tbuckley/cabot-search huggingface dataset:
Differential Expression of Metabotropic Glutamate Receptors 2 and 3 in Schizophrenia: A Mechanism for Antipsychotic Drug Action?
Authors: Subroto Ghose, Kelly A Gleason, Bryan W Potts, Kelly Lewis-Amezcua, Carol A Tamminga
Journal: American Journal of Psychiatry (2009)

Preclinical and clinical data implicate the group II metabotropic glutamate receptors mGluR2 and mGluR3 in the pathophysiology of schizophrenia. Moreover, a recent phase II clinical trial demonstrated the antipsychotic efficacy of a mGluR2/mGluR3 agonist. The purpose of the present study was to distinguish the expression of mGluR2 and mGluR3 receptor proteins in schizophrenia and to quantify glutamate carboxypeptidase II (GCP II) in order to explore a role for the metabotropic receptors in schizophrenia therapeutics. GCP II is an enzyme that metabolizes N-acetyl-aspartyl-glutamate (NAAG), which is the only known specific endogenous agonist of mGluR3 in the mammalian brain.The normal expression levels of mGluR2, mGluR3, and GCP II were determined for 10 regions of the postmortem human brain using specific antibodies. Differences in expression levels of each protein were examined in the dorsolateral prefrontal cortex, temporal cortex, and motor cortex in 15 postmortem schizophrenia subjects and 15 postmortem matched normal comparison subjects. Chronic antipsychotic treatment in rodents was conducted to examine the potential effect of antipsychotic drugs on expression of the three proteins.Findings revealed a significant increase in GCP II protein and a reduction in mGluR3 protein in the dorsolateral prefrontal cortex in schizophrenia subjects, with mGluR2 protein levels unchanged. Chronic antipsychotic treatment in rodents did not influence GCP II or mGluR3 levels.Increased GCP II expression and low mGluR3 expression in the dorsolateral prefrontal cortex suggest that NAAG-mediated signaling is impaired in this brain region in schizophrenia. Further, these data implicate the mGluR3 receptor in the antipsychotic action of mGluR2/mGluR3 agonists.
Molecular Breast Imaging: Potential New Tool for Detecting Cancers
Authors: Charlie Schmidt
Journal: JNCI Journal of the National Cancer Institute (2008)

Mammography may be a “gold standard” for breast cancer screening, but for some women, its interpretation amounts to little more than a coin flip. In women with dense breasts, which contain more stromal and epithelial tissues than fat, interpretation of mammograms is difficult. Among these women, tumor detection rates with mammography barely exceed 60%. Both tumors and breast tissues appear white on a mammogram, but fat looks black. Clinicians can easily detect cancerous lesions against the darker fat backdrop, whereas dense tissues obscure tumors that could be life threatening.

Now researchers at the Mayo Clinic in Rochester, Minn., say that a different screening method—molecular breast imaging (MBI)—may offer a promising alternative for women with dense breasts, who make up much of the female population. Deborah Rhodes, M.D., an assistant professor at the Mayo Clinic, said roughly a quarter of all women older than 40 years have breast tissue that is more than 50% mammographically dense.

Compared with mammography, she said, MBI detected three times as many cancers among a population of 940 dense-breasted women who also had at least one additional breast cancer risk factor, such as a family history of the disease. These preliminary findings, announced in September at the American Society of Clinical Oncology's 2008 Breast Cancer Symposium in Washington, D.C., came from an ongoing, comparative study of MBI and mammography that was launched at the Mayo Clinic in 2005. “We're talking about a supplement to mammography that could be readily adopted by communities, instead of just major academic institutions,” said Rhodes, who is also the study's principal investigator. “While [mammography is] terrific for some women, it doesn't work well for others. For them, we need a better test, and that's what MBI could provide.”
Interferon-α2a and 13-cis-retinoic acid with radiation treatment for high-grade glioma
Authors: Robert O. Dillman, W. Michael Shea, D. Fritz Tai, Khosrow Mahdavi, Neil M. Barth, Bharati R. Kharkar, Marshall M. Poor, Curtis K. Church, Carol DePriest
Journal: Neuro-Oncology (2001)

