tbuckley/cabot-search huggingface dataset:
The role of sodium in the uptake of ursodeoxycholic acid in isolated hamster hepatocytes
Authors: Bernard Bouscarel, Robert Nussbaum, Howard Dubner, Hans Fromm
Journal: Hepatology (1995)

The uptake of ursodeoxycholic acid (UDCA) was studied in isolated hamster hepatocytes. The uptake was rapid and linear up to 60 seconds for each concentration studied. When the uptake rate was plotted against UDCA concentration, the curve was nonlinear, indicating both saturable and nonsaturable uptake mechanisms. The nonsaturable process had a diffusion constant of 0.01 nmol.s-1.g of cell.mumol/L-1. The saturable component was characterized by a maximum rate of uptake (Vmax) of 5.68 nmol.s-1.g of cell-1 and a Michaelis constant (Km) of 224 mumol/L. In the presence of monensin, ouabain, and amiloride, the uptake of UDCA was significantly decreased by 35% to 55%, whereas the sodium-independent uptake of UDCA was not affected by either monensin or amiloride, thereby confirming sodium dependence of UDCA uptake. The sodium-dependent uptake of UDCA was characterized by a Vmax and a Km of 1.57 nmol.s-1.g of cell-1 and 46 mumol/L, respectively. The rate of uptake of UDCA was maximal at extracellular sodium concentrations > or = 20 mmol/L. Furthermore, the uptake of UDCA was competitively inhibited by both taurocholic acid and cholic acid with an inhibitory constant (Ki) of 60 mumol/L and 48 mumol/L, respectively. Finally, 1 mmol/L of 4,4'-diisothiocyano-2,2'-disulfonic stilbene (DIDS) inhibited solely the sodium-dependent uptake of cholic acid and UDCA. These findings confirm that the hepatocellular uptake of UDCA involves, at least in part, a sodium-dependent, ouabain, amiloride, and DIDS-sensitive transporter.
Aggressive treatment in early rheumatoid arthritis: a randomised controlled trial
Authors: C H van Jaarsveld, J W Jacobs, M J van der Veen, A A Blaauw, A A Kruize, D M Hofman, H L Brus, G A van Albada-Kuipers, A H Heurkens, E J ter Borg, H C Haanen, C van Booma-Frankfort, Y Schenk, J W Bijlsma
Journal: Annals of the Rheumatic Diseases (2000)

<h3>OBJECTIVES</h3> To compare three therapeutic strategies using slow acting antirheumatic drugs (SAARDs) in early rheumatoid arthritis (RA), for their disease modifying properties, toxicity, and lag time until treatment effect. <h3>METHODS</h3> Patients with recent onset RA from six hospitals were randomly assigned to immediate initiation of one of three treatment strategies: (I) a “mild SAARD with a long lag time” (hydroxychloroquine, if necessary replaced by auranofin); (II) a “potent SAARD with a long lag time” (intramuscular gold, if necessary replaced byd-penicillamine); (III) a “potent SAARD with a short lag time” (methotrexate, if necessary replaced by sulfasalazine). Comparisons included two years of follow up. <h3>RESULTS</h3> All SAARD strategies reduced mean disease activity. A greater percentage of patients improved clinically with strategies II and III than with strategy I: percentages of patients improved on joint score with strategies II and III (79% and 82%, respectively), which was statistically different from strategy I (66%). The same was true for remission percentages: 31% and 24% <i>v</i> 16%, respectively). Longitudinal analysis showed significantly less disability with strategy III, and a lower erythrocyte sedimentation rate with strategy II than with strategy I. In addition, radiological damage after one and two years, was significantly lower in strategies II and III (at two years median scores were 11 and 10<i>v</i> 14 in strategy I, p&lt;0.05). Toxicity was increased in strategy II compared with the other strategies. <h3>CONCLUSION</h3> Strategy III, comprising methotrexate or sulfasalazine, produced the best results weighing effectiveness and toxicity. Strategy I (hydroxychloroquine or auranofin) was slightly less effective, and strategy II (intramuscular gold or d-penicillamine) was associated with increased toxicity.
Thymic selection of H-2-incompatible bone marrow cells in SCID mice. Differences in T help for induction of B cell IgG responses versus cytotoxic T cells.
Authors: R M Zinkernagel, E Rüedi, A Althage, H Hengartner, G Reimann
Journal: The Journal of Experimental Medicine (1988)

