tbuckley/cabot-search huggingface dataset:
Dysregulation of the ALS-associated gene TDP-43 leads to neuronal death and degeneration in mice
Authors: Lionel M. Igaz, Linda K. Kwong, Edward B. Lee, Alice Chen-Plotkin, Eric Swanson, Travis Unger, Joe Malunda, Yan Xu, Matthew J. Winton, John Q. Trojanowski, Virginia M.-Y. Lee
Journal: Journal of Clinical Investigation (2011)

Amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration (FTLD) are characterized by cytoplasmic protein aggregates in the brain and spinal cord that include TAR-DNA binding protein 43 (TDP-43). TDP-43 is normally localized in the nucleus with roles in the regulation of gene expression, and pathological cytoplasmic aggregates are associated with depletion of nuclear protein. Here, we generated transgenic mice expressing human TDP-43 with a defective nuclear localization signal in the forebrain (hTDP-43-ΔNLS), and compared them with mice expressing WT hTDP-43 (hTDP-43-WT) to determine the effects of mislocalized cytoplasmic TDP-43 on neuronal viability. Expression of either hTDP-43-ΔNLS or hTDP-43-WT led to neuron loss in selectively vulnerable forebrain regions, corticospinal tract degeneration, and motor spasticity recapitulating key aspects of FTLD and primary lateral sclerosis. Only rare cytoplasmic phosphorylated and ubiquitinated TDP-43 inclusions were seen in hTDP-43-ΔNLS mice, suggesting that cytoplasmic inclusions were not required to induce neuronal death. Instead, neurodegeneration in hTDP-43 and hTDP-43-ΔNLS–expressing neurons was accompanied by a dramatic downregulation of the endogenous mouse TDP-43. Moreover, mice expressing hTDP-43-ΔNLS exhibited profound changes in gene expression in cortical neurons. Our data suggest that perturbation of endogenous nuclear TDP-43 results in loss of normal TDP-43 function(s) and gene regulatory pathways, culminating in degeneration of selectively vulnerable affected neurons.
Histological Indications of a Progressive Snorers Disease in an Upper Airway Muscle
Authors: DANIELLE FRIBERG, TOR ANSVED, KRISTIAN BORG, BRITT CARLSSON-NORDLANDER, HÅKAN LARSSON, EVA SVANBORG
Journal: American Journal of Respiratory and Critical Care Medicine (1998)

The etiology of upper airway collapsibility in patients with snoring and obstructive sleep apnea (OSA) remains unclear. Local muscular abnormalities, including neurogenic lesions, could be a contributory factor. The aim of this study was to histologically evaluate the hypothesis of a progressive snorers disease. Biopsies of palatopharyngeal muscle were obtained from 21 patients with habitual snoring and different degrees of upper airway obstruction (10 patients with OSA) and 10 nonsnoring control subjects. Morphological abnormalities, including neurogenic signs (e.g., type grouping), were blindly quantified. The degree of abnormality was significantly increased in patients compared with control subjects. The individual score of abnormalities was significantly correlated to the percentage periodic obstructive breathing but not to oxygen desaturation index. Analyses of the individual fiber-size spectra demonstrated a significantly increased number of hypertrophied and/or atrophied fibers in patients compared with controls. The subjects were also divided into three groups according to their type of nocturnal breathing, i.e., nonsnorers, patients with < 20%, and patients with > or = 45% obstructive breathing. These groups correlated significantly with the degree of abnormality and pathological fiber-size spectra. In conclusion, these results support the hypothesis of a progressive local neurogenic lesion, caused by the trauma of snoring, as a possible contributory factor to upper airway collapsibility.
Low Metastatic Potential of Clone From Murine Colon Adenocarcinoma 26 Increased by Transfection of Activated c-erbB-2 Gene
Authors: Keisuke Yusa, Yoshikazu Sugimoto, Takao Yamori, Tadashi Yamamoto, Kumao Toyoshima, Takashi Tsuruo
Journal: JNCI Journal of the National Cancer Institute (1990)

