tbuckley/cabot-search huggingface dataset:
Ventilatory and cerebrovascular responses in normocapnic and hypercapnic COPD patients
Authors: M.J.T. Van de Ven, W.N.J.M. Colier, M.C. Van der Sluijs, B.T.P. Kersten, B. Oeseburg, H. Folgering
Journal: European Respiratory Journal (2001)

This study investigated the hypothesis that hypercapnia in some chronic obstructive pulmonary disease (COPD) patients may be related to a high cerebrovascular response to carbon dioxide (CO 2 ). The relationship between responses of ventilation and of cerebral blood volume (CBV) to acute changes in carbon dioxide tension in arterial blood ( P a,CO 2 ) was measured in 17 chronic hypercapnic ( P a,CO 2 &gt;6.0 kPa) and 16 normocapnic ( P a,CO 2 ⪕6.0 kPa) COPD patients, who were matched for degree of airway obstruction (forced expiratory volume in one second 27% predicted). Results were compared with 15 age-matched healthy subjects. CBV was measered using near infrared spectroscopy during normo- and hypercapnia and related to inspired minute ventilation ( V ′ I ) and mouth occlusion pressure ( P 0.1 ). Hypercapnia (end-tidal pressure of carbon dioxide (Δ P ET,CO 2 ) &gt;1 kPa) was induced by giving adequate amounts of CO 2 in the inspired air. During normocapnia, CBV (mL·100 g −1 ) was 2.41±0.66 and 2.90±0.60 (mean±sd) in the normocapnic and chronic hypercapnic patients, respectively, which was significantly lower compared to healthy subjects (3.53±0.77). All slopes of CO 2 responsiveness (ΔCBV/Δ P a,CO 2 , Δ V ′ I /Δ P a,CO 2 , Δ P 0.1 /Δ P a,CO 2 ) were significantly lower in both COPD groups relative to healthy subjects, but were not significantly different between the COPD groups. A poor but positive correlation between ventilatory and cerebrovascular CO 2 responsiveness (ΔCBV/Δ P a,CO 2 and Δ V ′ I /Δ P a,CO 2 ) was found in COPD patients and healthy subjects. The findings do not support the hypothesis of abnormal cerebrovascular responses to carbon dioxide in hypercapnic chronic obstructive pulmonary disease patients.
Dual role of the p75 tumor necrosis factor (TNF) receptor in TNF cytotoxicity.
Authors: J Bigda, I Beletsky, C Brakebusch, Y Varfolomeev, H Engelmann, J Bigda, H Holtmann, D Wallach
Journal: The Journal of Experimental Medicine (1994)

Whereas there is ample evidence for involvement of the p55 tumor necrosis factor (TNF) receptor (p55-R) in the cytocidal effect of TNF, the role of the p75 TNF receptor (p75-R) in this effect is a matter of debate. In this study, we probed the function of p75-R in cells sensitive to the cytotoxicity of TNF using a wide panel of antibodies (Abs) against the receptor's extracellular domain. Two distinct Ab effects were observed. The Abs triggered signaling for cytotoxicity. This effect: (a) was correlated with the extent of p75-R expression by the cells; (b) was dependent on receptor cross-linking by the Abs; (c) occurred in HeLa cells, but not in A9 cells transfected with human p75-R or in HeLa cells expressing cytoplasmically truncated p75-R mutants, indicating that it involves cell-specific activities of the intracellular domain of the receptor; (d) was synergistic with the cytocidal effect of Abs against p55-R. Moreover, it seemed to reverse induced desensitization to the cytocidal effect of anti p55-R Abs, suggesting that it involves mechanisms different from those of the signaling by the p55 TNF-R. In addition, the Abs affected the response to TNF in a way that does not involve the signaling activity of p75-R. These effects: (a) could be observed also in cells in which only p55-R signaled for the cytocidal effect; (b) were not dependent on receptor cross-linking by the Abs; (c) varied according to the site at which the Abs bound to the receptor; and (d) were correlated inversely with the effects of the Abs on TNF binding to p75-R. That is, Abs binding to the membrane-distal part of the receptor's extracellular domain displaced TNF from the p75 receptor and enhanced cytocidal effect, whereas Abs that bind to the membrane-proximal part of the extracellular domain--a region at which a conformational change seems to take place upon TNF binding--decreased the dissociation of TNF from p75-R and inhibited its cytocidal effect. The above findings suggest that p75-R contributes to the cytocidal effect of TNF both by its own signaling and by regulating the access of TNF to p55-R.
Inflammation and Neuroprotection in Traumatic Brain Injury
Authors: Kara N. Corps, Theodore L. Roth, Dorian B. McGavern
Journal: JAMA Neurology (2015)

