tbuckley/cabot-search huggingface dataset:
A2.16 Synovial Fluid Neutrophils Undergoing Netosis Contribute to Joint Inflammation by Producing Citrullinated Autoantigens
Authors: Julia Spengler, Bozo Lugonja, Andrew Creese, Anthony Nicholas, Mike Milward, Mark Pearson, Christopher D Buckley, Andrew Filer, Karim Raza, Paul R Cooper, Iain LC Chapple, Dagmar Scheel-Toellner
Journal: Annals of the Rheumatic Diseases (2013)

<h3>Objectives</h3> Anti-citrullinated protein antibodies (ACPA) are characteristically detected in patients with rheumatoid arthritis (RA) and growing evidence suggests that they are involved in disease pathogenesis. During disease flares large numbers of neutrophils enter the joint space of RA patients. These cells can extrude genomic DNA in an active process termed NETosis. NETosis critically depends on histone citrullination by peptidyl deiminase 4 (PAD4). Here we tested the hypothesis that activation and release of PAD4 during NETosis contributes to the production of autoantigens in the inflamed joint. <h3>Materials and Methods</h3> Levels of extracellular DNA in the synovial fluid (SF) of patients with RA (n = 23) and osteoarthritis (OA) (n = 15) or crystal arthritis (n = 6) were quantified using the non cell-permeable DNA dye SYTOX Green. PAD4, neutrophil elastase, citrullinated proteins and bound human IgG were labelled in association with DNA on smear preparations of RA SF and detected by immunofluorescence. NETs from SF and in vitro stimulated neutrophils were isolated and western blotting and mass spectrometry were used to identify proteins released during NET formation and proteins co-fractionated with NETs. PAD enzymatic activity was determined after NETosis in vitro and in the SF of patients with RA (n = 9) and OA (n = 9). <h3>Results</h3> Extracellular DNA was detected in SF from patients with RA and crystal arthritis at significantly higher levels than in OA SF (RA versus OA p &lt; 0.0001). Association of neutrophil elastase with decondensed DNA both on smear preparations and in NETs isolated from RA SF suggests that the extracellular DNA is derived from NETosis. On smear preparations PAD4 co-localised with decondensed chromatin in the SF of RA patients. PAD2 and PAD4 are released into the supernatant of in vitro stimulated neutrophils and were detected in NET fractions isolated from RA SFs. PAD enzymatic activity was released from neutrophils during in vitro activated NETosis while PAD activity in SF from RA patients was significantly higher than in OA patients (p &lt; 0.001). The products of PAD activity, citrullinated proteins, were released into the supernatant and co-fractionated with extracellular DNA during in vitro NETosis. Furthermore, citrullinated proteins and bound human immune complexes were detected on NETs isolated from RA SF. <h3>Conclusions</h3> These findings suggest that neutrophil NETosis, as a source of extracellular activated PAD enzymes, is involved in the production of auto-antigens in the joints of RA patients. In ACPA positive patients the resulting immune complexes can contribute to the perpetuation of the inflammatory response.
Membrane Targeting and Secretion of Mutant Uromodulin in Familial Juvenile Hyperuricemic Nephropathy
Authors: Paul Jennings, Sonia Aydin, Peter Kotanko, Judith Lechner, Karl Lhotta, Sian Williams, Rajesh V. Thakker, Walter Pfaller
Journal: Journal of the American Society of Nephrology (2006)

Familial juvenile hyperuricemic nephropathy (FJHN) is an autosomal dominant genetic disorder that is characterized by hyperuricemia, gout, and tubulointerstitial nephritis. FJHN is caused by mutations in the UMOD gene, which encodes for uromodulin, the most abundant urinary protein. Herein is demonstrated that patients with FJHN and renal insufficiency exhibit a profound reduction in urinary uromodulin together with either elevated or decreased plasma uromodulin. One young patient with FJHN, however, had normal serum creatinine and normal urinary uromodulin with elevated plasma uromodulin. These observations suggest that there are different urinary and plasma uromodulin profiles in early and late disease and that there may be an altered direction of uromodulin secretion in the course of FJHN as a result of improper intracellular sorting of the mutated protein in the thick ascending limb. With the use of immunohistochemistry and a quantitative immunoassay, targeting and secretion of wild-type and mutant (C77Y and N128S) uromodulin were investigated in the polarized renal epithelial cell line LLC-PK1. In transfected cells, uromodulin mutants were targeted properly to the apical membrane but were secreted less efficiently to the apical compartment than wild-type protein. The expression of mutant uromodulin had no effect on caspase 3 activity. These results indicate that the mutations studied do not impair glycosyl-phosphatidylinositol–mediated apical targeting of the protein but do affect apical secretion. Because the mutant proteins are secreted as efficiently as wild type to the basolateral compartment, the possibility arises that interactions with the immune system at the site of secretion are a contributing factor to the development of tubulointerstitial nephritis in FJHN.
Use of Canakinumab in the Cryopyrin-Associated Periodic Syndrome
Authors: Helen J. Lachmann, Isabelle Kone-Paut, Jasmin B. Kuemmerle-Deschner, Kieron S. Leslie, Eric Hachulla, Pierre Quartier, Xavier Gitton, Albert Widmer, Neha Patel, Philip N. Hawkins
Journal: New England Journal of Medicine (2009)

