tbuckley/cabot-search huggingface dataset:
Depressed levels of dehydroepiandrosterone sulphate in postmenopausal women with rheumatoid arthritis but no relation with axial bone density.
Authors: G M Hall, L A Perry, T D Spector
Journal: Annals of the Rheumatic Diseases (1993)

The sex hormones dehydroepiandrosterone sulphate (DHEAS), oestradiol, and sex hormone binding globulin (SHBG) were measured in 185 postmenopausal women (aged 45-65 years) with rheumatoid arthritis (RA) and related to assessments of bone mineral density at the spine and proximal femur. Compared with 518 postmenopausal control women (aged 45-65 years), DHEAS levels were below normal in the 120 patients with RA who had never taken corticosteroids and levels were further depressed in 39 patients currently using steroids. Twenty six patients who had completed steroid treatment also had lower DHEAS levels, suggesting a delayed recovery of adrenal androgen secretion. Oestradiol and SHBG levels were similar in all groups. There was no correlation between sex hormones and disease activity. Oestradiol correlated with bone mineral density at all sites. Although oestradiol correlated with DHEAS, there was no relation between DHEAS and bone mineral density. The cause of below normal levels of DHEAS in RA is unclear, whether a consequence of chronic illness, immune dysfunction, or a defect of adrenal androgen synthesis.
The use of combined ultrasonic and isotope scanning in the diagnosis of amoebic liver disease
Authors: A. W. Matthews, K. R. Gough, E. R. Davies, F. G. M. Ross, A. Hinchliffe
Journal: Gut (1973)

The use of combined isotope and ultrasonic scanning in the diagnosis of amoebic liver abscess is described, together with details of three cases of this condition seen in the Bristol area in a period of two years. The addition of ultrasonic scanning greatly increases the accuracy of diagnosis by demonstrating a fluid-filled, space-occupying lesion and should ideally be employed whenever liver abscess is suspected.
Modulation of T-cell response to phospholipase A2 and phospholipase A2–derived peptides by conventional bee venom immunotherapy☆☆☆★★★
Authors: Regine Kämmerer, Yolande Chvatchko, Alexander Kettner, Nathalie Dufour, Giampietro Corradin, François Spertini
Journal: Journal of Allergy and Clinical Immunology (1997)
The Wiskott-Aldrich syndrome protein is required for iNKT cell maturation and function
Authors: Michela Locci, Elena Draghici, Francesco Marangoni, Marita Bosticardo, Marco Catucci, Alessandro Aiuti, Caterina Cancrini, Laszlo Marodi, Teresa Espanol, Robbert G.M. Bredius, Adrian J. Thrasher, Ansgar Schulz, Jiri Litzman, Maria Grazia Roncarolo, Giulia Casorati, Paolo Dellabona, Anna Villa
Journal: The Journal of Experimental Medicine (2009)

The Wiskott-Aldrich syndrome (WAS) protein (WASp) is a regulator of actin cytoskeleton in hematopoietic cells. Mutations of the WASp gene cause WAS. Although WASp is involved in various immune cell functions, its role in invariant natural killer T (iNKT) cells has never been investigated. Defects of iNKT cells could indeed contribute to several WAS features, such as recurrent infections and high tumor incidence. We found a profound reduction of circulating iNKT cells in WAS patients, directly correlating with the severity of clinical phenotype. To better characterize iNKT cell defect in the absence of WASp, we analyzed was−/− mice. iNKT cell numbers were significantly reduced in the thymus and periphery of was−/− mice as compared with wild-type controls. Moreover analysis of was−/− iNKT cell maturation revealed a complete arrest at the CD44+ NK1.1− intermediate stage. Notably, generation of BM chimeras demonstrated a was−/− iNKT cell-autonomous developmental defect. was−/− iNKT cells were also functionally impaired, as suggested by the reduced secretion of interleukin 4 and interferon γ upon in vivo activation. Altogether, these results demonstrate the relevance of WASp in integrating signals critical for development and functional differentiation of iNKT cells and suggest that defects in these cells may play a role in WAS pathology.
Disruptions of occludin and claudin-5 in brain endothelial cells in vitro and in brains of mice with acute liver failure
Authors: Feng Chen, Norifumi Ohashi, Wensheng Li, Christopher Eckman, Justin H. Nguyen
Journal: Hepatology (2009)

