tbuckley/cabot-search huggingface dataset:
Effects of Alzheimer's disease severity on cerebrospinal fluid norepinephrine concentration
Authors: R Elrod, E R Peskind, L DiGiacomo, K I Brodkin, R C Veith, M A Raskind
Journal: American Journal of Psychiatry (1997)

Although loss of noradrenergic neurons in the locus ceruleus has been consistently demonstrated postmortem in Alzheimer's disease, several small studies suggest that indices of central noradrenergic activity increase with the severity of Alzheimer's disease in living patients. The authors estimated the effect of Alzheimer's disease severity on central noradrenergic activity by comparing the CSF norepinephrine concentrations of subjects with Alzheimer's disease in earlier and advanced stages. The effect of normal aging on CSF norepinephrine also was determined.Lumbar punctures were performed in 49 subjects with Alzheimer's disease of mild or moderate severity, 25 subjects with advanced Alzheimer's disease, 42 normal older subjects, and 54 normal young subjects. Advanced Alzheimer's disease was defined prospectively by a Mini-Mental State score of less than 12. Norepinephrine was measured by radioenzymatic assay.CSF norepinephrine concentration was significantly higher in the patients with advanced Alzheimer's disease (mean = 279 pg/ml, SD = 122) than in those with mild to moderate severity (mean = 198 pg/ml, SD = 89), normal older subjects (mean = 219 pg/ml, SD = 88), or normal young subjects (mean = 154 pg/ml, SD = 53). CSF and plasma norepinephrine levels and mean arterial blood pressure all were higher in the older subjects than in the young subjects.Despite the loss of locus ceruleus neurons in Alzheimer's disease, the aging-associated high concentration of CSF norepinephrine is retained in the earlier stages of Alzheimer's disease and increases further as the disease progresses. Increased brain noradrenergic activity may contribute to the agitated behaviors or cognitive deficits of patients with advanced Alzheimer's disease.
Case 38-2012
Authors: John H. Stone, Virendra I. Patel, George R. Oliveira, James R. Stone
Journal: New England Journal of Medicine (2012)

A 60-year-old man with abdominal pain had abdominal and thoracic aortic aneurysms suggestive of mycotic aneurysms. The abdominal aneurysm was resected. Cultures were negative; fever persisted. Six weeks later, chest pain developed and the thoracic aneurysm had enlarged.
SP0012 ERA in the adolescent age: One or two diseases
Authors: J. Ioannou
Journal: Annals of the Rheumatic Diseases (2013)

Enthesitis related arthritis (ERA) is a sub-type of juvenile idiopathic arthritis (JIA) that typically affects young males with onset most commonly seen in late childhood or early adolescents. It is said to be a distinct disease entity from ankylosing spondylitis (AS), with peripheral joint involvement and entheseal disease common at presentation and axial involvement a late feature. However, little is known about the natural history of ERA, with no long-term observational studies. The rationale for current treatment is largely based on extrapolation of evidence from other conditions, such as adult AS or other forms of JIA. With greater use of MRI in children and adolescents, it is emerging that spinal disease in fact occurs earlier than previously thought in a significant proportion of patients with ERA. This talk will discuss the evidence from our cohort of around 70 patients along with some evidence from other published patient cohorts to suggest that there may in fact be 2 distinct clinical phenotypes of ERA: a predominantly axial from of ERA, whereby sacroiliitis as confirmed by MRI scanning is found early in the course of the disease which is strongly associated with hip arthritis and HLAB27 positivity and a second group who lack sacroiliitis but have a greater frequency of ankle arthritis and enthesitis and lower rates of HLAB27 positivity. Both groups fulfill the revised ILAR classification criteria for ERA. Further characterization of these clinical phenotypes through long-term observational studies coupled with basic science research investigating the aetiopathogenic mechanisms driving these two clinical patterns of disease may lead to a better understanding of ERA and how best to treat it. <h3>Disclosure of Interest</h3> None Declared
OP0004 Predictors of achievement of inactive disease in children with juvenile idiopathic arthritis treated with etanercept
Authors: N. Solari, E. Palmisani, A. Consolaro, A. Pistorio, S. Lanni, S. Dalprà, B. Schiappapietra, G. Bracciolini, A. Frisina, A. Martini, A. Ravelli
Journal: Annals of the Rheumatic Diseases (2013)

