tbuckley/cabot-search huggingface dataset:
Calcium:Magnesium Ratio in Local Groundwater and Incidence of Acute Myocardial Infarction among Males in Rural Finland
Authors: Anne Kousa, Aki S. Havulinna, Elena Moltchanova, Olli Taskinen, Maria Nikkarinen, Johan Eriksson, Marjatta Karvonen
Journal: Environmental Health Perspectives (2006)

Several epidemiologic studies have shown an association between calcium and magnesium and coronary heart disease mortality and morbidity. In this small-area study, we examined the relationship between acute myocardial infarction (AMI) risk and content of Ca, Mg, and chromium in local groundwater in Finnish rural areas using Bayesian modeling and geospatial data aggregated into 10 km times symbol 10 km grid cells. Data on 14,495 men 35-74 years of age with their first AMI in the years 1983, 1988, or 1993 were pooled. Geochemical data consisted of 4,300 measurements of each element in local groundwater. The median concentrations of Mg, Ca, and Cr and the Ca:Mg ratio in well water were 2.61 mg/L, 12.23 mg/L, 0.27 microg/L, and 5.39, respectively. Each 1 mg/L increment in Mg level decreased the AMI risk by 4.9%, whereas a one unit increment in the Ca:Mg ratio increased the risk by 3.1%. Ca and Cr did not show any statistically significant effect on the incidence and spatial variation of AMI. Results of this study with specific Bayesian statistical analysis support earlier findings of a protective role of Mg and low Ca:Mg ratio against coronary heart disease but do not support the earlier hypothesis of a protective role of Ca.
First-Line Single Agent Treatment With Gefitinib in Patients With Advanced Non–Small-Cell Lung Cancer: A Phase II Study
Authors: Seiji Niho, Kaoru Kubota, Koichi Goto, Kiyotaka Yoh, Hironobu Ohmatsu, Ryutaro Kakinuma, Nagahiro Saijo, Yutaka Nishiwaki
Journal: Journal of Clinical Oncology (2005)

Purpose We conducted a phase II study of single agent treatment with gefitinib in chemotherapy-naïve patients with advanced non–small-cell lung cancer (NSCLC) to assess its efficacy and toxicity. Patients and Methods Patients received 250 mg doses of gefitinib daily. Administration of gefitinib was terminated if partial response (PR) was not achieved within 8 weeks or if tumor reduction was not observed within 4 weeks. In these cases, platinum-based doublet chemotherapy was given as a salvage treatment. We evaluated mutation status of the epidermal growth factor receptor (EGFR) gene in cases with available tumor samples. Results Forty-two patients were enrolled between March and November 2003, with 40 of these patients being eligible. The response rate was 30% (95% CI, 17% to 47%). The most common toxicity included grade 1 or 2 acne-like rash (50%) and grade 1 diarrhea (18%). Grade 2 or 3 hepatic toxicity was observed in 8% of patients. Four patients developed grade 5 interstitial lung disease (ILD). Thirty patients received second-line chemotherapy. Median survival time was 13.9 months (95% CI, 9.1 to 18.7 months), and the 1-year survival rate was 55%. Tumor samples were available in 13 patients, including four cases of PR, six cases of stable disease, and three cases of progressive disease. EGFR mutations (deletions in exon 19 or point mutations [L858R or E746V]) were detected in four tumor tissues. All four patients with EGFR mutation achieved PR with gefitinib treatment. Conclusion Single agent treatment with gefitinib is active in chemotherapy-naïve patients with advanced NSCLC, but produces unacceptably frequent ILD in the Japanese population.
Steroid-Resistant Relapsing IgG4-Related Pachymeningitis Treated With Methotrexate
Authors: Jae-Won Hyun, Su-Hyun Kim, Heon Yoo, Eun-kyung Hong, So-Young Huh, Ho Jin Kim
Journal: JAMA Neurology (2013)

