tbuckley/cabot-search huggingface dataset:
Reasons to consider earlier treatment of chronic HBV infections
Authors: Fabien Zoulim, William S Mason
Journal: Gut (2011)

CYP2S1 is a recently described dioxin-inducible cytochrome P450. We previously demonstrated that human CYP2S1 oxidizes a number of carcinogens but only via the peroxide shunt. In this article, we investigated whether human CYP2S1 can metabolize cyclooxygenase- and lipoxygenase-derived lipid peroxides in a NADPH-independent fashion. Human CYP2S1 metabolizes prostaglandin G<sub>2</sub> (PGG<sub>2</sub>) (<i>K</i><sub>m</sub> = 0.267 ± 0.072 μM) into several products including 12<i>S</i>-hydroxy-5<i>Z</i>,8<i>E</i>,10<i>E</i>-heptadecatrienoic acid (12-HHT). It also metabolizes prostaglandin H<sub>2</sub> (PGH<sub>2</sub>) (<i>K</i><sub>m</sub> = 11.7 ± 2.8 μM) into malondialdehyde, 12-HHT, and thromboxane A<sub>2</sub> (TXA<sub>2</sub>). The turnover to 12-HHT by human CYP2S1 (1.59 ± 0.04 min<sup>−1</sup>) is 40-fold higher than that of TXA<sub>2</sub> (0.04 min<sup>−1</sup>). In addition to PGG<sub>2</sub> and PGH<sub>2</sub> metabolism, human CYP2S1 efficiently metabolizes the hydroperoxyeicosatetraenoic acids (5<i>S</i>-, 12<i>S</i>-, and 15<i>S</i>-) and 13<i>S</i>-hydroperoxyoctadecadienoic acid into 5-oxo-eicosatetraenoic acid (turnover = 16.7 ± 0.3 min<sup>−1</sup>), 12-oxo-eicosatetraenoic acid 1 (11.5 ± 0.9 min<sup>−1</sup>), 15-oxo-eicosatetraenoic acid (16.9 ± 0.8 min<sup>−1</sup>), and 13-octadecadienoic acid (20.2 ± 0.9 min<sup>−1</sup>), respectively. Other cytochromes P450 such as CYP1A1, 1A2, 1B1, and 3A4 underwent similar conversions but at slower rates. The fatty acid hydroperoxides were also converted by human CYP2S1 to several epoxyalcohols. Our data indicate that fatty acid endoperoxides and hydroperoxides represent endogenous substrates of CYP2S1 and suggest that the enzyme CYP2S1 may play an important role in the inflammatory process because some of the products that CYP2S1 produces play important roles in inflammation.
Lipid Metabolism: A New Frontier in Sleep Apnea Research
Authors: Luciano Drager, Vsevolod Polotsky
Journal: American Journal of Respiratory and Critical Care Medicine (2011)

CAM-ICU seems to be a very simple and time-efficient instrument.While the CAM-ICU attempts to capture disturbances in attention and cognition, it fails to capture the fluctuating nature of these disturbances since the evaluations are done at one point in time.Importantly, this may lead to underdiagnosis of delirium when compared with a comprehensive evaluation that takes into account documentation of these disturbances fluctuating over time, as investigators in this study found.The results of this study raise several important questions.(1) Was it the CAM-ICU as a screening instrument or the failure to actually follow each and every step that lead to its poor performance?(2) Are other tests of ICU delirium (e.g., Intensive Care Delirium Screening Checklist [ICDSC]) (10) subject to the same problems as the CAM-ICU?(3) What is/are the specific shortcoming(s) of the CAM-ICU?(4) Are the findings from this Netherlands study reproducible in other settings?If so, can the CAM-ICU be modified to overcome its potential shortcomings?(5) How, if at all, do the outcomes (short term and long term) that ICU delirium portends differ among patients with "gold standard" delirium versus delirium diagnosed by CAM-ICU?A screening tool must have a high sensitivity to be clinically useful.Are there inherent limitations to the CAM-ICU as a useful instrument for identifying ICU delirium?Such a finding would be analogous to the inherent limitation of ultrasound screening for asymptomatic deep vein thrombosis (11,12).On the other hand, improper use of any instrument may lead to a perception of limitations that is untrue.Further studies are needed to better answer this important question raised by this study.In the meantime, we should be cautious when using the CAM-ICU to screen patients for delirium, both in clinical and research settings.When it is used we must be certain that each step is followed precisely, and we should await further research to shed light on this important issue.
The economic burden of asthma: direct and indirect costs in Switzerland
Authors: T.d. Szucs, H. Anderhub, M Rutishauser
Journal: European Respiratory Journal (1999)

