tbuckley/cabot-search huggingface dataset:
Fatty Acids as Modulators of the Immune Response
Authors: Kevin Fritsche
Journal: Annual Review of Nutrition (2006)

Research describing fatty acids as modulators of inflammation and immune responses abounds. Many of these studies have focused on one particular group of fatty acids, omega-3. The data from animal studies have shown that these fatty acids can have powerful anti-inflammatory and immunomodulatory activities in a wide array of diseases (e.g., autoimmunity, arthritis, and infection). However, the evidence from human trials is more equivocal. In this review, a historical framework for understanding how and why fatty acids may affect the immune system is provided. Second, highlights of two recent landmark reports from the Agency for Healthcare Research and Quality are presented. These reports critically evaluate the evidence from human clinical trials of omega-3 fatty acids and rheumatoid arthritis, asthma, and a few other immune-mediated diseases. Third, the data from human clinical trials investigating the impact of various bioactive fatty acids on ex vivo and in vivo immune response are reviewed. Limitations in experimental design and immune assays commonly used are discussed. The discordance between expectation and evidence in this field has been a disappointment. Recommendations for improving both animal-based and human studies are provided.
Rejuvenation of Human Cardiac Progenitor Cells With Pim-1 Kinase
Authors: Sadia Mohsin, Mohsin Khan, Jonathan Nguyen, Monique Alkatib, Sailay Siddiqi, Nirmala Hariharan, Kathleen Wallach, Megan Monsanto, Natalie Gude, Walter Dembitsky, Mark A. Sussman
Journal: Circulation Research (2013)

Myocardial function is enhanced by adoptive transfer of human cardiac progenitor cells (hCPCs) into a pathologically challenged heart. However, advanced age, comorbidities, and myocardial injury in patients with heart failure constrain the proliferation, survival, and regenerative capacity of hCPCs. Rejuvenation of senescent hCPCs will improve the outcome of regenerative therapy for a substantial patient population possessing functionally impaired stem cells.Reverse phenotypic and functional senescence of hCPCs by ex vivo modification with Pim-1.C-kit-positive hCPCs were isolated from heart biopsy samples of patients undergoing left ventricular assist device implantation. Growth kinetics, telomere lengths, and expression of cell cycle regulators showed significant variation between hCPC isolated from multiple patients. Telomere length was significantly decreased in hCPC with slow-growth kinetics concomitant with decreased proliferation and upregulation of senescent markers compared with hCPC with fast-growth kinetics. Desirable youthful characteristics were conferred on hCPCs by genetic modification using Pim-1 kinase, including increases in proliferation, telomere length, survival, and decreased expression of senescence markers.Senescence characteristics of hCPCs are ameliorated by Pim-1 kinase resulting in rejuvenation of phenotypic and functional properties. hCPCs show improved cellular properties resulting from Pim-1 modification, but benefits were more pronounced in hCPC with slow-growth kinetics relative to hCPC with fast-growth kinetics. With the majority of patients with heart failure presenting advanced age, infirmity, and impaired regenerative capacity, the use of Pim-1 modification should be incorporated into cell-based therapeutic approaches to broaden inclusion criteria and address limitations associated with the senescent phenotype of aged hCPC.
Sofosbuvir and Ribavirin in HCV Genotypes 2 and 3
Authors: Stefan Zeuzem, Geoffrey M. Dusheiko, Riina Salupere, Alessandra Mangia, Robert Flisiak, Robert H. Hyland, Ari Illeperuma, Evguenia Svarovskaia, Diana M. Brainard, William T. Symonds, G. Mani Subramanian, John G. McHutchison, Ola Weiland, Hendrik W. Reesink, Peter Ferenci, Christophe Hézode, Rafael Esteban
Journal: New England Journal of Medicine (2014)

