tbuckley/cabot-search huggingface dataset:
In vivo costimulatory role of B7-DC in tuning T helper cell 1 and cytotoxic T lymphocyte responses
Authors: Tahiro Shin, Kiyoshi Yoshimura, Takako Shin, Emily B. Crafton, Haruo Tsuchiya, Franck Housseau, Haruhiko Koseki, Richard D. Schulick, Lieping Chen, Drew M. Pardoll
Journal: The Journal of Experimental Medicine (2005)

B7-DC, one of the recently described B7 family members, has the capacity to inhibit T cell responses via engagement of the immunoreceptor tyrosine-based inhibitory motif–containing inhibitory PD-1 receptor as well as enhance responses via an as yet unidentified costimulatory receptor. B7-DC is highly homologous to a coinhibitory B7 family member, B7-H1, which also binds PD-1. It is currently unclear which B7-DC function—costimulation or inhibition—predominates in vivo. To study in vivo functions of B7-DC, we evaluated immune responses in B7-DC knockout (KO) mice. Although not eliminated, interferon-γ (IFN-γ) production by CD4 T cells and IFN-γ–dependent humoral responses were reduced in B7-DC KO mice relative to wild type mice. Antigen-specific CD8 T cell responses and cytotoxic T lymphocyte (CTL) activity were also diminished in B7-DC KO mice. Hepatic tumors grew more quickly in B7-DC KO mice, associated with a decrease in intrahepatic tumor-specific CD8 T cells. These results highlight the contrasting in vivo roles of B7-DC and B7-H1 and indicate that B7-DC functions as a tuning molecule, selectively augmenting T helper 1 and CTL responses.
Prophylaxis in Haemophilic Arthropathy
Authors: J. B. King
Journal: BMJ (1967)

faces.These faces were not of people person- ally known to her but of famous historical figures such as Darwin, Browning, and Thomas Arnold.In yet another case the figure of a rabbit was constantly present.There seems little doubt that these phenomena do arise from an irritative involvement by the arterial process of appro- priate cortical areas.
Complete Regressions of Mycosis Fungoides With Topical Mechlorethamine Hydrochloride
Authors: Eugene J. Van Scott
Journal: JAMA (1972)

Survival of patients with mycosis fungoides, a lymphoma initially appearing in the skin and thereafter spreading to internal organs, has not been substantially improved by chemotherapeutic measures in use over the past two decades. In only a few instances has the disease been reported to undergo complete regression following therapy.  In the past four years we have intensively treated more than 70 patients with topical mechlorethamine hydrochloride (nitrogen mustard) preparations, usually consisting of 10 mg of drug dissolved in 2 oz of water. These solutions have been applied to the entire body surface daily, or three times weekly, until disappearance of disease. Thereafter applications have been continued at less frequent intervals.  In patients with disease limited to the skin, prior to lymph node involvement, complete regression of disease has been achieved and maintained in more than 50% of cases. Duration of therapy necessary to achieve complete disappearance of disease has
Aberrant Receptor-Mediated Endocytosis of Schistosoma mansoni Glycoproteins on Host Lipoproteins
Authors: Hein Sprong, Monika Suchanek, Suzanne M van Dijk, Alexandra van Remoortere, Judith Klumperman, Diana Avram, Joke van der Linden, Jeanette H. W Leusen, Jaap J van Hellemond, Christoph Thiele
Journal: PLoS Medicine (2006)

