tbuckley/cabot-search huggingface dataset:
High Basal Protein Kinase A–Dependent Phosphorylation Drives Rhythmic Internal Ca <sup>2+</sup> Store Oscillations and Spontaneous Beating of Cardiac Pacemaker Cells
Authors: Tatiana M. Vinogradova, Alexey E. Lyashkov, Weizhong Zhu, Abdul M. Ruknudin, Syevda Sirenko, Dongmei Yang, Shekhar Deo, Matthew Barlow, Shavsha Johnson, James L. Caffrey, Ying-Ying Zhou, Rui-Ping Xiao, Heping Cheng, Michael D. Stern, Victor A. Maltsev, Edward G. Lakatta
Journal: Circulation Research (2006)

Local, rhythmic, subsarcolemmal Ca 2+ releases (LCRs) from the sarcoplasmic reticulum (SR) during diastolic depolarization in sinoatrial nodal cells (SANC) occur even in the basal state and activate an inward Na + -Ca 2+ exchanger current that affects spontaneous beating. Why SANC can generate spontaneous LCRs under basal conditions, whereas ventricular cells cannot, has not previously been explained. Here we show that a high basal cAMP level of isolated rabbit SANC and its attendant increase in protein kinase A (PKA)-dependent phosphorylation are obligatory for the occurrence of spontaneous, basal LCRs and for spontaneous beating. Gradations in basal PKA activity, indexed by gradations in phospholamban phosphorylation effected by a specific PKA inhibitory peptide were highly correlated with concomitant gradations in LCR spatiotemporal synchronization and phase, as well as beating rate. Higher levels of basal PKA inhibition abolish LCRs and spontaneous beating ceases. Stimulation of β-adrenergic receptors extends the range of PKA-dependent control of LCRs and beating rate beyond that in the basal state. The link between SR Ca 2+ cycling and beating rate is also present in vivo, as the regulation of beating rate by local β-adrenergic receptor stimulation of the sinoatrial node in intact dogs is markedly blunted when SR Ca 2+ cycling is disrupted by ryanodine. Thus, PKA-dependent phosphorylation of proteins that regulate cell Ca 2+ balance and spontaneous SR Ca 2+ cycling, ie, phospholamban and L-type Ca 2+ channels (and likely others not measured in this study), controls the phase and size of LCRs and the resultant Na + -Ca 2+ exchanger current and is crucial for both basal and reserve cardiac pacemaker function.
Two-Photon Microscopy of Cells and Tissue
Authors: Michael Rubart
Journal: Circulation Research (2004)

Two-photon excitation fluorescence imaging provides thin optical sections from deep within thick, scattering specimens by way of restricting fluorophore excitation (and thus emission) to the focal plane of the microscope. Spatial confinement of two-photon excitation gives rise to several advantages over single-photon confocal microscopy. First, penetration depth of the excitation beam is increased. Second, because out-of-focus fluorescence is never generated, no pinhole is necessary in the detection path of the microscope, resulting in increased fluorescence collection efficiency. Third, two-photon excitation markedly reduces overall photobleaching and photodamage, resulting in extended viability of biological specimens during long-term imaging. Finally, localized excitation can be used for photolysis of caged compounds in femtoliter volumes and for diffusion measurements by two-photon fluorescence photobleaching recovery. This review aims to provide an overview of the use of two-photon excitation microscopy. Selected applications of this technique will illustrate its excellent suitability to assess cellular and subcellular events in intact, strongly scattering tissue. In particular, its capability to resolve differences in calcium dynamics between individual cardiomyocytes deep within intact, buffer-perfused hearts is demonstrated. Potential applications of two-photon laser scanning microscopy as applied to integrative cardiac physiology are pointed out.
Does Donepezil Treatment Slow the Progression of Hippocampal Atrophy in Patients With Alzheimer’s Disease?
Authors: Mamoru Hashimoto, Hiroaki Kazui, Keiji Matsumoto, Yoko Nakano, Minoru Yasuda, Etsuro Mori
Journal: American Journal of Psychiatry (2005)

