuries or who have other medical problems. They also decide whether individuals are fit to be detained or interviewed.

The role of police surgeons in the criminal justice process has been highlighted, not always positively, in a series ofreports and court cases over recent years. Although the vast majority of them discharge their duties well, police surgeonshave been implicated in several high profile cases of injustice in the British courts. Carole Richardson, one of the “Guildford four,” was convicted of an IRA bombing substantially on the basis of a statement made after having been given a sedative for drug withdrawal.2 Enghin Raghip's admissions of involvement in the murder of …
758. Towards Gene Knock out Therapy for AIDS/HIV: Targeted Disruption of CCR5 Using Engineered Zinc Finger Protein Nucleases (ZFNs)
Authors: Elena Perez, Yann Jouvenot, Jeffrey C. Miller, Olga Liu, Jianbin Wang, Dmitry Guschin, Victor Bartsevich, Kenneth Kim, Ya-Li Lee, Edward J. Rebar, Dale Ando, Philip D. Gregory, James Riley, Michael C. Holmes, Carl June
Journal: Molecular Therapy (2006)

HIV entry into target cells requires binding of the envelope protein GP120 to the CD4 co-receptors CCR5 or CXCR4. Loss of these HIV co-receptors is therefore attractive as a potential therapy for HIV patients, yet no current methods permit the efficient therapeutic disruption of a chosen gene in the human genome. To this end, we have developed designed zinc-finger protein nucleases (ZFNs) to target predetermined sequences within the CCR5 gene. Once these ZFNs create a double strand break (DSB) in the targeted DNA, natural DNA repair pathways, including Non-Homologous End Joining (NHEJ), subsequently repair the DSB. Importantly, however, NHEJ is error prone and thus can result in permanent disruption of the targeted gene. Designed ZFNs that recognize coding sequences within the CCR5 gene were generated and their DNA-binding and cleavage properties were determined in vitro. Vectors encoding the validated ZFNs were introduced into human cells for in vivo assessment of function. ZFNs targeted to the CCR5 co-receptor efficiently cleaved their expected DNA target sites, leading to high efficiency target gene disruption (>5%) in transiently transfected cells even in the absence of selective pressure. These results have been confirmed in relevant primary cell types (monocytes, CD4+ T cells, CD34+ hematopoietic precursors). We also demonstrated that PM-1 and GHOST cells modified by the CCR5-ZFNs became resistant to HIV infection. Challenge assays using T cells pre-treated with these ZFNs are in progress, although it is well established that a patients cells carrying a deletion within the CCR5 gene are resistant to infection despite repeated exposure to R5-tropic virus. Moreover, the frequency of gene disruption observed supports its examination as a possible method for the therapeutic modification of isolated patient cells to generate HIV resistant T cells or hematopoietic precursors. Full-time employee of Sangamo BioSciences.
Assessment of coronary artery disease severity by positron emission tomography. Comparison with quantitative arteriography in 193 patients.
Authors: L L Demer, K L Gould, R A Goldstein, R L Kirkeeide, N A Mullani, R W Smalling, A Nishikawa, M E Merhige
Journal: Circulation (1989)

To assess the accuracy of positron emission tomography (PET) for evaluation of coronary artery disease (CAD), cardiac PET perfusion images were obtained at rest and with dipyridamole-handgrip stress in 193 patients undergoing coronary arteriography. PET images were reviewed by two independent readers blinded to clinical data. Subjective defect severity scores were assigned to each myocardial region on a 0 (normal) to 5 (severe) scale. Results were compared with arteriographic stenosis severity expressed as stenosis flow reserve (SFR), with continuous values ranging from 0 (total occlusion) to 5 (normal), calculated from quantitative arteriographic dimensions using automated detection of the vessel borders. There were 115 patients with significant CAD (SFR less than 3), 37 patients with mild CAD (3 less than or equal to SFR less than 4), and 41 patients with essentially normal coronaries (SFR greater than or equal to 4). With increasingly severe impairment of stenosis flow reserve, subjective PET defect severity increased. Despite wide scatter, a PET score of 2 or more was highly predictive of significant flow reserve impairment (SFR less than 3). For each patient, the score of the most severe PET defect correlated with the SFR of that patient's most severe stenosis (rs = 0.77 +/- 0.06). For each of 243 stenoses, PET defect score correlated with the SFR of the corresponding artery (rs = 0.63 +/- 0.08). PET defect location closely matched the region supplied by the diseased artery, and readers agreed whether the most severe PET defect was less than or more than 2 for 89% of patients.
Meeting the needs of elderly people in China
Authors: Tuohong Zhang, Yude Chen
Journal: BMJ (2006)

