tbuckley/cabot-search huggingface dataset:
327. Muscle Specific and Efficient Transgene Expression Using the Fast and Slow Troponin I Promoters in Cell Culture
Authors: Marilyne Blain, Angela Kumar, Kenneth E. Hastings, George Karpati, Bernard Massie, Renald Gilbert
Journal: Molecular Therapy (2006)

Gene replacement therapy for muscular diseases, such as Duchenne muscular dystrophy, using viral vectors requires strong promoters with the ability to confer muscle specific expression of the therapeutic gene product. Because skeletal muscle consists of a mixture of slow and fast muscle fibers, an ideal promoter for such application should direct efficient expression in both muscle fiber types. The genetic elements regulating expression of the fast and slow isoforms of troponin I (TnI), an abundant muscle protein, are relatively well characterized. Theoretically, a combination of vectors expressing transgenes regulated by TnIfast and TnIslow enhancers/promoters could be used to deliver strong and muscle specific transgene expression in every skeletal muscle fiber of the body. To evaluate the usefulness of the TnIfast and TnIslow enhancers/promoters for gene therapy, we have compared their strengths with the cytomegalovirus (CMV) and with the short (1.3-kb) murine muscle creatine kinase (MCK) promoters in cell culture. Plasmids expressing β-galactosidase (β-gal) regulated by MCK, CMV or TnIfast/TnIslow enhancers/promoters were constructed. The TnIfast construct includes the minimal promoter (200-bp) of the quail TnIfast gene linked to three copies (150-bp each) of that gene's first-intron enhancer element (IRE). The TnIslow construct includes the minimal promoter (100-bp) of the human TnIslow gene linked to that gene's upstream enhancer element of 160-bp (USE). Except for MCK, a small intron (100-bp) derived from SV40 was inserted between the promoter and β-bal. 293A cells and C2C12 myoblasts were transfected with the different constructs and β-gal expression was compared 48 hrs later. Analyses were also performed in culture of C2C12 myotubes 10 days after serum withdrawal. In 293 cells, MCK-, TnIfast-, and TnIslow-driven expression was at least 1300 folds weaker than CMV. In non-differentiated myoblasts, TnIslow-driven expression was 3.5 and 15 times better than TnIfast- and MCK-driven expression, respectively. Both TnIfast and TnIslow enhancers/promoters provided high-level β- gal expression in myotubes (35-40 % of CMV, and at least 10 times stronger than MCK). Our data confirmed the excellent muscle specificity and strength of TnIfast and TnIslow enhancer/promoter elements. Their relative small size makes them very attractive for usage in vectors with limited insert capacity such as AAV. These excellent properties warrant further in vivo gene transfer studies using viral vectors.
Freud and the Imaginative World
Authors: Jonathan M. Raines
Journal: JAMA (1986)

As the author notes in his preface, "This book is about Freud's link with the humanities. It rests on the assumptions that psychoanalysis is the product of a humanist tradition and that Freud's work extends and illuminates that tradition." In<i>Freud and the Imaginative World</i>, Harry Trosman, MD, a faculty member and training and supervising analyst at the Chicago Institute for Psychoanalysis and Professor of Psychiatry at the University of Chicago, explores the origins of psychoanalysis with respect to its relationship to creativity and the development of psychoanalytic views of the creative process. The book is divided into two major sections. In Part 1, "The Claims of Humanism—Influence and Identity," Trosman reviews the milieu in which Freud lived and worked. Particular attention is given to the political, artistic, and scientific zeitgeist of the "formative culture"—its impact on and response to Freud the individual/artist/scientist. Part 2, "Psychoanalysis and the Arts," which
Volumetric Intravascular Ultrasound Analysis of Paclitaxel-Eluting and Bare Metal Stents in Acute Myocardial Infarction
Authors: Akiko Maehara, Gary S. Mintz, Alexandra J. Lansky, Bernhard Witzenbichler, Giulio Guagliumi, Bruce Brodie, Mirle A. Kellett, Helen Parise, Roxana Mehran, Gregg W. Stone
Journal: Circulation (2009)

