tbuckley/cabot-search huggingface dataset:
Index to Predict Invasive Mold Infection in High-Risk Neutropenic Patients Based on the Area Over the Neutrophil Curve
Authors: Rodrigo D. Portugal, Marcia Garnica, Marcio Nucci
Journal: Journal of Clinical Oncology (2009)

Patients with prolonged and profound neutropenia are at high risk to develop invasive mold infections (IMIs). We developed an index (D-index) that combines duration and severity of neutropenia. The aim of this study was to test the D-index as a predictor of IMI.The D-index was based on a graph plotting the absolute neutrophil counts during neutropenia and was the area over the neutrophil curve. We tested the D-index in 11 patients with acute myeloid leukemia (AML) who developed IMI during neutropenia and 33 AML patients without IMI (controls). We also calculated a cumulative D-index (c-D-index), defined as the cumulative D-index from the start of neutropenia until the date of the first clinical manifestation of IMI in patient cases. We compared the D-index and c-D-index with duration of neutropenia and defined a cutoff for IMI using the receiver operating characteristic (ROC) curve.The median duration of neutropenia and profound neutropenia of patient cases were significantly higher compared with controls (P = .002 and P = .001, respectively), as were the D-index (P < .001) and c-D-index (P = .02). The D-index and c-D-index performed better than duration of neutropenia in ROC curve analysis. For a cutoff point of 5,800 of the c-D-index, the sensitivity and specificity were 91% and 58%, respectively, and for a prevalence of IMI of 5%, 10%, and 15%, the negative predictive values were 99%, 98%, and 97%, respectively.The high negative predictive value of the c-D-index may be of help in defining different risks for IMI in febrile neutropenic patients.
Alveolar macrophage dysfunction in malignant lung tumours.
Authors: E Lemarie, P Carre, M F Legrand, M Lavandier, E Boissinot, M Renoux, G Renoux
Journal: Thorax (1984)

Alveolar macrophage chemotaxis was measured in 129 individuals--13 normal volunteers, 15 tumour free patients with recent bronchopulmonary infections, 10 patients with chronic bronchitis, 29 patients with endothoracic sarcoidosis, 48 patients with primary bronchial carcinoma and 14 patients with pulmonary metastases from various origins. Chemotaxis was tested in the presence of either zymosan activated autologous serum, N-formyl-methionine-leucyl-phenylalanine (F-Met-Leu-Phe), or zymosan activated human AB serum. Alveolar macrophage chemotaxis was significantly less in patients with bronchial carcinoma than in healthy volunteers (p less than 0.01). Chemotaxis was significantly more depressed in samples obtained from the neighbourhood of the tumour than in samples from the opposite lung. Defective chemotaxis was also found in patients with sarcoidosis. In contrast, the presence of lung metastases did not affect chemotaxis. A recent bronchopulmonary infection was associated with significantly increased (p less than 0.02) chemotaxis in tumour free patients but not in patients with a primary lung tumour. The findings suggest that an intrinsic functional defect of alveolar macrophages might favour the development of bronchogenic carcinoma.
Benefits of Information Technology–Enabled Diabetes Management
Authors: Davis Bu, Eric Pan, Janice Walker, Julia Adler-Milstein, David Kendrick, Julie M. Hook, Caitlin M. Cusack, David W. Bates, Blackford Middleton
Journal: Diabetes Care (2007)

To determine the financial and clinical benefits of implementing information technology (IT)-enabled disease management systems.A computer model was created to project the impact of IT-enabled disease management on care processes, clinical outcomes, and medical costs for patients with type 2 diabetes aged >25 years in the U.S. Several ITs were modeled (e.g., diabetes registries, computerized decision support, remote monitoring, patient self-management systems, and payer-based systems). Estimates of care process improvements were derived from published literature. Simulations projected outcomes for both payer and provider organizations, scaled to the national level. The primary outcome was medical cost savings, in 2004 U.S. dollars discounted at 5%. Secondary measures include reduction of cardiovascular, cerebrovascular, neuropathy, nephropathy, and retinopathy clinical outcomes.All forms of IT-enabled disease management improved the health of patients with diabetes and reduced health care expenditures. Over 10 years, diabetes registries saved $14.5 billion, computerized decision support saved $10.7 billion, payer-centered technologies saved $7.10 billion, remote monitoring saved $326 million, self-management saved $285 million, and integrated provider-patient systems saved $16.9 billion.IT-enabled diabetes management has the potential to improve care processes, delay diabetes complications, and save health care dollars. Of existing systems, provider-centered technologies such as diabetes registries currently show the most potential for benefit. Fully integrated provider-patient systems would have even greater potential for benefit. These benefits must be weighed against the implementation costs.
Neurokinin-1 receptor expression in inflammatory bowel disease: molecular quantitation and localisation
Authors: T Goode
Journal: Gut (2000)