Mice with congenital severe combined immunodeficiency disease (SCID) failed to mount either a T cell-independent IgM or T cell-dependent IgG anti-vesicular stomatitis virus (VSV) Indiana (IND) response. They did not generate cytotoxic T cells against lymphocytic choriomeningitis virus (LCMV) or vaccinia virus, but exhibited NK cell-like activities. When SCID mice were given bone marrow from syngeneic BALB/c (H-2d) nu/nu mice, all immune responses were expressed at control levels. If SCID mice were reconstituted with allogeneic H-2b C57BL/6 nu/nu bone marrow, the following primary anti-viral immune responses were measured. T-independent IgM anti-VSV-IND were normal, but T-dependent IgG anti-VSV-IND responses were absent. Cytotoxic T cell responses to LCMV and vaccinia virus were within normal ranges, were donor cell mediated, and were specific exclusively for the recipient SCID H-2d type. Since antigen presentation by spleen cells was functional in these chimaeras, the presented results indicate that (a) thymic selection of T cell restriction is strict; and (b) the type of T help necessary for B cells depends upon H-2-restricted contact between T and B cells, whereas, such contact-dependent help is not mandatory for the induction of virus-specific cytotoxic T cells.
Maternal Embryonic Leucine Zipper Kinase/Murine Protein Serine-Threonine Kinase 38 Is a Promising Therapeutic Target for Multiple Cancers
Authors: Daniel Gray, Adrian M. Jubb, Deborah Hogue, Patrick Dowd, Noelyn Kljavin, Sothy Yi, Wei Bai, Gretchen Frantz, Zemin Zhang, Hartmut Koeppen, Frederic J. de Sauvage, David P. Davis
Journal: Cancer Research (2005)

To identify genes that could serve as targets for novel cancer therapeutics, we used a bioinformatic analysis of microarray data comparing gene expression between normal and tumor-derived primary human tissues. From this approach, we have found that maternal embryonic leucine zipper kinase (Melk), a member of the AMP serine/threonine kinase family, exhibits multiple features consistent with the potential utility of this gene as an anticancer target. An oligonucleotide microarray analysis of multiple human tumor samples and cell lines suggests that Melk expression is frequently elevated in cancer relative to normal tissues, a pattern confirmed by quantitative reverse transcription-PCR and Western blotting of selected primary tumor samples. In situ hybridization localized Melk expression to malignant epithelial cells in 96%, 23%, and 13% of colorectal, lung, and ovarian tissue tumor samples, respectively. Expression of this gene is also elevated in spontaneous tumors derived from the ApcMin and Apc1638N murine models of intestinal tumorigenesis. To begin addressing whether Melk is relevant for tumorigenesis, RNA interference-mediated silencing within human and murine tumor cell lines was done. We show that Melk knockdown decreases proliferation and anchorage-independent growth in vitro as well as tumor growth in a xenograft model. Together, these results suggest that Melk may provide a growth advantage for neoplastic cells and, therefore, inactivation may be therapeutically beneficial.
Cholesterol lowering in low density lipoprotein receptor knockout mice overexpressing apolipoprotein E.
Authors: J Osuga, M Yonemoto, N Yamada, H Shimano, H Yagyu, K Ohashi, K Harada, T Kamei, Y Yazaki, S Ishibashi
Journal: Journal of Clinical Investigation (1998)