Bilharzia is one of the major parasitic infections affecting the public health and socioeconomic circumstances in (sub) tropical areas. Its causative agents are schistosomes. Since these worms remain in their host for decades, they have developed mechanisms to evade or resist the immune system. Like several other parasites, their surface membranes are coated with a protective layer of glycoproteins that are anchored by a lipid modification.We studied the release of glycosyl-phosphatidylinositol (GPI)-anchored proteins of S. mansoni and found them in the circulation associated with host lipoprotein particles. Host cells endocytosed schistosomal GPI-anchored proteins via their lipoprotein receptor pathway, resulting in disturbed lysosome morphology. In patients suffering from chronic schistosomiasis, antibodies attacked the parasite GPI-anchored glycoproteins that were associated with the patients' own lipoprotein particles. These immunocomplexes were endocytosed by cells carrying an immunoglobulin-Fc receptor, leading to clearance of lipoproteins by the immune system. As a consequence, neutral lipids accumulated in neutrophils of infected hamsters and in human neutrophils incubated with patient serum, and this accumulation was associated with apoptosis and reduced neutrophil viability. Also, Trypanosoma brucei, the parasite that causes sleeping sickness, released its major GPI-anchored glycoprotein VSG221 on lipoprotein particles, demonstrating that this process is generalizable to other pathogens/parasites.Transfer of parasite antigens to host cells via host lipoproteins disrupts lipid homeostasis in immune cells, promotes neutrophil apoptosis, may result in aberrant antigen presentation in host cells, and thus cause an inefficient immune response against the pathogen.
cAMP crosses junctions
Authors: Hema Bashyam
Journal: The Journal of Experimental Medicine (2007)

Regulatory T (T reg) cells that cozy up to other T cells send inhibitory molecules through cell–cell gap junctions, according to a new study by Bopp et al. (page 1303).

Some thymus-born natural T reg cells need little more than direct contact with their T cell victims to suppress their immune functions. But the mechanism or molecule that controls this contact-dependent inhibition has not yet been found.

One known potent immune suppressor is the intracellular second messenger cyclic adenosine monophophate (cAMP), which blocks T cell proliferation. cAMP levels are low in resting T cells and only marginally increase after activation. T reg cells, however, have constantly high levels of cAMP.

The team now shows that T reg cells use their abundant cAMP to flood conventional T cells and thereby shut them down. The cAMP transfer occurred through gap junctions, which formed upon contact between a T reg cell and an activated T cell. The subsequent increase in cAMP shut down T cell proliferation. cAMP transfer into activated T cells failed when gap junction formation was disrupted.

Together with Deaglio et al. (page 1257; and see “Regulatory cells get new ID” JEM 204:1241), these studies confirm that T reg cells use cAMP and the adenosine-generating pathway to rein in immune activation.
TNF receptor associated factor 3 plays a key role in development and function of invariant natural killer T cells
Authors: Zuoan Yi, Laura L. Stunz, Gail A. Bishop
Journal: The Journal of Experimental Medicine (2013)

TCR signaling is a prerequisite for early stage development of invariant natural killer T (iNKT) cells, whereas IL-15 signaling is required for expansion and maturation at later stages. In this study, we show that TNF receptor associated factor 3 (TRAF3) plays a critical role in the transition between these two distinct signaling pathways and developmental stages. TRAF3-deficient iNKT cells in CD4CreTRAF3flox/flox (T-TRAF3−/−) mice exhibit defective up-regulation of T-bet and CD122, two critical molecules for IL-15 signaling, and as a consequence, IL-15–mediated iNKT cell proliferation and survival are impaired. Consistently, development of iNKT cells in T-TRAF3−/− mice shows a major defect at developmental stages 2 and 3, but not stages 0 and 1. We further demonstrated that defective T-bet up-regulation occurring during the stage 1 to stage 2 transition results from reduced TCR signaling in TRAF3−/− iNKT cells. In addition, mature TRAF3−/− iNKT cells displayed defective cytokine responses upon TCR stimulation. Collectively, our results reveal that by modulating the relative strength of TCR signaling, TRAF3 is an important regulator of iNKT cell development and functions.
Profiling RE1/REST-mediated histone modifications in the human genome
Authors: Deyou Zheng, Keji Zhao, Mark F Mehler
Journal: Genome biology (2009)

