tbuckley/cabot-search huggingface dataset:
Association of Asthma Control with Health Care Utilization and Quality of Life
Authors: WILLIAM M. VOLLMER, LEONA E. MARKSON, ELIZABETH O'CONNOR, LESLY L. SANOCKI, LESLYE FITTERMAN, MARC BERGER, A. SONIA BUIST
Journal: American Journal of Respiratory and Critical Care Medicine (1999)

Asthma severity and level of asthma control are two related, but conceptually distinct, concepts that are often confused in the literature. We report on an index of asthma control developed for use in population-based disease management. This index was measured on 5,181 adult members of a large health maintenance organization (HMO), as were various self-reported measures of health care utilization (HCU) and quality of life (QOL). A simple index of number of control problems, ranging from none through four, exhibited marked and highly significant cross-sectional associations with self- reported HCU and with both generic and disease-specific QOL instruments, suggesting that each of the four dimensions of asthma control represented by these problems correlates with clinically significant impairment. Qualitatively similar results were found for control problems assessed relative to the past month and relative to the past year. Asthma control is an important “vital sign” that may be useful both for population-based disease management as well as for the management of individual patients. Vollmer WM, Markson LE, O'Connor E, Sanocki LL, Fitterman L, Berger M, Buist AS. Association of asthma control with health care utilization and quality of life.
Macrophages Promote Cyst Growth in Polycystic Kidney Disease
Authors: Anil Karihaloo, Farrukh Koraishy, Sarah C. Huen, Yashang Lee, David Merrick, Michael J. Caplan, Stefan Somlo, Lloyd G. Cantley
Journal: Journal of the American Society of Nephrology (2011)

Polycystic kidney disease (PKD) exhibits an inflammatory component, but the contribution of inflammation to cyst progression is unknown. Macrophages promote the proliferation of tubular cells following ischemic injury, suggesting that they may have a role in cystogenesis. Furthermore, cultured Pkd1-deficient cells express the macrophage chemoattractants Mcp1 and Cxcl16 and stimulate macrophage migration. Here, in orthologous models of both PKD1 and PKD2, abnormally large numbers of alternatively activated macrophages surrounded the cysts. To determine whether pericystic macrophages contribute to the proliferation of cyst-lining cells, we depleted phagocytic cells from Pkd1(fl/fl);Pkhd1-Cre mice by treating with liposomal clodronate from postnatal day 10 until day 24. Compared with vehicle-treated controls, macrophage-depleted mice had a significantly lower cystic index, reduced proliferation of cyst-lining cells, better-preserved renal parenchyma, and improved renal function. In conclusion, these data suggest that macrophages home to cystic areas and contribute to cyst growth. Interruption of these homing and proliferative signals could have therapeutic potential for PKD.
Chemosensitization by Knockdown of Adenine Nucleotide Translocase-2
Authors: Morgane Le Bras, Annie Borgne-Sanchez, Zahia Touat, Ossama Sharaf El Dein, Aurélien Deniaud, Evelyne Maillier, Gael Lecellier, Dominique Rebouillat, Christophe Lemaire, Guido Kroemer, Etienne Jacotot, Catherine Brenner
Journal: Cancer Research (2006)

