tbuckley/cabot-search huggingface dataset:
PET Imaging of Dopamine D2 Receptors in Monkey Models of Cocaine Abuse: Genetic Predisposition Versus Environmental Modulation
Authors: Michael A Nader, Paul W Czoty
Journal: American Journal of Psychiatry (2005)

OBJECTIVE: Animals self-administer many of the drugs that humans abuse, including cocaine. This article describes studies using preclinical animal models to differentiate the influences of neurobiological predisposition from environmental modulation of cocaine addiction, including studies from the authors' laboratory using nonhuman primates. METHOD: Addiction is described in terms of vulnerability, maintenance, and abstinence. This review focuses on dopamine receptor function, in particular that of the D2-like receptors, as measured by the noninvasive imaging procedure positron emission tomography. Findings from human studies of addiction and animal models are reviewed. RESULTS: There appears to be an inverse relationship between D2 receptor availability and vulnerability to the reinforcing effects of cocaine. Environmental variables can increase or decrease D2 receptor binding in an orderly fashion, and the resulting changes in D2 function influence the vulnerability to abuse cocaine. In maintenance, chronic cocaine exposure produces decreases in D2 receptor binding, which may be a mechanism that contributes to continued drug use. Finally, during abstinence there are individual differences in rates of recovery of D2 receptor availability. CONCLUSIONS: The goal of the preclinical research described in this review is to achieve a better understanding of individual differences in susceptibility and vulnerability to the reinforcing effects of cocaine. It is clear that the development of novel animal models will extend our understanding of the neurobiological basis of drug addiction to include a greater appreciation of the role of environmental factors in affecting predisposition, mediating continued drug use, and triggering relapse.
Extracorporeal shock wave therapy for plantar fasciitis: randomised controlled multicentre trial
Authors: M. Haake
Journal: BMJ (2003)

<b>Objective</b> To determine the effectiveness of extracorporeal shock wave therapy compared with placebo in the treatment of chronic plantar fasciitis. <b>Design</b> Randomised, blinded, multicentre trial with parallel group design. <b>Setting</b> Nine hospitals and one outpatient clinic in Germany. <b>Participants</b> 272 patients with chronic plantar fasciitis recalcitrant to conservative therapy for at least six months: 135 patients were allocated extracorporeal shock wave therapy and 137 were allocated placebo. <b>Main outcome measures</b> Primary end point was the success rate 12 weeks after intervention based on the Roles and Maudsley score. Secondary end points encompassed subjective pain ratings and walking ability up to a year after the last intervention. <b>Results</b> The primary end point could be assessed in 94% (n=256) of patients. The success rate 12 weeks after intervention was 34% (n=43) in the extracorporeal shock wave therapy group and 30% (n=39) in the placebo group (95% confidence interval - 8.0% to 15.1%). No difference was found in the secondary end points. Few side effects were reported. <b>Conclusions</b> Extracorporeal shock wave therapy is ineffective in the treatment of chronic plantar fasciitis.
Nephrotic syndrome, renal failure, and renal malignancy
Authors: M Ahmed, K Solangi, R Abbi, S Adler
Journal: Journal of the American Society of Nephrology (1997)

The association between malignancy and glomerular disease has been appreciated for over three decades. Although the relationship between membranous glomerulonephritis or minimal-change nephrotic syndrome and carcinoma or lymphoma, respectively, are the most widely known, several other glomerular lesions have been described in patients with malignancy. In this article, a patient who presented with nephrotic syndrome, volume overload, and renal failure, who was subsequently found to have a renal mass, is described. Resection of the mass, which proved to be a renal cell carcinoma, led to resolution of proteinuria and improvement of renal function. Pathology on the noninvolved portion of the kidney revealed a membranoproliferative glomerular lesion, a lesion usually associated with lymphomas and not previously described with renal carcinoma. Although a role of tumor antigens and anti-tumor antibodies in producing glomerular immune deposits has been speculated upon, the evidence for this assertion was spotty. However, reports of remission of proteinuria after tumor treatment or removal support a role of tumor products in pathogenesis. Although the association between proteinuria and malignancy is rare, it should be kept in mind, particularly in older patients with membranous glomerulonephritis where the possibility of malignancy needs to be further evaluated.
An overview of conditioning regimens for haploidentical stem cell transplantation with post‐transplantation cyclophosphamide
Authors: Munira Shabbir‐Moosajee, Lindsey Lombardi, Stefan O. Ciurea
Journal: American Journal of Hematology (2015)

