tbuckley/cabot-search huggingface dataset:
NSR-seq transcriptional profiling enables identification of a gene signature of Plasmodium falciparum parasites infecting children
Authors: Marissa Vignali, Christopher D. Armour, Jingyang Chen, Robert Morrison, John C. Castle, Matthew C. Biery, Heather Bouzek, Wonjong Moon, Tomas Babak, Michal Fried, Christopher K. Raymond, Patrick E. Duffy
Journal: Journal of Clinical Investigation (2011)

Malaria caused by Plasmodium falciparum results in approximately 1 million annual deaths worldwide, with young children and pregnant mothers at highest risk. Disease severity might be related to parasite virulence factors, but expression profiling studies of parasites to test this hypothesis have been hindered by extensive sequence variation in putative virulence genes and a preponderance of host RNA in clinical samples. We report here the application of RNA sequencing to clinical isolates of P. falciparum, using not-so-random (NSR) primers to successfully exclude human ribosomal RNA and globin transcripts and enrich for parasite transcripts. Using NSR-seq, we confirmed earlier microarray studies showing upregulation of a distinct subset of genes in parasites infecting pregnant women, including that encoding the well-established pregnancy malaria vaccine candidate var2csa. We also describe a subset of parasite transcripts that distinguished parasites infecting children from those infecting pregnant women and confirmed this observation using quantitative real-time PCR and mass spectrometry proteomic analyses. Based on their putative functional properties, we propose that these proteins could have a role in childhood malaria pathogenesis. Our study provides proof of principle that NSR-seq represents an approach that can be used to study clinical isolates of parasites causing severe malaria syndromes as well other blood-borne pathogens and blood-related diseases.
Patients with m2 antibodies: what diagnosis and follow-up are they given?
Authors: E. A. L. Byrne, R. Katbamna, C. Scott, C. Blanshard, R. Marley, S. W. Coppack, G. R. Foster
Journal: Gut (2010)

In a recent issue of Gut Feuchinger et al report a novel marker antibody for primary biliary cirrhosis (PBC) which may become useful in the diagnosis of PBC in the future.1 At present diagnosis is based on the presence of the M2 substrate of anti-mitochondrial antibody (AMA) in the sera and liver function tests. The American Association for the Study of Liver Disease (AASLD) recommend that a diagnosis of PBC can be made with a positive M2 antibody and cholestatic liver biochemistry (biopsy can be used to confirm) and that patients who are M2 positive only should be followed up with annual …
Effect of cessation of short-term therapy with ipratropium bromide on lung function and airway responsiveness
Authors: PJ Wilding, MM Clark, ID Pavord, D Parker, JA Bennett, AE Tattersfield
Journal: European Respiratory Journal (1996)

Regular exposure to antimuscarinic drugs would be expected to upregulate airway muscarinic receptors and could cause a transient increase in airways obstruction if treatment was stopped or omitted. We have examined peak expiratory flow rate (PEFR) during treatment and forced expiratory flow in one second (FEV1) and airway responsiveness to three constrictor agonists (as the provocative dose of agonist causing a 20% fall in FEV1, (PD20)) following cessation of regular inhaled ipratropium bromide, in 13 subjects with mild stable asthma. Subjects inhaled placebo and ipratropium bromide, 80 microg q.i.d. for 14 days in a cross-over fashion with a 1 week run-in/wash-out period before and after each treatment period. Subjects recorded symptom scores and PEFR throughout the study, and FEV1 and PD20 to histamine, methacholine and metabisulphite were measured before and after cessation of treatment. When compared to baseline, FEV1 was lower after cessation of ipratropium than after placebo, with a significant difference 30 h after the last dose (difference 190 mL; 95% confidence interval (95% CI) 310-70 mL; p&lt;0.02). FEV1 measured 6-10 days later, did not differ significantly. PEFR was significantly lower after cessation of ipratropium than after placebo on Day 15 (19-37 h after the last dose) (mean difference 4.6%; 95% CI 1.6-7.5%; p&lt;0.01) but not on Day 16. There were no significant changes in PD20 histamine, methacholine and metabisulphite, symptom scores or rescue bronchodilator use after cessation of treatment. Thus, transient bronchoconstriction was found around 30 h after cessation of regular therapy with inhaled ipratropium for 2 weeks. The mechanism is unclear, as no evidence of muscarinic receptor upregulation was found. Although the changes were small and unlikely to be important for most patients, the results of this study indicate that the timing of lung function measurements relative to the last dose of ipratropium is important when interpreting the course of lung function in long-term studies.
FACTORS MODIFYING HOST RESISTANCE TO VIRAL INFECTION
Authors: Brian R. Murphy, Lowell A. Glasgow
Journal: The Journal of Experimental Medicine (1968)

