tbuckley/cabot-search huggingface dataset:
Sudden unexpected death in a mouse model of Dravet syndrome
Authors: Franck Kalume, Ruth E. Westenbroek, Christine S. Cheah, Frank H. Yu, John C. Oakley, Todd Scheuer, William A. Catterall
Journal: Journal of Clinical Investigation (2013)

Sudden unexpected death in epilepsy (SUDEP) is the most common cause of death in intractable epilepsies, but physiological mechanisms that lead to SUDEP are unknown. Dravet syndrome (DS) is an infantile-onset intractable epilepsy caused by heterozygous loss-of-function mutations in the SCN1A gene, which encodes brain type-I voltage-gated sodium channel NaV1.1. We studied the mechanism of premature death in Scn1a heterozygous KO mice and conditional brain- and cardiac-specific KOs. Video monitoring demonstrated that SUDEP occurred immediately following generalized tonic-clonic seizures. A history of multiple seizures was a strong risk factor for SUDEP. Combined video-electroencephalography-electrocardiography revealed suppressed interictal resting heart-rate variability and episodes of ictal bradycardia associated with the tonic phases of generalized tonic-clonic seizures. Prolonged atropine-sensitive ictal bradycardia preceded SUDEP. Similar studies in conditional KO mice demonstrated that brain, but not cardiac, KO of Scn1a produced cardiac and SUDEP phenotypes similar to those found in DS mice. Atropine or N-methyl scopolamine treatment reduced the incidence of ictal bradycardia and SUDEP in DS mice. These findings suggest that SUDEP is caused by apparent parasympathetic hyperactivity immediately following tonic-clonic seizures in DS mice, which leads to lethal bradycardia and electrical dysfunction of the ventricle. These results have important implications for prevention of SUDEP in DS patients.
Cromolyn Therapy in Patients With Bronchial Asthma
Authors: Ung Yun Ryo
Journal: JAMA (1976)

The action mechanism of cromolyn sodium and its effect on bronchial sensitivity to allergen, methacholine chloride, and histamine inhalations were studied in 17 asthmatic subjects. Cromolyn capsules or placebo was administered by an inhaler (Spinhaler) randomly on alternate days 30 minutes before aerosol challenge. Cromolyn and placebo did not differ in their effect on bronchial response to histamine or methacholine. However, the degree of decrease in forced vital capacity and forced expiratory volume in one second after allergen challenge was significantly reduced by cromolyn in 15 of 17 subjects. Immediate and delayed reactions of itching, tightness, or wheezing developed in 14 subjects after allergen challenges following placebo intake and were prevented or substantially inhibited by cromolyn.
Ideology as cooperative affordance
Authors: Joseph Bulbulia, Richard Sosis
Journal: Behavioral and Brain Sciences (2009)

Abstract McKay &amp; Dennett (M&amp;D) observe that beliefs need not be true in order to evolve. We connect this insight with Schelling's work on cooperative commitment to suggest that some beliefs – ideologies – are best approached as social goals. We explain why a social-interactive perspective is important to explaining the dynamics of belief formation and revision among situated partners.
Level of Fecal Calprotectin Correlates With Endoscopic and Histologic Inflammation and Identifies Patients With Mucosal Healing in Ulcerative Colitis
Authors: Klaus Theede, Susanne Holck, Per Ibsen, Steen Ladelund, Inge Nordgaard-Lassen, Anette Mertz Nielsen
Journal: Clinical Gastroenterology and Hepatology (2015)
CLINICAL, IMMUNOLOGICAL, AND VIROLOGICAL EFFECTS OF AMPLIGEN, A MISMATCHED DOUBLE-STRANDED RNA, IN PATIENTS WITH AIDS OR AIDS-RELATED COMPLEX
Authors: WilliamA. Carter, Isadore Brodsky, MichaelG. Pellegrino, HoraceF. Henriques, DavidM. Parenti, RichardS. Schulof, W.Edward Robinson, DavidJ. Volsky, Helene Paxton, Katalin Karikó, RobertJ. Suhadolnik, DavidR. Strayer, Mark Lewin, Leo Einck, GaryL. Simon, RochelleG. Scheib, DavidC. Montefiori, WilliamM. Mitchell, Deborah Paul, WilliamA. Meyer, Nancy Reichenbach, DavidH. Gillespie
Journal: The Lancet (1987)
Intravenous Glargine and Regular Insulin Have Similar Effects on Endogenous Glucose Output and Peripheral Activation/Deactivation Kinetic Profiles
Authors: Sunder Mudaliar, Pharis Mohideen, Reena Deutsch, Theodore P. Ciaraldi, Debra Armstrong, Bo Kim, Xue Sha, Robert R. Henry
Journal: Diabetes Care (2002)

