tbuckley/cabot-search huggingface dataset:
Platelets in Early Antibody-Mediated Rejection of Renal Transplants
Authors: Hsiao-Hsuan Kuo, Ran Fan, Nina Dvorina, Andres Chiesa-Vottero, William M. Baldwin
Journal: Journal of the American Society of Nephrology (2014)

Antibody-mediated rejection is a major complication in renal transplantation. The pathologic manifestations of acute antibody-mediated rejection that has progressed to functional impairment of a renal transplant have been defined in clinical biopsy specimens. However, the initial stages of the process are difficult to resolve with the unavoidable variables of clinical studies. We devised a model of renal transplantation to elucidate the initial stages of humoral rejection. Kidneys were orthotopically allografted to immunodeficient mice. After perioperative inflammation subsided, donor-specific alloantibodies were passively transferred to the recipient. Within 1 hour after a single transfer of antibodies, C4d was deposited diffusely on capillaries, and von Willebrand factor released from endothelial cells coated intravascular platelet aggregates. Platelet-transported inflammatory mediators platelet factor 4 and serotonin accumulated in the graft at 100- to 1000-fold higher concentrations compared with other platelet-transported chemokines. Activated platelets that expressed P-selectin attached to vascular endothelium and macrophages. These intragraft inflammatory changes were accompanied by evidence of acute endothelial injury. Repeated transfers of alloantibodies over 1 week sustained high levels of platelet factor 4 and serotonin. Platelet depletion decreased platelet mediators and altered the accumulation of macrophages. These data indicate that platelets augment early inflammation in response to donor-specific antibodies and that platelet-derived mediators may be markers of evolving alloantibody responses.
Long-Term Outcome of Patients With Intermediate-Risk Exercise Electrocardiograms Who Do Not Have Myocardial Perfusion Defects on Radionuclide Imaging
Authors: Raymond J. Gibbons, David O. Hodge, Daniel S. Berman, Olakunle O. Akinboboye, Jaekyeong Heo, Rory Hachamovitch, Kent R. Bailey, Ami E. Iskandrian
Journal: Circulation (1999)

Background —The appropriate management of patients with intermediate-risk Duke treadmill scores is not established. The purpose of this study was to determine the long-term risk of subsequent cardiovascular events in patients with an intermediate-risk treadmill score who do not have myocardial perfusion defects on radionuclide imaging. Methods and Results —The existing databases of the nuclear cardiology laboratories of 4 academic institutions were searched retrospectively. A total of 4649 patients were identified who had intermediate-risk Duke treadmill scores (−10 to 4), normal or near-normal exercise single photon-emission computed tomographic myocardial perfusion images using either thallium-201 or technetium-99m sestamibi, and no previous coronary revascularization. Follow-up was 95% complete. Cardiovascular survival was 99.8% at 1 year, 99.0% at 5 years, and 98.5% at 7 years. Cardiac survival free of myocardial infarction was similarly high at 96.6% at 7 years. Cardiac survival free of myocardial infarction or revascularization was 87.1% at 7 years. Near-normal scans and cardiac enlargement were independent predictors of time to cardiac death. Seven-year cardiac survival was still high at 97.0% in the 357 patients with near-normal scans and normal cardiac size and somewhat lower, at 89.0%, in the 167 patients with cardiac enlargement. Conclusions —Patients with an intermediate-risk treadmill score but with normal or near-normal exercise myocardial perfusion images and normal cardiac sizes are at low risk for subsequent cardiac death and can be safely managed medically until their symptoms warrant revascularization. The appropriate management of patients with cardiac enlargement will remain a matter of clinical judgment.
Inhaled therapies, azithromycin and<i>Mycobacterium abscessus</i>in cystic fibrosis patients
Authors: Emilie Catherinot, Anne-Laure Roux, Marie-Anne Vibet, Gil Bellis, Lydie Lemonnier, Evelyne Le Roux, Claire Bernède-Bauduin, Muriel Le Bourgeois, Jean-Louis Herrmann, Didier Guillemot, Jean-Louis Gaillard
Journal: European Respiratory Journal (2012)