Abstract Background The transcriptional repressor REST (RE1 silencing transcription factor, also called NRSF for neuron-restrictive silencing factor) binds to a conserved RE1 motif and represses many neuronal genes in non-neuronal cells. This transcriptional regulation is transacted by several nucleosome-modifying enzymes recruited by REST to RE1 sites, including histone deacetylases (for example, HDAC1/2), demethylases (for example, LSD1), and methyltransferases (for example, G9a). Results We have investigated a panel of 38 histone modifications by ChIP-Seq analysis for REST-mediated changes. Our study reveals a systematic decline of histone acetylations modulated by the association of RE1 with REST (RE1/REST). By contrast, alteration of histone methylations is more heterogeneous, with some methylations increased (for example, H3K27me3, and H3K9me2/3) and others decreased (for example, H3K4me, and H3K9me1). Furthermore, the observation of such trends of histone modifications in upregulated genes demonstrates convincingly that these changes are not determined by gene expression but are RE1/REST dependent. The outcomes of REST binding to canonical and non-canonical RE1 sites were nearly identical. Our analyses have also provided the first direct evidence that REST induces context-specific nucleosome repositioning, and furthermore demonstrate that REST-mediated histone modifications correlate with the affinity of RE1 motifs and the abundance of RE1-bound REST molecules. Conclusions Our findings indicate that the landscape of REST-mediated chromatin remodeling is dynamic and complex, with novel histone modifying enzymes and mechanisms yet to be elucidated. Our results should provide valuable insights for selecting the most informative histone marks for investigating the mechanisms and the consequences of REST modulated nucleosome remodeling in both neural and non-neural systems.
Measurement of exhaled nitric oxide in man.
Authors: C Borland, Y Cox, T Higenbottam
Journal: Thorax (1993)

BACKGROUND--Nitric oxide is released from pulmonary endothelial cells and contributes to the low pulmonary vascular resistance. The resistance pulmonary arteries are in close anatomical proximity to membranous airways, so it is likely that some pulmonary endothelial nitric oxide will enter the airspace to allow its measurement in the exhaled breath. METHODS--Exhaled air was collected from a single full exhalation and during tidal breathing. This was analysed for concentrations of nitric oxide, nitrogen dioxide, and carbon dioxide to give alveolar (FA) and mixed expired (FE) concentrations. Eight normal subjects were studied and laboratory air was similarly analysed using, respectively, chemiluminescent and infrared analysers. RESULTS--There was no relation between FA concentrations and the laboratory air concentrations. From the single breath, the ratio of (Fano/Faco2) x (Feco2/Feno) had a mean value of 0.92 (95% confidence interval 0.7 to 1.14). As this does not differ from unity, nitric oxide is likely to be derived from the same regions of the lungs as carbon dioxide. During tidal breathing the Feno ranged from 8.3 to 20.3 parts per billion. CONCLUSIONS--It is possible to measure endogenous pulmonary nitric oxide production in the exhaled air in man.
Coronary Artery Disease in Heterozygous Familial Hypercholesterolemia Patients With the Same LDL Receptor Gene Mutation
Authors: J. Ferrières, J. Lambert, S. Lussier-Cacan, J. Davignon
Journal: Circulation (1995)