Apo E is a key molecule in the lipoprotein metabolism; thus, genetic manipulation of apo E may prove useful in the treatment of hypercholesterolemia. To test the feasibility of this idea, we have generated low density lipoprotein receptor (LDLR) knockout mice that overexpress the rat apo E transgene (ETg+/+:LDLRKO), and compared their plasma lipoprotein profiles with those of nonexpressing LDLR knockout mice (ETg-/-:LDLRKO). On a normal chow diet, the mean plasma cholesterol level of ETg+/+:LDLRKO mice was significantly lower than that of ETg-/-:LDLRKO mice (189 versus 240 mg/dl, P < 0. 01). The LDL fraction was selectively reduced in the ETg+/+:LDLRKO mice. Despite the challenge with an atherogenic diet, cholesterol lowering was persistently observed and fatty streak lesions in the aortic sinus were significantly suppressed in the mice overexpressing apo E. These results imply that stimulation of hepatic production of apo E may be used as a promising adjunctive therapy for homozygous familial hypercholesterolemia.
Identification of 15 new psoriasis susceptibility loci highlights the role of innate immunity
Authors: Lam C Tsoi, Sarah L Spain, Jo Knight, Eva Ellinghaus, Philip E Stuart, Francesca Capon, Jun Ding, Yanming Li, Trilokraj Tejasvi, Johann E Gudjonsson, Hyun M Kang, Michael H Allen, Ross McManus, Giuseppe Novelli, Lena Samuelsson, Joost Schalkwijk, Mona Ståhle, A David Burden, Catherine H Smith, Michael J Cork, Xavier Estivill, Anne M Bowcock, Gerald G Krueger, Wolfgang Weger, Jane Worthington, Rachid Tazi-Ahnini, Frank O Nestle, Adrian Hayday, Per Hoffmann, Juliane Winkelmann, Cisca Wijmenga, Cordelia Langford, Sarah Edkins, Robert Andrews, Hannah Blackburn, Amy Strange, Gavin Band, Richard D Pearson, Damjan Vukcevic, Chris C A Spencer, Panos Deloukas, Ulrich Mrowietz, Stefan Schreiber, Stephan Weidinger, Sulev Koks, Külli Kingo, Tonu Esko, Andres Metspalu, Henry W Lim, John J Voorhees, Michael Weichenthal, H Erich Wichmann, Vinod Chandran, Cheryl F Rosen, Proton Rahman, Dafna D Gladman, Christopher E M Griffiths, Andre Reis, Juha Kere, Rajan P Nair, Andre Franke, Jonathan N W N Barker, Goncalo R Abecasis, James T Elder, Richard C Trembath
Journal: Nature Genetics (2012)
DOES RUNNING SHOE MIDSOLE HARDNESS INFLUENCE RUNNING-RELATED INJURIES? RESULTS FROM A DOUBLE BLIND RANDOMIZED CONTROLLED TRIAL
Authors: D Theisen, L Malisoux, N Delattre, R Seil, A Urhausen
Journal: British Journal of Sports Medicine (2014)

Background The shock absorption qualities of running shoes are thought to have an important influence on running-related injuries (RRIs). However, scientific evidence of this relationship is still lacking. Objective To test if midsole hardness of standard running shoes was related to RRIs. Design Double-blind randomized controlled trial. Setting Free-roaming leisure-time distance runners. Participants Study participants were recruited through newspaper advertisements, posts on specialized internet sites and via mouth-to-ear. They were required to report any running activity, sport practice and injury using a dedicated internet platform. Recorded information was systematically verified, if necessary through direct contacts with the participants. Risk factor assessment Leisure-time runners were provided with identical running shoes, except for their midsole hardness which was either hard (H; n=113) or soft (S; n=134). They were followed prospectively for 5 months. Main outcome measurements The primary outcome measure was exposure volume (hours) to running practice until first-time RRI (Cox proportional hazards regression analyses). Results Overall, 12.1 RRIs were recorded per 1000 hours of running. There was a 15% difference between the shoe types regarding midsole stiffness. The type of shoe used for running was not related to RRI (hazard ratio (HR)=0.92; 95% confidence interval (CI)=0.57–1.48). Furthermore, no difference was detected regarding RRI patterns (location, severity, etc.). Significant risk factors for RRIs were body mass index (HR=1.13; 95% CI 1.03–1.23), injury in the 12 months preceding the study (HR=1.74; 95% CI 1.04–2.90) and average session intensity (HR=1.40; 95% CI 1.04–1.87). Previous regular running practice (HR=0.42; 95% CI 0.23–0.78) and volume of other sport activities (HR=0.70; 95% CI 0.56–0.88) were significant protective factors. Conclusions RRI risk was not associated with running shoe midsole hardness in this study.
Regulation of PBX3 expression by androgen and Let-7d in prostate cancer
Authors: Håkon Ramberg, Ayham Alshbib, Viktor Berge, Aud Svindland, Kristin Austlid Taskén
Journal: Molecular Cancer (2011)

