tbuckley/cabot-search huggingface dataset:
MULTIMODAL REPRESENTATION OF SPACE IN THE POSTERIOR PARIETAL CORTEX AND ITS USE IN PLANNING MOVEMENTS
Authors: Richard A. Andersen, Lawrence H. Snyder, David C. Bradley, Jing Xing
Journal: Annual Review of Neuroscience (1997)

▪ Abstract Recent experiments are reviewed that indicate that sensory signals from many modalities, as well as efference copy signals from motor structures, converge in the posterior parietal cortex in order to code the spatial locations of goals for movement. These signals are combined using a specific gain mechanism that enables the different coordinate frames of the various input signals to be combined into common, distributed spatial representations. These distributed representations can be used to convert the sensory locations of stimuli into the appropriate motor coordinates required for making directed movements. Within these spatial representations of the posterior parietal cortex are neural activities related to higher cognitive functions, including attention. We review recent studies showing that the encoding of intentions to make movements is also among the cognitive functions of this area.
Exercise capacity and physical activity in new GOLD classification
Authors: Anna Rodo-Pin, Diego A. Rodriguez, Angela Roig Andreu, Laura Guiterrez Martin, Ana Balaña, Mireia Admetllo, Juana Mª Martinez-Llorens, Joaquim Gea
Journal: European Respiratory Journal (2013)

Introduction: The new GOLD guideline is based on the joint evaluation of the impact of patients symptoms and the risk of future adverse events on health. Exercise capacity (EC) and physical activity (PA), two factors with relevant prognostic implications, have not been included in the new strategy.  Methods: The aim of the study was to evaluate EC and PA and their relationships with the new GOLD classification. To this objective, 100 COPD patients were prospectively recruited. EC was evaluated by the 6-minute walk test (6MWT) whereas PA was assessed by the short version of International Physical Activity Questionnaire (IPAQ).  Results: COPD patients (78% male) showed severe airflow limitation (mean ± SD; FEV1; 44±14%predicted) and 18% had obesity. The distribution according to new GOLD stages was: A: 13.8%, B: 22.8%, C: 18.2%, D: 47.2%. Subjects in stage D showed a reduced walking distance (378±90m) when compare with those in stage A (441±76m) or B (457±86m) (p=0,009), without differences with stage C (380±90m). Moreover, a low level of PA was detected in 29% of the patients and higher in 34%. Vigorous physical activities were significantly reduced in stage D when compared with all the other stages (p=0.036). However, the time that usually spend sitting was similar in all stages (p=0.185). A moderate but significant correlation between 6MWT (m) and total PA (MET-minutes week) was observed (r, 0.45, p=0,001).  Conclusion: EC and PA showed poor association with new GOLD stages. Further studies should evaluate the consequences of such a lack of relationship in prognosis.
Long-Term Observations in Patients with Angina and Normal Coronary Arteriograms
Authors: CARL R. BEMILLER, CARL J. PEPINE, ALBERT K. ROGERS
Journal: Circulation (1973)

Thirty-seven patients (mean age 42.7 years) with angina pectoris (AP), ischemic myocardial abnormalities, and normal coronary arteriograms were followed for 4.1 years (mean). Twenty patients had typical and 17 atypical AP. Ten had abnormal serum lipids, and eight had abnormal glucose tolerance tests. Rest-to-exercise hemodynamics revealed increased left ventricular (LV) end-diastolic pressure (mean 11.2 ± 2.6 mm Hg → 19.1 ± 3.6, P &lt; 0.05), while stroke-work index increased (+29%). LV ischemia was detected by abnormal lactate extraction with atrial pacing in 10 or ≧1 mm S-T segment depression during exercise or pacing in 27 patients. After a mean follow-up period of 4.1 years, AP decreased in 80% of cases and remained stable in the other 20% of cases. One patient died suddenly, and autopsy revealed normal coronary arteries and myocardium. In the remainder, complications of ischemia, i.e. progression of symptoms, infarction, and heart failure were absent. Seven patients restudied 4.5 years (mean) later had no changes in their previously documented hemodynamic abnormalities and normal coronary arteriograms. The fate of patients with AP and normal coronaries with ischemic LV abnormalities (ECG, metabolic, or hemodynamic) appears favorable. AP responds to nitrate and propranolol therapy. These long-term clinical observations with angiographic and hemodynamic restudies suggest a nonprogressive disorder.
Nod1 acts as an intracellular receptor to stimulate chemokine production and neutrophil recruitment in vivo
Authors: Junya Masumoto, Kangkang Yang, Sooryanarayana Varambally, Mizuho Hasegawa, Scott A. Tomlins, Su Qiu, Yukari Fujimoto, Akiko Kawasaki, Simon J. Foster, Yasuo Horie, Tak W. Mak, Gabriel Núñez, Arul M. Chinnaiyan, Koichi Fukase, Naohiro Inohara
Journal: The Journal of Experimental Medicine (2006)

