tbuckley/cabot-search huggingface dataset:
Enhancing Nrf2 Pathway by Disruption of Keap1 in Myeloid Leukocytes Protects against Sepsis
Authors: Xiaoni Kong, Rajesh Thimmulappa, Florin Craciun, Christopher Harvey, Anju Singh, Ponvijay Kombairaju, Sekhar P. Reddy, Daniel Remick, Shyam Biswal
Journal: American Journal of Respiratory and Critical Care Medicine (2011)

Sepsis syndrome is characterized by inappropriate amplified systemic inflammatory response and bacteremia that promote multiorgan failure and mortality. Nuclear factor-erythroid 2 p45-related factor 2 (Nrf2) regulates a pleiotropic cytoprotective defense program including antioxidants and protects against several inflammatory disorders by inhibiting oxidative tissue injuries. However, the role of enhanced Nrf2 activity in modulating innate immune responses to microbial infection and pathogenesis of sepsis is unclear.To determine whether Nrf2 in myeloid leukocytes alters inflammatory response and protects against sepsis.Mice with deletion of Nrf2 or kelch-like ECH-associated protein (Keap1) in myeloid leukocyte cells and respective floxed controls were subjected to cecal ligation and puncture-induced sepsis and were assessed for survival, organ injury, systemic inflammation, and bacteremia. Using LPS-stimulated peritoneal macrophages, Toll-like receptor (TLR) 4 surface trafficking and downstream signaling events were analyzed.Mortality, organ injury, circulating levels of inflammatory mediators, and bacteremia were markedly reduced in LysM-Keap1(-/-) compared with respective floxed controls (Keap1(f/f) or Nrf2(f/f)) and significantly elevated in LysM-Nrf2(-/-) mice after cecal ligation and puncture. Peritoneal macrophages from septic LysM-Keap1(-/-) mice showed a greater bacterial phagocytic activity compared with LysM-Nrf2(-/-) and floxed controls. LPS stimulation resulted in greater reactive oxygen species-induced cell surface transport of TLR4 from trans-Golgi network and subsequent TLR4 downstream signaling (recruitment of MYD88 and TRIF, phosphorylation of IkB and IRF3, and cytokine expression) in macrophages of LysM-Nrf2(-/-) compared with LysM-Keap1(-/-) mice and floxed controls.Our study shows that Nrf2 acts as a critical immunomodulator in leukocytes, controls host inflammatory response to bacterial infection, and protects against sepsis.
Contrast-Enhanced Endoscopic Ultrasonography with Galactose Microparticles: SHU508 A (Levovist)
Authors: M. S. Bhutani, B. J. Hoffman, A. van Velse, R. H. Hawes
Journal: Endoscopy (1997)

To evaluate the utility of a suspension of galactose microparticles available as SHU508 A (Levovist) as a contrast agent during endoscopic ultrasonography (EUS).Three sets of experiments were performed on three 20-25 kg swine (Sus scrofa) under general anesthesia. Upper EUS was performed with an echo endoscope with color Doppler capability (Pentax FG-32 UA). The celiac artery, superior mesenteric artery, aorta, portal vein, pancreas, and gastrointestinal wall were imaged by EUS. Multiple intravenous bolus injections of 400 mg/ml of SHU508 A were made, and their effect on color Doppler and gray-scale imaging during EUS was studied.After contrast injection there was a significant, visually noticeable enhancement of the color Doppler signals from the celiac artery, superior mesenteric artery, and portal vein. Vessels with weak to no color Doppler signals before injection of SHU508 A--for example, the celiac artery and superior mesenteric artery--were observed to have strong color signals after injection. The effect of SHU508 A on color Doppler imaging was easily appreciated subjectively without the need for complex quantitative measurements. No visually noticeable color Doppler enhancement was seen in vessels such as the aorta that had a very pronounced color Doppler signal even prior to the injection of contrast. Movement of particulate matter was seen in the portal vein on the gray scale.Intravenous SHU508 A as a contrast agent significantly enhances color Doppler signals during EUS. Vascualar contrast of this sort could potentially have a significant role in improving the accuracy of EUS in diagnosing malignant vascular invasion, the detection of occult pancreatic neoplasms, and the diagnosis of vascular thrombosis.
Risks of a range of alcohol intake on hepatitis C-related fibrosis
Authors: Alexander Monto, Keyur Patel, Alan Bostrom, Stephen Pianko, Paul Pockros, John G. McHutchison, Teresa L. Wright
Journal: Hepatology (2004)

