tbuckley/cabot-search huggingface dataset:
The Ile585Val TRPV1 variant is involved in risk of painful knee osteoarthritis
Authors: A. M. Valdes, G. De Wilde, S. A. Doherty, R. J. Lories, F. L. Vaughn, L. L. Laslett, R. A. Maciewicz, A. Soni, D. J. Hart, W. Zhang, K. R. Muir, E. M. Dennison, M. Wheeler, P. Leaverton, C. Cooper, T. D. Spector, F. M. Cicuttini, V. Chapman, G. Jones, N. K. Arden, M. Doherty
Journal: Annals of the Rheumatic Diseases (2011)

<h3>Objective</h3> To assess if a coding variant in the gene encoding transient receptor potential cation channel, subfamily V, member 1 (<i>TRPV1</i>) is associated with genetic risk of painful knee osteoarthritis (OA). <h3>Methods</h3> The Ile585Val <i>TRPV1</i> variant encoded by rs8065080 was genotyped in 3270 cases of symptomatic knee OA, 1098 cases of asymptomatic knee OA and 3852 controls from seven cohorts from the UK, the USA and Australia. The genetic association between the low-pain genotype Ile–Ile and risk of symptomatic and asymptomatic knee OA was assessed. <h3>Results</h3> The <i>TRPV1</i> 585 Ile–Ile genotype, reported to be associated with lower thermal pain sensitivity, was associated with a lower risk of symptomatic knee OA in a comparison of symptomatic cases with healthy controls, with an odds ratio (OR) of 0.75 (95% CI 0.64 to 0.88; p=0.00039 by meta-analysis) after adjustment for age, sex and body mass index. No difference was seen between asymptomatic OA cases and controls (OR=1.02, 95% CI 0.82 to 1.27 p=0.86) but the Ile–Ile genotype was associated with lower risk of symptomatic versus asymptomatic knee OA adjusting for covariates and radiographic severity (OR=0.73, 95% CI 0.57 to 0.94 p=0.0136). <i>TRPV1</i> expression in articular cartilage was increased by inflammatory cytokines (tumour necrosis factor α and interleukin 1). However, there were no differences in <i>TRPV1</i> expression in healthy and arthritic synovial tissue. <h3>Conclusions</h3> A genotype involved in lower peripheral pain sensitivity is significantly associated with a decreased risk of painful knee OA. This indicates a role for the pro-nociceptive gene <i>TRPV1</i> in genetic susceptibility to symptomatic knee OA, which may also be influenced by a role for this molecule in cartilage function.
Inflammation, vascular injury and repair in rheumatoid arthritis
Authors: A J van Zonneveld, H C de Boer, E P van der Veer, T J Rabelink
Journal: Annals of the Rheumatic Diseases (2009)

The systemic pro-inflammatory state present in patients with rheumatoid arthritis (RA) accelerates the progression of atherosclerosis through chronic endothelial activation. Uncoupling of endothelial nitric oxide synthase plays a central role in the amplification of oxidative signalling pathways that chronically activate and, ultimately, injure the endothelium. Recent studies indicate that the resultant loss of endothelial integrity in patients with RA may also involve defects in the vascular regenerative potential provided by circulating endothelial progenitor cells (EPC). This is most likely the consequence of endothelial cell dysfunction in the bone marrow stroma, which hampers the mobilisation of these EPC to the circulation. In addition, mediators of systemic inflammation in RA can affect a second pathway of vascular regeneration. Under normal circumstances, myeloid CD14+ cells can adopt a pro-angiogenic phenotype that plays a key role in vascular remodelling and collateral formation. However, the chronic systemic inflammation observed in patients with RA may skew the differentiation of bone marrow and circulating CD14+ cells in such a way that these cells lose their capacity to support collateral formation, increasing the risk of cardiovascular disease. Taken together, in patients with RA, the impaired capacity of circulating cells to support vascular regeneration may comprise a novel pathway in the development of premature atherosclerosis.
The Tie2 receptor antagonist angiopoietin 2 facilitates vascular inflammation in systemic lupus erythematosus
Authors: P Kumpers, S David, M Haubitz, J Hellpap, R Horn, V Brocker, M Schiffer, H Haller, T Witte
Journal: Annals of the Rheumatic Diseases (2008)

