tbuckley/cabot-search huggingface dataset:
Airways dilate to simulated inspiratory but not expiratory manoeuvres
Authors: Adrian R. West, Elangovan Thaya Needi, Howard W. Mitchell, Peter K. McFawn, Peter B. Noble
Journal: European Respiratory Journal (2012)

In a healthy human, deep inspirations produce bronchodilation of contracted airways, which probably occurs due to the transient distension of the airway smooth muscle (ASM). We hypothesised that deep expiratory manoeuvres also produce bronchodilation due to transient airway wall and ASM compression. We used porcine bronchial segments to assess the effects of deep inspirations, and maximal and partial expiration (submaximal) on airway calibre. Respiratory manoeuvres were simulated by varying transmural pressure using a hydrostatic pressure column: deep inspiration 5 to 30 cmH 2 O, maximal expiration 30 to -15 cmH 2 O, partial expiration 10 to -15 cmH 2 O; amidst a background of tidal oscillations, 5 to 10 cmH 2 O at 0.25 Hz. Changes in luminal cross-sectional area in carbachol-contracted airways were measured using video endoscopy. Deep inspirations produce an immediate bronchodilation (∼40–60%, p=0.0076) that lasts for up to 1 min (p=0.0479). In comparison, after maximal expiration there was no immediate change in airway calibre; however, a delayed bronchodilatory response was observed from 4 s after the manoeuvre (p=0.0059) and persisted for up to 3 min (p=0.0182). Partial expiration had little or no effect or airway calibre. The results observed demonstrate that the airway wall dilates to deep inspiration manoeuvres but is unresponsive to deep expiratory manoeuvres.
Testing Cardiovascular Drug Safety and Efficacy in Randomized Trials
Authors: Garret A. FitzGerald
Journal: Circulation Research (2014)

Randomized trials provide the gold standard evidence on which rests the decision to approve novel therapeutics for clinical use. They are large and expensive and provide average but unbiased estimates of efficacy and risk. Concern has been expressed about how unrepresentative populations and conditions that pertain in randomized trials might be of the real world, including concerns about the homogeneity of the biomedical and adherence characteristics of volunteers entered into such trials, the dose and constancy of drug administration and the mixture of additional medications that are restricted in such trials but might influence outcome in practice. A distinction has been drawn between trials that establish efficacy and those that demonstrate effectiveness, drugs that patients actually consume in the real world for clinical benefit. However, randomized controlled trials remain the gold standard for establishing efficacy and the testing of effectiveness with less rigorous approaches is a secondary, albeit important consideration. Despite this, there is an appreciation that average results may conceal considerable interindividual variation in drug response, leading to a failure to appreciate clinical value or risk in subsets of patients. Thus, attempts are now being made to individualize risk estimates by modulating those derived from large randomized trials with the individual baseline risk estimates based on demographic and biological criteria—the individual Numbers Needed to Treat to obtain a benefit, such as a life saved. Here, I will consider some reasons why large phase 3 trials—by far the most expensive element of drug development—may fail to address the unmet medical needs, which should justify such effort and investment.
Body Size and Composition and the Risk of Lymphohematopoietic Malignancies
Authors: Robert J. MacInnis, Dallas R. English, John L. Hopper, Graham G. Giles
Journal: JNCI Journal of the National Cancer Institute (2005)

Reports of associations between body size and composition and risk of lymphohematopoietic malignancies have been inconsistent. In a prospective study of 40,909 people aged 27-75 years and followed up for an average of 8.4 years, we measured fat mass and fat-free mass (using bioelectrical impedance analysis) and measured waist circumference directly. All malignancies were ascertained via the population cancer registry. The risk of myeloid leukemia was positively associated with body mass index (compared with those < 25 kg/m2, overweight and obese persons' hazard ratios [HRs] = 5.3, 95% confidence interval [CI] = 1.9 to 15.2 and HR = 5.0, 95% CI = 1.6 to 15.5, respectively; P = .006), fat-free mass (per 10-kg increase HR = 1.83, 95% CI = 1.15 to 2.90; P = .01), and waist circumference (per 10-cm increase HR = 1.35, 95% CI = 1.06 to 1.72; P = .02). Lymphoproliferative malignancies and subgroups showed little relationship with body size.
New horizons in the regulation of bile acid and lipid homeostasis: critical role of the nuclear receptor FXR as an intracellular bile acid sensor
Authors: M ARRESE
Journal: Gut (2001)

