tbuckley/cabot-search huggingface dataset:
Effects of ambient ozone on lung function in children over a two-summer period
Authors: MV Kopp, W Bohnet, T Frischer, C Ulmer, M Studnicka, G Ihorst, C Gardner, J Forster, R Urbanek, J Kuehr
Journal: European Respiratory Journal (2000)

There is a general consensus that short term exposure to ozone (O3) causes a decrease in lung function parameters such as forced vital capacity (FVC) and forced expiratory volume in one second (FEV1). The objective of this study was to assess the reproducibility of lung function decrements after ambient O3 exposure over a two-summer period. The authors studied 797 children with a mean age of 8.2 yrs (95% confidence interval: 6.9-9.5) from the second and third grades of ten elementary schools in Austria and southwestern Germany. At the outset the various study locations were stratified into three groups with low (L), medium (M) and high (H) O3 exposure (range of mean O3 concentration in the locations April-October 1994: 24-30 (L); 33-38 (M); 44-52 (H) parts per billion (ppb)). Four lung function tests were performed on each child between March 1994 and November 1995. The increases in FVC and FEV1 recorded from one test period to the next were expressed as mL x day(-1). A significantly lower FVC and FEV1 increase was observed in children exposed to high ambient O3 concentration during the summer season. (FVC in summer 1994: 0.83 (L); 0.56 (M); 0.55 (H) mL x day(-1); p=0.004; and summer 1995: 0.80 (L); 0.63 (M); 0.56 (H) mL x day(-1); p=0.011; FEV1 in summer 1994: 0.48 (L); 0.34 (M); 0.18 (H) mL x day(-1); p=0.004 and summer 1995: 0.68 (L); 0.45 (M); 0.41 (H) mL x day(-1), p=0.006). There was no significant difference in FVC or FEV1 increase between the groups during the winter period. Adjusting for sex, age, height and passive smoke exposure, linear regression revealed a statistically significant negative association of average ambient O3 concentration with the FVC and FEV1 increase in both summers. During the winter period no association of O3 with FVC or FEV1 was observed. In conclusion, in two consecutive summer periods the authors found reproducible lung function decrements in children exposed to high levels of ambient ozone. Reoccurrence of ozone associated lung function deficits might increase the likelihood of persisting effects on the childrens' airways.
Fructose Induces Transketolase Flux to Promote Pancreatic Cancer Growth
Authors: Haibo Liu, Danshan Huang, David L. McArthur, Laszlo G. Boros, Nicholas Nissen, Anthony P. Heaney
Journal: Cancer Research (2010)

Carbohydrate metabolism via glycolysis and the tricarboxylic acid cycle is pivotal for cancer growth, and increased refined carbohydrate consumption adversely affects cancer survival. Traditionally, glucose and fructose have been considered as interchangeable monosaccharide substrates that are similarly metabolized, and little attention has been given to sugars other than glucose. However, fructose intake has increased dramatically in recent decades and cellular uptake of glucose and fructose uses distinct transporters. Here, we report that fructose provides an alternative substrate to induce pancreatic cancer cell proliferation. Importantly, fructose and glucose metabolism are quite different; in comparison with glucose, fructose induces thiamine-dependent transketolase flux and is preferentially metabolized via the nonoxidative pentose phosphate pathway to synthesize nucleic acids and increase uric acid production. These findings show that cancer cells can readily metabolize fructose to increase proliferation. They have major significance for cancer patients given dietary refined fructose consumption, and indicate that efforts to reduce refined fructose intake or inhibit fructose-mediated actions may disrupt cancer growth.
Specific binding of soluble fibrin to macrophages.
Authors: L A Sherman, J Lee
Journal: The Journal of Experimental Medicine (1977)

