tbuckley/cabot-search huggingface dataset:
Ambient Urban Baltimore Particulate-induced Airway Hyperresponsiveness and Inflammation in Mice
Authors: DIANNE M. WALTERS, PATRICK N. BREYSSE, MARSHA WILLS-KARP
Journal: American Journal of Respiratory and Critical Care Medicine (2001)

Airborne particulate matter (PM) is hypothesized to play a role in increases in asthma prevalence, although a causal relationship has yet to be established. To investigate the effects of real-world PM exposure on airway reactivity (AHR) and bronchoalveolar lavage (BAL) cellularity, we exposed naive mice to a single dose (0.5 mg/ mouse) of ambient PM, coal fly ash, or diesel PM. We found that ambient PM exposure induced increases in AHR and BAL cellularity, whereas diesel PM induced significant increases in BAL cellularity, but not AHR. On the other hand, coal fly ash exposure did not elicit significant changes in either of these parameters. We further examined ambient PM-induced temporal changes in AHR, BAL cells, and lung cytokine levels over a 2-wk period. Ambient PM-induced AHR was sustained over 7 d. The increase in AHR was preceded by dramatic increases in BAL eosinophils, whereas a decline in AHR was associated with increases in macrophages. A Th2 cytokine pattern (IL-5, IL-13, eotaxin) was observed early on with a shift toward a Th1 pattern (IFN-gamma). In additional studies, we found that the active component(s) of ambient PM are not water-soluble and that ambient PM-induced AHR and inflammation are dose- dependent. We conclude that ambient PM can induce asthma-like parameters in naive mice, suggesting that PM exposure may be an important factor in increases in asthma prevalence.
Increased Nitric Oxide Synthase Activity and Expression in the Human Uterine Artery During Pregnancy
Authors: Sharon H. Nelson, Odd S. Steinsland, Yu Wang, Chandra Yallampalli, Y.-L. Dong, Jennifer M. Sanchez
Journal: Circulation Research (2000)

Evidence exists that NO plays a role in the vasodilation that occurs during pregnancy. The purpose of the present study was to determine whether the role of NO is associated with an increase in the activity and protein expression of NO synthase (NOS) in the human uterine artery. Uterine arteries were obtained from pregnant patients (P arteries) and nonpregnant patients (NP arteries). NOS activity was estimated with the L-[(3)H]-arginine-to-L-[(3)H]-citrulline conversion method and on the basis of changes in tissue levels of cGMP. Western immunoblotting and immunohistochemistry were used to assess NOS protein expression. Ca(2+)-dependent NOS activity was 8 times greater (P:<0.01) in P than in NP arteries. Although most of this pregnancy-induced increase in NOS activity was Ca(2+) dependent (64%), a considerable portion was Ca(2+) independent. Expressions of endothelial NOS (eNOS) and neuronal NOS, but not inducible NOS, were demonstrated in P and NP arteries. The eNOS was located in the endothelium and stained with a qualitative order of P arteries>NP arteries (follicular)>NP arteries (luteal). The neuronal NOS was located in the adventitia of P and NP arteries. Basal NO-dependent and bradykinin-stimulated levels of cGMP were higher (P:<0.05) in P than in NP arteries. These results indicate that an upregulation of eNOS protein expression could account for the increased NO synthesis/release in the human uterine artery during pregnancy.
Voters and Health Reform in the 2008 Presidential Election
Authors: Robert J. Blendon, Drew E. Altman, John M. Benson, Mollyann Brodie, Tami Buhr, Claudia Deane, Sasha Buscho
Journal: New England Journal of Medicine (2008)

Voters view health care as an important issue in the 2008 U.S. presidential election. Most voters favor major changes in our health care system. Registered voters who planned to vote for Senator Obama placed higher priority on increasing coverage for the uninsured, and Senator McCain's supporters gave higher priority to health care reforms that would not raise taxes.
The Challenge of Choosing Appropriate End Points in Single-Arm Phase II Studies of Rare Diseases
Authors: Stefan Sleijfer, Andrew J. Wagner
Journal: Journal of Clinical Oncology (2012)

