tbuckley/cabot-search huggingface dataset:
Genetic Locus in Mice That Blocks Development of Atherosclerosis Despite Extreme Hyperlipidemia
Authors: Margarete Mehrabian, Jack Wong, Xuping Wang, Zhiming Jiang, Weibin Shi, Alan M. Fogelman, Aldons J. Lusis
Journal: Circulation Research (2001)

The genes contributing to the common forms of atherosclerosis are largely unknown. One approach to dissecting complex traits such as atherosclerosis is to use animal models, such as the mouse, to map and characterize the genetic loci involved. We now report the identification of a locus for aortic lesion formation on mouse chromosome 6 that exhibits a highly significant lod score of 6.7 in a genetic cross between the susceptible strain, C57BL/6J, and the resistant strain, CAST/Ei. The locus was confirmed by constructing a congenic strain in which the chromosome 6 segment from CAST/Ei was transferred to a C57BL/6J background in a series of backcrosses. The congenic strain was almost completely resistant to diet-induced atherosclerosis. The chromosome 6 segment was also transferred onto the background of an LDL receptor-null mutation and resulted again in almost complete resistance to aortic lesion formation. This locus also influenced insulin levels but did not affect plasma lipoprotein levels, blood pressure, or body fat. The chromosome 6 gene, which we call Artles (for arterial lesions), did not affect endothelial cell responses to oxidized LDL, but lesion formation was partially reduced through bone marrow transplantation. The locus contains the candidate gene peroxisome proliferator-activated receptor-gamma, and the congenic mice exhibited significantly reduced expression of peroxisome proliferator-activated receptor-gamma.
Response to Comment on: Jeffery et al. Age Before Stage: Insulin Resistance Rises Before the Onset of Puberty: A 9-Year Longitudinal Study (EarlyBird 26). Diabetes Care 2012;35:536–541
Authors: Alison N. Jeffery, Brad S. Metcalf, Joanne Hosking, Adam J. Streeter, Linda D. Voss, Terence J. Wilkin
Journal: Diabetes Care (2012)

We thank Thukral et al. (1) for their interest in our article (2) and welcome the opportunity to respond. We are aware of the findings of Bavdekar et al. (3) who reported on Indian children studied at the age of 8 years in whom low birth weight was associated with insulin resistance. In our population of Caucasian children, the mean birth weight was 3.5 kg (SD 0.56), and only 5% weighed …
Bortezomib induces canonical nuclear factor-κB activation in multiple myeloma cells
Authors: Teru Hideshima, Hiroshi Ikeda, Dharminder Chauhan, Yutaka Okawa, Noopur Raje, Klaus Podar, Constantine Mitsiades, Nikhil C. Munshi, Paul G. Richardson, Ruben D. Carrasco, Kenneth C. Anderson
Journal: Blood (2009)
Phase III Double-Blind Trial of Arzoxifene Compared With Tamoxifen for Locally Advanced or Metastatic Breast Cancer
Authors: VijayaLaxmi Deshmane, S. Krishnamurthy, Allen S. Melemed, Patrick Peterson, Aman U. Buzdar
Journal: Journal of Clinical Oncology (2007)

To compare the efficacy of arzoxifene with tamoxifen for the treatment of locally advanced or metastatic breast cancer.Women with estrogen- or progesterone-receptor-positive breast cancer who had not received prior systemic therapy, or who had relapsed more than 12 months after stopping adjuvant hormonal therapy, were randomly assigned to receive 20 mg arzoxifene or 20 mg tamoxifen daily. Each treatment arm was to have 240 patients enrolled. The primary end point was progression-free survival. Secondary end points included other measures of tumor response, overall survival, and safety.Enrollment was stopped when a planned interim analysis of the first 200 patients suggested arzoxifene to be significantly inferior to tamoxifen. The median progression-free survival for the 352 patients who had been randomly assigned when enrollment was stopped was 4.0 months (95% CI, 3.4 to 5.6 months) for the arzoxifene group and 7.5 months (95% CI, 5.9 to 8.8 months) for the tamoxifen group. On-study progression-free survival (P = .011) and time to treatment failure (P = .029) also favored tamoxifen. Overall tumor response rate and median response duration were comparable between the groups. Adverse events were similar between the treatments, except for nausea (more frequent with arzoxifene) and vaginal discharge (more frequent with tamoxifen).Tamoxifen produced significantly longer progression-free survival and time to treatment failure compared with arzoxifene in the treatment of locally advanced and metastatic breast cancer. There were no significant differences between tumor response rate, clinical benefit rate, or median response duration.
Coagulopathy Associated with Hematin Treatment for Acute Intermittent Porphyria
Authors: D. LYNN MORRIS
Journal: Annals of Internal Medicine (1981)