<h3>Importance</h3> Traumatic brain injury (TBI) is a significant public health concern that affects individuals in all demographics. With increasing interest in the medical and public communities, understanding the inflammatory mechanisms that drive the pathologic and consequent cognitive outcomes can inform future research and clinical decisions for patients with TBI. <h3>Objectives</h3> To review known inflammatory mechanisms in TBI and to highlight clinical trials and neuroprotective therapeutic manipulations of pathologic and inflammatory mechanisms of TBI. <h3>Evidence Review</h3> We searched articles in PubMed published between 1960 and August 1, 2014, using the following keywords:<i>traumatic brain injury, sterile injury, inflammation, astrocytes, microglia, monocytes, macrophages, neutrophils, T cells, reactive oxygen species, alarmins, danger-associated molecular patterns, purinergic receptors, neuroprotection,</i>and<i>clinical trials.</i>Previous clinical trials or therapeutic studies that involved manipulation of the discussed mechanisms were considered for inclusion. The final list of selected studies was assembled based on novelty and direct relevance to the primary focus of this review. <h3>Findings</h3> Traumatic brain injury is a diverse group of sterile injuries induced by primary and secondary mechanisms that give rise to cell death, inflammation, and neurologic dysfunction in patients of all demographics. Pathogenesis is driven by complex, interacting mechanisms that include reactive oxygen species, ion channel and gap junction signaling, purinergic receptor signaling, excitotoxic neurotransmitter signaling, perturbations in calcium homeostasis, and damage-associated molecular pattern molecules, among others. Central nervous system resident and peripherally derived inflammatory cells respond to TBI and can provide neuroprotection or participate in maladaptive secondary injury reactions. The exact contribution of inflammatory cells to a TBI lesion is dictated by their anatomical positioning as well as the local cues to which they are exposed. <h3>Conclusions and Relevance</h3> The mechanisms that drive TBI lesion development as well as those that promote repair are exceedingly complex and often superimposed. Because pathogenic mechanisms can diversify over time or even differ based on the injury type, it is important that neuroprotective therapeutics be developed and administered with these variables in mind. Due to its complexity, TBI has proven particularly challenging to treat; however, a number of promising therapeutic approaches are now under pre-clinical development, and recent clinical trials have even yielded a few successes. Given the worldwide impact of TBI on the human population, it is imperative that research remains active in this area and that we continue to develop therapeutics to improve outcome in afflicted patients.
Midkine Enhances Soft-Tissue Sarcoma Growth: A Possible Novel Therapeutic Target
Authors: Zeming Jin, Guy Lahat, Borys Korchin, Theresa Nguyen, Quan-Sheng Zhu, Xuemei Wang, Alexander J. Lazar, Jonathan Trent, Raphael E. Pollock, Dina Lev
Journal: Clinical Cancer Research (2008)

New therapeutic targets for soft-tissue sarcoma (STS) treatment are critically needed. Midkine (MK), a multifunctional cytokine, is expressed during midgestation but is highly restricted in normal adult tissues. Renewed MK expression was shown in several malignancies where protumorigenic properties were described. We evaluated the expression and function of MK in STS.Immunohistochemistry, reverse transcription-PCR, and Western blotting (WB) evaluated MK expression in human STS tissues and cell lines. WB and flow cytometry analyzed MK receptor expression. Cell growth assays evaluated the effect of MK on STS cell growth, and WB assessed MK downstream signaling. MK knock-in and knockout experiments further evaluated MK function. The growth of parental versus MK-transfected human fibrosarcoma cells was studied in vivo.MK was found to be overexpressed in a variety of human STS histologies. Using a rhabdomyosarcoma (RMS) tissue microarray, cytoplasmic and nuclear MK was identified; nuclear MK expression was significantly increased in metastases. Similarly, several STS cell lines expressed and secreted MK; RMS cells exhibited nuclear MK. STS cells also expressed the MK receptors protein tyrosine phosphatase zeta and lipoprotein receptor-related protein. MK significantly enhanced STS cell growth potentially via the Src and extracellular signal-regulated kinase pathways. STS cells stably transfected with MK exhibited increased growth in vitro and in vivo. MK-expressing human STS xenografts showed increased tumor-associated vasculature. Furthermore, MK knockdown resulted in decreased STS cell growth, especially in RMS cells.MK enhances STS tumor growth; our results support further investigation of MK and its receptors as therapeutic targets for human STS.
The Role of the Floor Plate in Axon Guidance
Authors: S A Colamarino, M Tessier-Lavigne
Journal: Annual Review of Neuroscience (1995)

