tbuckley/cabot-search huggingface dataset:
Activation of human dendritic cells through CD40 cross-linking.
Authors: C Caux, C Massacrier, B Vanbervliet, B Dubois, C Van Kooten, I Durand, J Banchereau
Journal: The Journal of Experimental Medicine (1994)

Dendritic cells, the professional antigen-presenting cells (APC) involved in T cell priming, express CD40, a molecule which triggering plays a key role in B cell growth and differentiation as well as monocyte activation. Herein we demonstrate that dendritic Langerhans cells (D-Lc) generated by culturing cord blood CD34+ progenitor cells with granulocyte/macrophage colony-stimulating and tumor necrosis factor alpha (TNF-alpha) express functional CD40 at a density higher than that found on B cells. Culturing D-Lc on CD40-ligand (CD40L) transfected L cells allowed D-Lc survival as 50 +/- 15% of seeded cells were recovered after 4 d while only 5% survived over control L cells. CD40 activation induced important morphological changes with a reduction of cytoplasmic content and a remarkable increase of dendrite development as well as an altered phenotype. In particular, CD40 triggering induced maintenance of high levels of major histocompatibility complex class II antigens and upregulation of accessory molecules such as CD58, CD80 (B7-1) and CD86 (B7-2). CD40 engagement also seems to turn on D-Lc maturation as illustrated by upregulation of CD25, a molecule usually expressed on interdigitating dendritic cells of secondary lymphoid organs. Finally, CD40 activated D-Lc secreted a limited set of cytokines (TNF-alpha, IL-8, and macrophage inflammatory protein 1 alpha [MIP-1 alpha]) whereas a similar activation induced elutriated monocytes to secrete IL-1 alpha, IL-1 beta, IL-6, IL-8, IL-10, TNF-alpha, and MIP-1 alpha. As D-Lc activated T cells upregulated CD40L, it is likely that CD40 activation of D-Lc observed herein with a fibroblast cell line stably expressing CD40L, mimics physiological interactions between dendritic cells and T cells.
The G proteins of the G alpha i and G alpha q family couple the bradykinin receptor to the release of endothelium-derived relaxing factor.
Authors: J K Liao, C J Homcy
Journal: Journal of Clinical Investigation (1993)

Bradykinin stimulates diverse functions in endothelial cells including the release of endothelium-derived relaxing factor (EDRF). Little is known, however, regarding the identity of the G protein(s) involved. Here we demonstrate that G proteins of the G alpha i and G alpha q family are coupled to the bradykinin receptor (BKR) in bovine aortic endothelial cells by using specific antisera directed against the COOH-terminal region of G alpha i2 (P4), G alpha i3 (EC), and G alpha q (QL). These antisera are specific since their effects are blocked by the decapeptides from which they were derived. The degree of receptor-G protein coupling was assessed by the formation of high affinity agonist binding sites (HABS) and GTP hydrolysis. In a concentration-dependent manner, the QL antisera reduced HABS and GTPase activity by 65 and 60%, respectively, and effectively abolished them in membranes from pertussis toxin-treated cells. The combination of P4 and EC antisera produced a loss of HABS (41%) and GTPase activity (40%) comparable to the effects of pertussis toxin. These findings indicate that G alpha i and G alpha q proteins mediate the cellular responses to bradykinin in bovine aortic endothelial cells and support the observation that bradykinin-stimulated EDRF release is relatively insensitive to pertussis toxin.
Designing Inhibitors of Cyclin-Dependent Kinases
Authors: Ian R. Hardcastle, Bernard T. Golding, Roger J. Griffin
Journal: The Annual Review of Pharmacology and Toxicology (2002)

Cyclin-dependent kinases (cdks) play a pivotal role in controlling progression through the cell cycle. The complex mechanisms that control cdks have been elucidated and, in the case of cdk2, explained with reference to X-ray crystal structures of the catalytically active and inactive kinase. Deregulation of the cell cycle is commonly observed in cancer, so cdks are potential targets for experimental therapeutic agents. A number of distinct structural classes of cdk inhibitors have been discovered. Good selectivity among these ATP competitive inhibitors for cdks over other kinases has been established, and selectivity between individual cdks is often observed. The crystal structures of a number of key inhibitors bound to cdk2 can be used to explain the observed structure-activity relationships within the compound series and to guide the design of more potent inhibitors.
Oxygen cycling in conjunction with stem cell transplantation induces NOS3 expression leading to attenuation of fibrosis and improved cardiac function
Authors: Mahmood Khan, Sarath Meduru, Rajan Gogna, Esha Madan, Lucas Citro, Muthulakshmi L. Kuppusamy, Muzzammil Sayyid, Mahmoud Mostafa, Robert L. Hamlin, Periannan Kuppusamy
Journal: Cardiovascular Research (2011)

