tbuckley/cabot-search huggingface dataset:
The COPD assessment test (CAT): response to pulmonary rehabilitation. A multicentre, prospective study
Authors: J. W. Dodd, L. Hogg, J. Nolan, H. Jefford, A. Grant, V. M. Lord, C. Falzon, R. Garrod, C. Lee, M. I. Polkey, P. W. Jones, W. D.-C. Man, N. S. Hopkinson
Journal: Thorax (2011)

<h3>Background</h3> The COPD (chronic obstructive pulmonary disease) assessment test (CAT) is a recently introduced, simple to use patient-completed quality of life instrument that contains eight questions covering the impact of symptoms in COPD. It is not known how the CAT score performs in the context of clinical pulmonary rehabilitation (PR) programmes or what the minimum clinically important difference is. <h3>Methods</h3> The introduction of the CAT score as an outcome measure was prospectively studied by PR programmes across London. It was used alongside other measures including the St George9s Respiratory Questionnaire, the Chronic Respiratory Disease Questionnaire, the Clinical COPD Questionnaire, the Hospital Anxiety and Depression score, the Medical Research Council (MRC) dyspnoea score and a range of different walking tests. Patients completed a 5-point anchor question used to assess overall response to PR from ‘I feel much better’ to ‘I feel much worse’. <h3>Results</h3> Data were available for 261 patients with COPD participating in seven programmes: mean (SD) age 69.0 (9.0) years, forced expiratory volume in 1 s (FEV<sub>1</sub>) 51.1 (18.7) % predicted, MRC score 3.2 (1.0). Mean change in CAT score after PR was 2.9 (5.6) points, improving by 3.8 (6.1) points in those scoring ‘much better’ (n=162), and by 1.3(4.5) in those who felt ‘a little better’ (n=88) (p=0.002). Only eight individuals reported no difference after PR and three reported feeling ‘a little worse’, so comparison with these smaller groups was not possible. <h3>Conclusion</h3> The CAT score is simple to implement as an outcome measure, it improves in response to PR and can distinguish categories of response.
Predictors of Long-Term Outcomes in Older Breast Cancer Survivors: Perceptions Versus Patterns of Care
Authors: Jeanne S. Mandelblatt, Stephen B. Edge, Neal J. Meropol, Ruby Senie, Theodore Tsangaris, Luther Grey, Burt M. Peterson, Yi-Ting Hwang, Jon Kerner, Jane Weeks
Journal: Journal of Clinical Oncology (2003)

There are few data on sequelae of breast cancer treatments in older women. We evaluated posttreatment quality of life and satisfaction in a national population.Telephone surveys were conducted with a random cross-sectional sample of 1,812 Medicare beneficiaries 67 years of age and older who were 3, 4, and 5 years posttreatment for stage I and II breast cancer. Regression models were used to estimate the adjusted risk of decrements in physical and mental health functioning by treatment. In a subset of women (n = 732), additional data were used to examine arm problems, impact of cancer, and satisfaction, controlling for baseline health, perceptions of ageism and racism, demographic and clinical factors, region, and surgery year.Use of axillary dissection was the only surgical treatment that affected outcomes, increasing the risk of arm problems four-fold (95% confidence interval, 1.56 to 10.51), controlling for other factors. Having arm problems, in turn, exerted a consistently negative independent effect on all outcomes (P </=.001). Processes of care were also associated with quality of life and satisfaction. For example, women who perceived high levels of ageism or felt that they had no choice of treatment reported significantly more bodily pain, lower mental health scores, and less general satisfaction. These same factors, as well as high perceived racism, were significantly associated with diminished satisfaction with the medical care system.With the exception of axillary dissection, the processes of care, and not the therapy itself, are the most important determinants of long-term quality of life in older women.
Phosphorylation of Endothelial Nitric Oxide Synthase in Response to Fluid Shear Stress
Authors: Marshall A. Corson, Natalie L. James, Shawn E. Latta, Robert M. Nerem, Bradford C. Berk, David G. Harrison
Journal: Circulation Research (1996)

