tbuckley/cabot-search huggingface dataset:
The Role of the Human Prefrontal Cortex in Social Cognition and Moral Judgment
Authors: Chad E. Forbes, Jordan Grafman
Journal: Annual Review of Neuroscience (2010)

Results from functional magnetic resonance imaging and lesion studies indicate that the prefrontal cortex (PFC) is essential for successful navigation through a complex social world inundated with intricate norms and moral values. This review examines regions of the PFC that are critical for implicit and explicit social cognitive and moral judgment processing. Considerable overlap between regions active when individuals engage in social cognition or assess moral appropriateness of behaviors is evident, underscoring the similarity between social cognitive and moral judgment processes in general. Findings are interpreted within the framework of structured event complex theory, providing a broad organizing perspective for how activity in PFC neural networks facilitates social cognition and moral judgment. We emphasize the dynamic flexibility in neural circuits involved in both implicit and explicit processing and discuss the likelihood that neural regions thought to uniquely underlie both processes heavily interact in response to different contextual primes.
Valproic acid inhibits Aβ production, neuritic plaque formation, and behavioral deficits in Alzheimer's disease mouse models
Authors: Hong Qing, Guiqiong He, Philip T. T. Ly, Christopher J. Fox, Matthias Staufenbiel, Fang Cai, Zhuohua Zhang, Shengcai Wei, Xiulian Sun, Chia-Hsiung Chen, Weihui Zhou, Ke Wang, Weihong Song
Journal: The Journal of Experimental Medicine (2008)

Neuritic plaques in the brains are one of the pathological hallmarks of Alzheimer's disease (AD). Amyloid β-protein (Aβ), the central component of neuritic plaques, is derived from β-amyloid precursor protein (APP) after β- and γ-secretase cleavage. The molecular mechanism underlying the pathogenesis of AD is not yet well defined, and there has been no effective treatment for AD. Valproic acid (VPA) is one of the most widely used anticonvulsant and mood-stabilizing agents for treating epilepsy and bipolar disorder. We found that VPA decreased Aβ production by inhibiting GSK-3β–mediated γ-secretase cleavage of APP both in vitro and in vivo. VPA treatment significantly reduced neuritic plaque formation and improved memory deficits in transgenic AD model mice. We also found that early application of VPA was important for alleviating memory deficits of AD model mice. Our study suggests that VPA may be beneficial in the prevention and treatment of AD.
The Need to Revise the Declaration of Helsinki
Authors: R J Levine
Journal: New England Journal of Medicine (1999)

The Declaration of Helsinki requires revision because it is defective in two important respects. First, it relies on a distinction between therapeutic and nontherapeutic research; all documents that rely on this spurious distinction contain errors not intended by their authors.1 Second, it includes several provisions that are seriously out of touch with contemporary ethical thinking. As a consequence, many researchers routinely violate its requirements. Such routine violations and their associated attitudes rob the declaration of its credibility.Therapeutic and Nontherapeutic ResearchThe nature of the errors that arise from a reliance on the distinction between therapeutic and nontherapeutic research is . . .
Peptide YY Is Critical for Acylethanolamine Receptor Gpr119-Induced Activation of Gastrointestinal Mucosal Responses
Authors: Helen M. Cox, Iain R. Tough, Anne-Marie Woolston, Lei Zhang, Amy D. Nguyen, Amanda Sainsbury, Herbert Herzog
Journal: Cell Metabolism (2010)

SummaryPeptide YY (PYY) is released following food intake and regulates intestinal function and glucose homeostasis, but the mechanisms underpinning these processes are unclear. Enteroendocrine L cells contain PYY and express the acylethanolamine receptor, Gpr119. Here, we show that Gpr119 activation inhibited epithelial electrolyte secretion in human and mouse colon in a glucose-sensitive manner. Endogenous PYY selectively mediated these effects, since PYY−/− mice showed no Gpr119 response, but responses were observed in NPY−/− mice. Importantly, Gpr119 responses in wild-type (WT) mouse tissue and human colon were abolished by Y1 receptor antagonism, but were not enhanced by dipeptidylpeptidase IV blockade, indicating that PYY processing to PYY(3-36) was not important. In addition, Gpr119 agonism reduced glycemic excursions after oral glucose delivery to WT mice but not PYY−/− mice. Taken together, these data demonstrate a previously unrecognized role of PYY in mediating intestinal Gpr119 activity and an associated function in controlling glucose tolerance.Highlights•Endogenous PYY, but not NPY, mediates Gpr119 effects in human and mouse colon mucosa•The action of endogenous PYY is mediated specifically via epithelial Y1 receptors•Apical and basolateral Gpr119 responses are glucose sensitive•Gpr119 agonism reduced glycemia after oral glucose in WT but not PYY−/− mice
Metabolic Effects of Total Parenteral Nutrition
Authors: P. D. Greig, J. P. Baker, K. N. Jeejeebhoy
Journal: Annual Review of Nutrition (1982)