The resistance of mice to encephalomyocarditis (EMC) virus was markedly decreased by prior exposure to whole body X-irradiation. In contrast to non-irradiated controls, the course of EMC virus infection in X-irradiated animals was characterized by (a) an enhanced mortality, (b) shortening of the incubation period, (c) higher levels of virus in the blood during the viremic phase and persistence of the viremia until death, (d) failure to develop detectable serum levels of neutralizing antibody, and (e) the earlier appearance and higher levels of virus in brain and heart tissue. The level of interferon in the serum during the course of infection was similar in both groups. The administration of relatively small quantities of anti-EMC virus neutralizing antibody to X-irradiated mice during the early phases of the infection with EMC virus restored their resistance to levels comparable to nonirradiated animals. An alteration of local organ defense mechanisms in the central nervous system could not be demonstrated. It is proposed that (a) the inability of the X-irradiated animal to elaborate specific neutralizing antibody was a critical determinant in their failure to clear the viremia, (b) this increase in the level and duration of the viremic phase resulted in the exposure of target organs to a greater inoculum of virus, and (c) the enhanced mortality observed in irradiated mice reflected this greater target organ involvement. The experimental model presented, therefore, suggests that the immunologic response is a critical determinant of host resistance during this primary systemic virus infection.
Novel Gain-of-Function Mechanism in K <sup>+</sup> Channel–Related Long-QT Syndrome:
Authors: James P. Lees-Miller, Yanjun Duan, Guo Qi Teng, Kelly Thorstad, Henry J. Duff
Journal: Circulation Research (2000)

Abstract —The N629D mutation, adjacent to the GFG signature sequence of the HERG1 A K + channel, causes long-QT syndrome (LQTS). Expression of N629D in Xenopus oocytes produces a rapidly activating, noninactivating current. N629D is nonselective among monovalent cations; permeation of K + was similar to that of Na + or Cs + . During repolarization to potentials between −30 and −70 mV, N629D manifested an inward tail current, which was abolished by replacement of extracellular Na + (Na + e ) with extracellular N -methyl- d -glucamine (NMG e ). Because LQTS occurs in heterozygous patients, we coexpressed N629D and wild type (WT) at equimolar concentrations. Heteromultimer formation was demonstrated by analyzing the response to 0 [K + ] e . The outward time-dependent current was nearly eliminated for WT at 0 [K + ] e , whereas no reduction was observed for homomultimeric N629D or for the equimolar coexpressed current. To assess physiological significance, dofetilide-sensitive currents were recorded during application of simulated action potential clamps. During phase 3 repolarization, WT manifested outward currents, whereas homomultimeric N629D manifested inward depolarizing currents. During coexpression studies, variable phenotypes were observed ranging from a reduction in outward repolarizing current to net inward depolarizing current during phase 3. In summary, N629D replaces the WT outward repolarizing tail current with an inward depolarizing sodium current, which is expected to delay later stages of repolarization and contribute to arrhythmogenesis. Thus, the consequences of N629D resemble the pathophysiology seen in LQT3 Na + channel mutations and may be considered the first LQTS K + channel mutation that exhibits gain of function.
Transfection with CD40L induces tumour suppression by dendritic cell activation in an orthotopic mouse model of pancreatic adenocarcinoma
Authors: S Serba, J Schmidt, N Wentzensen, E Ryschich, A Marten
Journal: Gut (2007)

Patients with adenocarcinoma of the pancreas have only limited promising therapy options. Therefore, immunotherapeutic approaches might be considered promising and have gained importance over the last few years. In this study, CD40L gene transfer was tested as potent immunotherapy.The efficacy of CD40L gene transfer in initiating anti-tumour immune response was investigated in a pancreatic ductal adenocarcinoma orthotopic syngeneic mouse model. In addition, the role of dendritic cells was determined.A significantly slower tumour growth rate and less metastasis were observed following administration of the CD40L plasmid. Such an effect of the plasmid was not observed in immunodeficient mice. Tumours of treated mice were found to be infiltrated with T cells and dendritic cells. The latter were mature and of myeloid origin. Tumour-infiltrating lymphocytes were tumour-specific as shown in IFN-gamma ELISPot assays. Using intravital microscopy it was possible to show a significant induction of leukocytes sticking to the tumour endothelium after CD40L treatment. Adoptive cell transfer experiments have revealed that tumour-derived dendritic cells and CD8 cells from CD40L-treated donor mice either harbour anti-tumour activity or induce it in the recipients. Distinctly, CD8 cells from donor spleens were found to migrate directly into the recipient's tumour.The induction of anti-tumour activity initiated after treating mice with the CD40L plasmid was achieved. Further investigations showed that this is mediated by mature myeloid dendritic cells which activate CD8 cells. Clinical trials investigating CD40L-based therapies should be extended.
Serum chemerin is increased in patients with chronic plaque psoriasis and normalizes following treatment with infliximab
Authors: P. Gisondi, V. Lora, C. Bonauguri, A. Russo, G. Lippi, G. Girolomoni
Journal: British Journal of Dermatology (2012)