Heavy alcohol use contributes to liver disease in the setting of chronic hepatitis C virus (HCV) infection. Whether this is true for light or moderate alcohol use has not been demonstrated. Light alcohol use has survival benefits at a population level and is practiced by most patients with chronic HCV infection. In this study, 800 patients with HCV undergoing liver biopsy at three sites had detailed alcohol histories recorded and the relationship between alcohol and hepatic fibrosis was assessed. On univariate analysis, heavy alcohol use (>50 g/day) was associated with an increase in mean fibrosis (P =.01). Such an association could not be demonstrated for light and moderate alcohol use. For each category of alcohol intake (none, light, moderate, and heavy), a spectrum of fibrosis was observed. On multivariate analysis, age, serum alanine aminotransferase (ALT), and histological inflammation were the independent predictors of fibrosis (P = <.0001,.0003, <.0001, respectively). In conclusion, heavy alcohol use exerts a greater effect on fibrosis than light or moderate use. There is a range of fibrosis at each level of alcohol use. Age, serum ALT, and inflammation are independently associated with fibrosis in multivariate analysis, highlighting the fact that variables other than alcohol intake predominate in the production of hepatic fibrosis.
Tubulin-Targeted Drug Action: Functional Significance of Class II and Class IVb β-Tubulin in <i>Vinca</i> Alkaloid Sensitivity
Authors: Pei Pei Gan, Maria Kavallaris
Journal: Cancer Research (2008)

Abstract Aberrant expression of β-tubulin isotypes is frequently described in tumor tissues and tubulin-binding agent (TBA)–resistant cell lines. There is limited understanding of the role of specific β-tubulin isotypes in cellular sensitivity to TBAs, and to gain insights into the functional role of βII- and βIVb-tubulin, we examined these isotypes in lung cancer cell lines NCI-H460 (H460) and Calu-6. Drug-treated clonogenic assays revealed that small interfering RNA–mediated knockdown of either βII- or βIVb-tubulin hypersensitized the lung cancer cell lines to Vinca alkaloids, with the effects more pronounced following βIVb-tubulin knockdown. In contrast, there was no change in paclitaxel sensitivity following knockdown of either isotype. Cell cycle analysis revealed a greater propensity for the βII- and βIVb-tubulin knockdown cells to undergo G2-M cell cycle block following 5 nmol/L vincristine treatment, with the βIVb knockdown cells being more sensitive than the βII-tubulin knockdown cells compared with control. In contrast to βII-tubulin knockdown, βIVb-tubulin knockdown cells showed a significant increase in the sub-G1 population (cell death) following treatment with both 5 and 40 nmol/L of vincristine compared with controls. Importantly, βIVb-tubulin knockdown in H460 cells caused a significant dose-dependent increase in Annexin V staining in response to vincristine but not paclitaxel. Therefore, increased sensitivity to induction of apoptosis is one mechanism underlying the Vinca alkaloid hypersensitivity. This study provides direct evidence that βII- or βIVb-tubulins have functionally distinct roles and expression of these isotypes may serve as strong predictors of Vinca alkaloid response and resistance. [Cancer Res 2008;68(23):9817–24]
1186 ANTICOAGULANT THERAPY IS SAFE AND EFFECTIVE IN PREVENTING PORTAL VEIN THROMBOSIS (PVT) IN ADVANCED CIRRHOTIC PATIENTS: A PROSPECTIVE RANDOMIZED CONTROLLED STUDY
Authors: R. Zecchini, A. Ferrari, V. Bernabucci, B. Lei, R. Vukotic, N. De Maria, F. Schepis, M. Marietta, G. Fornaciari, S. Schianchi, E. Villa
Journal: Journal of Hepatology (2010)
Brachioradial pruritus: a tropical dermopathy
Authors: PATRICIA J. WALCYK, D.J. ELPERN
Journal: British Journal of Dermatology (1986)

Data on 42 patients with brachioradial pruritus seen in Hawaii over a 2-year period are presented. In contrast to previous reports, the sex ratio was 1:1 with a preponderance of patients in the younger age groups. All patients had developed the disorder after having lived in Hawaii for at least one year. More than half the cases had no history of neck trauma or arthritis, ruling out a peripheral neuropathy as the cause. Radiographs of 15 patients showed changes only in the patients in the older, arthritis-age groups. Brachioradial pruritus appears to be peculiar to the tropics.
Abstract 428: Post-translational phosphorylation is essential for nanog-mediated tumorigenesis
Authors: Xiujie Xie, Longzhu Piao, Greg S. Cavey, Theodoros N. Teknos, Quintin Pan
Journal: Cancer Research (2012)