Like its neighbours Thailand and South Korea,1-3 China is facing the challenge of a rapidly ageing population. The proportion of people aged over 65 reached 6.9% in 2000 and is predicted to be as high as 22.7% in 2050.4 Although the Chinese population is currently younger than the UK population (which in 2002 had 16% of people over 65),5 the proportion of older people is growing faster than in the UK. People over 60 currently make up 10.9% of the population in China, projected to rise to 31.0% in 2050, compared with 21.2% rising to 29.4% in the United Kingdom.6
Stratification of pediatric ALL by in vitro cellular responses to DNA double-strand breaks provides insight into the molecular mechanisms underlying clinical response
Authors: Eliot Marston, Victoria Weston, Jennifer Jesson, Esther Maina, Carmel McConville, Angelo Agathanggelou, Anna Skowronska, Katie Mapp, Katrin Sameith, Judith E. Powell, Sarah Lawson, Pamela Kearns, Francesco Falciani, Malcolm Taylor, Tatjana Stankovic
Journal: Blood (2008)
Deubiquitination of type 2 iodothyronine deiodinase by von Hippel–Lindau protein–interacting deubiquitinating enzymes regulates thyroid hormone activation
Authors: Cyntia Curcio-Morelli, Ann Marie Zavacki, Marcelo Christofollete, Balazs Gereben, Beatriz C.G. de Freitas, John W. Harney, Zaibo Li, Guan Wu, Antonio C. Bianco
Journal: Journal of Clinical Investigation (2003)

The type 2 iodothyronine deiodinase (D2) is an integral membrane ER-resident selenoenzyme that activates the pro-hormone thyroxine (T4) and supplies most of the 3,5,3′-triiodothyronine (T3) that is essential for brain development. D2 is inactivated by selective conjugation to ubiquitin, a process accelerated by T4 catalysis and essential for the maintenance of T3 homeostasis. A yeast two-hybrid screen of a human-brain library with D2 as bait identified von Hippel–Lindau protein–interacting deubiquitinating enzyme-1 (VDU1). D2 interaction with VDU1 and VDU2, a closely related deubiquitinase, was confirmed in mammalian cells. Both VDU proteins colocalize with D2 in the ER, and their coexpression prolongs D2 half-life and activity by D2 deubiquitination. VDU1, but not VDU2, is markedly increased in brown adipocytes by norepinephrine or cold exposure, further amplifying the increase in D2 activity that results from catecholamine-stimulated de novo synthesis. Thus, deubiquitination regulates the supply of active thyroid hormone to brown adipocytes and other D2-expressing cells.
A clinical assessment of a patch test kit marketed to U.K. hairdressers for detecting hair dye allergy
Authors: D.I. Orton
Journal: British Journal of Dermatology (2007)

In 2004 a U.K.-based company developed and marketed a patch test kit (Colourstart); Trichocare, Ridgmont, Beds, U.K.) for use by hairdressers. It is intended to assess whether clients have a 'problem with hair dye' and promotes itself as the 'only practical solution to sensitivity testing'. However, a patient presented with a hair dye reaction that had not been detected while using this patch test system.To assess the Colourstart system in the next seven consecutive patients presenting with a history of adverse reactions to hair dyes.The Colourstart system was tested in parallel with commercially available hair dye patch test reagents, where applicable.Only three of seven patients allergic to p-phenylenediamine were detected using this system and one patient allergic to toluene-2,5-diamine sulphate was not detected using this system.The results raise concerns about the sensitivity of this kit for consumer protection, but also wider questions about the regulation, use and interpretation of 'home diagnostic patch test kits' in general.
Risk Factors for Underimmunization in Poor Urban Infants
Authors: Ann S. Bates
Journal: JAMA (1994)