Chronic plaque psoriasis is associated with obesity, which is a metabolic and inflammatory disorder. Adipokines are involved in the pathogenesis of psoriasis and they are biomarkers of obesity-related inflammation.To measure serum adipokines in patients with chronic plaque psoriasis treated with infliximab.Serum levels of chemerin, resistin, visfatin, C-reactive protein (CRP), lipids, glycaemia and liver enzymes were measured in 40 patients with psoriasis and 40 controls matched by age, sex and body mass index (BMI). Adipokines were measured at baseline and after 2-12 months of treatment with infliximab 5 mg kg(-1).At baseline, levels of chemerin (195·9±48·5 vs. 145·6±27·1 ng mL(-1)), resistin (2·03±0·9 vs. 1·4±0·5 ng mL(-1)) and CRP (5·5±7·3 vs. 1·9 ±4·4 mg L(-1)) were higher (P<0·01) in patients with psoriasis compared with controls. Psoriasis was associated with elevated chemerin level independently of age, sex, BMI and levels of cholesterol and triglycerides. Chemerin was linearly correlated to CRP (r=0·4, P=0·01) and resistin (r=0·3, P=0·01). Chemerin levels were higher in patients affected by psoriatic arthritis than in patients with psoriasis without arthritis (195·5±49·1 vs. 158·1±37·5 ng mL(-1), P=0·01). After 2 months of infliximab treatment a significant reduction of chemerin, resistin and CRP levels was observed.Patients with psoriasis have higher blood levels of adipokines, which normalize during therapy with infliximab. Whether this reduction is a direct effect of infliximab or secondary to a reduction of inflammation should be further investigated.
Impaired selection of invariant natural killer T cells in diverse mouse models of glycosphingolipid lysosomal storage diseases
Authors: Stephan D. Gadola, Jonathan D. Silk, Aruna Jeans, Petr A. Illarionov, Mariolina Salio, Gurdyal S. Besra, Raymond Dwek, Terry D. Butters, Frances M. Platt, Vincenzo Cerundolo
Journal: The Journal of Experimental Medicine (2006)

Glycolipid ligands for invariant natural killer T cells (iNKT cells) are loaded onto CD1d molecules in the late endosome/lysosome. Accumulation of glycosphingolipids (GSLs) in lysosomal storage diseases could potentially influence endogenous and exogenous lipid loading and/or presentation and, thus, affect iNKT cell selection or function. The percentages and frequency of iNKT cells were reduced in multiple mouse models of lysosomal GSL storage disease, irrespective of the specific genetic defect or lipid species stored. Reduced numbers of iNKT cells resulted in the absence of cytokine production in response to α-galactosylceramide (α-GalCer) and reduced iNKT cell–mediated lysis of wild-type targets loaded with α-GalCer. The reduction in iNKT cells did not result from defective expression of CD1d or a lack of antigen-presenting cells. Although H-2 restricted CD4+ T cell responses were generally unaffected, processing of a lysosome-dependent analogue of α-GalCer was impaired in all the strains of mice tested. These data suggest that GSL storage may result in alterations in thymic selection of iNKT cells caused by impaired presentation of selecting ligands.
Regulation of Vascular Smooth Muscle Cell Apoptosis
Authors: Hong-zhi Bai, Matthew J. Pollman, Yoji Inishi, Gary H. Gibbons
Journal: Circulation Research (1999)