Cystic fibrosis (CF) patients are at particularly high risk of developing lung disease caused by Mycobacterium abscessus complex (MABSC). Over the last 10 years, changes in CF treatment, with increasing use of inhaled therapies and low-dose azithromycin, have been accompanied by an increase in the prevalence of MABSC infections in CF patients. There is therefore some concern about the role of new CF treatments in the emergence of MABSC infections. We addressed this issue by means of a case–control study including 30 MABSC-positive cases and 60 nontuberculous mycobacteria-negative CF controls matched for age, sex and centre. We also compared practices at the CF centres with the highest prevalence of MABSC with those at the other centres. No positive association was found between MABSC lung disease and the use of inhaled therapies or low-dose azithromycin in the 4 years preceding MABSC isolation. These treatments were not significantly more frequently used at the CF centres with the highest MABSC prevalence rates. In conclusion, there is no evidence for a link between M. abscessus complex lung disease and inhaled therapies or low-dose azithromycin in patients with CF.
Tregs and transplantation tolerance
Authors: Patrick T. Walsh, Devon K. Taylor, Laurence A. Turka
Journal: Journal of Clinical Investigation (2004)

The induction and maintenance of immune tolerance to transplanted tissues constitute an active process involving multiple mechanisms that work cooperatively to prevent graft rejection. These mechanisms are similar to inherent tolerance toward self antigens and have a requirement for active immunoregulation, largely T cell mediated, that promotes specific unresponsiveness to donor alloantigens. This review outlines our current understanding of the Treg subsets that contribute to allotolerance and the mechanisms by which these cells exert their effects as well as their potential for therapy.
A Nonfucosylated Anti-HER2 Antibody Augments Antibody-Dependent Cellular Cytotoxicity in Breast Cancer Patients
Authors: Eiji Suzuki, Rinpei Niwa, Shigehira Saji, Mariko Muta, Makiko Hirose, Shigeru Iida, Yukimasa Shiotsu, Mitsuo Satoh, Kenya Shitara, Masahide Kondo, Masakazu Toi
Journal: Clinical Cancer Research (2007)

Abstract Purpose: Removal of fucose residues from the oligosaccharides of human antibody is a powerful approach to enhance antibody-dependent cellular cytotoxicity (ADCC), a potential important antitumor mechanism of therapeutic antibodies. To provide clinically relevant evidence of this mechanism, we investigated ADCC of a fucose-negative version of trastuzumab [anti–human epidermal growth factor receptor 2 (HER2) humanized antibody] using peripheral blood mononuclear cells (PBMC) from breast cancer patients as effector cells. Experimental Design: Thirty volunteers, including 20 breast cancer patients and 10 normal healthy control donors, were recruited randomly, and aliquots of peripheral blood were collected. ADCC of commercial trastuzumab (fucosylated) and its fucose-negative version were measured using PBMCs drawn from the volunteers as effector cells and two breast cancer cell lines with different HER2 expression levels as target cells. Relationships between cytotoxicity and characteristics of the patients, such as content of natural killer cells in PBMCs, type of therapy, FCGR3A genotypes, etc. were also analyzed. Results: ADCC was significantly enhanced with the fucose-negative antibody compared with the fucose-positive antibody using PBMCs from either normal donors or breast cancer patients. Enhancement of ADCC was observed irrespective of the various clinical backgrounds of the patients, even in the chemotherapy cohort that presented with a reduced number of natural killer cells and weaker ADCC. Conclusions: This preliminary study suggests that the use of fucose-negative antibodies may improve the therapeutic effects of anti-HER2 therapy for patients independent of clinical backgrounds.
Diagnosis and Management of Urinary Tract Infections in the Outpatient Setting
Authors: Larissa Grigoryan, Barbara W. Trautner, Kalpana Gupta
Journal: JAMA (2014)