<h3>BACKGROUND</h3> Substantial evidence implicates the neuropeptide substance P (SP) in mucosal immunoinflammatory responses. Autoradiographic studies have suggested a disturbance in SP receptor expression in inflammatory bowel disease (IBD). <h3>AIMS</h3> Because of technical limitations such as poor cellular resolution with autoradiography, we used molecular methods to specifically localise the cellular expression of the neurokinin-1 receptor (NK-1R) in IBD colon, and to quantitate NK-1R mRNA expression levels therein. <h3>METHODS</h3> In situ hybridisation and immunohistochemistry were used to localise NK-1R mRNA and protein, respectively, in normal, ulcerative colitis (UC), and Crohn9s disease (CD) colonic resections. NK-1R mRNA expression levels of normal, UC, and CD mucosal biopsies were quantitated by competitive reverse transcription-polymerase chain reaction. <h3>RESULTS</h3> NK-1R expression was localised to lamina propria mononuclear cells, epithelium, submucosal vasculature, smooth muscle, and myenteric plexus of normal and IBD colon. No ectopic NK-1R expression was observed in IBD. However, we found increased numbers of NK-1R expressing lymphoid cells in IBD tissue, aberrant negative epithelial expression of NK-1R in UC, and increased expression of NK-1R in CD myenteric plexus. Quantitation of NK-1R mRNA expression in IBD colonic mucosal biopsies revealed marked upregulation of NK-1R mRNA levels compared with non-inflamed mucosal expression levels (p&lt;0.01). <h3>CONCLUSIONS</h3> This report demonstrates the strategic localisation and upregulation of NK-1R expression in IBD colon, and thereby suggests the involvement of substance P in the pathophysiological symptoms of IBD.
Hydrogen Peroxide Decreases pH<sub>i</sub>in Human Aortic Endothelial Cells by Inhibiting Na<sup>+</sup>/H<sup>+</sup>Exchange
Authors: Qinghua Hu, Yong Xia, Stefano Corda, Jay L. Zweier, Roy C. Ziegelstein
Journal: Circulation Research (1998)

Abstract —Postischemic endothelial dysfunction may occur as a result of the effects of endogenous oxidants like hydrogen peroxide. Since endothelium-dependent vasodilator function may be affected by pH i , the effect of hydrogen peroxide on endothelial pH i was examined. Hydrogen peroxide (100 μmol/L for 10 minutes) decreased pH i from 7.24±0.01 to 7.02±0.02 and inhibited recovery from an ammonium chloride–induced intracellular acid load in carboxy SNARF 1 (c-SNARF 1)–loaded human aortic endothelial cells in bicarbonate-free solution. Prior inhibition of Na + /H + exchange with 5-( N -ethyl- N -isopropyl)amiloride (10 μmol/L), by removal of extracellular Na + , or by glycolytic inhibition with iodoacetic acid blocked the subsequent effect of hydrogen peroxide on pH i . A 2-minute exposure to 100 μmol/L H 2 O 2 decreased intracellular ATP levels by ≈40%; this was prevented by 3-aminobenzamide and nicotinamide (1 mmol/L each), inhibitors of the DNA repair enzyme poly(ADP-ribose) polymerase. Both 3-aminobenzamide and nicotinamide significantly inhibited the hydrogen peroxide–induced intracellular acidification and the effect of hydrogen peroxide on recovery from an intracellular acid load. Hydrogen peroxide decreases pH i in human endothelial cells by inhibiting Na + /H + exchange. This appears to be mediated by activation of the DNA repair enzyme poly(ADP-ribose) polymerase and subsequent depletion of intracellular ATP. Since a decrease in pH i in this range may alter the activity of NO synthase or affect the synthesis of vasodilator prostaglandins, the effect of hydrogen peroxide on the endothelial Na + /H + exchanger may be important in the pathogenesis of postischemic endothelial dysfunction.
Quality of Life and Cost-Effectiveness Assessment of Radioiodine Ablation Strategies in Patients With Thyroid Cancer: Results From the Randomized Phase III ESTIMABL Trial
Authors: Isabelle Borget, Julia Bonastre, Bogdan Catargi, Désirée Déandréis, Slimane Zerdoud, Daniela Rusu, Stéphane Bardet, Laurence Leenhardt, Delphine Bastie, Claire Schvartz, Pierre Vera, Olivier Morel, Daniele Benisvy, Claire Bournaud, Francoise Bonichon, Antony Kelly, Marie-Elisabeth Toubert, Sophie Leboulleux, Florence Journeau, Ellen Benhamou, Martin Schlumberger
Journal: Journal of Clinical Oncology (2015)