Haploidentical related donors are an attractive alternative source of stem cells for allogeneic stem cell transplantation due to widespread availability and ease of stem cell procurement. Historically, haploidentical stem cell transplantation (HaploSCT) with extensive T-cell depletion has been associated with high rates of infectious complications and nonrelapse mortality (NRM). Post-transplantation cyclophosphamide (PTCy) has been shown to induce immune tolerance, effectively control graft-versus-host-disease (GVHD), and is associated with lower NRM, making it a preferred option for patients undergoing HaploSCT. Over the last decade, several groups investigated PTCy for GVHD prevention in HaploSCT; it is now successfully utilized with both myeloablative and nonmyeloablative conditioning regimens with survival comparable to HLA-matched transplantation. Future directions will focus on optimizing conditioning regimens by diagnosis, improving donor selection, and enhancing graft-versus-leukemia effect.
Biallelic Germline Transcription at the κ Immunoglobulin Locus
Authors: Nandita Singh, Yehudit Bergman, Howard Cedar, Andrew Chess
Journal: The Journal of Experimental Medicine (2003)

Rearrangement of antigen receptor genes generates a vast array of antigen receptors on lymphocytes. The establishment of allelic exclusion in immunoglobulin genes requires differential treatment of the two sequence identical alleles. In the case of the κ immunoglobulin locus, changes in chromatin structure, methylation, and replication timing of the two alleles are all potentially involved in regulating rearrangement. Additionally, germline transcription of the κ locus which precedes rearrangement has been proposed to reflect an opening of the chromatin structure rendering it available for rearrangement. As the initial restriction of rearrangement to one allele is critical to the establishment of allelic exclusion, a key question is whether or not germline transcription at the κ locus is monoallelic or biallelic. We have used a sensitive reverse transcription-polymerase chain reaction (RT-PCR) assay and an RNA–fluorescence in situ hybridization (FISH) to show that germline transcription of the κ locus is biallelic in wild-type immature B cells and in recombination activating gene (RAG)−/−, μ+ B cells. Therefore, germline transcription is unlikely to dictate which allele will be rearranged first and rather reflects a general opening on both alleles that must be accompanied by a mechanism allowing one of the two alleles to be rearranged first.
The Cellular Thermal Shift Assay: A Novel Biophysical Assay for In Situ Drug Target Engagement and Mechanistic Biomarker Studies
Authors: Daniel Martinez Molina, Pär Nordlund
Journal: The Annual Review of Pharmacology and Toxicology (2015)

A drug must engage its intended target to achieve its therapeutic effect. However, conclusively measuring target engagement (TE) in situ is challenging. This complicates preclinical development and is considered a key factor in the high rate of attrition in clinical trials. Here, we discuss a recently developed, label-free, biophysical assay, the cellular thermal shift assay (CETSA), which facilitates the direct assessment of TE in cells and tissues at various stages of drug development. CETSA also reveals biochemical events downstream of drug binding and therefore provides a promising means of establishing mechanistic biomarkers. The implementation of proteome-wide CETSA using quantitative mass spectrometry represents a novel strategy for defining off-target toxicity and polypharmacology and for identifying downstream mechanistic biomarkers. The first year of CETSA applications in the literature has focused on TE studies in cell culture systems and has confirmed the broad applicability of CETSA to many different target families. The next phase of CETSA applications will likely encompass comprehensive animal and patient studies, and CETSA will likely serve as a very valuable tool in many stages of preclinical and clinical drug development.
Myocardial Proinflammatory Cytokine Expression and Left Ventricular Remodeling in Patients With Chronic Mitral Regurgitation
Authors: Hakan Oral, Natarajan Sivasubramanian, David B. Dyke, Rajendra H. Mehta, P. Michael Grossman, Kerri Briesmiester, William P. Fay, Francis D. Pagani, Steven F. Bolling, Douglas L. Mann, Mark R. Starling
Journal: Circulation (2003)