Hematin has been shown to be effective therapy for acute intermittent porphyria. Few complications have been found. We cared for a patient who developed a markedly prolonged prothrombin time, partial thromboplastin time, thrombocytopenia, mild hypofibrinogenemia, mild elevation of fibrin split products, and a 10% fall in hematocrit while receiving hematin. No other cause for the coagulopathy could be found. The abnormal coagulation variables returned to normal when hematin was discontinued. Patients receiving hematin for acute intermittent porphyria should be closely observed for signs of coagulopathy.
A placebo-controlled, double-blind, randomized trial of an extract of Ginkgo biloba for dementia. North American EGb Study Group
Authors: P. L. Le Bars
Journal: JAMA (1997)

EGb 761 is a particular extract of Ginkgo biloba used in Europe to alleviate symptoms associated with numerous cognitive disorders. Its use in dementias is based on positive results from only a few controlled clinical trials, most of which did not include standard assessments of cognition and behavior.To assess the efficacy and safety of EGb in Alzheimer disease and multi-infarct dementia.A 52-week, randomized double-blind, placebo-controlled, parallel-group, multicenter study.Mildly to severely demented outpatients with Alzheimer disease or multi-infarct dementia, without other significant medical conditions.Patients assigned randomly to treatment with EGb (120 mg/d) or placebo. Safety, compliance, and drug dispensation were monitored every 3 months with complete outcome evaluation at 12, 26, and 52 weeks.Alzheimer's Disease Assessment Scale-Cognitive subscale (ADAS-Cog), Geriatric Evaluation by Relative's Rating Instrument (GERRI), and Clinical Global Impression of Change (CGIC).From 309 patients included in an intent-to-treat analysis, 202 provided evaluable data for the 52-week end point analysis. In the intent-to-treat analysis, the EGbgroup had an ADAS-Cog score 1.4 points better than the placebo group (P=.04) and a GERRI score 0.14 points better than the placebo group (P=.004). The same patterns were observed with the evaluable data set in which 27% of patients treated with EGb achieved at least a 4-point improvement on the ADAS-Cog, compared with 14% taking placebo (P=.005); on the GERRI, 37% were considered improved with EGb, compared with 23% taking placebo (P=.003). No difference was seen in the CGIC. Regarding the safety profile of EGb, no significant differences compared with placebo were observed in the number of patients reporting adverse events or in the incidence and severity of these events.EGb was safe and appears capable of stabilizing and, in a substantial number of cases, improving the cognitive performance and the social functioning of demented patients for 6 months to 1 year. Although modest, the changes induced by EGb were objectively measured by the ADAS-Cog and were of sufficient magnitude to be recognized by the caregivers in the GERRI.
Protective effect of chlorpromazine on endotoxin toxicity and TNF production in glucocorticoid-sensitive and glucocorticoid-resistant models of endotoxic shock.
Authors: M Gadina, R Bertini, M Mengozzi, M Zandalasini, A Mantovani, P Ghezzi
Journal: The Journal of Experimental Medicine (1991)

The present study was designed to define the potential of chlorpromazine (CPZ) as a protective agent against lipopolysaccharide (LPS) toxicity in comparison with glucocorticoids, and to obtain initial correlations with its effects on the levels of tumor necrosis factor (TNF), a pivotal mediator of endotoxic shock. It was found that CPZ protects mice, normal or adrenalectomized, and guinea pigs against lethality of LPS, and inhibited TNF serum levels, like dexamethasone (DEX), a well-known inhibitor of TNF synthesis. CPZ protected against LPS lethality when administered 30 minutes (min) before, simultaneously, or up to 10 min after LPS and was ineffective when given 30 min after LPS, paralleling the inhibitory effect on TNF production. In another experimental model, where mice were sensitized to LPS toxicity by actinomycin D, CPZ significantly inhibited LPS lethality and hepatotoxicity, whereas under these conditions DEX was inactive. These experiments indicate that CPZ has a protective action in both glucocorticoid-sensitive and -resistant models of endotoxic shock.
Antigen-specific suppression in genetic responder mice to L-glutamic acid60-L-alanine30-L-tyrosine10 (GAT). Characterization of conventional and hybridoma-derived factors produced by suppressor T cells from mice injected as neonates with syngeneic GAT macrophages.
Authors: C M Sorensen, C W Pierce
Journal: The Journal of Experimental Medicine (1982)