<h3>Objective.</h3> —To assess risk factors for underimmunization in poor urban infants. <h3>Design.</h3> —Prospective cohort study. <h3>Setting.</h3> —A large municipal teaching hospital in the Midwest. <h3>Participants.</h3> —A total of 464 healthy, full-term newborn infants delivered at a large municipal teaching hospital who were to be discharged to the care of their mothers. Mothers were interviewed 24 to 72 hours post partum regarding personal and financial characteristics and 9 to 12 months later to determine where immunizations had been received. <h3>Main Outcome Measures.</h3> —Immunization status at 3 and 7 months of age. <h3>Results.</h3> —Despite availability of free vaccine to most patients, only 67% had received their first set of immunizations by 3 months of age, and only 29% were up-to-date by 7 months of age. Marital status, coresidence with the infant's grandmother, adequacy of prenatal care, and perceived barriers to care were significant independent predictors of initiation of immunizations by 3 months and completion of immunization by 7 months. Poverty was also an independent predictor of immunization status at 7 months. Perceived susceptibility to common symptoms and perceived benefit of medical care to prevent disease were inversely related to immunization status at 7 months. <h3>Conclusions.</h3> — These data suggest that poor urban infants of single mothers and of mothers who received inadequate prenatal care, and those not living with their grandmother should be targeted for tracking and follow-up to ensure adequate immunization. The provision of free vaccine alone will not guarantee adequate immunization coverage of poor urban children. (<i>JAMA</i>. 1994;272:1105-1110)
Methysergide as a Treatment for Mania
Authors: MICHAEL S. McCABE, THEODORE REICH, GEORGE WINOKUR
Journal: American Journal of Psychiatry (1970)

Reports of dramatically successful treatment of acute mania with methysergide led the authors to undertake a small study. Twelve patients with acute mania were treated with doses of methysergide that had been reported to be effective. Only one patient recovered; all the others required further therapy. Possible reasons for the failure of methysergide to terminate the manic episode are discussed.
Cardiac imaging using a phased array ultrasound system. II. Clinical technique and application.
Authors: J Kisslo, O T vonRamm, F L Thurstone
Journal: Circulation (1976)

A new two-dimensional ultrasound imaging system capable of producing high resolution tomographic images of the heart in real time has been developed. This system relies on phased array principles to rapidly steer the ultrasound beam through the structures under investigation. A hand-held linear array of 16 ultrasound transducers with overall dimensions of 14 mm at the site of contanct may be readily manipulated to image various cardiac structures. The resulting images are displayed in a circular sector format, 60 degrees in azimuth and typically 15 cm in range. At his maximum range, image frames consisting of 256 lines are generated at the rate of 20 frames/second. High azimuthal resolution throughout the field of view is assured by a focused transmit beam and by sweeping the focus of the receiver is synchrony with the range of returning echoes. Azimuthal resolution varies from 2 to 5 mm throughout the field of view while range resolution is 1.5 mm. This imaging system has proven particularly useful for the delineation of left ventricular spatial geometry by the identification of endocardium, myocardium, papillary muscles and interventricular septum. High quality images of anterior and posterior mitral leaflets, aortic root and aortic leaflets as well as left atrium and other cardiac structures have been obtained.
Arthrographic joint distension with saline and steroid improves function and reduces pain in patients with painful stiff shoulder: results of a randomised, double blind, placebo controlled trial
Authors: R Buchbinder
Journal: Annals of the Rheumatic Diseases (2004)

