tbuckley/cabot-search huggingface dataset:
Validity of Messenger RNA Expression Analyses of Human Saliva
Authors: Jack Ballantyne
Journal: Clinical Cancer Research (2007)

To the Editors: In the September 1, 2006 issue of Clinical Cancer Research, Kumar et al. (1) cast doubt on the potential efficacy of saliva as a noninvasive source for the analysis of clinically important gene transcripts. The investigators claim that their data indicate that the cell-free portion of saliva contains no bona fide mRNA species. The investigators report a failure to detect mRNA transcripts from the 36B4, β-actin, and GAPDH housekeeping genes. Instead they detected pseudogene signals originating from contaminating genomic DNA.Previously, we have reported the presence of a number of housekeeping and tissue-specific gene transcripts in saliva, including GAPDH, statherin, and histatin 3 (2, 3). As forensic scientists, we are interested in detecting the presence of tissue-specific mRNAs in dried body fluid stains, including saliva, as a means of positively identifying the tissue source of origin of a physiologic stain recovered from the crime scene (2–4). We have not expressly determined whether the varieties of mRNA species that are routinely detected in saliva originate from the cellular or noncellular "supernatant" fractions of whole saliva because, in the forensic context, the cellular versus noncellular source is immaterial. Nevertheless, the presence of mRNA species in whole saliva is irrefutable and we routinely isolate mRNA of sufficient quality and quantity from whole saliva for routine reverse transcription-PCR and quantitative reverse transcription-PCR analyses. The persistence and stability is such that we can detect and analyze mRNA from small quantities of dried saliva stains collected weeks or even months after the initial deposition.Given our own experience, it is surprising, therefore, that Kumar et al. failed to detect mRNA either in the centrifuged pellet (i.e., cellular fraction) or in whole saliva (which contains cellular components). This may suggest a problem with their experimental technique that puts the validity of their conclusions about the nonpersistence of mRNA in the cell-free portion of saliva in doubt.
Bone Marrow–Derived Myofibroblasts Contribute to the Renal Interstitial Myofibroblast Population and Produce Procollagen I after Ischemia/Reperfusion in Rats
Authors: Martine Broekema, Martin C. Harmsen, Marja J.A. van Luyn, Jasper A. Koerts, Arjen H. Petersen, Theo G. van Kooten, Harry van Goor, Gerjan Navis, Eliane R. Popa
Journal: Journal of the American Society of Nephrology (2006)

Bone marrow-derived cells (BMDC) have been proposed to exert beneficial effects after renal ischemia/reperfusion injury (IRI) by engraftment in the tubular epithelium. However, BMDC can give rise to myofibroblasts and may contribute to fibrosis. BMDC contribution to the renal interstitial myofibroblast population in relation to fibrotic changes after IRI in rats was investigated. A model of unilateral renal IRI (45 min of ischemia) was used in F344 rats that were reconstituted with R26-human placental alkaline phosphatase transgenic BM to quantify BMDC contribution to the renal interstitial myofibroblast population over time. After IRI, transient increases in collagen III transcription and interstitial protein deposition were observed, peaking on days 7 and 28, respectively. Interstitial infiltrates of BMDC and myofibroblasts reached a maximum on day 7 and gradually decreased afterward. Over time, an average of 32% of all interstitial alpha-smooth muscle actin-positive myofibroblasts coexpressed R26-human placental alkaline phosphatase and, therefore, were derived from the BM. BMD myofibroblasts produced procollagen I protein and therefore were functional. The postischemic kidney environment was profibrotic, as demonstrated by increased transcription of TGF-beta and decreased transcription of bone morphogenic protein-7. TGF-beta protein was present predominantly in interstitial myofibroblasts but not in BMD myofibroblasts. In conclusion, functional BMD myofibroblasts infiltrate in the postischemic renal interstitium and are involved in extracellular matrix production.
Simvastatin improves endothelial function in patients with rheumatoid arthritis
Authors: Frank Hermann, Adrian Forster, Rémy Chenevard, Frank Enseleit, David Hürlimann, Roberto Corti, Lukas E. Spieker, Diana Frey, Matthias Hermann, Walter Riesen, Michel Neidhart, Beat A. Michel, Jens P. Hellermann, Renate E. Gay, Thomas F. Lüscher, Steffen Gay, Georg Noll, Frank Ruschitzka
Journal: Journal of the American College of Cardiology (2005)
Identification of the MEK1(F129L) Activating Mutation as a Potential Mechanism of Acquired Resistance to MEK Inhibition in Human Cancers Carrying the <i>B-Raf</i>V600E Mutation
Authors: Huisheng Wang, Sherif Daouti, Wen-hui Li, Yang Wen, Christine Rizzo, Brian Higgins, Kathryn Packman, Neal Rosen, John F. Boylan, David Heimbrook, Huifeng Niu
Journal: Cancer Research (2011)

