tbuckley/cabot-search huggingface dataset:
Ambulatory management of primary spontaneous pneumothorax: the good is (not always) the enemy of the better (evidence)
Authors: Arschang Valipour
Journal: European Respiratory Journal (2014)

Pneumothorax is defined as the presence of air in the pleural cavity. A pneumothorax might occur spontaneously in patients without underlying lung disease (primary spontaneous pneumothorax (PSP)) or in patients with an underlying lung disease (secondary spontaneous pneumothorax), most commonly chronic obstructive pulmonary disease. The underlying cause of spontaneous pneumothorax is likely to be the rupture of “emphysema-like changes” (small bullae or blebs) on the pleural surface, which allows air from the lung into the pleural space. Smoking, male sex and height are the major risk factors for the development of a PSP. There is evidence of a pleural inflammatory reaction in patients with PSP, involving an increase in eosinophils and neutrophils as well as elevated inflammatory cytokines compared with blood levels [1].

From an epidemiological point of view, PSP remains a significant health problem, with an annual incidence of 18–28 per 100 000 in males and 1.2–6.0 per 100 000 in females [2, 3]. Primary therapeutic goals for PSP include removal of air from the pleural space and prevention of recurrences. Air evacuation may be achieved by simple manual needle aspiration, by a small bore tube or a conventional chest tube, the tubes being attached to a one-way valve or to a water-seal device, with or without active suctioning [4].

The treatment of PSP would lend itself well to ambulatory management, since patients are usually young, without relevant comorbidities, and the condition itself caries a low morbidity and mortality [5]. Furthermore, outpatient-orientated treatment rather than hospitalisation might be favoured by many patients and would substantially reduce health-cost expenses. Unfortunately, however, the adherence to recommendations of outpatient management of patients with PSP in clinical practice is rather low [5, 6]. The lack …
Comparison of Pharmacokinetics and Dynamics of the Long-Acting Insulin Analogs Glargine and Detemir at Steady State in Type 1 Diabetes: a Double-Blind, Randomized, Crossover Study
Authors: Salomon Banarer
Journal: Diabetes Care (2008)

I congratulate Porcellati et al. (1) for a long-awaited comparison of glargine and detemir pharmacodynamics. They clearly show that the duration of action for glargine (but not detemir) is greater than 24 h.

One of the major differences can be seen in the glucose infusion rate (GIR). At 12 h postinjection, glargine has higher area under the curve (AUC) GIR remaining (42 vs. 15%). The presence of GIR, a marker of insulin-mediated glucose disposal, proves the longer pharmacodynamic effect of glargine.

Even so, the report of the insulin activity profile is confusing. The authors state …
Transfection of a glycosylated phosphatidylinositol-anchored folate-binding protein complementary DNA provides cells with the ability to survive in low folate medium.
Authors: C A Luhrs, C A Raskin, R Durbin, B Wu, E Sadasivan, W McAllister, S P Rothenberg
Journal: Journal of Clinical Investigation (1992)

KB cells express a folate-binding protein that is anchored to the plasma membrane by a glycosylated phosphatidylinositol (GPI) tail and these cells can grow in medium containing a very low folate concentration (1 nM). In contrast, mouse 3T3 cells do not express a membrane-associated folate-binding protein and cannot grow under similar low folate conditions. In these studies, 3T3 cells were transfected with a vector containing the cDNA that codes for the KB cell folate-binding protein. In contrast to the wild-type 3T3 cells, the transfected 3T3 cells express a level of folate-binding protein similar to KB cells, 1 and 1.4 ng/micrograms protein, respectively. The capacity for binding [3H] folate to the surface of transfected 3T3 cells cultured in folate-deficient medium is 7.7 pmol/10(6) cells, and this is approximately 50% of the surface binding capacity of KG cells under similar culture conditions. Moreover, after treatment of the transfected 3T3 cells with phospholipase C specific for phosphatidylinositol, the binding of [3H] folate to the surface of these cells is reduced by 90%, indicating that, like the KB cells, the folate-binding protein is anchored to the plasma membrane by a GPI tail. Although the doubling time of wild-type 3T3 cells markedly increases after 13 d of culture in folate-deficient medium, the doubling time of both the transfected 3T3 cells and KB cells do not change. The results of these experiments indicate that the GPI-anchored folate-binding protein provides a mechanism to maintain a level of folate that permits the folate-dependent metabolic functions necessary for cell survival under low folate conditions.
The perils of locomotion
Authors: Heather L. Van Epps
Journal: The Journal of Experimental Medicine (2006)