The cryopyrin-associated periodic syndrome (CAPS) is a rare inherited inflammatory disease associated with overproduction of interleukin-1. Canakinumab is a human anti-interleukin-1beta monoclonal antibody.We performed a three-part, 48-week, double-blind, placebo-controlled, randomized withdrawal study of canakinumab in patients with CAPS. In part 1, 35 patients received 150 mg of canakinumab subcutaneously. Those with a complete response to treatment entered part 2 and were randomly assigned to receive either 150 mg of canakinumab or placebo every 8 weeks for up to 24 weeks. After the completion of part 2 or at the time of relapse, whichever occurred first, patients proceeded to part 3 and received at least two more doses of canakinumab. We evaluated therapeutic responses using disease-activity scores and analysis of levels of C-reactive protein (CRP) and serum amyloid A protein (SAA).In part 1 of the study, 34 of the 35 patients (97%) had a complete response to canakinumab. Of these patients, 31 entered part 2, and all 15 patients receiving canakinumab remained in remission. Disease flares occurred in 13 of the 16 patients (81%) receiving placebo (P<0.001). At the end of part 2, median CRP and SAA values were normal (<10 mg per liter for both measures) in patients receiving canakinumab but were elevated in those receiving placebo (P<0.001 and P=0.002, respectively). Of the 31 patients, 28 (90%) completed part 3 in remission. In part 2, the incidence of suspected infections was greater in the canakinumab group than in the placebo group (P=0.03). Two serious adverse events occurred during treatment with canakinumab: one case of urosepsis and an episode of vertigo.Treatment with subcutaneous canakinumab once every 8 weeks was associated with a rapid remission of symptoms in most patients with CAPS. (ClinicalTrials.gov number, NCT00465985.)
Hepatitis C virus (HCV) specific immune responses in anti-HCV positive patients without hepatitis C viraemia
Authors: M E Cramp, P Carucci, S Rossol, S Chokshi, G Maertens, R Williams, N V Naoumov
Journal: Gut (1999)

BACKGROUND/AIMS Most patients infected with hepatitis C virus (HCV) develop chronic infection and persistent viraemia. The immune mechanisms responsible for resolution of viraemia remain poorly understood. HCV specific humoral and cellular immune responses in patients with and without viraemia were investigated. METHODS In vitro T helper (T H ) lymphocyte responses to structural and non-structural HCV proteins were determined by means of proliferative response and cytokine production in 35 anti-HCV positive/HCV RNA negative patients and in 31 patients with chronic HCV infection and persistent viraemia. Humoral responses were determined by measuring HCV specific antibody quantity and specificity. RESULTS A T H response to two or more HCV proteins was present in 18 of 35 patients with serological viral clearance compared with just one of 31 viraemic patients (p = 0.00001). HCV specific interferon-γ production was increased only in the former group. In contrast, the antibody levels were significantly lower and directed at fewer HCV antigens in patients with undetectable HCV RNA. CONCLUSIONS Patients without viraemia after HCV infection frequently have strong T H lymphocyte responses of the T H 1 type to multiple HCV antigens many years after the onset of infection, whereas antibody responses are less marked. These results suggest that control of HCV replication may depend on effective T H lymphocyte activation.
Efficacy of issuing guidelines on acne management to general practitioners
Authors: C.M. Cusack, C.C. Buckley
Journal: British Journal of Dermatology (2005)