The only approved pharmacological approach for the symptomatic treatment of Alzheimer's disease in Japan is the use of a cholinesterase inhibitor, donepezil hydrochloride. Recent in vivo and in vitro studies raise the possibility that cholinesterase inhibitors can slow the progression of Alzheimer's disease. The purpose of the present study was to determine whether donepezil has a neuroprotective effect in Alzheimer's disease by using the rate of hippocampal atrophy as a surrogate marker of disease progression.In a prospective cohort study, 54 patients with Alzheimer's disease who received donepezil treatment and 93 control patients with Alzheimer's disease who never received anti-Alzheimer drugs underwent magnetic resonance imaging (MRI) twice at a 1-year interval. The annual rate of hippocampal atrophy of each subject was determined by using an MRI-based volumetric technique. Background characteristics, age, sex, disease duration, education, MRI interval, apolipoprotein E (APOE) genotype, and baseline Alzheimer's Disease Assessment Scale score were comparable between the treated and control groups.The mean annual rate of hippocampal volume loss among the treated patients (mean=3.82%, SD=2.84%) was significantly smaller than that among the control patients (mean=5.04%, SD=2.54%). Upon analysis of covariance, where those confounding variables (age, sex, disease duration, education, MRI interval, APOE genotype, and baseline Alzheimer's Disease Assessment Scale score) were entered into the model as covariates, the effect of donepezil treatment on hippocampal atrophy remained significant.Donepezil treatment slows the progression of hippocampal atrophy, suggesting a neuroprotective effect of donepezil in Alzheimer's disease.
Response to Dr Bredemeier's letter
Authors: Edward M Vital, Shouvik Dass, Maya H Buch, Andrew C Rawstron, Paul Emery
Journal: Annals of the Rheumatic Diseases (2014)

We thank Dr Bredemeier for his interest in our work.1 The need to measure duration as well as initial quality of response to a single cycle of rituximab has been recognised since the earliest trials using rituximab. Indeed, concomitant methotrexate was included in rituximab's license for rheumatoid arthritis because of improved duration of response, despite no difference in American College of Rheumatology (ACR) or European League Against Rheumatism (EULAR) response rates at 6 months.2 We therefore consider duration of response to be a meaningful outcome measure. We do not …
Predominant Brenner Tumor Combined with Struma Ovarii Containing a Papillary Microcarcinoma Associated with Benign Peritoneal Strumosis: Report of a Case and Histologic Features
Authors: Simone Sibio, Francesco Borrini, Paolo Sammartino, Fabio Accarpio, Daniele Biacchi, Giuliana Caprio, Franco Iafrate, Anna Maria Baccheschi, Tommaso Cornali, Angelo Di Giorgio
Journal: Endocrine Pathology (2010)
Chemokines and Transplant Immunobiology
Authors: Wayne W. Hancock
Journal: Journal of the American Society of Nephrology (2002)

The importance of showing up at the right place at the right time is instilled in leukocytes, just as it is in each one of us, by our parents. The fact that leukocyte infiltration of a newly established allograft typically presages the development of acute rejection is the downside of having an
Role of Tumor Pericytes in the Recruitment of Myeloid-Derived Suppressor Cells
Authors: JongWook Hong, Nicholas P Tobin, Helene Rundqvist, Tian Li, Marion Lavergne, Yaiza García-Ibáñez, Hanyu Qin, Janna Paulsson, Manuel Zeitelhofer, Milena Z Adzemovic, Ingrid Nilsson, Pernilla Roswall, Johan Hartman, Randall S Johnson, Arne Östman, Jonas Bergh, Mirjana Poljakovic, Guillem Genové
Journal: JNCI Journal of the National Cancer Institute (2015)