The protein that keeps the Legionnaires' disease bacterium in motion also causes its demise, according to a study on page 1093. Molofsky and colleagues show that bacterial flagellin, which leaks out of phagosomal pores in infected mouse cells, triggers bacterial degradation and cell death.






Figure 1

Legionella pneumophila flagellin (green) is sensed by the cytosolic sensor Naip5 in mouse macrophages.




Like many motile bacteria, Legionella pneumophila uses whip-like flagella in its natural aquatic environment. Genes that control the assembly of flagella are also required for the bug to replicate in human macrophages, a process that occurs when humans inhale aerosols from contaminated water.

In macrophages, L. pneumophila avoids degradation by blocking the fusion of bacteria-containing phagosomes with degradative lysosomes—a feat that requires its pore-forming type IV secretion system.

Molofsky and colleagues now show that the cytosolic pathogen recognition receptor Naip5—which mice require to fight off L. pneumophila—responds to bacterial flagellin. The authors think that small amounts of flagellin inadvertently leak out of the type IV secretion pores in the phagosomes. This tips off Naip5-expressing macrophages, which then trigger bacterial degradation and caspase-1–dependent cell death.

Macrophages also detected cytosolic flagellin from other bacteria, such as Salmonella typhimurium. To avoid discovery by mammalian cells, S. typhimurium turns off the expression of flagellin, which is also sensed by Toll-like receptor 5. But L. pneumophila, has had no evolutionary incentive to mask its motor, as it does not normally spread between mammals.
Reduced Central Serotonin Transporters in Alcoholism
Authors: Andreas Heinz, Paul Ragan, Douglas W. Jones, Dan Hommer, Wendol Williams, Michael B. Knable, Julia G. Gorey, Linda Doty, Christopher Geyer, Kan S. Lee, Richard Coppola, Daniel R. Weinberger, Markku Linnoila
Journal: American Journal of Psychiatry (1998)

Dysfunction of monoamine uptake mechanisms has been implicated in the pathogenesis of alcohol dependence. The authors explored whether serotonergic dysfunction is associated with anxiety and depression, which increase the risk of relapse in alcoholics.The availability of serotonin and dopamine transporters in 22 male alcoholics and 13 healthy male volunteers was measured with the use of [123I] beta-CIT and single photon emission computed tomography, and psychopathological correlates were assessed.A significant reduction (a mean of about 30%) in the availability of brainstem serotonin transporters was found in the alcoholics, which was significantly correlated with lifetime alcohol consumption and with ratings of depression and anxiety during withdrawal.The findings support the hypothesis of serotonergic dysfunction in alcoholism and in withdrawal-emergent depressive symptoms.
Envenomation by the Spiders Chiracanthium inclusum and Argiope aurantia
Authors: J. Richard Gorham
Journal: JAMA (1968)

Two cases of arachnidism were caused by<i>Chiracanthium inclusum</i>and<i>Argiope aurantia</i>, both common spiders in the domestic environment. Other spiders capable of producing dermal or systemic reactions may be recognized. The hypersensitivity phenomenon makes any spider bite potentially dangerous. Epidemiologic study of arachnidism and the evaluation of its role as a public health problem are frustrated because most cases are unrecognized or unreported. The study of arachnidism and other forms of envenomation would be facilitated by a national repository of information on spider bites and venomous spiders.
Apoptotic hepatocyte DNA inhibits hepatic stellate cell chemotaxis via toll-like receptor 9
Authors: Azuma Watanabe, Ardeshir Hashmi, Dawidson Assis Gomes, Terrence Town, Abdallah Badou, Richard Anthony Flavell, Wajahat Zafar Mehal
Journal: Hepatology (2007)