therapy.They found that patients treated with two cycles of escalated doses of bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine, and prednisone (Esc BEACOPP) plus two cycles of ABVD followed by 30 Gy of IF-XRT (the 2ϩ2 regimen) had an estimated 5-year progression-free survival of 95.4% compared with 89.1% for those who were treated with the standard four cycles of ABVD followed by the same dose of radiation (P Ͻ .001).The 2ϩ2 regimen was associated with more acute hematologic toxicity, but there were no differences between the two regimens with respect to female fertility.Furthermore, there was no overall survival difference between the two groups.So how would these excellent results influence the choice of treatment regimens in the clinical setting?The answer will depend on how one defines early stage and what risk features are used.As stated, in North America, patients with bulky mediastinal stage I/II disease are typically treated with six to eight cycles of ABVD plus 36 Gy of IF-XRT. 4 The HD14 study provides another option for these patients (Fig 1).An obvious advantage for the 2ϩ2 regimen is the shorter number of chemotherapy cycles and the use of lower doses of radiation.At the present time, there are no data to demonstrate that one approach is better than the other, and therefore, both options seem to be reasonable.It is clear that four cycles of ABVD plus 30 Gy of IF-XRT is not an optimal regimen for patients with bulky stage I/II disease.What is the added value of the 2ϩ2 regimen compared with the standard four cycles of ABVD in patients with unfavorable-stage I/II disease without bulk or B symptoms?On the basis of the analysis provided in Figure 3 of the online supplement to the GHLSG article, 6 it is clear that there is no difference in the progression-free survival between the two regimens.Given the equal number of cycles and doses of radiation of these two regimens but the increased acute hematologic toxicity associated with the 2ϩ2 regimen, it is likely that patients with unfavorable-stage I/II nonbulky disease who are without B symptoms will continue to be treated with four cycles of ABVD plus 30 Gy of IF-XRT in most parts of the world (Fig 1).Future research should continue to work to eliminate treatmentrelated toxicity while maintaining or even improving the cure rate for patients with early-and advanced-stage HL.New regimens that may incorporate the newly approved anti-CD30 antibody drug-conjugate brentuximab vedotin, and the use of interim biomarkers such as [ 18 F]fluorodeoxyglucose positron emission tomography 7,8 or serum thymus and activation-regulated chemokine levels, 9-11 may indeed achieve this goal.For those who have been observing the GHLSG during the last few decades, one can be assured that the HD14 study will not be the final answer; it is part of their continuous tradition of pursuing perfection.
Geranylgeranyltransferase type I (GGTase-I) deficiency hyperactivates macrophages and induces erosive arthritis in mice
Authors: Omar M. Khan, Mohamed X. Ibrahim, Ing-Marie Jonsson, Christin Karlsson, Meng Liu, Anna-Karin M. Sjogren, Frida J. Olofsson, Mikael Brisslert, Sofia Andersson, Claes Ohlsson, Lillemor Mattsson Hultén, Maria Bokarewa, Martin O. Bergo
Journal: Journal of Clinical Investigation (2011)

RHO family proteins are important for the function of inflammatory cells. They are modified with a 20-carbon geranylgeranyl lipid in a process catalyzed by protein geranylgeranyltransferase type I (GGTase-I). Geranylgeranylation is viewed as essential for the membrane targeting and activity of RHO proteins. Consequently, inhibiting GGTase-I to interfere with RHO protein activity has been proposed as a strategy to treat inflammatory disorders. However, here we show that mice lacking GGTase-I in macrophages develop severe joint inflammation resembling erosive rheumatoid arthritis. The disease was initiated by the GGTase-I-deficient macrophages and was transplantable and reversible in bone marrow transplantation experiments. The cells accumulated high levels of active GTP-bound RAC1, CDC42, and RHOA, and RAC1 remained associated with the plasma membrane. Moreover, GGTase-I deficiency activated p38 and NF-κB and increased the production of proinflammatory cytokines. The results challenge the view that geranylgeranylation is essential for the activity and localization of RHO family proteins and suggest that reduced geranylgeranylation in macrophages can initiate erosive arthritis.
Outcome of Childhood Acute Promyelocytic Leukemia With All-<i>Trans</i>-Retinoic Acid and Chemotherapy
Authors: S. de Botton, V. Coiteux, S. Chevret, C. Rayon, E. Vilmer, M. Sanz, J. de La Serna, N. Philippe, A. Baruchel, G. Leverger, A. Robert, J. San Miguel, E. Conde, J.J. Sotto, D. Bordessoule, N. Fegueux, M. Fey, A. Parry, C. Chomienne, L. Degos, P. Fenaux
Journal: Journal of Clinical Oncology (2004)