Although targeting the Ras/Raf/MEK pathway remains a promising anticancer strategy, mitogen-activated protein/extracellular signal-regulated kinase (ERK) kinase (MEK) inhibitors in clinical development are likely to be limited in their ability to produce durable clinical responses due to the emergence of acquired drug resistance. To identify potential mechanisms of such resistance, we established MEK inhibitor-resistant clones of human HT-29 colon cancer cells (HT-29R cells) that harbor the B-RafV600E mutation. HT-29R cells were specifically resistant to MEK inhibition in vitro and in vivo, with drug-induced elevation of MEK/ERK and their downstream targets primarily accountable for drug resistance. We identified MEK1(F129L) mutation as a molecular mechanism responsible for MEK/ERK pathway activation. In an isogenic cell system that extended these findings into other cancer cell lines, the MEK1(F129L) mutant exhibited higher intrinsic kinase activity than wild-type MEK1 [MEK1(WT)], leading to potent activation of ERK and downstream targets. The MEK1(F129L) mutation also strengthened binding to c-Raf, suggesting an underlying mechanism of higher intrinsic kinase activity. Notably, the combined use of Raf and MEK inhibitors overcame the observed drug resistance and exhibited greater synergy in HT-29R cells than the drug-sensitive HT-29 parental cells. Overall, our findings suggested that mutations in MEK1 can lead to acquired resistance in patients treated with MEK inhibitors and that a combined inhibition of Raf and MEK may be potentially useful as a strategy to bypass or prevent drug resistance in the clinic.
Travellers' diarrhoea--an insoluble problem.
Authors: G C Cook
Journal: Gut (1983)

Leading articleTravellers' diarrhoea -an insoluble problem It has been estimated that 250 million people travel each year from one country to another.In many, that experience expands the mind, but in addition loosens the bowels.One estimate suggests that at least 100 million of those travellers experience travellers' diarrhoea (Delhi Belly, Hongkong Dog, Tokyo Trots, Aztec Two Step, GI Trots, Basrah Belly, Rangoon Runs, Ho Chi Minhs, Montezuma's Revenge, Casablanca Crud, Turista, Emporiatric Diarrhoea, Gyppi Tummy, Simla Trots, etc, 43)* Of those, 30% are confined to bed and 40% have to change their programme.4Symptoms usually start within 14 days of arrival and the disease usually resolves untreated in 48 to 72 hours.The incidence of this self-limiting disease is higher in travellers moving from temperate to the less developed countries than vice versa.In some areasfor example, south-east Asia and Mexico -the incidence of travellers' diarrhoea is higher than in some others, such as East Africa.Many different pathogens can be responsible for the symptoms and the ratios of those vary in different locations.The major causative agents are4 Escherichia coli, 40-70%; Shigella, 5-20%; Campylobacter, Rotavirus, Norwalk agent, variable; unidentified, 25-30%.In some areas Salmonellae and Giardia lamblia are also important.Overall, enteropathogenic E coli and shigellae are statistically the most important pathogens, in that order.Various serotypes of E coli produce heat labile and heat stable enterotoxins respectively (in some cases both).Heat labile (like cholera toxin) activates adenylate cyclase, while heat stable specifically activates intestinal guanylate cyclase to produce fluid secretion.In contrast to the smaller heat stable molecule, the heat labile molecule is readily immunogenic.Other enterotoxins might also be present.5The importance of adherence of E coli is not yet clear.6Some share with shigellae the ability to penetrate and multiply within the enterocyte.5There seems no doubt that some cases proceed unrelentlessly to postinfective tropical malabsorption (tropical sprue).2A mixed group of organisms has also been shown in the small intestine of children with persisting symptoms (chronic diarrhoea and weight loss) after travellers' diarrhoea contracted in Pakistan, India, or Morocco.7 In that study, enteropathic E coli, Shigella flexneri, Campylobacter spp, Klebsiella spp, Pseudomonas aeruginosa, adenovirus spp, Candida spp, and Pentatrichomonas hominis were present in different individuals, and in one of them, serology for Giardia lamblia was positive; jejunal biopsies showed villous atrophy and crypt hypertrophy. PROPHYLAXISObviously avoidance of infected food (especially fresh fruit and 1105
The global burden of other musculoskeletal disorders: estimates from the Global Burden of Disease 2010 study
Authors: Emma Smith, Damian G Hoy, Marita Cross, Theo Vos, Mohsen Naghavi, Rachelle Buchbinder, Anthony D Woolf, Lyn March
Journal: Annals of the Rheumatic Diseases (2014)