<h3>Objective:</h3> To investigate the role of the angiopoietin–tyrosine kinase with Ig-like and epidermal growth factor-like domains (Ang–Tie) system in systemic lupus erythematosus (SLE). Endothelial activation is emerging as a key event for leukocyte recruitment and accelerated atherosclerosis in SLE. Recently, the endothelial-specific Ang–Tie ligand–receptor system has been identified as a major regulator of vascular responsiveness to inflammatory stimuli. <h3>Methods:</h3> Ang1 (by immunoradiometric sandwich assay (IRMA)) and Ang2 (by ELISA) were measured in sera of 43 patients with SLE and 30 healthy controls. Expression of Ang2 was studied by immunohistochemistry in biopsies of human lupus nephritis. <h3>Results:</h3> Circulating Ang2 concentrations were increased and concentrations of Ang1 decreased in patients with active SLE compared to healthy controls. This tendency was still present in inactive SLE, although less pronounced. Individual Ang2 concentrations correlated well with SLE Disease Activity Index (SLEDAI) score, proteinuria, double-stranded DNA (dsDNA) titre and soluble vascular cell adhesion molecule 1 (sVCAM-1). In a multivariate regression analysis, renal involvement was the only independent predictor for elevated Ang2. Serum Ang2 was identified as a strong predictor for disease activity by receiver operating characteristic (ROC) procedures and regression tree models. Protein expression of Ang2 was upregulated in glomeruli of patients with lupus nephritis. <h3>Conclusions:</h3> These data indicate that Ang2-mediated disruption of protective Ang1/Tie2 signalling is operational in SLE. Ang2 might facilitate endothelial inflammation, permeability and contribute to premature atherosclerosis. Furthermore, circulating Ang2 may be a valuable new biomarker for disease activity in SLE. Strategies to control the deleterious effects of Ang2 may open new perspectives to prevent endothelial inflammation in SLE.
Spanish transplant model would save 20 000 lives a year in EU
Authors: A. Garcia Rada
Journal: BMJ (2010)

A possible new European directive on transplantations that is based on the Spanish system could save 20 000 lives in the European Union each year, Spain’s minister for health and social policy has said.

Trinidad Jimenez was speaking on 23 March at a conference in Madrid on organ donation and transplantation that aimed to promote collaboration among EU countries to reduce differences in transplantation rates.

Spain has been the world leader in organ donation since the early 1990s, with 34.4 donations per million inhabitants, double the European average of 18.1 per million. However, while other countries also have high rates, such as Portugal (31) and France (23.2), rates are …
Expression and functional pharmacology of the bradykinin B1 receptor in the normal and inflamed human gallbladder
Authors: E. Andre, D. Gazzieri, E. Bardella, J. Ferreira, M. A. Mori, V. V. Saul, M. Bader, J. B. Calixto, R. De Giorgio, R. Corinaldesi, P. Geppetti, M. Trevisani
Journal: Gut (2008)

