tbuckley/cabot-search huggingface dataset:
A125: Immunomodulatory Factors Produced by Mesenchymal Stem Cells After<i>in vitro</i>Priming with Danger Signals
Authors: Hulya Bukulmez, Asuman Bilgin, Gurkan Bebek, Arnold I. Caplan, Olcay Jones
Journal: Arthritis & Rheumatology (2014)

Background/Purpose:

We have previously shown that pre-exposure to IL-1β augments the immunosuppressive activity of MSC using the mixed lymphocyte reaction as a readout assay. In this project, we studied the profiles of inflammatory cytokines secreted by MSCs at the protein level to identify biomarkers in in vitroprimed MSCs. The objective of this study was to determine the MSC response to “danger signals.”



Methods:

MSCs were isolated from a healthy donor and cultured as per a protocol published earlier by the Skeletal Research Center. After three passages, 200,000 cells per 35 mm culture dish were incubated in 2 ml DMEM with 10% fetal bovine serum at 37°C for 5 days until 90% confluent. The MSCs were then treated with LPS (10 μg/ml), IL-1β (25 ng/ml), TNF-α (50 ng/ml), or poly (I:C) (30 ng/ml) overnight (18 hours). Control and treatment groups were done in triplicate. The culture media were then collected and analyzed for secreted mediators using the RayBiotech® Human Cytokine Array (2000), as per the manufacturer's protocol. Chemiluminescense was detected using Kodak BioMax MR film, and was analyzed using the ImageJ program (rsbweb.nih.gov). Normalization and fold-difference computations were then performed in MS Excel. Pathway analysis for biomarker detection was performed using the Ingenuity (ingenuity.com) program by the CWRU proteomics center.



Results:

There were clear distinctions in the patterns of inflammatory mediators produced by MSC upon exposure to LPS versus poly (I:C). LPS stimulated the production of mediators that affect mostly neutrophil chemotaxis and activation, including IL-8 (1.8 fold), CXCL7 (2 fold), CXCL5 (2.4 fold), CXCL1 (1.6 fold). However, poly (I:C) induced mediators with activities on T cells and NK cells including IL-15 (18 fold), IL-4 (23 fold), TGF-β3 (9.7 fold), CCL-18 (4.6 fold). While poly (I:C) stimulated IL-1β production (2.6 fold), LPS did not (0.7 fold), and neither agent increased TNF-α significantly (1.3 and 2.1 fold). Interestingly, there was marked production of CCL1 (12 fold) upon exposure of MSC to IL-1β but not to LPS (0.6 fold), TNF-α (1.3) or poly (I:C) (2.1 fold).



Conclusion:

Priming MSC by TLRs ligands triggered different cytokine and chemokine expression profiles. These profile patterns may signify framework of the upcoming immune responses in the tissue. Accordingly, the candidate biomarkers for ongoing MSC immunomodulatory activities should include those for neutrophils versus those for T/NK cells. Furthermore, our results strongly suggest involvement of IL-1β in MSCmediated activation of T-regulatory cells by induction of the CCR-8 ligand, CCL-1. CCR-8 is a known biomarker identifying CD4+ memory T-cells enriched for FoxP3+ T-regulatory cells and is involved in delivery of immunosuppression.
At 68 years, unrecognised sleep apnoea is associated with elevated ambulatory blood pressure
Authors: Frédéric Roche, Jean-Louis Pépin, Emilie Achour-Crawford, Renaud Tamisier, Vincent Pichot, Sébastien Celle, Delphine Maudoux, Florian Chouchou, Hourfil G. Ntougou-Assoumou, Patrick Lévy, Jean Claude Barthélémy
Journal: European Respiratory Journal (2012)

