tbuckley/cabot-search huggingface dataset:
Pathogenesis of tracheal stenosis following tracheostomy with a cuffed tube: An experimental study in dogs
Authors: M. Goldberg, F. G. Pearson
Journal: Thorax (1972)

A study was undertaken to clarify the pathogenesis of tracheal stenosis complicating the use of cuffed tracheostomy tubes, a complication of increasing clinical significance. Tracheostomy with a cuffed inflated tube was established in dogs and was maintained for two weeks. The effects of tracheostomy were assessed by bronchoscopy, tracheography, and histology at the time of killing, eight weeks after extubation. Animals were divided into four groups, each mimicking a common clinical situation. A control group had uncuffed tubes. A method was designed to determine the pressure developed between the cuff and the tracheal wall. Cuff inflation was maintained at low pressure and at high pressure in a second and third group of animals. A fourth group of animals received prednisone during the two weeks of low pressure inflation. Tracheal stenosis, resembling the defect we have encountered in humans, occurred at the tracheostome in all animals. The greater the diameter of the tracheostomy tube relative to the tracheal diameter, the more severe was the resultant stenosis. Greater degrees of tracheal injury occurred with cuffed than with uncuffed tubes, and still greater injury was observed in animals in which high inflationary pressures or steroids were used. These findings suggest that tracheal stenosis complicating cuffed tracheostomy tubes is the result of ischaemic death of tracheal cartilage due to pressure and infection. Steroids used concomitantly accelerate these changes.
Dysfunction of the Epithelial Sodium Channel Expressed in the Kidney of a Mouse Model for Liddle Syndrome
Authors: Sylvain Pradervand, Alain Vandewalle, Marcelle Bens, Ivan Gautschi, Johannes Loffing, Edith Hummler, Laurent Schild, Bernard C. Rossier
Journal: Journal of the American Society of Nephrology (2003)

The Liddle syndrome is a dominant form of salt-sensitive hypertension resulting from mutations in the β or γ subunit of ENaC. A previous study established a mouse model carrying a premature Stop codon corresponding to the R566stop mutation (L) found in the original pedigree that recapitulates to a large extent the human disease. This study investigated the renal Na+ transport in vivo, ex vivo (intact perfused tubules), and in vitro (primary cultured cortical collecting ducts [CCD]). In vivo, upon 6 to 12 h of salt repletion, after 1 week of low-salt diet, the L/L mice showed a delayed urinary sodium excretion, despite a lower aldosterone secretion as compared with controls. After 6 h salt of repletion, ENaC γ subunit is rapidly removed from the apical plasma membrane in wild-type mice, whereas it is retained at the apical membrane in L/L mice. Ex vivo, isolated perfused CCD from L/L mice exhibited higher transepithelial potential differences than perfused CCD isolated from +/+ mice. In vitro, confluent primary cultures of CCD microdissected from L/L kidneys grown on permeable filters exhibited significant lower transepithelial electrical resistance and higher negative potential differences than their cultured L/+ and +/+ CCD counterparts. The equivalent short-circuit current (Ieq) and the amiloride-sensitive Ieq was approximately twofold higher in cultured L/L CCD than in +/+ CCD. Aldosterone (5 × 10−7M for 3 h) further increased Ieq from cultured L/L CCD. Thus, this study brings three independent lines of evidence for the constitutive hyperactivity of ENaC in CCD from mice harboring the Liddle mutation. e-mail: [email protected]
Physiotherapy in Rheumatology
Authors: E. Harvey
Journal: Annals of the Rheumatic Diseases (1982)

Society and no mean intellect and an observant clinician, even he in his Bowman lecture on gout and conditions of the eye confesses, 'I must admit little or no evidence as to deposits of urate of soda in any ocular structures....I doubt if it has been shown even in a single case though several observers have suggested its presence....I trust, however, that we are long past the stage of belief which regards such deposit as essential to a gouty inflammation'.It would seem at this point in time that William Heberden's and A. B. Garrod's observations had fallen on relatively stony ground.Even Sherlock Holmes would have had dif- ficulties in this misty diagnostic jungle, and his creator was merely following up current ideas.
Impaired P2X signalling pathways in renal microvascular myocytes in genetic hypertension
Authors: Dmitri Gordienko, Oleksandr Povstyan, Khrystyna Sukhanova, Maylis Raphaël, Maksym Harhun, Yulia Dyskina, V'yacheslav Lehen'kyi, Abdirahman Jama, Zhi-Liang Lu, Roman Skryma, Natalia Prevarskaya
Journal: Cardiovascular Research (2014)