Purpose In the ESTIMABL phase III trial, the thyroid ablation rate was equivalent for the two thyroid-stimulating hormone (TSH) stimulation methods (thyroid hormone withdrawal [THW] and recombinant human TSH [rhTSH]) and the two iodine-131 ( 131 I) activities (1.1 or 3.7 GBq). The objectives of this article were to present health-related quality-of-life (HRQoL) results and a cost-effectiveness evaluation performed alongside this trial. Patients and Methods HRQoL and utility were longitudinally assessed, from random assignment to the follow-up visit at 8 ± 2 months for the 752 patients with thyroid cancer, using the Short Form-36 and the EuroQoL-5D questionnaires, respectively. A cost-effectiveness analysis was performed from the societal perspective in the French context. Resource use (hospitalization for 131 I administration, rhTSH, sick leaves, and transportation) was collected prospectively. We used the net monetary benefit approach and computed cost-effectiveness acceptability curves for both TSH stimulation methods and 131 I activities. Sensitivity analyses of the costs of rhTSH were performed. Results At 131 I administration, THW caused a clinically significant deterioration of HRQoL, whereas HRQoL remained stable with rhTSH. This deterioration was transient with no difference 3 months later. rhTSH was more effective than THW in terms of quality-adjusted life-years (QALYs; +0.013 QALY/patient) but more expensive (+€474/patient). The probability that rhTSH would be cost effective at a €50,000/QALY threshold was 47% in France. The use of 1.1 GBq of 131 I instead of 3.7 GBq reduced per-patient costs by €955 (US$1,018) but with slightly decreased efficacy (−0.007 QALY/patient). Conclusion rhTSH avoids the transient THW-induced deterioration of HRQoL but is unlikely to be cost effective at its current price.
Abnormal Functional Brain Connectivity and Personality Traits in Myotonic Dystrophy Type 1
Authors: Laura Serra, Gabriella Silvestri, Antonio Petrucci, Barbara Basile, Marcella Masciullo, Elena Makovac, Mario Torso, Barbara Spanò, Chiara Mastropasqua, Neil A. Harrison, Maria L. E. Bianchi, Manlio Giacanelli, Carlo Caltagirone, Mara Cercignani, Marco Bozzali
Journal: JAMA Neurology (2014)

Myotonic dystrophy type 1 (DM1), the most common muscular dystrophy observed in adults, is a genetic multisystem disorder affecting several other organs besides skeletal muscle, including the brain. Cognitive and personality abnormalities have been reported; however, no studies have investigated brain functional networks and their relationship with personality traits/disorders in patients with DM1.To use resting-state functional magnetic resonance imaging to assess the potential relationship between personality traits/disorders and changes to functional connectivity within the default mode network (DMN) in patients with DM1.We enrolled 27 patients with genetically confirmed DM1 and 16 matched healthy control individuals. Patients underwent personality assessment using clinical interview and Minnesota Multiphasic Personality Inventory-2 administration; all participants underwent resting-state functional magnetic resonance imaging. Investigations were conducted at the Istituto di Ricovero e Cura a Carattere Scientifico Santa Lucia Foundation, Catholic University of Sacred Heart, and Azienda Ospedaliera San Camillo Forlanini.Resting-state functional magnetic resonance imaging.Measures of personality traits in patients and changes in functional connectivity within the DMN in patients and controls. Changes in functional connectivity and atypical personality traits in patients were correlated.We combined results obtained from the Minnesota Multiphasic Personality Inventory-2 and clinical interview to identify a continuum of atypical personality profiles ranging from schizotypal personality traits to paranoid personality disorder within our DM1 patients. We also demonstrated an increase in functional connectivity in the bilateral posterior cingulate and left parietal DMN nodes in DM1 patients compared with controls. Moreover, patients with DM1 showed strong associations between DMN functional connectivity and schizotypal-paranoid traits.Our findings provide novel biological evidence that DM1 is a clinical condition that also involves an alteration of functional connectivity of the brain. We speculate that these functional brain abnormalities, similarly to frank psychiatric disorders, may account for the atypical personality traits observed in patients with DM1.
Divergent Role of Donor Dendritic Cells in Rejection versus Tolerance of Allografts
Authors: Takuya Ueno, Katsunori Tanaka, Mollie Jurewicz, Takaya Murayama, Indira Guleria, Paolo Fiorina, Jesus C. Paez, Andrea Augello, Andrea Vergani, Masie Wong, R. Neal Smith, Reza Abdi
Journal: Journal of the American Society of Nephrology (2009)

