tbuckley/cabot-search huggingface dataset:
S130 Exogenous Macrophages Are Retained in Mouse Lungs After Injury and Target Therapeutic Transgenes to the Injured Lung Parenchyma
Authors: K McNulty, EK Sage, R Alexander, CJ Scotton, SM Janes
Journal: Thorax (2012)

<h3>Introduction</h3> Pulmonary fibrosis evolves in response to epithelial injury in a number of lung diseases, and carries a poor prognosis; novel therapies are urgently needed. The epithelial mitogen keratinocyte growth factor (KGF) has been shown to prevent fibrosis in a number of animal models however its therapeutic utility is limited by its short half-life. There is a growing interest in cell therapy approaches, and we hypothesised that macrophages could be used as vehicles to target KGF therapy to injured lung. <h3>Methods</h3> Lentiviral vectors expressing luciferase, KGF and GFP (control) were generated and used to transduce the IC-21 macrophage cell line. Appropriate transgene expression was confirmed. KGF macrophages were co-cultured with primary mouse tracheal epithelial cells in a proliferation bioassay. Luciferase-expressing macrophages were tracked longitudinally using bioluminescence imaging after oropharyngeal delivery to the lungs of mice given bleomycin to induce injury, or saline control. Immunostaining was used to localise macrophages within lung sections. KGF and GFP-macrophages were delivered during bleomycin-induced lung injury; endpoint measures included lung histology, micro-CT analysis, and quantification of inflammatory cell infiltrates, vascular leak, lung collagen by HPLC, and inflammatory and fibrotic mediators by ELISA and qPCR. <h3>Results</h3> Exogenously delivered macrophages were retained in the lungs of bleomycin-injured mice, but not uninjured controls, when given during either the inflammatory or fibrotic phases of injury, and localised to injured lung parenchyma. KGF-transduced macrophages induced proliferation of mouse tracheal epithelial cells during co-culture, but delivery to bleomycin-injured mice was not associated with overall improvements in endpoints when delivered during either the inflammatory or fibrotic phases of injury. Delivery of macrophages <i>per se</i> was associated with an increase in inflammatory mediators consistent with classical M1 macrophage activation, which may have off-set any beneficial effects of KGF-transduced macrophages. <h3>Conclusions</h3> Exogenously delivered macrophages are preferentially retained in injured lung and show potential as vehicles to target therapeutic transgenes by localising to damaged areas. Whilst KGF-transduced macrophages induced epithelial proliferation <i>in vitro</i>, any protective effects <i>in vivo</i> may have been negated by the exacerbatory effects of macrophage delivery. Future work will determine whether <i>ex vivo</i> manipulation of macrophage phenotype can confer therapeutic benefit.
Changes in pCO2 levels during 6-minute walking test in patients with very severe COPD
Authors: Inga Heinzelmann, Rainer Gloeckl, Stella Seeberg, Thomas Damisch, Antje Stegemann, Maren Plagmann, Andreas Jerrentrup, Klaus Kenn
Journal: European Respiratory Journal (2014)

Background

Current literature provides only scarce information on the development of carbon dioxide pressure (pCO2) in patients with COPD during physical activities. Therefore aim of this study was to investigate pCO2 levels during exercise (6-minute walking test; 6MWT) and at night rest in patients with very severe COPD.

Methods

75 COPD patients (age: 63±8y, FEV1: 33±9 % pred.) participated in this prospective study. PCO2 was transcutaneously measured by the Sentec® device during a 6MWT and during one night. These measurements where repeated after 1 week and mean values were used for analyses. Peak pCO2 during 6MWT was the primary outcome parameter.

Results

Patients increased their pCO2 level by 3.4±3.7 mmHg to a peak value of 43.6±6.5 mmHg during the 6MWT. A higher pCO2 during the 6MWT correlated slightly with higher perceived dyspnoe (r=0.32, p<0.05). It seems to be more likely that a higher pCO2 level during the 6MWT occurs in patients that are younger (correlation with age: r=-0.34, p<0.001) and who suffer from more airflow limitation (correlation with FEV1: r=-0.28, p<0.05). Additionally there was a positive correlation (r=0.63, p<0.0001) between the peak pCO2 values measured at night and during 6MWT. In 36% of the patients pCO2 level increased more than 5mmHg. This group of pCO2-increasers reached a level of 47.4 mmHg at the end of 6MWT.

