tbuckley/cabot-search huggingface dataset:
New pathological findings in emphysema of childhood: 1. Polyalveolar lobe with emphysema
Authors: A. Hislop, L. Reid
Journal: Thorax (1970)

A new pathological entity is here described—a polyalveolar lobe with or without emphysema—giving rise to the clinical features of childhood lobar emphysema. A detailed and quantitative study of the airways, alveoli and arteries was carried out on the left upper lobe removed because of shortness of breath, thought to be due to `childhood lobar emphysema9. The child was 17 days old and the radiograph showed hypertransradiancy of the left lung. The alveolar number was increased five-fold. Alveolar size was normal, so it was found that emphysema, accepted today as a structural diagnosis, was not present. The increase in alveolar number seemed confined to the apical, posterior, and anterior segments, the lingula being unaffected. By contrast, the airways and arteries were normal for age in number, size and structure, suggesting that the condition was a `giantism9 of the alveolar region. The blood flow was probably too low for the lobar volume; certainly the excessive alveolar number could not be due to increase in blood flow. In two further specimens, previously dissected, a similar polyalveolar condition was found, associated with emphysema. The patients were older at the time of surgical resection and the emphysema may have developed post-natally. In all three cases the radiographic features had suggested emphysema. It is suggested that the condition be called `polyalveolar lobe9, `with emphysema9 or `without emphysema9 being added as a separate item to the description.
MicroRNA-144 Regulates Hepatic ATP Binding Cassette Transporter A1 and Plasma High-Density Lipoprotein After Activation of the Nuclear Receptor Farnesoid X Receptor
Authors: Thomas Q. de Aguiar Vallim, Elizabeth J. Tarling, Tammy Kim, Mete Civelek, Ángel Baldán, Christine Esau, Peter A. Edwards
Journal: Circulation Research (2013)

Rationale: The bile acid receptor farnesoid X receptor (FXR) regulates many aspects of lipid metabolism by variouscomplex and incompletely understood molecular mechanisms. We set out to investigate the molecular mechanisms for FXR-dependent regulation of lipid and lipoprotein metabolism. Objective: To identify FXR-regulated microRNAs that were subsequently involved in regulating lipid metabolism. Methods and Results: ATP binding cassette transporter A1 (ABCA1) is a major determinant of plasma high-density lipoprotein (HDL)-cholesterol levels. Here, we show that activation of the nuclear receptor FXR in vivo increases hepatic levels of miR-144, which in turn lowers hepatic ABCA1 and plasma HDL levels. We identified 2 complementary sequences to miR-144 in the 3′ untranslated region of ABCA1 mRNA that are necessary for miR-144–dependent regulation. Overexpression of miR-144 in vitro decreased both cellular ABCA1 protein and cholesterol efflux to lipid-poor apolipoprotein A-I protein, whereas overexpression in vivo reduced hepatic ABCA1 protein and plasma HDL-cholesterol. Conversely, silencing miR-144 in mice increased hepatic ABCA1 protein and HDL-cholesterol. In addition, we used tissue-specific FXR-deficient mice to show that induction of miR-144 and FXR-dependent hypolipidemia requires hepatic, but not intestinal, FXR. Finally, we identified functional FXR response elements upstream of the miR-144 locus, consistent with direct FXR regulation. Conclusions: We have identified a novel pathway involving FXR, miR-144, and ABCA1 that together regulate plasma HDL-cholesterol.
Targeting heat shock protein 90 with non-quinone inhibitors: A novel chemotherapeutic approach in human hepatocellular carcinoma
Authors: Marco Breinig, Eloisi Caldas-Lopes, Benjamin Goeppert, Mona Malz, Ralf Rieker, Frank Bergmann, Peter Schirmacher, Matthias Mayer, Gabriela Chiosis, Michael André Kern
Journal: Hepatology (2009)

