tbuckley/cabot-search huggingface dataset:
T cell receptor- and beta 1 integrin-mediated signals synergize to induce tyrosine phosphorylation of focal adhesion kinase (pp125FAK) in human T cells.
Authors: J E Maguire, K M Danahey, L C Burkly, G A van Seventer
Journal: The Journal of Experimental Medicine (1995)

The beta 1 subfamily of integrins is thought to play an important role in both the adhesion/migration and proliferation/differentiation of T cells. beta 1 integrins can provide T cell costimulation through interaction of very late antigen (VLA) 4 (VLA-4) (alpha 4 beta 1) and VLA-5 (alpha 5 beta 1) with the extracellular matrix protein fibronectin (FN), or by VLA-4 binding to its cell surface ligand, vascular cell adhesion molecule (VCAM) 1. The mechanism by which beta 1 integrin members transduce T cell-costimulatory signals is poorly understood. Studies in non-T cells have demonstrated regulation of the tyrosine focal adhesion kinase pp125FAK by beta 1 integrin engagement and, most recently, indicate a role for pp125FAK in linking integrin-mediated signal transduction to the Ras pathway (Schaller, M. D., and J. T. Parsons, 1994, Curr. Opin. Cell. Biol. 6: 705-710; Schlaepfer, D. D., S. K. Hanks, T. Hunter, and P. Van der Geer. 1994. Nature (Lond.), 372:786-790). Although pp125FAK kinase occurs in T cells, there are no reports on its regulation in this cell type. The studies described in this article characterize novel regulation of pp125FAK by the T cell receptor (TCR)-CD3 antigen complex and beta 1 integrins, and provide the first account, in any cell type, of integrin alpha 4 beta 1-mediated pp125FAK tyrosine phosphorylation. We demonstrate a rapid and sustained synergistic increase in tyrosine phosphorylation of human pp125FAK in Jurkat T cells after simultaneous (a) triggering of the TCR-CD3 complex, and (b) alpha 4 beta 1 and alpha 5 beta 1 integrin-mediated binding of these cells to immobilized FN or alpha 4 beta 1 integrin-mediated binding to immobilized VCAM-1. Studies with normal peripheral blood-derived CD4+ human T blasts confirm the synergistic action of a TCR-CD3 complex-mediated costimulus with a FN- or VCAM-1-dependent signal in the induction of T cell pp125FAK tyrosine phosphorylation. In vitro kinase assays performed on pp125FAK immunoprecipitates isolated from Jurkat cells and normal CD4+ T cells identified a coprecipitating 57-kD tyrosine-phosphorylated protein (pp57), distinct from pp59fyn or pp56lck. These results indicate, for the first time, the involvement of a specific kinase, pp125FAK, in alpha 4 beta 1- and alpha 5 beta 1-mediated T cell-costimulatory signaling pathways. In addition, the data demonstrate novel regulation of pp125FAK tyrosine phosphorylation by the TCR-CD3 complex.
Regimen Simplification to Atazanavir-Ritonavir Alone as Maintenance Antiretroviral Therapy After Sustained Virologic Suppression
Authors: Susan Swindells
Journal: JAMA (2006)