Brain edema in acute liver failure (ALF) remains lethal. The role of vasogenic mechanisms of brain edema has not been explored. We previously demonstrated that matrix metalloproteinase-9 (MMP-9) contributes to the pathogenesis of brain edema. Here, we show that MMP-9 mediates disruptions in tight junction (TJ) proteins in vitro and in brains of mice with ALF. We transfected murine brain endothelial cells (ECs) with MMP-9 complementary DNA (cDNA) using pc DNA3.1 (+)/Myc-His A expression vector. Tissue inhibitor of matrix metalloproteinases (TIMP-1) cDNA transfection or GM6001 was used to inhibit MMP-9. ALF was induced in mice with azoxymethane. Endogenous overexpression of MMP-9 in brain ECs resulted in significant degradation of the TJ proteins occludin and claudin-5. The alterations in TJ proteins correlated with increased permeability to fluorescein isothiocyanate–dextran molecules. The degradation of TJ proteins and the increased permeability were reversed by TIMP-1 and GM6001. Similar results were found when MMP-9 was exogenously added to brain ECs. We also found that TJ protein degradation was reversed with GM6001 in the brains of mice with ALF. Conclusion: TJ proteins are significantly perturbed in brains of mice with ALF. These data corroborate the important role of MMP-9 in the vasogenic mechanism of brain edema in ALF. (HEPATOLOGY 2009.)
Lymphoma endothelium preferentially expresses Tim-3 and facilitates the progression of lymphoma by mediating immune evasion
Authors: Xiaoyuan Huang, Xiangyang Bai, Yang Cao, Jingyi Wu, Mei Huang, Duozhuang Tang, Si Tao, Tao Zhu, Yanling Liu, Yang Yang, Xiaoxi Zhou, Yanxia Zhao, Mingfu Wu, Juncheng Wei, Daowen Wang, Gang Xu, Shixuan Wang, Ding Ma, Jianfeng Zhou
Journal: The Journal of Experimental Medicine (2010)

Angiogenesis is increasingly recognized as an important prognosticator associated with the progression of lymphoma and as an attractive target for novel modalities. We report a previously unrecognized mechanism by which lymphoma endothelium facilitates the growth and dissemination of lymphoma by interacting with circulated T cells and suppresses the activation of CD4(+) T cells. Global gene expression profiles of microdissected endothelium from lymphoma and reactive lymph nodes revealed that T cell immunoglobulin and mucin domain-containing molecule 3 (Tim-3) was preferentially expressed in lymphoma-derived endothelial cells (ECs). Clinically, the level of Tim-3 in B cell lymphoma endothelium was closely correlated to both dissemination and poor prognosis. In vitro, Tim-3(+) ECs modulated T cell response to lymphoma surrogate antigens by suppressing activation of CD4(+) T lymphocytes through the activation of the interleukin-6-STAT3 pathway, inhibiting Th1 polarization, and providing protective immunity. In a lymphoma mouse model, Tim-3-expressing ECs promoted the onset, growth, and dissemination of lymphoma by inhibiting activation of CD4(+) T cells and Th1 polarization. Our findings strongly argue that the lymphoma endothelium is not only a vessel system but also a functional barrier facilitating the establishment of lymphoma immune tolerance. These findings highlight a novel molecular mechanism that is a potential target for enhancing the efficacy of tumor immunotherapy and controlling metastatic diseases.
Where there's smoke... there's tuberculosis
Authors: S. Gordon, J. Rylance
Journal: Thorax (2009)