Abstract Background The pre-leukemia transcription factor 3 (PBX) is part of the PBX family of transcription factors, which is known to regulate genes involved in differentiation of urogenital organs and steroidogenesis. This is of interest with regard to prostate cancer progression as regulation of steroidogenesis is one of the mechanisms involved in the development of castration-resistant prostate cancer. In light of this we wanted to investigate the possible involvement of androgen regulation of PBX3 expression in prostate cancer. Results In this study, we show that PBX3 is post-transcriptionally regulated by androgen in prostate cancer cells and that the effect might be independent of the androgen receptor. Furthermore, PBX3 was identified as a target of Let-7d, an androgen regulated microRNA. Let-7d was down-regulated in malignant compared to benign prostate tissue, whereas up-regulation of PBX3 expression was observed. Conclusions We demonstrate that PBX3 is up-regulated in prostate cancer and post- transcriptionally regulated by androgen through Let-7d.
Tazarotene-Induced Gene 1 (TIG1) Expression in Prostate Carcinomas and Its Relationship to Tumorigenicity
Authors: C. Jing
Journal: JNCI Journal of the National Cancer Institute (2002)

Background: Prostate cancer is the most common noncutaneous male cancer and one of the least understood malignant diseases. Identifying key genetic factors involved in the metastasis of prostate cancer cells is critical. In this study, we used selective subtractive differential gene display to identify a gene whose decreased expression may contribute to the growth and expansion of prostate cancer. Methods: We used 192 primer pair combinations and polymerase chain reaction technology to identify genes expressed in the benign prostate cell line PNT-2 but not in the malignant prostate cancer cell lines LNCaP, Du-145, PC-3, or PC-3M. The tazarotene-induced gene 1 (TIG1) was chosen for further study. TIG1 expression in normal tissues and cell lines was analyzed by northern blot and in normal and tumor prostate tissue sections by in situ hybridization. The in vitro invasiveness (migration through extracellular matrix) and in vivo tumorigenicity (growth in nude mice) were assessed for the highly malignant PC-3M cell line transfected with TIG1 or control cDNA. All statistical tests were two-sided. Results: TIG1 mRNA was expressed in a variety of normal tissues other than prostate tissue. TIG1 mRNA was detected in all 10 normal human prostate tissues and all 51 benign prostatic hyperplastic tissues analyzed but in only four of 51 malignant prostate tissues analyzed. Compared with vector-transfected cells, transfection of PC-3M cells with TIG1 decreased in vitro invasiveness from 14.7% to 3.7%, (mean difference = 11%; 95% confidence interval [CI] = 9.2% to 12.8%, P<.001) and decreased in vivo tumorigenicity from an average tumor weight of 1.31 g to 0.55 g, (mean difference = 0.76 g; 95% CI = 0.43 to 1.09 g, P<.001). Conclusion: TIG1 may be a tumor suppressor gene whose diminished expression is involved in the malignant progression of prostate cancer.
Chemokine receptor CCR6-dependent accumulation of γδ T cells in injured liver restricts hepatic inflammation and fibrosis
Authors: Linda Hammerich, Jörg M. Bangen, Olivier Govaere, Henning W. Zimmermann, Nikolaus Gassler, Sebastian Huss, Christian Liedtke, Immo Prinz, Sergio A. Lira, Tom Luedde, Tania Roskams, Christian Trautwein, Felix Heymann, Frank Tacke
Journal: Hepatology (2013)