Spleen cells from C57BL/10 mice injected with syngeneic B10 L-glutamic acid60-L-alanine30-L-tyrosine10 (GAT)-pulsed macrophages (GAT-M phi) within 18 h of birth were unable to respond to soluble GAT, GAT-methylated bovine serum albumin, or B10 GAT-M phi as adults. Spleen cells from these neonatally treated mice responded at control levels to GAT presented in allogeneic M phi and to sheep erythrocytes. Partially purified T cells from these neonatally treated mice suppressed responses by syngeneic virgin, but not primed, spleen cells in an antigen-specific manner and acted during the early phases of the response. These responder GAT-specific suppressor T cells (GAT-TSR) were sensitive to anti-Thy-1 + C and 500-rad irradiation and have the phenotype Ly-1-2+, I-J+; GAT-TSR cells can only suppress responses by spleen cells syngeneic with the GAT-TSR cells at the I-J subregion of H-2. Restimulation of these Ts cells with syngeneic GAT-M phi induces an antigen-specific suppressor factor within the supernatant fluid. The factor, GAT-TsFR, is a glycoprotein with a molecular weight between 48,000 and 63,000, as determined by gel filtration chromatography using isotonic buffers; it bears serologically detectable determinants encoded by the I-J subregion of the H-2 complex, has an antigen-binding site for GAT and L-glutamic acid50-L-tyrosine50, and shares idiotypic determinants with anti-GAT antibodies. The presence of GAT-TsFR in the first 36 h of in vitro culture is required for significant suppression. Furthermore, only responses by spleen cell syngeneic with the cells producing GAT-TsFR at the I-J subregion are suppressed. The fusion of GAT-TsFR-producing cells with BW5147 resulted in generation of two hybridomas with properties and characteristics identical to those of the conventional GAT-TsFR with one exception: conventional and hybridoma 372.D6.5 GAT-TsFR only suppress responses by spleen cells of the I-Jb haplotype, whereas suppression mediated by the second hybridoma GAT-TsFR (372.B3.5) is genetically unrestricted. These hybridoma GAT-TsFR are compared with nonresponder GAT-Ts factor (GAT-TsF) and these responder and nonresponder GAT-TsF are considered in the context of suppressor pathways.
<b><i>Helicobacter pylori</i></b>Induces Plasminogen Activator Inhibitor 2 in Gastric Epithelial Cells through Nuclear Factor-κB and RhoA
Authors: Andrea Varro, P-J. M. Noble, D. Mark Pritchard, Susan Kennedy, C. Anthony Hart, Rod Dimaline, Graham J. Dockray
Journal: Cancer Research (2004)

Abstract The gastric pathogen Helicobacter pylori is associated with a progression to gastric cancer. The specific targets of H. pylori that might influence this progression are still unclear. Previous studies indicated that the gastric hormone gastrin, which may be increased in H. pylori infection, stimulates gastric expression of plasminogen activator inhibitor (PAI)-2, which is an inhibitor of the urokinase plasminogen activator and has previously been shown to be increased in gastric adenocarcinoma. Here, we report that H. pylori also increases PAI-2 expression. In gastric biopsies of H. pylori-positive subjects there was increased PAI-2, including subjects with plasma gastrin concentrations in the normal range. PAI-2 was expressed mainly in chief and mucous cells. In a gastric cancer cell line (AGS), H. pylori increased PAI-2 expression, which was associated with inhibition of H. pylori-stimulated cell invasion and apoptosis. The induction of PAI-2 by H. pylori was mediated by release of interleukin-8 and activation of cyclooxygenase-2, and interestingly, gastrin stimulated PAI-2 expression by similar paracrine pathways. The activation of NFκB was required for interleukin-8 and cyclooxygenase-2 activation but did not occur in cells responding to these paracrine mediators. The data suggest that induction of PAI-2 is a specific target in H. pylori infection, mediated at least partly by paracrine factors; induction of PAI-2 inhibits cell invasion and apoptosis and is a candidate for influencing the progression to gastric cancer.
Allergy and the Guillain-Barré Syndrome
Authors: L. Bruce Anderson
Journal: JAMA (1972)

