tbuckley/cabot-search huggingface dataset:
Correlations Between O6-Methylguanine DNA Methyltransferase Promoter Methylation Status, 1p and 19q Deletions, and Response to Temozolomide in Anaplastic and Recurrent Oligodendroglioma: A Prospective GICNO Study
Authors: Alba A. Brandes, Alicia Tosoni, Giovanna Cavallo, Michele Reni, Enrico Franceschi, Laura Bonaldi, Roberta Bertorelle, Marina Gardiman, Claudio Ghimenton, Paolo Iuzzolino, Annalisa Pession, Valeria Blatt, Mario Ermani
Journal: Journal of Clinical Oncology (2006)

Purpose To date, no data are available on the relationship between 1p/19q deletions and the response to temozolomide (TMZ) in primary anaplastic oligodendroglioma (AO) and anaplastic oligoastrocytoma (AOA) recurrent after surgery and standard radiotherapy. The aim of this study was to evaluate correlations between 1p/19q deletions, O6-methylguanine DNA methyltransferase (MGMT) promoter methylation, and response rate to TMZ in this setting. Patients and Methods From June 2000 to February 2005, 67 patients were enrolled; 39 patients (58%) had AO and 28 patients (42%) had AOA. All patients received 150 to 200 mg/m 2 of TMZ every 28 days. Chromosome 1p and 19q deletions were detected by fluorescence in situ hybridization and MGMT promoter methylation was analyzed using methylation specific polymerase chain reaction. Results The overall response rate was 46.3% (17 complete responses and 14 partial responses). The response rate was higher in patients with AO than in those with AOA (61.5% v 25%, P = .003). Combined 1p/19q allelic loss was found in 32 patients (47.8%), while MGMT methylation occurred in 37 (68.5%) of 54 assessable patients. 1p/19q loss was significantly correlated with response rate (P = .04), time-to-progression (P = .003), and overall survival (P = .0001). Despite the significant concordance found between MGMT promoter methylation and 1p/19q deletions (P = .02), MGMT promoter methylation showed only a borderline correlation with overall survival (P = .09). Conclusion TMZ is active in anaplastic oligodendroglial tumors treated at first recurrence. In this setting, 1p/19q allelic loss is an important predictive and prognostic factor. Further studies on MGMT promoter methylation should be performed in randomized trials to test its correlation with survival.
Gender-based differences in mechanisms of protection in myocardial ischemia–reperfusion injury
Authors: E MURPHY, C STEENBERGEN
Journal: Cardiovascular Research (2007)

Pre-menopausal women have reduced risk for cardiovascular disease, and cardiovascular disease rises after menopause. Studies in animal models have also suggested that females have reduced injury following ischemia and reperfusion (I/R). However, a large clinical trial, the Women's Health Initiative, found an increase in cardiovascular incidents in women on hormone replacement therapy. Taken together, these data suggest that we need a better understanding regarding the mechanisms for the protection observed in the animal studies. In some studies, particularly in the rat, females show less I/R injury; however, in many animal studies no gender difference in I/R injury is observed. Under conditions where calcium is elevated or contractility is increased just prior to ischemia, females have been reported to have less I/R injury than males. Also, estrogen administration has been shown to reduce I/R injury. The protection observed under conditions of increased contractility has been shown to involve an increase in nitric oxide signaling leading to S-nitrosylation of the L-type calcium channel, which reduces calcium loading during ischemia and early reperfusion thereby reducing I/R injury. Estrogen binding to nuclear estrogen receptors results in altered expression of a number of cardioprotective genes such as nitric oxide synthase and heat shock proteins. Estrogen also alters a number of genes involved in metabolism such as lipoprotein lipase, prostaglandin D2 synthase, and peroxisome proliferator activated receptor gamma coactivator 1 alpha (PGC-1-alpha). The effects of these alterations in gene expression may depend on the context of other hormonal stimuli and gene expression as well as physiological stimuli. Furthermore, addition of estrogen has acute non-genomic responses that involve activation of the phosphatidylinositol 3-kinase (PI 3-kinase) pathway, which has been shown to be protective, at least when activated for short durations. This review will summarize the data showing protection in females in animal studies and will summarize the data on possible mechanisms of cardioprotection in females.
Remarks on Cases in which the Whole or Part of the Placenta was Retained for a Longer Period than Usual after Delivery of the Child: Removal of the Retained Portion by Hand, with Remarks
Authors: J. B. Hicks
Journal: BMJ (1882)