Endothelial cells release nitric oxide (NO) more potently in response to increased shear stress than to agonists which elevate intracellular free calcium concentration ([Ca 2+ ] i ). To determine mechanistic differences in the regulation of endothelial constitutive NO synthase (ecNOS), we measured NO production by bovine aortic endothelial cells exposed to shear stress in a laminar flow chamber or treated with Ca 2+ ionophores in static culture. The kinetics of cumulative NO production varied strikingly: shear stress (25 dyne/cm 2 ) stimulated a biphasic increase over control that was 13-fold at 60 minutes, whereas raising [Ca 2+ ] i caused a monophasic 6-fold increase. We hypothesized that activation of a protein kinase cascade mediates the early phase of flow-dependent NO production. Immunoprecipitation of ecNOS showed a 210% increase in phosphorylation 1 minute after flow initiation, whereas there was no significant increase after Ca 2+ ionophore treatment. Although ecNOS was not tyrosine-phosphorylated, the early phase of flow-dependent NO production was blocked by genistein, an inhibitor of tyrosine kinases. To determine the Ca 2+ requirement for flow-dependent NO production, we measured [Ca 2+ ] i with a novel flow-step protocol. [Ca 2+ ] i increased with the onset of shear stress, but not after a step increase. However, the step increase in shear stress was associated with a potent biphasic increase in NO production rate and ecNOS phosphorylation. These studies demonstrate that shear stress can increase NO production in the absence of increased [Ca 2+ ] i , and they suggest that phosphorylation of ecNOS may importantly modulate its activity during the imposition of increased shear stress.
Injury and repair responses of parenchymal fibroblasts in advanced chronic obstructive pulmonary disease
Authors: Nicola J. Green, Anna Lagan, Andrew Walker, Gisli Jenkins, Simon Johnson, Donna K. Finch, Alan Knox, Andrew J. Fisher, Copdmap Study
Journal: European Respiratory Journal (2014)

Background  COPD exacerbations contribute to progressive disease by inducing acute on chronic inflammation. Leukocytes have traditionally been considered orchestrators of this inflammation. We hypothesise tissue injury and release of damage associated molecular patterns(DAMPs) such as IL-1α drive inflammation and dysfunctional repair in parenchymal lung fibroblasts.  Methods  Lung fibroblasts were cultured from control(n=6) and COPD(n=6 GOLD stage III/IV) lung tissue. Cells were stimulated with Interleukin- 1alpha(IL1α) or Tissue Growth Factor- beta(TGFβ). Smad2 phosporylation(ELISA) was measured at 1hr and pro-inflammatory cytokine concentrations(multiplex MSD) and MMP2 activity(zymography) in supernatants measured at 24hr.  Results  IL1α induced a dose dependent increase in inflammatory cytokines(IL6,IL8, IL1β, GM-CSF and TNFα) from both control and COPD fibroblasts. The COPD fibroblasts demonstrated a more dramatic response to IL1α than controls. Constitutive Smad2 phosphorylation was higher in control than COPD fibroblasts and increased further in response to TGFβ stimulation. This increase was attenuated in COPD fibroblasts. MMP2 activity was detected in both control and COPD fibroblasts with no additional response to either TGFβ or IL1α stimulation.  Conclusion  Lung fibroblasts respond to the DAMP IL1α, adopting a potent pro-inflammatory phenotype a response which is exaggerated in COPD. In addition, COPD fibroblasts have a blunted signalling response to TGFβ compared to controls. These preliminary observations suggest COPD fibroblasts adopt a pro-inflammatory phenotype with reduced repair capacity in response to tissue injury implicating them in the pathophysiology of the disease.
Effect of Maternal Smoking on Ventilatory Responses to Changes in Inspired Oxygen Levels in Infants
Authors: KERRY A. POOLE, HILDA HALLINAN, CAROLINE S. BEARDSMORE, JOHN R. THOMPSON
Journal: American Journal of Respiratory and Critical Care Medicine (2000)