Purpose To determine the results of treatment combining all-trans-retinoic acid (ATRA) and chemotherapy (CT) in childhood acute promyelocytic leukemia (APL). Patients and Methods Children (&lt; 18 years) with newly diagnosed APL were included in the APL93 trial, treated by ATRA followed or combined with daunorubicin-cytarabine, and then randomly assigned between no maintenance, intermittent ATRA, continuous CT, or both. Results Of the 576 patients included in APL93 trial, 31 (5%) were children, including 22 girls (71%) and nine boys (29%). Thirty of the children (97%) obtained complete remission (CR). ATRA syndrome occurred in four children (13%), who all achieved CR, and headaches occurred in 12 children (39%), with signs of pseudotumor cerebri in five children (16%). Seven patients (23%) relapsed. None of the eight patients who received both ATRA and CT for maintenance relapsed. All relapsing patients achieved a second CR. Twenty-two patients remained in first CR after 43+ to 96+ months, six remained in second CR after 17+ to 66+ months, and three patients had died. The 5-year event-free survival (EFS), relapse, and overall survival rates were 71%, 27%, and 90%, respectively. No difference between adults and children included in the APL93 trial was seen for CR rate, 5-year relapse rate, EFS, and overall survival, but significantly better survival was seen in children after adjustment on WBC counts (P = .02) and incidence of microgranular M3 variant (P = .04). Conclusion ATRA combined with CT for induction and also probably for maintenance provides as favorable results in children with APL as in adults and currently constitutes the reference first-line treatment in both age groups.
A therapeutic effect of STAT6 decoy oligodeoxynucleotide ointment in atopic dermatitis: a pilot study in adults
Authors: K. Igawa, T. Satoh, H. Yokozeki
Journal: British Journal of Dermatology (2009)

Journal Article A therapeutic effect of STAT6 decoy oligodeoxynucleotide ointment in atopic dermatitis: a pilot study in adults Get access K. Igawa, K. Igawa Department of Dermatology, Tokyo Medical and Dental University, 1‐5‐45 Yushima, Bunkyo‐ku, Tokyo 113‐8519, Japan E‐mail: k.igawa.derm@tmd.ac.jp Search for other works by this author on: Oxford Academic Google Scholar T. Satoh, T. Satoh Department of Dermatology, Tokyo Medical and Dental University, 1‐5‐45 Yushima, Bunkyo‐ku, Tokyo 113‐8519, Japan E‐mail: k.igawa.derm@tmd.ac.jp Search for other works by this author on: Oxford Academic Google Scholar H. Yokozeki H. Yokozeki Department of Dermatology, Tokyo Medical and Dental University, 1‐5‐45 Yushima, Bunkyo‐ku, Tokyo 113‐8519, Japan E‐mail: k.igawa.derm@tmd.ac.jp Search for other works by this author on: Oxford Academic Google Scholar British Journal of Dermatology, Volume 160, Issue 5, 1 May 2009, Pages 1124–1126, https://doi.org/10.1111/j.1365-2133.2009.09070.x Published: 01 May 2009
Effect of Computerized Physician Order Entry and a Team Intervention on Prevention of Serious Medication Errors
Authors: David W. Bates
Journal: JAMA (1998)

Context.—Adverse drug events (ADEs) are a significant and costly cause of injury during hospitalization.Objectives.—To evaluate the efficacy of 2 interventions for preventing nonintercepted serious medication errors, defined as those that either resulted in or had potential to result in an ADE and were not intercepted before reaching the patient.Design.—Before-after comparison between phase 1 (baseline) and phase 2 (after intervention was implemented) and, within phase 2, a randomized comparison between physican computer order entry (POE) and the combination of POE plus a team intervention.Setting.—Large tertiary care hospital.Participants.—For the comparison of phase 1 and 2, all patients admitted to a stratified random sample of 6 medical and surgical units in a tertiary care hospital over a 6-month period, and for the randomized comparison during phase 2, all patients admitted to the same units and 2 randomly selected additional units over a subsequent 9-month period.Interventions.—A physician computer order entry system (POE) for all units and a team-based intervention that included changing the role of pharmacists, implemented for half the units.Main Outcome Measure.—Nonintercepted serious medication errors.Results.—Comparing identical units between phases 1 and 2, nonintercepted serious medication errors decreased 55%, from 10.7 events per 1000 patient-days to 4.86 events per 1000 (P=.01). The decline occurred for all stages of the medication-use process. Preventable ADEs declined 17% from 4.69 to 3.88 (P=.37), while nonintercepted potential ADEs declined 84% from 5.99 to 0.98 per 1000 patient-days (P=.002). When POE-only was compared with the POE plus team intervention combined, the team intervention conferred no additonal benefit over POE.Conclusions.—Physician computer order entry decreased the rate of nonintercepted serious medication errors by more than half, although this decrease was larger for potential ADEs than for errors that actually resulted in an ADE.
Cytochemical identification of ATPase-positive Langerhans cells in EDTA-separated sheets of mouse epidermis
Authors: I.C. MACKENZIE, C.A. SQUIER
Journal: British Journal of Dermatology (2006)