Guinea pig peritoneal macrophages were demonstrated to bind selectively soluble 125I-fibrin and fibrin/fibrinogen complexes as compared with fibrinogen, fibrinogen degradation products, and fibrin degradation products. Cellular uptake was considered to be surface receptor binding on the basis of removal of bound 125I-fibrin by trypsin and because uptake occurred in the presence of metabolic inhibitors. 125I-fibrin uptake could be blocked by nonradioactive fibrin but not by IgG or immune complexes. Binding was uneffected by prior treatment with plasmin or trypsin but was calcium dependent. Only limited reversibility of binding could be demonstrated after prolonged incubation. Scatchard plots permitted an estimate of the number of bound molecules. At saturation 6.92 X 10(6) 125I-fibrin molecules were bound per cell. Similar binding of fibrin was noted in polymorphonuclear leukocytes, but not lymphocytes or fibroblasts. Soluble fibrin binding may be a host defense mechanism whereby the reticuloendothelial system can remove fibrin from the blood before the development of microthrombi.
Direct airway resistance response after deep inspiration in symptomatic asthmatics
Authors: Karin van der Velden-van Etten, Karin Nietzman-Lammering, H.C. Hoogsteden
Journal: European Respiratory Journal (2011)

Introduction: Immediately after a deep inspiration there is a response in the airway resistance. In patients with asthma the response to deep inspiration (DI) is impaired compared with healthy subjects.

Aim: We want to investigate the airway resistance response after DI changes when subjects are exposed to a bronchoconstrictor.

Methods: All subjects were symptomatic asthmatics. They all preformed a tidal breathing challenge test (Mch) with methacholinebromide from 0.039–39.6 mg/ml in doubling doses. After each inhalation the airway resistance was measured by impulse oscillometry (IOS/PFT, Care Fusion, Wurzburg) during 60-80 seconds with a DI at 30s. At 90s FEV1 was measured. P-values >0.05 were assumed to be significant.

Results: We analyzed 24 tests. One patient was excluded because of spirometric induced asthma. In 12 cases we found a PC20  16.

View this table:

Results





We found a significant difference in ΔR5 between baseline and the highest concentration both in cases and non cases (resp. p=0.024 and p=0.022).

Conclusion: When PC20 is reached there is still an overall decrease in airway resistance after DI. Compared to those who didn't reach PC20 <16 the decrease is not significant but both groups had a high SE. The response to DI is highly variable in asthmatics.
Suppressor of cytokine signaling 3 expression is diminished in sinonasal tissues from patients with chronic rhinosinusitis with nasal polyps
Authors: Kathryn E. Hulse, Katrina Chaung, Sudarshan Seshadri, Lydia Suh, James E. Norton, Roderick G. Carter, Robert C. Kern, David B. Conley, Rakesh K. Chandra, Bruce K. Tan, Anju T. Peters, Leslie C. Grammer, Kathleen E. Harris, Troy R. Torgerson, Atsushi Kato, Robert P. Schleimer
Journal: Journal of Allergy and Clinical Immunology (2013)
The Macrophage Mediates the Renoprotective Effects of Endotoxin Preconditioning
Authors: Takashi Hato, Seth Winfree, Rabih Kalakeche, Shataakshi Dube, Rakesh Kumar, Momoko Yoshimoto, Zoya Plotkin, Pierre C. Dagher
Journal: Journal of the American Society of Nephrology (2014)

Preconditioning is a preventative approach, whereby minimized insults generate protection against subsequent larger exposures to the same or even different insults. In immune cells, endotoxin preconditioning downregulates the inflammatory response and yet, preserves the ability to contain infections. However, the protective mechanisms of preconditioning at the tissue level in organs such as the kidney remain poorly understood. Here, we show that endotoxin preconditioning confers renal epithelial protection in various models of sepsis in vivo. We also tested the hypothesis that this protection results from direct interactions between the preconditioning dose of endotoxin and the renal tubules. This hypothesis is on the basis of our previous findings that endotoxin toxicity to nonpreconditioned renal tubules was direct and independent of immune cells. Notably, we found that tubular protection after preconditioning has an absolute requirement for CD14-expressing myeloid cells and particularly, macrophages. Additionally, an intact macrophage CD14-TRIF signaling pathway was essential for tubular protection. The preconditioned state was characterized by increased macrophage number and trafficking within the kidney as well as clustering of macrophages around S1 proximal tubules. These macrophages exhibited increased M2 polarization and upregulation of redox and iron-handling molecules. In renal tubules, preconditioning prevented peroxisomal damage and abolished oxidative stress and injury to S2 and S3 tubules. In summary, these data suggest that macrophages are essential mediators of endotoxin preconditioning and required for renal tissue protection. Preconditioning is, therefore, an attractive model to investigate novel protective pathways for the prevention and treatment of sepsis.
A Systematic Review of Interventions to Improve Diabetes Care in Socially Disadvantaged Populations
Authors: Richard H. Glazier, Jana Bajcar, Natalie R. Kennie, Kristie Willson
Journal: Diabetes Care (2006)