The long-term adverse effects, expense, and difficulty of adherence to antiretroviral regimens have led to studies of simpler maintenance therapies. Maintenance therapy with ritonavir-boosted atazanavir alone is a possible option because of low pill burden, once-daily dosing, safety, and unique resistance profile.To assess whether simplified maintenance therapy with atazanavir-ritonavir alone after virologic suppression increases the risk of virologic failure (2 consecutive human immunodeficiency virus type 1 [HIV-1] RNA measurements of > or =200 copies/mL).Single-group, open-label, multicenter, 24-week pilot study of 36 HIV-infected adults with virologic suppression for 48 weeks or longer receiving their first protease inhibitor (PI)-based regimen. The study was conducted between September 1, 2004, and April 18, 2006, at 12 participating AIDS clinical trial units in the United States.Participants switched PIs to atazanavir-ritonavir at entry and discontinued nucleoside analog reverse transcriptase inhibitors (NRTIs) after 6 weeks.Virologic failure within 24 weeks of discontinuing NRTIs. Other measures included HIV-1 drug resistance, plasma atazanavir concentrations, adverse events, CD4 cell counts, plasma lipid levels, and HIV-1 RNA levels in seminal plasma.Thirty-six participants enrolled and 2 discontinued before simplification to atazanavir-ritonavir alone. Thirty-four patients were included in the analysis of the primary end point after 24 weeks: 1 withdrew voluntarily, and 33 continued the regimen. Virologic success (absence of failure) through 24 weeks of simplified therapy occurred in 91% (31 of 34 patients; lower 90% confidence interval limit = 85%). Three participants experienced virologic failure 12, 14, and 20 weeks after simplification, with plasma HIV-1 RNA levels of 4730, 1285, and 28 397 copies/mL, respectively. Resistance testing at failure did not identify PI resistance mutations. Plasma atazanavir concentrations at failure were low or below detection in 2 of 3 participants experiencing failure. There were no treatment discontinuations for adverse events after simplification; no significant changes in CD4 cell counts or plasma lipid levels; and no detectable HIV-1 RNA in seminal plasma from all 8 participants tested.These preliminary data suggest that simplified maintenance therapy with atazanavir-ritonavir alone may be efficacious for maintaining virologic suppression in carefully selected patients with HIV infection. These findings require confirmation in larger, randomized trials of this strategy.clinicaltrials.gov Identifier: NCT00084019.
Length-Tension Relationship of Smooth Muscle of the Hog Carotid Artery
Authors: JEREMIAH T. HERLIHY, RICHARD A. MURPHY
Journal: Circulation Research (1973)

The length-tension relationships for arterial smooth muscle were determined using vascular strips teased from the media of hog carotid arteries. Histological examination revealed that the strips were (1) free of adventitia and (2) composed of smooth muscle cells oriented parallel to the long axis of the strips. Measurements from electron micrographs indicated that 60% of the cross-sectional area consisted of smooth muscle. At L 0 (the optimal length for tension development) the total cross-sectional area of the strips varied from 0.3 to 0.8 mm 2 . Potassium-induced depolarization was the most effective stimulus for force development. Norepinephrine and electric field stimulation elicited responses which were 70% and 30%, respectively, of that produced by potassium-induced depolarization. At L 0 the intrinsic load-bearing capacity (P 0 ) of the contractile system was 2.22 x 10 6 dynes/cm 2 . Tension development fell off gradually at lengths shorter than L 0 and more rapidly at lengths greater than L 0 . Passive length-tension curves were determined after quick releases from higher to lower lengths to avoid complications arising from tone. Passive tension was negligible at lengths below 0.9 L 0 . At L 0 the passive tension was 10% of P 0 .
IL-17-producing CD4<sup>−</sup>CD8<sup>−</sup>T cells are expanded in the peripheral blood, infiltrate salivary glands and are resistant to corticosteroids in patients with primary Sjögren's syndrome
Authors: Alessia Alunno, Onelia Bistoni, Elena Bartoloni, Sara Caterbi, Barbara Bigerna, Alessia Tabarrini, Roberta Mannucci, Brunangelo Falini, Roberto Gerli
Journal: Annals of the Rheumatic Diseases (2012)

<h3>Objectives</h3> It has been recently observed that a T-cell subset, lacking of both CD4 and CD8 molecules and defined as double negative (DN), is expanded in the blood of patients with systemic lupus erythematosus, produces IL-17 and accumulates in the kidney during nephritis. Since IL-17 production is enhanced in salivary gland infiltrates of primary Sjögren9s syndrome (SS) patients, we investigated whether DN T cells may be involved in the pathogenesis of salivary gland damage. <h3>Methods</h3> Phenotypic characterisation of peripheral blood mononuclear cells from SS patients and controls was performed by flow cytometry in freshly isolated and anti-CD3-stimulated cells. SS minor salivary glands were processed for immunofluorescence staining. <h3>Results</h3> CD3<sup>+</sup>CD4<sup>−</sup>CD8<sup>−</sup> DN T cells were major producers of IL-17 in SS and expressed ROR-γt. They were expanded in the peripheral blood, spontaneously produced IL-17 and infiltrated salivary glands. In addition, the expansion of αβ-TCR<sup>+</sup> DN T cells was associated with disease activity. Notably, IL-17-producing DN T cells from SS patients, but not from healthy controls, were strongly resistant to the in vitro effect of dexamethasone. <h3>Conclusions</h3> These findings appear to be of great interest since the identification of a peculiar T-cell subset with pro-inflammatory activity, but resistant to corticosteroids, in an autoimmune disorder such as SS may help to design new specific treatments for the disease.
A Common <i>MLP</i> (Muscle LIM Protein) Variant Is Associated With Cardiomyopathy
Authors: Ralph Knöll, Sawa Kostin, Stefanie Klede, Kostas Savvatis, Lars Klinge, Ina Stehle, Sylvia Gunkel, Sebastian Kötter, Kamila Babicz, Melanie Sohns, Snjezana Miocic, Michael Didié, Gudrun Knöll, Wolfram Hubertus Zimmermann, Paul Thelen, Heike Bickeböller, Lars S. Maier, Wolfgang Schaper, Jutta Schaper, Theresia Kraft, Carsten Tschöpe, Wolfgang A. Linke, Kenneth R. Chien
Journal: Circulation Research (2010)