Maternal smoking is a major independent risk factor for sudden infant death syndrome (SIDS). Respiratory control deficits have been implicated in SIDS. The aim of this study was to test the hypothesis that infants born to smoking mothers have reduced ventilatory responses to changes in inspired oxygen. Smoking and nonsmoking women were recruited in midpregnancy and smoking status confirmed by measurement of urinary cotinine. To control for confounding factors of smoking each mother–infant pair in the smoking group was matched to a pair in the nonsmoking group for social class, maternal age and parity, feeding, birthweight, gestational age, and infant sex. Infants were seen overnight at approximately 10 wk of age for tests of respiratory control, using the alternating breath test. Ventilation was measured by respiratory inductance plethysmography and inspired and end-tidal oxygen levels were determined by mass spectrometry. Data were obtained from 40 infants (17 in the smoking group). Responses were similar in both groups for 10 respiratory parameters including respiratory drive and timing, and there were no significant differences. The mean end-tidal oxygen level when 40% O2 was delivered was an average of 1.13% higher in the smoking group (p = 0.0067), although the inspired oxygen levels were not different. In conclusion, we did not find an independent effect of maternal smoking on respiratory control. The differences in end-tidal oxygen levels during the alternating breath test may represent differences in alveolar ventilation.
Rhinoviruses and Cells: Molecular Aspects
Authors: D. J. Rowlands
Journal: American Journal of Respiratory and Critical Care Medicine (1995)

Recent developments in our understanding of the molecular structure and functioning of the human rhinoviruses are briefly reviewed. The determination of virus structure at near atomic resolution has provided a wealth of information that can be used to help interpret dynamic properties of the virus. The mechanisms involved in capsid assembly, attachment to cell surfaces, uncoating, and the initiation of infection and antibody-mediated neutralization of infectivity can all be examined afresh in the light of the structural data. In addition, molecular techniques for manipulating and analyzing the biological properties of nucleic acids and proteins are providing a wealth of information on details of the replication machinery of the viruses. Probably one of the least understood aspects of viral replication is the precise nature of the interactions between host and viral components during infection. Unfortunately, despite all of these impressive scientific advances the cure for the common cold is still elusive. Rowlands DJ. Rhinoviruses and cells: molecular aspects.
Noninvasive mechanical ventilation in acute respiratory failure
Authors: N Ambrosino
Journal: European Respiratory Journal (1996)

Mechanical ventilation (MV) has been indicated in the treatment of acute respiratory failure (ARF) if conservative treatment fails. Invasive MV is associated to a variety of complications. The recent innovations of noninvasive methods of MV (NMV) avoid the complications of invasive MV, whilst ensuring a similar degree of efficacy. A review of the literature from 1989 to 1995 shows that use of NMV in ARF has been reported in several studies involving more than 400 patients most of them COPD. NMV was successful from 51 to 91%, the severity of ARF being widely different among the different studies. Most of the studies compared effectiveness of NMV with historical groups of patients treated with "conventional" medical therapy whilst controlled studies of NMV versus ET intubation are lacking. Type of mask, mode of ventilation, compliance to treatment, type of patient and severity of disease may influence the success rate. Success with NMV was associated with less severely abnormal baseline clinical and functional parameters and to less severe levels of acidosis assessed during an initial trial of NMV. Therefore, NMV may be useful in selected patients with ARF. Patients should have clinical and physiological evidence of ARF and should be sufficiently cooperative. It is commonly said that NMV should be avoided, and endotracheal (ET) intubation performed in patients with haemodynamic instability, uncontrolled arrhythmias, gastrointestinal bleeding, high risk for aspiration. With these limitations NMV in selected patients with ARF is well tolerated and may be useful in avoiding ET intubation in most cases of COPD and with a wide range of success rates in other disease. This in turn has several advantages in terms of avoiding complications of invasive MV, reducing the length of stay in ICU and probably the number of ICU readmissions. Side effects of NMV seem less severe than those induced by invasive MV. In conclusion in selected patients a trial of noninvasive mechanical ventilation, as an adjunct to medical therapy, should be instituted at an early stage of ARF episodes before severe acidosis ensures, to avoid ET intubation.
Tauroursodeoxycholate (TUDCA) inhibits neointimal hyperplasia by suppression of ERK via PKCα-mediated MKP-1 induction
Authors: Seo Yoon Kim, Yoo-Wook Kwon, Il Lae Jung, Jong-Hyuk Sung, Sang Gyu Park
Journal: Cardiovascular Research (2011)