Tis very important rule, of longstanding, that the'placenta, if retained, should always be removed, is now, almost without exception, so
RORγt drives production of the cytokine GM-CSF in helper T cells, which is essential for the effector phase of autoimmune neuroinflammation
Authors: Laura Codarri, Gabor Gyülvészi, Vinko Tosevski, Lysann Hesske, Adriano Fontana, Laurent Magnenat, Tobias Suter, Burkhard Becher
Journal: Nature Immunology (2011)
United Kingdom Beryllium Registry: mortality and autopsy study.
Authors: W J Williams
Journal: Environmental Health Perspectives (1996)

This report is based on 30 deaths from chronic beryllium disease (CBD) in the United Kingdom with details of 19 autopsies. The majority were fluorescent lamp workers and machinists who died from respiratory failure. There were no cases of lung cancer. The survival times ranged from less than 1 to 29 years and was longest in machinists. All of the workers showed interstitial pulmonary fibrosis with varying degrees of cystic change. The majority showed hyalinized, and a few active sarcoid-type, granulomas. Extrathoracic granulomas, as in a U.K. sarcoid autopsy series, were rare. A notable difference was the absence of myocardial involvement in CBD compared to an incidence of 20% in the sarcoid autopsies. The detection of beryllium in the criteria for diagnosis is emphasized and the cases classified as definite include 12 of 19 positive analysis, 6 of 19, negative or unavailable analysis. The remaining case was classified as dubious because, despite a positive analysis, granulomas were absent. The main differential diagnosis is sarcoidosis.
High-resolution genomic profiling of childhood ALL reveals novel recurrent genetic lesions affecting pathways involved in lymphocyte differentiation and cell cycle progression
Authors: R P Kuiper, E F P M Schoenmakers, S V van Reijmersdal, J Y Hehir-Kwa, A Geurts van Kessel, F N van Leeuwen, P M Hoogerbrugge
Journal: Leukemia (2007)
Vasodilator-Stimulated Phosphoprotein–Deficient Mice Demonstrate Increased Platelet Activation but Improved Renal Endothelial Preservation and Regeneration in Passive Nephrotoxic Nephritis
Authors: Bernd Hohenstein, Laura Kasperek, Dieter-Johannes Kobelt, Christoph Daniel, Stepan Gambaryan, Thomas Renné, Ulrich Walter, Kerstin U. Amann, Christian P.M. Hugo
Journal: Journal of the American Society of Nephrology (2005)

Vasodilator-stimulated phosphoprotein (VASP), an actin cytoskeletal protein, is expressed in various cell types including renal cells. In vitro studies provide evidence for a role of VASP regarding platelet activation, cell adhesion, migration, and capillary formation. The in vivo role of VASP was investigated in experimental inflammatory renal disease. Kidneys of healthy VASP deficient (−/−) and wild-type (wt) mice were compared regarding morphology and functional parameters. Passive nephrotoxic nephritis was induced in 28 VASP −/− and 28 wt mice; kidneys were harvested; and tissues were analyzed by morphometric, immunohistochemical, and electron microscopic techniques on days 3, 7, 14, and 28. The time course of disease in VASP −/− mice differed substantially and biphasically from that in wt controls. Early on, VASP −/− mice demonstrated increased platelet influx associated with augmented glomerular and tubulointerstitial inflammation and sclerosis. Whereas renal disease continuously worsened up to day 28 in wt controls, renal disease in VASP −/− mice hardly progressed after day 3 as assessed by various injury indices. This long-term improvement of renal histology in VASP −/− compared with wt mice was associated with remarkable capillary preservation/regeneration up to day 28 mediated via an increased proliferative and a reduced apoptotic activity of VASP-negative peritubular endothelial cells. Despite an enhanced injury response early on, VASP −/− mice are protected from long-term progression of nephrotoxic nephritis, which is associated with improved renal endothelial cell preservation and regeneration.
RET/Papillary Thyroid Carcinoma Oncogenic Signaling through the Rap1 Small GTPase
Authors: Valentina De Falco, Maria Domenica Castellone, Gabriella De Vita, Anna Maria Cirafici, Jerome M. Hershman, Carmen Guerrero, Alfredo Fusco, Rosa Marina Melillo, Massimo Santoro
Journal: Cancer Research (2007)