Nutritional support of the sick patient has become increasingly important, particularly in cases of prolonged serious illness. The need for attention to the nutritional requirements of the patients has arisen because improved treatment of sepsis, cardiovascular failure, and fluid and electrolyte abnor­ malities has allowed patients to survive to a point where nutrition becomes a limiting factor in their further progress. Despite advances in surgical and medical treatment of various disorders of the alimentary tract, the survival of the patient with gastrointestinal disease is often limited by continuing malnutrition as a result of the inability of the patient to eat and/or absorb a normal oral diet. Under such circumstances advances in the field of parenteral nutrition have revolutionized the outcome of these patients. The objective of nutritional support in the critically ill patient is to restore and maintain adequate nutritional status in the face of illness and inade­ quate oral nutrition. Central to the understanding of the utilization of parenterally infused nutrients and their effects on body composition is knowledge of the effects of starvation and acute injury on nutritional status.
Does the calcium current modulate the contraction of the accompanying beat? A study of E-C coupling in mammalian ventricular muscle using cobalt ions.
Authors: T F McDonald, D Pelzer, W Trautwein
Journal: Circulation Research (1981)

This study was prompted by a conclusion that emerged from experiments by others on mammalian ventricular muscle i.e., that the magnitude of the calcium current (Isi) does not influence contraction on the accompanying beat. In the key experiments, muscles were potentiated with paired pulses, rested for 2 minutes, and then re-stimulated. When Co2+ was present during the rest, the first post-rest action potential (and presumably Isi) was depressed but contraction was unchanged. In the present study, we have measured the effect of Co2+ on the action potential, Isi, and tension of bovine, cat, and rabbit ventricular muscle. All three parameters were depressed by 1-2 mM Co2+ when muscle was stimulated at 20/min. The key experiments of the earlier study were repeated. Co2+ (1-2 mM depressed both the action potential plateau and contraction on the first post-rest response. We conclude that the use of Co2+ in this type of experiment does not provide evidence against a role for Lsi in the modulation of contraction.
Forced spirometry reference values for Norwegian adults: the Bronchial Obstruction in Nord-Trøndelag study
Authors: A. Langhammer, R. Johnsen, A. Gulsvik, T.L. Holmen, L. Bjermer
Journal: European Respiratory Journal (2001)

The purpose of this study was to develop new prediction equations for flow/volume spirometry parameters in asymptomatic, never-smoking adults in Norway, and to assess any differences of these parameters when applying the new and most commonly used equation sets. Flow/volume spirometry was measured according to the American Thoracic Society criteria in 2,792 subjects aged ≥20 yrs, randomly selected from participants in the Nord-Trøndelag Health Study. Ever-smokers and subjects with respiratory symptoms and/or diseases reported in this questionnaire were excluded. A total of 546 females and 362 males met the inclusion criteria and were included in the analyses. Most lung function variables were nonlinear by age and had to be transformed. After a plateau in younger adults, the variables declined by age. The reference values for forced expiratory volume in one second and forced vital capacity from the present study, were higher than those given by prediction equations from the European Community for Coal and Steel, but in closer agreement with later studies from Europe, Australia and the USA. Healthcare providers should be encouraged to reconsider their choice of prediction equations of spirometry in order to improve management of obstructive lung diseases.
The cytoplasmic prolyl-tRNA synthetase of the malaria parasite is a dual-stage target of febrifugine and its analogs
Authors: Jonathan D. Herman, Lauren R. Pepper, Joseph F. Cortese, Guillermina Estiu, Kevin Galinsky, Vanessa Zuzarte-Luis, Emily R. Derbyshire, Ulf Ribacke, Amanda K. Lukens, Sofia A. Santos, Vishal Patel, Clary B. Clish, William J. Sullivan, Huihao Zhou, Selina E. Bopp, Paul Schimmel, Susan Lindquist, Jon Clardy, Maria M. Mota, Tracy L. Keller, Malcolm Whitman, Olaf Wiest, Dyann F. Wirth, Ralph Mazitschek
Journal: Science Translational Medicine (2015)