<h3>Background</h3> The results obtained with the novel biologic agents have increased the expectations of benefit of treatment of juvenile idiopathic arthritis (JIA), with disease remission being now the therapeutic goal in all patients. However, the assessment of remission has seldom been incorporated in clinical trials of biologics in JIA. Moreover, little information exists on the prediction of the efficacy of biologic medications. <h3>Objectives</h3> To evaluate the proportion of children with JIA treated with etanercept (ETN) who achieved the state of inactive disease (ID) and to search for predictors of ID. <h3>Methods</h3> The clinical chart of all consecutive JIA patients who were given ETN between 2002 and 2011, and had a follow-up of at least 6 months after ETN start were reviewed. The achievement of ID, defined by the Wallace criteria (J Rheum 2004;31:2290-4), was assessed at each visit from the start of ETN. The primary study outcomes were: 1) proportion of patients who had ID at last follow-up visit while still on ETN; 2) time to achievement of ID after ETN start. Predictors of treatment outcomes included demographic data, JIA subset, type of affected joints, medications received before and during ETN administration, and JIA activity measures at ETN start. The search for predictors was conducted by means of univariate and multivariate analyses. <h3>Results</h3> A total of 187 patients were given ETN at the standard dose of 0.8 mg/kg/week in the study period. The disease duration at ETN start ranged from 3 months to 21.2 years (median 5.0 years). Fourteen patients had received ETN for less than 6 months or were lost to follow-up. In the remaining 173 patients, treatment duration from baseline to last follow-up visit ranged from 6 months to 10.5 years (median 2.4 years). At last follow-up visit, 87 (50.3%) patients had ID. The time to ID ranged from 2 months to 6.3 years (median 0.7 years). An age at disease onset &lt;3.6 years and the lack of involvement of the wrist joint at treatment start were the strongest predictors of both the achievement of ID at last follow-up visit (adjusted odds ratio of 2.1 and 2.7, respectively, in logistic regression analysis) and a shorter time to the attainment of ID (adjusted odds ratio of 1.6 and 2.2, respectively, in Cox regression analysis). <h3>Conclusions</h3> Around half of our children with JIA treated with ETN achieved ID. Early disease onset and lack of involvement of the wrist joint at treatment baseline were associated with a greater likelihood and rapidity of achieving ID <h3>References</h3> Wallace criteria for inactive disease (J Rheum 2004;31:2290-4). <h3>Disclosure of Interest</h3> None Declared
Abstract 1828: Identification of MUC16/CA125-specific therapeutics through dual fluorescence high throughput screening
Authors: Dharmarao Thapi, Sahityasri Thapi, Nestor Rosales, Christophe Antczak, Ouathek Ouerfelli, David R. Spriggs, Hakim Djaballah
Journal: Cancer Research (2012)

Abstract BACKGROUND: The MUC16 gene encodes the CA125 ovarian cancer antigen. This glycoprotein is expressed in the majority of Epithelial Ovarian Cancers (EOC) but has limited expression elsewhere in the adult human. Expression of the carboxy-portion of MUC16 results in increased invasion, soft agar growth and in vivo growth. OBJECTIVES:. We seek to identify MUC16 specific small molecules as chemotherapy candidate drugs for development in ovarian cancer. METHODS: Our previously reported study of dual fluorescence isogenic high content screening for MUC16/CA125 selective agents (Mol.Can.Ther, 2011) was extended to a library of 74,942 compounds from NCI, to identify small molecules which have a differential effects against MUC16 positive cells compared to isogenic MUC16 negative ovarian cancer cell lines Carboxy-terminus portions of the human MUC16 gene were introduced into A2780 EOC cell lines labeled with mCherry and compared to GFP labeled isogenic controls in a 384 well co-culture assay for cellular viability by computerized fluorescence intensities and compared for the relative toxicity against MUC16+/MUC16- isogenic cell lines. Compounds with differential activity were selected, resupplied and examined by Vi Cell counting and Alamar Blue cytotoxic assays for confirmation in SK-OV-3 cell line pairs. RESULTS: A2780 isogenic pair was initially used and thirty compounds which selectively targeted MUC16 positive cells were identified. These 30 compounds were tested for growth inhibition with a secondary SKOV3 isogenic screen for confirmation. Two compounds were among the screen identified in the secondary SKOV3 isogenic pair testing. These compounds were studied using Alamar Blue Assay with a panel of ovarian cell lines including CAOV3; OV433; OV432; SKOV8 (WT and MUC16 knockdown and an isogenic T80 MUC16+/− pair (in vitro transformed normal ovarian surface epithelial cell line) and IGROV1-R10. We are in the process of examining the Structural Activity Relationship around these 2 compounds and will present their response. CONCLUSIONS: These MUC16 +/− dual fluorescence screens can be used as an example of single gene target, high throughput screening strategies to identify potentially specific therapeutics for key oncogenic targets. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 1828. doi:1538-7445.AM2012-1828
Carbohydrate-Induced Lipemia
Authors: Norton Spritz
Journal: New England Journal of Medicine (1964)

