tbuckley/cabot-search huggingface dataset:
Further Good News on Stroke, but No Time for Rest
Authors: Jose G. Romano, Peter B. Imrey, Ralph L. Sacco
Journal: Circulation (2011)

P rogressive reduction in stroke deaths over the last few decades has resulted in the recent preliminary announcement that stroke has declined from the third to the fourthleading cause of death in the United States. 1 Moreover, the 2010 American Heart Association goal of reducing coronary heart disease and stroke mortality by 25% in the first decade of this century was achieved early, with a 30.7% reduction in CHD mortality and a 29.2% reduction in stroke mortality from 1999 to 2008.
The Behavioral Economics of Health and Health Care
Authors: Thomas Rice
Journal: Annual Review of Public Health (2013)

People often make decisions in health care that are not in their best interest, ranging from failing to enroll in health insurance to which they are entitled, to engaging in extremely harmful behaviors. Traditional economic theory provides a limited tool kit for improving behavior because it assumes that people make decisions in a rational way, have the mental capacity to deal with huge amounts of information and choice, and have tastes endemic to them and not open to manipulation. Melding economics with psychology, behavioral economics acknowledges that people often do not act rationally in the economic sense. It therefore offers a potentially richer set of tools than provided by traditional economic theory to understand and influence behaviors. Only recently, however, has it been applied to health care. This article provides an overview of behavioral economics, reviews some of its contributions, and shows how it can be used in health care to improve people's decisions and health.
Massive induction of donor-type class I and class II major histocompatibility complex antigens in rejecting cardiac allografts in the rat.
Authors: A D Milton, J W Fabre
Journal: The Journal of Experimental Medicine (1985)

DA (RT1a) hearts were transplanted into PVG (RT1c) or DA recipients, excised on days 1, 3, 5, or 7 after grafting, and examined by immunohistological techniques and quantitative absorption analyses, using allospecific mouse anti-rat class I and class II major histocompatibility complex (MHC) monoclonal antibodies. Cryostat sections stained by the peroxidase technique demonstrated that, in the normal heart, class I antigens were largely restricted to vascular endothelium and interstitial cells, with no observable staining of the myocardial cells except at the intercalated discs. Class II antigens were found only on occasional interstitial dendritic cells. The picture at day 1 after transplantation was not noticeably different. By day 3, however, there was clear patchy induction of both class I and class II antigens on the myocardial cells, usually in the region of cellular infiltrates. By day 5, class I antigens had been strongly induced throughout the graft, with the myocardial cells being very strongly positive. Class II antigens were also uniformly expressed on myocardial cells at day 5, and at this stage the vascular endothelium was also strongly positive. Quantitative absorption analyses showed a 10-fold increase in class I antigen content in cardiac allografts at day 5 after transplantation when compared with normal DA heart. DA heart isografts showed no increase in class II antigens, but it was interesting that, by 5 d after grafting, there appeared to be some expression of class I antigens on the myocardial cells. Quantitative absorptions showed a threefold increase in class I antigens on 5-d isografts when compared with normal DA heart.
The utility of tumour necrosis factor blockade in orphan diseases
Authors: E C Keystone
Journal: Annals of the Rheumatic Diseases (2004)

A variety of rheumatic disorders have been successfully treated with tumour necrosis factor (TNF) blockers. However, TNF blockade may be useful in a number of rare diseases. Preliminary data suggest that several forms of vasculitis appear responsive to TNF antagonists-Behcet's disease, Churg-Strauss vasculitis, polyarteritis nodosa, and giant cell arteritis, among others. Wegener's granulomatosis and sarcoidosis have been shown to improve with infliximab but not with etanercept. These results lend further support for the concept of differential mechanism(s) of action of the two antagonists with infliximab being more effective for the treatment of granulomatous diseases. Polymyositis/dermatomyositis may also be responsive to TNF blockade. TNF likely plays little role in Sjogren's syndrome as evidenced by the lack of efficacy of both TNF antagonists. Etanercept has been shown to be useful in the treatment of hepatitis C both in reducing the viral load and improving liver function. A number of other more rare disorders also may be responsive to TNF blockade. Further studies with larger numbers of well characterised patients and treatment regimens are necessary to provide more definitive evidence of the utility of the TNF antagonists in these serious and often life threatening diseases.
Safety, Pharmacokinetics, and Immunomodulatory Effects of Lenalidomide in Children and Adolescents With Relapsed/Refractory Solid Tumors or Myelodysplastic Syndrome: A Children's Oncology Group Phase I Consortium Report
Authors: Stacey L. Berg, Mitchell S. Cairo, Heidi Russell, Janet Ayello, Ashish Mark Ingle, Henry Lau, Nianhang Chen, Peter C. Adamson, Susan M. Blaney
Journal: Journal of Clinical Oncology (2010)

