tbuckley/cabot-search huggingface dataset:
Activation of the STAT1 pathway in rheumatoid arthritis
Authors: P V Kasperkovitz, N L Verbeet, T J Smeets, J G I van Rietschoten, M C Kraan, T C T M van der Pouw Kraan, P P Tak, C L Verweij
Journal: Annals of the Rheumatic Diseases (2004)

Expression of signal transducer and activator of transcription 1 (STAT1), the mediator of interferon (IFN) signalling, is raised in synovial tissue (ST) from patients with rheumatoid arthritis (RA).To determine the extent to which this pathway is activated by phosphorylation in RA synovium. Additionally, to investigate the cellular basis of STAT1 activation in RA ST.ST specimens from 12 patients with RA and 14 disease controls (patients with osteoarthritis and reactive arthritis) were analysed by immunohistochemistry, using antibodies to STAT1, tyrosine phosphorylated STAT1, and serine phosphorylated STAT1. Lysates of cultured fibroblast-like synoviocytes stimulated with IFNbeta were analysed by western blotting. Phenotypic characterisation of cells expressing STAT1 in RA ST was performed by double immunolabelling for STAT1 and CD3, CD22, CD55, or CD68.Raised levels of total STAT1 protein and both its activated tyrosine and serine phosphorylated forms were seen in RA synovium as compared with controls. STAT1 was predominantly abundant in T and B lymphocytes in focal inflammatory infiltrates and in fibroblast-like synoviocytes in the intimal lining layer. Raised levels of STAT1 are sustained in cultured RA compared with OA fibroblast-like synoviocytes, and STAT1 serine and tyrosine phosphorylation is rapidly induced upon stimulation with IFNbeta.These results demonstrate activation of the STAT1 pathway in RA synovium by raised STAT1 protein expression and concomitantly increased tyrosine (701) and serine (727) phosphorylation. High expression of STAT1 is intrinsic to RA fibroblast-like synoviocytes in the intimal lining layer, whereas activation of the pathway by phosphorylation is an active process.
Trypanosoma brucei cathepsin-L increases arrhythmogenic sarcoplasmic reticulum-mediated calcium release in rat cardiomyocytes
Authors: Elspeth B. Elliott, Douglas McCarroll, Hisashi Hasumi, Claire E. Welsh, Amanda A. Panissidi, Nathaniel G. Jones, Charlotte L. Rossor, Andy Tait, Godfrey L. Smith, Jeremy C. Mottram, Liam J. Morrison, Christopher M. Loughrey
Journal: Cardiovascular Research (2013)

African trypanosomiasis, caused by Trypanosoma brucei species, leads to both neurological and cardiac dysfunction and can be fatal if untreated. While the neurological-related pathogenesis is well studied, the cardiac pathogenesis remains unknown. The current study exposed isolated ventricular cardiomyocytes and adult rat hearts to T. brucei to test whether trypanosomes can alter cardiac function independent of a systemic inflammatory/immune response. Using confocal imaging, T. brucei and T. brucei culture media (supernatant) caused an increased frequency of arrhythmogenic spontaneous diastolic sarcoplasmic reticulum (SR)-mediated Ca2+ release (Ca2+ waves) in isolated adult rat ventricular cardiomyocytes. Studies utilising inhibitors, recombinant protein and RNAi all demonstrated that this altered SR function was due to T. brucei cathepsin-L (TbCatL). Separate experiments revealed that TbCatL induced a 10–15% increase of SERCA activity but reduced SR Ca2+ content, suggesting a concomitant increased SR-mediated Ca2+ leak. This conclusion was supported by data demonstrating that TbCatL increased Ca2+ wave frequency. These effects were abolished by autocamtide-2-related inhibitory peptide, highlighting a role for CaMKII in the TbCatL action on SR function. Isolated Langendorff perfused whole heart experiments confirmed that supernatant caused an increased number of arrhythmic events. These data demonstrate for the first time that African trypanosomes alter cardiac function independent of a systemic immune response, via a mechanism involving extracellular cathepsin-L-mediated changes in SR function.
Hepatocyte growth factor/c-Met signalling is important for the selection of transplanted hepatocytes
Authors: Michaela Kaldenbach, Arne Giebeler, Darjus F Tschaharganeh, Stephanie Erschfeld, Hermann E Wasmuth, Laurent Dolle, Juergen Floege, Christian Trautwein, Konrad L Streetz
Journal: Gut (2012)