The data reviewed above have implicated the floor plate in directing axonal growth towards the midline, in directing the behavior of axons at the midline, and finally, in directing the longitudinal growth of axons alongside the midline. In the case of growth to the midline, there is clear evidence for the existence of two types of cues that collaborate to direct growth--short-range cues that can direct axons along the edge of the spinal cord and a long-range chemoattractant secreted by the floor plate cells whose main function may be to direct later-extending commissural axons that must migrate through the complex environment of the developing motor column. Determining the precise contribution of these cues will require identifying them and perturbing them in vivo. The cues that direct growth along the edge are unknown; their identification in the spinal cord would be of quite general significance, since the growth of axons parallel to (but not in contact with) the pial surface is a widespread feature of early axon growth at all axial levels of the neural tube. A strong candidate for the long-range chemoattractant is netrin-1, a homologue of the UNC-6 protein of C. elegans and a distant relative of laminin, which is expressed by floor plate cells and which can both promote and orient commissural axon outgrowth. Netrin-1 may also influence growth of other populations of neurons that exhibit stereotyped behaviors near the ventral midline. Much less is known about the exact role of the floor plate in directing axon growth at the midline, though it is clearly required for accurate guidance. In the absence of the floor plate, a range of errors has been found, the most prominent of which are aberrant midline crossings and errors in longitudinal growth near the ventral midline. The severity of these errors varies with species, which could result from either the variable importance of the floor plate in the different species or the fact that, so far, quite different manipulations of the ventral midline region have been performed in different species. The most specific perturbation of the ventral midline occurs in the zebrafish cyc-1 mutant, where the selective loss of the floor plate leads to stereotyped misrouting events. Perhaps surprisingly, virtually all axons that grow to the midline turn longitudinally (although sometimes in the wrong direction).(ABSTRACT TRUNCATED AT 400 WORDS)
SAT0447 Preliminary Definition of Cutoffs for High Disease Activity Based on Original and Simplified Jadas in Juvenile Idiopathic Arthritis
Authors: A. Consolaro, S. Verazza, S. Lanni, M. C. Gallo, G. Bracciolini, G. Negro, A. Frisina, N. Ruperto, A. Martini, A. Ravelli
Journal: Annals of the Rheumatic Diseases (2013)