Abstract Mitochondrial membrane permeabilization (MMP) is a rate-limiting step of apoptosis, including in anticancer chemotherapy. Adenine nucleotide translocase (ANT) mediates the exchange of ADP and ATP on the inner mitochondrial membrane in healthy cells. In addition, ANT can cooperate with Bax to form a lethal pore during apoptosis. Humans possess four distinct ANT isoforms, encoded by four genes, whose transcription depends on the cell type, developmental stage, cell proliferation, and hormone status. Here, we show that the ANT2 gene is up-regulated in several hormone-dependent cancers. Knockdown of ANT2 by RNA interference induced no major changes in the aspect of the mitochondrial network or cell cycle but provoked minor increase in mitochondrial transmembrane potential and reactive oxygen species level and reduced intracellular ATP concentration without affecting glycolysis. At expression and functional levels, ANT2 depletion was not compensated by other ANT isoforms. Most importantly, ANT2, but not ANT1, silencing facilitated MMP induction by lonidamine, a mitochondrion-targeted antitumor compound already used in clinical studies for breast, ovarian, glioma, and lung cancer as well as prostate adenoma. The combination of ANT2 knockdown with lonidamine induced apoptosis irrespective of the Bcl-2 status. These data identify ANT2 as an endogenous inhibitor of MMP and suggest that its selective inhibition could constitute a promising strategy of chemosensitization. (Cancer Res 2006; 66(18): 9143-52)
Retinoids Regulate Survival and Antigen Presentation by Immature Dendritic Cells
Authors: Frédéric Geissmann, Patrick Revy, Nicole Brousse, Yves Lepelletier, Claudia Folli, Anne Durandy, Pierre Chambon, Michel Dy
Journal: The Journal of Experimental Medicine (2003)

Maturation of dendritic cells (DCs) is a critical step for the induction of an immune response. We have examined the role of retinoid nuclear receptor pathways in this process. Retinoids induce DC apoptosis, in the absence of inflammatory signals, through retinoic acid receptor (RAR)α/retinoic X receptor (RXR) heterodimers. In contrast, via a cross talk with inflammatory cytokines, retinoids increase DNA binding activity of nuclear factor κB in DCs, trigger membrane major histocompatibility complex class II and costimulatory molecule expression, induce the differentiation of immature DCs into mature DCs, and enhance antigen-specific T cell response. This maturation of DCs is mediated via a RXR-dependent/RAR-independent pathway and via an RARα/RXR pathway distinct from the one responsible for apoptosis. Apoptosis and activation, mediated through distinct nuclear retinoid receptor pathways, can be dissociated from each other with selective synthetic retinoids. We identify a novel cellular function for retinoids and suggest that selective retinoids might be of interest for controlling antigen presentation.
Extracellular ATP triggers and maintains asthmatic airway inflammation by activating dendritic cells
Authors: Marco Idzko, Hamida Hammad, Menno van Nimwegen, Mirjam Kool, Monique A M Willart, Femke Muskens, Henk C Hoogsteden, Werner Luttmann, Davide Ferrari, Francesco Di Virgilio, J Christian Virchow, Bart N Lambrecht
Journal: Nature Medicine (2007)
A Mitochondrial Genome Sequence of the Tibetan Antelope (<i>Pantholops Hodgsonii</i>)
Authors: Shu-Qing Xu, Ying-Zhong Yang, Jun Zhou, Guo-En Jin, Yun-Tian Chen, Jun Wang, Huan-Ming Yang, Jian Wang, Jun Yu, Xiao-Guang Zheng, Ri-Li Ge
Journal: Genomics Proteomics & Bioinformatics (2005)

To investigate genetic mechanisms of high altitude adaptations of native mammals on the Tibetan Plateau, we compared mitochondrial sequences of the endangered Pantholops hodgsonii with its lowland distant relatives Ovis aries and Capra hircus, as well as other mammals. The complete mitochondrial genome of P. hodgsonii (16,498 bp) revealed a similar gene order as of other mammals. Because of tandem duplications, the control region of P. hodgsonii mitochondrial genome is shorter than those of O. aries and C. hircus, but longer than those of Bos species. Phylogenetic analysis based on alignments of the entire cytochrome b genes suggested that P. hodgsonii is more closely related to O. aries and C. hircus, rather than to species of the Antilopinae subfamily. The estimated divergence time between P. hodgsonii and O. aries is about 2.25 million years ago. Further analysis on natural selection indicated that the COXI (cytochrome c oxidase subunit I) gene was under positive selection in P. hodgsonii and Bos grunniens. Considering the same climates and environments shared by these two mammalian species, we proposed that the mitochondrial COXI gene is probably relevant for these native mammals to adapt the high altitude environment unique to the Tibetan Plateau.
Markers of airway inflammation and airway hyperresponsiveness remain stable in untreated asthmatics over time
Authors: Pernille Bækgaard Udesen, Celeste Porsbjerg, Christian Grabow Westergaard, Vibeke Backer
Journal: European Respiratory Journal (2011)