Background Familial hypercholesterolemia (FH), an autosomal codominant disease, is characterized by high levels of LDL cholesterol and a high incidence of coronary artery disease (CAD). To date, genetic heterogeneity has hindered the proper assessment of the relation between risk factors and CAD in FH patients. Methods and Results We studied the association between CAD and common risk factors in a sample of 263 French Canadian FH patients (147 women, 116 men) carrying the same &gt;10-kb deletion of the LDL receptor gene. Thirty-five women and 54 men had CAD. The mean age of onset of CAD was 45.6±12.7 years in women and 38.8±9.4 years in men. Multiple logistic regression analyses were performed to test the association between CAD and age, tendon xanthomas, cigarette smoking, hypertension, diabetes mellitus, apolipoprotein E polymorphism, total plasma cholesterol, triglycerides, VLDL cholesterol, LDL cholesterol, HDL cholesterol, and lipoprotein(a) [Lp(a)]. In FH women, significant multivariate predictors were age (odds ratio, 1.10 for 1 year; P &lt;.0001), VLDL cholesterol (odds ratio, 3.85 for 1 natural log unit; P &lt;.002), and LDL cholesterol (odds ratio, 1.42 for 1 mmol/L; P &lt;.02). In FH men, age (odds ratio, 1.08 for 1 year; P &lt;.0001) and HDL cholesterol (odds ratio, 0.14 for 1 mmol/L; P =.05) were significant predictors of disease. Lp(a) was not a significant predictor in univariate or multivariate analyses. Conclusions This study suggests that increased risk of CAD in FH is not solely due to elevated LDL cholesterol levels and demonstrates a sex-specific lipoprotein influence on CAD in a large sample of FH patients carrying the same LDL receptor gene defect.
Diseases of the liver, 6th ed. Edited by L. Schiff and E. R. Schiff, 1,506 pp. Philadelphia, Pennsylvania: J. B. Lippincott, 1987. $125.00
Authors: N. J. Talley
Journal: Hepatology (1988)

diagnostic imaging covered in more detail and actuality; some illustrations on histology; and a more detailed description of surgical techniques.But, the most glaring omission, to my mind, is that of liver transplantation.
Abnormal mitochondrial function in locomotor and respiratory muscles of COPD patients
Authors: L. Puente-Maestu, J. Pérez-Parra, R. Godoy, N. Moreno, A. Tejedor, F. González-Aragoneses, J-L. Bravo, F. Villar Álvarez, S. Camaño, A. Agustí
Journal: European Respiratory Journal (2009)

Several cellular and molecular alterations have been described in skeletal and respiratory muscles of patients with chronic obstructive pulmonary disease (COPD), but information on potential abnormalities of mitochondrial function is scarce. The aim of the present study was to investigate mitochondrial function in the vastus lateralis (VL) and external intercostalis (EI) of COPD patients. Biopsies from VL and EI were obtained during surgery for lung cancer in 13 patients with mild to moderate COPD (age 68±6 yrs, forced expiratory volume in one second (FEV 1 ) 66±15% predicted) and 19 control subjects (age 67±9 yrs, FEV 1 95±18% pred). State 3 and 4 mitochondrial oxygen consumption ( V ′ O 2 ,m ), ATP synthesis, citrate synthase, cytochrome oxidase (COX) and complex I–III activities, as well as reactive oxygen species (ROS) production, were determined. In COPD patients, in both muscles, COX activity (VL: COPD 3.0±0.8 versus control 2.0±0.8; EI: 3.7±1.6 versus 2.4±0.9 μmol·min −1 ·mg −1 ) and ROS production (VL: 1,643±290 versus 1,285±468; EI: 1,033±210 versus 848±288 arbitrary units) were increased, whereas state 3 V ′ O 2 ,m was reduced (VL: 2.9±0.3 versus 3.6±0.4; EI: 3.6±0.3 versus 4.1±0.4 mmol·min −1 ·kg −1 ). Skeletal muscle mitochondria of patients with chronic obstructive pulmonary disease show electron transport chain blockade and excessive production of reactive oxygen species. The concurrent involvement of both vastus lateralis and external intercostalis suggests a systemic (rather than a local) mechanism(s) already occurring in relatively early stages (Global Initiative for Chronic Obstructive Lung Disease stage II) of the disease.
The Spectrum of Human Herpesvirus 6 Infection: From Roseola Infantum to Adult Disease
Authors: Mark Young Stoeckle
Journal: Annual Review of Medicine (2000)