Chronic liver injury promotes hepatic inflammation, representing a prerequisite for organ fibrosis. We hypothesized a contribution of chemokine receptor CCR6 and its ligand, CCL20, which may regulate migration of T-helper (Th)17, regulatory, and gamma-delta (γδ) T cells. CCR6 and CCL20 expression was intrahepatically up-regulated in patients with chronic liver diseases (n = 50), compared to control liver (n = 5). Immunohistochemistry revealed the periportal accumulation of CCR6(+) mononuclear cells and CCL20 induction by hepatic parenchymal cells in liver disease patients. Similarly, in murine livers, CCR6 was expressed by macrophages, CD4 and γδ T-cells, and up-regulated in fibrosis, whereas primary hepatocytes induced CCL20 upon experimental injury. In two murine models of chronic liver injury (CCl4 and methionine-choline-deficient diet), Ccr6(-/-) mice developed more severe fibrosis with strongly enhanced hepatic immune cell infiltration, compared to wild-type (WT) mice. Although CCR6 did not affect hepatic Th-cell subtype composition, CCR6 was explicitly required by the subset of interleukin (IL)-17- and IL-22-expressing γδ T cells for accumulation in injured liver. The adoptive transfer of WT γδ, but not CD4 T cells, into Ccr6(-/-) mice reduced hepatic inflammation and fibrosis in chronic injury to WT level. The anti-inflammatory function of hepatic γδ T cells was independent of IL-17, as evidenced by transfer of Il-17(-/-) cells. Instead, hepatic γδ T cells colocalized with hepatic stellate cells (HSCs) in vivo and promoted apoptosis of primary murine HSCs in a cell-cell contact-dependent manner, involving Fas-ligand (CD95L). Consistent with γδ T-cell-induced HSC apoptosis, activated myofibroblasts were more frequent in fibrotic livers of Ccr6(-/-) than in WT mice. γδ T cells are recruited to the liver by CCR6 upon chronic injury and protect the liver from excessive inflammation and fibrosis by inhibiting HSCs.
Effects of nonsteroidal anti-inflammatory drugs on the bronchial hyperresponsiveness of middle-aged male smokers
Authors: TK Lim, NC Turner, A Watson, H Joyce, RW Fuller, NB Pride
Journal: European Respiratory Journal (1990)

Bronchial hyperresponsiveness (BHR) in smokers is believed to be a consequence of airway wall inflammation. We have examined the effects of treatment with nonsteroidal anti-inflammatory drugs (NSAID) on BHR to inhaled histamine, measured as the provocative concentration reducing forced expiratory volume in one second (FEV1) by 20% (PC20), in middle-aged male cigarette smokers in two separate double-blind, placebo-controlled, cross-over trials. Baseline FEV1 in these smokers ranged from 41-117% predicted values. In the first study 15 men (mean age 58 yrs, FEV1 2.20 l) were examined before and one hour after a single dose of 1.2 g aspirin. There was no significant change in PC20 (geometric mean 1.88 mg.ml-1 pre-aspirin, 1.89 mg.ml-1 post-aspirin) or baseline FEV1 and we observed no tachyphylaxis to the effects of inhaled histamine at one hour after placebo. In the second study 10 men (mean age 60 yrs, FEV1 2.53 l) were examined before and after three days' treatment with the NSAID flurbiprofen 50 mg t.d.s. Baseline PC20 was higher in this group than in the first study. There was no relationship between the excretion of urinary thromboxane metabolites and the intensity of BHR under baseline conditions; flurbiprofen greatly reduced the urinary excretion of thromboxane metabolites, but baseline FEV1 was not altered. Analysis of change in PC20 was complicated by a difference in baseline PC20 before the two treatments, but treatment with flurbiprofen did not significantly attenuate BHR. The results suggest that thromboxane or other cyclo-oxygenase products of arachidonic acid metabolism do not play an important role in the short-term maintenance of BHR to histamine in middle-aged male cigarette smokers.
Randomized trial of a chlorhexidine mouthwash for alleviation of radiation-induced mucositis.
Authors: R L Foote, C L Loprinzi, A R Frank, J R O'Fallon, S Gulavita, H H Tewfik, M A Ryan, J M Earle, P Novotny
Journal: Journal of Clinical Oncology (1994)

