tbuckley/cabot-search huggingface dataset:
RNA Interference Targeting Transforming Growth Factor-β Enhances NKG2D-Mediated Antiglioma Immune Response, Inhibits Glioma Cell Migration and Invasiveness, and Abrogates Tumorigenicity<b><i>In vivo</i></b>
Authors: Manuel A. Friese, Jörg Wischhusen, Wolfgang Wick, Markus Weiler, Günter Eisele, Alexander Steinle, Michael Weller
Journal: Cancer Research (2004)

Abstract Transforming growth factor (TGF)-β is the key molecule implicated in impaired immune function in human patients with malignant gliomas. Here we report that patients with glioblastoma, the most common and lethal type of human glioma, show decreased expression of the activating immunoreceptor NKG2D in CD8+ T and natural killer (NK) cells. TGF-β is responsible for the down-regulation of NKG2D expression in CD8+ T and NK cells mediated by serum and cerebrospinal fluid of glioma patients in vitro. Moreover, TGF-β inhibits the transcription of the NKG2D ligand MICA. Interference with the synthesis of TGF-β1 and TGF-β2 by small interfering RNA technology prevents the down-regulation of NKG2D on immune cells mediated by LNT-229 glioma cell supernatant and strongly enhances MICA expression in the glioma cells and promotes their recognition and lysis by CD8+ T and NK cells. Furthermore, TGF-β silencing results in a less migratory and invasive glioma cell phenotype in vitro. LNT-229 glioma cells deficient in TGF-β exhibit a loss of subcutaneous and orthotopic tumorigenicity in nude mice, and NK cells isolated from these mice show an activated phenotype. RNA interference targeting TGF-β1,2 results in a glioma cell phenotype that is more sensitive to immune cell lysis and less motile in vitro and nontumorigenic in nude mice, strongly confirming TGF-β antagonism as a major therapeutic strategy for the future treatment of malignant gliomas.
Cerebral Glucose Metabolism in Women With Panic Disorder
Authors: Adam Bisaga, Jack L. Katz, Angelo Antonini, C. Eugene Wright, Claude Margouleff, Jack M. Gorman, David Eidelberg
Journal: American Journal of Psychiatry (1998)

Objective: This study was undertaken to clarify earlier inconsistent findings in brain metabolic topography in panic disorder patients at rest.Method: Positron emission tomography (PET) with [18F]fluorodeoxyglucose was used to determine cerebral metabolic activity in six female patients with a DSM-III-R diagnosis of panic disorder and in six healthy female volunteers. All patients with panic disorder were medication free and were sensitive to lactate infusion. Results: A significant increase in glucose metabolism was found in the left hippocampus and parahippocampal area of the panic disorder subjects in comparison with that found in the healthy subjects. In addition, a significant decrease in metabolism was found in the right inferior parietal and right superior temporal brain regions of the panic disorder subjects in comparison with that of the normal subjects. There was no significant correlation between scores for the severity of panic disorder or for the severity of lactate-induced panic attack and the quantified PET abnormality. Conclusions: These data provide further support for the hypothesis of an abnormal brain metabolism in the hippocampal and parahippocampal area in individuals with panic disorder and also suggest other areas of aberrant brain metabolism in this disorder. Am J Psychiatry 1998; 155: 1178-1183
Influence of ursodeoxycholic acid on the mortality and malignancy associated with primary biliary cirrhosis: A population-based cohort study
Authors: Hannah Jackson, Masoud Solaymani-Dodaran, Tim R. Card, Guruprasad P. Aithal, Richard Logan, Joe West
Journal: Hepatology (2007)