<h3>Background</h3> Despite the remarkable benefits associated with the interventional treatment of melanomas (and other solid cancers) with immune checkpoint and Braf inhibitors (Brafi), most patients ultimately progress on therapy. The presence of multifocal/disseminated disease in patients increases their mortality risk. Hence, the development of novel strategies to effectively treat patients with melanomas that are resistant to anti-PD1 mAb (αPD1) and/or Brafi, particularly those with multifocal/disseminated disease remains a major unmet clinical need. <h3>Methods</h3> Mice developing induced/spontaneous Braf<sup>V600E</sup>/Pten<sup>−/−</sup> melanomas were treated by cutaneous immunization with a DNA vaccine encoding the melanoma-associated antigen TRP2, with Brafi or αPD1 alone, or with a combination of these treatments. Tumor progression, tumor-infiltration by CD4<sup>+</sup> and CD8<sup>+</sup> T cells, and the development of TRP2-specific CD8<sup>+</sup> T cells were then monitored over time. <h3>Results</h3> Vaccination led to durable antitumor immunity against PD1/Brafi-resistant melanomas in both single lesion and multifocal disease models, and it sensitized PD1-resistant melanomas to salvage therapy with αPD1. The therapeutic efficacy of the vaccine was associated with host skin-resident cells, the induction of a systemic, broadly reactive IFNγ<sup>+</sup>CD8<sup>+</sup> T cell repertoire, increased frequencies of CD8<sup>+</sup> TIL and reduced levels of PD1<sup>hi/int</sup>CD8<sup>+</sup> T cells. Extended survival was associated with improved TIL functionality, exemplified by the presence of enhanced levels of IFNγ<sup>+</sup>CD8<sup>+</sup> TIL and IL2<sup>+</sup>CD4<sup>+</sup> TIL. <h3>Conclusions</h3> These data support the use of a novel genetic vaccine for the effective treatment of localized or multifocal melanoma refractory to conventional αPD1-based and/or Brafi-based (immune)therapy.
The regulation of HIV-1 transcription: Molecular targets for chemotherapeutic intervention
Authors: Miguel Stevens, Erik De Clercq, Jan Balzarini
Journal: Medicinal Research Reviews (2006)

The regulation of transcription of the human immunodeficiency virus (HIV) is a complex event that requires the cooperative action of both viral and cellular components. In latently infected resting CD4(+) T cells HIV-1 transcription seems to be repressed by deacetylation events mediated by histone deacetylases (HDACs). Upon reactivation of HIV-1 from latency, HDACs are displaced in response to the recruitment of histone acetyltransferases (HATs) by NF-kappaB or the viral transcriptional activator Tat and result in multiple acetylation events. Following chromatin remodeling of the viral promoter region, transcription is initiated and leads to the formation of the TAR element. The complex of Tat with p-TEFb then binds the loop structures of TAR RNA thereby positioning CDK9 to phosphorylate the cellular RNA polymerase II. The Tat-TAR-dependent phosphorylation of RNA polymerase II plays an important role in transcriptional elongation as well as in other post-transcriptional events. As such, targeting of Tat protein (and/or cellular cofactors) provide an interesting perspective for therapeutic intervention in the HIV replicative cycle and may afford lifetime control of the HIV infection.
The Src family kinases Hck, Fgr, and Lyn are critical for the generation of the in vivo inflammatory environment without a direct role in leukocyte recruitment
Authors: Miklós Kovács, Tamás Németh, Zoltán Jakus, Cassian Sitaru, Edina Simon, Krisztina Futosi, Bálint Botz, Zsuzsanna Helyes, Clifford A. Lowell, Attila Mócsai
Journal: The Journal of Experimental Medicine (2014)