In clinical trials, treatment with a combination of the nucleotide polymerase inhibitor sofosbuvir and the antiviral drug ribavirin was associated with high response rates among patients with hepatitis C virus (HCV) genotype 2 infection, with lower response rates among patients with HCV genotype 3 infection.We conducted a study involving patients with HCV genotype 2 or 3 infection, some of whom had undergone previous treatment with an interferon-based regimen. We randomly assigned 91 patients with HCV genotype 2 infection and 328 with HCV genotype 3 infection, in a 4:1 ratio, to receive sofosbuvir-ribavirin or placebo for 12 weeks. On the basis of emerging data from phase 3 trials indicating that patients with HCV genotype 3 infection had higher response rates when they were treated for 16 weeks, as compared with 12 weeks, the study was unblinded, treatment for all patients with genotype 3 infection was extended to 24 weeks, the placebo group was terminated, and the goals of the study were redefined to be descriptive and not include hypothesis testing. The primary end point was a sustained virologic response at 12 weeks after the end of therapy.Of the 419 patients who were enrolled and treated, 21% had cirrhosis and 58% had received previous interferon-based treatment. The criterion for a sustained virologic response was met in 68 of 73 patients (93%; 95% confidence interval [CI], 85 to 98) with HCV genotype 2 infection who were treated for 12 weeks and in 213 of 250 patients (85%; 95% CI, 80 to 89) with HCV genotype 3 infection who were treated for 24 weeks. Among patients with HCV genotype 3 infection, response rates were 91% and 68% among those without and those with cirrhosis, respectively. The most common adverse events were headache, fatigue, and pruritus.Therapy with sofosbuvir-ribavirin for 12 weeks in patients with HCV genotype 2 infection and for 24 weeks in patients with HCV genotype 3 infection resulted in high rates of sustained virologic response. (Funded by Gilead Sciences; VALENCE ClinicalTrials.gov number, NCT01682720.).
Viral-Mediated Temporally Controlled Dopamine Production in a Rat Model of Parkinson Disease
Authors: Xiao-gang Li, Takashi Okada, Mika Kodera, Yuko Nara, Naomi Takino, Chieko Muramatsu, Kunihiko Ikeguchi, Fumi Urano, Hiroshi Ichinose, Daniel Metzger, Pierre Chambon, Imaharu Nakano, Keiya Ozawa, Shin-ichi Muramatsu
Journal: Molecular Therapy (2005)

Regulation of gene expression is necessary to avoid possible adverse effects of gene therapy due to excess synthesis of transgene products. To reduce transgene expression, we developed a viral vector-mediated somatic regulation system using inducible Cre recombinase. A recombinant adeno-associated virus (AAV) vector expressing Cre recombinase fused to a mutated ligand-binding domain of the estrogen receptor α (CreERT2) was delivered along with AAV vectors expressing dopamine-synthesizing enzymes to rats of a Parkinson disease model. Treatment with 4-hydroxytamoxifen, a synthetic estrogen receptor modulator, activated Cre recombinase within the transduced neurons and induced selective excision of the tyrosine hydroxylase (TH) coding sequence flanked by loxP sites, leading to a reduction in transgene-mediated dopamine synthesis. Using this strategy, aromatic l-amino acid decarboxylase (AADC) activity was retained so that l-3,4-dihydroxyphenylalanine (l-dopa), a substrate for AADC, could be converted to dopamine in the striatum and the therapeutic effects of l-dopa preserved, even after reduction of TH expression in the case of dopamine overproduction. Our data demonstrate that viral vector-mediated inducible Cre recombinase can serve as an in vivo molecular switch, allowing spatial and temporal control of transgene expression, thereby potentially increasing the safety of gene therapy.
Risk Factors for Decreased Visual Acuity in Preschool Children
Authors: Kristina Tarczy-Hornoch, Rohit Varma, Susan A. Cotter, Roberta McKean-Cowdin, Jesse H. Lin, Mark S. Borchert, Mina Torres, Ge Wen, Stanley P. Azen, James M. Tielsch, David S. Friedman, Michael X. Repka, Joanne Katz, Josephine Ibironke, Lydia Giordano
Journal: Ophthalmology (2011)
Outcome of endoscopic sphincterotomy in post cholecystectomy patients with sphincter of Oddi dysfunction as predicted by manometry and quantitative choledochoscintigraphy
Authors: M Cicala
Journal: Gut (2002)