Background— In an animal model, stretch was shown to induce myocardial tumor necrosis factor-α (TNF-α) expression. The purposes of this study were to determine whether the left ventricular (LV) volume overload that occurs in patients with chronic mitral regurgitation (MR) can induce myocardial and systemic TNF-α expression and whether there is a relationship between TNF-α expression and LV remodeling. Methods and Results— Plasma TNF-α and its receptors were measured before mitral valve (MV) repair surgery in 26 MR patients and 23±12 months after MV repair surgery in 9 MR patients. Myocardial mRNA copies of TNF-α were determined in 11 MR and 10 donor hearts using quantitative RT-PCR. Compared with 15 control subjects, pre-MV repair plasma TNF-α (3.59±1.81 versus 2.03±1.02 pg/mL, P &lt;0.005) and its receptor levels were elevated in MR patients. Myocardial TNF-α mRNA copies (corrected for β-actin mRNA expression) in MR patients and donor hearts were 38.96±42.74×10 6 and 0.88±0.75×10 6 , respectively ( P =0.01). After MV surgery, there was a decrease in the plasma levels of TNF-α (2.79±1.14 versus 3.51±1.34 pg/mL, P =0.02) and its receptors. There was a correlation between myocardial TNF-α expression and preoperative LV end-diastolic and end-systolic volumes. Moreover, there was an inverse correlation between myocardial TNF-α expression and regression in LV end-diastolic ( r =−0.76, P =0.007) and end-systolic ( r =−0.73, P =0.01) volumes after MV surgery. Conclusions— TNF-α is expressed in the myocardium and plasma of MR patients. Correction of the LV volume overload with MV surgery results in reversal of TNF-α expression. There is a relationship between TNF-α expression and parameters of LV remodeling, suggesting that TNF-α may play a role in the pathogenesis of the LV remodeling that occurs in MR.
Epistasis between two HLA antigens defines a subset of individuals at a very high risk for ankylosing spondylitis
Authors: Floris A van Gaalen, Willem Verduijn, Dave L Roelen, Stefan Böhringer, Tom W J Huizinga, Désirée M van der Heijde, René E M Toes
Journal: Annals of the Rheumatic Diseases (2012)

Objectives Susceptibility to spondyloarthritis (SpA) is largely genetically determined. To understand increasingly complex genetic associations, one approach is to study epistasis or genetic interactions. Several associations between HLA antigens and SpA including HLA-B27 have been reported. In this study, we investigated epistasis between common HLA class I risk antigens in ankylosing spondylitis (AS), the most typical form of SpA. Methods In 154 patients with AS and 5584 controls, HLA class I antigens were analysed for association with AS. Biological interaction was analysed by investigating whether the effects of the risk factors combined departed from additivity. Results Apart from the association with HLA-B27, we found an association between HLA-B60 and AS (OR 1.8; 95% CI 1.2 to 2.8). This was confirmed in a meta-analysis (OR 2.2; CI 1.8 to 2.8). While 18.2% of AS patients had both HLA-B27 and HLA-B60, this combination was found in only 0.4% of controls. Using AS patients without HLA-B27 and HLA-B60 as a reference, the relative risk (RR) for disease in HLA-B27−/HLA-B60+ patients was 1.2 (95% CI 0.3 to 4.1). For HLA-B27+/HLA-B60− the RR was 69 (95% CI 40 to 111) but increased to 342 (95% CI 147 to 708) in HLA-B27+/HLA-B60+ patients. For the interaction, the relative excess risk due to interaction was 251, the attributable proportion was 0.8 and the synergy index was 4.7. The interaction was confirmed in an independent cohort. Conclusions There is a strong epistatic interaction between HLA-B60 and HLA-B27 in AS susceptibility . As a result, individuals with the HLA-B27+/HLA-B60+ genotype are at a very high risk of developing AS.
Value of Serum Human Epidermal Growth Factor Receptor 2 (HER2)/<i>neu</i> Testing for Early Prediction of Response to HER2/<i>neu</i>-Directed Therapies Is Still an Open One and Deserves Further Study in Large Prospective Trials
Authors: Suhail M. Ali, Kim Leitzel, Allan Lipton, Walter P. Carney, Wolfgang J. Köstler
Journal: Journal of Clinical Oncology (2009)

TO THE EDITOR: The recent article by Lennon et al draws a very different conclusion about the value of the serum human epidermal growth factor receptor 2 (HER2)/neu test then did our previously published work by Ali et al. We wish to make the following observations. The number of patients who were HER2/neu tissue positive and treated with first-line trastuzumab and had both baseline and follow-up serum HER2/neu was 105 in the Lennon et al study versus 235 in the Ali et al study. Ali et al define a significant decline in serum HER2/neu as a 20% decrease from baseline at a median of 30 days after commencing trastuzumab. This is obtained from the receiver operating characteristic (ROC) curve analysis in the publication. Lennon et al describe the statistics they employed but do not give us a definition of significant HER2/neu change. Lennon et al present only overall and best tumor response. They do not tell us what criteria were employed. Ali et al utilize WHO or Response Evaluation Criteria in Solid Tumors and present data for tumor response, duration of response, time to progression, and overall survival. As in the publication, a decrease in serum HER2/neu of at least 20% from baseline resulted in significantly improved response rate, duration of response, time to progression, and overall survival. It would be most important for Lennon et al to look at these clinical end points. Lennon et al report a P value of .124 of overall response and a P value of .074 for best tumor response. These results are encouraging and might well turn out to be significant in a larger patient population. We feel that the question of the value of serum HER2/neu testing for early prediction of response to HER2/neu directed therapies is still an open one and deserves further study in large prospective trials.
Dynamic Changes During the Immune Response in T Cell–Antigen-presenting Cell Clusters Isolated from Lymph Nodes
Authors: Mirja Hommel, Bruno Kyewski
Journal: The Journal of Experimental Medicine (2003)