Introduction:  Airway hyperresponsiveness (AHR) and airway inflammation are important hallmarks of asthma that may be used in asthma monitoring, but may also vary between asthmatics as a potential indication of different clinical asthma phenotypes. The aim of this study was to assess whether two commonly used measures, AHR to mannitol and exhaled NO (eNO), were stable over a period of time in asthma patients who were not treated with steroids.   Materials and methods:  A total of 54 non-smoking, asthmatics not treated with steroids were enrolled in the study and assessed at baseline and again three to six months later, where spirometry, skin prick test and induced sputum was performed as well as measurements of hyperresponsiveness to mannitol and eNO. Subjects were excluded if they experienced a worsening of their asthma or commenced on steroid treatment.   Results:  A total of 41 subjects (21 females, mean age; 41 years, 70,70% atopics) completed both visits. Mean FEV1% predicted at baseline was 94,13% (SD 17,71).There was a significant correlation between the degree of AHR, defined by the Response Dose Ratio (RDR:% change/mg mannitol) at visit 1 and visit 2 (LogRDR, r = 0,80, p   Conclusion:  In asthmatics not treated with steroids, markers of AHR and airway inflammation remains at the same level over a three to six months period of observation, suggesting that these are stable markers of clinical disease.
Addition of Biphasic, Prandial, or Basal Insulin to Oral Therapy in Type 2 Diabetes
Authors: Rury R. Holman, Kerensa I. Thorne, Andrew J. Farmer, Melanie J. Davies, Joanne F. Keenan, Sanjoy Paul, Jonathan C. Levy
Journal: New England Journal of Medicine (2007)

Adding insulin to oral therapy in type 2 diabetes mellitus is customary when glycemic control is suboptimal, though evidence supporting specific insulin regimens is limited.In an open-label, controlled, multicenter trial, we randomly assigned 708 patients with a suboptimal glycated hemoglobin level (7.0 to 10.0%) who were receiving maximally tolerated doses of metformin and sulfonylurea to receive biphasic insulin aspart twice daily, prandial insulin aspart three times daily, or basal insulin detemir once daily (twice if required). Outcome measures at 1 year were the mean glycated hemoglobin level, the proportion of patients with a glycated hemoglobin level of 6.5% or less, the rate of hypoglycemia, and weight gain.At 1 year, mean glycated hemoglobin levels were similar in the biphasic group (7.3%) and the prandial group (7.2%) (P=0.08) but higher in the basal group (7.6%, P<0.001 for both comparisons). The respective proportions of patients with a glycated hemoglobin level of 6.5% or less were 17.0%, 23.9%, and 8.1%; respective mean numbers of hypoglycemic events per patient per year were 5.7, 12.0, and 2.3; and respective mean weight gains were 4.7 kg, 5.7 kg, and 1.9 kg. Rates of adverse events were similar among the three groups.A single analogue-insulin formulation added to metformin and sulfonylurea resulted in a glycated hemoglobin level of 6.5% or less in a minority of patients at 1 year. The addition of biphasic or prandial insulin aspart reduced levels more than the addition of basal insulin detemir but was associated with greater risks of hypoglycemia and weight gain. (Current Controlled Trials number, ISRCTN51125379 [controlled-trials.com].).
Requirement for Rac1-Dependent NADPH Oxidase in the Cardiovascular and Dipsogenic Actions of Angiotensin II in the Brain
Authors: Matthew C. Zimmerman, Ryan P. Dunlay, Eric Lazartigues, Yulong Zhang, Ram V. Sharma, John F. Engelhardt, Robin L. Davisson
Journal: Circulation Research (2004)

