tbuckley/cabot-search huggingface dataset:
Decreased Brain Volume in Adults with Childhood Lead Exposure
Authors: Kim M Cecil, Christopher J Brubaker, Caleb M Adler, Kim N Dietrich, Mekibib Altaye, John C Egelhoff, Stephanie Wessel, Ilayaraja Elangovan, Richard Hornung, Kelly Jarvis, Bruce P Lanphear
Journal: PLoS Medicine (2008)

Although environmental lead exposure is associated with significant deficits in cognition, executive functions, social behaviors, and motor abilities, the neuroanatomical basis for these impairments remains poorly understood. In this study, we examined the relationship between childhood lead exposure and adult brain volume using magnetic resonance imaging (MRI). We also explored how volume changes correlate with historic neuropsychological assessments.Volumetric analyses of whole brain MRI data revealed significant decreases in brain volume associated with childhood blood lead concentrations. Using conservative, minimum contiguous cluster size and statistical criteria (700 voxels, unadjusted p < 0.001), approximately 1.2% of the total gray matter was significantly and inversely associated with mean childhood blood lead concentration. The most affected regions included frontal gray matter, specifically the anterior cingulate cortex (ACC). Areas of lead-associated gray matter volume loss were much larger and more significant in men than women. We found that fine motor factor scores positively correlated with gray matter volume in the cerebellar hemispheres; adding blood lead concentrations as a variable to the model attenuated this correlation.Childhood lead exposure is associated with region-specific reductions in adult gray matter volume. Affected regions include the portions of the prefrontal cortex and ACC responsible for executive functions, mood regulation, and decision-making. These neuroanatomical findings were more pronounced for males, suggesting that lead-related atrophic changes have a disparate impact across sexes. This analysis suggests that adverse cognitive and behavioral outcomes may be related to lead's effect on brain development producing persistent alterations in structure. Using a simple model, we found that blood lead concentration mediates brain volume and fine motor function.
Methyl CpG–Binding Domain Protein 3 Mediates Cancer-Selective Cytotoxicity by Histone Deacetylase Inhibitors via Differential Transcriptional Reprogramming in Lung Cancer Cells
Authors: Eun Joo Noh, Eun Ryoung Jang, Gajin Jeong, You Mie Lee, Churl Ki Min, Jong-Soo Lee
Journal: Cancer Research (2005)

Abstract Histone deacetylase inhibitors (HDI) have been reported to inhibit the growth and survival of cancer cells while leaving normal cells untouched. However, the mechanisms underlying this selective cell death are poorly understood. Gene expression analysis revealed that HDI treatment induced up-regulation of p21WAF1/Cip1 and down-regulation of ErbB2 in cancer cells but not normal cells. Overexpression of p21WAF1/Cip1 and/or silencing of ErbB2 enhanced cancer cell growth inhibition, suggesting that HDI-induced up-regulation/down-regulation of these genes play critical roles in HDI-induced growth inhibition of cancer cells. Most importantly, we found that the gene silencing factor methyl CpG–binding domain protein 3 (MBD3) was not only released from cancer-selective promoter of the HDI up-regulated p21WAF1/Cip1 gene but also recruited to that of the HDI-down-regulated ErbB2 gene. Furthermore, silencing of MBD3 by small interfering RNA abrogated the HDI-induced gene regulation and growth inhibition in lung cancer but not in normal cells. Together, our results support the critical potential of MBD3 in HDI-induced cancer-selective cell death via cancer differential gene expression. (Cancer Res 2005; 65(24): 11400-10)
RAGE Mediates Podocyte Injury in Adriamycin-induced Glomerulosclerosis
Authors: Jiancheng Guo, Radha Ananthakrishnan, Wu Qu, Yan Lu, Nina Reiniger, Shan Zeng, Wanchao Ma, Rosa Rosario, Shi Fang Yan, Ravichandran Ramasamy, Vivette D'Agati, Ann Marie Schmidt
Journal: Journal of the American Society of Nephrology (2008)