To determine the maximum-tolerated or recommended phase II dose, dose-limiting toxicities (DLTs), pharmacokinetics (PK), and immunomodulatory effects of lenalidomide in children with recurrent or refractory solid tumors or myelodysplastic syndrome (MDS).Cohorts of children with solid tumors received lenalidomide once daily for 21 days, every 28 days at dose levels of 15 to 70 mg/m(2)/dose. Children with MDS received a fixed dose of 5 mg/m(2)/dose. Specimens for PK and immune modulation were obtained in the first cycle.Forty-nine patients (46 solid tumor, three MDS), median age 16 years (range, 1 to 21 years), were enrolled, and 42 were fully assessable for toxicity. One patient had a cerebrovascular ischemic event of uncertain relationship to lenalidomide. DLTs included hypercalcemia at 15 mg/m(2); hypophosphatemia/hypokalemia, neutropenia, and somnolence at 40 mg/m(2); and urticaria at 55 mg/m(2). At the highest dose level evaluated (70 mg/m(2)), zero of six patients had DLT. A maximum-tolerated dose was not reached. No objective responses were observed. PK studies (n = 29) showed that clearance is faster in children younger than 12 years of age. Immunomodulatory studies (n = 26) showed a significant increase in serum interleukin (IL) -2, IL-15, granulocyte-macrophage colony-stimulating factor, natural killer (NK) cells, NK cytotoxicity, and lymphokine activated killer (LAK) cytoxicity, and a significant decrease in CD4(+)/CD25(+) regulatory T cells.Lenalidomide is well-tolerated at doses up to 70 mg/m(2)/d for 21 days in children with solid tumors. Drug clearance in children younger than 12 years is faster than in adolescents and young adults. Lenalidomide significantly upregulates cellular immunity, including NK and LAK activity.
Methamphetamine-Evoked Depression of GABAB Receptor Signaling in GABA Neurons of the VTA
Authors: Claire L. Padgett, Arnaud L. Lalive, Kelly R. Tan, Miho Terunuma, Michaelanne B. Munoz, Menelas N. Pangalos, José Martínez-Hernández, Masahiko Watanabe, Stephen J. Moss, Rafael Luján, Christian Lüscher, Paul A. Slesinger
Journal: Neuron (2012)
Activation of Telomerase by Human Cytomegalovirus
Authors: K. Straat, C. Liu, A. Rahbar, Q. Zhu, L. Liu, N. Wolmer-Solberg, F. Lou, Z. Liu, J. Shen, J. Jia, S. Kyo, M. Bjorkholm, J. Sjoberg, C. Soderberg-Naucler, D. Xu
Journal: JNCI Journal of the National Cancer Institute (2009)

The mechanism by which human cytomegalovirus (HCMV) stimulates oncogenesis is unclear. Because cellular immortalization and transformation require telomerase activation by expression of the telomerase reverse transcriptase ( hTERT ) gene, we examined the role of HCMV in telomerase activation. Normal human diploid fibroblasts (HDFs) and human malignant glioma (MG) cell lines were infected with HCMV or transfected with expression vectors encoding HCMV immediate early (IE) antigen 72 or 86. hTERT expression and promoter activity and telomerase activity were evaluated using reverse transcription–polymerase chain reaction, a luciferase reporter assay, and a telomeric repeat amplification protocol, respectively. hTERT promoter occupancy by the transcription factor Sp1, IE antigens, and histone deacetylases (HDACs) was assessed by chromatin immunoprecipitation. hTERT and IE protein expression in human primary glioblastoma multiforme (GBM) was determined immunohistochemically. All statistical tests were two-sided. In telomerase and hTERT-negative HDFs, HCMV infection induced constitutive hTERT expression and telomerase activation. The hTERT promoter activity in HDFs and MG cell lines was statistically significantly enhanced by HCMV in a dose-dependent manner (mean luciferase activity [arbitrary units] in control HDFs and in HDFs infected with HCMV at multiplicities of infection [MOIs] of 0.1 = 6 and 521, respectively, difference = 515, 95% CI = 178 to 850; mean activity at MOI of 1 and 10 = 8828 and 59 923, respectively; P < .001 comparing control with HCMV-infected cells at all MOIs). Ectopic expression of HCMV IE-72 protein also stimulated hTERT promoter activity in HDFs. HCMV-mediated transactivation of the hTERT gene was dependent on the presence of Sp1-binding sites in the hTERT promoter and was accompanied by increases in Sp1 binding, acetylation of histone H3, and a reduction in HDAC binding at the core promoter. In specimens of GBM, HCMV IE and hTERT proteins were colocalized in malignant cells and their levels paralleled each other. HCMV activates telomerase in both HDFs and malignant cells. These findings begin to reveal a novel mechanism by which HCMV infection may be linked to or modulate oncogenesis through telomerase activation.
Vitamin A Metabolism in Rod and Cone Visual Cycles
Authors: John C. Saari
Journal: Annual Review of Nutrition (2012)