Abstract The inhibition of heat shock protein 90 (Hsp90) has emerged as a promising antineoplastic strategy in diverse human malignancies. Hsp90 has been predicted to be involved in hepatocellular carcinoma (HCC) development; however, its role in hepatocarcinogenesis remains elusive. Using chemically distinctive Hsp90 inhibitors, we show that Hsp90 capacitates the aberrant expression and activity of crucial hepatocarcinogenesis-driving factors (e.g., insulin-like growth factor receptor 1, hepatocyte growth factor receptor, protein kinase B, v-raf-1 murine leukemia viral oncogene homolog 1, and cyclin-dependent kinase 4). In vitro , Hsp90 inhibition with both geldanamycin analogs (17-allylamino-17-desmethoxygeldanamycin (17-AAG) and 17-dimethylaminoethylamino-17-desmethoxygeldanamycin (17-DMAG)) and the non-quinone compound 8-(6-iodobenzo[d][1,3]dioxol-5-ylthio)-9-(3-(isopropylamino)propyl)-9H-purin-6-amine (PU-H71) reduced the viability of various HCC cell lines, induced the simultaneous degradation of numerous hepatocarcinogenic factors, and caused substantial cell cycle arrest and apoptosis. In contrast, nontumorigenic hepatocytes were less susceptible to Hsp90 inhibition. Because conventional geldanamycin-derivate Hsp90 inhibitors induce dose-limiting liver toxicity, we tested whether novel Hsp90 inhibitors lacking the benzoquinone moiety, which has been deemed responsible for hepatotoxicity, can elicit antineoplastic activity without causing significant liver damage. In HCC xenograft mouse models, PU-H71 was retained in tumors at pharmacologically relevant concentrations while being rapidly cleared from nontumorous liver. PU-H71 showed potent and prolonged in vivo Hsp90 inhibitory activity and reduced tumor growth without causing toxicity. Conclusion: Hsp90 constitutes a promising therapeutic target in HCC. Non-quinone Hsp90 inhibitors exhibit tumor-specific accumulation and exert potent antineoplastic activity without causing significant hepatotoxicity. (Hepatology 2009.)
Pathophysiological mechanisms of Brugada syndrome: Depolarization disorder, repolarization disorder, or more?
Authors: P MEREGALLI, A WILDE, H TAN
Journal: Cardiovascular Research (2005)

After its recognition as a distinct clinical entity, Brugada syndrome is increasingly recognized worldwide as an important cause of sudden cardiac death. Brugada syndrome exhibits autosomal dominant inheritance with SCN5A, which encodes the cardiac sodium channel, as the only gene with a proven involvement in 20–30% of patients. Its signature feature is ST segment elevation in right precordial ECG leads and predisposition to malignant ventricular tachyarrhythmias. The pathophysiological mechanism of ST elevation and ventricular tachyarrhythmia, two phenomena strongly related, is controversial. Here, we review clinical and experimental studies as they provide evidence to support or disprove the two hypotheses on the mechanism of Brugada syndrome that currently receive the widest support: (1) nonuniform abbreviation of right ventricular epicardial action potentials ("repolarization disorder"), (2) conduction delay in the right ventricular outflow tract ("depolarization disorder"). We also propose a schematic representation of the depolarization disorder hypothesis. Moreover, we review recent evidence to suggest that other derangements may also contribute to the pathophysiology of Brugada syndrome, in particular, right ventricular structural derangements.
CONTROLLED TRIAL OF PLASMA EXCHANGE IN ACUTE INFLAMMATORY POLYRADICULONEUROPATHY
Authors: R.J. Greenwood, R.A.C. Hughes, A.N. Bowden, N.S. Gordon, P. Millac, J. Newsom-Davis, S. Aslan, D.W. Chadwick, D.L. Mclellan, R.B. Stott, P. Armitage
Journal: The Lancet (1984)
Role of NO in recovery from neonatal hypoxic pulmonary hypertension
Authors: R M R Tulloh, A A Hislop, S G Haworth
Journal: Thorax (1999)

<h3>BACKGROUND</h3> The management of sick newborn infants who have sustained a hypoxic insult is a common clinical problem but relatively little is known about the recovery process. The aim of this study was to investigate this process in newborn piglets. <h3>METHODS</h3> Thirty five newborn piglets were exposed to chronic hypobaric hypoxia for three days, either from birth, three or 14 days of age, and were allowed to recover for one, three, or six days. Control animals of relevant age were also studied. The heart weight ratio and pulmonary arterial muscularity were measured. Endothelial dependent and independent relaxation of the isolated intrapulmonary conduit arteries was determined in classical organ chamber studies, together with measurement of basal and stimulated cGMP accumulation. <h3>RESULTS</h3> After six days of recovery the hypoxia induced right ventricular hypertrophy and pulmonary arterial medial hypertrophy had decreased in all animals but values were still abnormal in the two younger age groups. Relaxation was still impaired during the first three days of recovery in all groups, had normalised by six days in the two youngest groups, but relaxation (both endothelium dependent and independent) remained impaired in older animals. In these older animals basal nitric oxide (NO) production and basal and stimulated cGMP accumulation was normal. <h3>CONCLUSIONS</h3> The recovery of the smooth muscle cells lags behind that of the endothelial cells. A normal stimulated increase in cGMP with reduced relaxation suggests an altered threshold for cGMP effected relaxation. These findings help to explain why some hypoxic infants require protracted NO therapy.
Improved analytical methods for microarray-based genome-composition analysis
Authors: Charles C Kim, Elizabeth A Joyce, Kaman Chan, Stanley Falkow
Journal: Genome biology (2002)