Mice lacking the nuclear bile acid receptor FXR/BAR developed normally and were outwardly identical to wild-type littermates.FXR/BAR null mice were distinguished from wild-type mice by elevated serum bile acid, cholesterol, and triglycerides, increased hepatic cholesterol and triglycerides, and a proatherogenic serum lipoprotein profile.FXR/BAR null mice also had reduced bile acid pools and reduced fecal bile acid excretion due to decreased expression of the major hepatic canalicular bile acid transport protein.Bile acid repression and induction of cholesterol 7alphahydroxylase and the ileal bile acid binding protein, respectively, did not occur in FXR/BAR null mice, establishing the regulatory role of FXR/BAR for the expression of these genes in vivo.These data demonstrate that FXR/BAR is critical for bile acid and lipid homeostasis by virtue of its role as an intracellular bile acid sensor.
EFFECTS OF SERUM ON MEMBRANE TRANSPORT
Authors: Phyllis R. Strauss, Richard D. Berlin
Journal: The Journal of Experimental Medicine (1973)

The effects of normal rabbit serum (NRS) on two transport systems in rabbit lung macrophages have been examined. A 20 min preincubation with serum was required for the effects, which were retained for at least 40 min after serum was removed. No serum was present during the transport studies. (a) Preincubation with 0.5 or 1.0% NRS resulted in depression of lysine transport to 59 +/- 2.6% (SE, 31 observations) of control levels. The activity was heat stable to 100 degrees C for 30 min and lost after dialysis. Pretreatment with serum did not alter the intracellular concentration of lysine attained when cells were then incubated with 10 mM lysine for 30 min. The relative depression of lysine transport by serum was unaltered by preloading with such high concentrations of lysine. (b) Preincubation with 5% NRS resulted in enhancement of adenosine transport by 35 +/- 2.3% (SE, 60 observations). Activity was stable to heating at 65 degrees C for 40 min but lost at 100 degrees C for 20 min. It was nondialyzable. Total radioactivity accumulated after 30 min incubation with 1 mM adenosine was unaffected by serum pretreatment. The two activities were separable by passage over Sephadex G25.
Risk behaviour and time as covariates for efficacy of the HIV vaccine regimen ALVAC-HIV (vCP1521) and AIDSVAX B/E: a post-hoc analysis of the Thai phase 3 efficacy trial RV 144
Authors: Merlin L Robb, Supachai Rerks-Ngarm, Sorachai Nitayaphan, Punnee Pitisuttithum, Jaranit Kaewkungwal, Prayura Kunasol, Chirasak Khamboonruang, Prasert Thongcharoen, Patricia Morgan, Michael Benenson, Robert M Paris, Joseph Chiu, Elizabeth Adams, Donald Francis, Sanjay Gurunathan, Jim Tartaglia, Peter Gilbert, Don Stablein, Nelson L Michael, Jerome H Kim
Journal: The Lancet Infectious Diseases (2012)
Autoimmunity, T-cells and STAT-4 in the pathogenesis of chronic obstructive pulmonary disease
Authors: M.G. Cosio
Journal: European Respiratory Journal (2004)