Nod1 is a member of family of intracellular proteins that mediate host recognition of bacterial peptidoglycan. To characterize immune responses mediated by Nod1, synthetic ligand compounds possessing enhanced ability to stimulate Nod1 were developed to study the function of Nod1. Stimulation of epithelial cells with Nod1 stimulatory molecules induced chemokines and other proinflammatory molecules that are important for innate immune responses and recruitment of acute inflammatory cells. Administration of Nod1 ligands into mice induced chemokines and recruitment of acute inflammatory cells, an activity that was abolished in Nod1-null mice. Microarray analysis revealed that Nod1 stimulation induces a restricted number of genes in intestinal epithelial cells compared with that induced by tumor necrosis factor (TNF) α. Nod1 stimulation did not induce TNFα, interleukin 12, and interferon γ, suggesting that the primary role of Nod1 is to induce the recruitment of immune cells. These results indicate that Nod1 functions as a pathogen recognition molecule to induce expression of molecules involved in the early stages of the innate immune response.
Connective Tissue Growth Factor Confers Drug Resistance in Breast Cancer through Concomitant Up-regulation of Bcl-xL and cIAP1
Authors: Ming-Yang Wang, Pai-Sheng Chen, Ekambaranellore Prakash, Hsing-Chih Hsu, Hsin-Yi Huang, Ming-Tsan Lin, King-Jen Chang, Min-Liang Kuo
Journal: Cancer Research (2009)

Connective tissue growth factor (CTGF) expression is elevated in advanced breast cancer and promotes metastasis. Chemotherapy response is only transient in most metastatic diseases. In the present study, we examined whether CTGF expression could confer drug resistance in human breast cancer. In breast cancer patients who received neoadjuvant chemotherapy, CTGF expression was inversely associated with chemotherapy response. Overexpression of CTGF in MCF7 cells (MCF7/CTGF) enhanced clonogenic ability, cell viability, and resistance to apoptosis on exposure to doxorubicin and paclitaxel. Reducing the CTGF level in MDA-MB-231 (MDA231) cells by antisense CTGF cDNA (MDA231/AS cells) mitigated this drug resistance capacity. CTGF overexpression resulted in resistance to doxorubicin- and paclitaxel-induced apoptosis by up-regulation of Bcl-xL and cellular inhibitor of apoptosis protein 1 (cIAP1). Knockdown of Bcl-xL or cIAP1 with specific small interfering RNAs abolished the CTGF-mediated resistance to apoptosis induced by the chemotherapeutic agents in MCF7/CTGF cells. Inhibition of extracellular signal-regulated kinase (ERK)-1/2 effectively reversed the resistance to apoptosis as well as the up-regulation of Bcl-xL and cIAP1 in MCF7/CTGF cells. A neutralizing antibody against integrin alpha(v)beta(3) significantly attenuated CTGF-mediated ERK1/2 activation and up-regulation of Bcl-xL and cIAP1, indicating that the integrin alpha(v)beta(3)/ERK1/2 signaling pathway is essential for CTGF functions. The Bcl-xL level also correlated with the CTGF level in breast cancer patients. We also found that a COOH-terminal domain peptide from CTGF could exert activities similar to full-length CTGF, in activation of ERK1/2, up-regulation of Bcl-xL/cIAP1, and resistance to apoptosis. We conclude that CTGF expression could confer resistance to chemotherapeutic agents through augmenting a survival pathway through ERK1/2-dependent Bcl-xL/cIAP1 up-regulation.
New Formulation of Paraquat: A Step Forward but in the Wrong Direction?
Authors: D. Nicholas Bateman
Journal: PLoS Medicine (2008)

Paraquat is a contact herbicide (one that kills plants by contact rather than being taken up in the roots and acting systemically) that is extensively used in agriculture, as it is fast-acting and non-persistent in the environment. It has, however, one major problem—its toxicity when ingested. The mechanisms of this toxicity are well understood and were described in detail over 20 years ago [1]. Paraquat is marketed for agricultural use as a concentrated solution, and in this form it is estimated that as little as a mouthful ingested is likely to be fatal.