Interferon-α (IFN-) has been safely given concurrently with radiation therapy (RT) in treating gliomas. As single agents, both IFN-α and cis-retinoic acid (CRA) have produced objective tumor regressions in patients with recurrent gliomas. In vitro, IFN-α2a and CRA enhance radiation therapy effects on glioblastoma cells more than either agent alone. This trial was conducted to determine the clinical effects of IFN-α2a and CRA when given concurrently with radiation therapy to patients with high-grade glioma. Newly diagnosed patients with high-grade glioma received IFN-α2a at a dosage of 3 to 6 million IU s.c. 4 times a day for 3 days per week and 1 mg/kg CRA by mouth 4 times a day for 5 days per week during the delivery of partial brain radiation therapy at 180 cGy × 33 fractions for 5 days per week for a total of 59.4 Gy during the 7-week period. Use of the antiepileptic phenytoin was prohibited after observing that the combination of IFN-α2a, CRA, and phenytoin was associated with a high rate of dermatologic toxicity not seen in a previous study with concurrent IFN-α2a and radiation therapy. Forty patients (26 men and 14 women) with a median age of 60 (range, 19 to 81 years) were enrolled between August 1996 and October 1998. Histopathologic diagnoses were glioblastoma multiforme or grade 4 anaplastic astrocytoma in 36 patients, and grade 3 anaplastic astrocytoma in 4 patients. Only 4 patients (10%) underwent a gross total resection of tumor prior to this therapy; 50% were asymptomatic when treatment was initiated. The planned 7-week course of concurrent therapy was completed by 75% of patients; 30% completed the 16-week course of IFN-α and CRA alone. At a median follow-up of 36 months, there were 37 deaths, with a median overall survival of 9.3 months and a 1-year survival rate of 42%. There was no improvement in survival compared with a similar group of 19 patients treated with concurrent IFN-α2a and radiation therapy in a previous trial. In the highrisk group of patients in the present study, concurrent treatment with IFN-α2a, CRA, and RT was feasible, but was not associated with a better outcome compared with a similar patient population treated with radiation therapy and IFN-α2a, or compared with radiation therapy alone in other trials.
Regulation of Murine Intestinal Inflammation by Reactive Metabolites of Oxygen and Nitrogen
Authors: Christian F. Krieglstein, Wolfgang H. Cerwinka, F. Stephen Laroux, James W. Salter, Janice M. Russell, Guido Schuermann, Matthew B. Grisham, Christopher R. Ross, D. Neil Granger
Journal: The Journal of Experimental Medicine (2001)

Several reports have implicated reactive oxygen and nitrogen metabolites (RONS) in the initiation and/or progression of inflammatory bowel diseases (IBDs). We have investigated the role of three key RONS-metabolizing enzymes (inducible nitric oxide synthase [iNOS], superoxide dismutase [SOD], nicotinamide adenine dinucleotide phosphate [NADPH] oxidase) in a murine model of IBD. Mice genetically deficient (−/−) in either iNOS or the p47phox subunit of NADPH oxidase, transgenic (Tg) mice that overexpress SOD, and their respective wild-type (WT) littermates were fed dextran sulfate sodium (DSS) in drinking water for 7 days to induce colitis. In addition, the specific iNOS inhibitor 1400W was used in DSS-treated WT and p47phox−/− mice. WT mice responded to DSS feeding with progressive weight loss, bloody stools, elevated serum NOX and colonic mucosal injury with neutrophil infiltration. Both the onset and severity of colitis were significantly attenuated in iNOS−/− and 1400W-treated WT mice. While the responses to DSS did not differ between WT and p47phox−/− mice, enhanced protection was noted in 1400W-treated p47phox−/− mice. Interestingly, SODTg mice exhibited more severe colitis than their WT littermates. These findings reveal divergent roles for superoxide and iNOS-derived NO in intestinal inflammation.
Causes of death in people with coeliac disease in England compared with the general population: a competing risk analysis
Authors: Alyshah Abdul Sultan, Colin J Crooks, Tim Card, Laila J Tata, Kate M Fleming, Joe West
Journal: Gut (2014)