<h3>Background and aims:</h3> It has recently been described that bradykinin B<sub>2</sub> receptors are expressed in the human gallbladder and that their activation induces a powerful contraction, especially in acute cholecystitis tissues. Here the role of the B<sub>1</sub> receptor in the contractility of control and inflamed human gallbladder was investigated. <h3>Methods:</h3> Strips of human gallbladder from either acute gallstone cholecystitis or elective gastro-entero-pancreatic surgery (control) were assessed in vitro and processed for reverse transcription-PCR analysis. Cumulative concentration–response curves with the selective B<sub>1</sub> receptor agonist, Lys-Des-Arg<sup>9</sup>-bradykinin, cholecystokinin and carbachol were performed in control and cholecystitis specimens. <h3>Results:</h3> Lys-Des-Arg<sup>9</sup>-bradykinin concentration-dependently contracted strips of control gallbladders and its motor effect was higher in inflamed gallbladders. Lys-Des-Arg<sup>9</sup>-bradykinin-induced contraction was not altered by pretreatment with the selective bradykinin B<sub>2</sub> receptor antagonist, HOE140 (1 μM), the NK<sub>1</sub> (SR140333), NK<sub>2</sub> (SR48968) and NK<sub>3</sub> (SR142801) tachykinin receptor antagonists (all 1 μM), the muscarinic acetylcholine receptor antagonist, atropine (1 μM), and the cyclo-oxygenase inhibitor, indomethacin (5 μM). In contrast, the Lys-Des-Arg<sup>9</sup>-bradykinin-induced motor response was significantly reduced by the selective B<sub>1</sub> receptor antagonist, R-715. Finally, quantitative real-time PCR analysis indicated that B<sub>1</sub> receptor mRNA levels were significantly higher in cholecystitis smooth muscle specimens, when compared with that observed in control tissues. <h3>Conclusions:</h3> Bradykinin B<sub>1</sub> receptor has an important role as a spasmogen of human gallbladder, and selective antagonists of the B<sub>1</sub> receptor may represent a valid therapeutic option to control pain in patients with acute cholecystitis.
The Man with a Shattered World
Authors: D. O'Neill
Journal: BMJ (2010)

The subjective experience of dementia is a difficult reality for doctors and lay people to grasp. This absorbing and brief monograph by the great Russian neuropsychologist A R Luria is short (and compelling) enough to read in one sitting and invites immediate rereading and reflection. Although it is based on a case study of a different illness—brain injury—the lessons and insights from this astonishing narrative have enormous relevance for those affected with dementia. Luria presents and comments on the diary of one of his patients, Sublieutenant Zasetsky, a soldier in the Soviet army whose severe left sided brain injury from a bullet wound in 1943 left him with profound perceptual, memory, and language problems.

Covering a process of rehabilitation and therapy extending over 25 years, …
CORRECTION OF NASAL DEFORMITIES
Authors: J. E. Sheehan
Journal: BMJ (1923)

COMRBOTION OF NASAL DEFORXITI:.;= g8r etc.-beloved of our psychological friends; but many are due to a biochemical disturbance, as pointed out by Dr. Hurst at the Cambridge meeting in 1920.It would appear acvisable, therefore, to make an investigation of the organs of internal secretion in cases of hysterical deaf- ness, functional aphonia, paraesthesia of the pharynx, etc., and treat the patient according to the findings.I am in the habit of prescribing mammary gland, ovarian extract, and adrenal gland in these cases, in many of them with the bappiest results.As it is in many cases impossible to say which of the endocrines is the fons et origo mali, a polyglandular blunderbuss must sometimes be used.This is the more necessary owing to the interactions of the ductless glands, many of which are as yet but imperfectly understood.Mrs. O., aged 33, was referred to me by Dr. W. C. Rigby, for an opinion as to whether the severe headaches from which she suffered were due to any intranasal condition.She com.
Effect of revaccination with BCG in early childhood on mortality: randomised trial in Guinea-Bissau
Authors: A. E. Roth, C. Stabell Benn, H. Ravn, A. Rodrigues, I. M. Lisse, M. Yazdanbakhsh, H. Whittle, P. Aaby
Journal: BMJ (2010)