<h3>Objective</h3> To estimate disability from the remainder of musculoskeletal (MSK) disorders (categorised as other MSK) not covered by the estimates made specifically for osteoarthritis (OA), rheumatoid arthritis (RA), gout, low back pain and neck pain, as part of the Global Burden of Disease (GBD) 2010 study. <h3>Methods</h3> Systematic reviews were conducted to gather the age-sex-specific epidemiological data for other MSK. The focus was on finding health surveys and published studies that measured the overall amount of MSK disorders and complaints, and classified the remainder of MSK disorders that was not RA, OA, gout, low back or neck pain. Six levels of severity were defined to derive disability weights (DWs) and severity distribution. The data, DWs and severity distribution were used to calculate years of life lived with disability (YLDs). Mortality was estimated for MSK-related deaths classified under other MSK. YLDs were added to years of life lost (YLLs) from the mortality estimates to derive overall burden in disability-adjusted life years (DALYs). <h3>Results</h3> Global prevalence of other MSK was 8.4% (95% uncertainty interval (UI) 8.1% to 8.6%). DALYs increased from 20.6 million (95% UI 17.0 to 23.3 million) in 1990 to 30.9 million (95% UI 25.8 to 34.6 million) in 2010. The burden of other MSK increased with age. Globally, other MSK disability burden (YLD) ranked sixth. <h3>Conclusions</h3> Ageing of the global population will further increase the burden of other MSK. Specific MSK conditions within this large category should be considered separately to enable more explicit estimates of their burden in future iterations of GBD.
Low Serum Cholesterol and Mortality
Authors: Carlos Iribarren, Dwayne M. Reed, Randi Chen, Katsuhiko Yano, James H. Dwyer
Journal: Circulation (1995)

Background Many studies have reported an association between a low or lowered blood total cholesterol (TC) level and subsequent nonatherosclerotic disease incidence or death. The question of whether low TC is a true risk factor or alternatively a consequence of occult disease at the time of TC measurement remains unsettled. To shed new light onto this problem, we analyzed TC change over a 6- year period (from exam 1 in 1965 through 1968 to exam 3 in 1971 through 1974) in relation to subsequent 16-year mortality in a cohort of Japanese American men. Methods and Results The study was based on 5941 men 45 to 68 years of age without prior history of coronary heart disease, stroke, cancer, or gastrointestinal-liver disease at exam 1 who also participated in exam 3 of the Honolulu Heart Program. The association of TC change with mortality end points was investigated with two different approaches (continuous and categorical TC change) with standard survival analysis techniques. Falling TC level was accompanied by a subsequent increased risk of death caused by some cancers (hemopoietic, esophageal, and prostate), noncardiovascular noncancer causes (particularly liver disease), and all causes. The risk-factor–adjusted rate of all-cause mortality was 30% higher (relative risk, 1.30; 95% CI, 1.06 to 1.59) among persons with a decline from middle (180 to 239 mg/dL) to low (&lt;180 mg/dL) TC than in persons remaining at a stable middle level. By contrast, there was no significant increase in all-cause mortality risk among cohort men with stable low TC levels. Nonillness mortality (deaths caused by trauma and suicide) was not related to either TC change or the average of TC levels in exams 1 and 3. Conclusions These results add strength to the reverse-causality proposition that catabolic diseases cause TC to decrease.
Identification of three stage-specific proteinases of Plasmodium falciparum.
Authors: P J Rosenthal, K Kim, J H McKerrow, J H Leech
Journal: The Journal of Experimental Medicine (1987)