Myocardial infarction (MI) is associated with irreversible loss of viable cardiomyocytes. Cell therapy is a potential option to replace the lost cardiomyocytes and restore cardiac function. However, cell therapy is faced with a number of challenges, including survival of the transplanted cells in the infarct region, which is characterized by abundant levels of oxidants and lack of a pro-survival support mechanism. The goal of the present study was to evaluate the effect of supplemental oxygenation on cell engraftment and functional recovery in a rat model. MI was induced in rats by a 60-min occlusion of the coronary artery, followed by restoration of flow. Mesenchymal stem cells (MSCs), isolated from adult rat bone marrow, were transplanted in the MI region. Rats with transplanted MSCs were exposed to hyperbaric oxygen (HBO: 100% O2, 2 atmospheres absolute) for 90 min, 5 days/week for 4 weeks. The experimental groups were: MI (control), Ox (MI + HBO), MSC (MI + MSC), and MSC + Ox (MI + MSC + HBO). HBO exposure (oxygenation) was started 3 days after induction of MI. MSCs were transplanted 1 week after induction of MI. Echocardiography showed a significant recovery of cardiac function in the MSC + Ox group, when compared with the MI or MSC group. Oxygenation increased the engraftment of MSCs and vascular density in the infarct region. Molecular analysis of infarct tissue showed a four-fold increase in NOS3 expression in the MSC + Ox group compared with the MI group. The results showed that post-MI exposure of rats to daily cycles of hyperoxygenation (oxygen cycling) improved stem cell engraftment, cardiac function, and increased NOS3 expression.
Broken necks in passengers in London taxi accidents.
Authors: P G Richards, H A Crockard
Journal: BMJ (1986)

Broken necks in passengers in London taxi accidents Travelling by London taxi cab is considered to be safe.We present two cases of odontoid fracture as a result of taxi accidents. Case historiesCase 1-A 62 year old woman was a passenger in the back of a London taxi which collided with another car.She was thrown forward and hit her head on the partition between the passengers' and driver's compartments.She immediately experienced severe neck pain aggravated by movement.Examination showed occipital bruising, torticollis, and spasm of the neck muscles.No pharyngeal swelling or abnormal neurological signs were detected.Cervical radiographs showed an undisplaced fracture at the base of the odontoid peg.She was placed in a Plastazote collar, which eased her pain.The fracture healed spontaneously.Case 2-A 55 year old man was in the back of a cab when it was in a collision.He struck the left side ofhis head on the partition.Within two hours he developed severe neck pain.Examination showed torticollis, spasm ofthe neck muscles, but no abnormal neurological signs.He was placed in a conventional soft collar.His
Comprehensive screening for a complete set of Japanese‐population‐specific filaggrin gene mutations
Authors: M. Kono, T. Nomura, Y. Ohguchi, O. Mizuno, S. Suzuki, H. Tsujiuchi, N. Hamajima, W. H. I. McLean, H. Shimizu, M. Akiyama
Journal: Allergy (2014)

Abstract Mutations in FLG coding profilaggrin cause ichthyosis vulgaris and are an important predisposing factor for atopic dermatitis. Until now, most case–control studies and population‐based screenings have been performed only for prevalent mutations. In this study, we established a high‐throughput FLG mutation detection system by real‐time PCR with a set of two double‐dye probes and conducted comprehensive screening for almost all of the Japanese‐population‐specific FLG mutations (ten FLG mutations). The present comprehensive screening for all ten FLG mutations provided a more precise prevalence rate for FLG mutations (11.1%, n = 820), which seemed high compared with data of previous reports based on screening for limited numbers of FLG mutations. Our comprehensive screening suggested that population‐specific FLG mutations may be a significant predisposing factor for hay fever (odds ratio = 2.01 [95% CI : 1.027–3.936, P &lt; 0.05]), although the sample sizes of this study were too small for reliable subphenotype analysis on the association between FLG mutations and hay fever in the eczema patients and the noneczema individuals, and it is not clear whether the association between FLG mutations and hay fever is due to the close association between FLG mutations and hay fever patients with eczema.
Methotrexate, cyclosporine, or both to prevent graft-versus-host disease after HLA-identical sibling bone marrow transplants for early leukemia?
Authors: O Ringden, MM Horowitz, P Sondel, RP Gale, JC Biggs, RE Champlin, HJ Deeg, K Dicke, T Masaoka, RL Powles
Journal: Blood (1993)
Increased endothelin-1 production in fibroblasts derived from patients with systemic sclerosis.
Authors: Y Kawaguchi, K Suzuki, M Hara, T Hidaka, T Ishizuka, M Kawagoe, H Nakamura
Journal: Annals of the Rheumatic Diseases (1994)

