tbuckley/cabot-search huggingface dataset:
Management of stones in the biliary tree.
Authors: R H Dowling
Journal: Gut (1983)

Leading articleManagement of stones in the biliary tree Stones in the biliary tree may coexist with gall-bladder stones, may be found only in the common duct (in the absence of gall-bladder stones) or, more rarely, may be present in the intrahepatic biliary tree -as in the Caroli syndrome.1One of the most frequent causes of choledocholithiasis, however, is the retained common duct stone which has been left behind inadvertently after elective or emergency cholecystectomy.Despite the routine use of intraoperative cholangiography, exploration of the common duct (where indicated) at the time of cholecystectomy and even, on occasions, the use of fibre optic choledochoscopy, there is still a 1-4% incidence of retained common duct stones after cholecystectomy.2When stones are discovered in the biliary tree, there are several therapeutic options -including, in selected patients, the use of oral chenodeoxycholic (CDCA) or ursodeoxycholic (UDCA) acid, the gall-stone dissolving agents which are more commonly used in the treatment of cholesterol-rich stones in the gall bladder.3Elsewhere in this issue Dr Gianfranco Salvioli and his colleagues from Modena in Italy describe the results of a random allocation, double masked trial in 28 patients with uncomplicated biliary stones, half of whom were treated with 12 mg UDCA/kg/day in three divided doses, while the other half received placebo.Seventeen of these patients had stones in the gall bladder while four had a radiologically normal gall bladder with stones only in the biliary tree.Although the end point of the study was intended to be 24 months, only four of the 28 patients actually completed the two year trial -either because the stones had disappeared completely before that time, or because the patients developed biliary colic, pain or cholangitis, underwent surgery or simply 'dropped out'.None of the 14 patients given placebo showed evidence of gall-stone dissolution, but seven of the 14 UDCA-treated patients showed complete disappearance of the stones, as judged by normal intravenous cholangiograms, after six, 12, or 18 months' treatment -while one showed partial gall stone dissolution (defined as at least a 25% reduction in stone diameter or the disappearance of one or more stones).If one arbitrarily classifies 'drop-outs' as treatment failures, then the complication rate, whether because of the stones or of the treatment, was higher in the placebo treated patients (12 out of 14) than in the UDCA-treated group (six out of 14).The reason for the 'drop-outs' in three of the 14 patients given UDCA is not stated.These patients may simply have defaulted from treatment because they lacked motivation or they may have become disenchanted with it for good reason -because of complications for example.Of the three other UDCA-treated patients who stopped, one underwent surgery for obstructive jaundice after three months, one developed colic, and one pain (the distinction between biliary colic and abdominal pain or discomfort, was not defined).
Vitamin D, magnesium and calcium do not correlate with COPD: A cross-sectional study
Authors: Sarah Hashim Ali Hussein, Lars Peter Nielsen, Mette Konow Bogebjerg Dolberg, Ronald Dahl
Journal: European Respiratory Journal (2013)

Background   Vitamin D-deficiency is associated with many chronic diseases. In chronic obstructive pulmonary disease (COPD), simultaneous vitamin D-, magnesium- and calcium deficiency is associated with increased risk of exacerbations, whereas associations with other aspects of COPD, i.e. lung function and quality of life (QoL), have been less extensively studied.   Aim   To investigate the relationship between serum vitamin D, magnesium and calcium in COPD and the effects of these three parameters on lung function and QoL in COPD patients.   Methods   The lung function test and blood samples were measured. The patients were characterized as well as their overall and the COPD-related QoL.   Results   This cross-sectional study included 143 patients with COPD.  Lung function was not correlated with serum vitamin D3 (25-(OH)D3), magnesium or calcium in COPD. Furthermore, the patients’ history of exacerbations and the overall and the COPD-related QoL showed no correlation with serum vitamin D, magnesium or calcium.   Discussion   We found no correlation between the lung function or QoL and the serum vitamin D, magnesium or calcium in COPD. Our findings are supported by most of the relatively sparse studies on the topics.
Tyrosine phosphorylation of mitogen-activated protein kinases is necessary for activation of murine macrophages by natural and synthetic bacterial products.
Authors: Z Dong, X Qi, I J Fidler
Journal: The Journal of Experimental Medicine (1993)