We have shown that intracellular superoxide (O 2 ·− ) production in CNS neurons plays a key role in the pressor, bradycardic, and dipsogenic actions of Ang II in the brain. In this study, we tested the hypothesis that a Rac1-dependent NADPH oxidase is a key source of O 2 ·− in Ang II–sensitive neurons and is involved in these central Ang II–dependent effects. We performed both in vitro and in vivo studies using adenoviral (Ad)-mediated expression of dominant-negative Rac1 (AdN17Rac1) to inhibit Ang II–stimulated Rac1 activation, an obligatory step in NADPH oxidase activation. Ang II induced a time-dependent increase in Rac1 activation and O 2 ·− production in Neuro-2A cells, and this was abolished by pretreatment with AdN17Rac1 or the NADPH oxidase inhibitors apocynin or diphenylene iodonium. AdN17Rac1 also inhibited Ang II–induced increases in NADPH oxidase activity in primary neurons cultured from central cardiovascular control regions. In contrast, overexpression of wild-type Rac1 (AdwtRac1) caused more robust NADPH oxidase-dependent O 2 ·− production to Ang II. To extend the in vitro studies, the pressor, bradycardic, and drinking responses to intracerebroventricularly (ICV) injected Ang II were measured in mice that had undergone gene transfer of AdN17Rac1 or AdwtRac1 to the brain. AdN17Rac1 abolished the increase in blood pressure, decrease in heart rate, and drinking response induced by ICV injection of Ang II, whereas AdwtRac1 enhanced these physiological effects. The exaggerated physiological responses in AdwtRac1-treated mice were abolished by O 2 ·− scavenging. These results, for the first time, identify a Rac1-dependent NADPH oxidase as the source of central Ang II–induced O 2 ·− production, and implicate this oxidase in cardiovascular diseases associated with dysregulation of brain Ang II signaling, including hypertension.
Impact of inspiratory muscle training in patients with COPD: what is the evidence?
Authors: R. Gosselink, J. De Vos, S.P. van den Heuvel, J. Segers, M. Decramer, G. Kwakkel
Journal: European Respiratory Journal (2011)

A meta-analysis including 32 randomised controlled trials on the effects of inspiratory muscle training (IMT) in chronic obstructive pulmonary disease (COPD) patients was performed. Overall and subgroup analyses with respect to training modality (strength or endurance training, added to general exercise training) and patient characteristics were performed. Significant improvements were found in maximal inspiratory muscle strength ( P I,max ; +13 cmH 2 O), endurance time (+261 s), 6- or 12-min walking distance (+32 and +85 m respectively) and quality of life (+3.8 units). Dyspnoea was significantly reduced (Borg score -0.9 point; Transitional Dyspnoea Index +2.8 units). Endurance exercise capacity tended to improve, while no effects on maximal exercise capacity were found. Respiratory muscle endurance training revealed no significant effect on P I,max , functional exercise capacity and dyspnoea. IMT added to a general exercise programme improved P I,max significantly, while functional exercise capacity tended to increase in patients with inspiratory muscle weakness ( P I,max &lt;60 cmH 2 O). IMT improves inspiratory muscle strength and endurance, functional exercise capacity, dyspnoea and quality of life. Inspiratory muscle endurance training was shown to be less effective than respiratory muscle strength training. In patients with inspiratory muscle weakness, the addition of IMT to a general exercise training program improved P I,max and tended to improve exercise performance.
Interaction of Risk Factors, Comorbidities, and Comedications with Ischemia/Reperfusion Injury and Cardioprotection by Preconditioning, Postconditioning, and Remote Conditioning
Authors: Péter Ferdinandy, Derek J. Hausenloy, Gerd Heusch, Gary F. Baxter, Rainer Schulz
Journal: Pharmacological Reviews (2014)