Asthma mortality increased in Switzerland between 1980 and 1994. This study aimed to assess the economic burden of asthma in this country. Chart reviews were conducted for the last five patients seen for asthma in physician practices in 1996 and 1997. Direct expenditures and indirect costs for asthma-related morbidity were determined. A total of 589 patient charts were completely analysed, including 117 children9s charts, obtained from 120 office-based physicians. The annual direct medical costs were CHF 1,778 and the mean annual indirect costs were CHF 1,019 per patient for all patients. The total estimated cost of asthma in Switzerland in 1997 was nearly CHF 1,252 million. Direct medical expenditures approached CHF 762 million, or 61% of the total. In 1997, the indirect costs for asthma were estimated to have exceeded CHF 490 million. Of these costs CHF 123 million (25%) was associated with morbidity and nearly CHF 368 million (75%) was associated with looking after asthmatic patients who had to be cared for at home. This study provides evidence that asthma is a major healthcare cost factor in Switzerland, amounting to approximately CHF 1,200 million per year. The data suggest that cost savings can be achieved by improving primary care for asthma in an ambulatory setting.
Transient Exposure of Neonatal Female Mice to Testosterone Abrogates the Sexual Dimorphism of Abdominal Aortic Aneurysms
Authors: Xuan Zhang, Sean E. Thatcher, Debra L. Rateri, Dennis Bruemmer, Richard Charnigo, Alan Daugherty, Lisa A. Cassis
Journal: Circulation Research (2012)

Abdominal aortic aneurysms (AAAs) exhibit marked sexual dimorphism with higher prevalence in men. Similarly, AAAs induced by angiotensin II (AngII) infusion into mice exhibit a higher prevalence in males. Testosterone promotes AAA pathology in adult male mice through regulation of angiotensin type 1A receptors (AT1aR) in abdominal aortas. However, mechanisms for sexual dimorphism of regional aortic angiotensin receptor expression and AAA formation are unknown.To define the role of developmental testosterone exposures in sexual dimorphism of AAAs, we determined if exposure of neonatal female mice to testosterone confers adult susceptibility to AngII-induced AAAs.One-day-old female hypercholesterolemic mice were administered a single dose of either vehicle or testosterone. Neonatal testosterone administration increased abdominal aortic AT1aR mRNA abundance and promoted a striking increase in AngII-induced AAAs in adult females exhibiting low serum testosterone concentrations. AngII-induced atherosclerosis and ascending aortic aneurysms were also increased by testosterone administration to neonatal females. In contrast, neonatal testosterone administration in males had no effect on AngII-induced vascular pathologies. Deficiency of AT1aR in smooth muscle cells reduced effects of neonatal testosterone to promote AAAs in adult females but did not alter atherosclerosis or ascending aortic aneurysms. Testosterone increased AT1aR mRNA abundance and hydrogen peroxide generation in cultured abdominal aortic SMCs. Increased AT1aR mRNA abundance was maintained during progressive passaging of female smooth muscle cells.These data reveal an unrecognized role of transient sex hormone exposures during neonatal development as long-lasting mediators of regional aortic AT1aR expression and sexual dimorphism of AAAs.
Melanotic and Amelanotic Melanomas in Xiphophorin Fish
Authors: Jürgen Vielkind, Ursula Vielkind, Fritz Anders
Journal: Cancer Research (1971)

Summary  Histological, electron microscopic, and biochemical studies on heritable melanotic and albino melanomas of platyfish-swordtail hybrids have been carried out. The very rapidly growing albino melanomas have been found to consist of less differentiated melanocytes than the more slowly growing melanotic melanomas. There seems to be a correlation between the degree of cytoplasmic differentiation of the melanoma cells and the rate of melanoma growth. Nucleic acid determination revealed that the albino melanomas possess a higher DNA content per unit fresh weight than the melanotic ones. Because of the lower degree of differentiation, the numerous autophagic vacuoles, and the higher DNA content, the albino melanomas seem to express a higher degree of malignancy than the melanotic ones.
Down-regulation of the Notch Pathway in Human Airway Epithelium in Association with Smoking and Chronic Obstructive Pulmonary Disease
Authors: Ann E. Tilley, Ben-Gary Harvey, Adriana Heguy, Neil R. Hackett, Rui Wang, Timothy P. O'Connor, Ronald G. Crystal
Journal: American Journal of Respiratory and Critical Care Medicine (2008)

