tbuckley/cabot-search huggingface dataset:
Myocardial Ischemia and Reperfusion Leads to Transient CD8 Immune Deficiency and Accelerated Immunosenescence in CMV-Seropositive Patients
Authors: Jedrzej Hoffmann, Evgeniya V. Shmeleva, Stephen E. Boag, Karel Fiser, Alan Bagnall, Santosh Murali, Ian Dimmick, Hanspeter Pircher, Carmen Martin-Ruiz, Mohaned Egred, Bernard Keavney, Thomas von Zglinicki, Rajiv Das, Stephen Todryk, Ioakim Spyridopoulos
Journal: Circulation Research (2014)

There is mounting evidence of a higher incidence of coronary heart disease in cytomegalovirus-seropositive individuals.The aim of this study was to investigate whether acute myocardial infarction triggers an inflammatory T-cell response that might lead to accelerated immunosenescence in cytomegalovirus-seropositive patients.Thirty-four patients with acute myocardial infarction undergoing primary percutaneous coronary intervention were longitudinally studied within 3 months after reperfusion (Cohort A). In addition, 54 patients with acute myocardial infarction and chronic myocardial infarction were analyzed in a cross-sectional study (Cohort B). Cytomegalovirus-seropositive patients demonstrated a greater fall in the concentration of terminally differentiated CD8 effector memory T cells (TEMRA) in peripheral blood during the first 30 minutes of reperfusion compared with cytomegalovirus-seronegative patients (-192 versus -63 cells/μL; P=0.008), correlating with the expression of programmed cell death-1 before primary percutaneous coronary intervention (r=0.8; P=0.0002). A significant proportion of TEMRA cells remained depleted for ≥3 months in cytomegalovirus-seropositive patients. Using high-throughput 13-parameter flow cytometry and human leukocyte antigen class I cytomegalovirus-specific dextramers, we confirmed an acute and persistent depletion of terminally differentiated TEMRA and cytomegalovirus-specific CD8(+) cells in cytomegalovirus-seropositive patients. Long-term reconstitution of the TEMRA pool in chronic cytomegalovirus-seropositive postmyocardial infarction patients was associated with signs of terminal differentiation including an increase in killer cell lectin-like receptor subfamily G member 1 and shorter telomere length in CD8(+) T cells (2225 versus 3397 bp; P<0.001).Myocardial ischemia and reperfusion in cytomegalovirus-seropositive patients undergoing primary percutaneous coronary intervention leads to acute loss of antigen-specific, terminally differentiated CD8 T cells, possibly through programmed cell death-1-dependent programmed cell death. Our results suggest that acute myocardial infarction and reperfusion accelerate immunosenescence in cytomegalovirus-seropositive patients.
Local genetic and environmental factors in asthma disease pathogenesis: chronicity and persistence mechanisms
Authors: S T Holgate, D E Davies, R M Powell, P H Howarth, H M Haitchi, J W Holloway
Journal: European Respiratory Journal (2007)

While asthma is an inflammatory disorder of the airways usually associated with atopy, an important additional component is involvement of the epithelium and underlying mesenchyme acting as a trophic unit (EMTU). In addition to allergens, a wide range of environmental factors interact with the EMTU, such as virus infections, environmental tobacco smoke and pollutants, to initiate tissue damage and aberrant repair responses that are translated into remodelling of the airways. While candidate gene association studies have revealed polymorphic variants that influence asthmatic inflammation, positional cloning of previously unknown genes is identifying a high proportion of novel genes in the EMTU. Dipeptidyl peptidase (DPP) 10 and disintegrin and metalloproteinase (ADAM)33 are newly identified genes strongly associated with asthma that are preferentially expressed in the airway epithelium and underlying mesenchyme, respectively. Also of increasing importance is the recognition that genes associated with asthma and atopy have important interactions with the environment through epigenetic mechanisms that influence their expression. This type of research will not only identify biomarkers of different types of asthma across the full range of phenotypic expression, but will also identify novel therapeutic targets that could influence the natural history of the heterogenes lung disease.
Early T-cell precursor leukaemia: a subtype of very high-risk acute lymphoblastic leukaemia
Authors: Elaine Coustan-Smith, Charles G Mullighan, Mihaela Onciu, Frederick G Behm, Susana C Raimondi, Deqing Pei, Cheng Cheng, Xiaoping Su, Jeffrey E Rubnitz, Giuseppe Basso, Andrea Biondi, Ching-Hon Pui, James R Downing, Dario Campana
Journal: The Lancet Oncology (2009)
Smoking and risk of cardiovascular disease
Authors: M J O'Donnell
Journal: BMJ (1993)