In the kidney, the receptor for advanced glycation end products (RAGE) is principally expressed in the podocyte at low levels, but is upregulated in both human and mouse glomerular diseases. Because podocyte injury is central to proteinuric states, such as the nephrotic syndrome, the murine adriamycin nephrosis model was used to explore the role of RAGE in podocyte damage. In this model, administration of the anthracycline antibiotic adriamycin provokes severe podocyte stress and glomerulosclerosis. In contrast to wild-type animals, adriamycin-treated RAGE-null mice were significantly protected from effacement of the podocyte foot processes, albuminuria, and glomerulosclerosis. Administration of adriamycin induced rapid generation of RAGE ligands, and treatment with soluble RAGE protected against podocyte injury and glomerulosclerosis. In vitro, incubation of RAGE-expressing murine podocytes with adriamycin stimulated AGE formation, and treatment with RAGE ligands rapidly activated nicotinamide adenine dinucleotide phosphate (NADPH)-oxidase, via p44/p42 MAP kinase signaling, and upregulated pro-fibrotic growth factors. These data suggest that RAGE may contribute to the pathogenesis of podocyte injury in sclerosing glomerulopathies such as focal segmental glomerulosclerosis.
Racial differences in biologic predictors of severe asthma: Data from the Severe Asthma Research Program
Authors: Christy Gamble, Evelyn Talbott, Ada Youk, Fernando Holguin, Bruce Pitt, Lori Silveira, Eugene Bleecker, William Busse, William Calhoun, Mario Castro, Kian Fan Chung, Serpil Erzurum, Elliot Israel, Sally Wenzel
Journal: Journal of Allergy and Clinical Immunology (2010)
Role of host cell traversal by the malaria sporozoite during liver infection
Authors: Joana Tavares, Pauline Formaglio, Sabine Thiberge, Elodie Mordelet, Nico Van Rooijen, Alexander Medvinsky, Robert Ménard, Rogerio Amino
Journal: The Journal of Experimental Medicine (2013)

Malaria infection starts when the sporozoite stage of the Plasmodium parasite is injected into the skin by a mosquito. Sporozoites are known to traverse host cells before finally invading a hepatocyte and multiplying into erythrocyte-infecting forms, but how sporozoites reach hepatocytes in the liver and the role of host cell traversal (CT) remain unclear. We report the first quantitative imaging study of sporozoite liver infection in rodents. We show that sporozoites can cross the liver sinusoidal barrier by multiple mechanisms, targeting Kupffer cells (KC) or endothelial cells and associated or not with the parasite CT activity. We also show that the primary role of CT is to inhibit sporozoite clearance by KC during locomotion inside the sinusoid lumen, before crossing the barrier. By being involved in multiple steps of the sporozoite journey from the skin to the final hepatocyte, the parasite proteins mediating host CT emerge as ideal antibody targets for vaccination against the parasite.
Risk factors for side-effects of isoniazid, rifampin and pyrazinamide in patients hospitalized for pulmonary tuberculosis
Authors: T Schaberg, K Rebhan, H Lode
Journal: European Respiratory Journal (1996)