Urinary tract infection is among the most common reasons for an outpatient visit and antibiotic use in adult populations. The increasing prevalence of antibacterial resistance among community uropathogens affects the diagnosis and management of this clinical syndrome.To define the optimal approach for treating acute cystitis in young healthy women and in women with diabetes and men and to define the optimal approach for diagnosing acute cystitis in the outpatient setting.Evidence for optimal treatment regimens was obtained by searching PubMed and the Cochrane database for English-language studies published up to July 21, 2014.Twenty-seven randomized clinical trials (6463 patients), 6 systematic reviews, and 11 observational studies (252,934 patients) were included in our review. Acute uncomplicated cystitis in women can be diagnosed without an office visit or urine culture. Trimethoprim-sulfamethoxazole (160/800 mg twice daily for 3 days), nitrofurantoin monohydrate/macrocrystals (100 mg twice daily for 5-7 days), and fosfomycin trometamol (3 g in a single dose) are all appropriate first-line therapies for uncomplicated cystitis. Fluoroquinolones are effective for clinical outcomes but should be reserved for more invasive infections. β-Lactam agents (amoxicillin-clavulanate and cefpodoxime-proxetil) are not as effective as empirical first-line therapies. Immediate antimicrobial therapy is recommended rather than delayed treatment or symptom management with ibuprofen alone. Limited observational studies support 7 to 14 days of therapy for acute urinary tract infection in men. Based on 1 observational study and our expert opinion, women with diabetes without voiding abnormalities presenting with acute cystitis should be treated similarly to women without diabetes.Immediate antimicrobial therapy with trimethoprim-sulfamethoxazole, nitrofurantoin, or fosfomycin is indicated for acute cystitis in adult women. Increasing resistance rates among uropathogens have complicated treatment of acute cystitis. Individualized assessment of risk factors for resistance and regimen tolerability is needed to choose the optimum empirical regimen.
The Future of Neuroscience Clinical Trials—Reply
Authors: Marissa N. Love, Hassan Fathallah-Shaykh
Journal: JAMA Neurology (2014)

In Reply We appreciate the kind and thorough response of McNeil and colleagues to our queries on the Network for Excellence in Neuroscience Clinical Trials (NeuroNEXT).1 We also thank them for their effort in putting together a framework that eases the immense burden of neurological disorders.
Mechanical ventilation increases substance P concentration in the vagus, sympathetic, and phrenic nerves.
Authors: E Balzamo, P Joanny, J G Steinberg, C Oliver, Y Jammes
Journal: American Journal of Respiratory and Critical Care Medicine (1996)

Substance P (SP), a neurotransmitter localized to primary sensory neurons, is found in the vagus nerve, nodose ganglion, sympathetic chain, and phrenic nerve in various animal species. However, the changes in endogeneous SP concentration under various circumstances that involve the participation of cardiorespiratory afferent nerves are still unexplored. In the present study, attention was focused on the variations in SP content measured by radioimmunoassay (RIA) in respiratory afferent nerves (vagus nerve, cervical sympathetic chain, phrenic nerve) and respiratory muscles (diaphragm, intercostal muscles) during positive inspiratory pressure (PIP) breathing alone or PIP with an expiratory threshold load (ETL) in rabbits. SP was found in all sampled structures in spontaneously breathing control animals, prevailing in the nodose ganglion. Left-versus right-sided differences were noticed in nerves. As compared with that in control animals, the SP concentration was markedly higher in vagal and sympathetic nervous structures during PIP or PIP with ETL, and also in the phrenic nerve during ETL breathing. The SP content did not vary in respiratory muscles. These observations suggest that two very common circumstances of mechanical ventilation are associated with an increased SP concentration in nervous structures participating in the control of breathing.
Monobenzylether of hydroquinone.
Authors: DAVID B. MOSHER, JOHN A. PARRISH, THOMAS B. FITZPATRICK
Journal: British Journal of Dermatology (1977)

Of 18 severely afffected vitiligo patients who used 20% monobenzylether of hydroquinone (MBEH, Benoquin) as a depigmenting agent, 8 achieved complete depigmentation after 10 months or more of use and 3 dramatic but no complete hypopigmentation. The 3 patients with no results did not use MBEH for more than 4 months. Complications were frequent particularly among those who did well, but only 1 case of contact dermatitis limited therapy. All patients who depigmented fully were very pleased with their results. As depigmentation induced by MBEH is generally irreversible, MBEH use must be reserved for induction of complete depigmentation of severely affected vitiligo patients who cannot or do not choose to repigment and who can accept the permanence of never tanning. The history, histology and mechanism of MBEH depigmentation are discussed.
Prior Misdemeanor Convictions as a Risk Factor for Later Violent and Firearm-Related Criminal Activity Among Authorized Purchasers of Handguns
Authors: Garen J. Wintemute
Journal: JAMA (1998)