We previously discovered the human 10T-->C (Trp4Arg) missense mutation in exon 2 of the muscle LIM protein (MLP, CSRP3) gene.We sought to study the effects of this single-nucleotide polymorphism in the in vivo situation.We now report the generation and detailed analysis of the corresponding Mlp(W4R/+) and Mlp(W4R/W4R) knock-in animals, which develop an age- and gene dosage-dependent hypertrophic cardiomyopathy and heart failure phenotype, characterized by almost complete loss of contractile reserve under catecholamine induced stress. In addition, evidence for skeletal muscle pathology, which might have implications for human mutation carriers, was observed. Importantly, we found significantly reduced MLP mRNA and MLP protein expression levels in hearts of heterozygous and homozygous W4R-MLP knock-in animals. We also detected a weaker in vitro interaction of telethonin with W4R-MLP than with wild-type MLP. These alterations may contribute to an increased nuclear localization of W4R-MLP, which was observed by immunohistochemistry.Given the well-known high frequency of this mutation in Caucasians of up to 1%, our data suggest that (W4R-MLP) might contribute significantly to human cardiovascular disease.
Differential Functional Activation of Chemokine Receptor CXCR4 Is Mediated by G Proteins in Breast Cancer Cells
Authors: Jane D. Holland, Marina Kochetkova, Chareeporn Akekawatchai, Mara Dottore, Angel Lopez, Shaun R. McColl
Journal: Cancer Research (2006)

Abstract CXCR4 is a G protein–coupled receptor of considerable biological significance, and among its numerous functions, it is suggested to play a critical role in cancer metastasis. We have investigated the expression and function of CXCR4 in a range of breast cancer cell lines covering a spectrum of invasive phenotypes and found that, while surface levels of CXCR4 were uniform across the entire panel, only highly invasive cells that are metastatic in immunocompromised mice expressed functional receptors. CXCL12/SDF-1 induced cellular responses such as calcium mobilization, actin polymerization, and chemotaxis in metastatic cells, whereas noninvasive cells were unresponsive. Moreover, CXCL12 activated multiple signaling pathways downstream of G proteins in highly invasive cells but failed to activate any of the examined kinase cascades in noninvasive cell lines. This blockade in nonmetastatic cell lines seems to be due to the inability of G protein α and β subunits to form a heterotrimeric complex with CXCR4. Gα and Gβ were able to bind to CXCR4 independently in all cell lines, but the association of G protein αβγ heterotrimers with the receptor, a prerequisite for signal transduction downstream from G protein–coupled receptors, was only observed in the highly invasive cell lines. Our findings show, for the first time, that CXCR4 function is subject to complex and potentially tightly controlled regulation in breast cancer cells via differential G protein–receptor complex formation, and this regulation may play a role in the transition from nonmetastatic to malignant tumors. (Cancer Res 2006; 66(8): 4117-24)
Effects of salbutamol therapy on pulmonary mechanics and chronic lung disease in very low birth weight infants
Authors: Oleksandr Mazulov, Olga Yablon, Konstantin Bertsun, Evgeniy Vzhetson
Journal: European Respiratory Journal (2012)