We have identified and characterized three stage-specific proteinases of Plasmodium falciparum that are active at neutral pH. We analyzed ring-, trophozoite-, schizont-, and merozoite-stage parasites by gelatin substrate PAGE and characterized the identified proteinases with class-specific proteinase inhibitors. No proteinase activity was detected with rings. Trophozoites had a 28 kD proteinase that was inhibited by inhibitors of cysteine proteinases. Mature schizonts had a 35-40 kD proteinase that also was inhibited by cysteine proteinase inhibitors. Merozoite fractions had a 75 kD proteinase that was inhibited by serine proteinase inhibitors. The stage-specific activity of these proteinases and the correlation between the effects of proteinase inhibitors on the isolated enzymes with the effects of the inhibitors on whole parasites suggest potential critical functions for these proteinases in the life cycle of malaria parasites.
Plasma Urokinase Antigen and Plasminogen Activator Inhibitor-1 Antigen Levels Predict Angiographic Coronary Restenosis
Authors: Bradley H. Strauss, Herbert K. Lau, Kimberley A. Bowman, John Sparkes, Robert J. Chisholm, M. Bernadette Garvey, Louis L. Fenkell, Madhu K. Natarajan, Inderbir Singh, Jerome M. Teitel
Journal: Circulation (1999)

The fibrinolytic system is intimately involved in several processes that contribute to restenosis, including clot dissolution, cell migration, and tissue remodeling. However, the role of the individual activators (urokinase [uPA] and tissue plasminogen [tPA] activators) and inhibitors (plasminogen activator inhibitor [PAI-1]) of the fibrinolytic system in maintaining patency after coronary artery angioplasty and stenting is unclear.We prospectively studied 159 patients with stable angina who underwent successful elective angioplasty (n=110) or stenting (n=49) of de novo native coronary artery lesions. Plasma samples were drawn at baseline (before angioplasty) and serially after angioplasty (immediately afterward and 6 hours, 24 hours, 3 days, 7 days, 1 month, 3 months, and 6 months afterward). Antigen and activity assays were performed for uPA, tPA, and PAI-1. Follow-up quantitative coronary angiography was performed in 92% of eligible patients. The overall angiographic restenosis rate (diameter stenosis >50%) was 31% (37% in PTCA patients, 17% in stented patients). At all time periods, including baseline, uPA antigen levels were significantly higher and PAI-1 antigen levels were significantly lower in patients with restenosis. Restenosis rates for patients in the upper tertile of baseline uPA antigen levels were 2-fold higher than for those in the lower 2 tertiles (46% versus 24% and 22%, respectively; P<0.004). In a stepwise regression multivariate analysis, obstruction diameter after the procedure and uPA antigen were significant predictors of follow-up diameter stenosis.Plasma uPA antigen levels and PAI-1 antigen levels identify patients at increased risk for restenosis after percutaneous coronary revascularization.
Evidence to the coroner.
Authors: J S Bailey
Journal: BMJ (1971)

describe four patients who developed acute myeloblastic leukaemia after treatment of a hypoplastic anaemia with oxymetholone.I should like to report a similar case.A 51-year-old man presented in April 1969.The blood count was: haemoglobin 9-4 g/100 ml, white cells 2,800/mm3 (neutrophils 44%0/, lymphocytes 500), plate- lets 58,000, and reticulocytes 0-8 %.The marrow aspirate was markedly hypoplastic, and there were no atypical cells.A trans- fusion was given but in July a similar blood count was found and treatment was there- after with oxymetholone 5 mg thrice daily and prednisone continuously, together with frequent blood transfusions.The total dosage of oxymetholone over the next 2 years was no more than 11 g.In July 1971 a rapid deterioration in the patient's health was observed and myelo- blasts appeared in the peripheral blood.These rapidly reached a total of 51iN of the white cells and the diagnosis of acute myeloblastic leukaemia was confirmed by marrow aspiration.A trephine biopsy failed to yield any marrow.Cytosine arabino- side and daunorubicin were given in five- day cycles removing the blast cells from the blood but not from the marrow, and the patient died early in September, two years and five months after the primary diagnosis of hypoplastic anaemia.-Iam, etc.,
Cross-Sectional Relations of Peripheral Microvascular Function, Cardiovascular Disease Risk Factors, and Aortic Stiffness
Authors: Gary F. Mitchell, Joseph A. Vita, Martin G. Larson, Helen Parise, Michelle J. Keyes, Elaine Warner, Ramachandran S. Vasan, Daniel Levy, Emelia J. Benjamin
Journal: Circulation (2005)