Abstract —Our objective was to define the signaling mechanisms by which mitogens such as insulin-like growth factor-I (IGF-I) regulate vascular smooth muscle cell (VSMC) apoptosis. We confirmed that IGF-I inhibits serum withdrawal–induced apoptosis of cultured VSMCs in a dose-dependent and time-dependent fashion. To test the hypothesis that the phosphatidylinositol (PI) 3-kinase signaling pathway regulates VSMC survival, we examined the relationship between PI 3-kinase activity and cell fate. PI 3-kinase was elevated in viable VSMCs maintained in serum-containing medium, declined significantly in response to serum withdrawal, and increased in response to IGF-I–induced survival. Moreover, blockade of PI 3-kinase with 2 structurally dissimilar inhibitors (wortmannin or LY294002) abolished the capacity of IGF-I to maintain VSMC viability. Similarly, transient transfection of a dominant-negative Δp85 PI 3-kinase mutant construct abrogated the capacity of IGF-I to prevent VSMC death. Thus, PI 3-kinase is a critical antiapoptotic signal in VSMCs. To define the distal element of the antiapoptotic cascade, we tested the hypothesis that IGF-I inhibits the influence of the proapoptotic gene Bad. Indeed, IGF-I stimulates increased expression of the inactive, phosphorylated form of Bad by a PI 3-kinase–dependent pathway. Moreover, the proapoptotic effect of Bad was attenuated by the stimulation of IGF-I. Thus, growth factors appear to prevent VSMC death by activating signal transduction pathways linked to apoptotic regulatory genes.
Nocturnal non-invasive ventilation in addition to rehabilitation in hypercapnic patients with COPD
Authors: M L Duiverman, J B Wempe, G Bladder, D F Jansen, H A M Kerstjens, J G Zijlstra, P J Wijkstra
Journal: Thorax (2008)

<h3>Background:</h3> Long-term non-invasive positive pressure ventilation (NIPPV) might improve the outcomes of pulmonary rehabilitation in patients with chronic obstructive pulmonary disease (COPD) with chronic respiratory failure. A study was undertaken to investigate whether nocturnal NIPPV in addition to pulmonary rehabilitation improves health-related quality of life, functional status and gas exchange compared with pulmonary rehabilitation alone in patients with COPD with chronic hypercapnic respiratory failure. <h3>Methods:</h3> 72 patients with COPD were randomly assigned to nocturnal NIPPV in addition to rehabilitation (n = 37) or rehabilitation alone (n = 35). Outcome measures were assessed before and after the 3-month intervention period. <h3>Results:</h3> The Chronic Respiratory Questionnaire total score improved 15.1 points with NIPPV + rehabilitation compared with 8.7 points with rehabilitation alone. The difference of 7.5 points was not significant (p = 0.08). However, compared with rehabilitation alone, the difference in the fatigue domain was greater with NIPPV + rehabilitation (mean difference 3.3 points, p&lt;0.01), as was the improvement in the Maugeri Respiratory Failure questionnaire total score (mean difference −10%, p&lt;0.03) and its cognition domain (mean difference −22%, p&lt;0.01). Furthermore, the addition of NIPPV improved daytime arterial carbon dioxide pressure (mean difference −0.3 kPa; p&lt;0.01) and daily step count (mean difference 1269 steps/day, p&lt;0.01). This was accompanied by an increased daytime minute ventilation (mean difference 1.4 l; p&lt;0.001). <h3>Conclusion:</h3> Non-invasive ventilation augments the benefits of pulmonary rehabilitation in patients with COPD with chronic hypercapnic respiratory failure as it improves several measures of health-related quality of life, functional status and gas exchange. <h3>Trial registration number:</h3> NCT00135538.
Surfactant dysfunction makes lungs vulnerable to repetitive collapse and reexpansion.
Authors: V Taskar, J John, E Evander, B Robertson, B Jonson
Journal: American Journal of Respiratory and Critical Care Medicine (1997)

Reexpansion of collapsed lung creates intrapulmonary shear forces. In an earlier study we showed that application of a negative end-expiratory airway pressure (NEEP) to normal rabbit lungs in vivo produced tidal collapse and reexpansion with transient changes in compliance and gas exchange but no histologic damage. In the present study we examined NEEP in a model of surfactant perturbation produced by an inhaled aerosol of 2% and 5% dioctyl sodium sulfosuccinate (DOSS). DOSS increased alveolocapillary permeability without affecting compliance or oxygenation. Repeated collapse and reexpansion (RECOREX), caused by NEEP for 3 h was compared with ventilation with positive-end expiratory pressure (PEEP). Groups ventilated with PEEP maintained normal lung mechanics and morphology even if pretreated with DOSS. NEEP disturbed lung mechanics and gas exchange with persistent dose-related histologic damage in animals pretreated with DOSS. Lungs subjected to NEEP without DOSS had normal morphology. We conclude that perturbation of the surfactant system makes lungs vulnerable to injury by RECOREX. The combination of DOSS and NEEP might lead to leakage of plasma proteins into alveoli, causing inactivation of surfactants and increased shear forces with resulting lung damage. Similar mechanisms may accelerate lung damage in the respiratory distress syndrome.
Left vocal cord paralysis after mobilisation of the internal mammary artery.
Authors: R R Jeffry, B M Fabri, M A Fox
Journal: Thorax (1988)