The aim of this study was to determine the current incidence of side-effects severe enough to cause intolerance of standard antituberculosis therapy with isoniazid, rifampin and pyrazinamide in patients hospitalized as a result of pulmonary tuberculosis. Five hundred and nineteen patients with proven pulmonary tuberculosis, who initially received standard antituberculosis therapy, were retrospectively studied in the department of infectious diseases in a teaching chest hospital. The incidence of severe side-effects related to the therapy, which led to the definitive termination of one of the three standard drugs, was measured and the risk factors for intolerance were analysed. Final termination of either isoniazid, rifampin or pyrazinamide because of severe side-effects was necessary in 121 of the 519 patients (23%). The most severe side-effects leading to final termination of one drug were hepatotoxicity (11%), exanthema (6%), and arthralgia (2%). Pyrazinamide showed more severe side-effects (15%) than isoniazid (7%) and rifampin (1.5%). Significant risk factors for intolerance of the standard therapy following a multivariate analysis were a history of hepatitis (odds ratio (OR) 3.4; 95% confidence interval (95% CI) 1.6-7.6; p = 0.0026) and an age > or = 60 yrs (OR 1.9; 95% CI 1.2-3.2; p = 0.017). Both of these risk factors were also significantly associated with the intolerance of pyrazinamide (history of hepatitis: OR 2.5; 95% CI 1.4-4.3; p = 0.0045; age > or = 60 yrs: OR 2.1, 95% CI 1.3-3.5; p = 0.0029) but not of isoniazid and rifampin. The side-effects of standard antituberculosis therapy are frequent in hospitalized patients aged > or = 60 yrs or with a history of previous hepatitis, and are probably due to pyrazinamide rather than to isoniazid or rifampin.
Histopathologically dysplastic neurofibromas in neurofibromatosis 1: diagnostic criteria, prevalence and clinical significance
Authors: L. Valeyrie-Allanore, N. Ortonne, L. Lantieri, S. Ferkal, J. Wechsler, M. Bagot, P. Wolkenstein
Journal: British Journal of Dermatology (2008)

Malignant peripheral nerve sheath tumours (MPNSTs) correspond to the most frequent and aggressive neoplasic complications associated with poor prognosis in neurofibromatosis 1.To define the dysplastic neurofibroma potentially at risk of transformation and evaluate its prevalence and incidence.According to our database, we retrospectively included, between 1 March 2000 and 31 August 2004, all patients who had subcutaneous and/or plexiform neurofibromas removed surgically. Tumour specimens were systematically reviewed; dysplastic neurofibroma was defined by the association of high cellularity and the presence of atypical cells. Clinically atypical and histopathologically dysplastic neurofibromas were analysed using Fisher's exact test. In addition, three high-grade MPNSTs were analysed retrospectively for the presence of associated histopathologically dysplastic neurofibroma.Among the 89 plexiform and/or subcutaneous neurofibromas surgically removed, high cellularity and cytonuclear atypia were observed in 19% and 17% of cases, respectively. Both criteria were associated in 8.9% of cases (n=8); Mib-1 immunostaining was negative in all cases (n=7). In univariate analysis, only neurological symptoms were significantly associated with dysplasia (P=0.02). Interestingly, dysplastic neurofibroma areas could be identified within or at the periphery of two MPNSTs.The association of hypercellularity and cytonuclear atypia could be considered as a potential histological prognostic factor of transformation leading to increased surveillance.
Blood Pressure in Young Adulthood and the Risk of Type 2 Diabetes in Middle Age
Authors: Sherita Hill Golden, Nae-Yuh Wang, Michael J. Klag, Lucy A. Meoni, Frederick L. Brancati
Journal: Diabetes Care (2003)