There is not much doubt that cigarette smoking is the main trigger for the development of chronic obstructive pulmonary disease (COPD).However, the mechanisms by which cigarettes produce the disease have been elusive.The consideration of new ideas could bring new insights.The paper by DI STEFANO et al. [1] in this issue of the European Respiratory Journal invites me to revisit a previously stated hypothesis [2][3][4], that the T-cell and autoimmunity may be the key in the mechanisms leading to COPD, since DI STEFANO et al. [1] provide another piece of evidence in favour of this paradigm.Let9s look at the autoimmune hypothesis with open eyes.Concepts evolve as new evidence settles in.Who would have believed 20 or even 10 yrs ago that peptic ulcer is an infectious disease, now treated with antibiotics, or that arteriosclerosis is an autoimmune disease, triggered by epitopes generated in the process of atherogenesis, such as oxidised low-density lipoproteins [5, 6]?Therefore, why not consider COPD as an autoimmune disease triggered by smoking?But why should we consider such as scenario?I will explain and, in doing so, how the DI STEFANO et al.[1] paper fits into this paradigm.For years, the inflammatory reaction in COPD was focused on neutrophils and their elastase, and macrophages and their metalloproteinases: the protease-antiprotease paradigm; an important mechanism, but probably only one step in the complex pathogenesis of COPD.Then, FINKELSTEIN et al. [7] introduced the T-cell as an important inflammatory component in the lungs of smokers, expanding the field of investigation of the inflammatory reaction in COPD to include the T-cells.For years, it was believed that because neutrophils and macrophages were increased in smokers, they were involved in the pathogenesis of the disease.T-cells are also increased in smokers9 lungs, thus it is necessary to determine why and what the consequences of this increase are.To start, let9s remember that naı ¨ve, nonstimulated T-cells cannot enter the lung, or any organ for that matter, because their homing receptors make them traffic to the lymphatic tissue [8].Thus, the cells found in the lungs of smokers with COPD have to be primed and stimulated in order to get there.How could they be stimulated?The concept of inflammation has evolved substantially since the findings of neutrophils and macrophages in the bronchoalveolar lavage (BAL) of smokers [9,10].It is now recognised that the inflammatory reaction composed of neutrophils and macrophages represents the innate immune reaction, and that the adaptive immune response involving B-and T-cells is intimately linked with innate immunity.Therefore, the traditional inflammation in smokers (neutrophils and macrophages) should be interpreted as the innate immune response to cigarettes, which could lead to an adaptive response with T-cells.
NITROGEN CLEARANCE RATES OF RIGHT AND LEFT LUNGS IN DIFFERENT POSITIONS *†‡
Authors: Glen A. Lillington, Ward S. Fowler, R. Drew Miller, H. Frederic Helmholz
Journal: Journal of Clinical Investigation (1959)

Uniform alveolar ventilation implies that dur- ing inspiration all alveoli simultaneously receive gas of the same chemical composition and of the same volume (relative to the previous preinspiratory volume) and that this mixes almost in- stantaneously with the preinspiratory alveolar gas.Studies with single or multiple inhalations of "reference" gases have shown that alveolar venti- lation is nonuniform (uneven) in most normal men (2).The two principal theoretic explana- tions for this observation have been a) that in- spired gases are stratified in the peripheral alveolar spaces or b) that different regions (central versus peripheral spaces of a lobe or segment; different lungs, lobes or segments) are ventilated at dif- ferent rates.Although Roos, Dahlstrom and Murphy (3) again proposed the stratification theory, it was noted by Forster (4) that some of their experimental results could be equally con- sistent with a regional explanation.The elimination rate (clearance) of pulmonary nitrogen (N2) from the. total lungs during in- halation of oxygen was found by Lundin (5) and by Svanberg (6) to be retarded in persons in the lateral decubitus position as compared with the rate in supine persons.The clearance curves of helium from the total lungs failed to demonstrate that alveolar ventilation was less uniform in the lateral decubitus than in the supine position (7).
Some Engineering Aspects of Insulin Delivery Systems
Authors: W J Spencer, R E Bair, G A Carlson, J T Love, R S Urenda, R P Eaton, D S Schade
Journal: Diabetes Care (1980)

The characteristics of electronically controlled insulin delivery systems are presented. Early experiments with an external system have shown promise in providing improved glycemic control over conventional methods of single or multiple subcutaneous insulin injections. The encouraging results with external insulin delivery systems have led to the development and early testing in dogs of an implantable system with remote controls to permit variable insulin flow rates. A number of questions remain to be answered before widespread experimentation with external and implanted insulin delivery systems is possible. There appears to be no major development problems with the engineering aspects of such systems.
Effect of motilin on the lower oesophageal sphincter.
Authors: A J Meissner, K L Bowes, R Zwick, E E Daniel
Journal: Gut (1976)

The effect of motilin on lower oesophageal sphincter (LES) pressure has been studied in unanesthetised specially trained dogs using an infusion manometric technique. Motilin produced significant rises in resting pressure and contractions of the LES after doses ranging from 0-009 mug/kg to 0-05 mug/kg. Doses greater than 0-05 mug/kg resulted in repetitive high amplitude contractions. Atropine 30 mug/kg completely abolished the effect of the lower doses of motilin. Higher doses of motilin in atropinised dogs still caused a small rise in baseline pressure and contractile activity still appeared. Hexamethonium 2 mg/kg resulted in both a diminished rise in LES pressure and the disappearance of contractions after motilin. Hexamethonium and atropine together completely abolished the LES response to motilin. We conclude that motilin increases LES pressure by acting on preganglionic cholinergic neurones to release acetylcholine which excites other cholinergic neurones supplying the circular muscle of the LES.
Regulation by vitamin D metabolites of parathyroid hormone gene transcription in vivo in the rat.
Authors: J Silver, T Naveh-Many, H Mayer, H J Schmelzer, M M Popovtzer
Journal: Journal of Clinical Investigation (1986)