P2X receptors (P2XRs) mediate sympathetic control and autoregulation of renal circulation triggering preglomerular vasoconstriction, which protects glomeruli from elevated pressures. Although previous studies established a casual link between glomerular susceptibility to hypertensive injury and decreased preglomerular vascular reactivity to P2XR activation, the mechanisms of attenuation of the P2XR signalling in hypertension remained unknown. We aimed to analyse molecular mechanisms of the impairment of P2XR signalling in renal vascular smooth muscle cells (RVSMCs) in genetic hypertension.We compared the expression of pertinent genes and P2XR-linked Ca(2+) entry and Ca(2+) release mechanisms in RVSMCs of spontaneously hypertensive rats (SHRs) and their normotensive controls, Wistar Kyoto (WKY) rats. We found that, in SHR RVSMCs, P2XR-linked Ca(2+) entry and Ca(2+) release from the sarcoplasmic reticulum (SR) are both significantly reduced. The former is due to down-regulation of the P2X1 subunit. The latter is caused by a decrease of the SR Ca(2+) load. The SR Ca(2+) load reduction is caused by attenuated Ca(2+) uptake via down-regulated sarco-/endoplasmic reticulum Ca(2+)-ATPase 2b and elevated Ca(2+) leak from the SR via ryanodine receptors (RyRs) and inositol 1,4,5-trisphosphate receptors. Spontaneous activity of these Ca(2+)-release channels is augmented due to up-regulation of RyR type 2 and elevated IP3 production by up-regulated phospholipase C-β1.Our study unravels the cellular and molecular mechanisms of attenuation of P2XR-mediated preglomerular vasoconstriction that elevates glomerular susceptibility to harmful hypertensive pressures. This provides an important impetus towards understanding of the pathology of hypertensive renal injury.
Various Approaches to Clinically Related Research Can Yield Helpful Insight. A Personal Perspective
Authors: Herbert Y. Reynolds
Journal: American Journal of Respiratory and Critical Care Medicine (2013)

Attending two recent meetings (the joint American Physician Scientists Association, American Society of Clinical Investigation, and Association of American Physicians meeting and the American Thoracic Society meeting) and listening to state of the art presentations, viewing research posters, and interacting with young scientists about so much new and exciting human research rekindled my thoughts about how one could now begin research. For me this occurred, with excellent mentoring and supervision, as first a descriptive “looking” approach to identify host immunity components in a variety of animal models and then manipulating these models to mimic disease processes, focusing on the respiratory tract and innate immunity. Next, we moved to characterize these host immunity components in normal humans, before applying these to in vitro and clinical illness situations for patients. The intent of this research sequence was to better describe and manipulate immunopathology relevant to disease. A bench-to-patient approach, mostly descriptive and “looking,” was the path. I have illustrated these steps with applicable references. Now seems such a crucial time to further scientific knowledge and to foster personalized medicine, despite a period of financial restraint. We need discussion of ways to best approach “looking” for still unknown basic information about the human respiratory system. Two special examples are identifying the still unknown cells in human lung tissue and their functions and manipulating the extensive respiratory microbiome.
High-Resolution Array-Based Comparative Genomic Hybridization of Bladder Cancers Identifies <i>Mouse Double Minute 4</i> (<i>MDM4</i>) as an Amplification Target Exclusive of <i>MDM2</i> and <i>TP53</i>
Authors: Abhi Veerakumarasivam, Helen E. Scott, Suet-Feung Chin, Anne Warren, Matthew J. Wallard, Donna Grimmer, Koichi Ichimura, Carlos Caldas, V. Peter Collins, David E. Neal, John D. Kelly
Journal: Clinical Cancer Research (2008)

Loss of p53 function in urothelial cell carcinoma (UCC) by mutation or inactivation disrupts normal cell cycle checkpoints, generating a favorable milieu for genomic instability, a hallmark of UCC. The aim of this study was to characterize novel DNA copy number changes to identify putative therapeutic targets.We report our findings using array comparative genomic hybridization on a whole-genome BAC/PAC/cosmid array with a median clone interval of 0.97 Mb to study a series of UCC cases. TP53 status was determined by direct sequencing, and an in-house tissue microarray was constructed to identify protein expression of target genes.Array comparative genomic hybridization allowed identification of novel regions of copy number changes in addition to those already known from previous studies. A novel amplification previously unreported in UCC was identified at 1q32. A chromosome 1 tile path array was used to analyze tumors that showed gains and amplification; the mouse double minute 4 (MDM4) homologue was identified as the amplified gene. MDM4 mRNA expression correlated with copy number and tumor grade. Copy number changes of MDM4 and MDM2 occurred exclusively in tumors with wild-type p53. Overexpression of MDM4 corresponded to disruption of p53 transcriptional activity. Immunohistochemistry on an independent series by tissue microarray identified an inverse relationship between Mdm4 and Mdm2, with Mdm4 expression highest in invasive UCC.The data indicate that gain/amplification and overexpression of MDM4 is a novel molecular mechanism by which a subset of UCC escapes p53-dependent growth control, thus providing new avenues for therapeutic intervention.
Dual mTORC2/mTORC1 Targeting Results in Potent Suppressive Effects on Acute Myeloid Leukemia (AML) Progenitors
Authors: Jessica K. Altman, Antonella Sassano, Surinder Kaur, Heather Glaser, Barbara Kroczynska, Amanda J. Redig, Suzanne Russo, Sharon Barr, Leonidas C. Platanias
Journal: Clinical Cancer Research (2011)