Pericytes are members of the tumor stroma; however, little is known about their origin, function, or interaction with other tumor components. Emerging evidence suggest that pericytes may regulate leukocyte transmigration. Myeloid-derived suppressor cells (MDSC) are immature myeloid cells with powerful inhibitory effects on T-cell-mediated antitumor reactivity.We generated subcutaneous tumors in a genetic mouse model of pericyte deficiency (the pdgfb (ret/ret) mouse) and littermate control mice (n = 6-25). Gene expression profiles from 253 breast cancer patients (stage I-III) were evaluated for clinic-pathological parameters and survival using Cox proportional hazard ratios (HRs) and 95% confidence intervals (CIs) based on a two-sided Wald test.We report that pericyte deficiency leads to increased transmigration of Gr1(+)/CD11b(+) cells in experimentally induced tumors. Pericyte deficiency produced defective tumor vasculature, resulting in a more hypoxic microenvironment promoting IL-6 upregulation in the malignant cells. Silencing IL-6 expression in tumor cells attenuated the observed differences in MDSC transmigration. Restoring the pericyte coverage in tumors abrogated the increased MDSC trafficking to pericyte-deficient tumors. MDSC accumulation in tumors led to increases in tumor growth and in circulating malignant cells. Finally, gene expression analysis from human breast cancer patients revealed increased expression of the human MDSC markers CD33 and S100A9 with concomitant decreased expression of pericyte genes and was associated with poor prognosis (HR = 1.88, 95% CI = 1.08 to 3.25, P = .03).Our data uncovers a novel paracrine interaction between tumor pericytes and inflammatory cells and delineates the cellular events resulting in the recruitment of MDSC to tumors. Furthermore, we propose for the first time a role for tumor pericytes in modulating the expression of immune mediators in malignant cells by promoting a hypoxic microenvironment.
HDAC inhibitor–dependent transcriptome and memory reinstatement in cognitive decline models
Authors: Eva Benito, Hendrik Urbanke, Binu Ramachandran, Jonas Barth, Rashi Halder, Ankit Awasthi, Gaurav Jain, Vincenzo Capece, Susanne Burkhardt, Magdalena Navarro-Sala, Sankari Nagarajan, Anna-Lena Schütz, Steven A. Johnsen, Stefan Bonn, Reinhardt Lührmann, Camin Dean, André Fischer
Journal: Journal of Clinical Investigation (2015)

Aging and increased amyloid burden are major risk factors for cognitive diseases such as Alzheimer's disease (AD). Effective therapies for these diseases are lacking. Here, we evaluated mouse models of age-associated memory impairment and amyloid deposition to study transcriptome and cell type–specific epigenome plasticity in the brain and peripheral organs. We determined that aging and amyloid pathology are associated with inflammation and impaired synaptic function in the hippocampal CA1 region as the result of epigenetic-dependent alterations in gene expression. In both amyloid and aging models, inflammation was associated with increased gene expression linked to a subset of transcription factors, while plasticity gene deregulation was differentially mediated. Amyloid pathology impaired histone acetylation and decreased expression of plasticity genes, while aging altered H4K12 acetylation–linked differential splicing at the intron-exon junction in neurons, but not nonneuronal cells. Furthermore, oral administration of the clinically approved histone deacetylase inhibitor vorinostat not only restored spatial memory, but also exerted antiinflammatory action and reinstated epigenetic balance and transcriptional homeostasis at the level of gene expression and exon usage. This study provides a systems-level investigation of transcriptome plasticity in the hippocampal CA1 region in aging and AD models and suggests that histone deacetylase inhibitors should be further explored as a cost-effective therapeutic strategy against age-associated cognitive decline.
High Telomerase RNA Expression Level Is an Adverse Prognostic Factor for Favorable-Histology Wilms' Tumor
Authors: Jeffrey S. Dome, Carol A. Bockhold, Sierra M. Li, Scott D. Baker, Daniel M. Green, Elizabeth J. Perlman, D. Ashley Hill, Norman E. Breslow
Journal: Journal of Clinical Oncology (2005)

A primary objective of the fifth National Wilms Tumor Study (NWTS-5) was to identify prognostic indicators for patients with favorable-histology Wilms' tumor. The prognostic significance of telomerase expression level in primary tumor samples was assessed.A case-cohort study was conducted involving 291 NWTS-5 registrants. Telomerase activity was measured using the telomeric repeat amplification protocol (TRAP). Expression levels of TERT mRNA (encoding the telomerase catalytic component) and TERC/hTR (the telomerase RNA template) were measured using quantitative real-time polymerase chain reaction.After excluding samples because of lack of viable tumor, RNA degradation, or insufficient clinical information, 244 patients remained for the final analysis (96 with relapse and 148 without relapse). Univariate analysis revealed a positive correlation between relative risk (RR) of relapse and levels of TERT mRNA and TERC expression. For each doubling in TERT mRNA and TERC level, the RR increased by a factor of 1.16 (95% CI, 1.04 to 1.29; P = .01) and 1.35 (95% CI, 1.11 to 1.64; P = .003), respectively. The one third of patients whose tumors had the highest TERC expression level had an RR of 2.06 (95% CI, 1.14 to 3.70; P = .02) compared with patients with the lowest level. TERC expression level remained a significant prognostic indicator in a multivariate analysis adjusting for TERT mRNA, tumor stage, and patient age. TRAP level did not correlate with RR of relapse. Telomerase expression levels were not predictive of overall survival.Telomerase RNA expression level may provide a clinically useful adjunct to the current risk classification schema for favorable-histology Wilms' tumor.
Lymphoid Neoplasia Associated with the Acquired Immunodeficiency Syndrome (AIDS)
Authors: D M Knowles, G A Chamulak, M Subar, J S Burke, M Dugan, J Wernz, C Slywotzky, G Pelicci, R Dalla-Favera, B Raphael
Journal: Annals of Internal Medicine (1988)