To the Editor.—  Allergic immunotherapy is frequently suspect as the source of other illnesses, particularly if the illness might be caused by hypersensitivity. While no one really believes that allergic treatment can cause the Guillain-Barre syndrome, its onset shortly after the start of injections as in the following case was cause for concern.  A 23-year-old white man with seasonal rhinitis was found to have marked sensitivity by scratch tests to pollens, dust, and molds, and injections of an appropriate extract were started in March 1969. He received a total of five injections by March 30, when an ascending paralysis typical of the Guillain-Barre syndrome developed, confirmed by the subsequent clinical course and cerebrospinal fluid analysis. He was completely recovered by early May, but during the summer he had severe hay fever and bravely requested that his hyposensitization injections be restarted. After a thorough search of the literature which revealed no
Regulation of hepatic fat and glucose oxidation in rats with lipid-induced hepatic insulin resistance
Authors: Tiago C. Alves, Douglas E. Befroy, Richard G. Kibbey, Mario Kahn, Roberto Codella, Rui A. Carvalho, Kitt Falk Petersen, Gerald I. Shulman
Journal: Hepatology (2011)

Pyruvate dehydrogenase plays a critical role in the regulation of hepatic glucose and fatty acid oxidation; however, surprisingly little is known about its regulation in vivo . In this study we examined the individual effects of insulin and substrate availability on the regulation of pyruvate dehydrogenase flux (VPDH) to tricarboxylic acid flux (VTCA) in livers of awake rats with lipid-induced hepatic insulin resistance. VPDH/VTCA flux was estimated from the [4-13C]glutamate/[3-13C]alanine enrichments in liver extracts and assessed under conditions of fasting and during a hyperinsulinemic-euglycemic clamp, whereas the effects of increased plasma glucose concentration on VPDH/VTCA flux was assessed during a hyperglycemic clamp in conjunction with infusions of somatostatin and insulin to maintain basal concentrations of insulin. The effects of increases in both glucose and insulin on VPDH/VTCA were examined during a hyperinsulinemic-hyperglycemic clamp. The effects of chronic lipid-induced hepatic insulin resistance on this flux were also examined by performing these measurements in rats fed a high-fat diet for 3 weeks. Using this approach we found that fasting VPDH/VTCA was reduced by 95% in rats with hepatic insulin resistance (from 17.2 ± 1.5% to 1.3 ± 0.7%, P &lt; 0.00001). Surprisingly, neither hyperinsulinemia per se or hyperglycemia per se were sufficient to increase VPDH/VTCA flux. Only under conditions of combined hyperglycemia and hyperinsulinemia did VPDH/VTCA flux increase (44.6 ± 3.2%, P &lt; 0.0001 versus basal) in low-fat fed animals but not in rats with chronic lipid-induced hepatic insulin resistance. Conclusion: These studies demonstrate that the combination of both hyperinsulinemia and hyperglycemia are required to increase VPDH/VTCA flux in vivo and that this flux is severely diminished in rats with chronic lipid-induced hepatic insulin resistance. (HEPATOLOGY 2011.)
William Hillary and sprue in the Caribbean: 230 years later.
Authors: C Bartholomew
Journal: Gut (1989)

Aretaeus from Cappadocchia, which was at that time part of the Greek Empire and is now part of present day Turkey, left us an account of sprue in Chapter VII of his extant works entitled 'On the Coeliac Affection'.'This was in the second or third century AD and probably refers to coeliac sprue.More than a millenium later, in 1747, an English- man, more specifically a Yorkshireman, migrated to the Caribbean island of Barbados which had been a British colony since 1627.This Yorkshireman, Dr William Hillary, came to practice medicine but was also a systematic observer of the weather and its relationship to disease.He began these observations in Ripon in England and resumed them in Barbados.In 1759, he published one of the earliest books in the English medical literature on tropical diarrhoeal disease which occurred more frequently in native Barbadians than in white settlers.It carried the
Controlled mechanical ventilation in septic animals: Effects on diaphragm function
Authors: Karen Maes, Debby Thomas, Cielen Nele, Smuder Asley, Powers Scott, Hermans Greet, Stamiris Angela, Sabah Hussain, Marc Decramer, Ghislaine Gayan-Ramirez
Journal: European Respiratory Journal (2013)