Conclusions

In general the increase of pCO2 in patients with very severe COPD during 6MWT seems to be slight and not to cause relevant clinical symptoms. However, younger patients with more advanced airflow limitation may need special attention with regard to hypercapnia.
Does doubling the dose of inhaled corticosteroids prevent asthma exacerbations?☆
Authors: Burton Zweiman, Marc E. Rothenberg
Journal: Journal of Allergy and Clinical Immunology (2004)

Many asthma management guidelines stress the importance of self-management plans to be used by suitably instructed patients in the overall care of asthma. In asthmatic individuals treated chronically with inhaled corticosteroids (ICSs), some self-management plans recommend doubling the maintenance dose of ICS when there is evidence of significant worsening of asthma symptoms or peak expiratory flow rates. But is there convincing evidence that doubling the dose of ICS will prevent further worsening of the asthma to the point of an acute exacerbation? This study investigated a group of 390 asthmatic individuals receiving chronic ICS therapy who were at increased risk for acute asthma exacerbations on the basis of their past medical histories. In a randomized, blind, parallel, controlled protocol, each of the patients added either a doubling dose of ICS or placebo at signs of worsening asthma. The primary study outcome was the percentage of individuals requiring use of a "burst" treatment with oral corticosteroids for an acute exacerbation of asthma during the 12-month study period. During this period, 53% of the patients felt the need to add inhaler therapy (doubling dose of ICS or placebo). A course of oral corticosteroids was subsequently needed in 11% of those adding ICS and in 12% of those adding placebo. The authors concluded that these findings did not support a beneficial effect in preventing asthma exacerbations for the addition of a doubling dose of ICS when asthma worsened. However, it was not clear whether the asthma symptoms and/or quality of life improved faster in those adding the doubling dose of ICS. Moreover, it is unclear whether the effect of doubling the dose of ICS was related to the baseline ICS dose in individual patients. A number of studies have shown that the beneficial effects of most ICSs begin to plateau at doses above 800-1000 μg/day in asthmatic adults.
Prognostic factors in Waldenström's macroglobulinemia: a report of 167 cases.
Authors: T Facon, M Brouillard, A Duhamel, P Morel, M Simon, J P Jouet, F Bauters, P Fenaux
Journal: Journal of Clinical Oncology (1993)

A single-center retrospective analysis was conducted in 167 patients with Waldenström's macroglobulinemia (WM) to delineate prognostic factors.One hundred sixty-seven patients diagnosed between January 1969 and December 1988, fulfilling diagnostic criteria of WM, were entered onto this study. One hundred twenty-eight patients were treated with chlorambucil (0.1 mg/kg/d): 117 at diagnosis and 11 during the disease course. Seventeen variables were analyzed in all patients and in treated patients for their prognostic value on survival using the Kaplan-Meier method and a Cox multivariate regression analysis.Median survival duration for all patients was 60 months. Pretreatment factors associated with shorter survival in the entire population were age > or = 60 years (P = .006), male sex (P = .0001), general symptoms (P = .01), hemoglobin less than 10 g/dL (P = .008), leukocytes less than 4 X 10(9)/L (P = .02), neutrophils less than 1.7 X 10(9)/L (P = .02), and platelets less than 150 X 10(9)/L (P = .0006). Organomegaly, signs of hyperviscosity, renal failure, monoclonal immunoglobulin M (M IgM) level, blood lymphocytosis, and percentage of marrow lymphoid cells were not significantly correlated with survival. In a Cox multivariate regression analysis, the combination of factors that gave the best prognostic value was the association of sex (P = .0002), neutrophils (P = .002), age (P = .008), and hemoglobin (P = .02).Our findings suggest that some pretreatment parameters, including older age, male sex, general symptoms, and cytopenias, carry a poor prognosis in WM. By contrast, high initial tumor burden (indicated by organomegaly, high IgM level, and high percentage of marrow lymphoid cells) does not seem to be significantly associated with short survival. Our results help define a high-risk population that could perhaps benefit from newer therapeutic approaches.
Who Provides Psychosocial Follow-Up Care for Post-Treatment Cancer Survivors? A Survey of Medical Oncologists and Primary Care Physicians
Authors: Laura P. Forsythe, Catherine M. Alfano, Corinne R. Leach, Patricia A. Ganz, Michael E. Stefanek, Julia H. Rowland
Journal: Journal of Clinical Oncology (2012)