<h3>Background</h3> At present hepatocyte transplantation is a promising option for cellular therapy of end-stage liver diseases. However, the underlying molecular mechanisms need to be better defined in order to translate this technique into clinical use. This study investigated the cursiv relevance of hepatocyte growth factor (HGF)/c-Met signalling for hepatocyte repopulation after transplantion. <h3>Methods</h3> Wild-type mice (c-Met<sup>loxP/loxP</sup>) and hepatocyte-specific conditional c-Met (HGF receptor) knockout (c-Met<sup>Δhepa</sup>) mice were used as donors and recipients for hepatocyte transplantation. <h3>Results</h3> Transplantation experiments revealed two major findings. First it was demonstrated that c-Met is indispensable in donor cells, as c-Met<sup>Δhepa</sup> cells did not repopulate recipient livers after transplantation. Second, genetic deletion of c-Met in recipient hepatocytes resulted in enhanced expansion of unmodified donor cells in host livers (up to 250-fold after 12 weeks). The relevant mechanisms for this observation in c-Met<sup>Δhepa</sup> host hepatocytes could be defined. c-Met<sup>Δhepa</sup> hepatocytes showed enhanced apoptosis, reduced cellular proliferation and a lack of AKT-kinase and STAT3 activation. In addition, tissue remodelling was changed in c-Met<sup>Δhepa</sup> recipient livers. Therefore, the lack of pro-proliferative transcription factors, increased apoptosis and changes in matrix-remodelling inhibit host cell proliferation in c-Met<sup>Δhepa</sup> recipient livers and thus favour repopulation of transplanted hepatocytes. Therapeutically liver repopulation could be increased through adenoviral expression of NK-4—an inhibitor of HGF signalling—in host hepatocytes. <h3>Conclusion</h3> HGF/c-Met plays a crucial role in host and donor cells of the liver for the cursiv selection of transplanted hepatocytes. Modulating HGF-dependent signalling seems a promising therapeutic option to favour expansion of transplanted hepatocytes.
Effect of digoxin and vitamin E in preventing cardiac damage caused by doxorubicin in acute myeloid leukaemia.
Authors: J A Whittaker, S A Al-Ismail
Journal: BMJ (1984)

Fat content and fatty acid composition of pooled banked milkThe amount of fat in human milk is influenced by diurnal variations in fat content, by the stage of lactation, and, more importantly, by the method of milk collection-namely, whether it is expressed or dripped.'In human milk banks milk is usually pooled, and pooling is generally assumed to result in a more uniform fat content.We compared the fat contents in pooled banked human milk and a commercially available formula milk.We also analysed the fatty acid composition of pooled banked human milk and compared our findings with those published by the Department of Health and Social Security.2 Methods and resultsWe obtained milk samples from 22 batches of pooled human milk arriving at the special care baby unit from the milk bank, and from SMA ready to feed formula milk for infants.The human milk had been collected by three or four mothers at home over one to five days and stored in the freezing compartment of a domestic refrigerator; after thawing this milk was pooled 8 0 6-O O 0 8 4-0000 Creamatocrit 0 (%) 0 00 0 0 2 0 Distribution of creamatocrit values in 22 samples of pooled banked milk and 22 of a formula milk.Each value is the mean of three determinations in a single milk specimen.Horizontal lines indicate mean values.in 200 ml corntainers.It consisted of expressed breast milk and milk that had dripped from the opposite breast when the baby was being fed.We measured the fat content of the milk by the creamatocrit method.3'vilk triglycerides were separated by thin layer chromatography, and the tatty acid composition was determined by gas-liquid chromatography.4Mlean creamatocrit values were compared by Student's t test.In pooled banked human milk the maximum creamatocrit, 7-26%, was nearly four times greater than the minimum creamatocrit, 1-72%, and a third of the creamatocrit values were below 4% (figure).By contrast, the creamatocrit values in formula milk were distributed over a fairly narrow range (4-75-5-26%).The mean creamatocrit in formula milk (5.16 (SD 0-19)%) was significantly greater than that in pooled human milk (4-21(1-24)) (p<0-001) (figure).Comparison of the fatty acid composition of our pooled banked human milk with that of mature human milk analysed by the Department of Health and Social Security2 showed that our milk contained more linoleic acid and linolenic acid (polyunsaturated fatty acids C18:2 and C18:3) but less lauric acid (saturated fatty acid C12:0).In our 22 specimens of pooled banked milk the mean proportions of linoleic, linolenic, and lauric acids were 1 12%, 1-2%, and 2-7%; the proportions reported by the Department of Health and Social Security were 7-2%, 0-8%, and 5-4% respectively.
Early disease onset is predicted by a higher genetic risk for lupus and is associated with a more severe phenotype in lupus patients
Authors: R. Webb, J. A. Kelly, E. C. Somers, T. Hughes, K. M. Kaufman, E. Sanchez, S. K. Nath, G. Bruner, M. E. Alarcon-Riquelme, G. S. Gilkeson, D. L. Kamen, B. C. Richardson, J. B. Harley, A. H. Sawalha
Journal: Annals of the Rheumatic Diseases (2010)