Journal Article Efficacy of issuing guidelines on acne management to general practitioners Get access C.M. Cusack, C.M. Cusack Department of Dermatology, Waterford Regional Hospital, Waterford, Ireland E‐mail: caitriona_55@hotmail.com Search for other works by this author on: Oxford Academic Google Scholar C.C. Buckley C.C. Buckley Department of Dermatology, Waterford Regional Hospital, Waterford, Ireland E‐mail: caitriona_55@hotmail.com Search for other works by this author on: Oxford Academic Google Scholar British Journal of Dermatology, Volume 152, Issue 6, 1 June 2005, Pages 1392–1393, https://doi.org/10.1111/j.1365-2133.2005.06641.x Published: 01 June 2005
Oxalobacter formigenes May Reduce the Risk of Calcium Oxalate Kidney Stones
Authors: David W. Kaufman, Judith P. Kelly, Gary C. Curhan, Theresa E. Anderson, Stephen P. Dretler, Glenn M. Preminger, David R. Cave
Journal: Journal of the American Society of Nephrology (2008)

Most kidney stones are composed primarily of calcium oxalate. Oxalobacter formigenes is a Gram-negative, anaerobic bacterium that metabolizes oxalate in the intestinal tract and is present in a large proportion of the normal adult population. It was hypothesized that the absence of O. formigenes could lead to increased colonic absorption of oxalate, and the subsequent increase in urinary oxalate could favor the development of stones. To test this hypothesis, a case-control study involving 247 adult patients with recurrent calcium oxalate stones and 259 age-, gender-, and region-matched control subjects was performed. The prevalence of O. formigenes, determined by stool culture, was 17% among case patients and 38% among control subjects; on the basis of multivariate analysis controlling demographic factors, dietary oxalate, and antibiotic use, the odds ratio for colonization was 0.3 (95% confidence interval 0.2 to 0.5). The inverse association was consistently present within strata of age, gender, race/ethnicity, region, and antibiotic use. Among the subset of participants who completed a 24-h urine collection, the risk for kidney stones was directly proportional to urinary oxalate, but when urinary factors were included in the multivariable model, the odds ratio for O. formigenes remained 0.3 (95% confidence interval 0.1 to 0.7). Surprisingly, median urinary oxalate excretion did not differ with the presence or absence of O. formigenes colonization. In conclusion, these results suggest that colonization with O. formigenes is associated with a 70% reduction in the risk for being a recurrent calcium oxalate stone former.
A NEW PHASE IN EARLYU SYPHILIS: A REPLY TO DR. BURKE
Authors: J. A. DRAKE, M. S. THOMSON
Journal: British Journal of Dermatology (1932)

Journal Article A NEW PHASE IN EARLYU SYPHILIS: A REPLY TO DR. BURKE Get access J. A. DRAKE, J. A. DRAKE Search for other works by this author on: Oxford Academic Google Scholar M. S. THOMSON M. S. THOMSON Search for other works by this author on: Oxford Academic Google Scholar British Journal of Dermatology and Syphilis, Volume 44, Issue 11, 1 November 1932, Pages 534–538, https://doi.org/10.1111/j.1365-2133.1932.tb09553.x Published: 01 November 1932
Cyclosporin A in Severe, Treatment-Refractory Rheumatoid Arthritis
Authors: D E Yocum, J H Klippel, R L Wilder, N L Gerber, H A Austin, S M Wahl, L Lesko, J R Minor, H G Preuss, C Yarboro
Journal: Annals of Internal Medicine (1988)

To assess the efficacy and toxicity of cyclosporin A in patients with severe, treatment-refractory rheumatoid arthritis.Prospective randomized, double-blind 6-month trial.Thirty-one patients who had classic seropositive rheumatoid arthritis with active synovitis unresponsive to conventional therapy.Patients were randomly assigned to high-dose (10 mg/kg body weight.d) or low-dose (1 mg/kg.d) cyclosporin A therapy. A reduction in the dose was permitted for adverse side effects. After 6 months of therapy, patients who showed clinically relevant improvement, defined as a 40% or greater reduction in their total joint activity score, were given the option to continue receiving the therapy for an additional 6 months.At 6 months, clinically relevant improvement occurred in 10 of 15 patients (95% CI, 38 to 88) receiving high-dose therapy and in 4 of 16 patients (CI, 7 to 52) receiving low-dose therapy (P = 0.02). Statistically significant improvements in individual measures were shown only in the high-dose group. Improvements were noted in the number of tender joints (-18.8; CI, -24.5 to -13.1) and swollen joints (-12.1; CI, -15.4 to -8.6), as well as in physician's global scores (-1.5; CI, -2.1 to -0.9) and patient's global scores (-1.1; CI, -1.9 to -0.5). Improvement in disease activity was maintained through 12 months in the high-dose group. The clinical responses to cyclosporin A were most evident in patients with depressed in-vitro proliferative responses of peripheral blood mononuclear lymphocytes to soluble recall antigens. Toxicities, such as fatigue, gastrointestinal and neurologic complaints, and hypertrichosis were frequent but often reversible with a reduction in the dose. Nephrotoxicity, with a 20% increase in the serum creatinine level, was seen in 27 of 31 patients (CI, 71 to 97).Cyclosporin A is an effective therapy for severe, treatment-refractory rheumatoid arthritis. Side effects, particularly nephrotoxicity, are common.
Broad Antitumor Activity in Breast Cancer Xenografts by Motesanib, a Highly Selective, Oral Inhibitor of Vascular Endothelial Growth Factor, Platelet-Derived Growth Factor, and Kit Receptors
Authors: Angela Coxon, Tammy Bush, Douglas Saffran, Stephen Kaufman, Brian Belmontes, Karen Rex, Paul Hughes, Sean Caenepeel, James B. Rottman, Andrew Tasker, Vinod Patel, Richard Kendall, Robert Radinsky, Anthony Polverino
Journal: Clinical Cancer Research (2008)