The airway epithelium of smokers is subject to a variety of mechanisms of injury with consequent modulation of epithelial regeneration and disordered differentiation. Several signaling pathways, including the Notch pathway, control epithelial differentiation in lung morphogenesis, but little is known about the role of these pathways in adults.We tested the hypotheses that Notch-related genes are expressed in the normal nonsmoker small airway epithelium of human adults, and that Notch-related gene expression is down-regulated in healthy smokers and smokers with chronic obstructive pulmonary disease (COPD).We used microarray technology to evaluate the expression of 55 Notch-related genes in the small airway epithelium of nonsmokers. We used TaqMan quantitative polymerase chain reaction (PCR) to confirm the expression of key genes and we used immunohistochemistry to assess the expression of Notch-related proteins in the airway epithelium. Changes in expression of Notch genes in healthy smokers and smokers with COPD compared with nonsmokers were evaluated by PCR.Microarray analysis demonstrated that 45 of 55 Notch-related genes are expressed in the small airway epithelium of adults. TaqMan PCR confirmed the expression of key genes with highest expression of the ligand DLL1, the receptor NOTCH2, and the downstream effector HES1. Immunohistochemistry demonstrated the expression of Jag1, Notch2, Hes1, and Hes5 in airway epithelium. Several Notch ligands, receptors, and downstream effector genes were down-regulated in smokers, with more genes down-regulated in smokers with COPD than in healthy smokers.These observations are consistent with the hypothesis that the Notch pathway likely plays a role in the human adult airway epithelium, with down-regulation of Notch pathway gene expression in association with smoking and COPD.
Phase I Dose-Escalation and Pharmacokinetic Study of Dasatinib in Patients with Advanced Solid Tumors
Authors: George D. Demetri, Patricia Lo Russo, Iain R.J. MacPherson, Ding Wang, Jeffrey A. Morgan, Valerie G. Brunton, Prashni Paliwal, Shruti Agrawal, Maurizio Voi, T.R. Jeffry Evans
Journal: Clinical Cancer Research (2009)

Abstract Purpose: To determine the maximum tolerated dose, dose-limiting toxicity (DLT), and recommended phase II dose of dasatinib in metastatic solid tumors refractory to standard therapies or for which no effective standard therapy exists. Experimental Design: In this phase I, open-label, dose-escalation study, patients received 35 to 160 mg of dasatinib twice daily in 28-day cycles either every 12 hours for 5 consecutive days followed by 2 nontreatment days every week (5D2) or as continuous, twice-daily (CDD) dosing. Results: Sixty-seven patients were treated (5D2, n = 33; CDD, n = 34). The maximum tolerated doses were 120 mg twice daily 5D2 and 70 mg twice daily CDD. DLTs with 160 mg 5D2 were recurrent grade 2 rash, grade 3 lethargy, and one patient with both grade 3 prolonged bleeding time and grade 3 hypocalcemia; DLTs with 120 mg twice daily CDD were grade 3 nausea, grade 3 fatigue, and one patient with both grade 3 rash and grade 2 proteinuria. The most frequent treatment-related toxicities across all doses were nausea, fatigue, lethargy, anorexia, proteinuria, and diarrhea, with infrequent hematologic toxicities. Pharmacokinetic data indicated rapid absorption, dose proportionality, and lack of drug accumulation. Although no objective tumor responses were seen, durable stable disease was observed in 16% of patients. Conclusion: Dasatinib was well tolerated in this population, with a safety profile similar to that observed previously in leukemia patients, although with much less hematologic toxicity. Limited, although encouraging, preliminary evidence of clinical activity was observed. Doses of 120 mg twice daily (5D2) or 70 mg twice daily (CDD) are recommended for further studies in patients with solid tumors. (Clin Cancer Res 2009;15(19):6232–40)
Farnesyltransferase Inhibitor, ABT-100, Is a Potent Liver Cancer Chemopreventive Agent
Authors: Vinicio Carloni, Francesco Vizzutti, Pietro Pantaleo
Journal: Clinical Cancer Research (2005)