<b>Objective</b> To determine whether BCG revaccination at 19 months of age reduces overall child mortality. <b>Design</b> Randomised trial, with follow-up to age 5. <b>Setting</b> A health project in Bissau, Guinea-Bissau, which maintains a health and demographic surveillance system in an urban area with 90 000 inhabitants. <b>Participants</b> 2871 children aged 19 months to 5 years with low or no reactivity to tuberculin and who were not severely sick on the day of enrolment. <b>Intervention</b> BCG vaccination or no vaccination (control). <b>Main outcome measure</b> Hazard ratios for mortality. <b>Results</b> 77 children died during follow-up. Compared with controls, the BCG revaccinated children had a hazard ratio of 1.20 (95% confidence interval 0.77 to 1.89). Two hundred and fifty children were admitted to hospital for the first time between enrolment and the end of the study, with an incidence rate ratio for BCG revaccinated children versus controls of 1.04 (0.81 to 1.33). The trial was stopped prematurely because of a cluster of deaths in the BCG arm of the study. This increase in mortality occurred at a time when many children had received missing vaccinations or vitamin A or iron supplementation; the hazard ratio for BCG revaccinated children compared with controls was 2.69 (1.05 to 6.88) in the period after these campaigns. Throughout the trial, the effect of BCG revaccination on mortality was significantly different (P=0.006) in children who had received diphtheria-tetanus-pertussis (DTP) booster vaccination before enrolment (hazard ratio 0.36, 0.13 to 0.99) and children who had not received the booster before enrolment (1.78, 1.04 to 3.04). <b>Conclusions</b> There was no overall beneficial effect of being revaccinated with BCG. The effect of BCG revaccination on mortality might depend on other health interventions. <b>Trial registration</b> Clinical Trials ICA4-CT-2002-10053-REVAC.
Impaired Direct Priming of CD8 T Cells by Donor-Derived Cytomegalovirus Following Kidney Transplantation
Authors: Shazia Shabir, Baksho Kaul, Annette Pachnio, Gemma D. Banham, Helen Smith, Sourabh Chand, Seema Jham, Lorraine Harper, Simon Ball, Afsar Rahbar, Cecilia Söderberg-Nauclér, Paul Moss, Richard Borrows
Journal: Journal of the American Society of Nephrology (2013)

Cytomegalovirus (CMV) infection increases the risk of complications after renal transplantation, but the mechanisms controlling donor-derived infection are not adequately characterized. Here, we assessed the risk of clinically significant CMV disease in donor-seropositive, recipient-seropositive (D+R+) renal transplantation and examined recipients' CMV antigen-specific cellular immune responses primed directly by donor cells. In a retrospective cohort of 569 patients administered standardized basiliximab-tacrolimus-mycophenolate-corticosteroid immunosuppressive therapy, CMV disease rates increased in D+R+ serostatus pairings compared with D-R+ pairings (hazard ratio [HR], 2.61; 95% confidence interval [CI], 1.36 to 5.01; P=0.004) and associated with increased donor-recipient HLA mismatch in the D+R+ group (HR [per class 1 mismatch], 1.43; 95% CI, 1.12 to 1.82]; P=0.02). D+R+ and D+R- transplants in which the donor and recipient differentially expressed at least one HLA class I allele were followed prospectively from the time of transplantation. During the first year after transplantation, four of eight seropositive recipients and one of three seronegative recipients displayed peripheral blood CD8+ T cell responses to CMV presented by recipient-specific HLA. Notably, no recipients mounted responses to CMV presented by donor-specific HLA, despite the detection of CMV antigen expression in all seropositive donor organs examined (n=10), suggesting that the allograft of Class I HLA-mismatched seropositive donors is inaccessible to CD8+ T cell responses. Finally, pretransplant assays of anti-CMV cellular immunity predicted post-transplant CMV replication less accurately in D+R+ pairings than in D-R+ pairings, possibly reflecting in vitro assay specificity for recipient, rather than donor, HLA. These findings are relevant to the clinical management and immunologic understanding of donor-transmitted viral infection.
Thapsigargin inhibits angiogenesis in the rat isolated aorta: studies on the role of intracellular calcium pools
Authors: N Shukla
Journal: Cardiovascular Research (2001)