Purpose Addressing psychosocial needs, including key components of psychologic distress, physical symptoms, and health promotion, is vital to cancer follow-up care. Yet little is known about who provides psychosocial care. This study examined physician-reported practices regarding care of post-treatment cancer survivors. We sought to characterize physicians who reported broad involvement in (ie, across key components of care) and shared responsibility for psychosocial care. Methods A nationally representative sample of medical oncologists (n = 1,130) and primary care physicians (PCPs; n = 1,021) were surveyed regarding follow-up care of breast and colon cancer survivors. Results Approximately half of oncologists and PCPs (52%) reported broad involvement in psychosocial care. Oncologist and PCP confidence, beliefs about who is able to provide psychosocial support, and preferences for shared responsibility for care predicted broad involvement. However, oncologists' and PCPs' perceptions of who provides specific aspects of psychosocial care differed (P &lt; .001); both groups saw themselves as the main providers. Oncologists' confidence, PCPs' beliefs about who is able to provide psychosocial support, and oncologist and PCP preference for models other than shared care were inversely associated with a shared approach to care. Conclusion Findings that some providers are not broadly involved in psychosocial care and that oncologists and PCPs differ in their beliefs regarding who provides specific aspects of care underscore the need for better care coordination, informed by the respective skills and desires of physicians, to ensure needs are met. Interventions targeting physician confidence, beliefs about who is able to provide psychosocial support, and preferred models for survivorship care may improve psychosocial care delivery.
Activated cell survival cascade protects cardiomyocytes from cell death in Tako‐Tsubo cardiomyopathy
Authors: Holger M. Nef, Helge Möllmann, Pirmin Hilpert, Christian Troidl, Sandra Voss, Andreas Rolf, Christopher B. Behrens, Michael Weber, Christian W. Hamm, Albrecht Elsässer
Journal: European Journal of Heart Failure (2009)
The European Union conference on chronic respiratory disease: purpose and conclusions
Authors: M. Decramer, Y. Sibille, A. Bush, K-H. Carlsen, K.F. Rabe, L. Clancy, A. Turnbull, B. Nemery, A. Simonds, T. Troosters
Journal: European Respiratory Journal (2011)

On October 19, 2010, the European Respiratory Society (ERS) organised, at the request of the Belgian presidency of the Council of the European Union, the first ever pre-ministerial conference on “Chronic respiratory disease – exploring solutions in the EU”. On October 20, the conclusions of this conference were presented to the conference of the ministers of health and the top policy makers of the 27 EU countries, under the presidency of L. Onkelinkx, the Belgian Health Minister. Finally, several elements of these conclusions were incorporated in European Council conclusions on chronic disease 1. This pre-ministerial conference was the first ever high level conference on chronic respiratory disease and it was a worthwhile milestone in the “Year of the Lung” effort proclaimed by the Forum of International Respiratory Societies (www.yearofthelung.org).

The main themes of the conference were prevention and care of respiratory disease, patient empowerment and innovative models of care. There was active participation of patients and patient organisations ( i.e. EFA, the European Federation of Allergy and Airway Disease Patients). Patient empowerment was defined as continuous education for patients, equal access to treatment and a meaningful involvement of patients in the decision making process. The importance of chronic respiratory disease cannot be overestimated. The big five respiratory disorders (chronic obstructive pulmonary disease, COPD, asthma, lung cancer, pneumonia and tuberculosis, are responsible for 20% of mortality worldwide 2, 3. The cost of treating these diseases in Europe is €100 billion annually. COPD affects 210 million people in the world, according to a recent estimation of the World Health Organization (WHO), and 44 million people in Europe 4. It is presently the fourth leading cause of death and it will become the third leading cause of death by 2030. It is currently the first leading cause of healthcare …
Interleukin 10 inhibits lipopolysaccharide-induced survival and cytokine production by human peripheral blood eosinophils.
Authors: S Takanaski, R Nonaka, Z Xing, P O'Byrne, J Dolovich, M Jordana
Journal: The Journal of Experimental Medicine (1994)

In this study we have investigated the effects of interleukin 10 (IL-10) on human peripheral blood eosinophils stimulated with granulocyte/macrophage colony stimulating factor (GM-CSF) and lipopolysaccharide (LPS). We show that LPS was able to enhance eosinophil survival in a dose-dependent manner, as well as release of the cytokines GM-CSF, tumor necrosis factor alpha, and IL-8. LPS-induced eosinophil survival was largely inhibited by an anti-GM-CSF neutralizing antibody and completely blocked by polymyxin B, suggesting GM-CSF involvement in the survival enhancing mechanism and LPS specificity, respectively. IL-10 significantly inhibited survival of, and cytokine production from, eosinophils induced by LPS, but did not inhibit the survival induced by GM-CSF. These observations suggest a novel activation mechanism of eosinophils and, also, that IL-10 may participate in the regulation of diseases characterized by eosinophil infiltration.
Survival with Newly Diagnosed Metastatic Prostate Cancer in the “Docetaxel Era”: Data from 917 Patients in the Control Arm of the STAMPEDE Trial (MRC PR08, CRUK/06/019)
Authors: Nicholas David James, Melissa R. Spears, Noel W. Clarke, David P. Dearnaley, Johann S. De Bono, Joanna Gale, John Hetherington, Peter J. Hoskin, Robert J. Jones, Robert Laing, Jason F. Lester, Duncan McLaren, Christopher C. Parker, Mahesh K.B. Parmar, Alastair W.S. Ritchie, J. Martin Russell, Räto T. Strebel, George N. Thalmann, Malcolm D. Mason, Matthew R. Sydes
Journal: European Urology (2014)