Abstract Purpose: Treatment of hepatocellular carcinoma raised on cirrhotic liver represents a major endeavor because surgery and chemotherapeutic management fail to improve the clinical course of the disease. Chemoprevention could represent an important means to inhibit the process of hepatocarcinogenesis. Farnesyltransferase inhibitors are a class of drugs blocking the growth of tumor cells with minimal toxicity towards normal cells. Experimental Design: In the present study, we investigated the effects of a novel farnesyltransferase inhibitor, ABT-100, on human liver cancer cell lines, HepG2 and Huh7, and on an animal model of hepatocarcinogenesis. Results: ABT-100 inhibited HepG2 and Huh7 cell growth as well as the invading ability of Huh7 on Matrigel. In HepG2 and Huh7 cells, ABT-100 inhibited growth factor–stimulated phosphoinositide 3-kinase and Akt/protein kinase B activity. Furthermore, ABT-100 inhibited Akt-dependent p27Kip1 phosphorylation and this event was associated with increased levels of p27Kip1 in the nucleus and reduced activity of the cyclin-dependent kinase 2. Moreover, ABT-100 treatment resulted in a significant reduction in tumor incidence and multiplicity. Conclusions: Taken together, these findings identify a mechanism of ABT-100 function and show the efficacy of ABT-100 as a chemopreventive agent of hepatocellular carcinoma.
Sex, health, and years of sexually active life gained due to good health: evidence from two US population based cross sectional surveys of ageing
Authors: S. T. Lindau, N. Gavrilova
Journal: BMJ (2010)

<b>Objectives</b> To examine the relation between health and several dimensions of sexuality and to estimate years of sexually active life across sex and health groups in middle aged and older adults. <b>Design</b> Cross sectional study. <b>Setting</b> Two samples representative of the US population: MIDUS (the national survey of midlife development in the United States, 1995-6) and NSHAP (the national social life, health and ageing project, 2005-6). <b>Participants</b> 3032 adults aged 25 to 74 (1561 women, 1471 men) from the midlife cohort (MIDUS) and 3005 adults aged 57 to 85 (1550 women, 1455 men) from the later life cohort (NSHAP). <b>Main outcome measures</b> Sexual activity, quality of sexual life, interest in sex, and average remaining years of sexually active life, referred to as sexually active life expectancy. <b>Results</b> Overall, men were more likely than women to be sexually active, report a good quality sex life, and be interested in sex. These gender differences increased with age and were greatest among the 75 to 85 year old group: 38.9% of men compared with 16.8% of women were sexually active, 70.8% versus 50.9% of those who were sexually active had a good quality sex life, and 41.2% versus 11.4% were interested in sex. Men and women reporting very good or excellent health were more likely to be sexually active compared with their peers in poor or fair health: age adjusted odds ratio 2.2 (P&lt;0.01) for men and 1.6 (P&lt;0.05) for women in the midlife study and 4.6 (P&lt;0.001) for men and 2.8 (P&lt;0.001) for women in the later life study. Among sexually active people, good health was also significantly associated with frequent sex (once or more weekly) in men (adjusted odds ratio 1.6 to 2.1), with a good quality sex life among men and women in the midlife cohort (adjusted odds ratio 1.7), and with interest in sex. People in very good or excellent health were 1.5 to 1.8 times more likely to report an interest in sex than those in poorer health. At age 30, sexually active life expectancy was 34.7 years for men and 30.7 years for women compared with 14.9 to 15.3 years for men and 10.6 years for women at age 55. This gender disparity attenuated for people with a spouse or other intimate partner. At age 55, men in very good or excellent health on average gained 5-7 years of sexually active life compared with their peers in poor or fair health. Women in very good or excellent health gained 3-6 years compared with women in poor or fair health. <b>Conclusion</b> Sexual activity, good quality sexual life, and interest in sex were higher for men than for women and this gender gap widened with age. Sexual activity, quality of sexual life, and interest in sex were positively associated with health in middle age and later life. Sexually active life expectancy was longer for men, but men lost more years of sexually active life as a result of poor health than women.
INTRACELLULAR LOCALIZATION OF ACID PHOSPHATASE
Authors: G. E. Palade
Journal: The Journal of Experimental Medicine (1951)