PATIENTS with lipemia have been divided into two general categories on the basis of the effect of dietary fat on their plasma triglyceride concentration.1 In one type lipemia is minimal when fat is excluded from the diet.1 2 3 In this disease, designated as "fat-induced lipemia," lipoprotein lipase is present in decreased concentration, and the disorder is thought to represent impaired clearing from the blood of chylomicrons formed during the absorption of dietary triglyceride.1 2 3 4 It is characteristically familial in its occurrence.In contrast to these patients, most subjects with hyperlipemia exhibit the highest level of plasma triglyceride concentration when dietary fat is . . .
Evaluation of endoscopic ultrasound-guided fine needle aspiration of space-occupying lesion of the pancreas
Authors: Ming Cheng Tian, Wen Guo, Shan Lei
Journal: Endoscopy (2011)

Objective: Endoscopic ultrasound-guided fine needle aspiration (EUS-FNA) has become a widely accepted effective modality for obtaining tissue for primary diagnosis of the pancreatic lesions. The aim of this paper is to report our initial experience of this procedure for 35 patients with space-occupying lesion of the pancreas. Methods: We retrospectively reviewed the data on 35 EUS-FNA procedures performed in 35 patients for evaluation of the space-occupying lesion of the pancreas detected by CT scanning, ultrasonography or clinically suspected diagnosis. The sensitivity, accuracy and safety of EUS-FNA were evaluated. Final diagnosis was based on histological and cytological evidence or on follow-up. Results: All these 35 patients with pancreatic lesions were detected by EUS, however 20 patients and 29 patients were detected by transabdominal ultrasonography or CT scanning, respectively. A total of 35 EUS-FNAs were performed during the study period and the diagnosis was made in 23 cases of pancreatic cancer, 9 cases of pancreatitis, 1 case of intraductal papillary mucinous neoplasm (IPMN), 1 case of pancreatic pseudocyst, and 1 case of serous cystadenoma. The sensitivity and accuracy of EUS-FNA for suspected pancreatic cancer were 73.91% and 82.86% respectively. After EUS-FNA, 5 patients developed acute mild pancreatitis, and recovered soon following the treatment. Conclusion: Our experience confirms that EUS-FNA is a safe and valuable diagnostic method in patients with suspected space-occupying lesion of the pancreas. This technique should be considered the preferred test when a pathological diagnosis of a pancreatic lesion is required.
FRI0051 HMGB-1 promotes the PGE2 biosynthesis pathway in synovial fibroblasts
Authors: P. Leclerc, H. Wähämaa, H. Idborg, P.-J. Jakobsson, H. Erlandson-Harris, M. Korotkova
Journal: Annals of the Rheumatic Diseases (2013)