Journal Article Low Metastatic Potential of Clone From Murine Colon Adenocarcinoma 26 Increased by Transfection of Activated c-erbB-2 Gene Get access Keisuke Yusa, Keisuke Yusa Search for other works by this author on: Oxford Academic PubMed Google Scholar Yoshikazu Sugimoto, Yoshikazu Sugimoto Search for other works by this author on: Oxford Academic PubMed Google Scholar Takao Yamori, Takao Yamori Search for other works by this author on: Oxford Academic PubMed Google Scholar Tadashi Yamamoto, Tadashi Yamamoto Search for other works by this author on: Oxford Academic PubMed Google Scholar Kumao Toyoshima, Kumao Toyoshima Search for other works by this author on: Oxford Academic PubMed Google Scholar Takashi Tsuruo Takashi Tsuruo Search for other works by this author on: Oxford Academic PubMed Google Scholar JNCI: Journal of the National Cancer Institute, Volume 82, Issue 20, 17 October 1990, Pages 1633–1636, https://doi.org/10.1093/jnci/82.20.1633 Published: 17 October 1990 Article history Received: 16 January 1990 Revision received: 23 July 1990 Accepted: 01 August 1990 Published: 17 October 1990
Remote Ischemic Preconditioning
Authors: Michael Rahbek Schmidt, Steen Buus Kristiansen, Hans Erik Bøtker
Journal: Circulation Research (2013)

D uring the past 3 decades, several experimental stud- ies have shown that ischemic conditioning reduces myocardial damage by modifying ischemia-reperfusion injury.A recent study in the Lancet indicates that remote ischemic preconditioning translates into clinical benefit in patients undergoing coronary artery bypass surgery.The implications of the study extend to patients undergoing elective and acute coronary angioplasty and beyond.Adjunctive therapies to reduce myocardial ischemiareperfusion injury related to cardiac surgery and percutaneous coronary interventions have yet to find their way into clinical practice, mainly because no pharmacological or mechanical cardioprotective strategy has convincingly shown clinically relevant benefit to the patient. 1 That may be about to change.In a recent study by Thielmann et al, 2 329 low-risk patients undergoing elective isolated on-pump first-time coronary artery bypass grafting (CABG) were randomized to either standard CABG or CABG preceded by remote ischemic preconditioning (RIPC), achieved by 3 cycles of 5-minute upper limb ischemia through inflation of a blood pressure cuff followed by 5-minute deflation.The results indicate that RIPC confers a prognostic benefit to the patient.The study was conducted as a single-center, double-blind, randomized, controlled trial.The primary end point was perioperative myocardial injury assessed by troponin I release measured at 6, 12, 24, 48, and 72 hours after surgery.The secondary end points comprised all-cause mortality, major adverse cardiac and cerebrovascular events (MACCE), and repeat revascularization at 30 days, 1 year, and at completion of follow-up, ranging from 1 to >4 years with a mean of 1.54 years.The group demographics were well-matched, and there were no significant differences in baseline risk factors.
Does a prior diagnosis of Barrett's oesophagus influence risk of dying from oesophageal adenocarcinoma?
Authors: David C Whiteman
Journal: Gut (2014)

In many industrialised populations, adenocarcinoma of the oesophagus holds the dubious distinction of being the cancer for which the proportional rise in incidence has been most rapid.1 The factors conferring increased risks are well established, including obesity, gastro-oesophageal acid reflux, smoking and male sex.2 It has also long been known that Barrett's oesophagus, the metaplastic precursor, has a measurable rate of progressing to cancer. This observation has given rise to the notion that screening or surveillance for Barrett's oesophagus should, in theory, reduce the risks of dying from oesophageal adenocarcinoma. However, screening for any cancer is a deceptively tricky business, and while the concept of screening holds considerable intuitive appeal, it is very difficult to establish that any screening programme confers benefits.

Bhat et al 3 attempt to infer the effect of a prior diagnosis of Barrett's oesophagus among patients with oesophageal adenocarcinoma, and to estimate the effects of two biases that are known to affect the interpretation of screening studies, namely, lead time bias and length bias.4 Lead time is the interval by which a diagnosis of cancer has been brought forward by screening; it has the effect of spuriously lengthening the time from diagnosis to death, even if no survival benefit is conferred by the screening activity. For example, it is reasonable to assume that patients with Barrett's oesophagus undergo more frequent endoscopies than other people, and therefore may have their cancers detected at an earlier point in time than would otherwise be the …
Which Patients With Cancer Die at Home? A Study of Six European Countries Using Death Certificate Data
Authors: Joachim Cohen, Dirk Houttekier, Bregje Onwuteaka-Philipsen, Guido Miccinesi, Julia Addington-Hall, Stein Kaasa, Johan Bilsen, Luc Deliens
Journal: Journal of Clinical Oncology (2010)