The chromophore of all known visual pigments consists of 11-cis-retinal (derived from either vitamin A1 or A2) or a hydroxylated derivative, bound to a protein (opsin) via a Schiff base. Absorption of a photon results in photoisomerization of the chromophore to all-trans-retinal and conversion of the visual pigment to the signaling form. Regeneration of the 11-cis-retinal occurs in an adjacent tissue and involves several enzymes, several water-soluble retinoid-binding proteins, and intra- and intercellular diffusional processes. Rod photoreceptor cells depend completely on the output of 11-cis-retinal from adjacent retinal pigment epithelial (RPE) cells. Cone photoreceptors cells can use 11-cis-retinal from the RPE and from a second more poorly characterized cycle, which appears to involve adjacent Müller (glial) cells. Recent progress in the characterization of rod and cone visual cycle components and reactions will result in the development of approaches to the amelioration of blinding eye diseases associated with visual cycle defects.
Abstract 2885: Therapeutic microparticle-based tumor lysate vaccination reduces spontaneous lung metastases in a murine breast cancer model
Authors: Brett P. Gross, Amaraporn Wongrapanich, Meghan Francis, Vijaya B. Joshi, Aliasger K. Salem, Lyse A. Norian
Journal: Cancer Research (2014)

Abstract Although existing interventions are highly efficacious for the treatment of localized breast cancers, disseminated tumors remain incurable. Therapeutic induction of systemic anti-tumor immunity is a promising approach for treating metastatic disease. We have developed a novel heterologous prime/boost vaccination protocol that significantly reduces metastatic tumor burdens in a pre-clinical murine model of breast cancer. In our studies, mice were orthotopically challenged with Luciferase-expressing 4T1 adenocarinoma cells. Six days later, mice received a priming therapy that consisted of parental 4T1 tumor lysates encapsulated in poly(lactic-co-glycolic) acid microparticles administered contralateral to the established tumor. On day eleven, mice received a boost therapy that consisted of 4T1 lysates and a cocktail of Toll-like receptor agonists. At the conclusion of the assay (day twenty-five), tumor burdens from excised lungs were quantified using bioluminescent imaging. Therapy-receiving mice showed a significant reduction in lung tumors (Student's T-test: p = 0.002, n = 37 control mice vs. 25 treated mice) with an average 46.66% decrease relative to no therapy control mice. Independent quantification of lung metastases was also performed using a standard 6-thioguanine assay. There was a strong correlation (R^2 = 0.8803) between bioluminescent intensity and 6-thioguanine colony number, demonstrating that the decrease in bioluminescence signal due to therapy is not merely explained by the in vivo loss of Luciferase expression by 4T1 cells. We are currently characterizing the vaccination-induced differences in the localized immune environment of metastatic lung tumors. Effector T cell activation/exhaustion kinetics and the influx of immunosuppressive cell populations (myeloid-derived suppressor cells and regulatory T cells) are now being explored. These studies will help elucidate the immunological mechanism(s) responsible for the diminished metastatic tumor outgrowth observed with our therapy. In conclusion, our data demonstrate that therapeutic vaccination of tumor lysates is efficacious in controlling spontaneous lung metastases in an aggressive model of murine breast cancer. Citation Format: Brett P. Gross, Amaraporn Wongrapanich, Meghan Francis, Vijaya B. Joshi, Aliasger K. Salem, Lyse A. Norian. Therapeutic microparticle-based tumor lysate vaccination reduces spontaneous lung metastases in a murine breast cancer model. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 2885. doi:10.1158/1538-7445.AM2014-2885
Use of partition tree to identify genetic marker combination predicting bronchodilator response by inhaled short-acting beta 2 agonist
Authors: Sung-Yoon Kang, Tae-Wan Kim, Jae-Woo Jung, Woo-Jung Song, Min-Hye Kim, Hye-Ryun Kang, Sang-Heon Cho, Kyung-Up Min, Heung-Woo Park
Journal: European Respiratory Journal (2011)