<h3>Background</h3> In the last decade, there have been major advances in the management of juvenile idiopathic arthritis (JIA), which include the shift towards early aggressive interventions and the development of new therapeutic agents and combination treatment strategies. A reliable documentation of the advances in therapeutic effectiveness creates the need for validated and clinically useful criteria that describe precisely the clinical states of the patient. <h3>Objectives</h3> To determine cut-off values for high disease activity (HDA) based on the original Juvenile Arthritis Disease Activity Score (JADAS) (1) and a simplified 3-item version of the JADAS (clinical JADAS- cJADAS), which does not include the acute phase reactant (2). <h3>Methods</h3> For the selection of cut-offs, data from a clinical database including 618 children with JIA followed at study center were used. 'Optimal' cut-offs were determined against external criteria by calculating the 25<sup>th</sup> percentile of cumulative score distribution and through receiver operating characteristic curve analysis. Patients were identified as being in HDA when the physician decided a major therapeutic intervention, defined as follows: 1) start of methotrexate therapy; 2) intraarticular corticosteroid injection (IAC); 3) start of biologic treatment; 4) start of systemic corticosteroid therapy. For each patient, 1 visit with HDA and 1 visit with no-HDA (i.e. visit in which none of the major therapeutic interventions listed above was made) were retained. The choice of cut-offs was made on clinical and statistical grounds. <h3>Results</h3> A total of 364 visits for oligoarticular-course patients (134 with HDA) and 412 visits for polyarticular-course patients (147 with HDA) were retained. The table shows the cutoffs (sensitivity/specificity) defined according to the different statistical methods and the AUC of the ROC curve. Proposed HDA cutoffs in oligoarticular-course JIA are 7.9 for JADAS10 and JADAS71, 7.2 for JADAS27, 7 for cJADAS10 and cJADAS71, and 6.5 for cJADAS 27. Proposed HDA cutoffs in polyarticular-course JIA are 12 for JADAS10 and JADAS71, 11 for JADAS27, cJADAS10 and cJADAS71, and 10 for cJADAS27. <h3>Conclusions</h3> We developed the HDA cutoffs for the JADAS and the cJADAS. The cutoffs need a thorough validation before being introduced in daily practice and clinical trials. <h3>References</h3> Consolaro A et al. Arthritis Rheum. 2009 May 15;61(5):658-66 McErlane F et al. Ann Rheum Dis. 2012 Epub ahead of print <h3>Disclosure of Interest</h3> None Declared
Clonal analysis of functionally distinct human CD4+ T cell subsets.
Authors: F T Rotteveel, I Kokkelink, R A van Lier, B Kuenen, A Meager, F Miedema, C J Lucas
Journal: The Journal of Experimental Medicine (1988)

A large number of CD4+ T cell clones, obtained from peripheral blood T lymphocytes by direct limiting dilution, allowed us to address the question whether functional heterogeneity exists within the human CD4+ T cell subset. Cytotoxic capacity of cloned T cells was analyzed with the use of anti-CD3 antibodies and target cells bearing FcR for murine IgG. 6 of 12 CD4+ clones obtained were able to lyse Daudi or P815 cells in the presence of anti-CD3 antibodies. The remaining six CD4+ T cell clones tested did not display anti-CD3-mediated cytotoxic activity and did not acquire this cytotoxic capacity during a culture period of 20 wk. In the absence of anti-CD3 mAb, no lytic activity against Daudi, P815, and K562 target cells was observed under normal culture conditions. Phenotypic analysis of these two distinct types of CD4+ T cells did not reveal differences with regard to reactivity with CDw29 (4B4) and CD45R (2H4) mAbs that have been described to recognize antigens associated with helper suppressor/inducer (respectively) CD4+ cells. The CD4+ clones without anti-CD3-mediated cytotoxic activities (Th2) consistently showed a high expression level of CD28 antigens, whereas the cytotoxic clones (Th1) expressed low amounts of CD28. Th1 CD4+ clones did produce IL-2, IFN-gamma, and TNF-alpha/beta, whereas the Th2 T cell clones produced minimal amounts of IL-2 and only low levels of INF-gamma and TNF-alpha/beta in response to anti-CD3 mAbs and PMA. Although not all CD4+ clones did release IL-4, there was no correlation with cytotoxic activity. Moreover, as compared with the Th1 CD4+ clones, Th2 CD4+ T cell clones proliferated moderately in response to immobilized anti-CD3 mAbs. However, proliferation reached the level of the cytotoxic clones when anti-CD28 mABs were present during culture. Both CD4+ subsets provided help for B cell differentiation upon stimulation with anti-CD3 mAbs. Our data suggest that the human CD4+ subset, in analogy to the murine system, comprises two functionally distinct T cell subpopulations, both of which are able to exert helper activity for polyclonal B cell differentiation, but which differ in cytotoxic capacity, lymphokine production, and requirements for proliferation. A function for these two types of T cells in the immune response is discussed.
Is Chronic Asthma Associated with Shorter Leukocyte Telomere Length at Midlife?
Authors: Daniel W. Belsky, Idan Shalev, Malcolm R. Sears, Robert J. Hancox, Hona Lee Harrington, Renate Houts, Terrie E. Moffitt, Karen Sugden, Benjamin Williams, Richie Poulton, Avshalom Caspi
Journal: American Journal of Respiratory and Critical Care Medicine (2014)