To compare the effects of intravenously administered long-acting insulin analog glargine and regular human insulin on activation and deactivation of endogenous glucose output (EGO) and peripheral glucose uptake.In this single-center, randomized, double-blind, crossover euglycemic glucose clamp study, 15 healthy male volunteers (aged 27 +/- 4 years, BMI 24.2 +/- 0.7 kg/m(2) [mean +/- SE]) received a primed continuous intravenous infusion of 40 mU/m(2) of insulin glargine or regular human insulin on 2 different study days in a randomized order. Euglycemia was maintained at 90 mg/dl using a simultaneous variable intravenous infusion of 20% dextrose containing D-[3-(3)H]glucose. EGO and peripheral glucose disposal kinetics were determined during a 4-h insulin infusion activation period and a 3-h deactivation period.The results demonstrated no significant difference in activation or deactivation kinetics with respect to EGO and peripheral glucose disposal between insulin glargine and regular human insulin when given intravenously. The mean +/- SE time required for 50% suppression of EGO after insulin infusion was 73 +/- 23 min for regular insulin and 57 +/- 20 min for insulin glargine (NS). The mean maximum rate of glucose disposal was 10.10 +/- 0.77 and 9.90 +/- 0.85 mg. kg(-1). min(-1) for regular insulin and insulin glargine, respectively (NS). The mean time required for 50% suppression of incremental glucose disposal rate (GDR), defined as the time required for activation from the basal glucose disappearance rate (R(d)) to half-maximum insulin-stimulated R(d), was 32 +/- 5 and 42 +/- 10 min for regular insulin and insulin glargine, respectively (NS). The time required for deactivation from maximum insulin-stimulated GDR to half-maximum GDR after cessation of insulin infusion was 63 +/- 5 and 57 +/- 4 min for regular insulin and insulin glargine, respectively (NS).Activation and deactivation kinetics of EGO and peripheral glucose uptake as well as absolute disposal rate are similar between regular human insulin and insulin glargine when administered intravenously. Thus, the various biological actions of these insulin preparations when given subcutaneously are completely due to their different absorption kinetics.
Enhanced Angiogenic and Cardiomyocyte Differentiation Capacity of Epigenetically Reprogrammed Mouse and Human Endothelial Progenitor Cells Augments Their Efficacy for Ischemic Myocardial Repair
Authors: Melissa A. Thal, Prasanna Krishnamurthy, Alexander R. Mackie, Eneda Hoxha, Erin Lambers, Suresh Verma, Veronica Ramirez, Gangjian Qin, Douglas W. Losordo, Raj Kishore
Journal: Circulation Research (2012)

Rationale: Although bone marrow endothelial progenitor cell (EPC)-based therapies improve the symptoms in patients with ischemic heart disease, their limited plasticity and decreased function in patients with existing heart disease limit the full benefit of EPC therapy for cardiac regenerative medicine. Objective: We hypothesized that reprogramming mouse or human EPCs, or both, using small molecules targeting key epigenetic repressive marks would lead to a global increase in active gene transcription, induce their cardiomyogenic potential, and enhance their inherent angiogenic potential. Method and Results: Mouse Lin-Sca1 + CD31 + EPCs and human CD34 + cells were treated with inhibitors of DNA methyltransferases (5-Azacytidine), histone deacetylases (valproic acid), and G9a histone dimethyltransferase. A 48-hour treatment led to global increase in active transcriptome, including the reactivation of pluripotency-associated and cardiomyocyte-specific mRNA expression, whereas endothelial cell–specific genes were significantly upregulated. When cultured under appropriate differentiation conditions, reprogrammed EPCs showed efficient differentiation into cardiomyocytes. Treatment with epigenetic-modifying agents show marked increase in histone acetylation on cardiomyocyte and pluripotent cell–specific gene promoters. Intramyocardial transplantation of reprogrammed mouse and human EPCs in an acute myocardial infarction mouse model showed significant improvement in ventricular functions, which was histologically supported by their de novo cardiomyocyte differentiation and increased capillary density and reduced fibrosis. Importantly, cell transplantation was safe and did not form teratomas. Conclusions: Taken together, our results suggest that epigenetically reprogrammed EPCs display a safe, more plastic phenotype and improve postinfarct cardiac repair by both neocardiomyogenesis and neovascularization.
Website of the week: Tobacco money
Authors: Christopher Martyn
Journal: BMJ (2001)

An article in this week's BMJ debates whether or not Nottingham University should give back £3.8m ($5.3m) in sponsorship from British American Tobacco (p 1118). In giving away money to support useful and blameless activities tobacco companies believe—and no doubt they have checked with focus groups—that their generosity helps to create positive feelings about their other activities in the public mind. To find out more about the message they are trying to get across, it is worth having a look at their websites.