As the first line of defense in the immune system, neutrophils may release a variety of potent agents upon exposure to infectious agents. In this study we have investigated the ability of human neutrophils to produce chemotactic cytokines, or chemokine in response to EBV. Exposure of neutrophils to EBV led to an increase in accumulation of mRNA for IL-8 and macrophage inflammatory protein-1alpha (MIP-1alpha). EBV stimulated a time-dependent production of immunoreactive IL-8 and MIP-1alpha by neutrophils. The ability of EBV to stimulate the synthesis of IL-8 and MIP-1alpha protein was reflected by both an accumulation of the protein in the intracellular compartment as well as increased secretion. A variety of control studies support the idea that infectious EBV is not required for induction of chemokine gene expression; however, the response is dependent on the interaction between the glycoprotein gp350 of the viral envelope and the neutrophil surface. Since both IL-8 and MIP-1alpha are reported to be chemoattractants in vitro for T cells and for T and B cells, respectively, the ability of EBV to induce their production by neutrophils may enhance the ability of this virus to infect B and T lymphocytes via increased recruitment to sites of infection.
Changes in physical activity and all-cause mortality in COPD
Authors: Anouk W. Vaes, Judith Garcia-Aymerich, Jacob L. Marott, Marta Benet, Miriam T.J. Groenen, Peter Schnohr, Frits M.E. Franssen, Jørgen Vestbo, Emiel F.M. Wouters, Peter Lange, Martijn A. Spruit
Journal: European Respiratory Journal (2014)

Little is known about changes in physical activity in subjects with chronic obstructive pulmonary disease (COPD) and its impact on mortality. Therefore, we aimed to study changes in physical activity in subjects with and without COPD and the impact of physical activity on mortality risk. Subjects from the Copenhagen City Heart Study with at least two consecutive examinations were selected. Each examination included a self-administered questionnaire and clinical examination. 1270 COPD subjects and 8734 subjects without COPD (forced expiratory volume in 1 s 67±18 and 91±15% predicted, respectively) were included. COPD subjects with moderate or high baseline physical activity who reported low physical activity level at follow-up had the highest hazard ratios of mortality (1.73 and 2.35, respectively; both p<0.001). In COPD subjects with low baseline physical activity, no differences were found in survival between unchanged or increased physical activity at follow-up. In addition, subjects without COPD with low physical activity at follow-up had the highest hazard ratio of mortality, irrespective of baseline physical activity level (p≤0.05). A decline to low physical activity at follow-up was associated with an increased mortality risk in subjects with and without COPD. These observational data suggest that it is important to assess and encourage physical activity in the earliest stages of COPD in order to maintain a physical activity level that is as high as possible, as this is associated with better prognosis.
Protection by superoxide dismutase from myocardial dysfunction and attenuation of vasodilator reserve after coronary occlusion and reperfusion in dog.
Authors: J L Mehta, W W Nichols, W H Donnelly, D L Lawson, L Thompson, M ter Riet, T G Saldeen
Journal: Circulation Research (1989)