<b>Objective:</b> To determine whether arthrographic distension with a mixture of saline and steroid, in patients with painful stiff shoulder for at least 3 months, is better than placebo in improving function, pain, and range of motion at 3, 6, and 12 weeks. <b>Methods:</b> A randomised, placebo controlled trial with participant and outcome assessor blinding in which shoulder joint distension with normal saline and corticosteroid was compared with placebo (arthrogram). Outcome measures, assessed at 3, 6, and 12 weeks, included a shoulder-specific disability measure (SPADI), a patient preference measure (Problem Elicitation Technique (PET)), pain, and range of active motion. <b>Results:</b> From 96 potential participants, 48 were recruited. Four withdrew from the placebo group after the 3 week assessment and three subsequently received arthrographic distension with saline and steroid. At 3 weeks, significantly greater improvement in SPADI (p = 0.005), PET, overall pain, active total shoulder abduction, and hand behind back was found in participants in the joint distension and steroid group than in the placebo group. At 6 weeks the results of the intention to treat analysis favoured joint distension, although the between-group differences were only significant for improvement in PET (difference in mean change in PET between groups = 45.9 (95% CI 3.2 to 88.7). Excluding the four withdrawals, the between-group differences for the disability and pain measures significantly favoured distension over placebo. At 12 weeks, both the intention to treat analysis and an analysis excluding the four withdrawals demonstrated a significantly greater improvement in PET score for the distension group. <b>Conclusions:</b> Short term efficacy of arthrographic distension with normal saline and corticosteroid over placebo was demonstrated in patients with painful stiff shoulder.
Loss of endothelium-dependent relaxant activity in the pulmonary circulation of rats exposed to chronic hypoxia.
Authors: S Adnot, B Raffestin, S Eddahibi, P Braquet, P E Chabrier
Journal: Journal of Clinical Investigation (1991)

To determine whether exposure to chronic hypoxia and subsequent development of pulmonary hypertension induces alterations of endothelium-dependent relaxation in rat pulmonary vascular bed, we studied isolated lung preparations from rats exposed to either room air (controls) or hypoxia (H) during 1 wk (1W-H), 3 wk (3W-H), or 3W-H followed by 48 h recovery to room air (3WH + R). In lungs pretreated with meclofenamate (3 microM), the endothelium-dependent vasodilator responses to acetylcholine (10(-9)-10(-6) M) and ionophore A23187 (10(-9)-10(-7) M) were examined during conditions of increased tone by U46619 (50 pmol/min). Acetylcholine or A23187 produced dose-dependent vasodilation in control lungs, this response was reduced in group 1W-H (P less than 0.02), abolished in group 3W-H (P less than 0.001), and restored in group 3WH + R. In contrast, the endothelium-independent vasodilator agent sodium nitroprusside remained fully active in group 3W-H. The pressor response to 300 pM endothelin was greater in group 3W-H than in controls (6.8 +/- 0.5 mmHg vs. 1.6 +/- 0.2 mmHg, P less than 0.001) but was not potentiated by the endothelium-dependent relaxing factor (EDRF) antagonists: hydroquinone (10(-4) M); methylene blue (10(-4) M); and pyrogallol (3 x 10(-5) M) as it was in controls. It was similar to controls in group 3W-H + R. Our results demonstrate that hypoxia-induced pulmonary hypertension is associated with a loss of EDRF activity in pulmonary vessels, with a rapid recovery on return to a normoxic environment.
Recurrence of tracheo-oesophageal fistula 32 years after primary repair.
Authors: M Ashour
Journal: Thorax (1986)

Recurrence of congenital tracheo-oesophageal fistula after repair is not unusual, occurring in about 10% of cases.' -3Most observers agree that symptoms probably related directly to the size of the fistula.Large fistulae produce more symptoms and are diagnosed earlier, while small fistulae may cause little trouble and are difficult to detect.4Recur- rent fistulae have been diagnosed from seven days to nine years after repair, but more than half are apparent within two months.3The purpose of this paper is to describe a case
AIDS and Testing for AIDS
Authors: David E. Dassey
Journal: JAMA (1986)

<h3>To the Editor.—</h3> The otherwise excellent update on human T-cell lymphotropic virus type III (HTLV-III) antibody testing<sup>1</sup>contains a statement that I believe needs correcting. It states that practitioners may receive referrals of antibody-positive persons for "medical counseling on a fatal and incurable disease... that has an incubation period of up to five years." Acquired immunodeficiency syndrome (AIDS) is not a disease; it is a syndrome whose criteria were strictly chosen for epidemiologic purposes. By definition, then, AIDS encompasses the fatal form of HTLV-III disease. Evidence mounts that those with irreversible disease due to HTLV-III represent only a small fraction of all those infected. The term "incubation" should not be used in regard to development of the terminal form of this viral infection; if anything, "incubation" should refer to the period between exposure and the development of biochemical or clinical objective findings. Used in this way, the incubation of