OBJECTIVE—Hypertension is known to accompany type 2 diabetes in middle age, but it is unknown how early in life blood pressure (BP) begins to rise among individuals who later develop diabetes. The objective of this study was to evaluate elevated BP as a long-term predictor of type 2 diabetes. RESEARCH DESIGN AND METHODS—We conducted a prospective cohort study of 1,152 white male medical students in The Johns Hopkins Precursors Study to longitudinally assess systolic BP (SBP) and diastolic BP (DBP) from young adulthood through middle age in men who went on to develop diabetes. Incident diabetes was identified by self-report through mailed questionnaires verified by medical record review. RESULTS—During a median follow-up of 38 years, 77 cases of incident diabetes occurred. The mean age of diabetes diagnosis was 58 years. As early as age 30 years, mean SBP and DBP were significantly higher in men who developed diabetes during follow-up than in those who remained nondiabetic (SBP 122 vs. 119 mmHg, P = 0.009; DBP 78 vs. 75 mmHg, P = 0.0005). The rate of increase in SBP and DBP over time in men who developed diabetes was greater than the rate of increase in men who did not develop diabetes (SBP 0.49 vs. 0.27 mmHg/year, P &amp;lt; 0.00003; DBP 0.24 vs. 0.17 mmHg/year; P = 0.09). After adjustment for BMI and other risk factors for diabetes, SBP and DBP at age 30 years remained significantly higher in individuals who developed diabetes than in their nondiabetic counterparts; however, the difference in the rate of increase in SBP was no longer significant following multivariate adjustment. CONCLUSIONS—BP elevations precede the development of type 2 diabetes in middle age by 20–25 years. Higher BP in the prediabetic state might contribute to the presence of vascular disease at the time of diagnosis of type 2 diabetes.
The Protein Phosphatase Activity of PTEN Regulates Src Family Kinases and Controls Glioma Migration
Authors: Nandini Dey, Hal E. Crosswell, Pradip De, Ramon Parsons, Qiong Peng, Jing Dong Su, Donald L. Durden
Journal: Cancer Research (2008)

Abstract Phosphatase and tensin homologue deleted on chromosome 10 (PTEN) is mutated or lost in 60% to 70% of advanced gliomas and is associated with malignant phenotypic changes such as migration, which contribute to the morbidity and mortality of this disease. Most of the tumor suppressor function of PTEN has been attributed to its ability to dephosphorylate the second messenger, phosphatidylinositol 3,4,5-triphosphate, resulting in the biological control of the phosphatidylinositol 3-kinase (PI3K)/AKT pathway. Despite recent work suggesting that the protein phosphatase activity of PTEN controls glioma cell migration, the mechanisms by which this occurs are unclear. Herein, we show using glioma cell lines (U87MG and U373MG) stably transfected with wild-type PTEN or catalytically altered mutants of PTEN that PTEN controls integrin-directed migration in a lipid phosphatase, PI3K/AKT–independent manner. Confirming this observation, we show that the stable overexpression of COOH-terminal Src kinase, the physiologic negative regulator of SRC family kinases (SFK), or treatment with the SFK inhibitor PP1 abrogates glioma migration. The results provide direct evidence that the downstream effect of the protein phosphatase activity of PTEN is to suppress SFK and FYN, and to regulate RAC-GTPase activity after αv integrin stimulation. Furthermore, studying vitronectin-directed migration using (a) Fyn small interfering RNA and (b) astrocytes from Fyn heterozygous (+/−) mice, Pten heterozygous (+/−) mice, Pten and Fyn double heterozygous (+/−) mice, or Fyn knockout (−/−) mice confirmed a role of FYN in αv integrin–mediated haptotaxis in glial cells. Our combined results provide direct biochemical and genetic evidence that PTEN's protein phosphatase activity controls FYN kinase function in glioma cells and regulates migration in a PI3K/AKT–independent manner. [Cancer Res 2008;68(6):1862–71]
Variegation of the phenotype induced by the Gata1low mutation in mice of different genetic backgrounds
Authors: Fabrizio Martelli, Barbara Ghinassi, Barbara Panetta, Elena Alfani, Valentina Gatta, Alessandro Pancrazzi, Costanza Bogani, Alessandro Maria Vannucchi, Francesco Paoletti, Giovanni Migliaccio, Anna Rita Migliaccio
Journal: Blood (2005)
Lower levels of surface B-cell-receptor expression in chronic lymphocytic leukemia are associated with glycosylation and folding defects of the μ and CD79a chains
Authors: Françoise Vuillier, Gérard Dumas, Christian Magnac, Marie-Christine Prevost, Ana Inés Lalanne, Pablo Oppezzo, Evie Melanitou, Guillaume Dighiero, Béatrice Payelle-Brogard
Journal: Blood (2005)
Assessing the Cure of the Zollinger-Ellison Syndrome after Gastrinoma Resection
Authors: Muhammad Hammami
Journal: Annals of Internal Medicine (1994)