Previous studies indicate impairment of coronary arterial ring relaxation and loss of coronary vasodilator reserve after coronary artery occlusion and reperfusion. These changes are mediated in part through loss of endothelium-derived relaxing factor (EDRF) and/or myocardial neutrophil accumulation. To examine if superoxide dismutase (SOD), a scavenger of superoxide radicals, would modify the diminished coronary vasodilator reserve after temporary coronary occlusion in the intact animal, open-chest mongrel dogs were subjected to 1 hour of circumflex (Cx) coronary artery occlusion followed by 1 hour of reperfusion and treated with saline or SOD. Before Cx occlusion, coronary blood flow increased, and vascular resistance decreased (both p less than 0.01) in response to EDRF-dependent vasodilator acetylcholine as well as EDRF-independent vasodilator nitroglycerin. After Cx reperfusion, resting Cx coronary blood flow and vascular resistance were similar to the preocclusion values. In the saline-treated animals, there was evidence of myocardial dysfunction, which was measured by segmental shortening (-6 +/- 2% vs. 10 +/- 2%). Furthermore, increase in Cx coronary blood flow and reduction in vascular resistance in response to both vasodilators were significantly (p less than 0.01) impaired; these occurrences suggested loss of coronary vasodilator reserve. Myocardial histology showed extensive capillary plugging by neutrophils in the Cx-supplied myocardium. Myocardial myeloperoxidase activity, an index of neutrophil infiltration, was also increased in the Cx compared with the left anterior descending coronary artery region (p less than 0.02). Treatment of dogs with SOD, started at the end of Cx occlusion and continued during reperfusion, exerted significant (p less than 0.01) protective effect against reperfusion-induced attenuation of coronary vasodilator reserve in response to both acetylcholine and nitroglycerin. Loss of myocardial function (segmental shortening 5 +/- 1% vs. 10 +/- 1%) was less than in the saline-treated animals (p less than 0.01). Cx region-myocardial neutrophil accumulation and myeloperoxidase activity were also less (p less than 0.02) in the SOD-treated than in the saline-treated dogs. These observations suggest that coronary reperfusion impairs coronary vasodilator reserve in intact dogs. This impairment can be modified by treatment of animals with SOD before reperfusion. Capillary plugging by neutrophils may contribute to the altered coronary vasodilator reserve observed in the immediate postreperfusion period, and SOD modifies this reperfusion-induced impairment.
Identification of two alternatively spliced forms of Human Tubulointerstitial Nephritis Antigen (TIN-Ag)
Authors: BING ZHOU, TODD R. NELSON, CLIFFORD KASHTAN, BILL GLEASON, ALFRED F. MICHAEL, METAXIA VLASSI, ARISTIDIS S. CHARONIS
Journal: Journal of the American Society of Nephrology (2000)

Abstract. Tubulointerstitial nephritis antigen (TIN-Ag) is a recently described basement membrane glycoprotein reactive with autoantibodies in some forms of immunologically mediated human tubulointerstitial nephritis. This report presents the complete cDNA and predicted amino acid sequences of two human TIN-Ag mRNA species referred to as TIN1 and TIN2. Translation through the open reading frames of these clones indicates the presence of a signal peptide and putative prepropeptide. TIN1 additionally contains a characteristic laminin-like epidermal growth factor (EGF) motif and significant homology within the carboxy terminus with the cysteine proteinase family of enzymes. The EGF motif bears important similarities in the positions of cysteines with two motifs in the propeptide of von Willebrand factor. The EGF motif and part of the region that is homologous with the cysteine proteinase family are removed from the TIN2 cDNA. However, the rest of the sequence is identical in these two forms, indicating an alternatively spliced TIN-Ag mRNA product. Both forms contain putative calcium-binding sites. Secondary structure predictions strongly suggest differences between TIN1 and TIN2 leading to the hypothesis that these two forms of TIN-Ag may exhibit differences in their function. Expression studies with appropriate probes demonstrate expression mainly in the kidney and in the intestinal epithelium and lack of expression in other tissues. In the kidney, both TIN1 and TIN2 transcripts are detected, however, TIN1 appears to be the predominant form.
A randomised prospective comparison of the Flamingo Wallstent and Ultraflex stent for palliation of dysphagia associated with lower third oesophageal carcinoma
Authors: T Sabharwal
Journal: Gut (2003)