Abstract Objectives: Nanog is a transcription factor intimately involved in embryonic stem cell pluripotency. Emerging evidence indicates that Nanog plays a critical role in oncogenesis, in part through regulation of the cancer initiating cell population. We investigated the role of post-translational phosphorylation as a regulatory mechanism to control Nanog function in head and neck squamous cell carcinoma (HNSCC). Methods: Liquid chromatography-mass spectrometry/mass spectrometry was used to identify the PKC∈-mediated phosphorylation sites on Nanog. Phosphorylation-insensitive Nanog mutants (T200A and T280A) were generated and assessed for in vitro and in vivo phenotype. Chromatin immunoprecipitation (ChIP) and co-immunoprecipitation experiments were performed to determine Nanog recruitment and association with p300. ChIP, electrophorectic mobility shift assay, and luciferase reporter assay were used to assess Nanog regulation of Bmi-1. Forward and reverse genetic experiments were carried out to determine the role of the Nanog-Bmi-1 signaling node in HNSCC. Results: Phosphopeptide mapping identified that Nanog is phosphorylated by PKC∈ at multiple resides, including T200 and T280. Phosphorylation-insensitive Nanog mutants (T200A and T280A) showed a loss-of-function phenotype due to impaired p300, a transcriptional co-activator, recruitment resulting in a defect in target gene promoter activation. Ectopic expression of phosphorylation-insensitive Nanog mutants in HNSCC cells significantly reduced cell proliferation, colony formation, invasion, migration, and the cancer initiating cell population. Additionally, in vivo tumor initiating ability was severely compromised in HNSCC cells expressing phosphorylation-insensitive Nanog mutants; 87.5% (14/16), 12.5% (1/8), and 0% (0/8) for empty vector, T200A, and T280A, respectively. Nanog occupied the promoter of Bmi-1 at two distinct regions to directly regulate Bmi-1 levels. Genetic ablation and rescue experiments demonstrate that Bmi-1 is a critical downstream signaling node for the pleotropic pro-oncogenic effects of Nanog. Conclusion:Taken together, our study revealed, for the first time, that post-translational phosphorylation of Nanog is essential to directly regulate Bmi-1 and promote tumorigenesis. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 428. doi:1538-7445.AM2012-428
Comparison of exogenous surfactants in the treatment of wood smoke inhalation.
Authors: G F Nieman, A M Paskanik, R R Fluck, W R Clark
Journal: American Journal of Respiratory and Critical Care Medicine (1995)

The goal of this study was to compare the effectiveness of the exogenous surfactants Infasurf and Exosurf in reestablishing surfactant function inhibited by severe smoke inhalation. Mongrel dogs (n = 17) were anesthetized, placed on a ventilator (40% O2), and surgically prepared for hemodynamic and blood gas measurements; venous admixture (QVA/QT) and static lung compliance (Cstat) were calculated. At the conclusion of the experiment, lung samples were taken for lung water and dynamic surface tension (DST, Wilhelmy balance) measurements. Following baseline measurements, dogs were randomly separated into four groups: Group I, smoke+sham instillation; Group II, smoke+saline instillation: Group III, smoke+Exosurf instillation; and Group IV, smoke+Infasurf instillation. The surfactants (Infasurf and Exosurf, 100 mg/kg) or saline (same volume as surfactants) were instilled into the lungs via suction catheter immediately following smoke exposure. Smoke inhalation caused a similar increase in QVA/QT and fall in PaO2 and Cstat in all groups that improved only with Infasurf instillation (Group IV). DST was significantly improved by Infasurf compared with all other groups. We conclude that Infasurf restores normal DST, inhibited by wood smoke, improving lung function. Exosurf was ineffective in the treatment of wood smoke inhalation.
The Effect of Chronic Ethanol Ingestion on Ethanol Metabolizing Enzymes in Isolated Periportal and Perivenous Rat Hepatocytes
Authors: Hannu Väänänen, Mikko Salaspuro, Kai Lindros
Journal: Hepatology (1984)