Although Src family kinases participate in leukocyte function in vitro, such as integrin signal transduction, their role in inflammation in vivo is poorly understood. We show that Src family kinases play a critical role in myeloid cell–mediated in vivo inflammatory reactions. Mice lacking the Src family kinases Hck, Fgr, and Lyn in the hematopoietic compartment were completely protected from autoantibody-induced arthritis and skin blistering disease, as well as from the reverse passive Arthus reaction, with functional overlap between the three kinases. Though the overall phenotype resembled the leukocyte recruitment defect observed in β2 integrin–deficient (CD18−/−) mice, Hck−/−Fgr−/−Lyn−/− neutrophils and monocytes/macrophages had no cell-autonomous in vivo or in vitro migration defect. Instead, Src family kinases were required for the generation of the inflammatory environment in vivo and for the release of proinflammatory mediators from neutrophils and macrophages in vitro, likely due to their role in Fcγ receptor signal transduction. Our results suggest that infiltrating myeloid cells release proinflammatory chemokine, cytokine, and lipid mediators that attract further neutrophils and monocytes from the circulation in a CD18-dependent manner. Src family kinases are required for the generation of the inflammatory environment but not for the intrinsic migratory ability of myeloid cells.
Waist belt and central obesity cause partial hiatus hernia and short-segment acid reflux in asymptomatic volunteers
Authors: Yeong Yeh Lee, Angela A Wirz, James G H Whiting, Elaine V Robertson, Donald Smith, Alexander Weir, Andrew W Kelman, Mohammad H Derakhshan, Kenneth E L McColl
Journal: Gut (2013)

<h3>Objective</h3> There is a high incidence of inflammation and metaplasia at the gastro-oesophageal junction (GOJ) in asymptomatic volunteers. Additionally, the majority of patients with GOJ adenocarcinomas have no history of reflux symptoms. We report the effects of waist belt and increased waist circumference (WC) on the physiology of the GOJ in asymptomatic volunteers. <h3>Design</h3> 12 subjects with normal and 12 with increased WC, matched for age and gender were examined fasted and following a meal and with waist belts on and off. A magnet was clipped to the squamo-columnar junction (SCJ). Combined assembly of magnet-locator probe, 12-channel pH catheter and 36-channel manometer was passed. <h3>Results</h3> The waist belt and increased WC were each associated with proximal displacement of SCJ within the diaphragmatic hiatus (relative to upper border of lower oesophageal sphincter (LOS), peak LOS pressure point and pressure inversion point, and PIP (all p&lt;0.05). The magnitude of proximal migration of SCJ during transient LOS relaxations was reduced by 1.6–2.6 cm with belt on versus off (p=0.01) and in obese versus non-obese (p=0.04), consistent with its resting position being already proximally displaced. The waist belt, but not increased WC, was associated with increased LOS pressure (vs intragastric pressure) and movement of pH transition point closer to SCJ. At 5 cm above upper border LOS, the mean % time pH &lt;4 was &lt;4% in all studied groups. Acid exposure 0.5–1.5 cm above SCJ was increased, with versus without, belt (p=0.02) and was most marked in obese subjects with belt. <h3>Conclusions</h3> Our findings indicate that in asymptomatic volunteers, waist belt and central obesity cause partial hiatus herniation and short-segment acid reflux. This provides a plausible explanation for the high incidence of inflammation and metaplasia and occurrence of neoplasia at the GOJ in subjects without a history of reflux symptoms.
PTH-007 Ercp Cannulation Success Benchmarking: Implications For Certification And Validation
Authors: D Sheppard, S Craddock, B Warner, M Wilkinson
Journal: Gut (2014)