Blood levels of paraquat are indicative of outcome [2], but many patients have levels over 100 times the estimated lethal concentration, making treatment extremely difficult. In these patients, death may occur within a few hours from multi-organ toxicity. In less severe cases renal failure and gastrointestinal upset occur, resulting in death within two or three days if untreated. If these complications are managed by haemodialysis and fluid resuscitation, pulmonary fibrosis follows due to redox recycling (repetitive oxidation and reduction of the molecule, using up cellular energy) of paraquat in the lung. Death is then secondary to anoxia several days later; early oxygen treatment is thought to increase the risk of lung damage as it fuels the redox process.

Twenty years ago it was clear that treatments for paraquat poisoning were ineffective and that new approaches to managing such poisoning were required [3]. In the intervening period, small-scale studies have suggested a potential role for immunosuppressants [4] in preventing death from lung injury, but the efficacy of this treatment remains in doubt [5].

Linked Research Article
This Perspective discusses the following new study published in PLoS Medicine:

Wilks MF, Fernando R, Ariyananda PL, Eddleston M, Berry DJ, et al. (2008) Improvement in survival after paraquat ingestion following introduction of a new formulation in Sri Lanka. PLoS Med 5(2): e49. doi:10.1371/journal.pmed.0050049

Martin Wilks and colleagues compared the outcome of paraquat self-poisoning with the standard formulation against a new formulation following its introduction into Sri Lanka.
Social position and mortality from respiratory diseases in males and females
Authors: E. Prescott, N. Godtfredsen, J. Vestbo, M. Osler
Journal: European Respiratory Journal (2003)

Although social differences in respiratory diseases are considerable, few studies have focused on this disease entity using mortality as an outcome. Does mortality from respiratory disease, including chronic obstructive pulmonary disease (COPD) differ with social position measured by education, income, housing and employment grade? The study population consisted of 26,392 males and females from pooling of two population studies in the Copenhagen area. Data was linked with information from social registers in Statistics Denmark. The relationship between socioeconomic factors and risk of death from respiratory disease and COPD was assessed with an average duration of follow-up of 12 yrs. Education was strongly associated with respiratory mortality in both sexes. The association was stronger in later birth cohorts comparing the highest level of education (&gt;11 yrs) with the lowest (&lt;8 yrs). Although smoking rates were inversely associated with the level of education, the social gradient was not affected by adjustment for smoking. In males, but not in females, there was an additional effect of other indicators of social position, i.e. employment grade (white collar versus blue collar), household income, housing conditions (less than one person per room versus more), and cohabitation (cohabiting versus living alone). Similar results were found for mortality from COPD. The results confirm the existence of a strong social gradient in respiratory mortality and chronic obstructive pulmonary disease, which is independent of smoking and is stronger in males. Social disadvantage is a potentially avoidable cause of death from respiratory disease and further research is needed to explain the excess risk in the socioeconomically disadvantaged.
REACTIONS OF RABBITS TO NON-HEMOLYTIC STREPTOCOCCI: III. A STUDY OF MODES OF SENSITIZATION
Authors: C. L. Derick
Journal: The Journal of Experimental Medicine (1930)

The most satisfactory method thus far found for the induction and maintenance of a high degree of hypersensitiveness-"allergy," "hyperergy"-against non-hemolytic streptococci consists in the repeated production of small focal lesions with minimal doses of bacteria. After a preliminary sensitizing period of about 2 weeks' duration with either large initial, or small multiple daily inoculations, the later foci need be produced only at 7 to 10 day intervals. Chronicity of low-grade infection appears to be an important factor in the attainment of a high degree of hypersensitiveness.
Association of Triglyceride–to–HDL Cholesterol Ratio With Heart Rate Recovery
Authors: Mehdi H. Shishehbor, Byron J. Hoogwerf, Michael S. Lauer
Journal: Diabetes Care (2004)