Pre-, post-, and remote conditioning of the myocardium are well described adaptive responses that markedly enhance the ability of the heart to withstand a prolonged ischemia/reperfusion insult and provide therapeutic paradigms for cardioprotection. Nevertheless, more than 25 years after the discovery of ischemic preconditioning, we still do not have established cardioprotective drugs on the market. Most experimental studies on cardioprotection are still undertaken in animal models, in which ischemia/reperfusion is imposed in the absence of cardiovascular risk factors. However, ischemic heart disease in humans is a complex disorder caused by, or associated with, cardiovascular risk factors and comorbidities, including hypertension, hyperlipidemia, diabetes, insulin resistance, heart failure, altered coronary circulation, and aging. These risk factors induce fundamental alterations in cellular signaling cascades that affect the development of ischemia/reperfusion injury per se and responses to cardioprotective interventions. Moreover, some of the medications used to treat these risk factors, including statins, nitrates, and antidiabetic drugs, may impact cardioprotection by modifying cellular signaling. The aim of this article is to review the recent evidence that cardiovascular risk factors and their medication may modify the response to cardioprotective interventions. We emphasize the critical need to take into account the presence of cardiovascular risk factors and concomitant medications when designing preclinical studies for the identification and validation of cardioprotective drug targets and clinical studies. This will hopefully maximize the success rate of developing rational approaches to effective cardioprotective therapies for the majority of patients with multiple risk factors.
Diagnostic rigid and flexible oesophagoscopy in carcinoma of the oesophagus: a comparison.
Authors: A J Ritchie, J McGuigan, K McManus, H M Stevenson, J R Gibbons
Journal: Thorax (1993)

BACKGROUND: Flexible oesophagoscopy is regarded as superior to rigid oesophagoscopy on the basis of perforation rates as an end point. This advantage may be more apparent than real because no comparison has been made in a diagnostic setting in patients with carcinoma of the oesophagus with both perforation rate and diagnostic efficacy as indices. METHODS: A retrospective analysis was carried out on data on 336 diagnostic oesophagoscopies in patients with carcinoma of the oesophagus, comparing rigid with flexible oesophagoscopy. RESULTS: Both rigid and flexible oesophagoscopies were performed without perforation when they were used for diagnosis only. Rigid biopsy achieved a diagnostic success rate of 99.3%, compared with 80.5% for flexible oesophagoscopy. CONCLUSIONS: Diagnostic oesophagoscopy can be achieved without perforation with either instrument, but the chance of diagnosing carcinoma was significantly greater with the rigid instrument.
Randomized phase III trial of amrubicin versus topotecan (Topo) as second-line treatment for small cell lung cancer (SCLC).
Authors: R. Jotte, J. Von Pawel, D. R. Spigel, M. A. Socinski, M. O'Brien, E. H. Paschold, J. Mezger, M. Steins, L. Bosquée, J. A. Bubis, K. Nackaerts, J. M. Trigo Perez, P. R. Clingan, W. Schuette, P. Lorigan, M. Reck, M. Domine, F. A. Shepherd, R. McNally, M. F. Renschler
Journal: Journal of Clinical Oncology (2011)