To identify and synthesize evidence about the effectiveness of patient, provider, and health system interventions to improve diabetes care among socially disadvantaged populations.Studies that were included targeted interventions toward socially disadvantaged adults with type 1 or type 2 diabetes; were conducted in industrialized countries; were measured outcomes of self-management, provider management, or clinical outcomes; and were randomized controlled trials, controlled trials, or before-and-after studies with a contemporaneous control group. Seven databases were searched for articles published in any language between January 1986 and December 2004. Twenty-six intervention features were identified and analyzed in terms of their association with successful or unsuccessful interventions.Eleven of 17 studies that met inclusion criteria had positive results. Features that appeared to have the most consistent positive effects included cultural tailoring of the intervention, community educators or lay people leading the intervention, one-on-one interventions with individualized assessment and reassessment, incorporating treatment algorithms, focusing on behavior-related tasks, providing feedback, and high-intensity interventions (>10 contact times) delivered over a long duration (>or=6 months). Interventions that were consistently associated with the largest negative outcomes included those that used mainly didactic teaching or that focused only on diabetes knowledge.This systematic review provides evidence for the effectiveness of interventions to improve diabetes care among socially disadvantaged populations and identifies key intervention features that may predict success. These types of interventions would require additional resources for needs assessment, leader training, community and family outreach, and follow-up.
Abstract P5-18-11: Pharmacokinetics and exposure-efficacy relationship of trastuzumab emtansine in EMILIA, a phase 3 study of trastuzumab emtansine vs capecitabine and lapatinib in HER2-positive locally advanced or metastatic breast cancer
Authors: B Wang, J Jin, R Wada, L Fang, O Saad, S Olsen, B Althaus, S Swain, M Untch, S Girish
Journal: Cancer Research (2012)

Abstract Background: Trastuzumab emtansine (T-DM1) is an antibody-drug conjugate composed of trastuzumab (T), the cytotoxic agent DM1, and a stable thioether linker; it is being evaluated for the treatment (tx) of HER2-positive cancer. EMILIA is a randomized, multicenter, open-label phase 3 study assessing the efficacy and safety of T-DM1 vs capecitabine (X) and lapatinib (L) in pts with HER2-positive locally advanced or metastatic breast cancer (MBC) previously treated with T and a taxane. We report the pharmacokinetics (PK) of T-DM1 in EMILIA and compare these data with historical data of single-agent T-DM1. The effects of T-DM1 exposure on efficacy outcomes in EMILIA are also reported. Methods: In EMILIA, pts were randomized 1:1 to receive T-DM1 3.6 mg/kg q3w (n = 495) or X + L (n = 496) in 21-day cycles. At least 1 PK sample was collected from 350 pts in the T-DM1 arm; 307 of these had adequate PK profiles for the estimation of ≥1 PK parameter in cycle 1. PK parameters were estimated by noncompartmental analysis for serum T-DM1, serum total T (conjugated and unconjugated T), and plasma DM1. A logistic regression model was used to evaluate the relationship between T-DM1 exposure (ie, T-DM1 AUC and DM1 Cmax) and objective response rates (ORR). Analyses of progression-free survival (PFS) and overall survival (OS), stratified by T-DM1 exposure, were conducted. Cox regression was used to evaluate the effect of T-DM1 exposure and other potential covariates on PFS and OS. Results: The PK parameters for T-DM1, total T, and DM1 in EMILIA and other studies of single-agent T-DM1 are summarized in Table 1. The PK parameters appear similar regardless of prior tx for MBC. No significant differences in mean serum T-DM1 AUC (P = 0.091) or plasma DM1 Cmax (P = 0.812) were observed between responders and non-responders following T-DM1 tx. Furthermore, variability in T-DM1 AUC and DM1 Cmax does not appear to affect the probability of response to therapy (P = 0.23 for T-DM1 AUC and P = 0.74 for DM1 Cmax). Based on Cox proportional hazards analysis, no significant exposure-efficacy relationship was observed between T-DM1 AUC (P = 0.23 for PFS and p = 0.53 for OS) or DM1 Cmax (P = 0.96 for PFS and P = 0.34 for OS) and PFS or OS, respectively. Conclusions: T-DM1 PK data in EMILIA pts were similar to those observed in previous phase 2 studies, which include pts who have and have not received prior therapy for MBC. Variation in T-DM1 exposure among pts who received T-DM1 3.6 mg/kg q3w had no significant impact on ORR, PFS, or OS. Detailed analyses will be presented. Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr P5-18-11.
The targeting of cyclophilin D by RNAi as a novel cardioprotective therapy: evidence from two-photon imaging
Authors: Masashi Kato, Masaharu Akao, Madoka Matsumoto-Ida, Takeru Makiyama, Moritake Iguchi, Toshihiro Takeda, Shigeomi Shimizu, Toru Kita
Journal: Cardiovascular Research (2009)