We identified 105 patients with lymphoid neoplasia associated with the acquired immunodeficiency syndrome (AIDS) at the New York University Medical Center from 1981 through 1986: 89 had non-Hodgkin lymphoma; 13, Hodgkin disease; and 3, chronic lymphocytic leukemia. Immunophenotypic and antigen receptor gene rearrangement analysis showed the B-cell origin of all non-Hodgkin lymphomas studied and the clonal suppressorcytotoxic T-cell subset origin of the chronic lymphocytic leukemias. We classified 69% of the non-Hodgkin lymphomas as high grade (small, noncleaved and large cell, immunoblastic-plasmacytoid) and 31% as intermediate grade (diffuse large cell). Each histopathologic category was correlated with distinct clinical features, including a statistically significant difference in median survival. Patients with Hodgkin disease had an atypical, aggressive clinical course, whereas patients with T-cell chronic lymphocytic leukemia had an indolent clinical course. These studies show the clinical, morphologic, and immunophenotypic spectrum of AIDS-associated lymphoid neoplasia, that the natural history of Hodgkin disease is altered in patients with AIDS, and support the Centers For Disease Control's recent revision in diagnostic criteria for AIDS to include intermediate-grade diffuse, aggressive non-Hodgkin lymphomas occurring in patients seropositive for human immunodeficiency virus.
AGGLUTINATION BY PRECIPITIN
Authors: F. S. Jones
Journal: The Journal of Experimental Medicine (1928)

The fact is shown that collodion particles sensitized with various proteins adsorb sufficient protein to agglutinate in the presence of precipitin specific for the adsorbed protein. The amount of adsorption, judged by agglutination, is not dependent on the concentration of the sensitizing protein beyond a certain maximum. The agglutination resulting from the addition of immune serum to particles sensitized with protein is immunologically specific. Particles exposed to a number of antigenic substances in succession are agglutinated by all of the appropriate antisera. Particles exposed to immune serum and subsequently washed fail to agglutinate in the presence of antigen although some of the protein constituents of the immune serum are fixed upon them and its antibody content diminishes.
MetaReg: A platform for modeling, analysis and visualization of biological systems using large-scale experimental data
Authors: Igor Ulitsky, Irit Gat-Viks, Ron Shamir
Journal: Genome biology (2008)

MetaReg http://acgt.cs.tau.ac.il/metareg/application.html is a computational tool that models cellular networks and integrates experimental results with such models. MetaReg represents established knowledge about a biological system, available today mostly in informal form in the literature, as probabilistic network models with underlying combinatorial regulatory logic. MetaReg enables contrasting predictions with measurements, model improvements and studying what-if scenarios. By summarizing prior knowledge and providing visual and computational aids, it helps the expert explore and understand her system better.
Association Between Platelet Receptor Occupancy After Eptifibatide (Integrilin) Therapy and Patency, Myocardial Perfusion, and ST-Segment Resolution Among Patients With ST-Segment–Elevation Myocardial Infarction
Authors: C. Michael Gibson, Lisa K. Jennings, Sabina A. Murphy, David P. Lorenz, Robert P. Giugliano, Robert A. Harrington, Shila Cholera, Rajini Krishnan, Robert M. Califf, Eugene Braunwald
Journal: Circulation (2004)