<b>Background:</b> Covered metallic oesophageal stents offer effective palliation of malignant oesophageal strictures. However, first generation devices were associated with a high rate of migration, particularly when used in the lower oesophagus. <b>Aim:</b> To compare the rate of complications and palliative effect of two newer covered metallic oesophageal stents. <b>Patients and methods:</b> We performed a prospective randomised study using two of these newer stent designs in the treatment of malignant lower third oesophageal tumours. Fifty three patients with dysphagia due to inoperable oesophageal carcinoma involving the lower third of the oesophagus were randomly selected to receive either a Flamingo covered Wallstent (Boston Scientific Inc., Watertown, Massachusetts, USA) or an Ultraflex covered stent (Boston Scientific Inc.). Dysphagia was scored on a five point scale, recorded before stent insertion, the day after, and at least one month later at follow up. Technical success, early and late complications (perforation, migration, severe gastro-oesophageal reflux, haematemesis, and reobstruction due to tumour overgrowth) were also recorded. <b>Results:</b> In both stent groups, a significant improvement in dysphagia score was seen both the next day post stenting and at late follow up (p&lt;0.05). No significant difference was seen in the improvement in dysphagia between the two groups (p&gt;0.1). The frequency of complications encountered in the two groups was similar. Three patients in the Ultraflex group required two stents at primary stenting. <b>Conclusion:</b> The two types of stent are equally effective in the palliation of dysphagia associated with lower third oesophageal malignancy and the complication rates associated with their use are comparable.
Role of Tissue Renin in the Regulation of Aldosterone Biosynthesis in the Adrenal Cortex of Nephrectomized Rats
Authors: Massimo Volpe, Bruna Gigante, Iolanda Enea, Antonio Porcellini, Rosaria Russo, Min Ae Lee, Paola Magri, Gerolama Condorelli, Carmine Savoia, Klaus Lindpaintner, Speranza Rubattu
Journal: Circulation Research (1997)

The aim of the study was to investigate whether the adrenal renin-angiotensin system plays an independent role in the regulation of mineralocorticoid biosynthesis in the adrenal gland and to explore the mechanisms of this action. Twelve-week-old male Sprague-Dawley rats were studied: 22 rats were maintained on a regular diet; 27 and 22 rats received a low salt diet with and without treatment, respectively, with the angiotensin II (Ang II) AT1-subtype receptor antagonist losartan (10 mg/kg per day). A fraction of each group of rats underwent bilateral nephrectomy (n = 12, 15, and 10, respectively) and was killed 48 hours later. In an additional group of 24 (12 intact and 12 nephrectomized) rats, the effects of the Ang II AT2-subtype receptor antagonist PD123319 were investigated. In intact rats, plasma renin activity (PRA) and adrenal renin activity and expression were progressively raised by salt restriction and losartan, whereas aldosterone synthase mRNA and plasma aldosterone (PA) levels were increased by salt restriction and reduced by losartan. Forty-eight hours after nephrectomy, PRA fell to undetectable levels; in contrast, adrenal renin expression, assessed by semiquantitative reverse-transcriptase polymerase chain reaction (using GAPDH as a standard for gene expression), showed an 18-fold increase and was further increased after salt restriction and losartan (all P < .05). Also, adrenal renin activity was raised after nephrectomy and further increased after salt restriction (P < .05) and losartan. Cytochrome P450 aldosterone synthase expression in the adrenal cortex was stimulated by nephrectomy alone and by nephrectomy combined with low salt intake (P < .05), with consequent increases in PA concentrations. In losartan-treated salt-restricted nephrectomized rats, cytochrome P450 aldosterone synthase expression (P < .05 versus nephrectomy alone and nephrectomy plus salt restriction) and PA concentrations were diminished (P < .05) in spite of the observed increases of adrenal renin expression. The AT2-receptor antagonism did not significantly affect PRA, adrenal renin, and aldosterone biosynthesis and production in either intact or nephrectomized salt-restricted rats. These results demonstrate that the adrenal renin-angiotensin system plays an independent role in the regulation of mineralocorticoid biosynthesis in vivo. This action is mediated primarily via the Ang II AT1-subtype receptors.
Nadolol plus isosorbide mononitrate alone or associated with band ligation in the prevention of recurrent bleeding: a multicentre randomised controlled trial
Authors: J. C. Garcia-Pagan, C. Villanueva, A. Albillos, R. Banares, R. Morillas, J. G. Abraldes, J. Bosch
Journal: Gut (2009)