Background— Aortic stiffness and small-artery structure and function share various risk factors; however, relations between these 2 measures of vascular function are complex and incompletely understood. Methods and Results— We examined hyperemic forearm blood flow, an indicator of microvascular structure and function, and aortic stiffness in 2045 participants (1107 women, mean age 61±9 years) in the Framingham Heart Study offspring cohort. Using arterial tonometry, we evaluated 3 measures of aortic stiffness: brachial pulse pressure; carotid-femoral pulse wave velocity (CFPWV), which is related directly to aortic wall stiffness; and forward pressure wave amplitude (P f ), which is related directly to aortic wall stiffness and inversely to aortic diameter. Using high-resolution ultrasound and Doppler, we evaluated brachial artery diameter, blood flow, and forearm vascular resistance (FVR) at baseline and during reactive hyperemia after 5 minutes of forearm ischemia. In multivariable models that adjusted for cardiovascular disease risk factors, local brachial pulse pressure, CFPWV, and P f , considered separately, were associated with increased baseline and hyperemic FVR ( P &lt;0.001). In models that further adjusted for mean arterial pressure, each measure of aortic stiffness was associated with reduced hyperemic flow ( P &lt;0.001). In risk factor–adjusted models that simultaneously considered CFPWV and P f , both were associated with increased FVR at baseline ( P &lt;0.01) and during hyperemia ( P &lt;0.001). Conclusions— Our findings indicate that abnormal aortic stiffness and increased pressure pulsatility are associated with blunted microvascular reactivity to ischemic stress that is in excess of changes attributable to conventional cardiovascular disease risk factors alone, including mean arterial pressure.
Effect of up-front daclizumab when combined with steroids for the treatment of acute graft-versus-host disease: results of a randomized trial
Authors: Stephanie J. Lee, David Zahrieh, Edward Agura, Margaret L. MacMillan, Richard T. Maziarz, Philip L. McCarthy, Vincent T. Ho, Corey Cutler, Edwin P. Alyea, Joseph H. Antin, Robert J. Soiffer
Journal: Blood (2004)
Elevated CSF levels of TACE activity and soluble TNF receptors in subjects with mild cognitive impairment and patients with Alzheimer's disease
Authors: Hong Jiang, Harald Hampel, David Prvulovic, Anders Wallin, Kaj Blennow, Rena Li, Yong Shen
Journal: Molecular Neurodegeneration (2011)

Abstract We recently reported that expression levels of tumor necrosis factor (TNF) receptors, TNFR1 and TNFR2, are significantly changed in the brains and cerebrospinal fluid (CSF) with Alzheimer's disease (AD). Moreover, we also found that, in an Alzheimer's mouse model, genetic deletion of TNF receptor (TNFR1) reduces amyloid plaques and amyloid beta peptides (Aβ) production through β-secretase (BACE1) regulation. TNF-α converting enzyme (TACE/ADAM-17) does not only cleave pro- TNF-α but also TNF receptors, however, whether the TACE activity was changed in the CSF was not clear. In this study, we examined TACE in the CSF in 32 AD patients and 27 age-matched healthy controls (HCs). Interestingly, we found that TACE activity was significantly elevated in the CSF from AD patients compared with HCs. Furthermore, we also assayed the CSF levels of TACE cleaved soluble forms of TNFR1 and TNFR2 in the same patients. We found that AD patients had higher levels of both TACE cleaved soluble TNFR1 (sTNFR1) and TNFR2 (sTNFR2) in the CSF compared to age- and gender-matched healthy controls. Levels of sTNFR1 correlated strongly with the levels of sTNFR2 (rs = 0.567-0.663, p &lt; 0.01). The levels of both sTNFR1 and sTNFR2 significantly correlated with the TACE activity (rs = 0.491-0.557, p &lt; 0.05). To examine if changes in TACE activity and in levels of cleaved soluble TNFRs are an early event in the course of AD, we measured these molecules in the CSF from 47 subjects with mild cognitive impairment (MCI), which is considered as a preclinical stage of AD. Unexpectedly, we found significantly higher levels of TACE activity and soluble TNFRs in the MCI group than that in AD patients. These results suggest that TACE activity and soluble TNF receptors may be potential diagnostic candidate biomarkers in AD and MCI.
Safety of pleurodesis with talc poudrage in malignant pleural effusion: a prospective cohort study
Authors: Julius P Janssen, Gareth Collier, Phillippe Astoul, Gian Franco Tassi, Marc Noppen, Francisco Rodriguez-Panadero, Robert Loddenkemper, Felix JF Herth, Stefano Gasparini, Charles H Marquette, Birgit Becke, Marios E Froudarakis, Peter Driesen, Chris T Bolliger, Jean-Marie Tschopp
Journal: The Lancet (2007)