Paradoxically, fibrinolytic agents may systemically activate platelets, which in turn secrete plasminogen activator inhibitor (PAI-1), an antagonist of the fibrinolytic process in proportion to total body platelet mass. We hypothesized that improved epicardial patency, myocardial perfusion, and ST-segment resolution would be associated with higher levels of platelet receptor occupancy (RO) by a glycoprotein IIb/IIIa antagonist in ST-elevation MI (STEMI).Patients were drawn from the low-dose tenecteplase plus eptifibatide arm of the INTEGRITI study. Angiographic and platelet RO data were analyzed at 2 independent core laboratories. To take into account the absolute platelet count and receptors available for cross-linking, absolute platelet count was multiplied by percent of available receptors to obtain the index of the absolute number of receptors available (IANRA). Percent RO was higher among patients with a patent artery (TIMI flow grade 2/3; 78.2+/-9.2, n=63 versus 63.9+/-29.7, n=7; P=0.005), those with TIMI myocardial perfusion grade 2/3 (79.6+/-9.5, n=40 versus 73.0+/-16.2, n=30; P=0.036), and those with complete (> or =70%) ST-segment resolution at 60 minutes (81.3+/-8.3%, n=27 versus 73.1+/-17.4%, n=24; P=0.034). The absolute number of glycoprotein IIb/IIIa receptors available for cross-linking was reduced (ie, the IANRA was lower) among patients with a patent artery (P=0.0015), patients with TIMI myocardial perfusion grade 2/3 (P=0.026), and patients with > or =70% ST-segment resolution (P=0.029).This study links restoration of epicardial flow, normal myocardial perfusion, and complete ST-segment resolution with higher levels of platelet glycoprotein IIb/IIIa receptor occupancy after therapy with eptifibatide administered with tenecteplase.
Is ASDAS better than BASDAI as a measure of disease activity in axial psoriatic arthritis?
Authors: Lihi Eder, Vinod Chandran, Hua Shen, Richard J Cook, Dafna D Gladman
Journal: Annals of the Rheumatic Diseases (2010)

Objective To assess the discriminative ability and correlation of the Ankylosing Spondylitis Disease Activity Score (ASDAS) and Bath Ankylosing Spondylitis Activity Disease Activity Index (BASDAI) with disease activity in axial psoriatic arthritis (AxPsA). Methods Patients with AxPsA were selected from a large prospective cohort study of psoriatic arthritis. Patient and physician global scores were used as constructs of disease activity. Patients were categorised into high and low disease activity states based on patient and physician global assessment scores and physician's decision to change treatment. Statistical analysis included descriptive statistics, linear and logistic regression. Results 201 patients with AxPsA were included in the study. ASDAS and BASDAI showed good correlation with disease activity as reflected by the patient global score (correlation coefficients (r) for BASDAI 0.84, ASDAS-B 0.77, ASDAS-C 0.81, p&lt;0.001) and the physician global score (r=0.53 for BASDAI, r=0.50 for ASDAS-B, r=0.55 for ASDAS-C, p&lt;0.001). Both scores showed good discriminative ability between high and low disease activity states. However, there were no significant differences between areas under the curve for the models that compared ASDAS with BASDAI for each definition of disease activity state. Conclusions In patients with AxPsA, ASDAS and BASDAI scores show similar good to moderate discriminative ability and correlation with different constructs of disease activity. ASDAS was not superior to BASDAI in its ability to discriminate between high and low disease activity states in AxPsA.
Is opportunistic disease prevention in the consultation ethically justifiable?
Authors: L. Getz
Journal: BMJ (2003)

Medical resources are increasingly shifting from making patients better to preventing them from becoming ill. Genetic testing is likely to extend the list of conditions that can be screened for. Is it time to stop and consider whom we screen and how we approach it 

Most medical experts and health authorities consider consultations in primary health care ideal for opportunistic health promotion and disease prevention. Doctors are thus expected to discuss preventive measures even when they are not among the reasons for contact. But are such opportunistic initiatives ethically justifiable in contemporary Western medicine? We argue that doctors should maintain a clear focus on each patient's reasons for seeking help rather than be distracted by an increasing list of standardised preventive measures with unpredictable relevance to the individual.

The cornerstone of medical practice is the consultation between a patient who seeks help and a doctor whomthe person trusts.1 Several theoretical models have been developed to analyse and improve the quality of the consultation. In 1979, Stott and Davis presented an influential model that elicited four potentials of the encounter between patient and doctor: management of presenting problems, modification of help seeking behaviour, management of continuing problems, and opportunistic health promotion.2 Since then, opportunistic preventive initiatives have become considered to be part of good medical practice.

From a moral point of view, preventive medicine– that is, initiatives to improve health among people who are currently free of symptoms–is fundamentally different from curative medicine, which is offered to patientswho seek medical help. The two disciplines imply different promises and have different obligations to the individuals whose lives they modify.3

When Stott and Davis developed their model, the number of relevant opportunistic initiatives was limited and seemed both technically feasible and ethically justifiable. However, interest in risk factors in healthy …