Objective:  To identify genetic marker to predict bronchodilator response by inhaled short-acting β2 agonist after methacholine-induced bronchoconstriction.   Methods:  A total of 480 patients were enrolled, who showed ≥20% decrease of FEV1 in methacholine bronchial provocation test and subsequently inhaled 2 puffs of salbutamol (200 mcg), then FEV1 was re-measured 10 minutes later. Twenty SNPs in 10 genes related with airway inflammation, structural changes, or smooth muscle function was scored by high throughput technique. They were TNFα (-308G>A), IL13 (-1111C>T,-1510A>C,431G>A), IL4RA (-3223T>C, 223G>A,1727A>G), VEGFR1 (-2021G>A, -59C>T, 3204T>A), VEGFR2 (889G>A, 1416A>T), TGFβR3 (44T>C, 2753G>A), FGFR4 (28A>G, 1162G>A, 538A>G), CSF2 (536C>T), IL3 (80T>C) and ADRβ2 (79C>G). The partition tree was used to investigate SNP combinations. The first partition was done by the most significant SNP discriminating good responders from poor in dominant model of minor frequency allele. Then subsequent partition was performed by the other SNPs until statistical significance disappeared.   Results:  The SNP, -2021G>A in VEGFR1, was the most significant and used in the first partition (25.7±19.8% vs. 20.0±13.8% increase, p A and CC of -1111C>T were discovered after second partition (30.3±16.7% increase). The poorest responders with GG of -2021G>A, GG of 2753G>A, and GG of 1162G>A were discovered after third partition (17.2±15.4% increase).   Conclusions:  The combination of genetic markers related to the airway inflammation or structural changes can be useful in predicting bronchodilator response by short-acting β2 agonist.
Maternal Sertraline Treatment and Serotonin Transport in Breast-Feeding Mother-Infant Pairs
Authors: Neill Epperson, Kathryn A. Czarkowski, Deborah Ward-O’Brien, Erica Weiss, Ralitza Gueorguieva, Peter Jatlow, George M. Anderson
Journal: American Journal of Psychiatry (2001)

OBJECTIVE: Pharmacological treatment of postpartum depression is frequently complicated by the mother's desire to breast-feed. Although breast milk levels of several selective serotonin reuptake inhibitors (SSRIs) have been reported to be relatively low, a critical question is whether SSRI exposure during nursing results in clinically significant blockade of serotonin (5-HT) reuptake in infants. This study determined the degree of transporter blockade in infants exposed to sertraline through maternal breast milk. METHOD: The extent of maternal and infant transporter blockade was assessed by measurement of platelet levels of 5-HT in 14 breast-feeding mother-infant pairs before and after 6–16 weeks of maternal treatment with sertraline for major depression with postpartum onset. Plasma sertraline and desmethylsertraline levels were obtained in 13 of these mothers and 11 of their infants. RESULTS: Marked declines in platelet 5-HT levels of 70%–96% were observed in mothers after sertraline treatment, 25–200 mg/day. In contrast, infants showed little or no change in platelet 5-HT levels after exposure through breast-feeding. Mean levels of maternal plasma sertraline and its major metabolite, desmethylsertraline, were 30.7 ng/ml and 45.3 ng/ml, respectively. Drug and drug metabolite concentrations in the infants were at or below the lower limit of quantitation. CONCLUSIONS: The data indicate that while mothers receiving clinical doses of sertraline experience substantial blockade of the platelet 5-HT transporter, platelet 5-HT uptake in nursing infants of treated mothers is unaltered. The observations suggest that mothers taking sertraline can breast-feed without appreciably affecting peripheral or central 5-HT transport in their infants.
MRI angiography is superior to helical CT for detection of HCC prior to liver transplantation: An explant correlation
Authors: Marta Burrel, Josep M. Llovet, Carmen Ayuso, Carmela Iglesias, Margarita Sala, Rosa Miquel, Teresa Caralt, Juan Ramon Ayuso, Manel Solé, Marcelo Sanchez, Concepció Brú, Jordi Bruix
Journal: Hepatology (2003)