To determine whether fibroblasts from patients with systemic sclerosis (SSc) produce excessive amounts of endothelin-1 (ET-1), which is recognised as having vasoconstrictive properties and as having a potent mitogenic effect on fibroblasts.Dermal fibroblasts were removed from 11 patients with SSc and from five normal controls (NC). The assay of ET-1 protein was measured by an ELISA that used two anti-ET-1 antibodies. The gene expression of prepro ET-1 mRNA was evaluated by a reverse-transcriptase polymerase chain reaction (RT-PCR) method.Levels of ET-1 protein were significantly higher in SSc fibroblast cultures than in those of normal fibroblasts (p < 0.01). The expression of prepro ET-1 mRNA was also higher in SSc fibroblasts than in normal fibroblasts. The addition of interleukin-1 beta (IL-1 beta) increased the production of ET-1 by fibroblasts.The findings indicate that the overproduction of ET-1 is a novel abnormal function in SSc fibroblasts, and that ET-1 induced by fibroblasts may play a role in the fibrosis and Raynaud's phenomenon of SSc.
Inhibition of Phosphatidylinositol 3′-Kinase/AKT Signaling Promotes Apoptosis of Primary Effusion Lymphoma Cells
Authors: Shahab Uddin, Azhar R. Hussain, Khaled A. Al-Hussein, Pulicat S. Manogaran, Amitha Wickrema, Marina I. Gutierrez, Kishor G. Bhatia
Journal: Clinical Cancer Research (2005)

Phosphatidylinositol 3'-kinase (PI3'-kinase) can be activated by the K1 protein of Kaposi sarcoma-associated herpes virus (KSHV). However, the role of PI3'-kinase in KSHV-associated primary effusion lymphoma (PEL) is not known. To assess this, we studied survival and apoptosis in PEL cell lines following inhibition of PI3'-kinase.Constitutive activation of several targets of PI3-kinase and apoptotic proteins were determined by Western blot analysis using specific antibodies. We used LY294002 to block PI3'-kinase/AKT activation and assess apoptosis by flow cytometric analysis.Blocking PI3'-kinase induced apoptosis in PEL cells, including BC1, BC3, BCBL1, and HBL6, whereas BCP1 was refractory to LY294002-induced apoptosis. LY294002-induced apoptosis did not seem to involve Fas/Fas-L but had an additive effect to CH11-mediated apoptosis. We also show that AKT/PKB is constitutively activated in all PELs and treatment with LY294002 causes complete dephosphorylation in all cell lines except BCP1 where a residual AKT phosphorylation remained after 24 hours of treatment. FKHR and GSK3 were also constitutively phosphorylated in PELs and treatment with LY294002 caused their dephosphorylation. Although inhibition of PI3'-kinase induced cleavage of BID in all cell lines, cytochrome c was released from the mitochondria and caspase-9 and caspase-3 were activated in LY294002-induced apoptotic BC1 but not in resistant BCP1. Similarly, XIAP, a target of AKT, was down-regulated after LY294002 treatment only in sensitive PEL cells.Our data show that the PI3'-kinase pathway plays a major role in survival of PEL cells and suggest that this cascade may be a promising target for therapeutic intervention in primary effusion lymphomas.
Treating inguinal hernias
Authors: Emilie ⊘berg, Jacob Rosenberg
Journal: BMJ (2004)

Editor—In his editorial Kingsnorth argues that open inguinal hernia repair with the Lichtenstein method is superior to the laparoscopic approach.1 We think that this is not the whole story.

In a recent Cochrane review six visceral and seven vascular injuries (in 2498 patients) were reported in the laparoscopic group compared with one and five (in 2758 patients) in the open group.2 In the laparoscopic group the convalescence was significantly shorter than after open surgery (7 days, P < 0.001). Furthermore, and probably most importantly, the review found a significant reduction in the rate of chronic groin pain (290/2101 v 459/2399, P < 0.001) after laparoscopic repair, with no difference in recurrence rates after the two procedures.

Although the direct cost of the laparoscopic technique is higher, this difference is eliminated by recommending a convalescence of one week only.3

Kingsnorth's concern about the complex nature of the laparoscopic procedure is legitimate, but, as the learning curve is 30-50 operations,4 this problem can be solved by establishing dedicated centres for laparoscopic hernia repair, as is commonly done in many countries when the Lichtenstein procedure is the preferred method.