The purpose of these studies was to determine the intracellular signal transduction pathways of bacterial products in murine macrophages from lipopolysaccharide (LPS)-responder C3H/HeN and LPS-nonresponder C3H/HeJ mice. Both LPS and synthetic lipopeptide CGP 31362 (LPP) induced production of tumor necrosis factor alpha (TNF-alpha) in C3H/HeN macrophages. In C3H/HeJ macrophages, however, TNF-alpha was induced only by incubation with LPP. Both LPS and LPP induced tyrosine phosphorylation on proteins with apparent molecular masses of 39, 41, and 45 kD (p35, p41, and p45) in C3H/HeN macrophages, whereas in C3H/HeJ macrophages, tyrosine phosphorylation was induced only by LPP. 20-h incubation with LPS or LPP downregulated TNF-alpha production/secretion and tyrosine phosphorylation in C3H/HeN macrophages induced by additional LPS or LPP. In C3H/HeJ macrophages, however, the downregulation of TNF-alpha production and tyrosine phosphorylation were observed only with LPP. Protein kinase assays, Western blotting analyses, phenyl-Sepharose chromatography, and immunocomplex kinase assay suggested that p45 and p39 were similar or identical to mitogen-activated protein (MAP) kinase 1 and 2, respectively. Pretreatment of macrophages with LPS or LPP did not change the amount of kinase proteins but inhibited the stimulation of kinase activity by the agents. These data suggest that MAP kinases are among target proteins involved in the transduction of LPS and LPP signals that lead to activation of murine macrophages to produce/secrete TNF.
Efficacy and Safety of Anti–Interleukin‐20 Monoclonal Antibody in Patients With Rheumatoid Arthritis: A Randomized Phase IIa Trial
Authors: Ladislav Šenolt, Piotr Leszczynski, Eva Dokoupilová, Marie Göthberg, Xavier Valencia, Brian Bekker Hansen, Juan D. Cañete
Journal: Arthritis & Rheumatology (2015)

Objective Interleukin‐20 (IL‐20) is implicated in the pathogenesis of rheumatoid arthritis (RA). The efficacy, safety, and tolerability of NNC0109‐0012, a selective anti–IL‐20 recombinant human monoclonal antibody (mAb), were assessed in patients with active RA who had an inadequate response to methotrexate therapy. Methods Sixty‐seven patients with RA were enrolled and randomized (2:1) to receive NNC0109‐0012 (3 mg/kg per week, subcutaneously) or placebo in a phase IIa, double‐blind, 12‐week trial with a 13‐week followup. The primary end point was change in the Disease Activity Score in 28 joints based on C‐reactive protein level (DAS28‐CRP) from baseline to week 12. Results In patients treated with NNC0109‐0012, the primary end point, improvement in the DAS28‐CRP at week 12, was achieved (estimated difference −0.88; P = 0.02), with significant improvement starting at week 1. A greater response was observed in seropositive patients (estimated difference −1.66; P &lt; 0.001), which was sustained through 13 weeks of followup, whereas no improvement was noted in patients with seronegative RA. A significant proportion of patients with seropositive RA receiving NNC0109‐0012, compared to those receiving placebo, achieved treatment responses according to the American College of Rheumatology 20% (ACR20) (59% versus 21%), ACR50 (48% versus 14%), and ACR70 (35% versus 0%) levels of improvement, and showed greater improvements in the Health Assessment Questionnaire disability index ( P = 0.047). The most frequent adverse events reported with NNC0109‐0012 were injection site reactions and infections (e.g., herpes, nasopharyngitis, respiratory, and urinary). No serious infections or discontinuations associated with NNC0109‐0012 were observed. Conclusion In this phase IIa trial, treatment with NNC0109‐0012 (anti–IL‐20 mAb) was effective in patients with seropositive RA as early as week 1, with further improvements to week 12. No safety or tolerability concerns were identified with weekly NNC0109‐0012 administration.
Soluble epoxide hydrolase is a susceptibility factor for heart failure in a rat model of human disease
Authors: Jan Monti, Judith Fischer, Svetlana Paskas, Matthias Heinig, Herbert Schulz, Claudia Gösele, Arnd Heuser, Robert Fischer, Cosima Schmidt, Alexander Schirdewan, Volkmar Gross, Oliver Hummel, Henrike Maatz, Giannino Patone, Kathrin Saar, Martin Vingron, Steven M Weldon, Klaus Lindpaintner, Bruce D Hammock, Klaus Rohde, Rainer Dietz, Stuart A Cook, Wolf-Hagen Schunck, Friedrich C Luft, Norbert Hubner
Journal: Nature Genetics (2008)
Hes1, a new target for interleukin 1 in chondrocytes
Authors: S. Ottaviani, K. Tahiri, A. Frazier, Z. N. Hassaine, M.-F. Dumontier, W. Baschong, F. Rannou, M.-T. Corvol, J.-F. Savouret, P. Richette
Journal: Annals of the Rheumatic Diseases (2009)