Whereas genome sequencing has given us high-resolution pictures of many different species of bacteria, microarrays provide a means of obtaining information on genome composition for many strains of a given species. Genome-composition analysis using microarrays, or 'genomotyping', can be used to categorize genes into 'present' and 'divergent' categories based on the level of hybridization signal. This typically involves selecting a signal value that is used as a cutoff to discriminate present (high signal) and divergent (low signal) genes. Current methodology uses empirical determination of cutoffs for classification into these categories, but this methodology is subject to several problems that can result in the misclassification of many genes. We describe a method that depends on the shape of the signal-ratio distribution and does not require empirical determination of a cutoff. Moreover, the cutoff is determined on an array-to-array basis, accounting for variation in strain composition and hybridization quality. The algorithm also provides an estimate of the probability that any given gene is present, which provides a measure of confidence in the categorical assignments. Many genes previously classified as present using static methods are in fact divergent on the basis of microarray signal; this is corrected by our algorithm. We have reassigned hundreds of genes from previous genomotyping studies of Helicobacter pylori and Campylobacter jejuni strains, and expect that the algorithm should be widely applicable to genomotyping data.
The classification of systemic mastocytosis should include mast cell leukemia (MCL) and systemic mastocytosis with a clonal hematologic non–mast cell lineage disease (SM-AHNMD)
Authors: Peter Valent, Michel Arock, Cem Akin, Wolfgang R. Sperr, Andreas Reiter, Karl Sotlar, Karin Hartmann, Tracy I. George, Knut Brockow, Hanneke C. Kluin-Nelemans, Jason Gotlib, Dean D. Metcalfe, Hans-Peter Horny
Journal: Blood (2010)
PWE-093 The NHS bowel cancer screening programme, Southern Hub—screening activity and outcomes
Authors: H Seaman, M Young, S Halloran
Journal: Gut (2012)

<h3>Introduction</h3> As part of the NHS Bowel Cancer Screening Programme (BCSP) in England, every man and woman registered with a GP, living in England and aged 60–74 years, is invited to take part in screening every 2 years. The BCSP Southern Hub, hosted by the Royal Surrey County Hospital and one of five Hubs in England, serves a total population of about 14.4 million people and manages the screening activity in the south of England (excluding London). The Southern Hub handles nearly one million gFOB test kits every year. Here we provide a high-level overview of screening activity and outcomes for the Southern Hub since the Programme9s launch in 2006. <h3>Methods</h3> Screening invitees are sent a guaiac-based faecal occult blood (gFOB) test kit and asked to provide a faecal sample. Test kits are returned to the Hub for analysis. Participants with a positive (“abnormal”) test are referred to a Specialist Screening Practitioner (SSP) for further assessment and investigation (usually colonoscopy) at one of 17 Screening Centres. All screening activity, including invitation uptake, gFOB test results, SSP referrals and colonoscopy outcomes are stored on a dedicated database—the Bowel Cancer Screening System (BCSS). The BCSS provides a rich source of data for observational analysis. <h3>Results</h3> The uptake of screening invitations (the proportion of invitees that was adequately screened) is approximately 56% overall. Uptake is generally higher for women (61% vs 55%), although improves with age in men. The proportion of positive test kits (“positivity”) is higher for men (2.6%) than for women (1.6%) at all ages. The number of colonoscopies performed at the Screening Centres has increased over time. About 40% of the screened population that tests positive and undergoes colonoscopy has significant neoplasia (cancer, high- or intermediate-risk adenomas). The prevalence of significant neoplasia is greater in men and increases with age. The proportion of significant neoplasia detected in screening episode 2 is lower than in episode 1, reflecting successful detection of lesions in the first episode. <h3>Conclusion</h3> The BCSS data are encouraging and indicate that the BCSP in England is likely to achieve its goal of reducing mortality from bowel cancer. <h3>Competing interests</h3> None declared.
Modeling the Cost of Management Options for Stage I Nonseminomatous Germ Cell Tumors: A Decision Tree Analysis
Authors: Richard E. Link, Mohamad E. Allaf, Roberto Pili, Louis R. Kavoussi
Journal: Journal of Clinical Oncology (2005)