Context.-Under current federal law, many persons with prior convictions for misdemeanor offenses pass criminal records background checks and legally purchase handguns.Objective.-Todetermine whether authorized handgun purchasers with prior misdemeanor convictions are more likely than those with no criminal history to be charged with new crimes, particularly offenses involving firearms and violence.Design.-Retrospective cohort study.Setting and Participants.-Atotal of 5923 authorized purchasers of handguns in California in 1977 who were younger than 50 years, identified by random sample.Main Outcome Measures.-Incidenceand relative risk (RR) of first charges for new criminal offenses after handgun purchase.Results.-Of the 5923 authorized purchasers, 3128 had at least 1 conviction for a misdemeanor offense prior to handgun purchase, and 2795 had no prior criminal history.Follow-up to the end of the 15-year observation period or to death was available for 77.8% of study subjects and for a median 8.9 years for another 9.6%.Handgun purchasers with at least 1 prior misdemeanor conviction were more than 7 times as likely as those with no prior criminal history to be charged with a new offense after handgun purchase (RR, 7.5; 95% confidence interval [CI], 6.6-8.7).Among men, those with 2 or more prior convictions for misdemeanor violence were at greatest risk for nonviolent firearm-related offenses such as weapon carrying (RR, 11.7; 95% CI, 6.8-20.0),violent offenses generally (RR, 10.4; 95% CI, 6.9-15.8),and Violent Crime Index offenses (murder or non-negligent manslaughter, forcible rape, robbery, or aggravated assault) (RR, 15.1; 95% CI, 9.4-24.3).However, even handgun purchasers with only 1 prior misdemeanor conviction and no convictions for offenses involving firearms or violence were nearly 5 times as likely as those with no prior criminal history to be charged with new offenses involving firearms or violence.Conclusions.-Handgunpurchasers with prior misdemeanor convictions are at increased risk for future criminal activity, including violent and firearm-related crimes.
Deletion of <i>LCE3C</i> and <i>LCE3B</i> genes is associated with psoriasis in a northern Chinese population
Authors: L. Xu, Y. Li, X. Zhang, H. Sun, D. Sun, X. Jia, C. Shen, J. Zhou, G. Ji, P. Liu, R. Guan, Y. Yu, Y. Jin, J. Bai, D. Sun, J. Yu, S. Fu
Journal: British Journal of Dermatology (2011)

Background It has been shown that a deletion in the late cornified envelope (LCE) gene cluster (LCE3C_LCE3B‐del) is associated with susceptibility to psoriasis in European populations. However, the relationship remains unclear in a northern Chinese population. Objectives The aim of the present study was to clarify this association in this population. Methods In total, 970 patients with psoriasis and 1064 healthy controls were recruited and a polymerase chain reaction assay was used to determine the frequency of this deletion. The effect of this deletion on susceptibility to psoriasis was assessed using SPSS software and the PLINK software package. Results The frequency of the LCE3C_LCE3B‐del differed significantly between patients and healthy controls. In subgroup analysis, the distribution was significantly different between patients with a positive family history of psoriasis and controls, as well as between patients with early‐onset psoriasis and controls. Conclusions The findings indicate that the LCE3C_LCE3B‐del is an important risk factor in the pathogenesis of psoriasis and that the LCE3C_LCE3B‐del does not show an epistatic effect with the HLA‐Cw6 allele on susceptibility to psoriasis in the northern Chinese population.
Oral proteases: a new approach to managing coeliac disease
Authors: N. Cerf-Bensussan, T. Matysiak-Budnik, C. Cellier, M. Heyman
Journal: Gut (2006)

A life-long but constraining gluten-free diet is the only treatment currently available for coeliac disease. The human gastrointestinal tract does not possess the enzymatic equipment to efficiently cleave the gluten-derived proline-rich peptides driving the abnormal immune intestinal response in patients with coeliac disease. Oral therapy by exogenous prolylendopeptidases able to digest ingested gluten was therefore propounded as an alternative treatment to the diet. The feasibility of this approach is discussed by reviewing recent data on the intestinal transport of gliadin peptides, properties of available enzymes and preliminary clinical assays. Development of new enzymes or enzymatic cocktails offers potentially more potent therapeutic tools that, however, need meticulous evaluation based on clinical, biological and histological criteria.
Dysregulation of protein trafficking in neurodegeneration
Authors: Xin Wang, Timothy Huang, Guojun Bu, Huaxi Xu
Journal: Molecular Neurodegeneration (2014)