Hyperplasia of vascular smooth muscle cells (VSMCs) after blood vessel injury is one of the major pathophysiological mechanisms associated with neointima. Tauroursodeoxycholate (TUDCA) is a cytoprotective agent in a variety of cells including hepatocytes as well as an inducer of apoptosis in cancer cells. In this study, we investigated whether TUDCA could prevent neointimal hyperplasia by suppressing the growth and migration of VSMCs. Transporters of TUDCA uptake in human VSMCs (hVSMCs) were analysed by RT–PCR and western blot. A knock-down experiment using specific si-RNA revealed that TUDCA was incorporated into hVSMCs via organic anion transporter 2 (OATP2). TUDCA reduced the viability of hVSMCs, which were mediated by inhibition of extracellular signal-regulated kinase (ERK) by induction of mitogen-activated protein kinase phosphatase-1 (MKP-1) via protein kinase Cα (PKCα). The anti-proliferative effect of TUDCA was reversed by treatment with 7-hydroxystaurosporine, an inhibitor of PKC, and by the knock-down of MKP-1. In addition, TUDCA suppressed hVSMC migration, which was mediated by reduced matrix metalloproteinase-9 (MMP-9) expression by ERK inhibition, as well as reduced viability of hVSMCs. Rats with carotid artery balloon injury received oral administration of TUDCA; this reduced the increase in ERK and MMP-9 caused by balloon injury. TUDCA significantly decreased the ratio of intima to media by reducing proliferation and inducing apoptosis of the VSMCs. TUDCA inhibits neointimal hyperplasia by reducing proliferation and inducing apoptosis of smooth muscle cells by suppression of ERK via PKCα-mediated MKP-1 induction.
Molecular Targets of Lithium Action
Authors: Christopher J Phiel, Peter S Klein
Journal: The Annual Review of Pharmacology and Toxicology (2001)

Lithium is highly effective in the treatment of bipolar disorder and also has multiple effects on embryonic development, glycogen synthesis, hematopoiesis, and other processes. However, the mechanism of lithium action is still unclear. A number of enzymes have been proposed as potential targets of lithium action, including inositol monophosphatase, a family of structurally related phosphomonoesterases, and the protein kinase glycogen synthase kinase-3. These potential targets are widely expressed, require metal ions for catalysis, and are generally inhibited by lithium in an uncompetitive manner, most likely by displacing a divalent cation. Thus, the challenge is to determine which target, if any, is responsible for a given response to lithium in cells. Comparison of lithium effects with genetic disruption of putative target molecules has helped to validate these targets, and the use of alternative inhibitors of a given target can also lend strong support for or against a proposed mechanism of lithium action. In this review, lithium sensitive enzymes are discussed, and a number of criteria are proposed to evaluate which of these enzymes are involved in the response to lithium in a given setting.
Review of microdialysis in brain tumors, from concept to application: First Annual Carolyn Frye-Halloran Symposium
Authors: Ramsis K. Benjamin, Fred H. Hochberg, Elizabeth Fox, Peter M. Bungay, William F. Elmquist, Clinton F. Stewart, James M. Gallo, Jerry M. Collins, Robert P. Pelletier, John F. de Groot, Robert C. Hickner, Idil Cavus, Stuart A. Grossman, O. Michael Colvin
Journal: Neuro-Oncology (2004)

In individuals with brain tumors, pharmacodynamic and pharmacokinetic studies of therapeutic agents have historically used analyses of drug concentrations in serum or cerebrospinal fluid, which unfortunately do not necessarily reflect concentrations within the tumor and adjacent brain. This review article introduces to neurological and medical oncologists, as well as pharmacologists, the application of microdialysis in monitoring drug metabolism and delivery within the fluid of the interstitial space of brain tumor and its surroundings. Microdialysis samples soluble molecules from the extracellular fluid via a semipermeable membrane at the tip of a probe. In the past decade, it has been used predominantly in neurointensive care in the setting of brain trauma, vasospasm, epilepsy, and intracerebral hemorrhage. At the first Carolyn Frye-Halloran Symposium held at Massachusetts General Hospital in March 2002, the concept of microdialysis was extended to specifically address its possible use in treating brain tumor patients. In doing so we provide a rationale for the use of this technology by a National Cancer Institute consortium, New Approaches to Brain Tumor Therapy, to measure levels of drugs in brain tissue as part of phase 1 trials.
Major Role for Arterial Disease in Morbidity and Mortality After Kidney Transplantation in Diabetic Recipients
Authors: Michael J Lemmer, John M Barry
Journal: Diabetes Care (1991)