Abstract RET/papillary thyroid carcinoma (PTC) oncoproteins result from the in-frame fusion of the RET receptor tyrosine kinase with protein dimerization motifs encoded by heterologous genes. Here, we show that RET/PTC1 activates the Rap1 small GTPase. The activation of Rap1 was dependent on the phosphorylation of RET Tyr1062. RET/PTC1 recruited a complex containing growth factor receptor binding protein 2–associated binding protein 1 (Gab1), CrkII (v-crk sarcoma virus CT10 oncogene homologue II), and C3G (Rap guanine nucleotide exchange factor 1). By using dominant-negative and small interfering duplex (small interfering RNA) oligonucleotides, we show that RET/PTC1–mediated Rap1 activation was dependent on CrkII, C3G, and Gab1. Activation of Rap1 was involved in the RET/PTC1–mediated stimulation of the BRAF kinase and the p42/p44 mitogen-activated protein kinases. Proliferation and stress fiber formation of RET/PTC1–expressing PC Cl 3 thyroid follicular cells were inhibited by the dominant-negative Rap1(N17) and by Rap1–specific GTPase-activating protein. Thus, Rap1 is a downstream effector of RET/PTC and may contribute to the transformed phenotype of RET/PTC–expressing thyrocytes. [Cancer Res 2007;67(1):381–90]
Bisphosphonate Use in Patients with Lung Cancer and Bone Metastases: Recommendations of a European Expert Panel
Authors: Filippo De Marinis, Wilfried Eberhardt, Peter G. Harper, Bartomeu Massuti Sureda, Kristiaan Nackaerts, Jens Benn Soerensen, Kostas Syrigos, Jean Trédaniel
Journal: Journal of Thoracic Oncology (2009)
A Randomized Trial of Genotype-Guided Dosing of Warfarin
Authors: Munir Pirmohamed, Girvan Burnside, Niclas Eriksson, Andrea L. Jorgensen, Cheng Hock Toh, Toby Nicholson, Patrick Kesteven, Christina Christersson, Bengt Wahlström, Christina Stafberg, J. Eunice Zhang, Julian B. Leathart, Hugo Kohnke, Anke H. Maitland-van der Zee, Paula R. Williamson, Ann K. Daly, Peter Avery, Farhad Kamali, Mia Wadelius
Journal: New England Journal of Medicine (2013)

The level of anticoagulation in response to a fixed-dose regimen of warfarin is difficult to predict during the initiation of therapy. We prospectively compared the effect of genotype-guided dosing with that of standard dosing on anticoagulation control in patients starting warfarin therapy.We conducted a multicenter, randomized, controlled trial involving patients with atrial fibrillation or venous thromboembolism. Genotyping for CYP2C9*2, CYP2C9*3, and VKORC1 (-1639G→A) was performed with the use of a point-of-care test. For patients assigned to the genotype-guided group, warfarin doses were prescribed according to pharmacogenetic-based algorithms for the first 5 days. Patients in the control (standard dosing) group received a 3-day loading-dose regimen. After the initiation period, the treatment of all patients was managed according to routine clinical practice. The primary outcome measure was the percentage of time in the therapeutic range of 2.0 to 3.0 for the international normalized ratio (INR) during the first 12 weeks after warfarin initiation.A total of 455 patients were recruited, with 227 randomly assigned to the genotype-guided group and 228 assigned to the control group. The mean percentage of time in the therapeutic range was 67.4% in the genotype-guided group as compared with 60.3% in the control group (adjusted difference, 7.0 percentage points; 95% confidence interval, 3.3 to 10.6; P<0.001). There were significantly fewer incidences of excessive anticoagulation (INR ≥4.0) in the genotype-guided group. The median time to reach a therapeutic INR was 21 days in the genotype-guided group as compared with 29 days in the control group (P<0.001).Pharmacogenetic-based dosing was associated with a higher percentage of time in the therapeutic INR range than was standard dosing during the initiation of warfarin therapy. (Funded by the European Commission Seventh Framework Programme and others; ClinicalTrials.gov number, NCT01119300.).
Government announces review of copayments in the NHS
Authors: Adrian O’Dowd
Journal: BMJ (2008)

The government is to review a longstanding rule that forbids NHS patients in England from topping up their treatment by buying drugs that are not available on the NHS.

The Department of Health is signalling that it may consider changing the rule on such copayments. Currently anyone who buys their own drugs has to become a private patient and thus pay for the whole of their care themselves.