The cytoplasmic prolyl-tRNA synthetase of Plasmodium falciparum is a dual-stage therapeutic target for drug development.
Nutrition and sport (briefing paper): The British Nutrition Foundation. 38 pp. ISBN 0907667171
Authors: L Burke
Journal: British Journal of Sports Medicine (2002)

According to the back cover of this booklet, The British Nutrition Foundation promotes the nutritional wellbeing of society by interpreting and disseminating scientifically based knowledge and advice. Here they tackle the science and practice of sports nutrition, acknowledging that although the information is underpinned by rigorous research in exercise physiology and metabolism, it must be …
Decreased Atherosclerotic Lesion Formation in Human Serum Paraoxonase Transgenic Mice
Authors: Aaron Tward, Yu-Rong Xia, Xu-Ping Wang, Yi-Shou Shi, Christina Park, Lawrence W. Castellani, Aldons J. Lusis, Diana M. Shih
Journal: Circulation (2002)

Background — Serum paraoxonase (PON1), an enzyme carried on HDL, inhibits LDL oxidation, and in human population studies, low PON1 activity is associated with atherosclerosis. In addition, PON1 knockout mice are more susceptible to lipoprotein oxidation and atherosclerosis. To evaluate whether PON1 protects against atherosclerosis and lipid oxidation in a dose-dependent manner, we generated and studied human PON1 transgenic mice. Methods and Results — Human PON1 transgenic mice were produced by using bacterial artificial chromosome genomic clones. The mice had 2- to 4-fold increased plasma PON1 levels, but plasma cholesterol levels were unchanged. Atherosclerotic lesions were significantly reduced in the transgenic mice when both dietary and apoE-null mouse models were used. HDL isolated from the transgenic mice also protected against LDL oxidation more effectively. Conclusions — Our results indicate that PON1 protects against atherosclerosis in a dose-dependent manner and suggest that it may be a potential target for developing therapeutic agents for the treatment of cardiovascular disease.
Simplified gemcitabine and platin regimen in patients with advanced or metastatic non-small cell lung cancer (NSCLC) to be proposed as neoadjuvant therapy
Authors: G. Cartei, S. Binato, C. Sacco, A. Bearz, S. Scalone, R. Ceravolo, S. Cingarlini, U. Fantoni, A. Palamidese, A. Iop, E. Colombrino
Journal: Annals of Oncology (2006)
Establishment and Treatment Of a Steroid Resistant Asthma Model By Adoptive Transfer Of Helper T Cell Clones
Authors: Akio Mori, Satoshi Kouyama, Miyako Yamaguchi, Yo Iijima, Jun Itoh, Hiroaki Hayashi, Takafumi Minami, Kentaro Watarai, Chihiro Mitsui, Chiyako Oshikata, Hidenori Tanimoto, Yuma Fukutomi, Kiyoshi Sekiya, Takahiro Tsuburai, Masami Taniguchi, Yuji Maeda, Mamoru Ohtomo, Maki Hasegawa, Kazuo Akiyama, Osamu Kaminuma
Journal: Journal of Allergy and Clinical Immunology (2014)
Pharmacokinetics and Pharmacodynamics of Imatinib in a Phase I Trial With Chronic Myeloid Leukemia Patients
Authors: Bin Peng, Michael Hayes, Debra Resta, Amy Racine-Poon, Brian J. Druker, Moshe Talpaz, Charles L. Sawyers, Marianne Rosamilia, John Ford, Peter Lloyd, Renaud Capdeville
Journal: Journal of Clinical Oncology (2004)

To evaluate the basic pharmacokinetic (PK) characteristics of imatinib mesylate and assess the relationship between the PK and pharmacodynamic (PD) properties of the drug.The PK and PD properties of imatinib were investigated during a phase I trial that included 64 adult patients with Philadelphia chromosome-positive leukemias. Patients received imatinib orally once or twice daily. PK parameters of imatinib, derived from the plasma concentration-time curves, were determined. PD response, defined as the WBC after 1 month of treatment with imatinib, was used to develop an efficacy model. A maximum inhibition-effect model was used to describe the relationship between reduction in WBC and drug exposure parameters.Imatinib exposure was dose proportional after oral administration for the dose range of 25 to 1,000 mg. There was a 1.5- to three-fold drug accumulation after repeated once-daily dosing. Mean plasma trough concentration was 0.57 microg/mL (approximately 1 micromol/L) 24 hours after administration of 350 mg of imatinib at steady-state, which exceeds the 50% inhibitory concentration required to inhibit proliferation of Bcr-Abl-positive leukemic cells. Analysis of PK/PD relationships indicates that the initial hematologic response depends on the administered dose for patients with chronic myeloid leukemia.Drug exposure (area under the concentration-time curve) is dose proportional for the dose range of 25 to 1,000 mg, and there is a 1.5- to three-fold drug accumulation at steady-state after once-daily dosing. Analysis of the relationship between PD (WBC reduction) and PK parameters at steady-state indicates that a dose of 400 mg or greater is required for maximal PD effect.
Remember elephants and icebergs... "Your lung function should be here, but it is there!"
Authors: J. B. Soriano, G. Parkes
Journal: European Respiratory Journal (2009)