Sphincter of Oddi dysfunction is diagnosed at manometry and, after cholecystectomy, non-invasively at quantitative choledochoscintigraphy. Patients may benefit from endoscopic sphincterotomy.The aim of this study was to assess the usefulness of choledochoscintigraphy compared with manometry in predicting outcome of sphincterotomy in post cholecystectomy patients with sphincter of Oddi dysfunction.Thirty patients with biliary-type pain complying with the Rome diagnostic criteria of sphincter of Oddi dysfunction and belonging to biliary group I and II were subjected to clinical evaluation, choledochoscintigraphic assessment of the hepatic hilum-duodenum transit time, endoscopic retrograde cholangiopancreatography, and perendoscopic manometry. Twenty two biliary group I and II patients with prolonged hepatic hilum-duodenum transit times were invited to undergo sphincterotomy. Fourteen patients underwent sphincterotomy; eight refused. Clinical and scintigraphic assessments were performed at follow up.Hepatic hilum-duodenum transit time was delayed in all patients with manometric evidence of sphincter of Oddi dysfunction, in all biliary group I patients and in 64% of biliary group II patients. At follow up, all patients who underwent sphincterotomy were symptom free and hepatic hilum-duodenum transit time had either normalised or significantly improved. A favourable post sphincterotomy outcome was predicted in 93% of cases at choledochoscintigraphy and in 57% at manometry.Quantitative choledochoscintigraphy is a useful and non-invasive test to diagnose sphincter of Oddi dysfunction as well as a reliable predictor of sphincterotomy outcome in post cholecystectomy biliary group I and II patients, irrespective of clinical classification and manometric findings.
Improved heart function follows enhanced inflammatory cell recruitment and angiogenesis in 11βHSD1-deficient mice post-MI
Authors: Sara J. McSweeney, Patrick W.F. Hadoke, Agnieszka M. Kozak, Gary R. Small, Hiba Khaled, Brian R. Walker, Gillian A. Gray
Journal: Cardiovascular Research (2010)

Mice unable to locally regenerate corticosterone due to deficiency of 11β-hydroxysteroid dehydrogenase type 1 (11βHSD1) have enhanced angiogenesis during acute myocardial infarct healing. The present study investigates the hypotheses that in these mice (i) inflammation and angiogenic signalling are promoted and (ii) longer-term remodelling and function are improved. Myocardial infarction (MI) was induced by coronary artery ligation in 11βHSD1−/− and wild-type (C57BL/6) mice. Studies were terminated 2, 4, 7, and 28 days post-surgery. Increased vessel density (CD31 immunoreactivity) on the infarct border was confirmed 7 days after MI in 11βHSD1−/− hearts (P < 0.05) and was accompanied by improved ejection fraction (ultrasound) compared with C57BL/6. During wound healing, recruitment of neutrophils (at 2 days after MI) and macrophages (from 4 days after MI) and expression of monocyte-chemoattractant protein-1 was increased in 11βHSD1−/− compared with C57BL/6 hearts (P < 0.05). Recruitment of alternatively activated YM1-positive macrophages was particularly enhanced in the period preceding increased vessel density and was accompanied by increased expression of pro-angiogenic IL-8. By 28 days post-MI, when the infarct scar had matured, higher vessel density was maintained in 11βHSD1−/− hearts and vessels were smooth-muscle coated. Infarct scars were thicker (P < 0.001) in 11βHSD1−/− compared with C57BL/6 hearts and ejection fraction was higher (P < 0.05). Increased vessel density in healing infarcts of mice deficient in 11−/−HSD1 follows recruitment of pro-reparative macrophages and increased pro-angiogenic signalling. Mature infarcts show less thinning and cardiac function is improved relative to wild-type mice, suggesting that 11βHSD1 may be a novel therapeutic target after MI.
The Pulmonary Circulation
Authors: Alfred P. Fishman
Journal: JAMA (1978)