Little is known about heart tissue/donor dendritic cells, which play a key role in mounting alloimmune responses. In this report, we focus on three primary features of donor dendritic cells: their generation, their trafficking after transplantation, and their role in regulating tolerance versus rejection. Using transgenic mice as donors of heart allografts enabled us to monitor trafficking of donor dendritic cells after transplantation. Donor dendritic cells rapidly migrated into secondary lymphoid tissues within 3 h of transplantation. We found that the chemokine receptor CX3CR1 regulates the generation of heart tissue dendritic cells constitutively. Compared with wild-type hearts, CX3CR1(-/-) hearts contained fewer dendritic cells, and heart allografts from CX3CR1(-/-) donors survived significantly longer without immunosuppression. Unexpectedly, though, co-stimulatory blockade with anti-CD154 or CTLA4-Ig induced long-term survival for wild-type heart allografts but not for CX3CR1(-/-) heart allografts. Increasing the dendritic cell frequency in CX3CR1(-/-) hearts by treatment with Flt3L restored the anti-CD154-induced prolongation of CX3CR1(-/-) heart allograft survival. Compared with wild-type donors, depleting transgenic donors of dendritic cells before heart transplantation also markedly worsened chronic rejection under anti-CD154 treatment. These data indicate the importance of the CX3CR1 pathway in the generation of heart tissue dendritic cells and the divergent role of tissue/dendritic cells in rejection versus tolerance.
4 Integrin blockade in inflammatory bowel disease
Authors: S Ghosh
Journal: Annals of the Rheumatic Diseases (2003)

Inflammatory bowel disease comprises Crohn’s disease (CD), a Th1 lymphocyte mediated chronic transmural inflammatory disease, and ulcerative colitis, resembling a Th2 lymphocyte mediated mucosal inflammation of the colon. Studies of patients with inflammatory bowel disease show that endothelial cells extracted from inflamed intestinal mucosa demonstrate increased α4 integrin dependent adhesiveness to leucocytes in vitro.1

Integrins form a large family of transmembrane proteins required for cell adhesion, morphogenesis, migration, and differentiation, attach the cell to the extracellular matrix or to other cells, and anchor the cytoskeleton to the plasma membrane. Integrins consist of two non-covalently bound α and β subunits of 120–180 kDa and 90–120 kDa, respectively. The α4 chain contains about 1000 amino acids and in association with the β7 chain defines an integrin subfamily specifically involved in the interaction of lymphocytes with the intestinal mucosa. The α4β7 integrin is widely expressed in the intestine and is present on most lamina propria T cells and IgA secreting B cells. The expression of α4β7 on intraepithelial lymphocytes is lower. The main ligand for α4β7 is mucosal vascular addressin cell adhesion molecule (MADCAM-1), a member of the immunoglobulin superfamily as mentioned below, but other ligands include fibronectin (an extracellular matrix protein), vascular cell adhesion molecule-1 (VCAM-1), and α4 integrin itself. α4 Integrin in the low affinity state, as well as L-selectin play a part in rolling of the lymphocytes in intestinal vascular epithelium, interacting with a number of ligands, including MADCAM-1. Activating signals to the lymphocytes, such as …
Identification of novel candidate target genes in amplicons of Glioblastoma multiforme tumors detected by expression and CGH microarray profiling
Authors: Yolanda Ruano, Manuela Mollejo, Teresa Ribalta, Concepción Fiaño, Francisca I Camacho, Elena Gómez, Angel Rodríguez de Lope, Jose-Luis Hernández-Moneo, Pedro Martínez, Bárbara Meléndez
Journal: Molecular Cancer (2006)