Abstract There is debate over the mortality and malignancy risk in people with primary biliary cirrhosis (PBC) and whether this risk is reduced by use of ursodeoxycholic acid. To investigate this issue, we identified 930 people with PBC and 9,202 control subjects from the General Practice Research Database in the United Kingdom. We categorized regular ursodeoxycholic acid as treatment with 6 or more prescriptions and nonregular treatment as less than 6. We found a 2.7-fold increase in mortality for the PBC cohort compared with the general population [adjusted hazard ratio (HR), 2.69; 95% CI, 2.35–3.09]. In those having regular ursodeoxycholic acid (43%), the mortality increase was 2.2-fold (HR, 2.19; 95% CI, 1.66–2.87) and in those not treated 2.7-fold (HR, 2.69; 95% CI, 2.18–3.33). This apparent reduction in mortality was not explained by less severe disease in the ursodeoxycholic acid–treated group. The increased risk of primary liver cancer in ursodeoxycholic acid–treated patients was 3-fold (HR, 3.17; 95% CI, 0.64–15.62), in contrast to an 8-fold increase in those not treated (HR, 7.77; 95% CI, 1.30–46.65). Conclusion: We found that people with PBC had a 3-fold mortality increase when compared with the general population, which was somewhat reduced by regular treatment with ursodeoxycholic acid. However, the observed effect of ursodeoxycholic acid was not statistically significant. (HEPATOLOGY 2007.)
Modafinil improves daytime sleepiness in patients with mild to moderate obstructive sleep apnoea not using standard treatments: a randomised placebo-controlled crossover trial
Authors: Julia L Chapman, Liora Kempler, Catherina L Chang, Shaun C Williams, Sheila Sivam, Keith K H Wong, Brendon J Yee, Ronald R Grunstein, Nathaniel S Marshall
Journal: Thorax (2013)

<h3>Introduction</h3> Patients with mild to moderate obstructive sleep apnoea (OSA) commonly suffer excessive daytime sleepiness. Continuous positive airway pressure (CPAP) has limited effectiveness in reducing sleepiness in milder OSA. Modafinil is a wake-promoting drug licensed to treat residual sleepiness in CPAP-treated OSA. We hypothesised that modafinil may effectively treat sleepiness in untreated mild to moderate OSA. <h3>Methods</h3> Untreated sleepy men with mild to moderate OSA (age 18–70, apnoea-hypopnoea index (AHI) 5–30/h, Epworth Sleepiness Scale (ESS) ≥10) were randomised to receive 200 mg modafinil or matching placebo daily for 2 weeks before crossing over to the alternative treatment after a minimum 2-week washout. Mixed model analysis of variance was used to compare the changes on modafinil to placebo while classifying all randomised patients as random factors. <h3>Results</h3> 32 patients were randomised (mean (SD) AHI 13 (6.4)/h, age 47 (10.7) years, ESS 13.6 (3.3), body mass index 28.2 (3.6) kg/m<sup>2</sup>), 29 of whom (91%) completed the trial. The primary outcome (ESS) improved more on modafinil than placebo (3.6 points, 95% CI 1.3 to 5.8, p=0.003) and the secondary outcome (40-min driving simulator performance) also improved more on modafinil than placebo (steering deviation 4.7 cm, 95% CI 0.8 to 8.5, p=0.018). Psychomotor Vigilance Task reciprocal reaction time improved significantly over placebo (0.15 (1/ms), 95% CI 0.03 to 0.27, p=0.016). Improvements on the Functional Outcomes of Sleep Questionnaire were not significant (5.3 points over placebo, 95% CI −1 to 11.6, p=0.093). <h3>Conclusions</h3> Modafinil significantly improved subjective sleepiness in patients with untreated mild to moderate OSA. The size of this effect is clinically relevant at 3–4 ESS points of improvement compared with only 1–2 points in CPAP clinical trials. Driving simulator performance and reaction time also improved on modafinil. <h3>Clinical Trial Registration</h3> ACTRN#12608000128392.
Benign sclerosing pneumocytoma of lung (sclerosing haemangioma)
Authors: K.-W. Chan, A. R Gibbs, W. Lo, G. Newman
Journal: Thorax (1982)

The clinical and histopathological features of 14 cases of so-called sclerosing haemangioma of the lung are described. All developed in Hong Kong Chinese women. Histochemical and ultrastructural study of these tumours indicates an epithelial origin. The term benign sclerosing pneumocytoma is suggested as being more appropriate for this unusual tumour.
Factors associated with hospital admissions and repeat emergency department visits for adults with asthma
Authors: Robert J Adams, Brian J Smith, Richard E Ruffin
Journal: Thorax (2000)