Objective: Since the role of Ca2+ in angiogenesis is not fully understood, we investigated the effect of thapsigargin (TG: depletes intracellular Ca2+ pools) and other Ca2+ modulators [ionomycin, calcium ionophore A23187 and dibutyrylhydroquinone (DBHQ)] on in vitro angiogenesis by rat aortic rings. Methods: Aortae from Sprague–Dawley rats were cut into 2-mm rings, embedded in a fibrin clot and cultured for 15 days in serum-free medium containing drugs and the microvessels counted. Rings were also pre-treated with TG and Ca2+ modulators for 1 h prior to embedding and culture. Viability was examined by the measurement of lactic acid dehydrogenase release. Rings were also treated with hydrocortisone and lavendustin A (a tyrosine kinase inhibitor), as positive controls. The effect of TG on the proliferation and migration of human umbilical artery endothelial cells (HUVECs) was studied in parallel. Results: TG significantly inhibited microvessel formation and HUVEC proliferation and migration in a dose-dependent manner, all at <10 nmol/l, without affecting viability. In contrast, ionomycin, A23187 and DBHQ were cytotoxic at inhibitory concentrations. Continual exposure to hydrocortisone and lavendusin A also inhibited angiogenesis without affecting viability. Conclusion: Since low concentrations of TG deplete intracellular Ca2+ stores, it is concluded that these pools play a central role in mediating angiogenesis.
Rearrangement status of the malignant cell determines type of secondary IgH rearrangement (V-replacement or V to DJ joining) in childhood B precursor acute lymphoblastic leukemia
Authors: EJ Steenbergen, OJHM Verhagen, H van den Berg, EF van Leeuwen, H Behrendt, RR Slater, AEG Kr von dem Borne, CE van der Schoot
Journal: Leukemia (1997)
How to Stay Cool in the Intensive Care Unit?
Authors: Kees H. Polderman
Journal: Circulation (2015)

D ozens of observational studies published over the past 2 decades have shown that fever in patients with acute neurological injury, regardless of its cause, is independently linked to higher mortality, poor neurological outcome, and increased length of stay in the intensive care unit and hospital.This has been demonstrated for traumatic brain injury, acute ischemic stroke, subarachnoid hemorrhage, intracranial hemorrhage, and cardiac arrest (CA). 1,2Therefore, therapeutic temperature management is a key goal of care in all patients with acute brain injury.In most cases the goal is strict fever control, ie, controlled normothermia; in patients with posthypoxic injuries, the goal is often to achieve below-normal core temperature, ie, to induce therapeutic hypothermia.
T200 cell surface glycoprotein of the mouse. Polymorphism defined by the Ly-5 system of alloantigens.
Authors: M B Omary, I S Trowbridge, M P Scheid
Journal: The Journal of Experimental Medicine (1980)

The cell line BW5147, and a mutant T200-negative cell line derived from BW5147, were studed by immunoprecipitation and peptide mapping, with xenogeneic monoclonal anti-T200 serum and with Ly-5 alloantiserum. It appears that the Ly-5 system defines a structural polymorphism of the cell surface glycoprotein T200, and that the monoclonal anti-T200 serum defines a feature of T200 that is common to mice of both Ly-5a and Ly-5b genotypes and may be invariable in the species.
Phase II study of liposomal muramyl tripeptide in osteosarcoma: the cytokine cascade and monocyte activation following administration.
Authors: E S Kleinerman, S F Jia, J Griffin, N L Seibel, R S Benjamin, N Jaffe
Journal: Journal of Clinical Oncology (1992)