<h3>Objectives</h3> To investigate the effects of interleukin 1β (IL1β) treatment on the Notch1/Hes1 pathway in chondrocytes in vitro. <h3>Methods</h3> Mouse articular chondrocytes in primary culture were challenged with IL1β, alone or combined with Notch1 and IL1β pathway inhibitors. Notch1 and Hes1 expressions were investigated by immunocytochemistry, western blot and real-time quantitative (q)PCR. IL1β-responsive genes were assessed by real-time qPCR and a specific siRNA against Hes1 was used to identify Hes1 target genes. <h3>Results</h3> Notch1 labelling remained nuclear and stable in intensity irrespective of treatment, suggesting a steady state activation of this pathway in our model. IL1β transiently increased Hes1 mRNA (2.5-fold) and protein expression in treated versus naive chondrocytes. Hes1 mRNA level then decreased below control and its cyclic pattern of expression was lost. This was associated with nuclear translocation of the cytoplasmic Hes1 protein. IL1β induced increase in Hes1 mRNA was transcriptional, occurred through nuclear factor (NF)κB activation and appeared to be associated with downregulation by its own protein. Hes1 induction was insensitive to the γ-secretase inhibitor <i>N</i>-(<i>N</i>-(3,5-difluorophenacetyl)-l-alanyl)-<i>S</i>-phenylglycine <i>t</i>-butyl ester (DAPT), which suggested its independence from novel Notch1 activation. Hes1 expression was efficiently silenced by a specific siRNA. This experiment revealed that Hes1 did not mediate IL1β-induced downregulation of Sox9, type II collagen and aggrecan transcription but mediated IL1β induction of matrix metalloproteinase (MMP)13 and ADAM metallopeptidase with thrombospondin type 1 motif, 5 (ADAMTS5). The Hes1-related repressor Hey1 was expressed at a very low level and was not inducible by IL1β. <h3>Conclusion</h3> Hes1 is a novel IL1β target gene in chondrocytes which influences a discrete subset of genes linked to cartilage matrix remodelling and/or degradation.
Homeostatic maintenance of natural <i>Foxp3</i>+ CD25+ CD4+ regulatory T cells by interleukin (IL)-2 and induction of autoimmune disease by IL-2 neutralization
Authors: Ruka Setoguchi, Shohei Hori, Takeshi Takahashi, Shimon Sakaguchi
Journal: The Journal of Experimental Medicine (2005)

Interleukin (IL)-2 plays a crucial role in the maintenance of natural immunologic self-tolerance. Neutralization of circulating IL-2 by anti–IL-2 monoclonal antibody for a limited period elicits autoimmune gastritis in BALB/c mice. Similar treatment of diabetes-prone nonobese diabetic mice triggers early onset of diabetes and produces a wide spectrum of T cell–mediated autoimmune diseases, including gastritis, thyroiditis, sialadenitis, and notably, severe neuropathy. Such treatment selectively reduces the number of Foxp3-expressing CD25+ CD4+ T cells, but not CD25− CD4+ T cells, in the thymus and periphery of normal and thymectomized mice. IL-2 neutralization inhibits physiological proliferation of peripheral CD25+ CD4+ T cells that are presumably responding to normal self-antigens, whereas it is unable to inhibit their lymphopenia-induced homeostatic expansion in a T cell–deficient environment. In normal naive mice, CD25low CD4+ nonregulatory T cells actively transcribe the IL-2 gene and secrete IL-2 protein in the physiological state. IL-2 is thus indispensable for the peripheral maintenance of natural CD25+ CD4+ regulatory T cells (T reg cells). The principal physiological source of IL-2 for the maintenance of T reg cells appears to be other T cells, especially CD25low CD4+ activated T cells, which include self-reactive T cells. Furthermore, impairment of this negative feedback loop via IL-2 can be a cause and a predisposing factor for autoimmune disease.
The impact of dasatinib on pregnancy outcomes
Authors: Jorge E. Cortes, Elisabetta Abruzzese, Ekaterina Chelysheva, Mausumee Guha, Nicola Wallis, Jane F. Apperley
Journal: American Journal of Hematology (2015)