Letters15 January 1994Assessing the Cure of the Zollinger-Ellison Syndrome after Gastrinoma ResectionMuhammad Hammami, MD, PhDMuhammad Hammami, MD, PhDKing Faisal Specialist Hospital and Research Centre; Riyadh 11211; Saudi ArabiaSearch for more papers by this authorAuthor, Article, and Disclosure Informationhttps://doi.org/10.7326/0003-4819-120-2-199401150-00012 SectionsAboutFull TextPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissions ShareFacebookTwitterLinkedInRedditEmail TO THE EDITOR:In their recent article on the best approach for follow-up of patients with the Zollinger-Ellison syndrome who had surgical exploration for gastrinoma resection, Fishbeyn and colleagues [1] suggested that a secretin provocative test and two fasting serum gastric determinations should be done after surgery and before hospital discharge; normal tests would be repeated 3 to 6 months and yearly thereafter. However, evaluation of patients in the immediate postoperative period seems to have little clinical utility and can be omitted. First, the authors do not recommend discontinuation of gastric acid antisecretory therapy if normal results are obtained. Second, ...REFERENCE1. Fishbeyn VA, Norton JA, Benya RV, Pisegna JR, Venzon DJ, Metz DC, et al. Assessment and prediction of long-term cure in patients with the Zollinger-Ellison syndrome: the best approach. Ann Intern Med. 1993; 119:199-206. Google Scholar Author, Article, and Disclosure InformationAuthors: Muhammad Hammami, MD, PhDAffiliations: King Faisal Specialist Hospital and Research Centre; Riyadh 11211; Saudi Arabia PreviousarticleNextarticle Advertisement FiguresReferencesRelatedDetails Metrics 15 January 1994Volume 120, Issue 2Page: 165KeywordsGastrinSecretinSurgerySurgical resectionZollinger Ellison syndrome ePublished: 15 August 2000 Issue Published: 15 January 1994 Copyright & PermissionsCopyright © 1994 by American College of Physicians. All Rights Reserved.PDF downloadLoading ...
The Trypanosoma cruzi L1Tc and NARTc Non-LTR Retrotransposons Show Relative Site Specificity for Insertion
Authors: Frédéric Bringaud, Daniella C. Bartholomeu, Gaëlle Blandin, Arthur Delcher, Théo Baltz, Najib M. A. El-Sayed, Elodie Ghedin
Journal: Molecular Biology and Evolution (2005)

The trypanosomatid protozoan Trypanosoma cruzi contains long autonomous (L1Tc) and short nonautonomous (NARTc) non–long terminal repeat retrotransposons. NARTc (0.25 kb) probably derived from L1Tc (4.9 kb) by 3′-deletion. It has been proposed that their apparent random distribution in the genome is related to the L1Tc-encoded apurinic/apyrimidinic endonuclease (APE) activity, which repairs modified residues. To address this question we used the T. cruzi (CL-Brener strain) genome data to analyze the distribution of all the L1Tc/NARTc elements present in contigs larger than 10 kb. This data set, which represents 0.91× sequence coverage of the haploid nuclear genome (∼55 Mb), contains 419 elements, including 112 full-length L1Tc elements (14 of which are potentially functional) and 84 full-length NARTc. Approximately half of the full-length elements are flanked by a target site duplication, most of them (87%) are 12 bp long. Statistical analyses of sequences flanking the full-length elements show the same highly conserved pattern upstream of both the L1Tc and NARTc retrotransposons. The two most conserved residues are a guanine and an adenine, which flank the site where first-strand cleavage is performed by the element-encoded endonuclease activity. This analysis clearly indicates that the L1Tc and NARTc elements display relative site specificity for insertion, which suggests that the APE activity is not responsible for first-strand cleavage of the target site.
Progression-Free Survival as a Surrogate Endpoint for Median Overall Survival in Metastatic Colorectal Cancer: Literature-Based Analysis from 50 Randomized First-Line Trials
Authors: Clemens Giessen, Ruediger Paul Laubender, Donna Pauler Ankerst, Sebastian Stintzing, Dominik Paul Modest, Ulrich Mansmann, Volker Heinemann
Journal: Clinical Cancer Research (2012)