Apoptosis of hepatocytes results in the development of liver fibrosis, but the molecular signals mediating this are poorly understood. Degradation and modification of nuclear DNA is a central feature of apoptosis, and DNA from apoptotic mammalian cells is known to activate immune cells via Toll-like receptor 9 (TLR9). We tested if DNA from apoptotic hepatocytes can induce hepatic stellate cell (HSC) differentiation. Our data show that apoptotic hepatocyte DNA and cytidine-phosphate-guanosine oligonucleotides induced up-regulation of transforming growth factor β1 and collagen 1 messenger RNA both in the human HSC line LX-2 and in primary mouse HSCs. These effects were opposed by TLR9 antagonists. We have recently shown that adenosine inhibits HSC chemotaxis, and we now show that apoptotic hepatocyte DNA also inhibits platelet-derived growth factor (PDGF)-mediated HSC chemotaxis. Inhibition of HSC chemotaxis by PDGF was blocked by TLR9 antagonists, and was absent in primary HSCs from mice deficient in TLR9 or the TLR adaptor molecule MyD88. Stimulation of TLR9 on HSCs blocked signaling by the PDGF signaling molecule inositol 1,4,5-triphosphate and reduced PDGF-mediated increase in cytosolic Ca2+. Conclusion: DNA from apoptotic hepatocytes acts as an important mediator of HSC differentiation by (1) providing a stop signal to mobile HSCs when they have reached an area of apoptosing hepatocytes and (2) inducing a stationary phenotype-associated up-regulation of collagen production.
When Walking Fails
Authors: Lisa I. lezzoni
Journal: JAMA (1996)

WALKING is the unthinking transportation of daily life, supporting countless but essential tiny trips within homes and beyond. Walking upright also holds profound symbolic importance. Bipedal locomotion, not intellect, defined the first human ancestors 3.6 million years ago. Nowadays, upright movement permeates American aphorisms, connoting independence, autonomy, self-reliance, and strength—"standing on your own two feet," "walking tall." Bipedal imagery suffuses watershed events—"One small step for man, one giant leap for mankind." Because I am increasingly unable to walk due to multiple sclerosis, I have lost not only my once-easy movement but also a core sense of value and place in the world. A simple discovery restored my independence and spirit—an electric wheelchair. Firmly in control of this conveyance, I now go where I want when I want, traveling frequently for my work. Of course, getting around this way has its faustrations, such as unanticipated physical barriers blocking even heavily
Decreased Catecholamine Degradation Associates with Shock and Kidney Injury after Cardiac Surgery
Authors: Anja Haase-Fielitz, Michael Haase, Rinaldo Bellomo, Gavin Lambert, George Matalanis, David Story, Laurie Doolan, Brian Buxton, Geoff Gutteridge, Friedrich C. Luft, Wolf-Hagen Schunck, Duska Dragun
Journal: Journal of the American Society of Nephrology (2009)

Enzymatic pathways involving catechol-O-methyltransferase (COMT) catabolize circulating catecholamines. A G-to-A polymorphism in the fourth exon of the COMT gene results in a valine-to-methionine amino acid substitution at codon 158, which leads to thermolability and low ("L"), as opposed to high ("H"), enzymatic activity. We enrolled 260 patients postbypass surgery to test the hypothesis that COMT gene variants impair circulating catecholamine metabolism, predisposing to shock and acute kidney injury (AKI) after cardiac surgery. In accordance with the Hardy-Weinberg equilibrium, we identified 64 (24.6%) homozygous (LL), 123 (47.3%) heterozygous (HL), and 73 (28.1%) homozygous (HH) patients. Postoperative catecholamines were higher in homozygous LL patients compared with heterozygous HL and homozygous HH patients (P < 0.01). During their intensive care stay, LL patients had both a significantly greater frequency of vasodilatory shock (LL: 69%, HL: 57%, HH: 47%; P = 0.033) and a significantly longer median duration of shock (LL: 18.5 h, HL: 14.0 h, HH: 11.0 h; P = 0.013). LL patients also had a greater frequency of AKI (LL: 31%, HL: 19.5%, HH: 13.7%; P = 0.038) and their AKI was more severe as defined by a need for renal replacement therapy (LL: 7.8%, HL: 2.4%, HH: 0%; P = 0.026). The LL genotype associated with intensive care and hospital length of stay (P < 0.001 and P = 0.002, respectively), and we observed a trend for higher mortality. Cross-validation analysis revealed a similar graded relationship of adverse outcomes by genotype. In summary, this study identifies COMT LL homozygosity as an independent risk factor for shock, AKI, and hospital stay after cardiac surgery. (ClinicalTrials.gov number, NCT00334009).
Myths and Facts on Adjuvant Carboplatin for Stage I Seminoma
Authors: Jorge Aparicio, José R. Germà
Journal: Journal of Clinical Oncology (2006)