Conventional cytogenetic and comparative genomic hybridization (CGH) studies in brain malignancies have shown that glioblastoma multiforme (GBM) is characterized by complex structural and numerical alterations. However, the limited resolution of these techniques has precluded the precise identification of detailed specific gene copy number alterations.We performed a genome-wide survey of gene copy number changes in 20 primary GBMs by CGH on cDNA microarrays. A novel amplicon at 4p15, and previously uncharacterized amplicons at 13q32-34 and 1q32 were detected and are analyzed here. These amplicons contained amplified genes not previously reported. Other amplified regions containing well-known oncogenes in GBMs were also detected at 7p12 (EGFR), 7q21 (CDK6), 4q12 (PDGFRA), and 12q13-15 (MDM2 and CDK4). In order to identify the putative target genes of the amplifications, and to determine the changes in gene expression levels associated with copy number change events, we carried out parallel gene expression profiling analyses using the same cDNA microarrays. We detected overexpression of the novel amplified genes SLA/LP and STIM2 (4p15), and TNFSF13B and COL4A2 (13q32-34). Some of the candidate target genes of amplification (EGFR, CDK6, MDM2, CDK4, and TNFSF13B) were tested in an independent set of 111 primary GBMs by using FISH and immunohistological assays. The novel candidate 13q-amplification target TNFSF13B was amplified in 8% of the tumors, and showed protein expression in 20% of the GBMs.This high-resolution analysis allowed us to propose novel candidate target genes such as STIM2 at 4p15, and TNFSF13B or COL4A2 at 13q32-34 that could potentially contribute to the pathogenesis of these tumors and which would require futher investigations. We showed that overexpression of the amplified genes could be attributable to gene dosage and speculate that deregulation of those genes could be important in the development and progression of GBM. Our findings highlight the important influence in GBM of signaling pathways such as the PI3K/AKT, consistent with the invasive features of this tumor.
Managed clinical networks in neonatal care
Authors: C. S. Phibbs
Journal: BMJ (2012)

Reduces morbidity after preterm births but regionalisation of obstetric care is key 

A large body of evidence supports the concept of regionalising neonatal intensive care. Both mortality and serious morbidity are significantly reduced for high risk infants who are born in hospitals that have a high volume of cases, tertiary level obstetric services, and neonatal intensive care units (NICUs).1 2 Although these benefits are most pronounced for the highest risk infants, such as those with extreme prematurity or major congenital anomalies, evidence suggests that benefits extend to all at risk deliveries and possibly to low risk ones as well.3 It is also much better to move women with high risk deliveries to these high volume tertiary centres than to move critically ill neonates after delivery.4 5

In a linked paper (doi:10.1136/bmj.e2105), Gale and colleagues study the effects of the reorganisation of neonatal services in England that occurred as a result of this evidence.6 In 2003, neonatal services in England were formed into managed clinical networks. The changes improved access to …
<i>In vivo</i> Activity of the Cleaved Form of Soluble Urokinase Receptor: A New Hematopoietic Stem/Progenitor Cell Mobilizer
Authors: Carmine Selleri, Nunzia Montuori, Patrizia Ricci, Valeria Visconte, Antonio Baiano, Maria Vincenza Carriero, Bruno Rotoli, Guido Rossi, Pia Ragno
Journal: Cancer Research (2006)

Abstract Cleaved forms of soluble urokinase receptor (c-suPAR) have been detected in body fluids from patients affected by various tumors. We recently reported increased c-suPAR levels in sera of healthy donors during granulocyte colony-stimulating factor (G-CSF)–induced mobilization of CD34+ hematopoietic stem cells (HSC). In vitro, c-suPAR or its derived chemotactic peptide (uPAR84-95) stimulated migration of human CD34+ HSCs and inactivated CXCR4, the chemokine receptor primarily responsible for HSC retention in bone marrow. These results suggested that c-suPAR could potentially contribute to regulate HSC trafficking from and to bone marrow. Therefore, we investigated uPAR84-95 effects on mobilization of mouse CD34+ hematopoietic stem/progenitor cells (HSC/HPC). We first showed that uPAR84-95 stimulated in vitro dose-dependent migration of mouse CD34+ M1 leukemia cells and inactivated murine CXCR4. uPAR84-95 capability to induce mouse HSC/HPC release from bone marrow and migration into the circulation was then investigated in vivo. uPAR84-95 i.p. administration induced rapid leukocytosis, which was associated with an increase in peripheral blood CD34+ HSCs/HPCs. In vitro colony assays confirmed that uPAR84-95 mobilized hematopoietic progenitors, showing an absolute increase in circulating colony-forming cells. uPAR84-95 mobilizing activity was comparable to that of G-CSF; however, neither synergistic nor additive effect was observed in combining the two molecules. These findings show for the first time in vivo biological effects of c-suPAR. Its capability to mobilize HSCs suggests potential clinical applications in HSC transplantation. (Cancer Res 2006; 66(22): 10885-90)