<h3>Background</h3> Synovial fibroblasts (SF) are activated in rheumatoid arthritis (RA) and show upregulation of enzymes of the PGE<sub>2</sub> pathway. HMGB1 has been shown to promote inflammation together with ligands such as LPS and IL-1β. As HMGB1 is overexpressed extracellularly in synovitis, it might constitute a potential inducer of the mPGES-1/Cox/PGE2 axis in RASF. To verify this hypothesis, we investigated the cytokine and prostanoid-inducing capacity of HMGB1 alone or together with IL-1β in RASF cultures. We also studied receptor requirements for PGE2 induction. <h3>Objectives</h3> To characterize the involvement of the PGE<sub>2</sub> pathway in the response of SF to HMGB1 alone or in combination with IL-1β. <h3>Methods</h3> SF obtained from RA patients were stimulated with recombinant HMGB1 or HMGB1 purified from thymus alone or together with low dose IL-1β (0.05 or 0.5 ng/ml). Pretreatment with IL-1RA was used to block IL-1RI-mediated signalling. IL-6, IL-8, RANTES and MCP-1 levels were measured by CBA and ELISA. Expression of enzymes of the PGE<sub>2</sub> pathway (mPGES-1, Cox-1, Cox-2, 15-PGDH) were analysed by Western blot. Prostanoid levels were measured by EIA and LC-MS/MS. <h3>Results</h3> HMGB1 alone did not induce either cytokine production or PGE<sub>2</sub> pathway up-regulation in SF. Low doses of IL-1β (0.05-0.5 ng/ml) resulted in limited effects on PGE<sub>2</sub> production and cytokines. In contrast, stimulation of RASF with HMGB1 in combination with trace amounts of IL-1β (0.05 or 0.5 ng/ml) exerted synergistic effects on the induction of mPGES-1 and COX-2 expression as well as PGE<sub>2</sub>, IL-6, IL-8, MCP-1 and RANTES production when compared to IL-1b stimulation alone. PGE<sub>2</sub> and cytokine production induced by HMGB1/IL-1β were completely abolished by pretreatment with IL-1RA, indicating that the synergistic effects were mediated through IL-1RI. Investigating the kinetics of the SF response, we showed that the induction of PGE<sub>2</sub> precedes that of IL-6 and IL-8. In line with this result, NS-398, a Cox-2 inhibitor, reduced the IL-6 and IL-8 production after a 24h incubation, indicating that the IL-1β/HMGB1 combination upregulates the IL-6 and IL-8 production in part through prostanoid synthesis. <h3>Conclusions</h3> HMGB1 amplified the inflammatory response to suboptimal amounts of IL-1β resulting in the induction of the mPGES-1/Cox-2/PGE<sub>2</sub> axis and the production of PGE<sub>2</sub> and pro-inflammatory cytokines in SF. Therefore, upregulation of PGE<sub>2</sub> synthesis constitutes an additional mechanism through which HMGB1 could perpetuate inflammatory and destructive activities in the arthritic joint. <h3>Disclosure of Interest</h3> None Declared
Causal history, actual and apparent
Authors: Jerrold Levinson
Journal: Behavioral and Brain Sciences (2013)

Abstract Attention is drawn to the distinction between the actual (or factual) and the apparent (or ostensible) causal history of a work of art, and how the authors' recommendation “to assume the design stance” in the name of understanding works of art blurs that distinction, thus inadvertently reinforcing the hoary idea, against which the authors otherwise rightly battle, that what one needs to properly appreciate an artwork can be found in even suitably framed observation of the work alone.
Abstract 2520: Synergistic combination of lurbinectedin and PARP inhibitors in breast cancer tumor cell lines
Authors: Gema Santamaría, Sonia Avila, Victoria Moneo, Carmen Cuevas, Luis F. García-Fernández, Carlos M. Galmarini
Journal: Cancer Research (2015)