▪ Abstract Human herpesvirus 6 is the causative agent of roseola infantum, a generally benign rash illness of infants. Most persons acquire HHV-6 infection by age 2 years, and HHV-6 infection is a common cause of fever and febrile seizures in infants. In adults, primary infection with HHV-6 can produce a mononucleosis-like illness and, more rarely, severe disease, including encephalitis. In addition to primary infections, HHV-6 can cause clinical illness during reactivation, particularly in immunocompromised persons.
NAC1 Is an Actin-Binding Protein That Is Essential for Effective Cytokinesis in Cancer Cells
Authors: Kai Lee Yap, Stephanie I. Fraley, Michelle M. Thiaville, Natini Jinawath, Kentaro Nakayama, Jianlong Wang, Tian-Li Wang, Denis Wirtz, Ie-Ming Shih
Journal: Cancer Research (2012)

NAC1 is a transcriptional corepressor protein that is essential to sustain cancer cell proliferation and migration. However, the underlying molecular mechanisms of NAC1 function in cancer cells remain unknown. In this study, we show that NAC1 functions as an actin monomer-binding protein. The conserved BTB protein interaction domain in NAC1 is the minimal region for actin binding. Disrupting NAC1 complex function by dominant-negative or siRNA strategies reduced cell retraction and abscission during late-stage cytokinesis, causing multinucleation in cancer cells. In Nac1-deficient murine fibroblasts, restoring NAC1 expression was sufficient to partially avert multinucleation. We found that siRNA-mediated silencing of the actin-binding protein profilin-1 in cancer cells caused a similar multinucleation phenotype and that NAC1 modulated the binding of actin to profillin-1. Taken together, our results indicate that the NAC1/actin/profilin-1 complex is crucial for cancer cell cytokinesis, with a variety of important biologic and clinical implications.
Adrenergic modulation of the transient outward current in isolated canine Purkinje cells.
Authors: T Nakayama, H A Fozzard
Journal: Circulation Research (1988)

Single canine Purkinje cells were voltage clamped under Ca2+-free conditions using the patch pipette. Depolarizing pulses from a holding potential of -42 mV induced a time-dependent rapidly activating-slowly inactivating outward current, which was identified as the transient outward current. The current showed two exponential time constants of inactivation (48,352 msec at +58 mV and 53,325 msec at +78 mV). Norepinephrine in concentrations exceeding 10(-9) M modified the inactivation kinetics of this current without affecting the activation kinetics. The half-maximum dose for norepinephrine effect was 1.9 X 10(-8) M, and the effect was saturated at 10(-6) M. Norepinephrine reduced the amplitude of the fast time constant component of inactivation, while increasing the amplitude of the slow component, without changing their time constants. Norepinephrine also increased the amplitude of a time-independent current component. The beta-antagonist sotalol blocked the norepinephrine effect on the transient outward current. On the other hand, both activation of adenyl cyclase by forskolin and increase of intracellular cAMP concentration produced the same effect as exposure to norepinephrine. These results suggest a role for neurotransmitter regulation of the transient outward current in cardiac cells, perhaps by channel phosphorylation.
Cerebral circulation
Authors: F M Faraci, G L Baumbach, D D Heistad
Journal: Journal of the American Society of Nephrology (1990)

New concepts have emerged in recent years concerning regulation of cerebral circulation. The purpose of this review is to summarize briefly several of these concepts. First, humoral mechanisms may have important effects on cerebral blood vessels and blood flow to choroid plexus. Recent evidence suggests that several vasoactive peptides may have major effects on fluid and ion balance in the brain by altering blood flow to the choroid plexus and possibly the production of cerebrospinal fluid. Second, chronic hypertension produces structural remodeling and hypertrophy of cerebral blood vessels and a shift in the relationship of cerebral blood flow to systemic blood pressure. Third, endothelium-dependent responses of cerebral arterioles to receptor and nonreceptor mediated agonists are impaired during chronic hypertension. Alterations in endothelium-dependent responses of cerebral arterioles during chronic hypertension appears to be due to release of an endothelium-derived contracting factor.
Central-Nervous-System Toxoplasmosis in Homosexual Men and Parenteral Drug Abusers
Authors: Brian Wong, Jonathan W. M. Gold, Arthur E. Brown, Michael Lange, Richard Fried, Michael Grieco, Donna Mildvan, José Giron, Michael L. Tapper, Chester W. Lerner, Donald Armstrong
Journal: Annals of Internal Medicine (1984)