In vitro 1,25-dihydroxycholecalciferol (1,25(OH)2D3) decreased levels of preproparathyroid(preproPTH) hormone mRNA. We have now pursued these studies in vivo in the rat. Rats were administered vitamin D metabolites i.p. and the levels of preproPTH mRNA were determined in excised parathyroid-thyroid glands by blot hybridization. PreproPTH mRNA levels were less than 4% of basal at 48 h after 100 pmol 1,25(OH)2D3, with no increase in serum calcium. Gel blots showed that 1,25(OH)2D3 decreased preproPTH mRNA levels without any change in its size (833 basepair). Microdissected parathyroids after 1,25(OH)2D3 (100 pmol) showed mRNA levels for preproPTH were 40 +/- 8% of controls, but for beta-actin were 100% of controls. The relative potencies of vitamin D metabolites were: 1,25(OH)2D3 greater than 24,25(OH)2D3 greater than 25(OH)D3 greater than vitamin D3. In vitro nuclear transcription showed that 1,25(OH)2D3-treated (100 pmol) rats' PTH transcription was 10% of control, while beta-actin was 100%. These results show that 1,25(OH)2D3 regulates PTH gene transcription. PTH stimulates 1,25(OH)2D3 synthesis, which then inhibits PTH synthesis, thus completing an endocrinological feedback loop.
Activation of Telomerase in Glioma Cells by Human Cytomegalovirus: Another Piece of the Puzzle
Authors: J. Cinatl, M. Nevels, C. Paulus, M. Michaelis
Journal: JNCI Journal of the National Cancer Institute (2009)

Comment on: J Natl Cancer Inst. 2009 Apr 1;101(7):488-97. Activation of telomerase in glioma cells by human cytomegalovirus: another piece of the puzzle. Cinatl J Jr, Nevels M, Paulus C, Michaelis M. Publication Types: Comment Editorial Review PMID: 19318630 [PubMed indexed for MEDLINE] A service of the U.S. National Library of Medicine and the National Institues of Health Page 1 of 1 PubMed Results Print Preview
Efficient gene delivery to the inflamed colon by local administration of recombinant adenoviruses with normal or modified fibre structure
Authors: S Wirtz, P R Galle, M F Neurath
Journal: Gut (1999)

BACKGROUND/AIMS Replication deficient recombinant adenoviruses represent an efficient means of transferring genes in vivo into a wide variety of dividing and quiescent cells from many different organs. Although the gastrointestinal tract is a potentially attractive target for gene therapy approaches, only a few studies on the use of viral gene transfer vehicles in the gut have been reported. The prospects of using recombinant adenoviruses for gene delivery into epithelial and subepithelial cells of the normal and inflamed colon are here analysed. METHODS An E1/E3 deleted recombinant adenovirus (denoted AdCMVβGal) and an adenovirus with modified fibre structure (denoted AdZ.F(pk7)) both expressing the bacterial lacZ gene under the control of a human cytomegalovirus promoter were used for reporter gene expression in vitro and in vivo. β-Galactosidase activity was determined by specific chemiluminescent reporter gene assay. RESULTS Intravenous or intraperitoneal injection of AdCMVβGal into healthy Balb/c mice caused strong reporter gene expression in the liver and spleen but not in the colon. In contrast, local administration of AdCMVβGal resulted in high reporter gene expression in colonic epithelial cells and lamina propria mononuclear cells. A local route of adenovirus administration in mice with experimental colitis induced by the hapten reagent trinitrobenzenesulphonic acid was next evaluated. Interestingly, rectal administration of AdCMVβGal caused a higher β-galactosidase activity in isolated lamina propria cells from infected mice with experimental colitis than in those from controls. Furthermore, isolated lamina propria cells from mice with colitis infected in vitro showed a significant increase in reporter gene activity compared with controls. Finally, AdZ.F(pk7) adenoviruses with modified fibre structure produced 10- to 40-fold higher reporter gene activity in spleen T cells and lamina propria mononuclear cells of colitic mice compared with standard AdCMVβGal vectors. CONCLUSIONS Local administration of recombinant adenoviruses with normal or modified fibre structure could provide a new reliable method for targeted gene expression in the inflamed colon. Such gene delivery could be used to specifically express signal transduction proteins with therapeutic potential in inflamed colonic tissue. In particular, adenoviruses with modified fibre structure may be useful in T cell directed therapies in intestinal inflammation.
P17.24 * OUTCOME OF GLIOBLASTOMA IN YOUNG PATIENTS: A SINGLE INSTITUTION EXPERIENCE
Authors: C. Dealis, I. Florio
Journal: Neuro-Oncology (2014)