After the age of 65 yrs the specific impact of unrecognised sleep-related breathing disorders (SRBD) on 24-h blood pressure (BP) levels remains under debate. We tested the cross-sectional relationship between the severity of obstructive sleep apnoea/hypopnoea (OSAH) and the increase of BP using ambulatory BP monitoring (ABPM) in the PROOF (PROgnostic indicator OF cardiovascular and cerebrovascular events study)-SYNAPSE (Autonomic Nervous System Activity, Aging and Sleep Apnea/Hypopnea study) cohort. 470 subjects (aged 68 yrs) neither treated for hypertension nor diagnosed for SRBD were included. All subjects underwent ABPM, and unattended at-home polygraphic studies. OSAH was defined by an apnoea/hypopnoea index (AHI) >15 · h(-1). The severity of the sleep apnoea was also quantified as the index of dips in oxyhaemoglobin saturation >3% (ODI). Results are expressed in per protocol analysis. Severe OSAH (AHI >30 · h(-1), 17% of subjects) was associated with a significant 5 mmHg increase in both diurnal and nocturnal systolic BP (SBP), and with a nocturnal 3 mmHg increase in diastolic BP (DBP). Systolic (mean SBP >135 mmHg) or diastolic (mean DBP >80 mmHg) hypertension were more frequently encountered in subjects suffering from moderate (AHI 15-30) or severe OSAH. After adjustment, the independent association between severe OSAH and 24-h systolic hypertension remained significant (OR 2.42, 95% CI 1.1-5.4). The relationship was further reinforced when SRBD severity was expressed using ODI >10 · h(-1). The impact of unrecognised SRBD on BP levels also exists at the age of 68 yrs. The hypoxaemic load appears to be the pathophysiological cornerstone for such a relationship.
Serum HMGB1 levels are increased in active Wegener's granulomatosis and differentiate between active forms of ANCA-associated vasculitis
Authors: D. Wibisono, E. Csernok, P. Lamprecht, J. U. Holle, W. L. Gross, F. Moosig
Journal: Annals of the Rheumatic Diseases (2010)

<h3>Abstract</h3> Biophysical modeling of neuronal networks helps to integrate and interpret rapidly growing and disparate experimental datasets at multiple scales. The widely used NEURON tool enables simulation ranging from the molecular to the network level. However, building data-driven large-scale network models and running parallel simulations using NEURON remains a technically difficult task. Additionally, the lack of standardization makes it hard to understand, reproduce and reuse many existing models. Here we present NetPyNE, a tool that provides both a programmatic and graphical interface to facilitate the definition, parallel simulation and analysis of data-driven multiscale network models in NEURON. Users can provide specifications at a high level via a standardized declarative language, e.g. a connectivity rule, instead of millions of explicit cell-to-cell connections. NetPyNE clearly separates model parameters from implementation code. With a single command, NetPyNE can then generate the NEURON network model and run efficiently parallelized simulations. The user can select from a variety of built-in functions to visualize and analyze the results, including connectivity matrices, voltage traces, raster plots, local field potentials or information transfer measures. NetPyNE also includes a graphical user interface, which allows users to intuitively access all key functionality, including interactive visualizations of the 3D network. NetPyNE models and results can be saved and loaded using common file formats, and imported/exported to the NeuroML standardized language, facilitating model sharing and simulator interoperability. NetPyNE automates parameter exploration via batch simulations and provides pre-defined, configurable setups to submit jobs in supercomputers. The tool's website (www.netpyne.org) includes comprehensive documentation, tutorials and Q&amp;A forums. NetPyNE is currently being used to develop models of different brain regions – including thalamus, cortex, claustrum, hippocampus and basal ganglia – and phenomena – including dendritic computations, oscillations, epilepsy, and transcranial magnetic stimulation. It is also employed by the Open Source Brain portal to run parallel simulation of NeuroML-based models, and by the Human Neocortical Solver (hnn.brown.edu) tool to flexibly build cortical models. NetPyNE enables both expert and inexperienced modelers to tackle challenging problems in neuroscience.
Targeting Phospholamban by Gene Transfer in Human Heart Failure
Authors: Federica del Monte, Sian E. Harding, G. William Dec, Judith K. Gwathmey, Roger J. Hajjar
Journal: Circulation (2002)