Central-nervous-system toxoplasmosis developed in 7 of 269 patients with the acquired immunodeficiency syndrome reported to the New York City Health Department through July 1982. Focal neurologic abnormalities, mass lesions on computed-tomographic brain scans, lymphocytic cerebrospinal fluid pleocytosis, and detectable IgG antibody to Toxoplasma gondii were common; but IgG titers of 1:1024 or more, IgM antibody to T. gondii, and positive open brain biopsies were uncommon. Serologic findings suggested that the disease resulted from recrudescent rather than primary infection. Four of five patients improved when treated with sulfonamides and pyrimethamine, but 2 had relapses. An aggressive diagnostic approach and sometimes even empiric therapy are warranted when central-nervous-system toxoplasmosis is suspected in a seropositive patient with the acquired immunodeficiency syndrome.
Hereditary progressive dystonia with marked diurnal fluctuation caused by mutations in the GTP cyclohydrolase I gene
Authors: Hiroshi Ichinose, Tamae Ohye, Ei-ichi Takahashi, Naohiko Seki, Tada-aki Hori, Masaya Segawa, Yoshiko Nomura, Kotaro Endo, Hajime Tanaka, Shoji Tsuji, Keisuke Fujita, Toshiharu Nagatsu
Journal: Nature Genetics (1994)
IMPACT OF LESION LENGTH ON OUTCOMES AFTER REVASCULARIZATION WITH EVEROLIMUS AND SIROLIMUS ELUTING STENTS. A SUBSTUDY OF THE SORT OUT IV TRIAL
Authors: Mikkel Hougaard, Lisette Okkels Jensen, Per Thayssen, Anne Kaltoft, Hans-Henrik Tilsted, Michael Maeng, Evald H&oslash;j Christiansen, Jan Ravkilde, Morten Madsen, Anders Junker, Leif Thuesen, Jens Lassen
Journal: Journal of the American College of Cardiology (2012)
Patients with ARDS show improvement but not normalisation of alveolar surface activity with surfactant treatment: putative role of neutral lipids
Authors: P. Markart, C. Ruppert, M. Wygrecka, T. Colaris, B. Dahal, D. Walmrath, H. Harbach, J. Wilhelm, W. Seeger, R. Schmidt, A. Guenther
Journal: Thorax (2007)

<b>Background:</b> Extensive biochemical and biophysical changes of the pulmonary surfactant system occur in the acute respiratory distress syndrome (ARDS). <b>Methods:</b> The effect of intrabronchial administration of a recombinant surfactant protein C-based surfactant preparation (Venticute) on gas exchange, surfactant composition and function was investigated in 31 patients with ARDS in a randomised controlled phase I/II clinical pilot trial. Bronchoalveolar lavage fluids for surfactant analysis were obtained 3 h before and 48 and 120 h after the first surfactant application. Potentially deleterious effects of surfactant neutral lipids in patients with ARDS were also identified. <b>Results:</b> Before treatment all patients had marked abnormalities in the surfactant phospholipid and protein composition. In response to surfactant treatment, gas exchange improved and surfactant phospholipid and protein content were almost normalised. Alveolar surface activity was dramatically impaired before treatment and only partially improved after surfactant administration. Further analysis of the bronchoalveolar lavage fluids revealed a twofold increase in neutral lipid content and altered neutral lipid profile in patients with ARDS compared with healthy controls. These differences persisted even after administration of large amounts of Venticute. Supplementation of Venticute or natural surfactant with a synthetic neutral lipid preparation, mimicking the profile in ARDS, caused a dose-dependent deterioration of surface activity in vitro. <b>Conclusion:</b> Intrabronchial surfactant treatment improves gas exchange in ARDS, but the efficacy may be limited by increased concentration and altered neutral lipid profile in surfactant under these conditions.