To determine whether mTORC2 and rapamycin-insensitive (RI)-mTORC1 complexes are present in acute myeloid leukemia (AML) cells and to examine the effects of dual mTORC2/mTORC1 inhibition on primitive AML leukemic progenitors.Combinations of different experimental approaches were used, including immunoblotting to detect phosphorylated/activated forms of elements of the mTOR pathway in leukemic cell lines and primary AML blasts; cell-proliferation assays; direct assessment of mRNA translation in polysomal fractions of leukemic cells; and clonogenic assays in methylcellulose to evaluate leukemic progenitor-colony formation.mTORC2 complexes are active in AML cells and play critical roles in leukemogenesis. RI-mTORC1 complexes are also formed and regulate the activity of the translational repressor 4E-BP1 in AML cells. OSI-027 blocks mTORC1 and mTORC2 activities and suppresses mRNA translation of cyclin D1 and other genes that mediate proliferative responses in AML cells. Moreover, OSI-027 acts as a potent suppressor of primitive leukemic precursors from AML patients and is much more effective than rapamycin in eliciting antileukemic effects in vitro.Dual targeting of mTORC2 and mTORC1 results in potent suppressive effects on primitive leukemic progenitors from AML patients. Inhibition of the mTOR catalytic site with OSI-027 results in suppression of both mTORC2 and RI-mTORC1 complexes and elicits much more potent antileukemic responses than selective mTORC1 targeting with rapamycin.
Neural Representation and the Cortical Code
Authors: R. Christopher deCharms, Anthony Zador
Journal: Annual Review of Neuroscience (2000)

The principle function of the central nervous system is to represent and transform information and thereby mediate appropriate decisions and behaviors. The cerebral cortex is one of the primary seats of the internal representations maintained and used in perception, memory, decision making, motor control, and subjective experience, but the basic coding scheme by which this information is carried and transformed by neurons is not yet fully understood. This article defines and reviews how information is represented in the firing rates and temporal patterns of populations of cortical neurons, with a particular emphasis on how this information mediates behavior and experience.
Mood-Incongruent Psychotic Features in Bipolar Disorder: Familial Aggregation and Suggestive Linkage to 2p11-q14 and 13q21-33
Authors: Fernando S. Goes, Peter P. Zandi, Kuangyi Miao, Francis J. McMahon, Jo Steele, Virginia L. Willour, Dean F. MacKinnon, Francis M. Mondimore, Barbara Schweizer, John I. Nurnberger, John P. Rice, William Scheftner, William Coryell, Wade H. Berrettini, John R. Kelsoe, William Byerley, Dennis L. Murphy, Elliot S. Gershon, None Bipolar Disorder Phenome Group, J. Raymond DePaulo, Melvin G. McInnis, James B. Potash
Journal: American Journal of Psychiatry (2007)