Abstract Purpose: Angiogenesis plays a critical role in breast cancer development and progression. Vascular endothelial growth factor (VEGF) is a potent angiogenic factor that regulates endothelial cell proliferation and survival. We investigated the effects of motesanib, a novel, oral inhibitor of VEGF receptors 1, 2, and 3; platelet-derived growth factor receptor; and Kit receptor, on the growth of xenografts representing various human breast cancer subtypes. Experimental Design: Athymic nude mice were implanted with MCF-7 (luminal) or MDA-MB-231 (mesenchymal) tumor fragments or Cal-51 (mixed/progenitor) tumor cells. Once tumors were established, animals were randomized to receive increasing doses of motesanib alone or motesanib plus cytotoxic chemotherapy (docetaxel, doxorubicin, or tamoxifen). Results: Across all three xenograft models, motesanib treatment resulted in significant dose-dependent reductions in tumor growth, compared with vehicle-treated controls, and in marked reductions in viable tumor fraction and blood vessel density. No significant effect on body weight was observed with compound treatment compared with control-treated animals. Motesanib did not affect the proliferation of tumor cells in vitro. There was a significantly greater reduction in xenograft tumor growth when motesanib was combined with docetaxel (MDA-MB-231 tumors) or with the estrogen receptor modulator tamoxifen (MCF-7 tumors), compared with either treatment alone, but not when combined with doxorubicin (Cal-51 tumors). Conclusions: Treatment with motesanib alone or in combination with chemotherapy inhibits tumor growth in vivo in various models of human breast cancer. These data suggest that motesanib may have broad utility in the treatment of human breast cancer.
Radiological Examination of the Stomach and Duodenum: WITH SPECIAL REFERENCE TO THE EARLY DIAGNOSIS OF CANCER
Authors: K. S. Cross
Journal: BMJ (1936)

In this paper I shall discuss some of the problems inherent in radiological investigation, particularly of the stomach and duodenum, not only from the diagnostic and technical viewpoint, but also as they involve the interrelationship of patient, physician, and radiologist.
Government says it would stockpile Tamiflu again
Authors: A. O'Dowd
Journal: BMJ (2014)

The government has said that it would stockpile the antiviral drug oseltamivir (marketed by Roche as Tamiflu) again, despite large amounts of previously bought supplies being written off and questions raised by experts over its effectiveness, MPs have been told.

Government witnesses appearing before the House of Commons Public Accounts Committee on 20 October insisted that oseltamivir, which was used to treat pandemic flu, was worth having. Between 2006-07 and 2012-13 the Department of Health for England purchased nearly 40 million units of oseltamivir, costing £424m (€535m; $685m). However, only 2.4 million units were consumed, mostly during the flu pandemic in 2009-10, and over the same period 10 million units were written off, many because of poor record keeping about their storage environment during the pandemic.

MPs asked witnesses if the conclusions of a review published in March this year by the Cochrane Collaboration were fair, on the basis of having finally received from …
Double-blind, randomized, placebo-controlled study of a lotion containing triethyl citrate and ethyl linoleate in the treatment of acne vulgaris
Authors: A. Charakida, M. Charakida, A.C. Chu
Journal: British Journal of Dermatology (2007)