Before you click on Philip Morris (www.philipmorrisusa.com), British American Tobacco (www.bat.com), or R J Reynolds (www.rjrt.com), take a guess at what a tobacco company website might look like. Promotional perhaps, seeking to win customers from the opposition with subliminal suggestions; strong on the life-enhancing properties of the brand, weak on its life-shortening properties. The surprise is how frank these guys are. They give it to you straight: smoking is bad for you. Teenagers shouldn't start. If you're a smoker who wants to quit, you should. To prove that they mean what they say, BAT has a link to www.givingupsmoking.co.uk and R J Reynolds won't even let you on to the website about its new cigarette (www.eclipse.rjrt.com) until you prove you are over 21 years old.

The dominating theme is that smoking is about intelligent, fully informed, adult choice. If you want to deny yourself a lifetime of pleasure to improve your mortality, that's up to you. Don't interfere with the habits of those who have decided to go the other way. It is at least a coherent argument. Indeed, it is probably the only coherent argument. But like the dog that famously didn't bark at night, the most significant thing about these sites is not what they give you but what they leave out. The World Health Organization estimates that 75% of tobacco related deaths over the next 20 years will be in the developing world. The RJ Reynolds site is so big that it has its own search engine, but typing in “developing world” produced not a single hit.
AN URGE TO EXPLAIN THE INCOMPREHENSIBLE: Geoffrey Harris and the Discovery of the Neural Control of the Pituitary Gland
Authors: G. Raisman
Journal: Annual Review of Neuroscience (1997)

Geoffrey Harris is responsible for our view that the brain controls the endocrine system by an exquisitely regulated pattern of synthesis and release of individual members of a family of peptide hormones. These hormones are carried through a portal vascular system that passes from the hypothalamus to the pituitary gland, where they selectively regulate the secretion of the six anterior pituitary hormones. This family of hypothalamic hormones is highly conserved in all vertebrates, including humans. They are essential for all aspects of reproduction--courtship, mating, pregnancy and young rearing--and they are responsible for the seasonal regulation of breeding. The hypothalamic control mechanism for reproduction is sexually dimorphic, with a basic female pattern that becomes masculinized under the influence of specific steroid hormones acting during development. Other members of the hypothalamic hormone family specifically regulate the secretion of pituitary growth hormone and the anterior pituitary hormones controlling the functions of the thyroid and adrenal glands. The secretion of the hypothalamic hormones is itself regulated by the feedback of the target gland hormones (such as estrogen and progesterone), which concurrently act on the brain to elicit appropriate behavior patterns. The hypothalamo-hypophysial axis plays a crucial role in the struggle for the survival of the species. By bringing the endocrine system under the control of the brain, it allows access to external environmental inputs, learned behavior patterns, and the whole of the central integrative machinery needed for the bodily functions to be sensitively and optimally adapted to the ever-changing challenges and opportunities in the outside world.
O<sup>6</sup>-Methylguanine-DNA Methyltransferase Expression Strongly Correlates With Outcome in Childhood Malignant Gliomas: Results From the CCG-945 Cohort
Authors: Ian F. Pollack, Ronald L. Hamilton, Robert W. Sobol, Judith Burnham, Allan J. Yates, Emiko J. Holmes, Tianni Zhou, Jonathan L. Finlay
Journal: Journal of Clinical Oncology (2006)

O6-methylguanine-DNA methyltransferase (MGMT) functions to counteract the cytotoxic effects of alkylating agents, such as nitrosoureas, which play a central role in the treatment of childhood malignant gliomas. Epigenetic silencing of MGMT has been associated with prolonged survival in adults with malignant gliomas, although the association between MGMT expression status and outcome in pediatric malignant gliomas has not been defined.We examined the association between MGMT expression and survival duration using tumor samples from the Children's Cancer Group 945 study, the largest randomized trial for childhood malignant gliomas completed to date. All patients received alkylator-based chemotherapy as a component of adjuvant therapy. Archival histopathologic material yielded tissue of sufficient quality for immunohistochemical assessment of MGMT expression status in 109 specimens.Twelve of the 109 samples demonstrated overexpression of MGMT compared with normal brain. Five-year progression-free survival was 42.1% +/- 5% in the 97 patients whose tumors had low levels of MGMT expression versus 8.3% +/- 8% in the 12 patients whose tumors overexpressed MGMT (P = .017, exact log-rank test). The association between MGMT overexpression and adverse outcome remained significant after stratifying for institutional histologic diagnosis (eg, anaplastic astrocytoma or glioblastoma multiforme), as well as age, amount of residual tumor, and tumor location.Overexpression of MGMT in childhood malignant gliomas is strongly associated with an adverse outcome in children treated with alkylator-based chemotherapy, independently of a variety of clinical prognostic factors.
β2-Microglobulin Is a Signaling and Growth-Promoting Factor for Human Prostate Cancer Bone Metastasis
Authors: Wen-Chin Huang, Daqing Wu, Zhihui Xie, Haiyen E. Zhau, Takeo Nomura, Majd Zayzafoon, Jan Pohl, Chia-Ling Hsieh, M. Neale Weitzmann, Mary C. Farach-Carson, Leland W.K. Chung
Journal: Cancer Research (2006)