IgG4-related disease, which is newly recognized, is characterized by lymphoplasmacytic infiltration with increased IgG4-secreting plasma cells. Although a favorable response to steroids has previously been reported, the durations of follow-up to confirm the long-term benefits and clinical courses were limited. We describe long-term favorable response of oral methotrexate in a patient with IgG4-related pachymeningitis who was resistant to steroid therapy.A patient in his mid-60s with pathologically proven IgG4-related pachymeningitis who was resistant to steroid therapy and experienced an exacerbation of symptoms 4 times is described. Low-dose oral methotrexate induced significant clinical and radiological improvement, with sustained remission of the disease over 2 years without complications.The long-term favorable response to oral methotrexate in the current patient suggests that methotrexate is a useful alternative treatment option in patients with IgG4-related pachymeningitis who are resistant to steroid therapy or who experience adverse effects from steroids.
A decrease in disease activity score (DAS) level is associated with a decrease in health assessment questionnaire (HAQ) score, independent of follow-up duration, during 5 years of tightly controlled treatment: results from the BeSt study
Authors: E. van der Kooi, N. B. Klarenbeek, M. Guler-Yuksel, P. J. S. M. Kerstens, P. A. H. M. van der Lubbe, M. L. Westedt, S. ten Wolde, T. W. J. Huizinga, B. A. C. Dijkmans, C. F. Allaart
Journal: Annals of the Rheumatic Diseases (2010)

To assess the relationship between a decrease in disease activity score (DAS) and functional ability during 5 years of DAS-steered treatment in recent-onset rheumatoid arthritis (RA) patients, taking into account absolute DAS levels and follow-up duration.Data from the BeSt study were used, in which treatment was aimed at achieving DAS ≤2.4. The longitudinal relationship between 3-monthly measured DAS and health assessment questionnaire (HAQ) score was assessed using linear mixed modelling during 5 years of treatment, with DAS and HAQ 3 months earlier, change in DAS in last 3 months (delta DAS), time (log-transformed) and their interactions as determinants.Predictors for HAQ were: previous DAS, delta DAS, ln time, the interaction previous DAS×delta DAS, and previous HAQ. The interaction ln time×delta DAS was non-significant, indicating that the association between delta DAS and HAQ was independent of follow-up duration. A decrease from a higher DAS was associated with a smaller HAQ decrease than for a similar decrease from a lower DAS, indicating a non-linear relationship between DAS and HAQ.At any time during 5 years of follow-up, a decrease in DAS was associated with a better functional ability. The magnitude of HAQ improvement depends on the DAS decrease and on the absolute DAS level.
Identification of<i>NTN4, TRA1</i>, and<i>STC2</i>as Prognostic Markers in Breast Cancer in a Screen for Signal Sequence Encoding Proteins
Authors: Selma Esseghir, Alan Kennedy, Pooja Seedhar, Ashutosh Nerurkar, Richard Poulsom, Jorge S. Reis-Filho, Clare M. Isacke
Journal: Clinical Cancer Research (2007)

Abstract Purpose: In a previous screen using a signal-trap library, we identified a number of secreted proteins up-regulated in primary tumor cells isolated from invasive breast cancers. The purpose of this study was to assess the expression of these genes in human invasive breast tumors and to determine the significance of their expression for prognosis in breast cancer. Experimental Design: A tissue microarray containing 245 invasive breast tumors from women treated with curative surgery followed by anthracycline-based chemotherapy and hormone therapy for the estrogen receptor (ER)–positive tumors was screened by in situ hybridization with probes against thrombospondin 3 (TSP3), insulin-like growth factor binding protein 7 (IGFBP7), tumor rejection antigen 1 (TRA1), stanniocalcin 2 (STC2), and netrin 4 (NTN4). Correlations between categorical variables were done using the χ2 test and Fisher's exact test. Cumulative survival probabilities were calculated using the Kaplan-Meier method and multivariate survival analysis was done with Cox hazard model. A series of breast cancers were also stained with NTN4 antibodies. Results: All five genes examined were expressed in invasive breast tumor cells. NTN4 protein expression was also confirmed by immunohistochemistry. Together, these data validate the design and screening of the signal-trap library. Univariate survival analysis revealed that expressions of TRA1, STC2, and NTN4 are correlated with longer disease-free survival and that TRA1 and NTN4 are associated with longer overall survival. Multivariate analysis showed that NTN4 is an independent prognostic factor of overall survival. Conclusions: This article describes the identification of three secreted proteins, NTN4, TRA1, and STC2, as potential novel prognostic markers in breast cancer.
Prediction of Drug Response in Breast Cancer Using Integrative Experimental/Computational Modeling
Authors: Hermann B. Frieboes, Mary E. Edgerton, John P. Fruehauf, Felicity R.A.J. Rose, Lisa K. Worrall, Robert A. Gatenby, Mauro Ferrari, Vittorio Cristini
Journal: Cancer Research (2009)