In the present issue of the European Respiratory Journal , Kotz et al. 1 report on a study aimed at determining the incremental benefit of spirometry in a smoking cessation intervention in individuals with as yet undiagnosed airflow obstruction compatible with mild and moderate chronic obstructive pulmonary disease (COPD). In a randomised clinical trial (RCT) study design, the authors compared an experimental group (nortriptyline and medium-intensity advice with spirometry) with two control groups: C1 (nortriptyline and medium-intensity advice without spirometry) and C2 (passive physician advice). The primary end-point was sustained cessation at week 52 with urinary cotinine-validated definitions. Regrettably, the study did not provide evidence that the confrontational approach increases the rate of long-term abstinence from smoking compared with an equally intensive treatment in which smokers were not confronted with spirometry.

In contrast, both the British Lung Age RCT by Parkes et al. 2 and the Swedish RCT by Stratelis et al. 3, along with the large Polish cross-sectional study by Bednarek et al. 4, add support to the notion that giving information about lung damage to smokers improves cessation rates. Why do these results differ? There are many possible explanations. It is likely that a reduced sample size and the high failure rates (>88%) in the trial by Kotz et al. 1 …
Left precordial isopotential mapping during supine exercise.
Authors: D M Mirvis, F W Keller, J W Cox, D G Zettergren, R F Dowdie, R E Ideker
Journal: Circulation (1977)

Junctional depression is often observed during physical exercise in overtly normal subjects. To explore its pathogenesis, 15 normal volunteers were studied during supine, bicycle ergometer, submaximal stress tests. Electrocardiograms were simultaneously recorded from 42 electrodes on the left anterior precordium at two minute intervals at rest and during exercise. Data were used to construct isopotential maps throughout the P-QRS-T intervals. At rest, maps throughout the ST segment were dominated by a single maximum along the upper left sternal border. During exercise, all subjects developed junctional depression that was maximal along the lower left sternal border. Exercise maps during the early to mid-ST segment showed an intense minimum along the lower left sternal border that was continuous with terminal QRS forces in both intensity and location. Later in ST, this minimum decreased in strength and was replaced by a maximum located in the same area as that observed at rest. These observations suggest that junctional depression is the result of competition between two effects, one being normal repolarization which is obscured in the early ST segment by the second, possibly representing delayed terminal depolarization forces.
Splenectomy inactivates the cholinergic antiinflammatory pathway during lethal endotoxemia and polymicrobial sepsis
Authors: Jared M. Huston, Mahendar Ochani, Mauricio Rosas-Ballina, Hong Liao, Kanta Ochani, Valentin A. Pavlov, Margot Gallowitsch-Puerta, Mala Ashok, Christopher J. Czura, Brian Foxwell, Kevin J. Tracey, Luis Ulloa
Journal: The Journal of Experimental Medicine (2006)

The innate immune system protects against infection and tissue injury through the specialized organs of the reticuloendothelial system, including the lungs, liver, and spleen. The central nervous system regulates innate immune responses via the vagus nerve, a mechanism termed the cholinergic antiinflammatory pathway. Vagus nerve stimulation inhibits proinflammatory cytokine production by signaling through the α7 nicotinic acetylcholine receptor subunit. Previously, the functional relationship between the cholinergic antiinflammatory pathway and the reticuloendothelial system was unknown. Here we show that vagus nerve stimulation fails to inhibit tumor necrosis factor (TNF) production in splenectomized animals during lethal endotoxemia. Selective lesioning of the common celiac nerve abolishes TNF suppression by vagus nerve stimulation, suggesting that the cholinergic pathway is functionally hard wired to the spleen via this branch of the vagus nerve. Administration of nicotine, an α7 agonist that mimics vagus nerve stimulation, increases proinflammatory cytokine production and lethality from polymicrobial sepsis in splenectomized mice, indicating that the spleen is critical to the protective response of the cholinergic pathway. These results reveal a specific, physiological connection between the nervous and innate immune systems that may be exploited through either electrical vagus nerve stimulation or administration of α7 agonists to inhibit proinflammatory cytokine production during infection and tissue injury.
Case presentation: a novel way of treating acute cauliflower ear in a professional rugby player: Figure 1
Authors: D J M Macdonald, N Calder, G Perrett, R G McGuiness
Journal: British Journal of Sports Medicine (2005)