A small proportion of patients with asthma account for a disproportionate number of acute health service events. To identify whether factors other than severity and low socioeconomic status were associated with this disproportionate use, a prospective study was undertaken to examine management and psychosocial factors associated with increased risk for admission to hospital with asthma and repeat visits to the emergency department over a 12 month period.A total of 293 patients with moderate or severe asthma managed at least in part at two teaching hospitals completed surveys of clinical status, acute events, sociodemographic, and psychological variables.Twenty three percent had a single admission to hospital and 16% had two or more hospital admissions. Twenty six percent had one emergency department visit and 32% had two or more visits to the emergency department. In a multiple logistic regression model, adjusted for age, sex, education and income, odds ratios (95% CI) for baseline factors associated with hospital admissions over the next 12 months were: moderate severity compared with severe asthma 0.6 (0.2 to 0.9); no hospital admissions in the past 12 months 0.1 (0.01 to 0.2); not possessing a written asthma action plan 4.0 (1.5 to 10.7); less use of an avoidance coping style 0.4 (0.3 to 0.7); lower preferences for autonomy in asthma management decisions 1.4 (0.96 to 2.0). Adjusted odds ratios (95% CI) for repeat emergency department visits were: moderate asthma severity 0.3 (0.1 to 0.8); current regular use of oral corticosteroids 10.0 (3.1 to 32.4); a hospital admission in the past 12 months 2.9 (1.8 to 4.8); not possessing a written asthma action plan 2.2 (1.1 to 5.6); less dislike of asthma medications 0.7 (0.5 to 0.9).In addition to factors relating to severity, not possessing a written asthma action plan, avoidance coping, and attitudes to self-management were related to acute use of health services in this at risk group. Interventions need to address or take these factors into account to reduce asthma morbidity.
Fibrosing alveolitis in systemic sclerosis: increase in memory T-cells in lung interstitium
Authors: AU Wells, S Lorimer, S Majumdar, NK Harrison, B Corrin, CM Black, PK Jeffery, RM du Bois
Journal: European Respiratory Journal (1995)

Despite the large numbers of T-cells present in the lungs in fibrosing alveolitis, their pathogenetic role is poorly understood. If these cells are involved in pathogenesis, they are more likely to express the CD45RO+ memory phenotype. To test this hypothesis, open lung biopsies from patients with fibrosing alveolitis associated with systemic sclerosis (FASSc) were compared with grossly normal lung taken from the periphery of lobes resected for lung cancer. Biopsies from eight patients with FASSc were compared with tissue from seven cancer controls. Paraffin sections were stained with a polyclonal anti-CD3 antibody for T-lymphocytes, monoclonal anti-CD45 antibody for leucocyte common antigen, and monoclonal anti-CD45RO antibody for primed T-lymphocytes. Staining was assessed quantitatively by computerized image analysis: in each case, the number of immunopositive cells was related to alveolar wall area and alveolar wall length. Mean alveolar wall thickness was increased in patients with FASSc (60.7 +/- 24.0 microns) compared with cancer controls (15.7 +/- 5.3 microns). Patients with FASSc had greater numbers of CD45+, CD3+ and CD45RO+ cells.mm-1 alveolar wall length compared with the controls. CD45RO+ cells made up 77% (median) of the CD3+ cells in FASSc, and their numbers per unit alveolar wall length were positively associated with alveolar wall thickness (r = 0.61). In conclusion, in fibrosing alveolitis of systemic sclerosis, most interstitial T-lymphocytes express the phenotype of memory cells; these cells are likely to be involved in the persistent inflammatory process.
Time course of differential mitochondrial energy metabolism adaptation to chronic hypoxia in right and left ventricles
Authors: K NOUETTEGAULAIN, M MALGAT, C ROCHER, J SAVINEAU, R MARTHAN, J MAZAT, F SZTARK
Journal: Cardiovascular Research (2005)

The present study was designed to characterize mitochondrial adaptation to chronic hypoxia (CH) in the rat heart. Mitochondrial energy metabolism was differentially examined in both left and right ventricles since CH selectively triggers pulmonary hypertension and right ventricular hypertrophy.Rats were exposed to a hypobaric environment for 2 or 3 weeks and compared with rats maintained in a normoxic environment. Oxidative capacity (oxygen consumption and ATP synthesis) was measured in saponin-skinned fibers with glutamate or palmitoyl carnitine as substrates. Enzymatic activities of mitochondrial respiratory chain complexes were measured on tissue homogenates. Morphometric analysis of mitochondria was performed on electron micrographs. Mitochondrial DNA was quantified using Southern blot analysis.Whereas oxidative capacity of both ventricles was decreased following 21 days of CH, oxygen consumption and ATP synthesis was maintained with the glutamate substrate in the right ventricle following 14 days of CH. As for the oxidative capacity, enzyme activities were decreased only in the left ventricle following 14 days of CH and in both ventricles following 21 days of CH. These functional alterations were associated with an increase in numerical density and a decrease in size of mitochondria without a change in volume density in both ventricles. Finally, 21 days of CH also decreased the ratio of mitochondrial DNA to nuclear DNA in both ventricles.CH alters morphometry and function of mitochondria in the heart, but this effect is delayed in the right compared to the left ventricle, suggesting some adaptive processes at the onset of right ventricular hypertrophy.
Interpreting thresholds for a clinically significant change in health status in asthma and COPD
Authors: P.W. Jones
Journal: European Respiratory Journal (2002)