Prolonged survival in patients with chronic myeloid leukemia treated with BCR-ABL1-targeted tyrosine kinase inhibitors allows consideration of parenthood for patients on chronic therapy, but there are limited data about the effects of dasatinib on pregnancy. Pregnancy-related outcomes in dasatinib-treated patients or their partners reported to Bristol-Myers Squibb from clinical trials or healthcare providers through December 2013 were reviewed. Outcomes were available in 46/78 dasatinib-treated women (59%) and 33/69 partners of dasatinib-treated men (48%). Fifteen women (33%) delivered a normal infant; 18 (39%) and 8 (17%) had an elective or spontaneous abortion; and 5 (11%) had an abnormal pregnancy. There were 7 reports of fetal/infant abnormalities (encephalocele, renal tract abnormalities, and hydrops fetalis). Thirty of 33 (91%) infants fathered by dasatinib-treated men were reported normal at birth. Also, animal studies evaluated the impact of dasatinib on fertility, embryo-fetal toxicity, and development, suggesting that dasatinib may be a selective developmental toxicant. The outcomes of most pregnancies conceived by men treated with dasatinib were normal, but due to the small number of cases, further monitoring is required. Significant effects on pregnancy outcomes in women treated with dasatinib were found, supporting current recommendations that women avoid becoming pregnant during dasatinib treatment and be informed of fetal risks.
Regulation of Murine Cardiac 20S Proteasomes
Authors: Chenggong Zong, Aldrin V. Gomes, Oliver Drews, Xiaohai Li, Glen W. Young, Beniam Berhane, Xin Qiao, Samuel W. French, Fawzia Bardag-Gorce, Peipei Ping
Journal: Circulation Research (2006)

Our recent studies have provided a proteomic blueprint of the 26S proteasome complexes in the heart, among which 20S proteasomes were found to contain cylinder-shaped structures consisting of both alpha and beta subunits. These proteasomes exhibit a number of features unique to the myocardium, including striking differences in post-translational modifications (PTMs) of individual subunits and novel PTMs that have not been previously reported. To date, mechanisms contributing to the regulation of this myocardial proteolytic core system remain largely undefined; in particular, little is known regarding PTM-dependent regulation of cardiac proteasomes. In this investigation, we seek to elucidate the function and regulation of 20S proteasome complexes in the heart. Functionally viable murine cardiac 20S proteasomes were purified. Tandem mass spectrometry analyses, combined with native gel electrophoresis, immunoprecipitation, and immunoblotting, revealed the identification of 2 previously unrecognized functional partners in the endogenous intact cardiac 20S complexes: protein phosphatase 2A (PP2A), and protein kinase A (PKA). Furthermore, our results demonstrated that PP2A and PKA profoundly impact the proteolytic function of 20S proteasomes: phosphorylation of 20S complexes enhances the peptidase activity of individual subunits in a substrate-specific fashion. Moreover, inhibition of PP2A or the addition of PKA significantly modified both the serine- and threonine-phosphorylation profile of proteasomes; multiple individual subunits of 20S (eg, alpha1 and beta2) were targets of PP2A and PKA. Taken together, these studies provide the first demonstration that the function of cardiac 20S proteasomes is modulated by associating partners and that phosphorylation may serve as a key mechanism for regulation.
Role of LDL receptors in the in vitro uptake and degradation of LDL in the media of rabbit thoracic aorta.
Authors: P A Curmi, G Renaud, L Juan, B Chiron, A Tedgui
Journal: Circulation Research (1989)