Background — Myocardial cells from failing human hearts are characterized by abnormal calcium handling, a negative force-frequency relationship, and decreased sarcoplasmic reticulum Ca 2+ ATPase (SERCA2a) activity. In this study, we tested whether contractile function can be improved by decreasing the inhibitory effects of phospholamban on SERCA2a with adenoviral gene transfer of antisense phospholamban (asPL). Methods and Results — Myocardial cells isolated from 9 patients with end-stage heart failure and 18 donor nonfailing hearts were infected with adenoviruses encoding for either the antisense of phospholamban (Ad.asPL), the SERCA2a gene (Ad.SERCA2a), or the reporter genes β-galactosidase and green fluorescent protein (Ad.βgal-GFP). Adenoviral gene transfer with Ad.asPL decreased phospholamban expression over 48 hours, increasing the velocity of both contraction and relaxation. Compared with cardiomyocytes infected with Ad.asPL (n=13), human myocytes infected with Ad.βgal-GFP (n=8) had enhanced contraction velocity (20.3±3.9% versus 8.7±2.6% shortening/second; P &lt;0.01) and relaxation velocity (26.0±6.2% versus 8.6±4.3% shortening/second; P &lt;0.01). The improvement in contraction and relaxation velocities was comparable to cardiomyocytes infected with Ad.SERCA2a. Failing human cardiomyocytes had decreased contraction and Ca 2+ release with increasing frequency (0.1 to 2 Hz). Phospholamban ablation restored the frequency response in the failing cardiomyocytes to normal; increasing frequency resulted in enhanced sarcoplasmic reticulum Ca 2+ release and contraction. Conclusion — These results show that gene transfer of asPL can improve the contractile function in failing human myocardium. Targeting phospholamban may provide therapeutic benefits in human heart failure.
Mouse Podocyte Complement Factor H
Authors: Jessy J. Alexander, Ying Wang, Anthony Chang, Alexander Jacob, Andrew W.M. Minto, Menaka Karmegam, Mark Haas, Richard J. Quigg
Journal: Journal of the American Society of Nephrology (2007)

Complement factor H (Cfh) is a key plasma protein in humans and animals that serves to limit alternative pathway complement activation in plasma, as well as in local sites such as capillaries of the glomerulus and eye. It was shown that rodent Cfh on platelets is the functional analogue to human erythrocyte complement receptor 1 with a role that is distinct from plasma Cfh and that Cfh is also on cultured rodent podocytes. For investigation of the role of Cfh in the kidney, renal transplants were performed between wild-type (WT) and Cfh(-/-) C57BL/6 mice. For these studies, bilateral native nephrectomies were done so that renal function was dependent solely on the transplanted kidney. Chronic serum sickness was induced by active immunization with apoferritin. Diffuse proliferative glomerulonephritis (GN) occurred in WT kidneys that were transplanted into Cfh(-/-) recipients (n = 8) but not into WT recipients (n = 14), consistent with the importance of plasma Cfh to dictate outcome in this disease model. Relative to the WT recipients of WT kidneys, WT mice with Cfh(-/-) kidneys (n = 12) developed glomerular disease features, including increased albuminuria (82.8 +/- 7.0 versus 45.1 +/- 3.6 microg/mg creatinine; P < 0.001) and blood urea nitrogen levels (54.4 +/- 6.1 versus 44.2 +/- 3.7 mg/dl; P < 0.01). In addition, they had substantial glomerular capillary wall deposits of IgG and C3, which by electron microscopy were present in subendothelial and subepithelial immune deposits, whereas WT kidneys in WT hosts had almost exclusive mesangial deposits. The IgG deposits in Cfh(-/-) kidneys were adjacent to Cfh-deficient podocytes, whereas WT kidneys in a Cfh(-/-) host had podocyte-associated Cfh with absent IgG deposits. These data suggest that locally produced podocyte Cfh is important to process immune complexes in the subepithelial space, where it also limits complement activation. Just as in platelets, rodent podocytes seem to use Cfh as the functional surrogate for human complement receptor 1.
Transtracheal oxygen delivery.
Authors: J Shneerson
Journal: Thorax (1992)