Intracellular protein trafficking plays an important role in neuronal function and survival. Protein misfolding is a common theme found in many neurodegenerative diseases, and intracellular trafficking machinery contributes to the pathological accumulation and clearance of misfolded proteins. Although neurodegenerative diseases exhibit distinct pathological features, abnormal endocytic trafficking is apparent in several neurodegenerative diseases, such as Alzheimer's disease (AD), Down syndrome (DS) and Parkinson's disease (PD). In this review, we will focus on protein sorting defects in three major neurodegenerative diseases, including AD, DS and PD. An important pathological feature of AD is the presence of extracellular senile plaques in the brain. Senile plaques are composed of β-amyloid (Aβ) peptide aggregates. Multiple lines of evidence demonstrate that over-production/aggregation of Aβ in the brain is a primary cause of AD and attenuation of Aβ generation has become a topic of extreme interest in AD research. Aβ is generated from β-amyloid precursor protein (APP) through sequential cleavage by β-secretase and the γ-secretase complex. Alternatively, APP can be cleaved by α-secretase within the Aβ domain to release soluble APPα which precludes Aβ generation. DS patients display a strikingly similar pathology to AD patients, including the generation of neuronal amyloid plaques. Moreover, all DS patients develop an AD-like neuropathology by their 40 s. Therefore, understanding the metabolism/processing of APP and how these underlying mechanisms may be pathologically compromised is crucial for future AD and DS therapeutic strategies. Evidence accumulated thus far reveals that synaptic vesicle regulation, endocytic trafficking, and lysosome-mediated autophagy are involved in increased susceptibility to PD. Here we review current knowledge of endosomal trafficking regulation in AD, DS and PD.
Prognostic Accuracy of Immunologic and Metabolic Markers for Type 1 Diabetes in a High-Risk Population
Authors: Ping Xu, Craig A. Beam, David Cuthbertson, Jay M. Sosenko, Jay S. Skyler, Jeffrey P. Krischer
Journal: Diabetes Care (2012)

To establish and compare the prognostic accuracy of immunologic and metabolic markers in predicting onset of type 1 diabetes in those with high risk in a prospective study.A total of 339 subjects from the Diabetes Prevention Trial-Type 1 (DPT-1) parenteral study, who were islet cell antibody (ICA)-positive, with low first-phase insulin response (FPIR) and/or abnormal glucose tolerance at baseline, were followed until clinical diabetes onset or study end (5-year follow-up). The prognostic performance of biomarkers was estimated using receiver operating characteristic (ROC) curve analysis and compared with nonparametric testing of ROC curve areas. Pearson correlation was used to assess the relationship between the markers.Individually, insulin autoantibody titer, ICA512A titer, peak C-peptide, 2-h glucose, FPIR, and FPIR/homeostasis model assessment of insulin resistance provided modest but significant prognostic values for 5-year risk with a similar level of area under ROC curve ranging between 0.61 and 0.67. The combination of 2-h glucose, peak C-peptide, and area under the curve C-peptide significantly improved the prognostic accuracy compared with any solitary index (P < 0.05) with an area under ROC curve of 0.76 (95% CI 0.70-0.81). The addition of antibody titers and/or intravenous glucose tolerance test (IVGTT) markers did not increase the prognostic accuracy further (P = 0.46 and P = 0.66, respectively).The combination of metabolic markers derived from the oral glucose tolerance test improved accuracy in predicting progression to type 1 diabetes in a population with ICA positivity and abnormal metabolism. The results indicate that the autoimmune activity may not alter the risk of type 1 diabetes after metabolic function has deteriorated. Future intervention trials may consider eliminating IVGTT measurements as an effective cost-reduction strategy for prognostic purposes.
STUDIES ON A NON-HEMOLYTIC STREPTOCOCCUS ISOLATED FROM THE RESPIRATORY TRACT OF HUMAN BEINGS
Authors: George S. Mirick, Lewis Thomas, Edward C. Curnen, Frank L. Horsfall
Journal: The Journal of Experimental Medicine (1944)

The results of studies on the antigenic structure and immunological specificity of a non-hemolytic streptococcus, designated streptococcus MG, are described. Evidence is presented to show that this microorganism possesses a capsule and that this structure contains a polysaccharide antigen which is responsible for the type specific serological reactions obtained with streptococcus MG.