THE HISTORY of the pulmonary circulation provides a measure of man's thinking about himself and his place in the universe. For centuries before De Motu Cordis in 1628, 1 the blood vessels of the lungs were incorporated into an elaborate scheme that explained the origin and distribution of  that animated and sustained the human being. Only after the circulation was described could the speculative  philosophy of ancient times give way to the observations and interpretations that we now take for granted.  THE GROWTH OF IDEAS  The thinking of the ancients was dominated by the views of Aristotle as updated by Galen in the second century AD. 2 According to Galen, the body was governed by a hierarchy of three principal organs: the liver, the heart, and the brain. According to this schema, the liver was the source of natural spirits that the veins distributed throughout the body. These
Hallucinogens on the Internet: A Vast New Source of Underground Drug Information
Authors: J H Halpern, H G Pope
Journal: American Journal of Psychiatry (2001)

OBJECTIVE: The illicit use of hallucinogens is reemerging in the United States, especially among well-educated adults and teenagers. These same groups are also frequent users of the Internet. The authors sought to characterize the extent of information about hallucinogens available to Internet users. METHOD: Using standard Internet search techniques, the authors located 81 hallucinogen-related sites and categorized the information provided. RESULTS: Internet sites offer thousands of pages of information—albeit of questionable accuracy—on how to obtain, synthesize, extract, identify, and ingest hallucinogens. Much of this information has yet to appear in textbooks. By contrast, the authors found few U.S. government agency sites offering cautionary material about hallucinogen use. CONCLUSIONS: Using the Internet, potential hallucinogen users can bypass traditional channels of medical information and learn in great detail how to obtain and use numerous drugs with unknown hazards.
Muscle imbalance among elite athletes
Authors: M Franettovich, J Hides, M D Mendis, H Littleworth
Journal: British Journal of Sports Medicine (2011)

Background Previous research in team sports, such as football and cricket, has found muscle imbalances in the lumbo-pelvic region, especially in muscles involved in joint stability and protection. It is thought that these muscle imbalances occur as a result of the specific requirements of the sport. However, this pattern of muscular imbalance may not be isolated to team sports and may potentially exist in elite athletes performing Olympic sports. Objective To investigate similarities in patterns of muscle imbalance among elite athletes performing team and individual sports. Design Comparative case studies. Setting MRI examinations were carried out in a hospital setting. Participants Elite athletes participating in a range of team and individual sports including cycling, heptathlon, marathon and skeleton racing. Main outcome measurements Muscle cross-sectional areas (CSA) of individual muscles of the trunk and pelvic region. Results CSA of the trunk muscles show variation across muscle groups but evidence of imbalance within these groups. Conclusion Muscle imbalances exist in a wide range of athletes performing at the elite level and may be related to injury occurrence. Identification of the pattern of imbalance for different sports will enable muscle specific rehabilitation.
Human papillomavirus detection and comorbidity: critical issues in selection of patients with oropharyngeal cancer for treatment De-escalation trials
Authors: M.M. Rietbergen, R.H. Brakenhoff, E. Bloemena, B.I. Witte, P.J.F. Snijders, D.A.M. Heideman, D. Boon, S. Koljenovic, R.J. Baatenburg-de Jong, C.R. Leemans
Journal: Annals of Oncology (2013)
A phase II trial (AGO 2.11) in platinum-resistant ovarian cancer: a randomized multicenter trial with sunitinib (SU11248) to evaluate dosage, schedule, tolerability, toxicity and effectiveness of a multitargeted receptor tyrosine kinase inhibitor monotherapy
Authors: K.H. Baumann, A. du Bois, W. Meier, J. Rau, P. Wimberger, J. Sehouli, C. Kurzeder, F. Hilpert, A. Hasenburg, U. Canzler, L.C. Hanker, P. Hillemanns, B. Richter, K. Wollschlaeger, T. Dewitz, D. Bauerschlag, U. Wagner
Journal: Annals of Oncology (2012)
The changing epidemiology of acquired drug-resistant tuberculosis in San Francisco, USA
Authors: Williamson Z Bradford, Jeffrey N Martin, Arthur L Reingold, Gisela F Schecter, Philip C Hopewell, Peter M Small
Journal: The Lancet (1996)