Health status (or Health-Related Quality of Life) measurement is an established method for assessing the overall efficacy of treatments for asthma and chronic obstructive pulmonary disease (COPD). Such measurements can indicate the potential clinical significance of a treatment's effect. This paper is concerned with methods of estimating the threshold of clinical significance for three widely used health status questionnaires for asthma and COPD: the Asthma Quality of Life Questionnaire, Chronic Respiratory Questionnaire and St George's Respiratory Questionnaire. It discusses the methodology used to obtain such estimates and shows that the estimates appear to be fairly reliable; i.e. for a given questionnaire, similar estimates may be obtained in different studies. These empirically derived thresholds are all mean estimates with confidence intervals around them. The presence of these confidence intervals affects the way in which the thresholds may be used to draw inferences concerning the clinical relevance of clinical trial results. A new system of judging the magnitude of clinically significant results is proposed. Finally, an attempt is made to translate these thresholds into scenarios that illustrate what a clinically significant change with treatment may mean to an individual patient.
Evaluation of a new interrupter device for measuring bronchial responsiveness and the response to bronchodilator in 3 year old children
Authors: S.B. Phagoo, N.M. Wilson, M. Silverman
Journal: European Respiratory Journal (1996)

The interrupter technique for measuring airway resistance is non-invasive and convenient, and therefore ideally suited for the assessment of induced changes in airway calibre in preschool children. The aim of this study was to evaluate a commercially available interrupter device (based on Microlab 4000), which calculates the interrupter resistance (Rint) from pressure and flow following a brief interruption of expiration during quiet breathing. The repeatability of Rint was assessed, and its response to methacholine challenge and the bronchodilator salbutamol were compared with an indirect technique, the fall in transcutaneous oxygen tension (Ptc,O2), using the sensitivity index (SI, i.e. the change after challenge expressed in multiples of the baseline standard deviation) in 12 wheezy children (aged 3 yrs +/- 2 months). The mean (SD) baseline value of Rint was 0.91 (0.20) kPa.L-1.s. Short-term repeatability and baseline variability were satisfactory for Rint (intraclass correlation coefficient = 0.6; mean intrasubject coefficient of variation = 13%). Although 10 of the 12 subjects obtained a significant response using Rint at maximal bronchoconstriction (i.e. SI &gt; 2), overall, Rint was five times less sensitive than Ptc,O2 (geometric mean SI: Rint 3 vs Ptc,O2 16; p &lt; 0.0001). Reversal of obstruction with administration of a bronchodilator was clearly demonstrated in almost all subjects: Rint after challenge (mean +/- SD) 1.25 (0.22) kPa.L-1.s; after salbutamol 0.78 (0.19) kPa.L-1.s; p &lt; 0.001. In conclusion, the convenient interrupter resistance method appears more promising for detecting bronchodilator responses than induced bronchoconstriction in wheezy preschool children; however, measurement of transcutaneous oxygen tension provides a reliable indirect means of detecting induced airway obstruction in this age-group.
Changes in right ventricular relaxation during acute anterior myocardial infarction in pigs
Authors: L. D LANCASTER, K. B KERN, D. A MORRISON, M. OLAJOS, S. GOLDMAN
Journal: Cardiovascular Research (1989)