Periportal (pp) and perivenous (pv) hepatocyte populations were separated using a two-directional closed perfusion technique with selective addition of collagenase either to direct or retrograde perfusions (Väänänen, H. et al., Liver 1983; 3:131). The activity of GPT in hepatocytes from the pp-area was 1.9 times higher than in cells from the pv-area (p less than 0.01). The distribution of glutamate dehydrogenase and pyruvate kinase activities was reversed; pp/pv ratios of 0.7 and 0.5, respectively, were observed (p less than 0.001, p less than 0.05). Chronic ethanol consumption for 12 weeks (mean daily ethanol intake 11.4 gm per body weight corresponding to 29% of total energy intake) did not cause histological changes but decreased GPT activity, increased glutamate dehydrogenase and pyruvate kinase activities and did not alter their pp/pv distribution. Alcohol dehydrogenase and aldehyde dehydrogenase activities were evenly distributed in pp- and pv-hepatocytes. Chronic ethanol treatment slightly decreased alcohol dehydrogenase activity (p less than 0.05) and increased the activity of low Km aldehyde dehydrogenase (p less than 0.001, p less than 0.05). The specific activity of NADPH-dependent microsomal ethanol oxidation was 50% higher in pv-hepatocytes (p less than 0.05). Chronic ethanol treatment did not increase the specific activity of microsomal ethanol oxidation but reduced the pp-pv activity difference. The results indicate that the enzymatic capacity to oxidize ethanol is evenly distributed in the acinus and that, after long-term moderate ethanol treatment, despite lack of parenchymal lesions, changes in the activity of enzymes involved in ethanol metabolism are observed.(ABSTRACT TRUNCATED AT 250 WORDS)
Cleft lip and palate services still need to be improved
Authors: D Roberts-Harry
Journal: BMJ (2003)

EDITOR—The report of the Clinical Standards Advisory Group in 1998 was highly critical of the care for people with cleft lips and palates in the United Kingdom. 1 2 Fundamental recommendations included reducing the 57 cleft units to between eight and 12. This represented roughly one cleft centre for each of the areas covered …
Expression of alternatively spliced variants of MAP2K4 gene in rheumatoid arthritis
Authors: Klementy Shchetynsky, Marcus Ronninger, Leonid Padyukov
Journal: Annals of the Rheumatic Diseases (2012)

<h3>Backgroundand objectives</h3> MAP2K4 encodes a mitogen activated protein kinase kinase 4 (MKK4), important for optimal activation of JNK1-3 and p38 – the two members of the MAP kinase family previously implicated in several rheumatic diseases, including rheumatoid arthritis (RA). Recently, MAP2K4 locus has been identified as being in statistical interaction with the major risk factor for RA - HLA-DRB1 shared epitope (SE) - in RA patients with anticitrullinated protein antibody (ACPA). In this study, the authors describe a novel splice variant of MAP2K4 (V2), and investigate the differential expression profile and phenotype associations of MAP2K4 splice variants in RA patients and healthy individuals. <h3>Methods</h3> The authors performed a discovery study to detect novel splice variants of MAP2K4 in human peripheral blood cells, and obtained sequence data for variants of interest. The relative expression of MAP2K4 forms in peripheral blood was investigated for 44 RA patients and 44 controls of Caucasian ancestry and analysed against available genotypic and phenotypic data. <h3>Results</h3> The authors detected a novel 'skipped exon' type splice variant of MAP2K4 in our study material. The MAP2K4 splice forms and were differently expressed in peripheral blood material from 88 RA cases and controls. Additionally, within the group of RA patients, a correlation was observed between MAP2K4 variants expression and phonotypical data for ACPA, rheumatoid factor, and SE. <h3>Conclusion</h3> Our results show differential expression ratio of the canonical and alternatively spliced MAP2K4 mRNAs in RA patients compared to healthy controls. This data implies that MAP2K4 splicing and expression profile may be associated with RA pathogenesis and should be assessed as a potential biomarker in the future.
The metabolic clearance rate and origin of plasma dihydrotestosterone in man and its conversion to the 5α-androstanediols
Authors: Jacques A. Mahoudeau, C. Wayne Bardin, Mortimer B. Lipsett
Journal: Journal of Clinical Investigation (1971)

Dihydrotestosterone metabolism was studied with a constant infusion technique in three men, three women, five hirsute women, and four estrogen-treated hirsute women. The mean dihydrotestosterone metabolic clearance rate was higher in men (336 liters/24 hr per m(2) [range, 239-448]) than in women (153 liters/24 hr per m(2) [range, 108-184]). The metabolic clearance rates in hirsute patients were intermediate between those men and women and were decreased by estrogen treatment. These observations demonstrate similarities in the metabolic rates of testosterone and dihydrotestosterone. The conversion of plasma testosterone and androstenedione to dihydrotestosterone was studied in men and hirsute women. Approximately 4 and 2% of plasma testosterone and androstenedione, respectively, were converted to plasma dihydrotestosterone in both groups. From these observations it was determined that a major fraction of plasma dihydrotestosterone was derived from these plasma precursors rather than from glandular secretion. Both 5alpha-androstan-3alpha,17beta-diol (3alpha-diol) and 5alpha-androstan-3beta,17beta-diol (3beta-diol) were identified in plasma during dihydrotestosterone and testosterone infusions. The conversion ratio of dihydrotestosterone to 3alpha-diol (C(BB) (DHT-3alpha)) was greater than the conversion ratio to the 3beta-isomer (C(BB) (DTH-3beta)) in all the patients studied. Both C(BB) (DHT-3alpha) and C(BB) (DHT-3beta) were higher in men (mean values of 0.151 [range, 0.110-0.222] and 0..031 [range, 0.022-0.042]) than in women (means of 0.044 [range, 0.037-0.048] and 0.012 [range 0.010-0.013]). A smaller fraction of testosterone was converted to 3alpha-diol and 3beta-diol.
KIT D816V–associated systemic mastocytosis with eosinophilia and FIP1L1/PDGFRA-associated chronic eosinophilic leukemia are distinct entities
Authors: Irina Maric, Jamie Robyn, Dean D. Metcalfe, Michael P. Fay, Melody Carter, Todd Wilson, Weiming Fu, Jennifer Stoddard, Linda Scott, Marilyn Hartsell, Arnold Kirshenbaum, Cem Akin, Thomas B. Nutman, Pierre Noel, Amy D. Klion
Journal: Journal of Allergy and Clinical Immunology (2007)