<h3>Introduction</h3> An investigation of success rates of cannulating a 'virgin' papilla during endoscopic retrograde cholangiopancreatography (ERCP) at a tertiary referral centre, compared against Joint Advisory Group (JAG) guidelines, and assessment of the reasons for failure. <h3>Methods</h3> Retrospective review of Endosoft database and radiology records of patients who underwent ERCP conducted between 2006–2012 (n = 1519) at the Gastroenterology department, St Thomas' Hospital, London. Specifically 'virgin' papillae were considered, defined as those with no evidence of prior cannulation, stents <i><i>in situ</i></i> or sphincterotomies (n = 795), as these represent the most challenging and repeatable targets for endoscopists. <h3>Results</h3> Over the 7 year period, the overall ERCP cannulation success rate per patient was 86, or 79% per virgin papilla procedure. By defining an 'accessible' (see Table) virgin papilla, a 90% success rate was achieved for each procedure, as well as per patient. Procedure success rates per consultant ranged from 79 – 89% for virgin, and 94 – 99% for non virgin cannulations, highlighting the need for careful definition of success criteria. Chronic pancreatitis was the only statistically significant indication associated with a failed cannulation (OR=3.3, CI: 1.7–6.4), and previous failure begat subsequent failure (OR=2.2, CI: 1.1- 4.4). Reasons for failure included previous gastroduodenal surgery (OR=48.9, CI: 6.3–379.2), papilla tumour impingement (OR=57.8, CI: 7.5–443.3), duodenal stricturing (OR=36.0, CI: 4.5 – 286.3). <h3>Conclusion</h3> The 79% success rate for virgin papilla cannulation at a tertiary referral centre needs to be understood in context of JAG's recommended 80% success for overall therapeutic intent. As can be seen, depending on the way we define the duct, and therapeutic intent, we can fall short or far exceed the JAG guidelines. We believe that our data shows that the JAG benchmark for therapeutic success at initial attempt for trainees, and even for established ERCP-ists is currently too ambitious, since therapy requires cannulation to be achieved, and therapeutic success is not universal after successful diagnostic ERCP. We also believe that any measure of success needs to include the minimum criteria of whether the papilla was virgin, accessible, or associated with either previous failure or intended pancreatic therapy. As a corollary of this work we hope to encourage other units to publish clearer definitions when defining success. <h3>Disclosure of Interest</h3> None Declared.
Apoptosis and Growth Inhibition in Malignant Lymphocytes After Treatment With Arsenic Trioxide at Clinically Achievable Concentrations
Authors: X.-H. Zhu, Y.-L. Shen, Y.-k. Jing, X. Cai, P.-M. Jia, Y. Huang, W. Tang, G.-Y. Shi, Y.-P. Sun, J. Dai, Z.-Y. Wang, S.-J. Chen, T.-D. Zhang, S. Waxman, Z. Chen, G.-Q. Chen
Journal: JNCI Journal of the National Cancer Institute (1999)

BACKGROUND: Arsenic trioxide (As 2 O 3 ) can induce clinical remission in patients with acute promyelocytic leukemia via induction of differentiation and programmed cell death (apoptosis). We investigated the effects of As 2 O 3 on a panel of malignant lymphocytes to determine whether growth-inhibitory and apoptotic effects of As 2 O 3 can be observed in these cells at clinically achievable concentrations. METHODS: Eight malignant lymphocytic cell lines and primary cultures of lymphocytic leukemia and lymphoma cells were treated with As 2 O 3 , with or without dithiothreitol (DTT) or buthionine sulfoximine (BSO) (an inhibitor of glutathione synthesis). Apoptosis was assessed by cell morphology, flow cytometry, annexin V protein level, and terminal deoxynucleotidyl transferase labeling of DNA fragments. Cellular proliferation was determined by 5-bromo-2′-deoxyuridine incorporation into DNA and flow cytometry and by use of a mitotic arrest assay. Mitochondrial transmembrane potential (ΔΨ m ) was measured by means of rhodamine 123 staining and flow cytometry. Protein expression was assessed by western blot analysis or immunofluorescence. RESULTS: Therapeutic concentrations of As 2 O 3 (1-2 μ M ) had dual effects on malignant lymphocytes: 1) inhibition of growth through adenosine triphosphate (ATP) depletion and prolongation of cell cycle time and 2) induction of apoptosis. As 2 O 3 -induced apoptosis was preceded by ΔΨ m collapse. DTT antagonized and BSO enhanced As 2 O 3 -induced ATP depletion, ΔΨ m collapse, and apoptosis. Caspase-3 activation, usually resulting from ΔΨ m collapse, was not always associated with As 2 O 3 -induced apoptosis. As 2 O 3 induced PML (promyelocytic leukemia) protein degradation but did not modulate expression of cell cycle-related proteins, including c-myc, retinoblastoma protein, cyclin-dependent kinase 4, cyclin D1, and p53, or expression of differentiation-related antigens. CONCLUSIONS: Substantial growth inhibition and apoptosis without evidence of differentiation were induced in most malignant lymphocytic cells treated with 1-2 μ M As 2 O 3 . As 2 O 3 may prove useful in the treatment of malignant lymphoproliferative disorders.
Proliferative activity of intrinsic cell populations in the normal human kidney.
Authors: T Nadasdy, Z Laszik, K E Blick, L D Johnson, F G Silva
Journal: Journal of the American Society of Nephrology (1994)