<h3>Background</h3> We investigated the benefits of the Collaborative <i>P</i>h<i>a</i>rmaceutical <i>C</i>are in <i>T</i>allaght Hospital (PACT) service versus standard ward-based clinical pharmacy in adult inpatients receiving acute medical care, particularly on prevalence of medication error and quality of prescribing. <h3>Methods</h3> Uncontrolled before-after study, undertaken in consecutive adult medical inpatients admitted and discharged alive, using at least three medications. Standard care involved clinical pharmacists being ward-based, contributing to medication history taking and prescription review, but not involved at discharge. The innovative PACT intervention involved clinical pharmacists being team-based, leading admission and discharge medication reconciliation and undertaking prescription review. Primary outcome measures were prevalence per patient of medication error and potentially severe error. Secondary measures included quality of prescribing using the Medication Appropriateness Index (MAI) in patients aged ≥65 years. <h3>Findings</h3> Some 233 patients (112 PACT, 121 standard) were included. PACT decreased the prevalence of any medication error at discharge (adjusted OR 0.07 (95% CI 0.03 to 0.15)); number needed to treat (NNT) 3 (95% CI 2 to 3) and no PACT patient experienced a potentially severe error (NNT 20, 95% CI 10 to 142). In patients aged ≥65 years (n=108), PACT improved the MAI score from preadmission to discharge (Mann–Whitney U p&lt;0.05; PACT median −1, IQR −3.75 to 0; standard care median +1, IQR −1 to +6). <h3>Conclusions</h3> PACT, a collaborative model of pharmaceutical care involving medication reconciliation and review, delivered by clinical pharmacists and physicians, at admission, during inpatient care and at discharge was protective against potentially severe medication errors in acute medical patients and improved the quality of prescribing in older patients.
Augmented Cardiac Hypertrophy in Response to Pressure Overload in Mice Lacking the Prostaglandin I <sub>2</sub> Receptor
Authors: Akiyoshi Hara, Koh-ichi Yuhki, Takayuki Fujino, Takehiro Yamada, Koji Takayama, Shuhko Kuriyama, Osamu Takahata, Hideji Karibe, Yuji Okada, Chun-Yang Xiao, Hong Ma, Shuh Narumiya, Fumitaka Ushikubi
Journal: Circulation (2005)

In the heart, the expressions of several types of prostanoid receptors have been reported. However, their roles in cardiac hypertrophy in vivo remain unknown. We intended to clarify the roles of these receptors in pressure overload-induced cardiac hypertrophy using mice lacking each of their receptors.We used a model of pressure overload-induced cardiac hypertrophy produced by banding of the transverse aorta in female mice. In wild-type mice subjected to the banding, cardiac hypertrophy developed during the observation period of 8 weeks. In mice lacking the prostaglandin (PG) I2 receptor (IP(-/-)), however, cardiac hypertrophy and cardiomyocyte hypertrophy were significantly greater than in wild-type mice at 2 and 4 weeks but not at 8 weeks, whereas there was no such augmentation in mice lacking the prostanoid receptors other than IP. In addition, cardiac fibrosis observed in wild-type hearts was augmented in IP(-/-) hearts, which persisted for up to 8 weeks. In IP(-/-) hearts, the expression level of mRNA for atrial natriuretic peptide, a representative marker of cardiac hypertrophy, was significantly higher than in wild-type hearts. In vitro, cicaprost, an IP agonist, reduced platelet-derived growth factor-induced proliferation of wild-type noncardiomyocytes, although it could not inhibit cardiotrophin-1-induced hypertrophy of cardiomyocytes. Accordingly, cicaprost increased cAMP concentration efficiently in noncardiomyocytes.IP plays a suppressive role in the development of pressure overload-induced cardiac hypertrophy via the inhibition of both cardiomyocyte hypertrophy and cardiac fibrosis. Both effects have been suggested as originating from the action on noncardiomyocytes rather than cardiomyocytes.
Absence of interleukin 2 production in a severe combined immunodeficiency disease syndrome with T cells.
Authors: J P DiSanto, C A Keever, T N Small, G L Nicols, R J O'Reilly, N Flomenberg
Journal: The Journal of Experimental Medicine (1990)

We have characterized a child with a severe combined immunodeficiency disease syndrome with increased numbers, but a normal distribution, of CD3+ T cells. This patient's immunological defect appears to be attributable to a selective deficiency in T cell production of IL-2, which may reflect a subtle abnormality in the IL-2 gene locus or a defect in a regulatory factor necessary for IL-2 transcription. The increased numbers of phenotypically normal T cells in this patient suggest that alternative pathways of T cell development exist in man or that IL-2 production intra- and extrathymically is controlled via distinct regulatory mechanisms.
Efficacy of inhaled salmeterol in the management of smokers with chronic obstructive pulmonary disease: a single centre randomised, double blind, placebo controlled, crossover study.
Authors: C S Ulrik
Journal: Thorax (1995)