<h3>Background</h3> Systemic lupus erythematosus (SLE) is a chronic, multiorgan, autoimmune disease that affects people of all ages and ethnicities. <h3>Objectives</h3> To explore the relationship between age at disease onset and many of the diverse manifestations of SLE. Additionally, to determine the relationship between age of disease onset and genetic risk in patients with SLE. <h3>Methods</h3> The relationship between the age at disease onset and SLE manifestations were explored in a multi-racial cohort of 1317 patients. Patients with SLE were genotyped across 19 confirmed genetic susceptibility loci for SLE. Logistic regression was used to determine the relationships between the number of risk alleles present and age of disease onset. <h3>Results</h3> Childhood-onset SLE had higher odds of proteinuria, malar rash, anti-dsDNA antibody, haemolytic anaemia, arthritis and leucopenia (OR=3.03, 2.13, 2.08, 2.50, 1.89, 1.53, respectively; p values &lt;0.0001, 0.0004, 0.0005, 0.0024, 0.0114, 0.045, respectively). In female subjects, the odds of having cellular casts were 2.18 times higher in childhood-onset than in adult-onset SLE (p=0.0027). With age of onset ≥50, the odds of having proteinuria, cellular casts, anti-nRNP antibody, anti-Sm antibody, anti-dsDNA antibody and seizures were reduced. However, late adult-onset patients with SLE have higher odds of developing photosensitivity than early adult-onset patients. Each SLE-susceptibility risk allele carried within the genome of patients with SLE increased the odds of having a childhood-onset disease in a race-specific manner: by an average of 48% in Gullah and 25% in African-Americans, but this was not significant in Hispanic and European-American lupus patients. <h3>Conclusions</h3> The genetic contribution towards predicting early-onset disease in patients with SLE is quantified for the first time. A more severe SLE phenotype is found in patients with early-onset disease in a large multi-racial cohort, independent of gender, race and disease duration.
Oral administration of GLPG0259, an inhibitor of MAPKAPK5, a new target for the treatment of rheumatoid arthritis: a phase II, randomised, double-blind, placebo-controlled, multicentre trial
Authors: René Westhovens, Filip De Keyser, Dmytro Rekalov, Evgeny L Nasonov, Johan Beetens, Annegret Van der Aa, Piet Wigerinck, Florence Namour, Frédéric Vanhoutte, Patrick Durez
Journal: Annals of the Rheumatic Diseases (2012)

<h3>Background</h3> Mitogen-activated protein (MAP) kinases are key regulators of cytokine production, and are therefore potential targets for treatment of rheumatoid arthritis (RA). <h3>Objective</h3> This two-part phase II study investigated the efficacy and safety of a once-daily 50 mg GLPG0259 (an inhibitor of MAP kinase-activated protein kinase 5) dose vs placebo (part A). An interim analysis after part A would determine whether the dose-finding part (part B) would be performed. <h3>Methods</h3> In part A, eligible methotrexate (MTX)-refractory patients with RA were randomised to receive either a once-daily 50 mg dose of GLPG0259 or placebo, in addition to a stable dose of MTX, for 12 weeks. The primary efficacy end point was the percentage of patients achieving an American College of Rheumatology 20% improvement (ACR20) response after 12 weeks. <h3>Results</h3> The interim analysis showed no difference between the percentage of subjects achieving the primary efficacy variable of ACR20 or the secondary efficacy variables (ACR50, ACR70 and Disease Activity Score 28) at week 12 in the GLPG0259-treated (n=19) and placebo-treated (n=11) groups. Owing to lack of efficacy, the study was terminated, and part B was not initiated. <h3>Conclusions</h3> This innovative study design quickly provided conclusive results on the lack of efficacy of GLPG0259 in patients with RA.
Captopril-induced pemphigus.
Authors: P S Parfrey, M Clement, M J Vandenburg, P Wright
Journal: BMJ (1980)