The acid phosphatase activity of rat liver homogenates and of nuclear and cytoplasmic fractions isolated therefrom (by differential centrifugation) was determined biochemically in a series of experiments. For each liver, Gomori's histochemical test for acid phosphatase was run in parallel. No correlation was found between the biochemical and the histochemical results. According to the former, the enzyme appears to be almost entirely (95 per cent) located in the cytoplasm, while according to the latter, the acid phosphatase is predominantly concentrated in the nuclei and in some peribiliary polymorphic structures identified as myelin figures. It was found that the precipitaion pattern obtained in the histochemical test does not reveal, as generally assumed, differences in enzyme concentration among the various cell structures, but actually reveals differences in their lead phosphatase affinity. The usefulnes of the histochemical test for intracellular localization studies was found to be further limited by considerable fixation damage and formation of myelin figure artifacts. The biochemical approach is to be preferred because of better preservation of the material and direct and more reliable methods for the demonstraton of enzyme activity.
Meta-analysis: Anticoagulant Prophylaxis to Prevent Symptomatic Venous Thromboembolism in Hospitalized Medical Patients
Authors: Francesco Dentali, James D. Douketis, Monica Gianni, Wendy Lim, Mark A. Crowther
Journal: Annals of Internal Medicine (2007)

Underutilization of anticoagulant prophylaxis may be due to lack of evidence that prophylaxis prevents clinically important outcomes in hospitalized medical patients at risk for venous thromboembolism.To assess the effects of anticoagulant prophylaxis in reducing clinically important outcomes in hospitalized medical patients.MEDLINE, EMBASE, and Cochrane databases were searched to September 2006 without language restrictions.Randomized trials comparing anticoagulant prophylaxis with no treatment in hospitalized medical patients.Any symptomatic pulmonary embolism (PE), fatal PE, symptomatic deep venous thrombosis, all-cause mortality, and major bleeding. Pooled relative risks and associated 95% CIs were calculated. For treatment effects that were statistically significant, the authors determined the absolute risk reduction and the number needed to treat for benefit (NNT(B)) to prevent an outcome.9 studies (n = 19 958) were included. During anticoagulant prophylaxis, patients had significant reductions in any PE (relative risk, 0.43 [CI, 0.26 to 0.71]; absolute risk reduction, 0.29%; NNT(B), 345) and fatal PE (relative risk, 0.38 [CI, 0.21 to 0.69]; absolute risk reduction, 0.25%; NNT(B), 400), a nonsignificant reduction in symptomatic deep venous thrombosis (relative risk, 0.47 [CI, 0.22 to 1.00]), and a nonsignificant increase in major bleeding (relative risk, 1.32 [CI, 0.73 to 2.37]). Anticoagulant prophylaxis had no effect on all-cause mortality (relative risk, 0.97 [CI, 0.79 to 1.19]).2 of 9 included studies were not double-blind.Anticoagulant prophylaxis is effective in preventing symptomatic venous thromboembolism during anticoagulant prophylaxis in at-risk hospitalized medical patients. Additional research is needed to determine the risk for venous thromboembolism in these patients after prophylaxis has been stopped.
The Mitochondrial Genome of the House Centipede Scutigera and the Monophyly Versus Paraphyly of Myriapods
Authors: E. Negrisolo
Journal: Molecular Biology and Evolution (2004)

Recent advances in molecular phylogenetics are continuously changing our perception of the phylogenetic relationships among the main arthropod lineages: crustaceans, hexapods, chelicerates, and myriapods. Besides the intrinsic interest in unraveling the evolution of the largest animal phylum, these studies are basic to an understanding of one of the major transitions in animal evolution—i.e., the conquest of land with all its associated structural and functional adaptations. Myriapods have been traditionally considered the closest relatives of hexapods, thus implying only one origin of terrestriality for the tracheate lineage, but this view is now challenged by molecular evidence. Sequence data available to date for centipedes and millipedes are very limited, and the taxon sampling is strongly biased. The most critical gap was the scutigeromorph centipedes, which are the sister group to all remaining Chilopoda from which they probably diverged in the Silurian if not earlier. We obtained the first complete mitochondrial sequence for a representative of this clade, the house centipede. In our phylogenetic analyses of the protein-coding genes in this mitochondrial genome, along with 16 further ones representing the other major arthropod clades plus two outgroups, the myriapods formed a clade with the chelicerates. This implies that water-to-land transition occurred at least three times (hexapods, myriapods, arachnids) during the evolution of the Arthropoda. In addition, in contrast to all previous studies, our best supported topologies favor paraphyly of the myriapods with respect to the chelicerates. This would increase to four the main events of land colonization in arthropods (once for centipedes, once for millipedes).