Laparoscopic hernia repair is not a dangerous procedure. The learning curve can be facilitated by establishing laparoscopic hernia centres, and the cost can be reduced effectively and equalised with the open procedure. Most importantly, laparoscopic hernia repair is followed by much less pain, and this must be one of the top priorities of a responsible surgeon.
Educational and Occupational Achievement in Primary Affective Disorder
Authors: ROBERT A. WOODRUFF, LEE N. ROBINS, GEORGE WINOKUR, BONNIE WALBRAN
Journal: American Journal of Psychiatry (1968)

There are suggestions in the literature on primary affective disorder of an association between the illness and occupational or educational achievement. To test this hypothesis the authors studied 100 patients with primary affective disorder, comparing their occupational and educational achievements with those of their same-sexed siblings. The data provided no clear evidence that persons suffering from primary affective disorder demonstrate unexpectedly high occupational or educational achievement, or that they show impaired occupational or educational achievement as a result of their illness.
A large lung gene expression study identifying fibulin-5 as a novel player in tissue repair in COPD
Authors: Corry-Anke Brandsma, Maarten van den Berge, Dirkje S Postma, Marnix R Jonker, Sharon Brouwer, Peter D Paré, Don D Sin, Yohan Bossé, Michel Laviolette, Juha Karjalainen, Rudolf S N Fehrmann, David C Nickle, Ke Hao, Anita I R Spanjer, Wim Timens, Lude Franke
Journal: Thorax (2014)

<h3>Background</h3> Chronic obstructive pulmonary disease (COPD) is a progressive, incurable lung disease characterised by abnormal tissue repair causing emphysema and small airways fibrosis. Since current therapy cannot modify this abnormal repair, it is crucial to unravel its underlying molecular mechanisms. Unbiased analysis of genome-wide gene expression profiles in lung tissue provides a powerful tool to investigate this. <h3>Methods</h3> We performed genome-wide gene expression profiling in 581 lung tissue samples from current and ex-smokers with (n=311) and without COPD (n=270). Subsequently, quantitative PCR, western blot and immunohistochemical analyses were performed to validate our main findings. <h3>Results</h3> 112 genes were found to be upregulated in patients with COPD compared with controls, whereas 61 genes were downregulated. Among the most upregulated genes were fibulin-5 (<i>FBLN5</i>), elastin (<i>ELN</i>), latent transforming growth factor β binding protein 2 (<i>LTBP2</i>) and microfibrillar associated protein 4 (<i>MFAP4</i>), all implicated in elastogenesis. Our gene expression findings were validated at mRNA and protein level. We demonstrated higher <i>ELN</i> gene expression in COPD lung tissue and similar trends for <i>FBLN5</i> and <i>MFAP4</i>, and negative correlations with lung function. FBLN5 protein levels were increased in COPD lung tissue and cleaved, possibly non-functional FBLN5 protein was present. Strong coexpression of <i>FBLN5</i>, <i>ELN</i>, <i>LTBP2</i> and <i>MFAP4</i> in lung tissue and in silico analysis indicated cofunctionality of these genes. Finally, colocalisation of FBLN5, MFAP4 and LTBP2 with elastic fibres was demonstrated in lung tissue. <h3>Conclusions</h3> We identified a clear gene signature for elastogenesis in COPD and propose FBLN5 as a novel player in tissue repair in COPD.
Reduction of postoperative mortality and morbidity with epidural or spinal anaesthesia: results from overview of randomised
Authors: A. Rodgers
Journal: BMJ (2000)