Patients with clinical stage I nonseminomatous germ cell tumors (NSGCTs) have been managed with surveillance, chemotherapy, or retroperitoneal lymphadenectomy (RPLND) with similar survival outcomes. Cost factors influencing the choice of therapy were evaluated using computer-based decision analysis.A detailed model was developed that integrates projected costs for more than 60 possible treatment outcomes. It incorporates primary, adjuvant, and salvage chemotherapy, primary and post-chemotherapy RPLND, and both laparoscopic and open surgical approaches. Starting values and probabilities were derived from a comprehensive meta-analysis of the last 25 years of testes cancer literature. Hypothesis testing was performed using sensitivity analysis.The model predicts a cost premium for both primary chemotherapy (18.7%) and RPLND (51.7%) compared with surveillance. If laparoscopic RPLND was practiced, the cost premium for primary surgery (29.1%) approached that of chemotherapy (26.4%). Open RPLND was 1.25x as costly as laparoscopic RPLND, primarily because of longer hospitalization. The choice of open RPLND yielded a 6.9% cost premium for a surveillance program in this model. For such a program, primary chemotherapy became cost advantageous when the probability of recurrence during surveillance was more than 46%.This model allows a variety of treatment cost hypotheses to be tested. Primary RPLND is never cost advantageous over surveillance or primary chemotherapy. Surgical costs can significantly increase the overall cost of a surveillance program. In stage I patients with high-risk tumor characteristics, primary chemotherapy may have a cost advantage over surveillance.
Further Evidence that Exclusive Breast-Feeding Reduces Mother-to-Child HIV Transmission Compared With Mixed Feeding
Authors: Mary Glenn Fowler
Journal: PLoS Medicine (2008)

The critical role of breast-feeding in improving infant and under-five-year survival in resource-limited settings has been well documented since the mid-1970s. A pooled analysis by the World Health Organization (WHO) of a number of studies on the impact of breast-feeding on child survival showed that the protective effect is strongest in the first six months of life, with a 4–6-fold survival benefit for breast-fed infants [1]. The benefit extends throughout the first year of life, with a 1.4–1.8-fold protective effect against mortality during months six through twelve [1].
The generation of killer cells to trinitrophenyl-modified allogeneic targets by lymphocyte populations negatively selected to strong alloantigens.
Authors: D B Wilson, K F Lindahl, D H Wilson, J Sprent
Journal: The Journal of Experimental Medicine (1977)

Negatively selected mouse and rat lymphocyte populations, specifically deprived of alloreactivity to a particular major histocompatibility complex (MHC) haplotype, are nevertheless fully capable of responding to trinitrophenyl (TNP)-modified allogeneic stimulator cells and developing cytotoxic T-lymphocyte activity to TNP-altered allogeneic target cells. As for syngeneic systems, lytic expression of those responder killer cells also requires MHC identity between the target and stimulator cell populations. Such a finding argues strongly against two variations of the dual recognition hypothesis: like-like interactions and adaptive differentiation. Instead, these data favor either the altered self model or a third variation of the dual receptor model, where one of the relevent receptors is specific for the modifying antigen and the second is a low affinity receptor unable to be triggered in the absence of a modifying antigen.
Effect of chest wall vibration on the canine diaphragm during breathing
Authors: D. Leduc, A. De Troyer
Journal: European Respiratory Journal (2002)

High-frequency mechanical vibration of the ribcage reduces dyspnoea in patients with chronic obstructive pulmonary disease, and the suggestion has been made that this effect might be related to a decrease in central respiratory drive resulting from an increase in afferent inputs from intercostal muscles. In the present studies, the effects of ribcage vibration on central respiratory drive have been assessed without the confounding influence of conscious reactions. The electromyographic (EMG) activity of the diaphragm and the changes in pleural ( P pl ) and abdominal ( P ab ) pressure were measured in six anaesthetized, spontaneously-breathing dogs while the rostral, the middle, or the caudal portion of the ribcage was vibrated at intervals during inspiration. The EMG activity of the external and parasternal intercostals was also measured. Ribcage vibration consistently elicited a marked increase in the inspiratory EMG activity recorded from the external intercostals, thus indicating that the procedure did activate intercostal muscle spindles. However, no alteration in diaphragmatic or parasternal intercostal EMG activity was seen in any animal. Transdiaphragmatic pressure and the relationship between Δ P ab and Δ P pl during inspiration were also unaltered. The authors conclude that ribcage vibration and, with it, stimulation of external intercostal muscle spindles has no significant influence on phrenic motoneurones or on medullary inspiratory neurones. It is unlikely, therefore, that the beneficial effect of the procedure on dyspnoea results from a specific reduction in central respiratory drive.
Mutant Metabolic Enzymes Are at the Origin of Gliomas
Authors: Hai Yan, Darell D. Bigner, Victor Velculescu, D. Williams Parsons
Journal: Cancer Research (2009)