Objective: Mood-incongruent psychotic features in bipolar disorder may signify a more severe form of the illness and might represent phenotypic manifestations of susceptibility genes shared with schizophrenia. This study attempts to characterize clinical correlates, familial aggregation, and genetic linkage in subjects with these features. Method: Subjects were drawn from The National Institute of Mental Health (NIMH) Genetics Initiative Bipolar Disorder Collaborative cohort, consisting of 708 families recruited at 10 academic medical centers. Subjects with mood-incongruent and mood-congruent psychotic features were compared on clinical variables. Familial aggregation was tested using a proband-predictive model and generalized estimating equations. A genome-wide linkage scan incorporating a mood-incongruence covariate was performed. Results: Mood-incongruent psychotic features were associated with an increased rate of hospitalization and attempted suicide. A proband with mood-incongruence predicted mood-incongruence in relatives with bipolar I disorder when compared with all other subjects and when compared with subjects with mood-congruent psychosis. The presence of mood-incongruent psychotic features increased evidence for linkage on chromosomes 13q21-33 and 2p11-q14. These logarithm of the odds ratio (LOD) scores and their increase from baseline met empirical genome-wide suggestive criteria for significance. Conclusions: Mood-incongruent psychotic features showed evidence of a more severe course, familial aggregation, and suggestive linkage to two chromosomal regions previously implicated in major mental illness susceptibility. The 13q21-33 finding supports prior evidence of bipolar disorder/schizophrenia overlap in this region, while the 2p11-q14 finding is, to the authors' knowledge, the first to suggest that this schizophrenia linkage region might also harbor a bipolar disorder susceptibility gene.
Effects of Dietary N-(4-Hydroxyphenyl)retinamide on N-Nitrosomethylbenzylamine Metabolism and Esophageal Tumorigenesis in the Fischer 344 Rat
Authors: A. Gupta, R. Nines, K. A. Rodrigo, R. A. Aziz, P. S. Carlton, D. L. Gray, V. E. Steele, M. A. Morse, G. D. Stoner
Journal: JNCI Journal of the National Cancer Institute (2001)

Background: 9-cis-Retinoic acid (9-cis-RA) and N-(4-hydroxyphenyl)retinamide (4-HPR) are effective chemopreventive agents against epithelial tumors in the oral cavity, breast, and prostate. We tested the inhibitory activity of these retinoids against N-nitrosomethylbenzylamine (NMBA)-induced tumorigenesis in the rat esophagus. Methods: Male Fischer 344 rats were randomly assigned to receive diets either lacking or containing 9-cis-RA or 4-HPR for 1 week before tumor initiation with NMBA and then for the duration of the study. NMBA metabolism, O6-methylguanine adduct formation, and cytochrome P450 messenger RNA (mRNA) expression in the esophagi of the rats were studied to investigate the mechanisms by which dietary 4-HPR affects tumorigenesis. All statistical tests were two-sided. Results: Dietary 4-HPR resulted in a dose-dependent and statistically significant enhancement (P<.05) of tumorigenesis in response to NMBA. In two different tumor bioassays, the mean tumor multiplicity for rats fed the highest concentration of dietary 4-HPR (0.8 g/kg diet) was increased by 5.9 tumors (95% confidence interval [CI] = 1.7 to 10.1 tumors) and 6.7 tumors (95% CI = 5.6 to 7.8 tumors) compared with the mean tumor multiplicity for rats that received the control diet lacking 4-HPR. Animals fed diets containing 9-cis-RA displayed no statistically significant increase in tumorigenesis. Compared with animals fed a diet lacking 4-HPR, animals fed 4-HPR had increased NMBA metabolism in esophageal explant cultures and had higher levels of O6-methylguanine DNA adducts and CYP2A3 mRNA in their esophagi. Conclusions: Dietary 4-HPR enhances tumorigenesis in response to NMBA in the rat esophagus by increasing tumor initiation events. Dietary 4-HPR may exert paradoxical effects at some sites, such as the aerodigestive tract, by modulating the bioactivation of carcinogens in target tissues.
Surveillance of microbial resistance in European Intensive Care Units: a first report from the Care-ICU programme for improved infection control
Authors: Håkan Hanberger, Dilek Arman, Hans Gill, Vlastimil Jindrák, Smilja Kalenic, Andrea Kurcz, Monica Licker, Paul Naaber, Elizabeth A. Scicluna, Václav Vanis, Sten M. Walther
Journal: Intensive Care Medicine (2008)
Novel HSP90 Inhibitor NVP-HSP990 Targets Cell-Cycle Regulators to Ablate Olig2-Positive Glioma Tumor–Initiating Cells
Authors: Jun Fu, Dimpy Koul, Jun Yao, Shuzhen Wang, Ying Yuan, Howard Colman, Erik. P. Sulman, Frederick. F. Lang, W.K. Alfred Yung
Journal: Cancer Research (2013)