To identify clinical characteristics of diabetic end-stage renal disease patients that place individual transplant candidates at high risk for arterial morbidity and mortality after transplantation.We studied the course of 101 sequential renal allograft recipients with insulin-dependent diabetes mellitus, transplanted between 10 November 1980 and 1 April 1986. Arterial disorders were tabulated from medical records and interviews with individual patients, their families, and their private physicians. Documentation of discrete arterial events included recorded physical examinations, radiographic studies, laboratory data, electrocardiograms, peripheral vascular flow studies, and operative reports. The prevalence of preoperative arterial disease was compared with the occurrence of new arterial events after kidney transplantation.Within a mean follow-up period of 47 mo, a 30% absolute mortality rate was observed. Of these deaths, 57% resulted from arterial disorders. Clinical manifestations of arterial disease were recognized in 41% of recipients before transplantation, and 78% of these patients suffered new vascular events after transplantation. Of the entire sample, 57% developed at least one new complication of arterial disease after transplantation, whereas only 34% had no vascular diagnosis before or after transplantation. Cerebral, coronary, and peripheral arterial complications after transplantation occurred in 14, 28, and 36% of the patients, respectively. The corresponding incidences of stroke, myocardial infarction, and amputation were 12, 14, and 25%. Pretransplant coronary artery disease predisposed to new coronary events after transplantation, but only peripheral arterial complications occurred more often after transplantation compared with the preoperative period. The probability of arterial complications or death correlated with patient age at first transplant and duration of diabetes but not with sex or smoking history.Intrinsic arterial disease in diabetic renal allograft recipients contributes heavily to the long-term morbidity and mortality after transplantation and poses the major threat to survival. Diabetic transplant candidates greater than 35 yr of age or with clinical evidence of arterial disease should undergo an extensive vascular assessment, including stress thallium myocardial imaging and/or coronary arteriography. Such recipients should receive careful preoperative counseling about their excess risk for subsequent arterial disorders.
Phase III Trial of Consolidation Therapy With Yttrium-90–Ibritumomab Tiuxetan Compared With No Additional Therapy After First Remission in Advanced Follicular Lymphoma
Authors: Franck Morschhauser, John Radford, Achiel Van Hoof, Umberto Vitolo, Pierre Soubeyran, Herve Tilly, Peter C. Huijgens, Arne Kolstad, Francesco d’Amore, Marcos Gonzalez Diaz, Mario Petrini, Catherine Sebban, Pier Luigi Zinzani, Marinus H.J. van Oers, Wim van Putten, Angelika Bischof-Delaloye, Ama Rohatiner, Gilles Salles, Jens Kuhlmann, Anton Hagenbeek
Journal: Journal of Clinical Oncology (2008)

We conducted an international, randomized, phase III trial to evaluate the efficacy and safety of consolidation with yttrium-90 ((90)Y)-ibritumomab tiuxetan in patients with advanced-stage follicular lymphoma in first remission.Patients with CD20(+) stage III or IV follicular lymphoma, who achieved a complete response (CR)/unconfirmed CR (CRu) or partial response (PR) after first-line induction treatment, were randomly assigned to receive (90)Y-ibritumomab tiuxetan (rituximab 250 mg/m(2) on day -7 and day 0 followed on day 0 by (90)Y-ibritumomab tiuxetan 14.8 MBq/kg; maximum of 1,184 MBq) or no further treatment (control). The primary end point was progression-free survival (PFS), which was calculated from the time of random assignment.A total of 414 patients (consolidation, n = 208; control, n = 206) were enrolled at 77 centers. (90)Y-ibritumomab tiuxetan consolidation significantly prolonged median PFS (after a median observation time of 3.5 years) in all patients (36.5 v 13.3 months in control arm; hazard ratio [HR] = 0.465; P < .0001) and regardless of whether patients achieved PR (29.3 v 6.2 months in control arm; HR = 0.304; P < .0001) or CR/CRu (53.9 v 29.5 months in control arm; HR = 0.613; P = .0154) after induction treatment. Median PFS with consolidation was prolonged in all Follicular Lymphoma International Prognostic Index risk subgroups. After (90)Y-ibritumomab tiuxetan consolidation, 77% of patients in PR after induction converted to CR/CRu, resulting in a final CR rate of 87%. The most common toxicity with (90)Y-ibritumomab tiuxetan was hematologic, and grade 3 or 4 infections occurred in 8% of patients.Consolidation of first remission with (90)Y-ibritumomab tiuxetan in advanced-stage follicular lymphoma is highly effective with no unexpected toxicities, prolonging PFS by 2 years and resulting in high PR-to-CR conversion rates regardless of type of first-line induction treatment.