Sheets of epidermis for incubation to demonstrate ATPase activity were obtained from specimens of mouse footpad using EDTA as the separation medium. The use of EDTA in place of the NaBr method previously described, resulted in a greatly reduced incubation time, precise localization of reaction product and preservation of ultrastructural detail. A population afclosely and regularly spaced ATPasepositive dendritic cells was demonstrated by light microscopy. Electron microscopy demonstrated that, with short incubation times, reaction product was found only in the extracellular space adjacent to dendritic cells, the majority of which possessed the typical ultrastructural features of Langerhans cells.
Interleukin-6, Secreted by Human Ovarian Carcinoma Cells, Is a Potent Proangiogenic Cytokine
Authors: Monique B. Nilsson, Robert R. Langley, Isaiah J. Fidler
Journal: Cancer Research (2005)

Abstract Angiogenesis, a key rate-limiting step in the growth and dissemination of malignant tumors, is regulated by the balance between positive and negative effectors. Recent studies indicate that the pleiotropic cytokine interleukin-6 (IL-6) may contribute to the vascularization of some tumors by disrupting the equilibrium between positive and negative angiogenic regulatory molecules. We determined whether IL-6 participates in the angiogenesis observed during the progression of ovarian carcinoma. We measured IL-6 production by human ovarian cancer cell lines in vitro and in vivo. Not all cell lines secreted IL-6 in vitro; however, when the cell lines were implanted into the peritoneal cavity of female nude mice, every line secreted IL-6. Most human ovarian carcinoma cell lines tested secreted significant levels of the soluble IL-6 receptor (sIL-6R). Endothelial cell lines established from the ovary and mesentery of female H-2Kb-tsA58 mice were tested for response to IL-6. Both endothelial cell lines expressed the IL-6R and their stimulation with the exogenous ligand significantly enhanced cell migration and activated the downstream signaling molecule signal transducers and activators of transcription 3. Dual immunohistochemical staining for IL-6R and CD31 revealed IL-6R expression on human endothelial cells within normal ovary and carcinoma specimens. Gelfoam sponges containing 0.4% agarose and IL-6 or basic fibroblast growth factor and implanted into the subcutis of BALB/c mice were vascularized to the same extent. Collectively, the data indicate that ovarian tumor cells secreted IL-6, a highly angiogenic cytokine that supports progression of disease.
Serum bilirubin is associated with lung function in a Swiss general population sample
Authors: I. Curjuric, M. Imboden, M. Adam, R. W. Bettschart, M. W. Gerbase, N. Kunzli, T. Rochat, L. Rohrer, T. B. Rothe, J. Schwartz, D. Stolz, J.-M. Tschopp, A. von Eckardstein, F. Kronenberg, N. M. Probst-Hensch
Journal: European Respiratory Journal (2013)

Bilirubin is a strong antioxidant. Increased serum levels have been associated with lower respiratory disease and mortality risk. We studied the association of bilirubin with lung function in the Swiss study on Air Pollution and Lung Disease in adults (SAPALDIA) cohort. Associations between natural logarithmised bilirubin and forced expiratory volume in 1 s (FEV<sub>1</sub>), forced vital capacity (FVC), FEV<sub>1</sub>/FVC and mean forced expiratory flow between 25%–75% of FVC (FEF<sub>25–75%</sub>) were tested using multiple linear regression in the whole study population (n=4195) and strata of ever-smoking and high body mass index (BMI, defined by the highest distribution quartile). Associations were retested with single nucleotide polymorphism rs6742078, a genetic determinant of bilirubin. High bilirubin levels were significantly associated with higher FEV<sub>1</sub>/FVC and FEF<sub>25–75%</sub> overall. Upon stratification, significant associations persisted in ever-smokers, amounting to 1.1% (95% CI 0.1–2.2%) increase in FEV<sub>1</sub>/FVC, and 116.2 mL·s<sup>−1</sup> (95% CI -15.9–248.4 mL·s<sup>−1</sup>) in FEF<sub>25–75%</sub> per interquartile range of bilirubin exposure in smokers with high BMI. Associations were positive but nonsignificant in never-smokers with high BMI. Similarly, rs6742078 genotype TT was associated with increased FEV<sub>1</sub>/FVC and FEF<sub>25–75%</sub>. Our results suggest a possible protective role of bilirubin on lung tissue, which could be important for prevention and therapy.
Effects of Sildenafil Citrate (Viagra) Combined With Nitrate on the Heart
Authors: Fuminobu Ishikura, Shintaro Beppu, Toshiaki Hamada, Bijoy K. Khandheria, James B. Seward, Ajay Nehra
Journal: Circulation (2000)