Abstract Genetic heterogeneity and signaling alterations diminish the effectiveness of single-agent therapies in glioblastoma multiforme (GBM). HSP90 is a molecular chaperone for several signaling proteins that are deregulated in glioma cells. Thus, HSP90 inhibition may offer an approach to coordinately correct multiple signaling pathways as a strategy for GBM therapy. In this study, we evaluated the effects of a novel HSP90 inhibitor, NVP-HSP990, in glioma tumor–initiating cell (GIC) populations, which are strongly implicated in the root pathobiology of GBM. In GIC cultures, NVP-HSP990 elicited a dose-dependent growth inhibition with IC50 values in the low nanomolar range. Two GIC subgroups with different responses were observed with an Olig2-expressing subset relatively more sensitive to treatment. We also showed that Olig2 is a functional marker associated with cell proliferation and response to NVP-HSP990, as NVP-HSP990 attenuated cell proliferation in Olig2-high GIC lines. In addition, NVP-HSP990 disrupted cell-cycle control mechanism by decreasing CDK2 and CDK4 and elevating apoptosis-related molecules. Mechanistic investigations revealed molecular interactions between CDK2/CDK4 and Olig2. Inhibition of CDK2/CDK4 activity disrupted Olig2–CDK2/CDK4 interactions and attenuated Olig2 protein stability. In vivo evaluation showed a relative prolongation of median survival in an intracranial model of GIC growth. Our results suggest that GBM characterized by high-expressing Olig2 GIC may exhibit greater sensitivity to NVP-HSP990 treatment, establishing a foundation for further investigation of the role of HSP90 signaling in GBM. Cancer Res; 73(10); 3062–74. ©2013 AACR.
Effect of urbanisation on asthma, allergy and airways inflammation in a developing country setting
Authors: C. L. Robinson, L. M. Baumann, K. Romero, J. M. Combe, A. Gomez, R. H. Gilman, L. Cabrera, G. Gonzalvez, N. N. Hansel, R. A. Wise, K. C. Barnes, P. N. Breysse, W. Checkley
Journal: Thorax (2011)

<h3>Background</h3> Asthma is a growing public health problem in developing countries. However, few studies have studied the role of urbanisation in this phenomenon. It was hypothesised that children living in a peri-urban setting in Peru have higher rates of asthma and allergy than rural counterparts. <h3>Methods</h3> 1441 adolescents aged 13–15 years were enrolled from two settings: a peri-urban shanty town in Lima (n=725) and 23 rural villages in Tumbes (n=716). Participants filled in questionnaires on asthma and allergy symptoms, environmental exposures and sociodemographics, and underwent spirometry, and exhaled nitric oxide (eNO) and allergy skin testing. Indoor particulate matter (PM) concentrations were measured in 170 households. <h3>Results</h3> Lima adolescents had higher rates of lifetime wheezing (22% vs 10%), current asthma symptoms (12% vs 3%) and physician-diagnosed asthma (13% vs 2%; all p &lt;0.001). Current rhinitis (23% vs 12%), eczema (12% vs 0.4%), atopy (56% vs 38%), personal history of cigarette smoking (7.4% vs 1.3%) and mean indoor PM (31 vs 13 μg/m<sup>3</sup>) were also higher in Lima (all p &lt;0.001). The peri-urban environment of Lima was associated with a 2.6-fold greater odds (95% CI 1.3 to 5.3) of asthma in multivariable regression. Forced expiratory volumes were higher and FEV<sub>1</sub>/FVC (forced expiratory volume in 1 s/forced vital capacity) ratios were lower in Lima (all p &lt;0.001). Higher eNO values in Lima (p &lt;0.001) were attributable to higher rates of asthma and atopy. <h3>Conclusions</h3> Peri-urban adolescents had more asthma, atopy and airways inflammation and were exposed to more indoor pollution. The findings provide evidence of the risks posed to lung health by peri-urban environments in developing countries.
The genetic basis for elite running performance
Authors: Ross Tucker, Jordan Santos-Concejero, Malcolm Collins
Journal: British Journal of Sports Medicine (2013)

The dominance of East African distance runners and sprinters of West African origin invites discussion around the contribution of genetic and lifestyle factors to performance. In this review, we focus on the genetic basis for performance. Previous research associating candidate genes such as ACE and ACTN3 to endurance and sprint performance in Caucasian populations has not been replicated in African populations. This may be influenced by numerous factors, including small sample sizes, comparisons across different ethnic populations and problems identifying appropriate control groups. Conceptually, these failures reveal the complex polygenic nature of physiology and performance, and the erroneous application of a candidate gene approach to more genetically diverse African populations. We argue that research has in fact established a role for genes in performance, and that the frequency, rather than the prevalence, of favourable genetic variants within certain populations may account for the performance dominance in these populations.
8-hydroxy-2′-deoxyguanosine (OHdG) DNA adduct formation is correlated to the inflammatory infiltration in hepatocellular carcinoma (HCC) and peritumor tissue
Authors: C. Jüngst, R. Gehrke, P. Schirmacher, P. Schramel, U. Grützner, V. Schmitz, J. Ramakers, T. Sauerbruch, W.H. Caselmann
Journal: Journal of Hepatology (1998)