OBJECTIVE—Insulin resistance is associated with autonomic dysfunction. An attenuated decrease in heart rate after exercise (or heart rate recovery [HRR]) predicts all-cause mortality and is believed to reflect decreased parasympathetic activity. Utilizing triglyceride/HDL cholesterol concentration as a marker of insulin resistance, we sought to assess the association between insulin resistance and HRR. RESEARCH DESIGN AND METHODS—Our study population included 4,963 healthy adults who participated in the Lipid Research Clinics Prevalence Study and underwent exercise testing. HRR was considered abnormal if it did not drop ≥42 bpm 2 min after completion of exercise. Fasting blood specimens were drawn. RESULTS—Individuals in the highest quartile of triglyceride/HDL cholesterol had a significantly higher prevalence of abnormal HRR (40 vs. 30%, multivariable-adjusted prevalence ratio 1.18, 95% CI 1.01–1.39; P = 0.04). As a continuous variable, an increase in 1 SD of triglyceride–to–HDL cholesterol ratio was associated with a greater likelihood of an abnormal HRR, even after adjusting for &amp;gt;20 covariates (adjusted OR 1.16, 95% CI 1.07–1.25; P &amp;lt; 0.001). During 12 years of follow-up, there were 284 deaths. In age- and sex-adjusted analysis, participants with an abnormal HRR and high triglyceride–to–HDL cholesterol ratio had significantly higher mortality than those with a normal HRR and high triglyceride–to–HDL cholesterol ratio (hazard ratio = 1.49, 95% CI 1.08–2.04; P = 0.015). CONCLUSIONS—HRR is associated with triglyceride–to–HDL cholesterol ratio and identifies patients with insulin resistance who are at increased risk of death.
Abstract A68: GPCRs as potential therapeutic targets in pancreatic cancer-associated fibroblasts
Authors: Shu Zhou, Randall French, Andrew M. Lowy, Paul A. Insel
Journal: Cancer Research (2015)

Abstract Pancreatic ductal adenocarcinoma (PDAC) is characterized by a dense fibrotic stromal matrix, composed of activated fibroblasts/stellate cells, inflammatory cells and other cell types. This unique tumor microenvironment has been increasingly recognized as a key mediator of PDAC progression and drug resistance. Thus, targeting the tumor stroma may be a novel therapeutic approach for PDAC. We hypothesized that G protein-coupled receptors (GPCRs) expressed by pancreatic cancer-associated fibroblasts (CAFs) may be potential therapeutic targets for PDAC. To begin to test this hypothesis, we used an unbiased GPCRomic array approach to identify and quantify the GPCRs expressed by pancreatic CAFs. We found 125 GPCRs, whose expression was shared in CAFs obtained from the primary tumors of five patients. Among those GPCRs, 35 had at least two-fold higher expression in the CAFs compared to normal pancreatic fibroblasts and included GPCRs that link to each of the major classes of G proteins. RT-PCR analysis of the 10 most up-regulated GPCRs correlated well (r2=0.88) with the data from the GPCR array. We conclude that: 1) GPCRomic array analysis can identify and quantify the profile of GPCRs expressed by pancreatic CAFs; 2) the CAF-expressed profile differs from that of normal pancreatic fibroblasts and 3) GPCRs expressed by CAFs may have functional roles and be novel therapeutic targets for PDAC. Citation Format: Shu Zhou, Randall French, Andrew M. Lowy, Paul A. Insel. GPCRs as potential therapeutic targets in pancreatic cancer-associated fibroblasts. [abstract]. In: Abstracts: AACR Special Conference on Cellular Heterogeneity in the Tumor Microenvironment; 2014 Feb 26-Mar 1; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2015;75(1 Suppl):Abstract nr A68. doi:10.1158/1538-7445.CHTME14-A68
Mutation-Biased Adaptation in a Protein NK Model
Authors: Arlin Stoltzfus
Journal: Molecular Biology and Evolution (2006)

Evolutionary trends responsible for systematic differences in genome and proteome composition have been attributed to GC:AT mutation bias in the context of neutral evolution or to selection acting on genome composition. A possibility that has been ignored, presumably because it is part of neither the Modern Synthesis nor the Neutral Theory, is that mutation may impose a directional bias on adaptation. This possibility is explored here with simulations of the effect of a GC:AT bias on amino acid composition during adaptive walks on an abstract protein fitness landscape called an "NK" model. The results indicate that adaptation does not preclude mutation-biased evolution. In the complete absence of neutral evolution, a modest GC:AT bias of realistic magnitude can displace the trajectory of adaptation in a mutationally favored direction, to such a degree that amino acid composition is biased substantially and persistently. Thus, mutational explanations for evolved patterns need not presuppose neutral evolution.
TLiSA1, a human T lineage-specific activation antigen involved in the differentiation of cytotoxic T lymphocytes and anomalous killer cells from their precursors.
Authors: G F Burns, T Triglia, J A Werkmeister, C G Begley, A W Boyd
Journal: The Journal of Experimental Medicine (1985)