Purpose This study examines the proportion of cancer deaths occurring at home in six European countries in relation to illness and to demographic and health care factors. Methods Death certificate data of all cancer-related deaths in 2002 in Italy and 2003 in Belgium, the Netherlands, Norway, England, and Wales (N = 238,216) were linked with regional health care and area statistics. Multivariate binomial logistic regressions were performed to examine factors associated with dying at home. Results The percentage of all cancer deaths occurring at home was 12.8 in Norway, 22.1 in England, 22.7 in Wales, 27.9 in Belgium, 35.8 in Italy, and 45.4 in the Netherlands. Having solid cancers and being married increased the chances of dying at home in all countries. Being older and being a woman decreased the chances of dying at home, except in Italy where the opposite was the case. A higher educational attainment was associated with better chances of dying at home in Belgium, Italy, and Norway (countries where information on educational attainment was available). Better chances of dying at home were also associated with living in less urbanized areas in all countries but England. The number of hospital and care home beds seemed not to be universally strong predictors of dying at home. Conclusion There are large country differences in the proportion of patients with cancer dying at home, and these seem influenced by country-specific cultural, social, and health care factors. Alongside cross-national differences, country-specific aspects need to be considered in the development of policy strategies facilitating home death.
Natriuretic and Diuretic Actions of a Highly Selective Adenosine A1 Receptor Antagonist
Authors: CHRISTOPHER S. WILCOX, WILLIAM J. WELCH, GEORGE F. SCHREINER, LUIZ BELARDINELLI
Journal: Journal of the American Society of Nephrology (1999)

Abstract. The natriuretic and diuretic action of a highly selective adenosine A 1 receptor (A 1 AdoR) antagonist, 1,3-dipropyl-8-[2-(5,6-epoxy)norbornyl]xanthine (CVT-124), was investigated in anesthetized rats. CVT-124 (0.1 to 1 mg/kg) caused dose-dependent increases in urine flow and fractional and absolute sodium excretion of by six- to 10-fold and, at 0.1 mg/kg, increased the GFR (1.6 ± 0.1 to 2.5 ± 0.2 ml/min; P &lt; 0.01). There were no changes in BP or heart rate. CVT-124 reduced absolute proximal reabsorption (26 ± 3 to 20 ± 2 nl/min; P &lt; 0.05) despite unchanged proximally measured, single-nephron GFR (SNGFR) (42 ± 5 to 44 ± 4 nl/min; NS) and thereby decreased fractional proximal reabsorption (60 ± 3 to 46 ± 4%; P &lt; 0.05). Despite increasing distal tubular fluid flow rate (5.4 ± 0.7 to 9.7 ± 0.9 nl/min; P &lt; 0.001), it reduced the proximal-distal difference in SNGFR (before: 9.4 ± 1.0 versus during CVT-124: 4.6 ± 1.5 nl/min; P &lt; 0.01), suggesting that it had blunted the effects of the macula densa on SNGFR. Direct measurements of maximal tubuloglomerular feedback (TGF) responses were made from proximal stop flow pressure (PSF) during orthograde loop perfusion from the proximal tubule with artificial tubular fluid at 40 nl/min. TGF was blunted by intravenous CVT-124 (0.5 mg/kg; ▵PSF with vehicle: 8.3 ± 0.6 versus CVT-124: 6.5 ± 0.3 mmHg; n = 9; P &lt; 0.01). In conclusion, A 1 AdoR blockade reduces proximal reabsorption and uncouples it from glomerular filtration. It increases distal delivery of fluid yet does not activate a macula densa-dependent fall in SNGFR because it blunts the TGF response. Natriuresis accompanied by blockade of proximal glomerulotubular balance and TGF characterizes a new class of diuretic drugs.
Chemical Assay of Phospholipid Renin Preinhibitor in Canine and Human Blood
Authors: D. OSTROVSKY, S. SEN, R. R. SMEBY, F. M. BUMPUS
Journal: Circulation Research (1967)

A phospholipid previously shown to be converted to a lysophospholipid renin inhibitor has been demonstrated in the plasma and red cells of man and the dog. This inhibitor precursor, designated preinhibitor, is chromatographically identical to the compound previously isolated from kidneys of dogs and hogs. A method for its quantitative measurement in plasma and red cells is presented. Normal dogs tested so far have an average of 119.6 µg of preinhibitor phospholipid/ml of blood; 16.3 µg of this is in the plasma. These concentrations are constant (in red cells even increased) 48 hr after bilateral nephrectomy. To assess the physiological importance of preinhibitor, it may be necessary to measure its active lyso derivative as well as the lipase(s) most directly involved in maintaining blood levels of these two phospholipids.
P187 The Use Of Moxifloxacin For The Treatment Of Ophthalmic Tuberculosis
Authors: J. Potter, R. Agrawal, C. Barraclough, F. Rahman, H. Kunst, M. Westcott
Journal: Thorax (2014)