<h3>Background and aims:</h3> Previous clinical trials suggest that adding non-selective beta-blockers improves the efficacy of endoscopic band ligation (EBL) in the prevention of recurrent bleeding, but no study has evaluated whether EBL improves the efficacy of beta-blockers + isosorbide-5-mononitrate. The present study was aimed at evaluating this issue in a multicentre randomised controlled trial (RCT) and to correlate changes in hepatic venous pressure gradient (HVPG) during treatment with clinical outcomes <h3>Methods:</h3> 158 patients with cirrhosis, admitted because of variceal bleeding, were randomised to receive nadolol+isosorbide-5-mononitrate alone (Drug: n = 78) or combined with EBL (Drug+EBL; n = 80). HVPG measurements were performed at randomisation and after 4–6 weeks on medical therapy. <h3>Results:</h3> Median follow-up was 15 months. One-year probability of recurrent bleeding was similar in both groups (33% vs 26%: p = 0.3). There were no significant differences in survival or need of rescue shunts. Overall adverse events or those requiring hospital admission were significantly more frequent in the Drug+EBL group. Recurrent bleeding was significantly more frequent in HVPG non-responders than in responders (HVPG reduction ⩾20% or ⩽12 mm Hg). Among non-responders recurrent bleeding was similar in patients treated with Drugs or Drugs+EBL. <h3>Conclusions:</h3> Adding EBL to pharmacological treatment did not reduce recurrent bleeding, the need for rescue therapy, or mortality, and was associated with more adverse events. Furthermore, associating EBL to drug therapy did not reduce the high rebleeding risk of HVPG non-responders. <h3></h3> ISRCTN26221020
Practical management of perinatal death.
Authors: G C Forrest, R S Claridge, J D Baum
Journal: BMJ (1981)

After the loss of a newborn baby the parents are usually too shocked and unfamiliar with the complicated administration procedures to cope with the registration of death and burial (or cremation). The medical and nursing staff also tend to be unfamiliar with the procedures. Some of these can be streamlined, thus reducing the stress caused to parents. By giving positive instruction the staff will in their turn be able to improve their care of the bereaved parents.
Silencing RNA: a novel treatment for pancreatic cancer?
Authors: N R Lemoine
Journal: Gut (2005)

The high sequence specificity of RNA interference may make it suitable to treat diseases that are linked to selective or elevated expression of particular identified genes, such as in pancreatic cancer

The antiapoptotic gene Bcl-2 has been a target for downregulation by nucleic acid based strategies for more than a decade but the recent failure of the synthetic antisense oligonucleotide agent Genasense in phase III clinical trial caused many to think again about the worth of this approach. However, a new optimism about this and other targets is spreading through the community following several encouraging applications of the recently discovered technology of RNA interference, which is essentially a new biological version of the antisense system.1

RNA interference is considered to have begun as an evolutionarily ancient mechanism for protecting organisms from viruses. Many viruses have RNA, rather than DNA, as their genetic material and go through at least one stage in their life cycle in which they make double stranded RNA. Perhaps not surprisingly, all multicellular organisms have evolved a well conserved protein apparatus that destroys double stranded RNA but this has also been found to play a role in maintenance of the organism’s own genome stability by suppressing the movement of mobile genetic elements, such as transposons and repetitive sequences.

The gene silencing process of RNA interference (RNAi) involves the manufacture of short double stranded RNA molecules by an enzyme called DICER, which cleaves RNA duplexes into 21–26 base pair oligomers. These small interfering …
Lyn, Jak2, and Raf-1 Kinases Are Critical for the Antiapoptotic Effect of Interleukin 5, whereas only Raf-1 Kinase Is Essential for Eosinophil Activation and Degranulation
Authors: Konrad Pazdrak, Barbara Olszewska-Pazdrak, Susan Stafford, Roberto P. Garofalo, Rafeul Alam
Journal: The Journal of Experimental Medicine (1998)

Interleukin (IL)-5 has been shown to activate many signaling molecules in eosinophils, but their functional relevance remains unknown. We have examined the functional relevance of Lyn, Jak2, and Raf-1 kinases in eosinophil survival, upregulation of adhesion molecules and degranulation. To this goal we used Lyn and Raf-1 antisense (AS) oligodeoxynucleotides (ODN) to inhibit the expression of these proteins and tyrphostin AG490 to specifically block the activation of Jak2. We have demonstrated that all three kinases are important for IL-5– induced suppression of eosinophil apoptosis. However, Lyn and Jak2 tyrosine kinases are not important for the upregulation of CD11b and the secretion of eosinophil cationic protein. In contrast, Raf-1 kinase is critical for both these functions. This is the first identification of specific signaling molecules responsible for three important functions of eosinophils. We have established a central role for Raf-1 kinase in regulating eosinophil survival, expression of β2 integrins and degranulation. Further, there appears to be a dissociation between two receptor-associated tyrosine kinases, i.e., Lyn and Jak2, and the activation of Raf-1 kinase. The delineation of the functional relevance of signaling molecules will help design therapeutic approaches targeting specific eosinophil function.