A case of vocal cord paralysis following mobilisation of the internal mammary artery is described. Of the various possible mechanisms, the most likely in this case is damage to the vagus nerve in the root of the neck, where it passes close to the origin of the internal mammary artery. Diathermy may have caused the damage, and this may be avoided by using a disposable automatic clip applier on any branches of the mammary artery in the area.
Development and Validation of a New Adenosine-Independent Index of Stenosis Severity From Coronary Wave–Intensity Analysis
Authors: Sayan Sen, Javier Escaned, Iqbal S. Malik, Ghada W. Mikhail, Rodney A. Foale, Rafael Mila, Jason Tarkin, Ricardo Petraco, Christopher Broyd, Richard Jabbour, Amarjit Sethi, Christopher S. Baker, Micheal Bellamy, Mahmud Al-Bustami, David Hackett, Masood Khan, David Lefroy, Kim H. Parker, Alun D. Hughes, Darrel P. Francis, Carlo Di Mario, Jamil Mayet, Justin E. Davies
Journal: Journal of the American College of Cardiology (2011)

The purpose of this study was to develop an adenosine-independent, pressure-derived index of coronary stenosis severity.Assessment of stenosis severity with fractional flow reserve (FFR) requires that coronary resistance is stable and minimized. This is usually achieved by administration of pharmacological agents such as adenosine. In this 2-part study, we determine whether there is a time when resistance is naturally minimized at rest and assess the diagnostic efficiency, compared with FFR, of a new pressure-derived adenosine-free index of stenosis severity over that time.A total of 157 stenoses were assessed. In part 1 (39 stenoses), intracoronary pressure and flow velocity were measured distal to the stenosis; in part 2 (118 stenoses), intracoronary pressure alone was measured. Measurements were made at baseline and under pharmacologic vasodilation with adenosine.Wave-intensity analysis identified a wave-free period in which intracoronary resistance at rest is similar in variability and magnitude (coefficient of variation: 0.08 ± 0.06 and 284 ± 147 mm Hg s/m) to those during FFR (coefficient of variation: 0.08 ± 0.06 and 302 ± 315 mm Hg s/m; p = NS for both). The resting distal-to-proximal pressure ratio during this period, the instantaneous wave-free ratio (iFR), correlated closely with FFR (r = 0.9, p < 0.001) with excellent diagnostic efficiency (receiver-operating characteristic area under the curve of 93%, at FFR <0.8), specificity, sensitivity, negative and positive predictive values of 91%, 85%, 85%, and 91%, respectively.Intracoronary resistance is naturally constant and minimized during the wave-free period. The instantaneous wave-free ratio calculated over this period produces a drug-free index of stenosis severity comparable to FFR. (Vasodilator Free Measure of Fractional Flow Reserve [ADVISE]; NCT01118481).
Rabbit and rat C-reactive proteins bind apolipoprotein B-containing lipoproteins.
Authors: I F Rowe, A K Soutar, I M Trayner, M L Baltz, F C de Beer, L Walker, D Bowyer, J Herbert, A Feinstein, M B Pepys
Journal: The Journal of Experimental Medicine (1984)

Immobilized rabbit and rat C-reactive protein (CRP) were found to selectively bind apolipoprotein B (apoB)-containing lipoproteins (low density lipoprotein, LDL and very low density lipoprotein, VLDL) from whole serum in a manner similar to that previously reported with human CRP. In acute phase human serum the CRP is in a free form, not complexed with lipoprotein or any other macromolecular ligand, and in acute phase serum from most rabbits fed on a normal diet the rabbit CRP was also free. However, in acute phase serum or heparinized plasma from hypercholesterolemic rabbits part or all of the CRP was found by gel filtration and immunoelectrophoretic techniques to be complexed with beta-VLDL, an abnormal apoB-containing plasma lipoprotein present in these animals. The presence of extent in different serum samples of CRP complexed with lipoprotein correlated closely with the serum apoB concentration. The formation of complexes between native, unaggregated rabbit CRP in solution and apoB-containing lipoproteins was readily demonstrable experimentally both with the isolated proteins and in whole serum. In all cases these interactions were calcium-dependent and inhibitable by free phosphoryl choline. The present findings extend earlier work in man and the rabbit and indicate that among the C-reactive proteins from different species, which are structurally highly conserved, the capacity for selective binding to apoB-containing plasma lipoproteins is also a constant feature. These interactions may therefore be related to the in vivo function of CRP in all species and this function may in turn be relevant to pathological conditions, such as atherosclerosis, in which lipoproteins are important.