Case reportA 28-year-old European woman presented with nausea and mild diarrhoea.She was taking pyrimethamine 25 mg twice weekly for malaria prophylaxis.A blood film showed malaria parasites.Unfortunately facilities were not available for species identification, but the malaria in the district was generally assumed to be due to Plasmodium falciparum.She was given a course of chloroquine by mouth to a total of 1800 mg.For a body weight of 45 kg that amply met the WHO recommended standards.She had no diarrhoea or vomiting while taking the drug.She had never had malaria before nor had she previously taken chloroquine.The treatment did not relieve her symp- toms-in fact, they were added to by the drug's side effects.Five days after her initial presentation a blood film, examined at a different laboratory, showed abundant parasites.Her haemoglobin concentration was 12 g/dl.She was therefore given Fansidar (pyrimethamine 25 mg, sulphadoxine 500 mg) three tablets immediately.Four days later she again attended, feeling weak and dizzy, with a tempera- ture of 38'C.There were still a few plasmodia in the blood film.She was given chloroquine 800 mg immediately, to be repeated once weekly for three weeks-although only one of these doses was taken.She slowly improved, and two weeks after her first attendance her blood film was clear.No parasites were found in a repeat film after a further two weeks.
Treating refractory epilepsy in adults
Authors: Edward Reynolds
Journal: BMJ (2006)

The choice of drug or drug combinations is bewildering 

M ost adult patients with refractory epilepsy have partial (focal) seizures with or without secondary generalisation. During the 1970s and early 1980s studies showed that in 70-80% of adults with newly diagnosed epilepsy, seizures were controlled successfully by carefully monitored monotherapy with any of the four standard antiepileptic drugs—phenobarbital, phenytoin, carbamazepine, or sodium valproate—all of which seemed to have similar efficacy in partial epilepsy in later comparative trials of monotherapy.1–4 Furthermore, adding a second drug for patients with continuing seizures on optimum monotherapy led to modest benefit in no more than one third, a deterioration in seizure control or unacceptable toxicity in about a quarter, and no change in the rest.2 5

These studies led to important questions. Should patients unresponsive to the optimum use of the first drug be switched to alternative monotherapy or treated with polytherapy? If so, …
Evolutionary Constraint in Flanking Regions of Avian Genes
Authors: Axel Künstner, Benoit Nabholz, Hans Ellegren
Journal: Molecular Biology and Evolution (2011)

An important comprehension from comparative genomic analysis is that sequence conservation beyond neutral expectations is frequently found outside protein-coding regions, indicating important functional roles of noncoding DNA. Understanding the causes of constraint on noncoding sequence evolution forms an important area of research, not least in light of the importance for understanding the evolution of gene expression. We aligned all orthologous genes of chicken and zebra finch together with 5 kb of their upstream and downstream noncoding sequences, to study the evolution of gene flanking sequences in the avian genome. Using ancestral repeats as a neutral reference, we detected significant evolutionary constraint in the 3′ flanking region, highest directly after termination (60%) and then gradually decreasing to about 20% 5 kb downstream. Constraint was higher in annotated 3′ untranslated regions (UTRs) than in non-UTRs at the same distance from the stop codon and higher in sequences annotated as microRNA (miRNA)-binding sites than in non–miRNA-binding sites within 3′ UTRs. Constraint was also higher when estimated for a smaller data set of genes from more closely related songbird species, indicating turnover of functional elements during avian evolution. On the 5′ flanking side constraint was readily seen within the first 125 bp immediately upstream of the start codon (34%) and was about 10% for remaining sequence within 5 kb upstream. Analysis of chicken polymorphism data gave further support for the highest constraint directly before and after the translated region. Finally, we found that genes evolving under the highest constraint measured by dN/dS also had the highest level of constraint in the 3′ flanking region. This study broadens the insights into gene flanking sequence evolution by adding new findings from a vertebrate lineage other than mammals.
Hormone Replacement Therapy and Lung Cancer Risk
Authors: Matthew B. Schabath, Xifeng Wu, Rena Vassilopoulou-Sellin, Ara A. Vaporciyan, Margaret R. Spitz
Journal: Clinical Cancer Research (2004)