The broad and overlapping clinical manifestations of D816V KIT-associated systemic mastocytosis with eosinophilia and FIP1L1/PDGFRA-associated chronic eosinophilic leukemia (CEL), coupled with the increase in activated eosinophils and mast cells seen in both disorders, have led to confusion in the nomenclature. It is of paramount importance, however, to distinguish between these 2 groups of patients because of differences in clinical sequelae, prognoses, and selection of treatment.We thus sought to identify clinical and laboratory features that could be used to distinguish these 2 diagnoses.We compared 12 patients with D816V-positive systemic mastocytosis with eosinophilia with 17 patients with FIP1L1/PDGFRA-positive CEL. Distinguishing features were used to create a risk factor scoring system.This system correctly classified 16 of 17 FIP1L1/PDGFRA-positive patients with CEL and all 12 patients with systemic mastocytosis with eosinophilia. Thirty-four FIP1L1/PDGFRA-positive patients described in the literature were also classified using this system, and although a complete set of data was not available for any of the historical patients, 21 were correctly classified.These results reinforce the hypothesis that the FIP1L1/PDGFRA gene fusion and D816V-KIT mutation cause distinct clinical syndromes.This novel diagnostic approach should prove helpful in clinical practice in the evaluation of patients with increased mast cells and peripheral eosinophilia.
Droughts, conflict, and lack of funding leave millions of east Africans at risk of famine
Authors: P. Moszynski
Journal: BMJ (2009)

A “severe and persistent five year drought” has left more than 20 million people in desperate need of food throughout east Africa. Launching an appeal this week, Oxfam said that the worst affected countries are Ethiopia, Kenya, Somalia, and Uganda. Other countries hit are Djibouti, Sudan, and Tanzania.

The charity, one of several to launch separate emergency appeals in the past few days, warned, “The aid response to the crisis needs to rapidly expand, but it is desperately short of funds.”

The United Nations World Food Programme is facing a $977m (£612m; €672m) shortfall in donations for its work in the Horn of Africa in the next …
Comments on "Transcapillary water and protein flux in the canine intestine with acute and chronic extrahepatic portal hypertension".
Authors: J H Henriksen, N A Lassen
Journal: Circulation Research (1984)

Recently, Witte et al. (1983) reported data on transcapillary water and protein flux in intestine from dogs with acute and chronic extrahepatic portal hypertension.Meaurements were made of lymph flow and total protein concentration in lymph and plasma.Additionally, plasma disappearance rate of radioiodinated albumin was determined in some animals.From these experiments, the authors concluded that about 80% of the transcapillary protein flux in control dogs was convective-filtrative, while a dissipative process (diffusion) was responsible for the rest.During both acute and chronic portal pressure elevation there was a shift from convective to diffusive protein transfer: diffusive fraction increased from 20% to 40% and convective fraction decreased from 80% to 60%.No relationship was found between transcapillary protein flux and portal pressure.In contrast to these experiments, we have estimated the transcapillary albumin flux from the plasma disappearance rate of radioiodinated albumin (Henriksen et al., 1981) in control pigs and during acute extrahepatic portal hypertension.As shown in Figure 1, the overall plasma clearance of albumin (plasma volume X fractional disappearance rate) was closely related to portal pressure.This indicates, to us, that convective-filtrative transcapillary albumin flux is dominant also during elevated portal pressure.In our experiments, the increase in albumin clearance was on the average three times that of Witte et al. (34 vs. 11 ^I/miri per kg), a finding which may, at least in part, be explained by the much larger digestive tract in pigs compared to dogs.