<h3>Introduction</h3> Quantifying excess cause-specific mortality among people with coeliac disease (CD) compared with the general population accounting for competing risks will allow accurate information to be given on risk of death from specific causes. <h3>Method</h3> We identified from the Clinical Practice Research Datalink all patients with CD linked to Office for National Statistics between 1998 and 2012. We selected controls by frequency matching from the registered general practice population within 10-year age bands. We calculated the adjusted cumulative incidence (including adjustment for competing risks) and excess cumulative incidence for different causes of death up to 10 years from diagnosis. <h3>Results</h3> Of the 10 825 patients with CD, 773 died within the study period. The overall mortality rate among patients with CD was 128/10 000 person years compared with 153/10 000 in controls (HR=0.94 95% CI 0.84 to 1.01). We found no overall difference in the cumulative incidence of respiratory disease, digestive disease or cancer related death among cases and controls. The adjusted cumulative incidence of death from cardiovascular deaths was slightly lower compared with those without CD diagnosis (CD 0.32% vs controls 0.41%) with a corresponding excess cumulative incidence of −0.08% (95% CI −0.13 to −0.04). However, patients with CD had 0.15% excess risk (95% CI 0.03 to 0.27) of deaths from non-Hodgkin9s lymphoma from the general population baseline risk. <h3>Conclusions</h3> Overall, people with CD have no major excess risk of cancer, digestive disease or respiratory disease related or cardiovascular mortality compared with the general population. These findings should be reassuring to patients with CD and clinicians managing their care.
Prospective evaluation of World Health Organization criteria to assist diagnosis of tuberculosis in children
Authors: KA Houwert, PA Borggreven, HS Schaaf, E Nel, PR Donald, J Stolk
Journal: European Respiratory Journal (1998)

Because of the difficulty in confirming childhood tuberculosis (TB), the World Health Organization (WHO) proposes a hierarchical approach to diagnosis using history and certain clinical features to help to improve the control of TB in communities. The objective of this study was to evaluate prospectively in children the diagnostic value of recent weight loss or failure to gain weight adequately, cough or wheezing for >2 weeks and recent household contact with an adult case of pulmonary TB. These evaluations were performed in 627 children presenting to the paediatric outpatient department of a tertiary hospital situated in the Western Cape Province of South Africa and serving a community with a very high incidence of TB (>1,000 per 100,000). If at least one of the criteria was present, the diagnosis of TB was investigated further by clinical investigation, Mantoux test, chest radiography and TB culture from gastric aspirate. One or more of the proposed criteria for diagnosing TB in childhood were present in 206 children (33%). TB confirmed by culture of Mycobacterium tuberculosis from gastric aspirate was found in 10 children (5%). After diagnostic work-up, 23 children (11%) were considered to have probable TB, whereas 173 (84%) were, after follow-up of 8 weeks, thought not to have TB. In this study the simultaneous presence of the three WHO criteria for suspecting TB had a positive predictive value of 63%. These results should assist in the more precise delineation of the predictive value of the proposed World Health Organization approach to the diagnosis of tuberculosis in childhood.
Reliability of ultrasonography in detecting shoulder disease in patients with rheumatoid arthritis
Authors: G A W Bruyn, E Naredo, I Möller, C Moragues, J Garrido, G H de Bock, M-A d’Agostino, E Filippucci, A Iagnocco, M Backhaus, W A A Swen, P Balint, C Pineda, S Milutinovic, D Kane, G Kaeley, F J Narvaez, R J Wakefield, J A Narvaez, J de Augustin, W A Schmidt
Journal: Annals of the Rheumatic Diseases (2008)

To assess the intra and interobserver reproducibility of musculoskeletal ultrasonography (US) among rheumatologists in detecting destructive and inflammatory shoulder abnormalities in patients with rheumatoid arthritis (RA) and to determine the overall agreement between US and MRI.A total of 14 observers examined 5 patients in 2 rounds independently and blindly of each other. US results were compared with MRI. Overall agreement of all findings, of positive findings on MRI, as well as intra and interobserver reliabilities, were calculated.Overall agreement between US and MRI was seen in 79% with regard to humeral head erosions (HHE), in 64% with regard to posterior recess synovitis (PRS), in 31% with regard to axillary recess synovitis (ARS), in 64% with regard to bursitis, in 50% with regard to biceps tenosynovitis (BT), and in 84% for complete cuff tear (CCT). Intraobserver and interobserver kappa was 0.69 and 0.43 for HHE, 0.29 and 0.49 for PRS, 0.57 and 1.00 for ARS, -0.17 and 0.51 for bursitis, 0.17 and 0.46 for BT and 0.52 and 0.6 for CCT, respectively. The intraobserver and interobserver kappa for power Doppler (PD) was 0.90 and 0.70 for glenohumeral signals and 0.60 and 0.51 for bursal signals, respectively.US is a reliable imaging technique for most shoulder pathology in RA especially with regard to PD. Standardisation of scanning technique and definitions of particular lesions may further enhance the reliability of US investigation of the shoulder.
Nanoparticle-Based Test Measures Overall Propensity for Calcification in Serum
Authors: Andreas Pasch, Stefan Farese, Steffen Gräber, Johanna Wald, Walter Richtering, Jürgen Floege, Willi Jahnen-Dechent
Journal: Journal of the American Society of Nephrology (2012)