An opening of the mitochondrial permeability transition pore (MPTP), which leads to the loss of mitochondrial membrane potential (DeltaPsi(m)), is the earliest event that commits cells to death, and this process is potentially a prime target for therapeutic intervention against myocardial ischaemia/reperfusion. We aimed to investigate the protective effects of RNA interference (RNAi)-mediated gene silencing of cyclophilin D (CypD), one of the putative components of the MPTP, against myocardial ischaemia/reperfusion using two-photon laser scanning microscopy.We created an adenovirus carrying short-interfering RNA (siRNA) that inactivates CypD. Transduction of CypD-siRNA in rat cardiomyocytes achieved a 61% reduction in CypD mRNA and a 63% reduction in protein levels as well as protection against oxidant-induced DeltaPsi(m) loss and cytotoxicity. To further investigate the effects in vivo, we monitored the spatio-temporal changes of DeltaPsi(m) in perfused rat hearts subjected to ischaemia/reperfusion using two-photon imaging. Adult rats received direct intramyocardial injections of the adenovirus. Two to three days after injection, rat hearts were perfused by the Langendorff method and DeltaPsi(m) levels of individual cells were monitored. The progressive loss of DeltaPsi(m) during ischaemia/reperfusion was significantly suppressed in CypD-siRNA-transduced cells compared with non-transduced cells. Furthermore, the protective effect of CypD-siRNA was dose-dependent.Therapeutic interventions designed to inactivate CypD may be a promising strategy for reducing cardiac injury against myocardial ischaemia/reperfusion. The two-photon imaging technique provides deeper insight into cardioprotective therapy that targets mitochondria.
Effects of fluticasone propionate on inflammatory cells in COPD: an ultrastructural examination of endobronchial biopsy tissue
Authors: M J Gizycki
Journal: Thorax (2002)

Inhaled corticosteroids (ICS) markedly reduce bronchial mucosal inflammation in asthma but whether they have an anti-inflammatory effect in airway tissue in chronic obstructive pulmonary disease (COPD) is unknown.A study of endobronchial biopsy samples was conducted as part of a double blind, placebo controlled, randomised trial of parallel design. Patients had mild to moderately severe COPD (FEV(1) 25-80% of predicted) and were given 3 months treatment with ICS, fluticasone propionate (FP; 500 micro g twice daily, n=14) or placebo (n=10). Biopsy tissue taken at baseline and after treatment was examined by transmission electron microscopy to count the numbers of all ultrastructurally distinct inflammatory cells.Compared with their baseline values, FP resulted in a significant decrease (on average 65%) in the numbers of mucosal mast cells (median 7.8 (range 1-33) v 2.8 (1-14), p<0.05). The reductive effect of FP held true when the post-treatment values of the placebo and FP groups were compared: 8.8 (1-24) v 2.8 (1-14) (p<0.05). Unexpectedly, there were significantly more neutrophils in the FP than in the placebo group: 4.0 (0-23) v 1.7 (0-8), respectively (p<0.05). There were no alterations to other cell types including mononuclear cells. Symptoms markedly improved in the patients treated with FP for 3 months.Fluticasone propionate given for 3 months to patients with COPD has selective effects on the inflammatory cells in the bronchial mucosa: the reduction in mast cell numbers may account for the improvement in symptoms over this time.
Inspiratory muscle training as a tool for the management of patients with COPD
Authors: A.K. McConnell, P. Weiner, L.M. Romer
Journal: European Respiratory Journal (2004)