Nearly 30% of women with early-stage breast cancer develop recurrent disease attributed to resistance to systemic therapy. Prevailing models of chemotherapy failure describe three resistant phenotypes: cells with alterations in transmembrane drug transport, increased detoxification and repair pathways, and alterations leading to failure of apoptosis. Proliferative activity correlates with tumor sensitivity. Cell-cycle status, controlling proliferation, depends on local concentration of oxygen and nutrients. Although physiologic resistance due to diffusion gradients of these substances and drugs is a recognized phenomenon, it has been difficult to quantify its role with any accuracy that can be exploited clinically. We implement a mathematical model of tumor drug response that hypothesizes specific functional relationships linking tumor growth and regression to the underlying phenotype. The model incorporates the effects of local drug, oxygen, and nutrient concentrations within the three-dimensional tumor volume, and includes the experimentally observed resistant phenotypes of individual cells. We conclude that this integrative method, tightly coupling computational modeling with biological data, enhances the value of knowledge gained from current pharmacokinetic measurements, and, further, that such an approach could predict resistance based on specific tumor properties and thus improve treatment outcome.
Carcinogenicity of polychlorinated biphenyls and polybrominated biphenyls
Authors: Béatrice Lauby-Secretan, Dana Loomis, Yann Grosse, Fatiha El Ghissassi, Véronique Bouvard, Lamia Benbrahim-Tallaa, Neela Guha, Robert Baan, Heidi Mattock, Kurt Straif, . Iarc Working Group, Jean Pierre J. P. Cravedi
Journal: The Lancet Oncology (2013)
Is Pneumonia a Risk Factor or a Risk Marker for Long-Term Mortality?
Authors: Carlos G. Grijalva
Journal: American Journal of Respiratory and Critical Care Medicine (2015)

Pneumonia is a leading cause of morbidity and short-term mortality (usually measured in the first 30 days after diagnosis) (1–4). However, the potential long-term consequences of pneumonia remain an area of intense evaluation. Several studies have focused on the long-term risk for mortality among patients with pneumonia. In most studies, patients with more severe pneumonia had a higher risk for long-term mortality relative to patients with less severe pneumonia. As older patients with debilitating comorbidities, including diabetes and glucose homeostasis disturbances, are usually classified in the higher-risk categories, this could explain, at least in part, the higher risk observed among patients with more severe pneumonia (3–8).
Remogliflozin Etabonate, a Selective Inhibitor of the Sodium-Glucose Transporter 2, Improves Serum Glucose Profiles in Type 1 Diabetes
Authors: Sunder Mudaliar, Debra A. Armstrong, Annie A. Mavian, Robin O’Connor-Semmes, Patricia K. Mydlow, June Ye, Elizabeth K. Hussey, Derek J. Nunez, Robert R. Henry, Robert L. Dobbins
Journal: Diabetes Care (2012)

Remogliflozin etabonate (RE), an inhibitor of the sodium-glucose transporter 2, improves glucose profiles in type 2 diabetes. This study assessed safety, tolerability, pharmacokinetics, and pharmacodynamics of RE in subjects with type 1 diabetes.Ten subjects managed with continuous subcutaneous insulin infusion were enrolled. In addition to basal insulin, subjects received five randomized treatments: placebo, prandial insulin, 50 mg RE, 150 mg RE, and mg RE 500.Adverse events and incidence of hypoglycemia with RE did not differ from placebo and prandial insulin groups. RE significantly increased urine glucose excretion and reduced the rise in plasma glucose concentration after oral glucose. RE reduced incremental adjusted weighted mean glucose (0-4 h) values by 42-49 mg/dL and mean glucose (0-10 h) by 52-69 mg/dL.RE can be safely administered with insulin in type 1 diabetes and reduces plasma glucose concentrations compared with placebo.
Systemic antithrombotic effects of ADAMTS13
Authors: Anil K. Chauhan, David G. Motto, Colin B. Lamb, Wolfgang Bergmeier, Michael Dockal, Barbara Plaimauer, Friedrich Scheiflinger, David Ginsburg, Denisa D. Wagner
Journal: The Journal of Experimental Medicine (2006)