Prostate cancer (PCa) is the second most common disease among men worldwide. It is important to know survival outcomes and prognostic factors for this disease. Recruitment for the largest therapeutic randomised controlled trial in PCa--the Systemic Therapy in Advancing or Metastatic Prostate Cancer: Evaluation of Drug Efficacy: A Multi-Stage Multi-Arm Randomised Controlled Trial (STAMPEDE)--includes men with newly diagnosed metastatic PCa who are commencing long-term androgen deprivation therapy (ADT); the control arm provides valuable data for a prospective cohort.Describe survival outcomes, along with current treatment standards and factors associated with prognosis, to inform future trial design in this patient group.STAMPEDE trial control arm comprising men newly diagnosed with M1 disease who were recruited between October 2005 and January 2014.Overall survival (OS) and failure-free survival (FFS) were reported by primary disease characteristics using Kaplan-Meier methods. Hazard ratios and 95% confidence intervals (CIs) were derived from multivariate Cox models.A cohort of 917 men with newly diagnosed M1 disease was recruited to the control arm in the specified interval. Median follow-up was 20 mo. Median age at randomisation was 66 yr (interquartile range [IQR]: 61-71), and median prostate-specific antigen level was 112 ng/ml (IQR: 34-373). Most men (n=574; 62%) had bone-only metastases, whereas 237 (26%) had both bone and soft tissue metastases; soft tissue metastasis was found mainly in distant lymph nodes. There were 238 deaths, 202 (85%) from PCa. Median FFS was 11 mo; 2-yr FFS was 29% (95% CI, 25-33). Median OS was 42 mo; 2-yr OS was 72% (95% CI, 68-76). Survival time was influenced by performance status, age, Gleason score, and metastases distribution. Median survival after FFS event was 22 mo. Trial eligibility criteria meant men were younger and fitter than general PCa population.Survival remains disappointing in men presenting with M1 disease who are started on only long-term ADT, despite active treatments being available at first failure of ADT. Importantly, men with M1 disease now spend the majority of their remaining life in a state of castration-resistant relapse.Results from this control arm cohort found survival is relatively short and highly influenced by patient age, fitness, and where prostate cancer has spread in the body.
Spontaneous fractures of pelvis in rheumatoid arthritis.
Authors: J Dequeker, H Heylen, A Burssens
Journal: BMJ (1972)

told me that she had had a sensation of impending death.I treated this particular episode with an intramuscular injection of chlorpromazinc and she was perfectly normal and rational the next morning.Needless to say, she was not given any more pentazocine.It is worth noting this particular side effect which was pointed out in your account of this drug (16 May, 1970, p. 409).It is extremely rare and pentazocine is an other- wise excellent analgesic, which we have used fairly extensively in this hospital and with good results.It provides an effective analgesic stronger than codeine but less likely to cause addiction and respiratory depression than morphia.
High Fat Intake Leads to Acute Postprandial Exposure to Circulating Endotoxin in Type 2 Diabetic Subjects
Authors: Alison L. Harte, Madhusudhan C. Varma, Gyanendra Tripathi, Kirsty C. McGee, Nasser M. Al-Daghri, Omar S. Al-Attas, Shaun Sabico, Joseph P. O’Hare, Antonio Ceriello, Ponnusamy Saravanan, Sudhesh Kumar, Philip G. McTernan
Journal: Diabetes Care (2011)