Activation of antigen-specific T cells by mature dendritic cells in secondary lymphoid organs is a key control point of the adaptive immune response. Here we describe the ex vivo isolation of preformed multicellular clusters between T cells and antigen-presenting cells. Adoptively transferred, antigen-specific T cells segregated into individual clusters where their activation and proliferation was initiated in vivo. Transit of the T cell cohort through the cluster compartment required 32–36 h. The precise timing of the response to agonistic epitopes was remarkably invariant regardless of the T cell lineage, the major histocompatibility complex haplotype, and the antigen dose. Interestingly, initiation of cell division of T cells specific for a subdominant epitope and a weak agonist was delayed by 6 h. The results provide a basis for the analysis of short range, mutual cell–cell interactions within such confined microenvironments.
The major parasite surface antigen associated with human resistance to schistosomiasis is a 37-kD glyceraldehyde-3P-dehydrogenase.
Authors: V Goudot-Crozel, D Caillol, M Djabali, A J Dessein
Journal: The Journal of Experimental Medicine (1989)

Schistosomiasis, due to Schistosoma mansoni, is a major health problem in many subtropical countries, and major efforts are being made to define a vaccine. In this regard, we have reported that sera from subjects with low susceptibility to infection by S. mansoni react with a major larval surface antigen (P-37), having an apparent molecular mass of 37 kD, against which sera of susceptible individuals show little reactivity. We have now cloned the cDNA for this antigen by screening a schistosome cDNA expression library with antibodies against the purified protein. The selected cDNAs encode a protein that is specifically identified by immune human sera containing antibodies against P-37, while sera exhibiting low or no reactivity toward P-37 fail to recognize the recombinant protein. The cloned cDNAs hybridize with a 1.2-kb RNA that is the transcript of a single copy gene. This RNA directs the synthesis of a 36.5-kD polypeptide that is precipitated by sera from the most resistant subjects. The amino acid sequence of the encoded polypeptide shows homology with the glycolytic enzyme Glyceraldehyde-3P-dehydrogenase (72.5% of positional identity with human Glyceraldehyde-3P-dehydrogenase). Antibodies against the recombinant protein identified P-37 on the larva. These findings, together with other reports, indicate that a number of conserved proteins may be major targets of host-protective immunity against S. mansoni. The hypothesis is discussed that genetic restriction of the immune response to these antigens may occur in heterogeneous human populations because of the limited number of T cell epitopes carried by these host-like proteins. Such genetic effects might allow parasite transmission through nonresponder (susceptible) individuals. This hypothesis and the protective properties of P-37 can now be tested using the recombinant protein and synthetic peptides derived from selected regions of the polypeptide chain.
Chlorination of Taurine by Human Neutrophils
Authors: Stephen J. Weiss, Roger Klein, Adam Slivka, Maria Wei
Journal: Journal of Clinical Investigation (1982)