The proliferative activity of various normal human renal cell populations is unknown. Recently, antibodies to cell proliferation-associated nuclear proteins, such as proliferating cell nuclear antigen (PCNA) and KI-67, which are applicable to archival paraffin sections, became available. With antibodies to PCNA and Ki-67 after microwave pretreatment of the paraffin sections, the proliferation indexes (ratio of positive nuclei with PCNA and Ki-67 antibodies/all nuclei counted x 100, i.e. percentage of positive cells) of 12 different intrinsic renal cell populations in 20 normal human kidneys have been determined. The following proliferation indexes (percentages of positive cells) were found with the PCNA and the Ki-67 antibodies, respectively: proximal tubular epithelium, 0.22, 0.24; thin limb of Henle, 0.29, 0.30; thick ascending limb of Henle, 0.32, 0.29; distal tubular epithelium (distal convoluted tubules and cortical collecting ducts, 0.33, 0.44; medullary collecting ducts, 0.32, 0.3; glomerular mesangial cells, 0.07, 0.12; glomerular visceral epithelial cells, 0.04, 0.08; glomerular parietal epithelial cells, 0.07, 0.1; glomerular capillary endothelium, 0.42, 0.47; peritubular capillary endothelial cells, 0.38, 0.43; endothelium of large intrarenal vessels (arteries and veins), 0.09, 0.12. Thus, normally capillary endothelium (glomerular and peritubular) appears to have the highest proliferation index in the human kidney by these techniques. These results indicate major variation in the proliferative activity of normal human renal cell populations, along with a significant correlation between PCNA and Ki-67 staining. Furthermore, this study provides normal values for the proliferative activity of different human renal cell populations.(ABSTRACT TRUNCATED AT 250 WORDS)
728 PROSPECTIVE STUDY OF HEPATITIS B VIRUS REACTIVATION IN HBSAG-NEGATIVE PATIENTS AFTER CHEMOTHERAPY WITH RITUXIMAB: HBV-DNA MONITORING AND ENTECAVIR PROPHYLAXIS
Authors: H. Kojima, H. Tsujimura, N. Mimura, T. Sugawara, M. Ise, C. Sakai, S. Yamada, T. Miyaki, K. Kumagai
Journal: Journal of Hepatology (2011)
Staff shortages persist at troubled Mid Staffordshire trust
Authors: A. O'Dowd
Journal: BMJ (2009)

Shortages of surgeons and nurses are still a problem at the Mid Staffordshire NHS Foundation Trust, despite a highly critical report into care there that insisted staffing levels be increased.

Two government reports published this week show that although there have been improvements at the trust, much more needs to be done.

The trust was heavily criticised for severe failings in a report published by the former regulator, the Healthcare Commission, in March, which, after studying the trust’s performance between 2005 and 2008, said that emergency care there was unsafe because of a lack of staff and equipment ( BMJ 2009;338:b1141, doi:10.1136/bmj.b1141).

The government and Monitor, the …