Vascular responses to drug-eluting stents in ST-segment elevation myocardial infarction are unknown. In the prospective, multicenter Harmonizing Outcomes With Revascularization and Stents in Acute Myocardial Infarction (HORIZONS-AMI) trial, patients with ST-segment elevation myocardial infarction within 12 hours of symptom onset were randomized 3:1 to TAXUS EXPRESS paclitaxel-eluting stents (PES) or EXPRESS bare metal stents (BMS).A formal intravascular ultrasound substudy enrolled 464 patients with baseline and 13-month follow-up imaging at 36 centers. Overall, 446 lesions in 402 patients were suitable for standard qualitative and quantitative analyses, which were performed at an independent blinded core laboratory. The primary prespecified end point was the in-stent percent net volume obstruction at follow-up. Median stent length measured 23.4 mm (first and third quartiles, 18.5 and 31.9 mm). PES compared with BMS significantly reduced 13-month percent net volume obstruction (6.5% [first and third quartiles, 2.2% and 10.8%] versus 15.6% [first and third quartiles, 7.2% and 28.8%]; P<0.0001). PES compared with BMS also resulted in more late-acquired stent malapposition (29.6% versus 7.9%; P=0.0005) resulting from positive vessel remodeling. Plaque and/or thrombus protrusion through stent struts was initially present in 70.4% of PES and 64.8% of BMS; all resolved during follow-up. New aneurysm formation, stent fracture, and subclinical thrombus were uncommon, although seen only in PES.PES compared with BMS significantly reduce neointimal hyperplasia in patients with ST-segment elevation myocardial infarction but also result in a high frequency of late-acquired stent malapposition as a result of positive vessel remodeling. Ongoing long-term follow-up is required to establish the clinical significance of these findings. Clinical Trial Registration- URL: http://www.clinicaltrials.gov. Unique identifier: NCT00433966.
BRONCHIECTASIS IN CHILDHOOD
Authors: SIDNEY DIAMOND
Journal: JAMA (1942)

Bronchiectasis was first described as a disease entity by Laënnec in 1819. For nearly a century, however, positive recognition of the condition was possible only at the autopsy table; its antemortem diagnosis was purely an inferential one. When Chevalier Jackson,<sup>1</sup>in 1918, demonstrated that the bronchial caliber in the living patient could be determined roentgenographically by the use of insufflated bismuth powder as a contrast medium, a new era in diagnosis was ushered in. In 1922 another radiopaque substance became available for bronchography with the introduction of iodized oil by Sicard and Forestier.<sup>2</sup>Widespread application of contrast roentgenography during the years that followed resulted in a considerable advance in the understanding of the salient points of bronchiectasis. While several features of the lesion continue to form the basis for controversial opinions among clinicians and pathologists, the progressive increase in knowledge has made two facts clearly evident. One is
258 ROSUVASTATIN COUNTERACTS VESSEL ARTERIALISATION, SINUSOID CAPILLARISATION, REDUCES TUMOR GROWTH AND PROLONGS SURVIVAL IN MURINE HEPATOCELLULAR CARCINOMA
Authors: A. Tijeras-Raballand, P. Hainaud, J.-O. Contreres, C. Gest, C. Le Hènaff, B.I. Levy, M. Pocard, C. Soria, E. Dupuy
Journal: Journal of Hepatology (2011)
Circulating Cardiac Troponin T in Potential Heart Transplant Donors
Authors: Bruno Riou, Sophie Dreux, Sabine Roche, Martine Arthaud, Jean-Pierre Goarin, Philippe Léger, Michel Saada, Pierre Viars
Journal: Circulation (1995)