The metalloprotease ADAMTS13 (a disintegrin-like and metalloprotease with thrombospondin type I repeats 13) cleaves highly adhesive large von Willebrand factor (VWF) multimers after their release from the endothelium. ADAMTS13 deficiency is linked to a life-threatening disorder, thrombotic thrombocytopenic purpura (TTP), characterized by platelet-rich thrombi in the microvasculature. Here, we show spontaneous thrombus formation in activated microvenules of Adamts13−/− mice by intravital microscopy. Strikingly, we found that ADAMTS13 down-regulates both platelet adhesion to exposed subendothelium and thrombus formation in injured arterioles. An inhibitory antibody to ADAMTS13 infused in wild-type mice prolonged adhesion of platelets to endothelium and induced thrombi formation with embolization in the activated microvenules. Absence of ADAMTS13 did not promote thrombi formation in αIIbβ3 integrin-inhibited blood. Recombinant ADAMTS13 reduced platelet adhesion and aggregation in histamine-activated venules and promoted thrombus dissolution in injured arterioles. Our findings reveal that ADAMTS13 has a powerful natural antithrombotic activity and recombinant ADAMTS13 could be used as an antithrombotic agent.
Precision of Larsen grading of radiographs in assessing progression of rheumatoid arthritis in individual patients.
Authors: M M O'Sullivan, P A Lewis, R G Newcombe, N J Broderick, D A Robinson, E C Coles, J D Jessop
Journal: Annals of the Rheumatic Diseases (1990)

A study was designed to evaluate observer variation in the assessment of radiographic deterioration of individual patients using the Larsen grading system. Radiographs of hands and feet of 52 patients were assessed by three observers. Each patient had paired films taken one year apart which were assessed together for change in score. To assess within-observer variation each set of films was read twice by all observers. The average progression was 11.6 (SD 9.0). Analysis of the source of variation showed the single observer replication SD to be 3.7 but that for different observers to be 5.5. This may be interpreted as indicating that to achieve 95% confidence of detecting a true change an increase in Larsen score of 8 is required if the same observer assesses or up to 11 if a different observer assesses.
Synergistic Proinflammatory Effects of the Antiviral Cytokine Interferon-α and Toll-Like Receptor 4 Ligands in the Atherosclerotic Plaque
Authors: Alexander Niessner, Min Sun Shin, Olga Pryshchep, Jörg J. Goronzy, Elliot L. Chaikof, Cornelia M. Weyand
Journal: Circulation (2007)

Background— Interferon (IFN)-α is a pluripotent inflammatory cytokine typically induced by viral infections. In rupture-prone atherosclerotic plaques, plasmacytoid dendritic cells produce IFN-α. In the present study we explored the contribution of IFN-α to inflammation and tissue injury in the plaque microenvironment. Methods and Results— In 53% of carotid plaques (n=30), CD123 + plasmacytoid dendritic cells clustered together with CD11c + myeloid dendritic cells, a distinct dendritic cell subset specialized in sensing danger signals from bacteria and tissue breakdown. Tissue concentrations of IFN-α and tumor necrosis factor (TNF)-α transcripts were tightly correlated ( r =0.76, P &lt;0.001), suggesting a regulatory role of IFN-α in TNF-α production. Plaque tissue stimulation with CpG ODN, a Toll-like receptor (TLR) 9 ligand, increased IFN-α production (57.8±23.7 versus 25.9±8.6 pg/mL; P &lt;0.001), whereas the TLR4 ligand lipopolysaccharide induced TNF-α secretion (225.1±3.0 versus 0.7±0.2 pg/mL; P &lt;0.001). Treating plaque tissue with IFN-α markedly enhanced lipopolysaccharide-triggered TNF-α secretion (559.0±25.9 versus 225.1±3.0 pg/mL; P &lt;0.001). IFN-α pretreatment also amplified the effects of lipopolysaccharide on interleukin-12, interleukin-23, and matrix metalloproteinase-9, suggesting that the antiviral cytokine sensitized myeloid dendritic cells and macrophages toward TLR4 ligands. Mechanistic studies demonstrated that IFN-α modulated the myeloid dendritic cell response pattern by upregulating TLR4 expression ( P &lt;0.001) involving both the STAT (signal transducer and activator of transcription) and the PI(3)K pathway. Conclusions— In the atherosclerotic plaque, IFN-α functions as an inflammatory amplifier. It sensitizes antigen-presenting cells toward pathogen-derived TLR4 ligands by upregulating TLR4 expression and intensifies TNF-α, interleukin-12, and matrix metalloproteinase-9 production, all implicated in plaque destabilization. Thus, IFN-α–inducing pathogens, even when colonizing distant tissue sites, threaten the stability of inflamed atherosclerotic plaque.
Recombination Shapes the Natural Population Structure of the Hyperthermophilic Archaeon Sulfolobus islandicus
Authors: Rachel J. Whitaker, Dennis W. Grogan, John W. Taylor
Journal: Molecular Biology and Evolution (2005)