Abstract The protein factor β2-microglobulin (β2M), purified from the conditioned medium of human prostate cancer cell lines, stimulated growth and enhanced osteocalcin (OC) and bone sialoprotein (BSP) gene expression in human prostate cancer cells by activating a cyclic AMP (cAMP)–dependent protein kinase A signaling pathway. When β2M was overexpressed in prostate cancer cells, it induced explosive tumor growth in mouse bone through increased phosphorylated cAMP-responsive element binding protein (CREB) and activated CREB target gene expression, including OC, BSP, cyclin A, cyclin D1, and vascular endothelial growth factor. Interrupting the β2M downstream signaling pathway by injection of the β2M small interfering RNA liposome complex produced an effective regression of previously established prostate tumors in mouse bone through increased apoptosis as shown by immunohistochemistry and activation of caspase-9, caspase-3, and cleavage of poly(ADP-ribose) polymerase. These results suggest that β2M signaling is an attractive new therapeutic target for the treatment of lethal prostate cancer bone metastasis. (Cancer Res 2006; 66(18): 9108-16)
Left ventricular response to experimentally induced chronic aortic regurgitation
Authors: R. R. TAYLOR, B. E. HOPKINS, P. BURROWS
Journal: Cardiovascular Research (1972)

Left ventricular characteristics in 13 dogs with aortic regurgitation of 36 to 468 days duration were compared with those of 15 normal dogs. The test group exhibited significant chronic dilatation and hypertrophy and elevated left ventricular end-diastolic pressure, but contractility (tension—velocity relations) was normal in the group as a whole. In animals with the more severe and prolonged duration of lesions, however, contractility was depressed, although this was not reflected in greater elevation of left ventricular end-diastolic pressure.
Effects of Evacuation and of Air Raids on City Children
Authors: W. M. Burbury
Journal: BMJ (1941)

An attempt is made in this article to assess the effects (a) of evacuation and (b) of air raids on the children attending the Manchester Child Guidance Clinic.So much has been written about the physical advantage to children of being out of big cities that it seems worth while to try in some way to assess and reduce to terms the psychological effects of war on them.Admittedly the numbers are small and represent a selected set of children in that they have been referred to a clinic of this nature, but in one group of figures these numbers are placed side by side with the total school population so that some comparison may be made.So far as the clinic is concerned the numbers represent all cases under treatment there in July, 1939, plus all those referred since that time up to March, 1941.From these figures only two groups have been excluded, the reason for exclusion being obvious: (1) cases coming from neutral and reception areas; (2) cases of proved mental defect.TABLE I.-Relation of Clinic Cases to School Population Total number of cases Total evacuated since September, 1939 Returned within 4 months Further returned by end of 6 months Still evacuated Evacuated after raiding began Returned within 3 months Still evacuated Clinic Cases 131 88 (67°') 65 (50%) 18 (15%) 5 (4%) 20 3 17
Clinical assessment after a life-threatening attack of asthma; the role of bronchial hyperreactivity
Authors: EM Pouw, GH Koeter, JG de Monchy, AJ Homan, HJ Sluiter
Journal: European Respiratory Journal (1990)