Vascular and soft tissue calcification contributes to cardiovascular morbidity and mortality in both the general population and CKD. Because calcium and phosphate serum concentrations are near supersaturation, the balance of inhibitors and promoters critically influences the development of calcification. An assay that measures the overall propensity for calcification to occur in serum may have clinical use. Here, we describe a nanoparticle-based assay that detects, in the presence of artificially elevated calcium and phosphate concentrations, the spontaneous transformation of spherical colloidal primary calciprotein particles (CPPs) to elongate crystalline secondary CPPs. We used characteristics of this transition to describe the intrinsic capacity of serum to inhibit the precipitation of calcium and phosphate. Using this assay, we found that both the sera of mice deficient in fetuin-A, a serum protein that inhibits calcification, and the sera of patients on hemodialysis have reduced intrinsic properties to inhibit calcification. In summary, we developed a nanoparticle-based test that measures the overall propensity for calcification in serum. The clinical use of the test requires evaluation in a prospective study.
Synergy of entry inhibitors with direct-acting antivirals uncovers novel combinations for prevention and treatment of hepatitis C
Authors: Fei Xiao, Isabel Fofana, Christine Thumann, Laurent Mailly, Roxane Alles, Eric Robinet, Nicolas Meyer, Mickaël Schaeffer, François Habersetzer, Michel Doffoël, Pieter Leyssen, Johan Neyts, Mirjam B Zeisel, Thomas F Baumert
Journal: Gut (2014)

<h3>Objective</h3> Although direct-acting antiviral agents (DAAs) have markedly improved the outcome of treatment in chronic HCV infection, there continues to be an unmet medical need for improved therapies in difficult-to-treat patients as well as liver graft infection. Viral entry is a promising target for antiviral therapy. <h3>Design</h3> Aiming to explore the role of entry inhibitors for future clinical development, we investigated the antiviral efficacy and toxicity of entry inhibitors in combination with DAAs or other host-targeting agents (HTAs). Screening a large series of combinations of entry inhibitors with DAAs or other HTAs, we uncovered novel combinations of antivirals for prevention and treatment of HCV infection. <h3>Results</h3> Combinations of DAAs or HTAs and entry inhibitors including CD81-, scavenger receptor class B type I (SR-BI)- or claudin-1 (CLDN1)-specific antibodies or small-molecule inhibitors erlotinib and dasatinib were characterised by a marked and synergistic inhibition of HCV infection over a broad range of concentrations with undetectable toxicity in experimental designs for prevention and treatment both in cell culture models and in human liver-chimeric uPA/SCID mice. <h3>Conclusions</h3> Our results provide a rationale for the development of antiviral strategies combining entry inhibitors with DAAs or HTAs by taking advantage of synergy. The uncovered combinations provide perspectives for efficient strategies to prevent liver graft infection and novel interferon-free regimens.
Phosphoglucose Isomerase/Autocrine Motility Factor Mediates Epithelial and Mesenchymal Phenotype Conversions in Breast Cancer
Authors: Tatsuyoshi Funasaka, Victor Hogan, Avraham Raz
Journal: Cancer Research (2009)

Phosphoglucose isomerase/autocrine motility factor (PGI/AMF) is a housekeeping gene product/cytokine that catalyzes a step in glycolysis and gluconeogenesis, and acts as a multifunctional cytokine associated with aggressive tumors. PGI/AMF has been correlated significantly with breast cancer progression and poor prognosis in breast cancer. We show here that ectopic expression of PGI/AMF induced epithelial-to-mesenchymal transition (EMT) in MCF10A normal human breast epithelial cells, and inhibition of PGI/AMF expression triggered mesenchymal-to-epithelial transition (MET) in aggressive mesenchymal-type human breast cancer MDA-MB-231 cells. EMT in MCF10A cells was shown by morphologic changes and loss of E-cadherin/beta-catenin-mediated cell-cell adhesion, which is concomitant with the induction of the E-cadherin transcriptional repressor Snail and proteosome-dependent degradation of beta-catenin protein. Molecular analysis showed that PGI/AMF suppressed epithelial marker expressions and enhanced mesenchymal marker expressions. Silencing of PGI/AMF expression by RNA interference in MDA-MB-231 cells induced the reverse processes of EMT including altered cell shape, gain of epithelial marker, and reduction of mesenchymal marker, e.g., MET. Taken together, the results show the involvement of PGI/AMF in both EMT and MET: overexpression of PGI/AMF induces EMT in normal breast epithelial cells and reduction of PGI/AMF expression led to MET in aggressive breast cancer cells. These results suggest for the first time that PGI/AMF is a key gene to both EMT in the initiating step of cancer metastasis and MET in the later stage of metastasis during breast cancer progression.
Capturing Alzheimer's disease genomes with induced pluripotent stem cells: prospects and challenges
Authors: Mason A Israel, Lawrence SB Goldstein
Journal: Genome Medicine (2011)