The increasing incidence of tuberculosis caused by drug-resistant Mycobacterium tuberculosis is thought in part to reflect inadequate implementation of standard tuberculosis control measures. However, in San Francisco, USA, which has an effective tuberculosis control programme, we have recently observed an increase in cases of acquired drug-resistance.To explore further this observation, we analysed the secular trend of acquired drug-resistance and conducted a population-based case-control study of all reported tuberculosis cases in the city of San Francisco between 1985 and 1994.We identified 14 patients with tuberculosis caused by fully susceptible M tuberculosis who subsequently developed drug-resistance. Of these acquired drug-resistance cases, two occurred between 1985 and 1989, whereas 12 occurred between 1990 and 1994 (p = 0.028). In the case-control study, AIDS (odds ratio 20.2, 95% CI 1.12-363.6), non-compliance with therapy (19.7, 1.66-234.4), and gastrointestinal symptoms (11.5, 1.23-107.0) were independently associated with acquired drug-resistance. Between 1990 and 1994, one in 16 tuberculosis patients with AIDS and either gastrointestinal symptoms or non-compliance developed acquired drug- resistance.The substantial increase in acquired drug- resistance in San Francisco seems to be a product of the increasing prevalence of HIV/M tuberculosis coinfection. Our data suggest that the interface of the HIV and tuberculosis epidemics fosters acquired drug-resistance, and that traditional tuberculosis control measures may not be sufficient in communities with high rates of HIV infection.
Changes in sensitivity to methacholine after inhalation with distilled water: the role of the bronchoconstrictive response
Authors: S Kivity, R Poterman, Y Schwarz, R Soferman, M Topilsky
Journal: European Respiratory Journal (1995)

The inhalation of distilled water can induce bronchoconstriction and a transient increase in sensitivity to methacholine in asthmatics. The purpose of this study was to determine the role of the induced bronchoconstriction in the increased sensitivity to methacholine which follows the challenge with distilled water. Eighteen asthmatic children (age 9-17 yrs) were challenged by inhalation of distilled water. Bronchial responsiveness, the provocative concentration of methacholine producing a 20% decrease in forced expiratory volume in one second (PC20), was determined before inhalation of distilled water, and 1.5 and 24 h thereafter. Following inhalation of distilled water, eight patients (Group I) had a greater than 15% decrease in FEV1 (mean 23%); whereas, in the remaining 10 (Group II) the decrease was less than 7% (mean 1%). PC20 to methacholine, geometric mean and 95% confidence interval (CI), decreased transiently only at 1.5 h following inhalation of distilled water. The decrease was from 0.78 mg.ml-1 (95% CI 0.11-5.54 mg.ml-1) at baseline to 0.25 mg.ml-1 (95% CI 0.03-2.14 mg.ml-1) after challenge in Group I; and from 2.67 mg.ml-1 (95% CI 0.35-20.34 mg.ml-1) at baseline to 0.72 mg.ml-1 (95% CI 0.18-14.87 mg.ml-1) after challenge in Group II. The transient increase in sensitivity to methacholine observed following inhalation of distilled water occurred independently of the bronchoconstrictive response. This finding may have important clinical implications when hypo-osmolar solutions are used for delivery of drugs.
Effect of Platelet Inhibition with Cangrelor during PCI on Ischemic Events
Authors: Deepak L. Bhatt, Gregg W. Stone, Kenneth W. Mahaffey, C. Michael Gibson, P. Gabriel Steg, Christian W. Hamm, Matthew J. Price, Sergio Leonardi, Dianne Gallup, Ezio Bramucci, Peter W. Radke, Petr Widimský, Frantisek Tousek, Jeffrey Tauth, Douglas Spriggs, Brent T. McLaurin, Dominick J. Angiolillo, Philippe Généreux, Tiepu Liu, Jayne Prats, Meredith Todd, Simona Skerjanec, Harvey D. White, Robert A. Harrington
Journal: New England Journal of Medicine (2013)