Background. To determine the changes in pulmonary mechanics before and during salbutamol therapy and to evaluate the effect of salbutamol on the duration of mechanical ventilation in very low birth weight (VLBW) ventilator-dependent infants.  Methods. A prospective single-centre trial was conducted. Forty-three patients (birth weight 600 to 1500 g, gestational age 24 to 32 weeks) who failed to be weaned from the respirator at 7 to 14 days of age were enrolled; 23 infants received a 7-day course of salbutamol (2.5 mg 4 times per day via nebulizer) and 20 patients were in the control group. A similar mean airway pressure (MAP) and fractional inspired oxygen concentration (FiO2), respiratory system mechanics (tidal volume (VT), respiratory compliance (Crs) and respiratory resistance (Rrs)) were measured before and on days 2, 5, and 7 of the study.  Results. There was a significant increase in Crs and VT in the salbutamol group as compared with the control group (P   0.21 at 36 weeks of corrected gestational age, chest radiograph changes) was significantly decreased in the salbutamol group (P   Conclusions. Our study indicate that salbutamol therapy in VLBW infants significantly improves lung9s mechanics and facilitates extubation in infants and reduces the duration of mechanical ventilation and decreases CLD (at 28 days and 36 weeks) in a population of VLBW infants.
Seroepidemiological study of relationships between Epstein-Barr virus and rheumatoid arthritis.
Authors: P B Ferrell, C T Aitcheson, G R Pearson, E M Tan
Journal: Journal of Clinical Investigation (1981)

To elucidate the relationship between Epstein-Barr virus (EBV) and rheumatoid arthritis (RA), we measured antibodies to RA-associated nuclear antigen (anti-RANA) and three other EBV-related antigens in the sera of RA patients and controls. Our study groups consisted of 89 patients with definite or classical RA, mean age 56, male/female ratio 47:42; and 53 normal and osteoarthritis controls, mean age 51, male/female ratio 25:28. In addition to anti-RANA, we measured antibodies to viral capsid antigen (anti-VCA), early antigen (anti-EA) and EBV-associated nuclear antigen (anti-EBNA). Anti-RANA was detected in 71% of RA patients but in only 6% of controls. Elevated anti-VCA titers (greater than 1:160) were more common in RA patients than controls, 31% compared with 15%. The geometric mean titer of anti-VCA was significantly higher iun the RA group, 133 compared with 58. Anti-EA was present in 53% of RA patients but only 19% of controls. Anti-EA in elevated titers (greater than 1:20) was present in 26% of RA patients but only 7% of controls. Characterization of the anti-EA antibodies revealed that the RA patients reacted primarily with the diffuse component, whereas the majority of the controls reacted with the restricted component of the EA complex. In contrast, the frequencies, distributions, and geometric mean titers of anti-EBNA were not significantly different between the two groups. Correlative analysis of these antibodies showed highly significant relationships between anti-VCA and anti-EA, and anti-RANA and anti-EBNA in the RA group. These data are compatible with the interpretation that RA patients have either more active EBV infections than controls or an altered regulation of their immune response to this infectious agent.
Amyloidosis-Associated Kidney Disease
Authors: Laura M. Dember
Journal: Journal of the American Society of Nephrology (2006)

The amyloidoses are a group of disorders in which soluble proteins aggregate and deposit extracellularly in tissues as insoluble fibrils, causing progressive organ dysfunction. The kidney is one of the most frequent sites of amyloid deposition in AL, AA, and several of the hereditary amyloidoses. Amyloid fibril formation begins with the misfolding of an amyloidogenic precursor protein. The misfolded variants self-aggregate in a highly ordered manner, generating protofilaments that interact to form fibrils. The fibrils have a characteristic appearance by electron microscopy and generate birefringence under polarized light when stained with Congo red dye. Advances in elucidating the mechanisms of amyloid fibril formation, tissue deposition, and tissue injury have led to new and more aggressive treatment approaches for these disorders. This article reviews the pathogenesis, diagnosis, clinical manifestations, and treatment of the amyloidoses, focusing heavily on the renal aspects of each of these areas.
Management of pleural infection in adults: British Thoracic Society pleural disease guideline 2010
Authors: H. E. Davies, R. J. O. Davies, C. W. H. Davies
Journal: Thorax (2010)

Pleural infection is a frequent clinical problem with an approximate annual incidence of up to 80 000 cases in the UK and USA combined. The associated mortality and morbidity is high; in the UK 20% of patients with empyema die and approximately 20% require surgery to recover within 12 months of their infection.1 2 Prompt evaluation and therapeutic intervention appears to reduce morbidity and mortality as well as healthcare costs.3

This article presents the results of a peer-reviewed systematic literature review combined with expert opinion of the preferred management of pleural infection in adults for clinicians in the UK. The clinical guidelines generated from this process are presented in figure 1. The guidelines are aimed predominantly at physicians involved in adult general and respiratory medicine and specifically do not cover in detail the complex areas of tuberculous empyema, paediatric empyema or the surgical management of post-pneumonectomy space infection.