BACKGROUND--The acute response to bronchodilators in patients with chronic obstructive pulmonary disease (COPD) is modest; it has, however, been suggested that these patients may benefit from long term treatment. METHODS--To investigate the efficacy of salmeterol in smokers with moderate to severe COPD a double blind, randomised, crossover comparison was performed between salmeterol (50 micrograms twice daily) and placebo in 63 patients with stable COPD (mean age 65 years). Prior to inclusion, all patients had a forced expiratory volume in one second (FEV1) of &lt; 60% of predicted and an improvement in FEV1 of &lt; 15% following 400 micrograms inhaled salbutamol. Patients received four weeks of therapy with each of the treatment regimens. Assessment of efficacy was made with recording of morning and evening peak expiratory flow rates (PEF), respiratory symptoms, and use of rescue salbutamol. FEV1 was measured before and after nebulised salbutamol prior to randomisation and at the end of each treatment period. RESULTS--Morning PEF values were higher during the salmeterol than during the placebo period, although the mean treatment difference was small (12 l/min (95% confidence limits 6 to 17)). No difference in mean evening PEF values was found. Diurnal variation in PEF, assessed as the difference between the morning PEF and that of the previous evening, was more pronounced during the placebo than during the salmeterol period. The mean spirometric values (including reversibility in FEV1) obtained at the end of the two treatment periods were similar. Compared with placebo, treatment with salmeterol was associated with lower daytime and night time symptom scores and less use of rescue salbutamol both during the day and the night. The patients rated the treatment with salmeterol better than treatment with placebo. CONCLUSIONS--This study shows that, compared with placebo, treatment with salmeterol produces an improvement in respiratory symptoms and morning PEF values in patients with moderate to severe COPD. Treatment with long acting beta agonists may therefore result in an improvement in functional status, even in patients suffering from apparently nonreversible obstructive pulmonary disease.
Apolipoprotein E associated with astrocytic glia of the central nervous system and with nonmyelinating glia of the peripheral nervous system.
Authors: J K Boyles, R E Pitas, E Wilson, R W Mahley, J M Taylor
Journal: Journal of Clinical Investigation (1985)

The plasma protein apolipoprotein (apo) E is an important determinant of lipid transport and metabolism in mammals. In the present study, immunocytochemistry has been used to identify apo E in specific cells of the central and peripheral nervous systems of the rat. Light microscopic examination revealed that all astrocytes, including specialized astrocytic cells (Bergmann glia of the cerebellum, tanycytes of the third ventricle, pituicytes of the neurohypophysis, and Müller cells of the retina), possessed significant concentrations of apo E. In all of the major subdivisions of the central nervous system, the perinuclear region of astrocytic cells, as well as their cell processes that end on basement membranes at either the pial surface or along blood vessels, were found to be rich in apo E. Extracellular apo E was present along many of these same surfaces. The impression that apo E is secreted by astrocytic cells was confirmed by electron microscopic immunocytochemical studies, which demonstrated the presence of apo E in the Golgi apparatus. Apo E was not present in neurons, oligodendroglia, microglia, ependymal cells, and choroidal cells. In the peripheral nervous system, apo E was present within the glia surrounding sensory and motor neurons; satellite cells of the dorsal root ganglia and superior cervical sympathetic ganglion as well as the enteric glia of the intestinal ganglia were reactive. Apo E was also present within the non-myelinating Schwann cells but not within the myelinating Schwann cells of peripheral nerves. These results suggest that apo E has an important, previously unsuspected role in the physiology of nervous tissue.
Epidemiology of primary biliary cirrhosis in a defined rural population in the northern part of Sweden
Authors: Äke Danielsson, Lennart Boqvist, Per Uddenfeldt
Journal: Hepatology (1990)

The northern part of Sweden is sparsely populated and must be regarded as a rural region. An investigation into the incidence and prevalence of primary biliary cirhosis was conducted and the course of the disease was followed. In total, 111 patients with primary biliary cirrhosis were identified for the 10–yr period 1973 to 1982 in the northern health region of Sweden. The mean annual incidence amounted to 13.3 per million and the point prevalence was 151 per million, which is the highest reported so far. There was a significantly higher prevalence in the most northern county of Sweden, both with respect to total number of primary biliary cirrhosis patients and symptomatic patients. Asymptomatic patients amounted to 37%. During the study period 25 patients out of the 111 died (23%), 14 as a direct consequence of the liver disease. Three patients died of primary hepatocellular carcinom, one having an asympatomatic liver disease without cirrhosis. Primary biliary cirrhosis seems to be more common in Sweden, especially in the northern part, than it is elsewhere. A high frequency of extrahepatic symptoms (85%), mainly musculoskeletal, was recorded. These symptoms may lead to the first contact with the health service, rather than signs of liver disease. Thus, an increasing number of patients are diagnosed with asymptomatic liver disease, who must be followed to check for the eventual development of symptoms.(Hepatology 1990;11:458-464.)