Asthma is prospectively associated with age-related chronic diseases and mortality, suggesting the hypothesis that asthma may relate to a general, multisystem phenotype of accelerated aging.To test whether chronic asthma is associated with a proposed biomarker of accelerated aging, leukocyte telomere length.Asthma was ascertained prospectively in the Dunedin Multidisciplinary Health and Development Study cohort (n = 1,037) at nine in-person assessments spanning ages 9-38 years. Leukocyte telomere length was measured at ages 26 and 38 years. Asthma was classified as life-course-persistent, childhood-onset not meeting criteria for persistence, and adolescent/adult-onset. We tested associations between asthma and leukocyte telomere length using regression models. We tested for confounding of asthma-leukocyte telomere length associations using covariate adjustment. We tested serum C-reactive protein and white blood cell counts as potential mediators of asthma-leukocyte telomere length associations.Study members with life-course-persistent asthma had shorter leukocyte telomere length as compared with sex- and age-matched peers with no reported asthma. In contrast, leukocyte telomere length in study members with childhood-onset and adolescent/adult-onset asthma was not different from leukocyte telomere length in peers with no reported asthma. Adjustment for life histories of obesity and smoking did not change results. Study members with life-course-persistent asthma had elevated blood eosinophil counts. Blood eosinophil count mediated 29% of the life-course-persistent asthma-leukocyte telomere length association.Life-course-persistent asthma is related to a proposed biomarker of accelerated aging, possibly via systemic eosinophilic inflammation. Life histories of asthma can inform studies of aging.
Salute to the stethoscope
Authors: Michael O’Donnell
Journal: BMJ (2008)

Is Spence really unaware of the pioneering work of the postwar generation of general practitioners who re-established the stethoscope as a valuable aid not to auscultation but to meditation?1 I can still recall the thrill of discovering that if I placed the business end of my stethoscope over an inert portion of a patient and used the other ends to plug my ears, …
Antisense Protein Kinase A RIα Inhibits 7,12-Dimethylbenz(<b> <i>a</i> </b>)anthracene-Induction of Mammary Cancer
Authors: Maria V. Nesterova, Yoon S. Cho-Chung
Journal: Clinical Cancer Research (2004)

Abstract Purpose: There are two types of cyclic AMP (cAMP)-dependent protein kinase (PKA), type I (PKA-I) and type II (PKA-II), which share a common catalytic (C) subunit but contain distinct regulatory (R) subunits, RI versus RII, respectively. Evidence suggests that increased expression of PKA-I and its regulatory subunit (RIα) correlates with tumorigenesis and tumor growth. We investigated the effect of sequence-specific inhibition of RIα gene expression at the initial phase of 7,12-dimethylbenz(αa)anthracene (DMBA)-induced mammary carcinogenesis. Experimental Design: Antisense RIα oligodeoxynucleotide (ODN) targeted against PKA RIα was administered (0.1 mg/day/rat, i.p.) 1 day before DMBA intubation and during the first 9 days post-DMBA intubation to determine the anticarcinogenic effects. Results: Antisense RIα, in a sequence-specific manner, inhibited the tumor production. At 90 days after DMBA intubation, untreated controls and RIα-antisense-treated rats exhibited an average mean number of tumors per rat of 4.2 and 1.8, respectively, and 90% of control and 45% of antisense-treated animals had tumors. The antisense also delayed the first tumor appearance. An increase in RIα and PKA-I levels in the mammary gland and liver preceded DMBA-induced tumor production, and antisense down-regulation of RIα restored normal levels of PKA-I and PKA-II in these tissues. Antisense RIα in the liver induced the phase II enzymes, glutathione S-transferase and quinone oxidoreductase, c-fos protein, and activator protein 1 (AP-1)- and cAMP response element (CRE)-directed transcription. In the mammary glands, antisense RIα promoted DNA repair processes. In contrast, the CRE transcription-factor decoy could not mimic these effects of antisense RIα. Conclusions: The results demonstrate that RIα antisense produces dual anticarcinogenic effects: (a) increasing DMBA detoxification in the liver by increasing phase II enzyme activities, increasing CRE-binding-protein phosphorylation and enhancing CRE- and Ap-1-directed transcription; and (b) activating DNA repair processes in the mammary gland by down-regulating PKA-I.