Although microorganisms make up the preponderance of the biodiversity on Earth, the ecological and evolutionary factors that structure microbial populations are not well understood. We investigated the genetic structure of a thermoacidophilic crenarchaeal species, Sulfolobus islandicus, using multilocus sequence analysis of six variable protein-coding loci on a set of 60 isolates from the Mutnovsky region of Kamchatka, Russia. We demonstrate significant incongruence among gene genealogies and a lack of association between alleles consistent with recombination rates greater than the rate of mutation.The observation of high relative rates of recombination suggests that the structure of this natural population does not fit the periodic selection model often used to describe populations of asexual microorganisms. We propose instead that frequent recombination among closely related individuals prevents periodic selection from purging diversity and provides a fundamental cohesive mechanism within this and perhaps other archaeal species.
Axotomy-induced neurotrophic withdrawal causes the loss of phenotypic differentiation and downregulation of NGF signalling, but not death of septal cholinergic neurons
Authors: Oscar M Lazo, Jocelyn C Mauna, Claudia A Pissani, Nibaldo C Inestrosa, Francisca C Bronfman
Journal: Molecular Neurodegeneration (2010)

Abstract Background Septal cholinergic neurons account for most of the cholinergic innervations of the hippocampus, playing a key role in the regulation of hippocampal synaptic activity. Disruption of the septo-hippocampal pathway by an experimental transection of the fimbria-fornix drastically reduces the target-derived trophic support received by cholinergic septal neurons, mainly nerve growth factor (NGF) from the hippocampus. Axotomy of cholinergic neurons induces a reduction in the number of neurons positive for cholinergic markers in the medial septum. In several studies, the reduction of cholinergic markers has been interpreted as analogous to the neurodegeneration of cholinergic cells, ruling out the possibility that neurons lose their cholinergic phenotype without dying. Understanding the mechanism of cholinergic neurodegeneration after axotomy is relevant, since this paradigm has been extensively explored as an animal model of the cholinergic impairment observed in neuropathologies such as Alzheimer's disease. The principal aim of this study was to evaluate, using modern quantitative confocal microscopy, neurodegenerative changes in septal cholinergic neurons after axotomy and to assess their response to delayed infusion of NGF in rats. Results We found that there is a slow reduction of cholinergic cells labeled by ChAT and p75 after axotomy. However, this phenomenon is not accompanied by neurodegenerative changes or by a decrease in total neuronal number in the medial septum. Although the remaining axotomized-neurons appear healthy, they are unable to respond to delayed NGF infusion. Conclusions Our results demonstrate that at 3 weeks, axotomized cholinergic neurons lose their cholinergic phenotype without dying and down-regulate their NGF-receptors, precluding the possibility of a response to NGF. Therefore, the physiological role of NGF in the adult septal cholinergic system is to support phenotypic differentiation and not survival of neurons. This evidence raises questions about the relationship between transcriptional regulation of the cholinergic phenotype by retrograde-derived trophic signaling and the transcriptional changes experienced when retrograde transport is impaired due to neuropathological conditions.
Deuterostome phylogeny and the sister group of the chordates: evidence from molecules and morphology.
Authors: J M Turbeville, J R Schulz, R A Raff
Journal: Molecular Biology and Evolution (1994)

Complete coding regions of the 18S rRNA gene of an enteropneust hemichordate and an echinoid and ophiuroid echinoderm were obtained and aligned with 18S rRNA gene sequences of all major chordate clades and four outgroups. Gene sequences were analyzed to test morphological character phylogenies and to assess the strength of the signal. Maximum-parsimony analysis of the sequences fails to support a monophyletic Chordata; the urochordates form the sister taxon to the hemichordates, and together this clade plus the echinoderms forms the sister taxon to the cephalochordates plus craniates. Decay, bootstrap, and tree-length distribution analyses suggest that the signal for inference of dueterostome phylogeny is weak in this molecule. Parsimony analysis of morphological plus molecular characters supports both monophyly of echinoderms plus enteropneust hemichordates and a sister group relationship of this clade to chordates. Evolutionary parsimony does not support chordate monophyly. Neighbor-joining, Fitch-Margoliash, and maximum-likelihood analyses support a chordate lineage that is the sister group to an echinoderm-plus-hemichordate lineage. The results illustrate both the limitations of the 18S rRNA molecule alone for high-level phylogeny inference and the importance of considering both molecular and morphological data in phylogeny reconstruction.