A crucial limitation to our understanding of Alzheimer's disease (AD) is the inability to test hypotheses on live, patient-specific neurons. Patient autopsies are limited in supply and only reveal endpoints of disease. Rodent models harboring familial AD mutations lack important pathologies, and animal models have not been useful in modeling the sporadic form of AD because of complex genetics. The recent development of induced pluripotent stem cells (iPSCs) provides a method to create live, patient-specific models of disease and to investigate disease phenotypes in vitro. In this review, we discuss the genetics of AD patients and the potential for iPSCs to capture the genomes of these individuals and generate relevant cell types. Specifically, we examine recent insights into the genetic fidelity of iPSCs, advances in the area of neuronal differentiation, and the ability of iPSCs to model neurodegenerative diseases.
Patella plasmacytoma: An unusual localization
Authors: Delphine Lebon, Lazhar Saidi, Lavinia Merlusca, Francois Leduc, Bruno Royer
Journal: American Journal of Hematology (2010)

In July 2010, a 66-year-old woman presented with pain, edema, and ankylosis of the left knee. She had a nonsecretory multitreated multiple myeloma since 2002, relapsing in October 2009, and treated with Bortezomib, Dexamethasone, and Cyclophosphamide. Blood count, renal function, and free light chains assay were normal. The X-rays of knees did not show pathological fractures. However positon emission tomography scan (PET-scan) showed hyperfixation of the left patella (Image 1) (top views). On resonance magnetic imagery, there was a lesion on the lower part of the kneecap with fat and adjacent loft tissue infiltration and a cortical injury (bottom views). Following a needle biopsy, the diagnosis of plasmacytoma was made: histopathological examination found tumoral cells which were CD138 and CD56 positive. Symptoms improved with radiotherapy and after chemotherapy with Revlimid, Anthracyclin, and Dexamethasone was initiated. Osteolytic lesions during multiple myeloma occur predominantly in axial skeleton (skull, spine, rib cage, and pelvis) and the proximal areas of the arms and legs [1]. Lesions are generally diagnosed by standard radiography. PET-scan is not recommended for routine use in the management of the myeloma patients [2], although this technique may be useful in selective cases like our patient. Positon emission tomography views (top) of legs (sagittal section on the left and frontal on the center) and knees (transversal section on the right); resonance magnetic imagery views (bottom) of knee (T1 sequence on the left and T2 on the center and the right). [Color figure can be viewed in the online issue, which is available at wileyonlinelibrary.com.]
Use of 2H2O for estimating rates of gluconeogenesis. Application to the fasted state.
Authors: B R Landau, J Wahren, V Chandramouli, W C Schumann, K Ekberg, S C Kalhan
Journal: Journal of Clinical Investigation (1995)

A method is introduced for estimating the contribution of gluconeogenesis to glucose production. 2H2O is administered orally to achieve 0.5% deuterium enrichment in body water. Enrichments are determined in the hydrogens bound to carbons 2 and 6 of blood glucose and in urinary water. Enrichment at carbon 6 of glucose is assayed in hexamethylenetetramine, formed from formaldehyde produced by periodate oxidation of the glucose. Enrichment at carbon 2 is assayed in lactate formed by enzymatic transfer of the hydrogen from glucose via sorbitol to pyruvate. The fraction gluconeogenesis contributes to glucose production equals the ratio of the enrichment at carbon 6 to that at carbon 2 or in urinary water. Applying the method, the contribution of gluconeogenesis in healthy subjects was 23-42% after fasting 14 h, increasing to 59-84% after fasting 42 h. Enrichment at carbon 2 to that in urinary water was 1.12 +/- 0.13. Therefore, the assumption that hydrogen equilibrated during hexose-6-P isomerization was fulfilled. The 3H/14C ratio in glucose formed from [3-3H,3-14C]lactate given to healthy subjects was 0.1 to 0.2 of that in the lactate. Therefore equilibration during gluconeogenesis of the hydrogen bound to carbon 6 with that in body water was 80-90% complete, so that gluconeogenesis is underestimated by 10-20%. Glycerol's contribution to gluconeogenesis is not included in these estimates. The method is applicable to studies in humans of gluconeogenesis at safe doses of 2H2O.