<h3>Background</h3> The number of patients we are treating for ophthalmic tuberculosis (TB) have increased year on year, from two in 2009 to twenty in 2013. A recent global review of the strategies used in the diagnosis and treatment of ophthalmic TB showed a wide disparity of diagnostic and treatment strategies. We present a review of our current practice and justification for out treatment regimens. <h3>Methods</h3> We identified all the cases in our hospital treated for ophthalmic TB between 2009 and 2013. Age, gender, ophthalmic examination findings, blood tests, treatment regimens, including durations and outcomes, and adverse drug reactions were collected and analysed. <h3>Results</h3> A total of 60 cases were identified. Mean age was 45.0 +/- 14.4 years. 61.7% were male. The most commonly used regimen was 2 months rifampicin, isoniazid, pyrazinamide and moxifloxacin followed by 10 months of rifampicin, isoniazid and moxifloxacin. A response to treatment, with no evidence of disease recurrence on cessation of therapy, was seen in 78.3% of cases. 5% experienced hepatotoxicity requiring a change in treatment. There was no significant difference in either the success of treatment (p = 0.102) or the risk of hepatotoxicity (p = 0.264) between regimens with moxifloxacin (n = 43) or without it (n = 17). 32 patients on moxifloxacin had ECGs of which 6 (18.8%) newly developed a raised QTc. This resulted in moxifloxacin being stopped during the step-down phase of treatment in two patients. Maximum QTc was never found to be above 500 milliseconds and there were no episodes of documented arrhythmias or syncope. <h3>Conclusions</h3> We recommend a treatment regimen including moxifloxacin in place of ethambutol so that any reported visual change is unlikely to be related to treatment, and we propose continuing moxifloxacin beyond the intensive phase, if tolerated, when culture is unavailable. We treat ophthalmic TB for the same duration as central nervous system TB. Our data shows that this is a safe and effective regimen but more evidence is required before recommending definitive guidelines.
Angiotensin II Signal Transduction in Vascular Smooth Muscle
Authors: Bradford C. Berk, Marshall A. Corson
Journal: Circulation Research (1997)

Abstract In this review, the role of tyrosine kinases in angiotensin II–mediated signal transduction pathways in vascular smooth muscle is discussed. Angiotensin II was isolated by virtue of its vasoconstrictor abilities and has long been thought to play a critical role in hypertension. However, recent studies indicate important roles for angiotensin II in inflammation, atherosclerosis, and congestive heart failure. The expanding role of angiotensin II indicates that multiple signal transduction pathways are likely to be activated in a tissue-specific manner. Exciting recent data show that angiotensin II directly stimulates tyrosine kinases, including pp60 c-src kinase (c-Src), focal adhesion kinase (FAK), and Janus kinases (JAK2 and TYK2). Angiotensin II may activate receptor tyrosine kinases, such as Axl and platelet-derived growth factor, by as-yet-undefined autocrine mechanisms. Finally, unknown tyrosine kinases may mediate tyrosine phosphorylation of Shc, Raf, and phospholipase C-γ after angiotensin II stimulation. These angiotensin II–regulated tyrosine kinases appear to be required for angiotensin II effects, such as vasoconstriction, proto-oncogene expression, and protein synthesis, on the basis of studies with tyrosine kinase inhibitors. Thus, understanding angiotensin II–stimulated signaling events, especially those related to tyrosine kinase activity, may form the basis for the development of new therapies for cardiovascular diseases.
Chemoattractant Receptors on Phagocytic Cells
Authors: R. Snyderman, M. C. Pike
Journal: Annual Review of Immunology (1984)

Exhausted CD8 T (Tex) cells are a distinct cell lineage that arise during chronic infections and cancers in animal models and humans. Tex cells are characterized by progressive loss of effector functions, high and sustained inhibitory receptor expression, ...Read More
Phylodynamic Analyses of Rotavirus Genotypes G9 and G12 Underscore Their Potential for Swift Global Spread
Authors: J. Matthijnssens, E. Heylen, M. Zeller, M. Rahman, P. Lemey, M. Van Ranst
Journal: Molecular Biology and Evolution (2010)