Abstract Lurbinectedin (PM1183) is a new tetrahydroisoquinoline derivative currently evaluated in phase II trials in BRCA1-mutated breast cancer and NSCLC patients. Two pivotal trials (in platinum-resistant ovarian cancer and in SCLC) will be launched in 2015. PM1183 shows antitumor activity against a wide variety of tumor cells with mean IC50 values in the low nanomolar range. In living cells, PM1183 inhibits trans-activated transcription and blocks NER-dependent DNA repair inducing the formation of dsDNA breaks and the collapse of replication forks that need to be repaired by homologous recombination (HR). As expected, PM1183 is more active against homologous recombination (HR)-deficient cell lines. In this work, we evaluated the in vitro antitumor effect of PM1183 when combined with the PARP inhibitors ABT-88 (Veliparib, PARP-1 and -2), AZD-2281 (Olaparib, PARP-1), BSI-201 (Iniparib, PARP-1) and BMN-673 (PARP-1 and -2) (Selleck Chemicals, Houston, TX, USA) in a panel of human breast carcinoma cells with different BRCA1 status, including MCF-7 (BRCA1 +/+), MDA-MB-231 (BRCA1 +/-), HCC-1937 (BRCA1 -/-) and MDA-MB-436 (BRCA1 -/-). The combination index (CI) of each different drug-drug combination was calculated by applying the Chou and Talalay method. Different degrees of synergism (CI &amp;lt; 1) were recorded when PM1183 was combined with AZD-2281 (Olaparib) and BMN-673, depending on the tumor cell line and the conditions tested. The highest degree of synergism with Olaparib was observed in MDA-MB-436 cells followed by MDA-MB-231, MCF7 and HCC-1937 cells. The highest degree of synergism with BMN-673 was observed in MCF-7 cells followed by MDA-MB-231 and HCC-1937 cells. In MDA-MB-231 cells, both combinations led to a synergistic induction of γ-H2AX expression and PARP-1 cleavage, as analyzed by western blot. Collectively, our results indicate that the combination of PM1183 and PARP inhibitors (Olaparib and BMN673) induces an artificial synthetic lethality that can be advantageously used to kill several breast cancer cells, independently from their BRCA1 status. Citation Format: Gema Santamaría, Sonia Avila, Victoria Moneo, Carmen Cuevas, Luis F. García-Fernández, Carlos M. Galmarini. Synergistic combination of lurbinectedin and PARP inhibitors in breast cancer tumor cell lines. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 2520. doi:10.1158/1538-7445.AM2015-2520
The Continuing Value of the Apgar Score for the Assessment of Newborn Infants
Authors: Brian M. Casey, Donald D. McIntire, Kenneth J. Leveno
Journal: New England Journal of Medicine (2001)

The 10-point Apgar score has been used to assess the condition and prognosis of newborn infants throughout the world for almost 50 years. Some investigators have proposed that measurement of pH in umbilical-artery blood is a more objective method of assessing newborn infants.
Validation of OncoVue®, a new individualized breast cancer risk estimator in the Marin County, California adolescent risk study.
Authors: KM Dalessandri, R Miike, MR Wrensch, JK Wiencke, CC Benz, TW Pugh, S Manjeshwar, ER Jupe
Journal: Cancer Research (2009)

Abstract Abstract #502 Background: Improved models for estimating individual breast cancer risk are urgently needed for guiding clinical decisions. The OncoVue model was developed by analysis of a large case-control study genotyped for 117 common, functional single nucleotide polymorphisms (SNPs) in candidate genes likely to influence breast carcinogenesis. Multivariate logistic regression analyses were used to develop a model employing 22 SNPs in 19 genes together with the Gail Model risk factors. In the original studies of the model building set and two independent validation sets, OncoVue exhibited improved individualized risk estimation, compared to the Gail Model alone, by correctly placing more cases and fewer controls at elevated risk. Here, we sought to examine the performance of OncoVue in women from the Marin County, California breast cancer adolescent risk factor study.&amp;#x2028; Materials and Methods: Buccal cell DNA was isolated from 177 controls and 169 age-matched women diagnosed with breast cancer between 1997 and 1999. All samples were anonymously coded to remove case-control status and provided to InterGenetics along with all other relevant personal history information. DNAs were genotyped for the 22 SNP variants in OncoVue and combined with personal factors to calculate the risk scores for the individual participants. OncoVue scores were then returned to the Marin County study investigators who conducted the analyses using case-control status.&amp;#x2028; Results: Positive likelihood ratios (PLR) were calculated as the proportion of patients with breast cancer with an elevated risk estimate (12%) divided by the proportion of disease-free individuals with an elevated risk estimate. For OncoVue the PLR was 2.2, whereas for the Gail Model the PLR was 0.9, demonstrating a 2.4-fold statistically significant (p=0.036) improvement. In additional comparisons using normalized control scores, OncoVue exhibited a 51% improvement compared to the Gail Model in assigning elevated risk to cases.&amp;#x2028; Conclusion: In this blinded validation study OncoVue exhibited significantly improved performance, compared to the Gail model alone, in estimating individual risk among Marin County, California women. The improved performance of OncoVue was similar to that observed in two previous independent validation sets, thus, supporting the clinical utility of OncoVue for more accurate individualized breast cancer risk estimation. Citation Information: Cancer Res 2009;69(2 Suppl):Abstract nr 502.