GBM is the most frequent brain tumor affecting adults. More than 80% of the patients are older than 50. Unfortunately the prognosis remains poor with a median overall survival of 14.6% and a 5 years survival of 9.8%. Between January 2002 and November 2013, 16 patients (7 men and 9 women; median age 40; range 26-50) affected by GBM were followed at our Institution. All patients had a diagnosis of GBM. Thirteen patients (81%) had a primary GBM, 3 patients (19%) had a secondary GBM arising from a low grade glioma diagnosed 3.6 years before (1-6 years). Eleven patients were radically operated (69%), 5 patients were submitted to partial exeresis (31%). After surgery, 13 patients (81%) received concomitant chemo- and radiotherapy (RT) (Stupp regimen); 3 patients were not submitted to RT (19%) as they received it years before, after the diagnosis of low grade glioma. Among the patients receiving chemoRT, 12 patients (92%) were submitted to adjuvant chemotherapy following Stupp regimen (number of cycles: 3-12), 1 patient (8%) died before starting adjuvant chemotherapy due to disease progression. Among the patients with a secondary GBM, 2 (67%) received Temozolomide as adjuvant treatment post-surgery, 1 patients (33%) received BCNU chemotherapy. Median time to progression (TTP) among the patients having completed adjuvant chemotherapy is 20 months (range 3-108). Among all the 16 patients described, 7 patients (44%) are alive at a median time of 32.7 months (range 6-90), 9 patients (56%) died and had a median overall survival (OS) of 27.4 months (range 4-108). Globally, patients under 50 affected by GBM have a longer median TTP and OS than patients over 50. Such a situation can be determined by the best Perfomance Status, the absence of comorbidities and the best physical reserve of the patients under 50 compared to the ones of older patients. Further studies are needed to evaluate the outcome of GBM in patients under 50.
MRI comes of age in RA clinical trials
Authors: Charles Peterfy, Mikkel Østergaard, Philip G Conaghan
Journal: Annals of the Rheumatic Diseases (2013)

The success of modern rheumatoid arthritis (RA) therapies and treatment strategies has led to extended placebo phases being unethical in RA randomised controlled trials (RCTs). Modern trials therefore increasingly involve active comparator designs, and this together with some technical issues has meant difficulties in differentiating structural progression using traditional radiographic outcome measures. Magnetic resonance imaging (MRI) has been demonstrated to assess damage more sensitively than radiographs, but importantly it can measure the upstream drivers of erosions and cartilage loss, synovitis and osteitis. An increasing number of recent RCTs using the RA MRI scoring system (RAMRIS) have demonstrated the ability of MRI to discriminate progression and treatment effect. Consistency of erosion progression determination was seen across the majority of these studies. In most studies, MRI demonstrated reduction in synovitis and osteitis at early (12 week) timepoints, and MRI predicted subsequent radiographic findings. Often small numbers of patients were required to demonstrate such changes. The time is right for regulatory authorities to include MRI as an alternative to radiographic data in support of claims of inhibition of progression of structural damage in RA trials.
The Fabry Cardiomyopathy: Models for the Cardiologist
Authors: Frank Weidemann, Markus Niemann, David G. Warnock, Georg Ertl, Christoph Wanner
Journal: Annual Review of Medicine (2011)

Fabry disease is an X-linked lysosomal storage disorder caused by α-galactosidase A deficiency. Intracellular accumulation of globotriaosylceramide starts in utero and progressively develops in various tissues and organs. Cardiac involvement is frequent, and its presentation as concentric nonobstructive left ventricular hypertrophy serves as a model for other hypertrophic cardiomyopathies. This review describes the Fabry cardiomyopathy, its treatment, and multidisciplinary patient care models. These models will help clinicians in diagnosing, assessing, and treating patients with Fabry disease. As the models can be extrapolated to other diseases, they might contribute to more optimal clinical management of patients with other cardiac disorders.