Acne vulgaris is a major clinical problem; despite a vast array of treatment modalities available for acne, there is considerable dissatisfaction in acne treatment among patients and doctors. Rising antibiotic drug resistance consequent to the widespread use of topical antibiotics is causing concern and effective nonantibiotic treatments are needed.To evaluate the efficacy and tolerability of a novel lotion containing triethyl citrate and ethyl linoleate in the treatment of mild to moderate acne vulgaris.This was a double-blind, placebo-controlled, randomized study comparing the active lotion containing triethyl citrate and ethyl linoleate with its vehicle as a placebo control. Patients were assessed by the modified Leeds acne grading system as well as by counting inflammatory and noninflammatory lesions on the face at weeks 0, 4, 8 and 12. Sebum production was assessed by the Sebutape method at weeks 0 and 12. All adverse events were recorded.Forty patients were recruited into the study, of whom 33 completed the study. Active treatment was statistically superior to placebo in reduction of Leeds grading and total, inflammatory and noninflammatory lesion counts. The active lotion showed a rapid response with obvious reduction in lesion counts and acne grading by 4 weeks. Sebum production was significantly reduced in the actively treated group, with a mean reduction of 53% in sebum production compared with baseline. One patient developed irritation to the active lotion and withdrew from the study.The new lotion containing triethyl citrate and ethyl linoleate has been shown to be an effective treatment for mild to moderate acne, with an effect on both inflammatory and noninflammatory acne lesions. The new lotion worked quickly and was generally well tolerated. A surprising finding was the significant impact the new lotion has on sebum production, suggesting a role in patients with seborrhoea. This nonantibiotic preparation will be a very useful addition to existing treatments for acne.
7-Hydroxystaurosporine (UCN-01) Inhibition of Akt Thr308 but not Ser473 Phosphorylation
Authors: Sudhir B. Kondapaka, MaryJane Zarnowski, Dena R. Yver, Edward A. Sausville, Samuel W. Cushman
Journal: Clinical Cancer Research (2004)

7-hydroxystaurosporine (UCN-01) infused for 72 hours by continuous i.v. infusion induced insulin resistance during phase I clinical trials. To understand the mechanism for this observation, we examined the effect of UCN-01 on insulin-stimulated glucose transport activity with 3-O-methylglucose in isolated rat adipose cells. UCN-01 inhibits glucose transport activity in a dose-dependent manner at all insulin concentrations. At the clinically relevant concentration of 0.25 mumol/L UCN-01, glucose transport is inhibited 66, 29, and 26% at insulin concentrations of 10, 50, and 100,000 (100K) microunits/mL respectively, thus shifting the dose-response curve to the right. Increasing concentrations of UCN-01 up to 2.5 mumol/L progressively shift the insulin dose-response curve even further. As Akt is known to mediate in part action initiated at the insulin receptor, we also studied the effect of UCN-01 on Akt activation in whole-cell homogenates of these cells. Decreased glucose transport activity directly parallels decreased Akt Thr308 phosphorylation in both an insulin and UCN-01 dose-dependent manner, whereas Akt Ser473 phosphorylation is inhibited only at the lowest insulin concentration, and then, only modestly. UCN-01 also inhibits insulin-induced Thr308 but not Ser473 phosphorylation of Akt associated with the plasma membranes and low-density microsomes and inhibits translocation of GLUT4 from low-density microsomes to plasma membranes as expected from the glucose transport activity measurements. These data suggest that UCN-01 induces clinical insulin resistance by blocking Akt activation and subsequent GLUT4 translocation in response to insulin, and this effect appears to occur by inhibiting Thr308 phosphorylation even in the face of almost completely unaffected Ser473 phosphorylation.
Portacaval anastomosis: The longest shunt
Authors: Harold O. Conn
Journal: Hepatology (1989)

A 34–year–old patient with cryptogenic cirrhosis underwent a portacaval shunt after four episodes of upper gastrointestinal bleeding. His subsequent course is remarkable not onle because of its 26–year duration, but also because of the absence of any subsequent hepatic decomensation such as jaundice, ascites, coagulopathy or encephalopathy. Currently, the shunt is patent.
Neu Differentiation Factor (NDF), a Dominant Oncogene, Causes Apoptosis In Vitro and In Vivo
Authors: Stefan Grimm, Edward J. Weinstein, Ian M. Krane, Philip Leder
Journal: The Journal of Experimental Medicine (1998)

Neu differentiation factor (NDF, also called neuregulin) is a potent inducer of epithelial cell proliferation and has been shown to induce mammary carcinomas in transgenic mice. Notwithstanding this proliferative effect, we have shown that a novel isoform of NDF can induce apoptosis when overexpressed. Here we report that this property also extends to other NDF isoforms and that the cytoplasmic portion of NDF is largely responsible for the apoptotic effect, whereas the proliferative activity is likely to depend upon the secreted version of NDF. In accordance with these contradictory properties, we find that tumors induced by NDF display extensive apoptosis in vivo. NDF is therefore an oncogene whose deregulation can induce transformation as well as apoptosis.