Figure 1 
Flow diagram describing the management of pleural infection.



This section provides background information for reference, interest and to set the management guidelines in context.

### Historical perspective

The Egyptian physician Imhotep initially described pleural infection around 3000 BC, although Hippocrates has been more famously credited with its recognition in 500 BC. Until the 19th century open thoracic drainage was the recommended treatment for this disorder but carried an associated mortality of up to 70%.4 5 This high mortality was probably due to respiratory failure produced by the large open pneumothorax left by drainage.5 This was particularly true of Streptococcus pyogenes infections which produce streptokinase and large alocular effusions free of adhesions.5 Closed tube drainage was first described in 1876 but was not widely adopted until the influenza epidemic of 1917–19. An Empyema Commission subsequently produced recommendations that remain the basis for treatment today. They advocated adequate pus drainage with a closed …
Psychopathy is a nonarbitrary class
Authors: Vernon L. Quinsey, Martin L. Lalumière
Journal: Behavioral and Brain Sciences (1995)

Abstract Recent evidence that psychopathy is a nonarbitrary population, such that the trait may be categorical rather than continuous, is consistent with Mealey's distinction between primary and secondary psychopaths. Thus, there are likely to be at least two routes to criminality, and psychopathic and nonpsychopathic criminals are likely to respond differently to interventions.
Usefulness of bone densitometry in postmenopausal women with clinically diagnosed vertebral fractures
Authors: J M Nolla
Journal: Annals of the Rheumatic Diseases (2002)

To analyse whether bone mineral density (BMD) assessment is required in postmenopausal women presenting with low trauma vertebral fracture.Women with vertebral fracture diagnosed over a 10 year period were recruited from our database. The following were excluded: (a) patients with high energy trauma; (b) patients with malignancies; (c) patients with a metabolic bone disease other than osteoporosis. All postmenopausal women were included in whom BMD had been evaluated at both the lumbar spine and femoral neck by dual energy x ray absorptiometry during the six months after the diagnosis. Patients with a potential cause of osteoporosis other than age and menopause were not considered. A total of 215 patients were identified.The mean (SD) age of the patients was 65.9 (6.9) years. BMD at the lumbar spine was 0.725 (0.128) g/cm(2) and the T score was -2.94 (1.22); BMD at the femoral neck was 0.598 (0.095) g/cm(2) and the T score was -2.22 (0.89). The BMD of the patients was significantly lower than that of the general population at both the lumbar spine and femoral neck. When the lowest value of the two analysed zones was considered, six patients (3%) showed a normal BMD, 51 (23.5%) osteopenia, and 158 (73.5%) osteoporosis. The prevalence of osteoporosis at the femoral neck increased with age; it was 25% in patients under 60, 35% in patients aged 60-70, and 60% in patients over 70.These results indicate that bone densitometry is not required in postmenopausal women with clinically diagnosed vertebral fractures if it is performed only to confirm the existence of a low BMD.
Recent Advances in Mitochondrial Research
Authors: Bradford G. Hill
Journal: Circulation Research (2013)

The goal of "Recent Developments" is to provide a concise but comprehensive overview of new advances in cardiovascular research, which we hope will keep our readers abreast of recent scientific discoveries and facilitate discussion, interpretation, and integration of the findings.This will enable readers who are not experts in a particular field to grasp the significance and impact of work performed in other fields.It
Chemokines: the times they are a-changin’
Authors: Gabriel Márquez, Carlos Martínez-A.
Journal: Journal of Clinical Investigation (2001)

What does a name mean?Don Quixote's reply to Sancho Panza was that a name is whatever you understand it to mean.This response certainly applies to the evolution of our thinking about chemokines over the ten years of their history.Initially perceived as simple chemoattractants, chemokines are now implicated at diverse phases of the immune response, and their significance is becoming apparent in many areas of biomedicine, including cancer, HIV-1 infection, asthma, and cardiovascular disease.