7000 Background: Amrubicin (AMR), a 3rd-generation anthracycline and potent topoisomerase II inhibitor, has shown promising activity in SCLC. The ACT-1 trial compared the safety and efficacy of AMR vs Topo for the 2nd-line treatment of SCLC. Methods: 637 patients (pts) were randomized 2:1 to AMR 40 mg/m2 IV on Day 1-3 (n=424) or to Topo 1.5 mg/m2 IV on Days 1-5 (n=213) with prophylactic WBC growth factors required in last 1/3 of trial. Endpoints were survival (OS, primary), response rate (RR), progression-free survival (PFS), and safety. Subgroup analyses used protocol-defined definitions: refractory pts had PD as best response to 1st-line therapy or progressed < 90 days. Results: Baseline characteristics were similar in the AMR vs Topo groups: median age 62 vs 61 years [yrs]; pts <65 yrs 60% vs 65%; men 58% vs 60%; performance status (PS) of 0 30% vs 34%; refractory 47% vs 45%. The covariates in the Cox model are PS of 0 (yes, no), age, response to 1st-line platinum-based therapy (refractory, sensitive), and disease stage (limited, extensive). Grade 3/4 adverse events in AMR and Topo groups, respectively, were: neutropenia (41% vs 53%), thrombocytopenia (21% vs 54%), anemia (16% vs 30%), infections (16% vs 10%), febrile neutropenia (10% vs 4%), all P<0.05, and cardiac disorders (5% vs 5%; P=0.84). Transfusion rates were 32% (AMR) and 53% (Topo), p<0.01. Conclusions: AMR is active in 2nd-line treatment of SCLC with significantly improved RR compared with Topo. Survival trended in favor of AMR (HR 0.88), especially in the subgroup of refractory patients (HR 0.77). Small numerical differences in pt characteristics in favor of the Topo group may have impacted OS. Quality of life data will be presented. N AMR Topo HR/OR 95% CI P value RR (%) 637 31 17 2.22 1.47-3.36 0.0002 PFS (mo) 637 4.1 4.0 0.999 0.84-1.19 0.98 OS (mo) 637 7.5 7.8 0.88 0.73-1.06 0.17 12-mo OS (%) 28 25 0.438 18-mo OS (%) 16 9 0.045 24-mo OS (%) 9 3 0.049 OS (Cox model) 637 - - 0.82 0.68-0.99 0.036 Subgroups OS sensitive pts (mo) 342 9.2 10 0.94 0.72-1.21 0.62 OS refractory pts (mo) 295 6.2 5.7 0.77 0.59-1.0 0.047 12-mo OS (%) 17 8 0.019 18-mo OS (%) 12 0 0.0006 Abbreviations: CI, confidence interval. Hazard ratio (HR) <1 and odds ratio (OR for RR only) > 1 favors AMR.
Expression and Targeting of CX3CL1 (Fractalkine) in Renal Tubular Epithelial Cells
Authors: Anne M. Durkan, R. Todd Alexander, Guang-Ying Liu, Min Rui, Giuseppe Femia, Lisa A. Robinson
Journal: Journal of the American Society of Nephrology (2006)

The chemokine CX3CL1 plays a key role in glomerulonephritis and can act as both chemoattractant and adhesion molecule. CX3CL1 also is upregulated in tubulointerstitial injury, but little is known about the subcellular distribution and function of CX3CL1 in renal tubular epithelial cells (RTEC). Unexpectedly, it was found that CX3CL1 is expressed predominantly on the apical surface of tubular epithelium in human renal transplant biopsy specimens with acute rejection or acute tubular necrosis. For studying the targeting of CX3CL1 in polarized RTEC, MDCK cells that expressed untagged or green fluorescent protein-tagged CX3CL1 were generated. The chemokine was present on the apical membrane and in subapical vesicles. Apical targeting of CX3CL1 was not due to signals that were conferred by its intracellular domain, to associations with lipid rafts, or to O-glycosylation but, rather, depended on N-linked glycosylation of the protein. With the use of fluorescence recovery after photobleaching, it was found that CX3CL1 is immobile in the apical membrane. However, CX3CL1 partitioned with the triton-soluble rather than -insoluble cellular fraction, indicating that it is not associated directly with the actin cytoskeleton or with lipid rafts. Accordingly, disruption of rafts through cholesterol depletion did not render CX3CL1 mobile. For exploration of potential functions of apical CX3CL1, binding of CX3CR1-expressing leukocytes to polarized RTEC was examined. Leukocyte adhesion to the luminal surface was enhanced significantly when CX3CL1 was present. These data demonstrate that CX3CL1 is expressed preferentially on the apical membrane of RTEC and suggest a novel function for the chemokine in recruitment and retention of leukocytes in tubulointerstitial inflammation.