Mutations of the isocitrate dehydrogenase (IDH) metabolic enzymes IDH1 and IDH2 have been found to be frequent and early genetic alterations in astrocytomas and oligodendrogliomas. All mutations identified to date affect a single amino acid located within the isocitrate binding site (R132 of IDH1 and the analogous R172 residue of IDH2). IDH1 and IDH2 mutations define a specific subtype of gliomas and may have significant utility for the diagnosis, prognosis, and treatment of patients with these tumors.
Chest trauma and aetiology of achalasia
Authors: R Penagini
Journal: Gut (2006)

Achalasia is a motility disorder caused by neural dysfunction which may involve both the myenteric plexus of the oesophagus, the vagal nerves, and the dorsal motor nucleus.1,2 The aetiology of the disorder is still obscure, viral infection and autoimmunity having been suggested. Recently, Park and Vaezi1 proposed that different environmental factors in patients with genetic predisposition could lead to the same clinical picture and manometric findings.

As part of an ongoing prospective study in patients with achalasia,3 we have investigated if chest trauma could be involved in the development of achalasia. Twenty consecutive achalasia patients (eight men), …
Simple Method for Removal of Intestinal Tubing from the Stomach
Authors: HERBERT L. DUPONT
Journal: Annals of Internal Medicine (1971)

When intestinal tubing cannot be removed by firm traction on the proximal end, spontaneous passage through the intestinal tract should occur, provided the tube is beyond the stomach. Mistakenly, a double-lumened vinyl tube was sectioned without position verification by roentgenogram, and it coiled in the stomach. The tube remained confined to the stomach for 29 days and was recovered by firm, slow removal of an orally inserted fishing line that was allowed to become entangled with the sampling tube. This approach offers an alternative to esophagoscopy or gastrotomy for removing intestinal tubing from the stomach.
Short-Term Effects of Cannabinoids in Patients with HIV-1 Infection
Authors: Donald I. Abrams, Joan F. Hilton, Roslyn J. Leiser, Starley B. Shade, Tarek A. Elbeik, Francesca T. Aweeka, Neal L. Benowitz, Barry M. Bredt, Bradley Kosel, Judith A. Aberg, Steven G. Deeks, Thomas F. Mitchell, Kathleen Mulligan, Peter Bacchetti, Joseph M. McCune, Morris Schambelan
Journal: Annals of Internal Medicine (2003)

Background: Cannabinoid use could potentially alter HIV RNA levels by two mechanisms: immune modulation or cannabinoidprotease inhibitor interactions (because both share cytochrome P-450 metabolic pathways). Objective: To determine the short-term effects of smoked marijuana on the viral load in HIV-infected patients. Design: Randomized, placebo-controlled, 21-day intervention trial. Setting: The inpatient General Clinical Research Center at the San Francisco General Hospital, San Francisco, California. Participants: 67 patients with HIV-1 infection. Intervention: Participants were randomly assigned to a 3.95%-tetrahydrocannabinol marijuana cigarette, a 2.5-mg dronabinol (delta-9-tetrahydrocannabinol) capsule, or a placebo capsule three times daily before meals. Measurements: HIV RNA levels, CD4+ and CD8+ cell subsets, and pharmacokinetic analyses of the protease inhibitors. Results: 62 study participants were eligible for the primary end point (marijuana group, 20 patients; dronabinol group, 22 patients; and placebo group, 20 patients). Baseline HIV RNA level was less than 50 copies/mL for 36 participants (58%), and the median CD4+ cell count was 340 × 109 cells/L. When adjusted for baseline variables, the estimated average effect versus placebo on change in log10 viral load from baseline to day 21 was 0.07 (95% CI, 0.30 to 0.13) for marijuana and 0.04 (CI, 0.20 to 0.14) for dronabinol. The adjusted average changes in viral load in marijuana and dronabinol relative to placebo were 15% (CI, 50% to 34%) and 8% (CI, 37% to 37%), respectively. Neither CD4+ nor CD8+ cell counts appeared to be adversely affected by the cannabinoids. Conclusions: Smoked and oral cannabinoids did not seem to be unsafe in people with HIV infection with respect to HIV RNA levels, CD4+ and CD8+ cell counts, or protease inhibitor levels over a 21-day treatment.