Rotaviruses (RVs) are responsible for more than 600,000 child deaths each year. The worldwide introduction of two life oral vaccines RotaTeq and Rotarix is believed to reduce this number significantly. Before the licensing of both vaccines, two new genotypes, G9 and G12, emerged in the human population and were able to spread across the entire globe in a very short time span. To quantify the VP7 mutation rates of these G9 and G12 genotypes and to estimate their most recent common ancestors, we used a Bayesian Markov chain Monte Carlo framework. Based on 356 sequences for G9 and 140 sequences for G12, we estimated mutation rates (nt substitutions/site/year) of 1.87 × 10−3 (1.45–2.27 × 10−3) for G9 and 1.66 × 10−3 (1.13–2.32 × 10−3) for G12. For both the G9 and G12 strains, one particular (sub) lineage was able to disseminate and cause disease across the world. The most recent common ancestors of these particular lineages were dated back to 1989 (1986–1992) and 1995 (1992–1998) for the G9 and G12 genotypes, respectively. These estimates suggest that a single novel RV (e.g., a vaccine escape mutant) can spread worldwide in little more than a decade. These results re-emphasize the need for thorough and continued RV surveillance in order to detect such potential spreading events at an early stage.
Integrin Agonists as Adjuvants in Chemotherapy for Melanoma
Authors: Martin A. Schwartz, Kevin McRoberts, Matthew Coyner, Kumari L. Andarawewa, Henry F. Frierson, John M. Sanders, Stephen Swenson, Frank Markland, Mark R. Conaway, Dan Theodorescu
Journal: Clinical Cancer Research (2008)

Abstract Purpose: Metastatic melanomas are generally resistant to chemotherapy and radiation, even when wild-type for p53. These tumors often grow in small nests where many of the cells have little contact with extracellular matrix (ECM). Previous work showed that M21 melanomas undergo apoptosis in response to chemotherapy when cells are adherent to ECM but not in suspension. Thus, reduced integrin-dependent adhesion to ECM could mediate therapy resistance. The goal of this study was to test whether stimulation of integrin signaling could increase chemotherapeutic efficacy. Experimental Design: Colony forming assays and survival assays were used to test the responses of melanoma lines in vitro. Severe combined immunodeficient mice with subcutaneous human melanomas received chemotherapy with or without reagents that stimulate integrin signaling; tumor volume was then monitored over time. Results: Clonal growth assays confirmed that M21 cells showed reduced sensitivity to the chemotherapeutic drug 1-β-d-arabinofuranosylcytosine (araC). When five additional primary melanoma lines were screened, 80% showed higher sensitivity when adherent compared with suspended. Subcutaneous M21 tumors in vivo showed minimal ECM between tumor cells. To evaluate the importance of integrin signaling in chemoresistance in this model, mice were treated with araC, with or without the multivalent snake venom disintegrin contortrostatin or the activating anti-β1 integrin antibody TS2/16. Although araC, TS2/16, or contortrostatin alone had little effect on M21 tumor growth, combining araC with either integrin signaling reagents strongly reduced growth (P = 0001). Conclusions: Loss of integrin-mediated adhesion is rate limiting for therapeutic response in this model. Combining chemotherapy with reagents that stimulate integrin signaling may therefore provide a new approach to therapy.
Single breath carbon monoxide transfer factor in different forms of chronic airflow obstruction in a general population sample.
Authors: R J Knudson, W T Kaltenborn, B Burrows
Journal: Thorax (1990)

The single breath transfer factor for carbon monoxide (TLCO), TLCO/alveolar volume (VA), and standard spirometric indices were measured in a survey of the randomly selected population sample of 1174 subjects enrolled in the Tucson epidemiological study of airways obstructive disease. Subjects were subdivided according to whether the FEV1/FVC ratio was under 65%, 65-75%, or over 75%. The influence of smoking on TLCO was accounted for by expressing TLCO as a percentage of the expected value-that is, of the value expected from the reported cigarette consumption. The 63 subjects who gave a history of physician confirmed asthma in reply to a questionnaire tended to have high values for TLCO, even when FEV1/FVC was reduced. In the absence of a given diagnosis of asthma, however, TLCO and TLCO/VA were reduced when the FEV1/FVC ratio was reduced, whether or not a clinical diagnosis of emphysema had been reported. This suggests that these subjects may have undiagnosed emphysema. This cross sectional analysis of our survey data suggests that subjects in our sample with spirometric evidence of chronic airflow obstruction have different forms of disease, characterised by different physiological features, in addition to the different risk factors and clinical courses reported earlier.