To evaluate progression-free survival (PFS) as a potential surrogate endpoint (SEP) for overall survival (OS) in metastatic colorectal cancer (mCRC) with a focus on applicability to trials containing targeted therapy with anti-VEGF- or anti-EGF receptor (EGFR)-directed monoclonal antibodies.A systematic literature search of randomized trials of first-line chemotherapy for mCRC reported from January 2000 to January 2012 was conducted. Adjusted weighted linear regression was used to calculate correlations within PFS and OS (endpoints; R(EP)) and between treatment effects on PFS and on OS (treatment effects; R(TE)).Fifty trials reflecting 22,736 patients met the inclusion criteria. Correlation between treatment effects on PFS and OS and between the endpoints PFS and OS was high across all studies (R(TE) = 0.87, R(EP) = 0.86). This was also observed in chemotherapy-only trials (R(TE) = 0.93, R(EP) = 0.81) but less so for trials containing monoclonal antibodies (R(TE) = 0.47; R(EP) = 0.52). Limiting the analysis to bevacizumab-based studies (11 trials, 3,310 patients) again yielded high correlations between treatment effects on PFS and on OS (R(TE) = 0.84), whereas correlation within PFS and OS was low (R(EP) = 0.45). In 7 trials (1,335 patients) investigating cetuximab- or panitumumab-based studies, contrasting correlations with very wide confidence intervals were observed (R(TE) = 0.28; R(EP) = 0.96).PFS showed consistently high correlation with OS of an order that would justify its use as an SEP in chemotherapy regimens. For validation of surrogacy in anti-VEGF and anti-EGFR-directed therapies, further research and a larger set of trials is needed.
HYPERTROPHIC CARDIOMYOPATHY IN ICELAND IS CHARACTERIZED BY LOW EVENT RATE CLINICAL COURSE AND MYBPC3 FOUNDER MUTATION
Authors: Berglind Adalsteinsdottir, Polakit Teekakirikul, Barry Maron, Daniel F. Gudbjartsson, Hilma Holm, Michael Burke, Ragnar Danielsen, Christine Seidman, Jonathan G. Seidman, Gunnar Gunnarsson
Journal: Journal of the American College of Cardiology (2014)
Neoplasia Posters
Authors: G. Walker, M. Chandrasekhar, K. Walker, E. Maguire, M. Srihanan, G. Rao, J. O'Donohue
Journal: Gut (2001)

PCS & MCS). Measurements were taken at baseline 1 (B1), two weeks later at baseline 2 (B2), approximately 8 weeks later at end of treatment (P), and a further 10 months later at followup (F).Results: There were no diVerences between the groups in terms of sex ratio, age, duration of IBS, and B1 outcomes measures.A repeated measures MANOVA to determine the immediate eVects of treatment (ie, B1, B2 and P) revealed no significant diVerences for group (F=0.74;df=10,144; p=0.686), nor a significant interaction (F=0.87;df=20,596; p=0.622).There was however a significant improvement over time (F=6.78;df=10,294; p<0.001).A STEPDOWN analyses revealed significant improvements in BSSS, HAD-A and PCS.Improvements occurred from B1 to B2 and continued to P. A second MANOVA to determine follow-up eVects from the 44% of subjects with complete data, revealed similar results with no treatment eVects, but a continual improvement over time in all groups.Conclusions: This study found that CBT, RT and RMC were equally eVective in managing IBS.While thoughts may have a role in the continuance of IBS, good routine medical care, with an emphasis on education and reassurance, can be as eVective as CBT and relaxation in reducing symptoms of IBS.