Pressure has been building for a change after cases in which patients in the final stages of cancer wanted to pay for drugs that were new and had not yet been approved for use …
Comparison of Phosphodiesterase Inhibitors of Differing Isoenzyme Selectivity Added to St. Thomas' Hospital Cardioplegic Solution Used for Hypothermic Preservation of Rat Lungs
Authors: ROLAND L. FEATHERSTONE, DAVID J. CHAMBERS, FRANK J. KELLY
Journal: American Journal of Respiratory and Critical Care Medicine (2000)

Raising intracellular cAMP or cGMP concentrations protects lungs from ischemia-reperfusion injury. These nucleotides are catabolized by a number of distinct phosphodiesterase (PDE) isoenzyme subfamilies. We examined the ability of PDE inhibitors of differing selectivities to protect lungs from the effects of prolonged hypothermic storage. Rat lungs were perfused with bicarbonate buffer mixed with rat blood (4:1 vol/vol, 37 ° C), ventilated, and vascular resistance, airway compliance, and resistance, and gas exchange measured. Lungs were then flushed with, and immersed in, St. Thomas' Hospital Solution (STH) (4 ° C) or STH containing rolipram, milrinone, zaprinast, or theophylline. After 8 h storage, function was reassessed during 40 min reperfusion. Lungs stored in STH containing rolipram or theophylline had improved function on reperfusion. After 40 min reperfusion, pulmonary compliance (Cstat) was 0.07 ± 0.01 ml/cm H2O in lungs stored in STH alone. Adding rolipram (100 μ M) or theophylline (3,000 μ M) to the STH used for flushing and storage improved Cstat after reperfusion to 0.17 ± 0.02 ml/cm H2O (p < 0.05) and 0.17 ± 0.02 ml/cm H2O (p < 0.05), respectively. Theophylline also improved the increase in perfusate Po 2 on transit through the lung after storage to 25.16 ± 2.33 compared with 4.72 ± 2.18 mm Hg in lungs stored in STH alone (p < 0.05). Of the selective PDE inhibitors tested, rolipram (type IV inhibitor) was most effective. However, the nonselective agent, theophylline, provided the best protection of function after storage and reperfusion of rat lungs.
The effect of Gu-Sui-Bu (Drynaria fortunei J. Sm) on bone cell activities
Authors: Jui-Sheng Sun, Chun-Yu Lin, Guo-Chung Dong, Shiow-Yunn Sheu, Feng-Huei Lin, Li-Ting Chen, Yng-Jiin Wang
Journal: Biomaterials (2002)
P186 The reliability of the respiratory physical examination
Authors: M. Newnham, E. Jones, D. Wall, R. Mukherjee
Journal: Thorax (2011)

<h3>Background</h3> We often teach and assess medical students performing the respiratory examination in a traditional way, rather than based on evidence. An essential component of the respiratory clinical examination is that it is precise. The reliability of the examination is a fundamental element of this precision. There needs to be agreement between physicians that a clinical sign can be elicited independently in the same patient when it is present. When learning about the respiratory examination, medical students should have knowledge of the reliability of the different elements. <h3>Aims</h3> To establish medical students9 knowledge of the reliability of different elements of the respiratory examination. <h3>Methods</h3> A cross sectional questionnaire survey of clinical medical students (years 3–5) was undertaken. The questionnaire assessed the reliability of tactile vocal fremitus, tracheal position, auscultation of wheeze, whispering pectoriloquy, auscultation of crackles and chest expansion using a five point Likert scale. Demographic data were also collected. The results of the perceived reliability of different elements of the respiratory examination was compared with Cohen9s κ coefficient values; a statistical measure of inter-observer reliability. <h3>Results</h3> Of 104 questionnaires completed, 33% were male, 36% attached to respiratory firm, 11% graduate entry. Crackles, wheeze and percussion note are all regarded as reliable to very reliable signs by students. Perceived reliability of whispering pectoriloquy decreased as students become more experienced (p=0.003). There was no relationship between perceived reliability and graduate entry, previous respiratory attachment or gender. Factor analysis identified that tactile vocal fremitus and whispering pectoriloquy were grouped together separately from the other respiratory signs. Linear regression showed good correlation between students answers and actual κ values of reliability (r=0.722). <h3>Conclusions</h3> Students have a good intuition of the reliability of elements of the respiratory examination. For example, as experience increases, they correctly perceive whispering pectoriloquy as a less reliable sign. Reliability of elements of the respiratory examination needs consideration when teaching and assessing students.
Lateralized Caudate Metabolic Abnormalities in Adolescent Major Depressive Disorder: A Proton MR Spectroscopy Study
Authors: Vilma Gabbay, David A. Hess, Songtao Liu, James S. Babb, Rachel G. Klein, Oded Gonen
Journal: American Journal of Psychiatry (2007)