The characteristics of a novel T lineage-specific activation antigen, termed TLiSA1, are described. The antigen was detected with a mouse monoclonal antibody, LeoA1, that was raised against activated human T cells generated in mixed lymphocyte culture (MLC). The antigen became strongly expressed on T cells 48-72 h after stimulation with phytohemagglutinin, and retained expression on MLC-activated T cells after 10 d of culture. The antigen was absent from a range of human T, B, myeloid, fibroblast, and tumour cell lines, but was present on the surface of the interleukin 2 (IL-2)-dependent gibbon cell line MLA-144. Analysis of the antigen by sodium dodecyl sulfate-polyacrylamide gel electrophoresis of immunoprecipitates obtained from activated human T cells demonstrated a broad band in the region of 70 kD, whereas precipitates obtained from MLA-144 revealed a single narrow band of 95 kD. The molecule was expressed with a maximum density of 66,000 copies per cell on the surface of MLC-activated T cell blasts, as assessed by Scatchard analysis. TLiSA1 was distinguished from the IL-2 receptor bound by the anti-Tac monoclonal antibody by demonstrating that the antigens did not comodulate or coprecipitate, and by constructing an IL-2-independent human T X T hybrid that expressed the TLiSA1 but not the Tac antigen. MLC with B lymphoblasts was used to generate cytotoxic T lymphocytes (CTL) specific for the stimulating cell, and anomalous killer (AK) cells able to kill melanoma target cells. The presence of LeoA1 or F(ab')2 fragments of the antibody from the beginning of coculture did not affect proliferation in these cultures, but did inhibit the induction of both CTL and AK cells from their precursors. This inhibition of differentiation by LeoA1 was confirmed under conditions of limiting dilution, where it was shown that the antibody reduced the frequency of CTL produced, and greatly (fourfold) reduced the frequency of AK cells generated from their precursors. We discuss the possibility that human CTL may express a differentiation factor receptor that is distinct from the receptor for IL-2.
Efficacy of Intravenous Ketamine for Treatment of Chronic Posttraumatic Stress Disorder
Authors: Adriana Feder, Michael K. Parides, James W. Murrough, Andrew M. Perez, Julia E. Morgan, Shireen Saxena, Katherine Kirkwood, Marije aan het Rot, Kyle A. B. Lapidus, Le-Ben Wan, Dan Iosifescu, Dennis S. Charney
Journal: JAMA Psychiatry (2014)

Few pharmacotherapies have demonstrated sufficient efficacy in the treatment of posttraumatic stress disorder (PTSD), a chronic and disabling condition.To test the efficacy and safety of a single intravenous subanesthetic dose of ketamine for the treatment of PTSD and associated depressive symptoms in patients with chronic PTSD.Proof-of-concept, randomized, double-blind, crossover trial comparing ketamine with an active placebo control, midazolam, conducted at a single site (Icahn School of Medicine at Mount Sinai, New York, New York). Forty-one patients with chronic PTSD related to a range of trauma exposures were recruited via advertisements.Intravenous infusion of ketamine hydrochloride (0.5 mg/kg) and midazolam (0.045 mg/kg).The primary outcome measure was change in PTSD symptom severity, measured using the Impact of Event Scale-Revised. Secondary outcome measures included the Montgomery-Asberg Depression Rating Scale, the Clinical Global Impression-Severity and -Improvement scales, and adverse effect measures, including the Clinician-Administered Dissociative States Scale, the Brief Psychiatric Rating Scale, and the Young Mania Rating Scale.Ketamine infusion was associated with significant and rapid reduction in PTSD symptom severity, compared with midazolam, when assessed 24 hours after infusion (mean difference in Impact of Event Scale-Revised score, 12.7 [95% CI, 2.5-22.8]; P = .02). Greater reduction of PTSD symptoms following treatment with ketamine was evident in both crossover and first-period analyses, and remained significant after adjusting for baseline and 24-hour depressive symptom severity. Ketamine was also associated with reduction in comorbid depressive symptoms and with improvement in overall clinical presentation. Ketamine was generally well tolerated without clinically significant persistent dissociative symptoms.This study provides the first evidence for rapid reduction in symptom severity following ketamine infusion in patients with chronic PTSD. If replicated, these findings may lead to novel approaches to the pharmacologic treatment of patients with this disabling condition.clinicaltrials.gov Identifier: NCT00749203.