5-year survival of 100%. 3,5 This relapse rate is in the range of that observed after radiation, recurrences are mostly retroperitoneal, and effective salvage is almost invariably obtained with four courses of cisplatin-based chemotherapy. Furthermore, an adequate follow-up (median, 72 months) in this pooled analysis precludes the chance of significant late adverse effects or late relapses, while showing a significant reduction in the probability of second germ-cell tumors. In this context, it is conceptually difficult to continue recommending systematic (indiscriminate) prophylactic radiation because more than 80% of these patients are cured with orchiectomy alone and the late hazards of radiotherapy (mainly second malignancies)arewellknown.Moreover,althoughpredictivefactorsfor
Suppression of interstitial nephritis by auto-anti-idiotypic immunity.
Authors: E G Neilson, M Phillips
Journal: The Journal of Experimental Medicine (1982)

Rats immunized with renal tubular antigens were protected from the development of interstitial nephritis by pretreatment with tubular antigen-reactive T lymphoblasts. Protected animals developed anti-idiotypic antibodies against idiotypes primarily within the antigen-binding region of monoclonal antitubular basement membrane antibodies. These studies extend the concept of auto-anti-idiotypic regulation to autoimmune disease, and they also provide an experimental basis for further efforts to develop biologically relevant mechanisms for attenuating the expression of other kidney diseases.
Epithelial-Mesenchymal Transition and Cell Cooperativity in Metastasis
Authors: Takanori Tsuji, Soichiro Ibaragi, Guo-fu Hu
Journal: Cancer Research (2009)

The role of epithelial-mesenchymal transition (EMT) in metastasis remains controversial. EMT has been postulated as an absolute requirement for tumor invasion and metastasis. Three different models including incomplete EMT, mesenchymal-epithelial transition (MET), and collective migration have been proposed for the role of EMT in cancer invasion and metastasis. However, skepticism remains about whether EMT truly occurs during cancer progression, and if it does, whether it plays an indispensible role in metastasis. Our recent findings suggest that EMT cells are responsible for degrading the surrounding matrix to enable invasion and intravasation of both EMT and non-EMT cells. Only non-EMT cells that have entered the blood stream are able to re-establish colonies in the secondary sites. Here, we discuss an alternative model for the role of EMT in cancer metastasis in which EMT and non-EMT cells cooperate to complete the entire process of spontaneous metastasis.
Gemcitabine in Combination With Oxaliplatin Compared With Gemcitabine Alone in Locally Advanced or Metastatic Pancreatic Cancer: Results of a GERCOR and GISCAD Phase III Trial
Authors: C. Louvet, R. Labianca, P. Hammel, G. Lledo, M.G. Zampino, T. André, A. Zaniboni, M. Ducreux, E. Aitini, J. Taïeb, R. Faroux, C. Lepere, A. de Gramont
Journal: Journal of Clinical Oncology (2005)