PURPOSE To determine whether a chlorhexidine mouthwash could alleviate radiation-induced oral mucositis. PATIENTS AND METHODS Patients scheduled to receive radiation therapy to include greater than one third of the oral cavity mucosa were selected for study. Following stratification, they were randomized in a double-blind manner to receive a chlorhexidine mouthwash or a placebo mouthwash. Both groups were then similarly evaluated for mucositis and mouthwash toxicity. RESULTS Twenty-five patients were randomized to receive the chlorhexidine mouthwash, while 27 received the placebo mouthwash. Treatment arms were well balanced. There was a trend for more mucositis and there was substantially more toxicity (eg, mouthwash-induced discomfort, taste alteration, and teeth staining) on the chlorhexidine arm. CONCLUSION In contrast to the prestudy hypothesis that a chlorhexidine mouthwash might provide benefit for patients receiving radiation therapy to the oral mucosa, this study provides strong evidence suggesting that a chlorhexidine mouthwash is detrimental in this clinical situation.
Stimulus and site specific induction of hiccups in the oesophagus of normal subjects
Authors: R Fass, L Higa, A Kodner, E A Mayer
Journal: Gut (1997)

Background —Hiccups that are induced by a large meal have been suggested to result from gastric overdistension. The role of the oesophagus in precipitating hiccups has never been defined. Aims —To determine the involvement of oesophageal mechanoreceptors in the hiccup reflex. Methods —Ten normal healthy subjects were prospectively evaluated at a university affiliated hospital. Controlled inflation of a polyethylene bag in the proximal and distal oesophagus was carried out using slow ramp and rapid phasic distensions, by an electronic distension device. Results —Hiccups were induced in four subjects only during rapid phasic distensions and only in the proximal oesophagus. The mean (SEM) minimal volume threshold for the hiccup reflex was 32.5 (4.8) ml, which was above the perception threshold. Hiccups appeared during inflation and resolved after deflation. Conclusions —Sudden rapid stretch of the mechanoreceptors in the proximal oesophagus can trigger the hiccup reflex in normal subjects. Only rapid distensions above a determined volume threshold will predictably induce hiccups in a given subject. This mechanism may play a role in the physiological induction of hiccups.
Authors' reply to Oussedik and colleagues
Authors: M. L. Costa
Journal: BMJ (2012)

Oussedik and colleagues make some interesting points about our trial and the place of hip resurfacing in treating patients with severe arthritis.1

The trial involved many surgeons using several different approaches and implants. This was a deliberate policy: a “pragmatic” trial reflects the variety of surgeons, approaches, and implants encountered across the NHS.

Radiographic outcomes and data on metal ions are important factors related …
Safety of unilateral and bilateral percutaneous cervical cordotomy in 80 terminally ill cancer patients.
Authors: M Sanders, W Zuurmond
Journal: Journal of Clinical Oncology (1995)

PURPOSE AND METHODS The safety of percutaneous cervical cordotomy (PCC) and bilateral percutaneous cervical cordotomy (BPCC) was studied in 62 and 18 patients, respectively, with intractable malignant pain. Cordotomy was indicated for pain that did not respond to any other therapy. RESULTS After PCC, 54 patients showed satisfactory, six partial, and two no pain relief. Concerning major permanent complications, urinary retention, hemiparesis, and mirror-image pain occurred in four (6.5%), five (8.1%), and four (6.5%) patients, respectively. After BPCC, nine patients showed satisfactory, six partial, and three no pain relief. The major permanent complications were the same as after PCC, and occurred in two (11.1%), two (11.1%), and one (5.6%) patient, respectively. Sleep-induced apnea was not observed in any patient. CONCLUSION In the treatment of intractable malignant pain, localized unilaterally, if other symptomatic management fails, PCC is a recommendable procedure, particularly when pain due to movement dominates. However, due to the high incidence of complications combined with the high failure rate, BPCC is not recommended.