Helical computerized tomography (CT) and magnetic resonance imaging (MRI) are used for staging of hepatocellular carcinoma (HCC) prior to curative treatments but underestimate tumor extension in 30% to 50% of cases when compared with pathologic explants. This study compares a new technology, MRI angiography (MRA), with triphasic helical CT in detection of HCC. Fifty cirrhotic patients, 29 with HCC, undergoing liver transplantation were analyzed. MRA was performed with a 3–D breath–hold fast spoiled gradient–echo sequence by using an effective section thickness of 2 to 2.5 mm. The gold standard was the pathologic examination (liver cut into 5–mm slices). One hundred twenty–seven lesions were identified at the explant: 76 HCC, 13 high–grade dysplastic nodules, 31 macroregenerative nodules, 7 hemangiomas. Diameter of the main HCC nodules was 29 ± 14 mm and 11 ± 7 mm for the 47 additional nodules. On a per nodule basis, sensitivity of MRA was superior to CT (58/76 [76%] vs. 43/70 [61%], respectively, P = .001). Sensitivity of MRA for detection of additional nodules decreased with size (&gt;20 mm: 6/6 [100%]; 10-20 mm: 16/19 [84%]; &lt;10 mm: 7/22 [32%]) and was superior to CT for nodules 10 to 20 mm (84% vs. 47%, P = .016). Nonspecific hypervascular nodules &gt;5 mm at MRA were HCC in two thirds of the cases. In conclusion, MRA has a high diagnostic accuracy for HCC ≥ 10 mm and is more sensitive than triphasic helical CT in nodules sized 10 to 20 mm. MRA is the optimal technique for HCC staging prior to curative therapies. (Hepatology 2003;38:1034-1042).
Thioredoxin Glutathione Reductase from Schistosoma mansoni: An Essential Parasite Enzyme and a Key Drug Target
Authors: Angela N Kuntz, Elisabeth Davioud-Charvet, Ahmed A Sayed, Lindsay L Califf, Jean Dessolin, Elias S. J Arnér, David L Williams
Journal: PLoS Medicine (2007)

Background Schistosomiasis—infection with helminth parasites in the genus Schistosoma, including S. mansoni—is a widespread, devastating tropical disease affecting more than 200 million people. No vaccine is available, and praziquantel, the only drug extensively utilized, is currently administered more than 100 million people yearly. Because praziquantel resistance may develop it is essential to identify novel drug targets. Our goal was to investigate the potential of a unique, selenium-containing parasite enzyme thioredoxin glutathione reductase (TGR) as a drug target. Methods and Findings Using RNA interference we found that TGR is essential for parasite survival; after silencing of TGR expression, in vitro parasites died within 4 d. We also found that auranofin is an efficient inhibitor of pure TGR (Ki = 10 nM), able to kill parasites rapidly in culture at physiological concentrations (5 μM), and able to partially cure infected mice (worm burden reductions of ~60%). Furthermore, two previously used antischistosomal compounds inhibited TGR activity, suggesting that TGR is a key target during therapy with those compounds. Conclusions Collectively, our results indicate that parasite TGR meets all the major criteria to be a key target for antischistosomal chemotherapy. To our knowledge this is the first validation of a Schistosoma drug target using a convergence of both genetic and biochemical approaches.
Clinical and Epidemiologic Characteristics of Mycobacterium haemophilum, an Emerging Pathogen in Immunocompromised Patients
Authors: Walter L. Straus
Journal: Annals of Internal Medicine (1994)

Objective: To describe 13 infections caused by Mycobacterium haemophilum. Design: Identification of patients by microbiologic record review, followed by medical record review and a case–control study. Setting: Seven metropolitan hospitals in New York. Patients: All patients with M. haemophilum infections diagnosed between January 1989 and September 1991 and followed through September 1992. Surviving patients were enrolled in the case–control study. Results: Infection with M. haemophilum causes disseminated cutaneous lesions, bacteremia, and diseases of the bones, joints, lymphatics, and the lungs. Improper culture techniques may delay laboratory diagnosis, and isolates may be identified incorrectly as other mycobacterial species. Persons with profound deficits in cell-mediated immunity have an increased risk for infection. These include persons with human immunodeficiency virus infection or lymphoma and those receiving medication to treat immunosuppression after organ transplant. Various antimycobacterial regimens have been used with apparent success to treat M. haemophilum infection. However, standards for defining antimicrobial susceptibility to the organism do not exist. Conclusions: Clinicians should consider this pathogen when evaluating an immunocompromised patient with cutaneous ulcerating lesions, joint effusions, or osteomyelitis. Microbiologists must be familiar with the fastidious growth requirements of this organism and screen appropriate specimens for mycobacteria using an acid-fast stain. If acid-fast bacilli are seen, M. haemophilum should be considered as the infecting organism as well as other mycobacteria, and appropriate media and incubation conditions should be used.