Brain death may induce myocardial dysfunction, the mechanisms of which are not yet fully understood. Circulating cardiac troponin T is considered a highly sensitive and specific marker of myocardial cell injury.We prospectively measured circulating cardiac troponin T in 100 brain-dead patients and measured the left ventricular ejection fraction area (LVEFa), using transesophageal echocardiography. Sixty-one patients had normal LVEFa, 25 had moderate decrease in LVEFa (30% to 50%), and 14 had severe decrease in LVEFa (< or = 30%). Circulating cardiac troponin T concentrations were significantly higher (1.68 +/- 1.03 micrograms/L-1, P < .01) in patients with a severe decrease in LVEFa than in the two other groups (0.42 +/- 0.43 and 0.12 +/- 0.16 microgram/L-1, respectively), and there was a significant correlation between LVEFa and cardiac troponin T concentration (p = -0.59, P < .0001). An elevated circulating cardiac troponin T concentration (> or = 0.5 microgram/L-1) was more accurate (sensitivity, 1.00; specificity, 0.84) in predicting a severe decrease in LVEFa than an elevated CKMB value or an increased CKMB/CK ratio.An elevated circulating cardiac troponin T was associated with a severe decrease in LVEFa in brain-dead patients, suggesting that severe and potentially irreversible myocardial cell damage occurred. In contrast, CKMB determination was not useful. Since the quality of the donor's heart is considered an important prognosis factor in heart transplantation, the determination of circulating cardiac troponin T concentration could be useful to the heart transplantation team.
Long term benefits need to be taken into account when evaluating family support projects
Authors: C. Goodhart
Journal: BMJ (2000)

EDITOR—Many voluntary sector initiatives offer community support, but we are aware that not all those who need help are ready to receive it. The Amalthea Project, discussed by Grant et al, was developed to bridge this gap by facilitating access to the voluntary sector from primary care.1 Grant et al's evaluation of this project makes a real contribution, measuring both the benefit to patients with psychosocial problems and the costs of such projects.

Grant et al confirmed that using referrals facilitators results in both clinical …
Organ specific cytokine therapy. Local activation of mononuclear phagocytes by delivery of an aerosol of recombinant interferon-gamma to the human lung.
Authors: H A Jaffe, R Buhl, A Mastrangeli, K J Holroyd, C Saltini, D Czerski, H S Jaffe, S Kramer, S Sherwin, R G Crystal
Journal: Journal of Clinical Investigation (1991)

In the context of the central role of the alveolar macrophage in host defense of the respiratory epithelial surface, and the ability of IFN-gamma to activate mononuclear phagocytes, we have evaluated strategies to use rIFN-gamma to activate human alveolar macrophages in vivo. To accomplish this, rIFN-gamma was administered to nonsmoking normals, the amounts of IFN-gamma quantified in serum and respiratory epithelial lining fluid (ELF) and the status of IFN-gamma related activation of blood monocytes and alveolar macrophages was evaluated by quantifying the expression of mRNA transcripts of IP-10, a gene induced specifically by IFN-gamma. Systemic administration (subcutaneous) of maximally tolerated amounts of rIFN-gamma (250 micrograms) was followed by detectable levels of IFN-gamma in serum but not ELF, the expression of IP-10 transcripts in blood monocytes but not alveolar macrophages, and multiple systemic adverse effects. To circumvent the inability of systemic administration to reach respiratory ELF and activate alveolar macrophages, rIFN-gamma (250-1,000 micrograms) was inhaled as an aerosol once daily for 3 d. Strikingly, while IFN-gamma was not detected in serum it was detectable in respiratory ELF in a dose-dependent fashion. Further, alveolar macrophages, but not blood monocytes, expressed IP-10 mRNA transcripts and, importantly, inhalation of aerosolized rIFN-gamma was not associated with local or systemic adverse effects. Thus, it is feasible to use rIFN-gamma to activate alveolar macrophages by targeting the cytokine directly to the lung. These data suggest a potential strategy for targeted cytokine therapy, without systemic side effects, to augment respiratory tract defenses in individuals at risk for or with lung infection.
P117 Ambulatory and Inpatient Pleural Service – The Way Forward
Authors: P Sura, E Hyde, E Afify, B Coker
Journal: Thorax (2012)