To the Editors: 

We have been compelled to write to you in response to the editorial by Polkey and Moxham 1 published in the European Respiratory Journal . In their editorial, the authors argue that there is still insufficient evidence to justify the use of inspiratory muscle training (IMT) in patients with chronic obstructive pulmonary disease (COPD). In contrast, we believe that there is a growing evidence base that favours the use of IMT in the overall management of patients with COPD.

Polkey and Moxham 1 argue that studies of IMT should assess efficacy based upon “functionally worthwhile” outcomes. This is a good point, but it appears to be contradicted in their closing paragraph, when they refer specifically to the work of one of us 2. A 50–60 m improvement in walking performance is dismissed on the basis that it was not accompanied by an improvement in inspiratory muscle function measured using a nonvolitional test of diaphragm function ( P di,tw). We are bound to ask which is the most “functionally worthwhile” outcome: …
Outcomes of HIV Vaccine Related to Genetic Variation
Authors: M. J. Friedrich
Journal: JAMA (2015)

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A Search for Malnutrition-Related Diabetes Mellitus Among Ethiopian Patients
Authors: Frances T Lester
Journal: Diabetes Care (1993)

To search for evidence of MRDM among Ethiopian patients.We reviewed the records from March 1976 to January 1991 of 1835 Ethiopian diabetic patients registered consecutively in the Diabetic Clinic of Yekatit 12 Hospital in Addis Ababa, Ethiopia.Of those aged 15-30 at onset, 41.3% had a BMI < 19 kg/m2 at diagnosis, and 55% of the latter had a history of normal weight before the onset of symptoms. The frequency of KA was similar in the very thin patients and others of the same age-group, and only 1 patient required > 1.5 IU insulin in 24 h. Pancreatic calcification was observed in only 4 middle-aged men with histories of alcohol abuse, and the very thin patients did not have other stigmata of malnutrition. Of the 1604 patients > or = 18 yr of age at diagnosis, only 21 of 1116 who knew their previous weight had a BMI < 19 kg/m2 before the onset of diabetic symptoms, and most of the 178 patients with a BMI < 19 kg/m2 on treatment had been normal or even overweight. In regression analysis, the factors associated with weight loss before diagnosis were the duration of symptoms in type I diabetes patients and the need for insulin from diagnosis, poverty certification, and symptom duration in type II diabetes patients. Weight gain with treatment was related to female sex, the duration of symptoms, and the absence of tuberculosis in type I diabetes patients and related to an address/birthplace not in Addis Ababa in type II diabetes patients.The undernutrition at presentation is probably caused by the untreated diabetic state and is reversible with treatment, even if the patient is poor and/or lives in a rural area. No convincing cases of MRDM fulfilling the published definition could be found.
Chemotherapeutic activity of clofazimine and its analogues against Mycobacterium tuberculosis. In vitro, intracellular, and in vivo studies.
Authors: C Jagannath, M V Reddy, S Kailasam, J F O'Sullivan, P R Gangadharam
Journal: American Journal of Respiratory and Critical Care Medicine (1995)

Clofazimine (CFM), a riminophenazine drug, is primarily used in therapy for leprosy and Mycobacterium avium infections. With an objective of identifying drugs active against Mycobacterium tuberculosis, including those with multi-drug resistance, we investigated CFM and nine of its chemical analogues. Among these, B746 and B4101 had better activity than CFM against six drug-susceptible and nine single/multiple drug-resistant M. tuberculosis strains. B746 also showed slightly better activity than CFM against intracellular M. tuberculosis in J774A.1 macrophages and was comparable to CFM in its in vivo activity against experimental tuberculosis in C57BL/6 mice. Interestingly, it caused less pigmentation in internal organs.