The possible role of plasma low-density protein (LDL) receptors in the uptake and degradation of LDL in the whole arterial wall was investigated by comparison of the in vitro uptake of 125I-native LDL (nLDL) and 131I-methylated LDL (mLDL) by the media of deendothelialized rabbit thoracic aorta excised at in vivo length and pressurized to 70 mm Hg, taking the advantage that mLDL is not recognized by the LDL receptor. The distribution of the relative concentrations of nLDL (Cn) and mLDL (Cm) across the wall was obtained using a serial frozen sectioning technique. The aorta was incubated under three different conditions for varying periods of incubation in order to analyze separately the processes of binding, binding-internalization, and degradation. At 39 degrees C, in which binding-internalization and degradation occurred, Cn was significantly higher than Cm at each position across the media. The mean medial Cn/Cm ratio was 1.36 +/- 0.15 (n = 5) after 1 hour of incubation, and decreased to 1.23 +/- 0.22 (n = 7) after 2 hours of incubation and to 1.13 +/- 0.11 (n = 5) after 4 hours of incubation. At 4 degrees C, in which internalization and degradation were blocked, the Cn/Cm ratio reflected the surface nLDL binding alone; the Cn/Cm ratio was 1.47 +/- 0.20 (n = 5) after 4 hours of incubation, higher than the value obtained at 39 degrees C. To investigate whether degradation of nLDL occurred after receptor binding, the interstitial LDL was washed out by an LDL-free solution after 2-hour incubation at 39 degrees C. After 30 minutes of washout, the Cn/Cm ratio decreased to 1.06 +/- 0.20 (n = 5) in the inner media and was unchanged in the outer media. After 1 hour of washout, the ratio declined to 0.57 +/- 0.18 (n = 7) in the inner part of the media and increased progressively to 1 at the media-adventitia boundary. The Cn/Cm ratio, at 0.67 +/- 0.12 (n = 5), was practically constant throughout the media after 2 hours of washout. The nLDL degradation rate across the media was obtained from the comparison of nLDL and mLDL before and after the washout. A steep decreasing gradient in nLDL degradation rate was observed from the luminal to the external surface. The mean medial nLDL degradation rate value was 9.6 +/- 4.5 microliters/cm3 wet tissue/hr. We concluded that functional LDL receptors participate in the uptake and degradation of LDL in the whole aorta.
Distinct Epitopes for Anti–Glomerular Basement Membrane Alport Alloantibodies and Goodpasture Autoantibodies within the Noncollagenous Domain of α3(IV) Collagen
Authors: Xu-Ping Wang, Agnes B. Fogo, Selene Colon, Giovanna Giannico, Sameh R. Abul-Ezz, Jeffrey H. Miner, Dorin-Bogdan Borza
Journal: Journal of the American Society of Nephrology (2005)

Alport posttransplantation anti–glomerular basement membrane (GBM) nephritis is mediated by alloantibodies against the noncollagenous (NC1) domains of the α3α4α5(IV) collagen network, which is present in the GBM of the allograft but absent from Alport kidneys. The specificity of kidney-bound anti-GBM alloantibodies from a patient who had autosomal recessive Alport syndrome (ARAS) and developed posttransplantation nephritis was compared with that of Goodpasture autoantibodies from patients with autoimmune anti-GBM disease. Allograft-eluted alloantibodies reacted specifically with α3α4α5 NC1 hexamers, targeting their α3NC1 and α4NC1 subunits, and recognized a noncontiguous alloepitope formed jointly by the EA and EB regions of α3NC1 domain. In contrast, human Goodpasture autoantibodies recognized the separate EA and EB autoepitopes of α3NC1 but not the composite alloepitope. Molecular modeling of α3NC1 revealed that the alloepitope is more accessible within the NC1 hexamers than the partially sequestered Goodpasture autoepitopes. Overall, the specificity of alloantibodies indicated a selective lack of immune tolerance toward the α3 and α4(IV) collagen chains not expressed in patients with ARAS. Using COL4A3 knockout mice, a model of ARAS, it was shown further that acid-dissociated rather than native α3α4α5 NC1 hexamers elicited murine anti-GBM antibodies most closely resembling human ARAS alloantibodies. In contrast, α3NC1 monomers elicited Goodpasture-like murine antibodies, targeting the EA and EB autoepitopes. Thus, the identity of α3NC1 epitopes targeted by anti-GBM antibodies is strongly influenced by the molecular organization of the immunogen. These findings suggest that different isoforms of α3(IV) collagen may be implicated in the pathogenesis of ARAS posttransplantation anti-GBM nephritis and Goodpasture disease.
Follicular atrophoderma with multiple basal cell carcinomas (Bazex)
Authors: D.J. Gould, D.J. Barker
Journal: British Journal of Dermatology (1978)

Five patients from a single family are reported who have an inherited condition of which the main features are follicular atrophoderma, abnormalities of scalp hair and multiple basal cell carcinomas. These abnormalities are consistent with the syndrome described by Bazex et al. (1964). The pattern of inheritance of this condition is discussed.
For Debate: Can contracts drive clinical care?
Authors: A. Hopkins, J. K Solomon
Journal: BMJ (1996)

The instrument through which a commissioner purchases health services from a provider is, as in other walks of life, a contract, so considerable importance has been attached by the NHS Executive to the contracting mechanism.A contract should in theory influence the quality of the serv- ice provided, but they are in many cases an inap- propriate vehicle for driving clinical care.Much clinical activity is related to the management of chronic diseases and the effects of aging.The implicit contract here is based not on process and outcome measures but on mutual trust between doctors and patients that the doctors will provide the best care they can within budgetary con- straints.