Between 1973 and 1986, 19 patients were treated on 21 occasions for life-threatening attacks of asthma. Twelve times mechanical ventilation was needed. None of the patients died. Most of the patients had been recognized as severely asthmatic before the life-threatening attack. Thirteen out of the 19 patients had previously been admitted with a severe asthmatic attack. All patients, except one, were already using maintenance treatment, and 17 had previously been referred to a pulmonologist. During follow-up the bronchial obstruction was, in most cases, fully reversible while using a rather extensive maintenance treatment (maximum forced expiratory volume in one second (FEV1), 69-138% of predicted). Recently, 17 of the 19 patients were reinvestigated, while in stable phase. The patients who had been mechanically ventilated were significantly more sensitive to inhaled histamine than the patients who had not been mechanically ventilated. This was not explained by any difference in basal FEV1 % pred or dosage of corticosteroids. A very low provocation concentration of histamine producing a 20% fall in FEV1 (PC20) may indicate the risk of a severe, life-threatening attack of asthma.
Phase I Trial of Sorafenib in Combination with IFN α-2a in Patients with Unresectable and/or Metastatic Renal Cell Carcinoma or Malignant Melanoma
Authors: Bernard Escudier, Nathalie Lassau, Eric Angevin, Jean Charles Soria, Linda Chami, Michele Lamuraglia, Eric Zafarana, Veronique Landreau, Brian Schwartz, Eric Brendel, Jean-Pierre Armand, Caroline Robert
Journal: Clinical Cancer Research (2007)

Abstract Purpose: To determine the safety, maximum tolerated dose, pharmacokinetics, and efficacy, and to evaluate biomarkers, of the multikinase inhibitor sorafenib plus IFN α-2a in advanced renal cell carcinoma (RCC) or melanoma. Experimental Design: Patients received 28-day cycles of continuous, oral sorafenib twice daily and s.c. IFN thrice weekly: sorafenib 200 mg twice daily plus IFN 6 million IU (MIU) thrice weekly (cohort 1); and sorafenib 400 mg twice daily plus IFN 6 MIU thrice weekly (cohort 2); or plus IFN 9 MIU thrice weekly (cohort 3). Tumor response was assessed by Response Evaluation Criteria in Solid Tumors and dynamic contrast-enhanced ultrasonography. Results: Thirteen patients received at least one dose of sorafenib plus IFN (12 RCC; one melanoma). The maximum tolerated dose was not reached [only one dose-limiting toxicity (grade 3 asthenia)]. Most frequently reported drug-related adverse events were grade 2 or less in severity, including fatigue, diarrhea, nausea, alopecia, and hand-foot skin reaction. One (7.7%) RCC patient achieved partial response and eight (61.5%) had stable disease (including the melanoma patient). Good responders assessed by dynamic contrast-enhanced ultrasonography had increased progression-free survival and overall survival, relative to poor responders. IFN had no effect on the pharmacokinetics of sorafenib. There were no significant changes in absolute values of lymphocytes, levels of proangiogenic cytokines, or inhibition of phosphorylated extracellular signal-regulated kinase in T cells or natural killer cells, with combination therapy. Conclusions: This sorafenib combination was well tolerated, with preliminary antitumor activity in advanced RCC and melanoma patients. There were no drug-drug interactions and the recommended dose for future studies is sorafenib 400 mg twice daily plus IFN 9 MIU.
Regulatory Role of mir-203 in Prostate Cancer Progression and Metastasis
Authors: Sharanjot Saini, Shahana Majid, Soichiro Yamamura, Laura Tabatabai, Seong O. Suh, Varahram Shahryari, Yi Chen, Guoren Deng, Yuichiro Tanaka, Rajvir Dahiya
Journal: Clinical Cancer Research (2010)

Advanced metastatic prostate cancer (PCa) is a fatal disease, with only palliative therapeutic options. Though almost 80% of cases of metastatic PCa present bone metastasis, our current understanding of the molecular mechanisms that govern this metastatic dissemination remains fragmentary. The main objective of the present study was to identify microRNA (miRNA) genes that regulate metastatic PCa.miRNA expression profiling was done in human prostate cell lines to identify dysregulated miRNA components of advanced PCa. miR-203 expression was assessed in prostate carcinoma cell lines and clinical specimens by real-time PCR and in situ hybridization. To assess the biological significance of miR-203, miR-203 was reexpressed in bone metastatic PCa cell lines followed by in vitro and in vivo functional assays.miR-203 expression is specifically attenuated in bone metastatic PCa suggesting a fundamental antimetastatic role for this miRNA. Reintroduction of miR-203 in bone metastatic PCa cell lines suppresses metastasis via inhibition of several critical steps of the metastatic cascade including epithelial-mesenchymal transition, invasion, and motility. Ectopic miR-203 significantly attenuated the development of metastasis in a bone metastatic model of PCa. Importantly, miR-203 regulates a cohort of pro-metastatic genes including ZEB2, Bmi, survivin, and bone-specific effectors including Runx2, a master regulator of bone metastasis.miR-203 is an "antimetastatic" miRNA in PCa that acts at multiple steps of the PCa metastatic cascade via repression of a cohort of prometastatic targets. miR-203 may be an attractive target for therapeutic intervention in advanced PCa.