Between January 2005 and March 2008, 12 deaths and 15 cases of severe harm relating to chest drain insertion were reported leading to NSPA alert. Live ultrasound-guidance for pleural interventions is now recommended (BTS Guidelines, 2010) and ultrasound marking (X-spot) is no longer acceptable. At our DGH, a new pleural service has been established to provide a high quality, patient-centered and streamlined service for patients with pleural effusions, performing therapeutic and diagnostic procedures under live ultrasound guidance. It has been designed to improve patient safety, reduce length of stay and offer training opportunities to trainees. A respiratory consultant, trained to level two in thoracic ultrasound, established the pleural service in May 2011. A dedicated side room was equipped with an ultrasound machine and a trolley filled with the necessary equipment for pleural procedures. Pleural service protocol has been developed and approved by the Acute Medicine and the Respiratory departments. Referrals are accepted from inpatient wards, Emergency department and outpatient clinics. The "Inpatient Pleural Service" provides diagnostic/therapeutic pleural procedures 5 days a week within working hours, while a "Ambulatory Pleural Service" is designed to treat patients in an ambulatory setting within 72 hours of referral. Between 01/05/2011 and 31/04/2012, 83 thoracic ultrasound scans were carried out and 72 ultrasound-guided interventions were performed (26 Seldinger chest drains, 2 PleurX catheters and 44 pleural aspirations). There were only 3 complications reported (2 small pneumothoraces, 1 vasovagal syncope). Patient feedback was excellent with patients particularly appreciating undergoing pleural procedures as a day case. Inpatient length of stay has reduced from 6 days (median) to 1 day (median). The number of thoracic ultrasounds performed by radiology department decreased significantly from 123 to 84, despite an 11% increase in Emergency department attendances related to closure of a nearby hospital. The collected data proves that the pleural service increased patient safety, reduced patient waiting times, reduced length of stay, helped avoid admissions, decreased radiology workload and made financial savings.
Abstract 3293: Activity and safety of an antiangiogenic peptide in spontaneous head and neck squamous cell carcinoma in cats
Authors: Elizabeth A. McNiel, Nicole J. Madrill, Jose O. Esteves-Villanueva, Pedro A. Dominguez, Ruud Dings, Kevin H. Mayo, Robert J. Griffin
Journal: Cancer Research (2011)

Abstract Anginex is a rationally designed, synthetic peptide that inhibits proliferation of human and mouse endothelial cells and demonstrates anti-tumor activity in murine tumor models. The anti-tumor and anti-angiogenic activity of Anginex is attributable, at least in part, to its interaction with galectin-1, a carbohydrate binding protein. As an intermediate step in the clinical translation of Anginex and related anti-vascular agents, we are investigating the effects of Anginex in spontaneous feline head and neck squamous cell carcinoma (HNSCC). Feline HNSCC shares morphology, clinical behavior, and biologic features such as intratumoral hypoxia and expression of EGFR, COX-2, and mutant p53 with its human counterpart. Our objectives were to investigate the activity of Anginex in feline cells and provide evidence of its safety in a phase I trial in cats with HNSCC. To establish Anginex activity in vitro, we evaluated the effect of 24 hour exposure to Anginex doses ranging from 2.5 – 25 uM on proliferation of both feline aortic endothelial cells (FAECs) and feline HNSCC cells (SCCF1) using flow cytometry and labeling with propidium iodide and bromodeoxyuridine (BrdU). With increasing Anginex dose, we observed accumulation of FAECs in G1 and decreased uptake of BrdU. We observed no effect in SCCF1 cells. To investigate safety, cats were treated with Anginex in cohorts of at least three animals at doses of 1, 3, and 9 mg/kg daily for 5 days. Clinical, laboratory and histologic features were evaluated before and after treatment. There were no serious adverse events during treatment. Continuous variables including body weight and laboratory variables were compared before and after treatment using a Wilcoxon signed rank test. No statistically significant changes occurred in these parameters. These data indicate that Aniginex is active against feline endothelial cells specifically and appears to be safe in cats. We are currently investigating the effects of Anginex on tumor physiology and in combination with radiation therapy for feline HNSCC. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 3293. doi:10.1158/1538-7445.AM2011-3293
The level of residual disease based on mutant NPM1 is an independent prognostic factor for relapse and survival in AML
Authors: Nona Shayegi, Michael Kramer, Martin Bornhäuser, Markus Schaich, Johannes Schetelig, Uwe Platzbecker, Christoph Röllig, Caroline Heiderich, Olfert Landt, Gerhard Ehninger, Christian Thiede
Journal: Blood (2013)
Measuring health outcomes
Authors: J. Cairns
Journal: BMJ (1996)