PURPOSE A phase II trial that uses liposome-encapsulated muramyl tripeptide phosphatidylethanolamine (L-MTP-PE) in patients with relapsed osteosarcoma is underway. To determine if in vivo cytokine induction plays a role in the mechanism of action of L-MTP-PE, we investigated the circulating cytokine levels of 16 patients who were undergoing therapy. PATIENTS AND METHODS Patients had histologically proven osteosarcoma and pulmonary metastases that developed either during adjuvant chemotherapy or that were present at diagnosis and persisted despite chemotherapy. Patients were rendered disease-free by surgery. The major goal of the study was to improve the disease-free interval in this high-risk group. L-MTP-PE 2 mg/m2 was infused during a 1-hour period twice a week for 12 weeks, then once a week for 12 weeks. Serial blood samples were collected after L-MTP-PE administration and were assayed for cytokine levels (tumor necrosis factor-alpha [TNF alpha] interleukin-1 alpha [IL-1 alpha], IL-1 beta, IL-6, interferon-gamma [IFN-gamma], neopterin, C-reactive protein). RESULTS After the infusion of L-MTP-PE, there was rapid induction of circulating TNF alpha and IL-6. TNF alpha levels peaked 1 to 2 hours after infusion in 10 of 16 patients, whereas peak IL-6 levels were detected at 2 to 3 hours in all patients. Induction of circulating TNF alpha and IL-6 was evident only after the first dose of L-MTP-PE. Neither IL-1 alpha nor IL-1 beta was detected in the plasma. Neopterin levels increased at 24 hours postinfusion, which indicated macrophage activation, and were not related to the induction of circulating IFN-gamma. C-reactive protein was elevated in all patients at 24 hours and decreased by 72 hours. Unlike circulating TNF alpha and IL-6, elevations in C-reactive protein and neopterin could be detected throughout the treatment course. CONCLUSION It is concluded that L-MTP-PE has specific biologic effects in patients with osteosarcoma that may be important to the drug's immunostimulatory capacity and its effectiveness as an antitumor agent.
Phase III Intergroup Study of Fludarabine Phosphate Compared With Cyclophosphamide, Vincristine, and Prednisone Chemotherapy in Newly Diagnosed Patients With Stage III and IV Low-Grade Malignant Non-Hodgkin's Lymphoma
Authors: Anton Hagenbeek, Houchingue Eghbali, Silvio Monfardini, Umberto Vitolo, Peter J. Hoskin, Christiane de Wolf-Peeters, Ken MacLennan, Elvira Staab-Renner, Joachim Kalmus, Astrid Schott, Ivana Teodorovic, Anastassia Negrouk, Martine van Glabbeke, Robert Marcus
Journal: Journal of Clinical Oncology (2006)

To compare the efficacy and safety of fludarabine phosphate with cyclophosphamide, vincristine, and prednisone (CVP) in 381 previously untreated, advanced-stage, low-grade (lg) non-Hodgkin's lymphoma (NHL) patients in a phase III, multicenter study.Between 1993 and 1997, patients were randomly assigned to treatment with either fludarabine (25 mg/m2 intravenously [IV] daily for 5 days every 4 weeks) or CVP (cyclophosphamide 750 mg/m2 IV on day 1; vincristine, 1.4 mg/m2 IV on day 1; and prednisone, 40 mg/m2 orally on days 1 through 5 every 4 weeks). Results Overall response (OR) rates were significantly improved in the fludarabine arm versus the CVP arm, both for the intent-to-treat (ITT) population and assessable patients (P < .001). Complete response (CR) rates in the ITT population were also higher after fludarabine treatment. The CR rate was 38.6% for fludarabine compared with 15.0% for CVP. There were no statistically significant differences in time to progression (TTP), time to treatment failure (TTF), and overall survival (OS) between treatment groups. WHO grades 3 and 4 hematologic adverse events were more common in the fludarabine arm. However, concerning the higher incidence of granulocytopenia, this did not translate to more infections in fludarabine-treated patients.Newly diagnosed lgNHL patients who received fludarabine achieved higher OR and CR rates compared with CVP-treated patients. No differences in TTP, TTF, and OS were noted. Fludarabine is a highly active single agent in lgNHL. Combination therapies incorporating fludarabine are now being further evaluated as first-line therapy in follicular NHL.
Closing some local services could save lives, report says
Authors: Adrian O'Dowd
Journal: BMJ (2006)

Closing some local hospital services could help to save around 1000 lives each year, says a report that heralds another wave of reconfiguration in the NHS. 

Despite numerous protests over proposed closures of some parts of district general hospitals, shutting down less effective services will help to boost survival rates, says a report from the think tank the Institute for Public Policy Research. 

The policy is also one that is being put this week to the health secretary, Patricia Hewitt, by chief medical officer Professor Liam Donaldson and the national clinical directors for emergency care and coronary heart disease, Professors George Alberti and …