The model hydrogen peroxide-myeloperoxidase-chloride system is capable of generating the powerful oxidant hypochlorous acid, which can be quantitated by trapping the generated species with the β-amino acid, taurine. The resultant stable product, taurine chloramine, can be quantitated by its ability to oxidize the sulfhydryl compound, 5-thio-2-nitro-benzoic acid to the disulfide, 5,5′-dithiobis(2-nitroben-zoic acid) or to oxidize iodide to iodine. Using this system, purified myeloperoxidase in the presence of chloride and taurine converted stoichiometric quantities of hydrogen peroxide to taurine chloramine. Chloramine generation was absolutely dependent on hydrogen peroxide, myeloperoxidase, and chloride and could be inhibited by catalase, myeloperoxidase inhibitors, or chloride-free conditions. In the presence of taurine, intact human neutrophils stimulated with either phorbol myristate acetate or opsonized zymosan particles generated a stable species capable of oxidizing 5-thio-2-nitrobenzoic acid or iodide. Resting cells did not form this species. The oxidant formed by the stimulated neutrophils was identified as taurine chloramine by both ultraviolet spectrophotometry and electrophoresis. Taurine chloramine formation by the neutrophil was dependent on the taurine concentration, time, and cell number. Neutrophil-dependent chloramine generation was inhibited by catalase, the myeloperoxidase inhibitors, azide, cyanide, or aminotriazole and by chloride-free conditions, but not by superoxide dismutase or hydroxyl radical scavengers. Thus, it appears that stimulated human neutrophils can utilize the hydrogen peroxide-myeloperoxidase-chloride system to generate taurine chloramine. Based on the demonstrated ability of the myeloperoxidase system to generate free hypochlorous acid we conclude that neutrophils chlorinate taurine by producing this powerful oxidant. The biologic reactivity and cytotoxic potential of hypochlorous acid and its chloramine derivatives suggest that these oxidants play an important role in the inflammatory response and host defense.
Daclatasvir for previously untreated chronic hepatitis C genotype-1 infection: a randomised, parallel-group, double-blind, placebo-controlled, dose-finding, phase 2a trial
Authors: Stanislas Pol, Reem H Ghalib, Vinod K Rustgi, Claudia Martorell, Greg T Everson, Harvey A Tatum, Christophe Hézode, Joseph K Lim, Jean-Pierre Bronowicki, Gary A Abrams, Norbert Bräu, David W Morris, Paul J Thuluvath, Robert W Reindollar, Philip D Yin, Ulysses Diva, Robert Hindes, Fiona McPhee, Dennis Hernandez, Megan Wind-Rotolo, Eric A Hughes, Steven Schnittman
Journal: The Lancet Infectious Diseases (2012)
Subclinical Atrial Fibrillation and the Risk of Stroke
Authors: Jeff S. Healey, Stuart J. Connolly, Michael R. Gold, Carsten W. Israel, Isabelle C. Van Gelder, Alessandro Capucci, C.P. Lau, Eric Fain, Sean Yang, Christophe Bailleul, Carlos A. Morillo, Mark Carlson, Ellison Themeles, Elizabeth S. Kaufman, Stefan H. Hohnloser
Journal: New England Journal of Medicine (2012)

One quarter of strokes are of unknown cause, and subclinical atrial fibrillation may be a common etiologic factor. Pacemakers can detect subclinical episodes of rapid atrial rate, which correlate with electrocardiographically documented atrial fibrillation. We evaluated whether subclinical episodes of rapid atrial rate detected by implanted devices were associated with an increased risk of ischemic stroke in patients who did not have other evidence of atrial fibrillation.We enrolled 2580 patients, 65 years of age or older, with hypertension and no history of atrial fibrillation, in whom a pacemaker or defibrillator had recently been implanted. We monitored the patients for 3 months to detect subclinical atrial tachyarrhythmias (episodes of atrial rate >190 beats per minute for more than 6 minutes) and followed them for a mean of 2.5 years for the primary outcome of ischemic stroke or systemic embolism. Patients with pacemakers were randomly assigned to receive or not to receive continuous atrial overdrive pacing.By 3 months, subclinical atrial tachyarrhythmias detected by implanted devices had occurred in 261 patients (10.1%). Subclinical atrial tachyarrhythmias were associated with an increased risk of clinical atrial fibrillation (hazard ratio, 5.56; 95% confidence interval [CI], 3.78 to 8.17; P<0.001) and of ischemic stroke or systemic embolism (hazard ratio, 2.49; 95% CI, 1.28 to 4.85; P=0.007). Of 51 patients who had a primary outcome event, 11 had had subclinical atrial tachyarrhythmias detected by 3 months, and none had had clinical atrial fibrillation by 3 months. The population attributable risk of stroke or systemic embolism associated with subclinical atrial tachyarrhythmias was 13%. Subclinical atrial tachyarrhythmias remained predictive of the primary outcome after adjustment for predictors of stroke (hazard ratio, 2.50; 95% CI, 1.28 to 4.89; P=0.008). Continuous atrial overdrive pacing did not prevent atrial fibrillation.Subclinical atrial tachyarrhythmias, without clinical atrial fibrillation, occurred frequently in patients with pacemakers and were associated with a significantly increased risk of ischemic stroke or systemic embolism. (Funded by St. Jude Medical; ASSERT ClinicalTrials.gov number, NCT00256152.).