To evaluate the changes in circulating endotoxin after a high-saturated fat meal to determine whether these effects depend on metabolic disease state.Subjects (n = 54) were given a high-fat meal (75 g fat, 5 g carbohydrate, 6 g protein) after an overnight fast (nonobese control [NOC]: age 39.9 ± 11.8 years [mean ± SD], BMI 24.9 ± 3.2 kg/m(2), n = 9; obese: age 43.8 ± 9.5 years, BMI 33.3 ± 2.5 kg/m(2), n = 15; impaired glucose tolerance [IGT]: age 41.7 ± 11.3 years, BMI 32.0 ± 4.5 kg/m(2), n = 12; type 2 diabetic: age 45.4 ± 10.1 years, BMI 30.3 ± 4.5 kg/m(2), n = 18). Blood was collected before (0 h) and after the meal (1-4 h) for analysis.Baseline endotoxin was significantly higher in the type 2 diabetic and IGT subjects than in NOC subjects, with baseline circulating endotoxin levels 60.6% higher in type 2 diabetic subjects than in NOC subjects (P < 0.05). Ingestion of a high-fat meal led to a significant rise in endotoxin levels in type 2 diabetic, IGT, and obese subjects over the 4-h time period (P < 0.05). These findings also showed that, at 4 h after a meal, type 2 diabetic subjects had higher circulating endotoxin levels (125.4%↑) than NOC subjects (P < 0.05).These studies have highlighted that exposure to a high-fat meal elevates circulating endotoxin irrespective of metabolic state, as early as 1 h after a meal. However, this increase is substantial in IGT and type 2 diabetic subjects, suggesting that metabolic endotoxinemia is exacerbated after high fat intake. In conclusion, our data suggest that, in a compromised metabolic state such as type 2 diabetes, a continual snacking routine will cumulatively promote their condition more rapidly than in other individuals because of the greater exposure to endotoxin.
Loss-of-Function of <i>Nkx3.1</i> Promotes Increased Oxidative Damage in Prostate Carcinogenesis
Authors: Xuesong Ouyang, Theodore L. DeWeese, William G. Nelson, Cory Abate-Shen
Journal: Cancer Research (2005)

Despite the significance of oxidative damage for carcinogenesis, the molecular mechanisms that lead to increased susceptibility of tissues to oxidative stress are not well-understood. We now report a link between loss of protection against oxidative damage and loss-of-function of Nkx3.1, a homeobox gene that is known to be required for prostatic epithelial differentiation and suppression of prostate cancer. Using gene expression profiling, we find that Nkx3.1 mutant mice display deregulated expression of several antioxidant and prooxidant enzymes, including glutathione peroxidase 2 and 3 (GPx2 and GPx3), peroxiredoxin 6 (Prdx6), and sulfyhydryl oxidase Q6 (Qscn6). Moreover, the formation of prostatic intraepithelial neoplasia in these mutant mice is associated with increased oxidative damage of DNA, as evident by increased levels of 8-hydroxy-2'-deoxyguanosine. We further show that progression to prostate adenocarcinoma, as occurs in compound mutant mice lacking Nkx3.1 as well as the Pten tumor suppressor, is correlated with a further deregulation of antioxidants, including superoxide dismutase enzymes, and more profound accumulations of oxidative damage to DNA and protein, the latter manifested by increased levels of 4-hydroxynonenal. We propose that the essential role of Nkx3.1 in maintaining the terminally differentiated state of the prostate epithelium provides protection against oxidative damage and, thereby, suppression of prostate cancer. Thus, our findings provide a molecular link between a gene whose inactivation is known to be involved in prostate carcinogenesis, namely Nkx3.1, and oxidative damage of the prostatic epithelium.
Outcomes of screening for diabetes in high-risk Hong Kong Chinese subjects.
Authors: G T Ko, J C Chan, L W Tsang, V T Yeung, C C Chow, C S Cockram
Journal: Diabetes Care (2000)

To examine the significance of individual risk factors on the development of diabetes in subjects who underwent screening for diabetes.A total of 1,649 Chinese subjects underwent screening for diabetes. They were asymptomatic but had known risk factors for diabetes, including a positive family history of diabetes, a past history of gestational diabetes, obesity, hypertension, and/or dyslipidemia. Another 799 age-matched subjects from the community who had no risk factors for diabetes were used as the comparison group.Of the 1,649 subjects who underwent screening, 241 (14.6%) had diabetes. In these subjects, 989 (60.0%) had 1 risk factor, 502 (30.4%) had 2 risk factors, 141 (8.6%) had 3 risk factors, and 17 (1.0%) had 4 or 5 risk factors for diabetes. Of the 799 control subjects, 29 (3.6%) had diabetes. Compared with the comparison group, the odds ratio (95% CI) of having diabetes after adjustment for age was 5.2 (3.5-7.7) in the 1,649 subjects with known risk factors. The odds ratio of having diabetes increased from 3.7 in subjects with 1 risk factor to 28.4 in subjects with 4 or 5 risk factors.In men, age, BMI, family history of diabetes, and dyslipidemia, and in women, age, BMI, hypertension, dyslipidemia, total cholesterol, and history of gestational diabetes are associated with increased odds of developing diabetes. These risk factors have additive effects on the odds of having diabetes. Early and regular screening for diabetes and other cardiovascular risk factors is essential in these high-risk individuals.