Sildenafil citrate (Viagra) is indicated for the treatment of erectile dysfunction. Large and sudden decreases in systemic blood pressure were reported in a substantial number of patients taking sildenafil citrate combined with nitroglycerin. We studied the effect of sildenafil citrate on the relationship between changes in systemic blood pressure and coronary blood flow.Healthy male beagles were used to assess systemic blood pressure, pulmonary arterial pressure, and flow in the left circumflex artery (in which a critical stenosis was established) and left anterior descending coronary artery. After measurement of the hemodynamic variables, 2 mg/kg sildenafil citrate was administered via a nasogastric tube. Hemodynamic changes were monitored for 1 hour. Subsequently, the acute effect of nitrate combined with sildenafil citrate was studied by the bolus injection of 0.2 mg isosorbide dinitrate before and after sildenafil citrate. Systemic blood and pulmonary arterial pressures and circumflex flow did not change during this study; however, left anterior descending coronary arterial flow increased from 16.0+/-5.8 to 24.6+/-8.7 mL/min 1 hour after administration of sildenafil citrate. The prolongation of systemic blood pressure decrease and the circumflex flow decrement induced by isosorbide dinitrate after sildenafil citrate were significantly larger and longer than those before sildenafil citrate.Sildenafil citrate had the effect of vasodilation in a normal coronary artery; however, a combined effect with nitrate resulted in large and protracted decreases in systemic blood pressure and coronary blood flow in vessels with critical stenosis.
Forkhead Transcription Factor FOXO1 is a Direct Target of Progestin to Inhibit Endometrial Epithelial Cell Growth
Authors: Satoru Kyo, Junko Sakaguchi, Tohru Kiyono, Yutaka Shimizu, Yoshiko Maida, Yasunari Mizumoto, Noriko Mori, Mitsuhiro Nakamura, Masahiro Takakura, Kiyohiko Miyake, Masaru Sakamoto, Masaki Inoue
Journal: Clinical Cancer Research (2010)

Despite the therapeutic utility of progestin in invasive and preinvasive endometrial neoplasias, the molecular mechanisms through which it exerts inhibitory effects on endometrial epithelial growth are largely unknown. The aim of the study was to clarify the molecular mechanisms of progestin action to endometrial epithelial cells using originally established in vitro and in vivo treatment models for immortalized and transformed endometrial epithelial cell lines that express progesterone receptor.In this model, progestin effectively inhibited the cell growth, inducing G0/G1 arrest rather than apoptosis without p21/WAF-1 induction. Using DNA microarray analysis, we identified 24 genes whose expression increased more than 10-fold on progestin treatment. Of these genes, we paid special attention to forkhead box transcription factor FOXO1, known as a key gene for endometrial decidualization. Progestin markedly induced FOXO1 gene expression mainly in the nuclei in vitro and in vivo. This induction was not due to the canonical activation of FOXO1 via protein dephosphorylation but due to FOXO1 promoter activation and mRNA induction. siRNA inhibition of FOXO1 significantly attenuated the effects of progestin to inhibit endometrial epithelial cell growth. Disrupting Akt activity by the introduction of the dominant negative form of Akt increased nuclear FOXO1 accumulation and enhanced the effect of progestin.These findings suggest that FOXO1 is a direct target of progestin, implicating novel molecular mechanisms of progestin to eradicate endometrial neoplasia.
Regulatory T cells use “Itch” to control asthma
Authors: WanJun Chen
Journal: Journal of Clinical Investigation (2013)

Regulatory T cells (Tregs) control type 2 T helper cell–mediated (Th2-mediated) lung inflammation, but the molecular mechanisms by which Tregs execute this activity remain elusive. In this issue of the JCI, Jin et al. reveal that Itch, a HECT-type E3 ubiquitin ligase in Tregs, plays a specific role in restraining Th2 cell responses. This finding has important implications for understanding the pathogenesis of allergy and asthma.