To determine the effect of an anteroseptal myocardial infarction on right ventricular systolic and diastolic function, we studied 12 pigs before and 1 h after left anterior descending coronary artery occlusion. Total arterial occlusion was achieved by the percutaneous, transcatheter placement of a 1 mm Teflon plug into the mid portion of the artery. The resulting infarction involved 28 (SEM 3)% of the left ventricular wall, in the anterior and septal regions. A small rim of the right ventricular free wall adjacent to the septum and the right ventricular apex were also affected. End diastolic pressures in both ventricles rose significantly: left ventricular from 12(1) to 20(2) mm Hg and right ventricular from 8(1) to 10(1) mm Hg. Right ventricular peak systolic pressure increased from 29(2) to 35(2) mm Hg while left ventricular peak systolic pressure did not change. One hour after infarction the half time of isovolumic relaxation of the right ventricle was prolonged from 6.9(0.5) to 8.7(0.4) ms. Ejection fraction in both ventricles was depressed: from 46(1) to 34(2)% in the right ventricle and from 69(3) to 49(3) in the left ventricle. There was no change in either right or left ventricular dP/dt. These data suggest that right ventricular systolic and diastolic dysfunction occurs as the result of an anteroseptal myocardial infarction in pigs.
Identification of a novel cell type in peripheral lymphoid organs of mice. V. Purification of spleen dendritic cells, new surface markers, and maintenance in vitro.
Authors: R M Steinman, G Kaplan, M D Witmer, Z A Cohn
Journal: The Journal of Experimental Medicine (1979)

Dendritic cells (DCs; 1) have been purified from mouse spleen in good yield. Spleen cell suspensions were floated on dense bovine plasma albumin (BPA) columns, and the low density fraction was adhered to glass (2). The adherent cells consisted of DCs and immature macrophages most of which eluted in a viable state from the culture dish after overnight incubation. The macrophages were then removed by selective rosetting with opsonized erythrocytes and recentrifugation on dense BPA. This protocol resulted in a purified DC fraction, containing 1--3 X 10(5) DCs/spleen, which was homogeneous and distinctive in its properties. All cells exhibited the phase contrast and transmission electron microscopy (EM) cytologic features that were previously described for freshly isolated adherent DCs. By scanning EM, most purified DCs exhibited a remarkable array of bulbous protrusions of varying length and shape, unlike any other lymphoid cell. All DCs expressed surface Ia and other major histocompatibility complex (MHC)-linked alloantigens. DCs, however, lacked surface Ig and T-cell antigens, and did not bind or interiorize opsonized erythrocytes. Purified DCs have been maintined in vitro for 3 days. Recovery of cultured purified cells was 70% or more of starting cell numbers. When [3H]uridine-tagged DCs were mixed with nonlabeled heterogeneous spleen cells, 70--80% of the labeled DCs were recovered as viable cells 2--3 days later. Purified DCs did not readhere to tissue culture surfaces and did not proliferate, even when cultured with mitogenic doses of concanavalin A and lipopolysaccharide. Finally, DCs did not change their cytologic or surface properties after 3 days of culture. These observations extend the evidence that DCs are a novel cell type and provide useful properties and techniques for their further study.
Bcl-2 Cooperates with Promyelocytic Leukemia Retinoic Acid Receptor α Chimeric Protein (Pmlrarα) to Block Neutrophil Differentiation and Initiate Acute Leukemia
Authors: Scott C. Kogan, Diane E. Brown, David B. Shultz, Bao-Tran H. Truong, Valerie Lallemand-Breitenbach, Marie-Claude Guillemin, Eric Lagasse, Irving L. Weissman, J. Michael Bishop
Journal: The Journal of Experimental Medicine (2001)

The promyelocytic leukemia retinoic acid receptor α (PMLRARα) chimeric protein is associated with acute promyelocytic leukemia (APL). PMLRARα transgenic mice develop leukemia only after several months, suggesting that PMLRARα does not by itself confer a fully malignant phenotype. Suppression of apoptosis can have a central role in tumorigenesis; therefore, we assessed whether BCL-2 influenced the ability of PMLRARα to initiate leukemia. Evaluation of preleukemic animals showed that whereas PMLRARα alone modestly altered neutrophil maturation, the combination of PMLRARα and BCL-2 caused a marked accumulation of immature myeloid cells in bone marrow. Leukemias developed more rapidly in mice coexpressing PMLRARα and BCL-2 than in mice expressing PMLRARα alone, and all mice expressing both transgenes succumbed to leukemia by 7 mo. Although both preleukemic, doubly transgenic mice and leukemic animals had abundant promyelocytes in the bone marrow, only leukemic mice exhibited thrombocytopenia and dissemination of immature cells. Recurrent gain of chromosomes 7, 8, 10, and 15 and recurrent loss of chromosome 2 were identified in the leukemias. These chromosomal changes may be responsible for the suppression of normal hematopoiesis and dissemination characteristic of the acute leukemias. Our results indicate that genetic changes that inhibit apoptosis can cooperate with PMLRARα to initiate APL.