Acute auricular haematoma is a common problem in rugby players and can be difficult to treat due to re-accumulation of the fluid and can subsequently cause the unsightly cauliflower ear. We present a case of auricular haematoma affecting the central part of the pinna in a professional rugby player. This was treated successfully by aspiration and the use of silicone splints which allowed the player to continue training and competing.
Genomic sequencing of meningiomas identifies oncogenic SMO and AKT1 mutations
Authors: Priscilla K Brastianos, Peleg M Horowitz, Sandro Santagata, Robert T Jones, Aaron McKenna, Gad Getz, Keith L Ligon, Emanuele Palescandolo, Paul Van Hummelen, Matthew D Ducar, Alina Raza, Ashwini Sunkavalli, Laura E MacConaill, Anat O Stemmer-Rachamimov, David N Louis, William C Hahn, Ian F Dunn, Rameen Beroukhim
Journal: Nature Genetics (2013)
Transcellular migration of leukocytes is mediated by the endothelial lateral border recycling compartment
Authors: Zahra Mamdouh, Alexei Mikhailov, William A. Muller
Journal: The Journal of Experimental Medicine (2009)

Leukocyte migration across endothelial cell borders (paracellular) and through endothelial cells (transcellular) appear to be distinct processes. During paracellular migration, membrane from a parajunctional reticulum of interconnected vesicles, the endothelial lateral border recycling compartment (LBRC), moves to surround the leukocyte in a kinesin-mediated, microtubule-dependent manner. We show that transcellular migration likewise requires targeted trafficking of LBRC membrane. We show that in addition to platelet/endothelial cell adhesion molecule (PECAM; CD31), CD99 and junctional adhesion molecule A (JAM-A), but apparently not vascular endothelial cell-specific cadherin (cadherin 5, CD144), are components of the LBRC. During transcellular migration, LBRC membrane invests the transmigrating leukocyte. Intracellular adhesion molecule 1 (ICAM-1) on the apical endothelial surface is enriched around adherent leukocytes. Depolymerization of microtubules has no effect on ICAM-1 enrichment but blocks targeted trafficking of LBRC membrane and transcellular migration by >90%. Similar to their effects on paracellular transmigration, antibodies against PECAM or CD99, but not JAM-A, block transcellular migration. We conclude that similar molecular mechanisms promote both para- and transcellular migration.
Phase I Study of Gefitinib Plus Celecoxib in Recurrent or Metastatic Squamous Cell Carcinoma of the Head and Neck
Authors: Lori J. Wirth, Robert I. Haddad, Neal I. Lindeman, Xiaojun Zhao, Jeffrey C. Lee, Victoria A. Joshi, Charles M. Norris, Marshall R. Posner
Journal: Journal of Clinical Oncology (2005)

Effective and tolerable palliative treatments are needed for patients with incurable squamous cell carcinoma of the head and neck (SCCHN). Single-agent targeted therapies have limited activity in this setting. The feasibility of adding celecoxib to gefitinib for the treatment of incurable SCCHN is unknown.Nineteen patients with unresectable recurrent locoregional and/or distant metastatic SCCHN with progressive disease after at least one prior chemotherapy or chemoradiotherapy regimen were enrolled onto this single-institution phase I study. Three dose levels were explored: (1) celecoxib 200 mg twice daily plus gefitinib 250 mg daily; (2) celecoxib 400 mg twice daily plus gefitinib 250 mg daily; and (3) celecoxib 400 mg twice daily plus gefitinib 500 mg daily.No dose-limiting toxicities were encountered at any dose level. The most common toxicities were acneiform rash, diarrhea, hand reaction, dyspepsia, and anemia. Four of 18 patients assessable for response (22%; 95% CI, 2% to 42%) achieved a confirmed partial response.The combination of gefitinib 500 mg daily plus celecoxib 400 mg twice daily is well-tolerated. The encouraging responses seen in this early study suggest further evaluation of epidermal growth factor receptor and cyclooxygenase-2 inhibitors in SCCHN is warranted.