The intensity of antiplatelet therapy during percutaneous coronary intervention (PCI) is an important determinant of PCI-related ischemic complications. Cangrelor is a potent intravenous adenosine diphosphate (ADP)-receptor antagonist that acts rapidly and has quickly reversible effects.In a double-blind, placebo-controlled trial, we randomly assigned 11,145 patients who were undergoing either urgent or elective PCI and were receiving guideline-recommended therapy to receive a bolus and infusion of cangrelor or to receive a loading dose of 600 mg or 300 mg of clopidogrel. The primary efficacy end point was a composite of death, myocardial infarction, ischemia-driven revascularization, or stent thrombosis at 48 hours after randomization; the key secondary end point was stent thrombosis at 48 hours. The primary safety end point was severe bleeding at 48 hours.The rate of the primary efficacy end point was 4.7% in the cangrelor group and 5.9% in the clopidogrel group (adjusted odds ratio with cangrelor, 0.78; 95% confidence interval [CI], 0.66 to 0.93; P=0.005). The rate of the primary safety end point was 0.16% in the cangrelor group and 0.11% in the clopidogrel group (odds ratio, 1.50; 95% CI, 0.53 to 4.22; P=0.44). Stent thrombosis developed in 0.8% of the patients in the cangrelor group and in 1.4% in the clopidogrel group (odds ratio, 0.62; 95% CI, 0.43 to 0.90; P=0.01). The rates of adverse events related to the study treatment were low in both groups, though transient dyspnea occurred significantly more frequently with cangrelor than with clopidogrel (1.2% vs. 0.3%). The benefit from cangrelor with respect to the primary end point was consistent across multiple prespecified subgroups.Cangrelor significantly reduced the rate of ischemic events, including stent thrombosis, during PCI, with no significant increase in severe bleeding. (Funded by the Medicines Company; CHAMPION PHOENIX ClinicalTrials.gov number, NCT01156571.).
Are Impairments of Action Monitoring and Executive Control True Dissociative Dysfunctions in Patients With Schizophrenia?
Authors: And U. Turken, Patrik Vuilleumier, Daniel H. Mathalon, Diane Swick, Judith M. Ford
Journal: American Journal of Psychiatry (2003)

OBJECTIVE: Impaired self-monitoring is considered a critical deficit of schizophrenia. The authors asked whether this is a specific and isolable impairment or is part of a global disturbance of cognitive and attentional functions. METHOD: Internal monitoring of erroneous actions, as well as three components of attentional control (conflict resolution, set switching, and preparatory attention) were assessed during performance of a single task by eight high-functioning patients with schizophrenia and eight comparison subjects. RESULTS: The patients exhibited no significant dysfunction of attentional control during task performance. In contrast, their ability to correct errors without external feedback and, by inference, to self-monitor their actions was markedly compromised. CONCLUSIONS: This finding suggests that dysfunction of self-monitoring in schizophrenia does not necessarily reflect a general decline in cognitive function but is evidence of disproportionately pronounced impairment of action monitoring, which may be mediated by a distinct subsystem within the brain's executive attention networks.