Proton magnetic resonance spectroscopy ((1)H-MRS) has been increasingly used to examine striatal neurochemistry in adult major depressive disorder. This study extends the use of this modality to pediatric major depression to test the hypothesis that adolescents with major depression have elevated concentrations of striatal choline and creatine and lower concentrations of N-acetylaspartate.Fourteen adolescents (ages 12-19 years, eight female) who had major depressive disorder for at least 8 weeks and a severity score of 40 or higher on the Children's Depression Rating Scale-Revised and 10 healthy comparison adolescents (six female) group-matched for gender, age, and handedness were enrolled. All underwent three-dimensional 3-T (1)H-MRS at high spatial resolution (0.75-cm(3) voxels). Relative levels of choline, creatine, and N-acetylaspartate in the left and right caudate, putamen, and thalamus were scaled into concentrations using phantom replacement, and levels were compared for the two cohorts.Relative to comparison subjects, adolescents with major depressive disorder had significantly elevated concentrations of choline (2.11 mM versus 1.56 mM) and creatine (6.65 mM versus 5.26 mM) in the left caudate. No other neurochemical differences were observed between the groups.These findings most likely reflect accelerated membrane turnover and impaired metabolism in the left caudate. The results are consistent with prior imaging reports of focal and lateralized abnormalities in the caudate in adult major depression.
Racial Disparity of Eye Examinations Among the U.S. Working-Age Population With Diabetes: 2002–2009
Authors: Qian Shi, Yingnan Zhao, Vivian Fonseca, Marie Krousel-Wood, Lizheng Shi
Journal: Diabetes Care (2014)

Diabetes care differs across racial and ethnic groups. This study aimed to assess the racial disparity of eye examinations among U.S. adults with diabetes.Working-age adults (age 18-64 years) with diabetes were studied using data from the Medical Expenditure Panel Survey Household Component (2002-2009) including the Diabetes Care Survey. Racial and ethnic groups were classified as non-Hispanic whites and minorities. People reporting one or more dilated eye examination were considered to have received an eye examination in a particular year. Eye examination rates were compared between racial/ethnic groups for each year, and were weighted to national estimates. Multivariate adjusted odds ratios (aORs) and 95% CIs for racial/ethnic difference were assessed annually using logistic regression models. Other influencing factors associated with eye examination were also explored.Whites had consistently higher unadjusted eye examination rates than minority populations across all 8 years. The unadjusted rates increased from 56% in 2002 to 59% in 2009 among whites, while the rates in minorities decreased from 56% in 2002 to 49% in 2009. The largest significant racial gap of 15% was observed in 2008, followed by 11%, 10%, and 7% in 2006, 2009, and 2005, respectively (P < 0.05). Minorities were less likely to receive eye examination (2006: aOR 0.75 [95% CI 0.57-0.99]; 2008: 0.61 [0.45-0.84]).The racial/ethnic differences in eye examinations for patients with diabetes have persisted over the last decade. National programs to improve screening and monitoring of diabetic retinopathy are needed to target minority populations.
Effect of Metformin on Glucagon-Like Peptide 1 (GLP-1) and Leptin Levels in Obese Nondiabetic Subjects
Authors: Edoardo Mannucci, Agostino Ognibene, Francesco Cremasco, Gianluca Bardini, Antonella Mencucci, Enrica Pierazzuoli, Silvia Ciani, Gianni Messeri, Carlo M. Rotella
Journal: Diabetes Care (2001)

OBJECTIVE—To evaluate the effects of metformin on glucagon-like peptide 1 (GLP-1) and leptin levels. RESEARCH DESIGN AND METHODS—A total of 10 obese nondiabetic male patients were studied before and after a 14-day treatment with 2,550 mg/day metformin and were compared with 10 untreated obese control subjects. On days 0 and 15, leptin and GLP-1(7–36)amide/(7–37) levels were assessed before and after an oral glucose load during a euglycemic hyperinsulinemic clamp to avoid the interference of variations of insulinemia and glycemia on GLP-1 and leptin secretion. The effects of metformin on GLP-1(7–36)amide degradation in human plasma and in a buffer solution containing dipeptidyl peptidase IV (DPP-IV) were also studied. RESULTS—Leptin levels were not affected by the oral glucose load, and they were not modified after metformin treatment. Metformin induced a significant (P &amp;lt; 0.05) increase of GLP-1(7–36)amide/(7–37) at 30 and 60 min after the oral glucose load (63.8 ± 29.0 vs. 50.3 ± 15.6 pmol/l and 75.8 ± 35.4 vs. 46.9 ± 20.0 pmol/l, respectively), without affecting baseline GLP-1 levels. No variations of GLP-1 levels were observed in the control group. In pooled human plasma, metformin (0.1–0.5 μg/ml) significantly inhibited degradation of GLP-1(7–36)amide after a 30-min incubation at 37°C; similar results were obtained in a buffer solution containing DPP-IV. CONCLUSIONS—Metformin significantly increases GLP-1 levels after an oral glucose load in obese nondiabetic subjects; this effect could be due to an inhibition of GLP-1 degradation.