The authors emphasise the importance of getting the diagnosis right, and few would argue with them.But it is interesting to note that all 17 patients who were found to be conscious were severely disabled; all were severely paralysed and anarthric, most were either blind or severely visually impaired, some were substantially cognitively impaired, and all were presumably dependent on feeding tubes.Reasonable people may differ in their views of the quality of life of these conscious individuals, but I would speculate that most people would find this condition far more horrifying than the vegetative state itself, and some might think it an even stronger reason for stopping treatment than complete unconsciousness.But whether being in the vegetative state is viewed as preferable to being just outside it, and whatever your views on withdrawal of tube feeding in such patients, careful examination of every patient is essential to determine their consciousness and ability to suffer.It would be dreadful indeed to stop treatmnent in patients who were thought to be unconscious but who could in fact experience thirst and hunger when treatment, including artificial nutrition and hydration, was stopped.Equally important is the need to maximise quality of life for those who are capable of communicating.Some may even be able to contribute to decisions about their medical treatment.
Defective neutrophil chemotaxis in bone marrow transplant patients.
Authors: R A Clark, F L Johnson, S J Klebanoff, E D Thomas
Journal: Journal of Clinical Investigation (1976)

Infection is a frequent cause of death in patients receiving bone marrow transplants. Although lymphocyte dysfunction has been observed in a few such patients, no systematic study of neutrophil function has yet been reported. Neutrophil chemotaxis was evaluated by a 51Cr-radioassay after bone marrow transplantation in 34 patients with acute leukemia or aplastic anemia. The response to a chemotactic stimulus (C5a) was severely depressed (less than 35% of normal) in 18 patients, moderately depressed (35-65% of normal) in an additional 6, and normal in 10 subjects. The mean response in the absence of graft vs. host disease and antithymocyte globulin administration was 73.3+/-9.2% (SE) in contrast to 29.7+/-9.6% (P is less than 0.01) in patients with graft vs. host disease treated with antithymocyte golbulin. Both graft vs. host disease and antithymocyte globulin were implicated since the presence of either factor alone was associated with depressed chemotaxis (31.1+/-4.9% for graft vs. host disease, P is less than 0.01; 17.0+/-7.8% for antithymocyte globulin, P is less than 0.02). When normal neutrophils were incubated with antithymocyte globulin in vitro, their chemotactic response was markedly suppressed in the absence of a cytotoxic effect. Transplant patients with defective chemotaxis experienced significantly more infections than those with normal chemotaxis, and analysis of specific etiologic agents showed that this was predominantly related to bacterial pathogens. Chemotactic inhibitors were detected in the sera of seven patients and elevated IgE levels were found in nine subjects, eight of whom had graft vs. host disease. Generation of chemotactic activity by endotoxin activation of serum was reduced in five patients. The results demonstrate a severe defect in neutrophil chemotaxis in some bone marrow transplant patients and suggest that neutrophil dysfunction may predispose to infection in such patients.
Regulation of lymphokine production and human T lymphocyte activation by 1,25-dihydroxyvitamin D3. Specific inhibition at the level of messenger RNA.
Authors: W F Rigby, S Denome, M W Fanger
Journal: Journal of Clinical Investigation (1987)

The steroid hormone, 1 alpha,25-dihydroxyvitamin D3 (calcitriol), has been shown to inhibit T cell proliferation, primarily through inhibition of interleukin 2 (IL-2) production. In these experiments, we show that calcitriol also markedly inhibited production of the lymphokine, gamma interferon (IFN-gamma), by activated human T lymphocytes. Regulation of both IL-2 and IFN-gamma production as well as transferrin receptor (TfR) expression by calcitriol was apparent at the messenger RNA (mRNA) level as determined by Northern blotting. The decrease in IL-2 and IFN-gamma mRNA that occurred with calcitriol treatment was coordinate and not apparent up to 12 h after phytohemagglutinin stimulation, whereas decreased accumulation of TfR mRNA was not present before 24-36 h. Furthermore, the effects of calcitriol on IL-2, IFN-gamma, and TfR mRNA accumulation were specific; actin mRNA accumulation was comparable between control and treated cells. These data indicate that calcitriol regulated proteins associated with T cell activation at the transcriptional level and that these effects were mediated in a specific, coordinate fashion.