<h3>Abstract</h3> <b>Objectives:</b> To obtain reliable estimates of the effects of neuraxial blockade with epidural or spinal anaesthesia on postoperative morbidity and mortality. <b>Design:</b> Systematic review of all trials with randomisation to intraoperative neuraxial blockade or not. <b>Studies:</b> 141 trials including 9559 patients for which data were available before 1 January 1997. Trials were eligible irrespective of their primary aims, concomitant use of general anaesthesia, publication status, or language. Trials were identified by extensive search methods, and substantial amounts of data were obtained or confirmed by correspondence with trialists. <b>Main outcome measures:</b> All cause mortality, deep vein thrombosis, pulmonary embolism, myocardial infarction, transfusion requirements, pneumonia, other infections, respiratory depression, and renal failure. <b>Results:</b> Overall mortality was reduced by about a third in patients allocated to neuraxial blockade (103 deaths/4871 patients versus 144/4688 patients, odds ratio=0.70, 95% confidence interval 0.54 to 0.90, P=0.006). Neuraxial blockade reduced the odds of deep vein thrombosis by 44%, pulmonary embolism by 55%, transfusion requirements by 50%, pneumonia by 39%, and respiratory depression by 59% (all P&lt;0.001). There were also reductions in myocardial infarction and renal failure. Although there was limited power to assess subgroup effects, the proportional reductions in mortality did not clearly differ by surgical group, type of blockade (epidural or spinal), or in those trials in which neuraxial blockade was combined with general anaesthesia compared with trials in which neuraxial blockade was used alone. <b>Conclusions:</b> Neuraxial blockade reduces postoperative mortality and other serious complications. The size of some of these benefits remains uncertain, and further research is required to determine whether these effects are due solely to benefits of neuraxial blockade or partly to avoidance of general anaesthesia. Nevertheless, these findings support more widespread use of neuraxial blockade.
Comparison of CT colonography, colonoscopy, sigmoidoscopy and faecal occult blood tests for the detection of advanced adenoma in an average risk population
Authors: A Graser, P Stieber, D Nagel, C Schafer, D Horst, C R Becker, K Nikolaou, A Lottes, S Geisbusch, H Kramer, A C Wagner, H Diepolder, J Schirra, H J Roth, D Seidel, B Goke, M F Reiser, F T Kolligs
Journal: Gut (2008)

<h3>Background and aims:</h3> This prospective trial was designed to compare the performance characteristics of five different screening tests in parallel for the detection of advanced colonic neoplasia: CT colonography (CTC), colonoscopy (OC), flexible sigmoidoscopy (FS), faecal immunochemical stool testing (FIT) and faecal occult blood testing (FOBT). <h3>Methods:</h3> Average risk adults provided stool specimens for FOBT and FIT, and underwent same-day low-dose 64-multidetector row CTC and OC using segmentally unblinded OC as the standard of reference. Sensitivities and specificities were calculated for each single test, and for combinations of FS and stool tests. CTC radiation exposure was measured, and patient comfort levels and preferences were assessed by questionnaire. <h3>Results:</h3> 221 adenomas were detected in 307 subjects who completed CTC (mean radiation dose, 4.5 mSv) and OC; 269 patients provided stool samples for both FOBT and FIT. Sensitivities of OC, CTC, FS, FIT and FOBT for advanced colonic neoplasia were 100% (95% CI 88.4% to 100%), 96.7% (82.8% to 99.9%), 83.3% (95% CI 65.3% to 94.4%), 32% (95% CI 14.9% to 53.5) and 20% (95% CI 6.8% to 40.7%), respectively. Combination of FS with FOBT or FIT led to no relevant increase in sensitivity. 12 of 45 advanced adenomas were smaller than 10 mm. 46% of patients preferred CTC and 37% preferred OC (p&lt;0.001). <h3>Conclusions:</h3> High-resolution and low-dose CTC is feasible for colorectal cancer screening and reaches sensitivities comparable with OC for polyps &gt;5 mm. For patients who refuse full bowel preparation and OC or CTC, FS should be preferred over stool tests. However, in cases where stool tests are performed, FIT should be recommended rather than FOBT.
Susceptibility to primary biliary cirrhosis is associated with the HLA-DR8-DQB1*0402 haplotype
Authors: James Underhill, Peter Donaldson, Gary Bray, Derek Doherty, Bernard Portmann, Roger Williams
Journal: Hepatology (1992)

In studies to date seeking associations between human leukocyte antigens (HLA) and primary biliary cirrhosis, no class I association but several different class II associations have been described. The aims of this study were to reassess the DR associations in primary biliary cirrhosis and to examine for the first time the role of DQB. DRB genotypes were determined on standard Taq1 restriction-fragment-length polymorphism analysis in 159 white northern European patients with the disease and 162 racially matched local controls. Polymerase chain reaction gene amplification and sequence-specific oligonucleotide analysis were used to determine DQB genotypes in 89 patients and 181 controls. An increased frequency of human leukocyte antigen DR8 was observed in the patient group (11% vs 4%; relative risk = 3.3; p < 0.01). Although we saw an increased frequency of the DQB1*0402 allele (11% vs. 3%; relative risk = 3.5; p < 0.025), this was not significant after correction for multiple testing. The strongest association was with the two-locus haplotype DR8-DQB1*0402 (11% vs. 2.2%; relative risk 5.5; p < 0.001). The DRB data reported here confirm the findings of previous studies, although the described association with DR8 is considerably weaker. The weak genetic contribution of human leukocyte antigen in the susceptibility to primary biliary cirrhosis is in contrast to its role in other autoimmune liver diseases.