Controlled mechanical ventilation (CMV) was shown to result in diaphragmatic dysfunction and atrophy in healthy animals. Whether mechanical ventilation results in more severe diaphragm dysfunction in animals with already weakened diaphragms is not known and was examined in septic animals. Male Wistar rats were either treated with lipopolysaccharide (5 mg/kg) to induce sepsis or with saline. After 12 hours they were divided into 3 groups: sepsis, sepsis+12hCMV and saline+12hCMV. The levels of IL-6 in plasma and in diaphragm were significantly increased in the sepsis+12hCMV group compared to the other groups. Diaphragm force was significantly lower in septic animals compared to saline+12hCMV with an additional decrease in the sepsis+12hCMV group compared to the sepsis group. mRNA expression of diaphragm MuRF1 and atrogin-1, markers of the proteasome system, were significantly higher in the sepsis+12hCMV group compared to the other groups. Diaphragm fiber dimensions and 4-HNE, a marker of oxidative stress, were similar in all groups. LC3B protein lipidation, used as an indirect assessment of autophagy, was increased in sepsis+12hCMV compared to the other groups. Similarly, protein levels of several autophagy-related genes including those involved in the initiation of autophagosome formation (ULK1, BECLIN1, PI3KC3), and targeting of the mitochondria by autophagosomes (SQSTM1, BNIP3 and PARKIN) were significantly increased in sepsis+12hCMV compared to the others. These data clearly show that CMV in septic animals further compromises diaphragm function, activates atrophic pathway and favors autophagosome formation.  Supported by FWO-Flanders G.0893.11 and AstraZeneca Pharmaceuticals.
Impact of changes in the IOC-MC asthma criteria: a British perspective
Authors: J W Dickinson
Journal: Thorax (2005)

<b>Background:</b> Since 2001 the International Olympic Committee-Medical Commission (IOC-MC) has required athletes using inhaled β<sub>2</sub> agonists to provide clinical evidence of their asthmatic condition. The aim of this study was to compare the reported prevalence of asthma at the 2000 and 2004 Olympic Games in the Great British Olympic team (Team GB). <b>Methods:</b> Following local ethics committee approval, 271 athletes (165 men) from the 2004 Team GB volunteered and provided written informed consent. An athlete was confirmed asthmatic if he or she had a positive bronchoprovocation or bronchodilator test as defined by the IOC-MC. Pre-Olympic medical forms from the 2000 Team GB were also examined to establish the prevalence of asthma among the members of Team GB at the 2000 Olympic Games. <b>Results:</b> The prevalence of asthma in the two teams at the 2000 and 2004 Olympic Games was similar (21.2% and 20.7%, respectively). In the 2004 Olympic Games 13 of 62 athletes (21.0%) with a previous diagnosis of asthma tested negative. A further seven with no previous diagnosis of asthma tested positive. <b>Conclusions:</b> The prevalence of asthma within Team GB remained unchanged between 2000 and 2004. The IOC-MC requirement that asthmatic athletes must submit documented evidence of asthma has highlighted that 13 (21.0%) previously diagnosed as asthmatic failed to demonstrate evidence of asthma while seven athletes with no previous history or diagnosis of asthma tested positive. Screening for asthma within elite athletic populations using bronchoprovocation challenges appears warranted to assist athletes in preparing more effectively for major sporting events.
Nucleolin as Activator of Human Papillomavirus Type 18 Oncogene Transcription in Cervical Cancer
Authors: Edgar Grinstein, Peter Wernet, Peter J.F. Snijders, Frank Rösl, Inge Weinert, Wentao Jia, Regine Kraft, Christiane Schewe, Michael Schwabe, Steffen Hauptmann, Manfred Dietel, Chris J.L.M. Meijer, Hans-Dieter Royer
Journal: The Journal of Experimental Medicine (2002)

High risk human papillomaviruses (HPVs) are central to the development of cervical cancer and the deregulated expression of high risk HPV oncogenes is a critical event in this process. Here, we find that the cell protein nucleolin binds in a sequence-specific manner to the HPV18 enhancer. The DNA binding activity of nucleolin is primarily S phase specific, much like the transcription of the E6 and E7 oncoproteins of HPV18 in cervical cancer cells. Antisense inactivation of nucleolin blocks E6 and E7 oncogene transcription and selectively decreases HPV18+ cervical cancer cell growth. Furthermore, nucleolin controls the chromatin structure of the HPV18 enhancer. In contrast, HPV16 oncogene transcription and proliferation rates of HPV16+ SiHa cervical cancer cells are independent of nucleolin activity. Moreover, nucleolin expression is altered in HPV18+ precancerous and cancerous tissue from the cervix uteri. Whereas nucleolin was homogeneously distributed in the nuclei of normal epithelial cells, it showed a speckled nuclear phenotype in HPV18+ carcinomas. Thus, the host cell protein nucleolin is directly linked to HPV18-induced cervical carcinogenesis.