Abstract Purpose: To date, there are few published data regarding the use of hormone replacement therapy (HRT) and lung cancer risk. Therefore, we analyzed data regarding HRT use from a large case-control study designed to study genetic susceptibility to lung cancer to determine whether HRT affected risk of lung cancer. Experimental Design: In a secondary analysis, we compared self-reported HRT use among 499 women with lung cancer and 519 healthy age-matched controls. Results: HRT use was associated with an overall reduced risk of 34% [odds ratio (OR), 0.66; 95% confidence interval (CI), 0.51–0.89] of lung cancer, after adjusting for age, ethnicity, smoking status, education, body mass index, and menopausal status. The use of estrogen replacement therapy alone was associated with a 35% reduction in lung cancer risk (OR, 0.65; 95% CI, 0.47–0.89) and the use of combination therapy (estrogen and progestin) was associated with a 39% reduction in lung cancer risk (OR, 0.61; 95% CI, 0.40–0.92). HRT use was also associated with a statistically significantly reduced risk of lung cancer in current smokers (OR, 0.59; 95% CI, 0.38–0.92), but the risk estimates were not statistically significant in never (OR, 0.72; 95% CI, 0.37–1.40) or former smokers (OR, 0.73; 95% CI, 0.46–1.15). In addition, as the cigarette pack-years increased among ever smokers, the protective effect diminished, so that light smokers appeared to benefit the most from HRT use. Decreased lung cancer risks were also evident when the data were stratified by age, ethnicity, and body mass index. The joint effects of HRT use and mutagen sensitivity suggest that HRT use modifies lung cancer risk for genetically susceptible women. HRT use was also associated with a lower risk of death and improved survival compared with the women not taking HRT. To provide a possible biological mechanism to explain our findings, we compared plasma levels of insulin-like growth factor I in users and nonusers, and demonstrated that HRT use was associated with statistically significantly lower insulin-like growth factor I levels for both cases and controls compared with non-HRT users. Conclusions: These data suggest an association of HRT use with a decrease in lung cancer risk. However, there are several limitations to this secondary analysis, requiring that the data be viewed with caution, and confirmation is required in well-designed hypothesis driven studies. The biological role of HRT in lung cancer remains understudied, and only extensive research can yield new insights into the mechanisms underlying a protective effect of HRT for lung cancer.
Melatonin inhibits nuclear factor kappa B activation and oxidative stress and protects against thioacetamide induced liver damage in rats
Authors: Rafael Bruck, Hussein Aeed, Yona Avni, Haim Shirin, Zipora Matas, Mark Shahmurov, Ilana Avinoach, Galina Zozulya, Nir Weizman, Ayala Hochman
Journal: Journal of Hepatology (2003)
Patterns of Use and Cost for Inappropriate Radioactive Iodine Treatment for Thyroid Cancer in the United States
Authors: Paolo Goffredo, Samantha M. Thomas, Michaela A. Dinan, Jennifer M. Perkins, Sanziana A. Roman, Julie A. Sosa
Journal: JAMA Internal Medicine (2015)

Roy Xiao, MD, MS; Vinay K. Rathi, MD, MBA; Cary P. Gross, MD; Joseph S. Ross, MD, MHS; Rosh K. V. Sethi, MD, MPH
Decreases in Renal Functional Reserve and Proximal Tubular Fluid Output in Conscious Oophorectomized Rats
Authors: Camilla Birch Nielsen, Allan Flyvbjerg, Jens Meldgaard Bruun, Axel Forman, Lise Wogensen, Klaus Thomsen
Journal: Journal of the American Society of Nephrology (2003)

Age-dependent glomerulosclerosis with reduced GFR develops earlier among men than among women. Therefore, whether female sex hormones could prevent the age-dependent decrease in GFR was investigated. The kidney function in oophorectomized rats treated with placebo (OOX group), estrogen (OOX+E(2) group), or estrogen plus progesterone (OOX+E(2)+P group) for 5 mo and in sham-operated rats (sham group) was examined. The rats were 13 mo of age at the time of the investigation. They were conscious and chronically instrumented. The results demonstrated that estrogen, alone or in combination with progesterone, was without effect on the baseline GFR and effective renal plasma flow but prevented severe decreases in the renal functional reserve and fractional proximal tubular fluid output (lithium clearance technique, fractional lithium excretion), which were observed in the OOX group. The renal functional reserve (estimated by stimulation with glycine) was -223 +/- 151, 483 +/- 129, 675 +/- 76, and 208 +/- 140 micro l/min in the OOX, OOX+E(2), OOX+E(2)+P, and sham groups, respectively. Fractional lithium excretion was 12.4 +/- 3.1, 26.8 +/- 2.0, 31.8 +/- 2.5, and 23.6 +/- 3.3% in the OOX, OOX+E(2), OOX+E(2)+P, and sham groups, respectively. In conclusion, oophorectomy at the age of 8 mo did not produce a decrease in baseline GFR in female rats within a period of 5 mo. However, oophorectomy led to severe decreases in the renal functional reserve and fractional proximal tubular fluid output. Both effects were prevented with administration of estrogen. Sham-operated rats demonstrated values for renal functional reserve and fractional lithium excretion that were between those observed for the OOX group and the groups treated with sex hormones.