Gemcitabine (Gem) is the standard treatment for advanced pancreatic cancer. Given the promising phase II results obtained with the Gem-oxaliplatin (GemOx) combination, we conducted a phase III study comparing GemOx with Gem alone in advanced pancreatic cancer.Patients with advanced pancreatic cancer were stratified according to center, performance status, and type of disease (locally advanced v metastatic) and randomly assigned to either GemOx (gemcitabine 1 g/m2 as a 100-minute infusion on day 1 and oxaliplatin 100 mg/m2 as a 2-hour infusion on day 2 every 2 weeks) or Gem (gemcitabine 1 g/m2 as a weekly 30-minute infusion).Three hundred twenty-six patients were enrolled; 313 were eligible, and 157 and 156 were allocated to the GemOx and Gem arms, respectively. GemOx was superior to Gem in terms of response rate (26.8% v 17.3%, respectively; P = .04), progression-free survival (5.8 v 3.7 months, respectively; P = .04), and clinical benefit (38.2% v 26.9%, respectively; P = .03). Median overall survival (OS) for GemOx and Gem was 9.0 and 7.1 months, respectively (P = .13). GemOx was well tolerated overall, although a higher incidence of National Cancer Institute Common Toxicity Criteria grade 3 and 4 toxicity per patient was observed for platelets (14.0% for GemOx v 3.2% for Gem), vomiting (8.9% for GemOx v 3.2% for Gem), and neurosensory symptoms (19.1% for GemOx v 0% for Gem).These results confirm the efficacy and safety of GemOx, but this study failed to demonstrate a statistically significant advantage in terms of OS compared with Gem. Because GemOx is the first combined treatment to be superior to Gem alone in terms of clinical benefit, this promising regimen deserves further development.
TALEN-based Gene Correction for Epidermolysis Bullosa
Authors: Mark J Osborn, Colby G Starker, Amber N McElroy, Beau R Webber, Megan J Riddle, Lily Xia, Anthony P DeFeo, Richard Gabriel, Manfred Schmidt, Christof Von Kalle, Daniel F Carlson, Morgan L Maeder, J Keith Joung, John E Wagner, Daniel F Voytas, Bruce R Blazar, Jakub Tolar
Journal: Molecular Therapy (2013)

Recessive dystrophic epidermolysis bullosa (RDEB) is characterized by a functional deficit of type VII collagen protein due to gene defects in the type VII collagen gene (COL7A1). Gene augmentation therapies are promising, but run the risk of insertional mutagenesis. To abrogate this risk, we explored the possibility of using engineered transcription activator-like effector nucleases (TALEN) for precise genome editing. We report the ability of TALEN to induce site-specific double-stranded DNA breaks (DSBs) leading to homology-directed repair (HDR) from an exogenous donor template. This process resulted in COL7A1 gene mutation correction in primary fibroblasts that were subsequently reprogrammed into inducible pluripotent stem cells and showed normal protein expression and deposition in a teratoma-based skin model in vivo. Deep sequencing-based genome-wide screening established a safety profile showing on-target activity and three off-target (OT) loci that, importantly, were at least 10 kb from a coding sequence. This study provides proof-of-concept for TALEN-mediated in situ correction of an endogenous patient-specific gene mutation and used an unbiased screen for comprehensive TALEN target mapping that will cooperatively facilitate translational application.
Gene expression profiling: good housekeeping and a clean message
Authors: R C Chambers
Journal: Thorax (2002)

Microarray technology offers us the means of monitoring gene expression on a scale which was hard to envisage only a few years ago.

There is no doubt that gene expression studies based on evaluating mRNA levels for single or multiple genes of interest in human lung biopsy tissue have had a major impact on our understanding of the molecular mechanisms underlying respiratory disease. The recent advent of microarray technology has added further impetus to the central paradigm that mRNA quantification in lung tissue can shed light on pathogenesis and identify new targets for therapeutic intervention. This technology is now so advanced that it allows the parallel monitoring of entire genomes using microarrays with a surface area equivalent to just a few square centimetres and as little as 5 μg RNA starting material.

Since its first application in the mid 1990s,1 microarray technology has been applied to all aspects of biomedical research with over 60 papers in respiratory research alone. It has been successfully used for the classification and molecular diagnosis of lung cancer,2 the identification of potential target genes for therapeutic intervention in idiopathic pulmonary fibrosis,3 mechanistic studies in animal models of asthma4 and pulmonary fibrosis,5 and for profiling lung development.6 Global expression profiling of cellular responses in vitro has provided new insights into the transcriptional programs involved in cytokine signalling,7 growth arrest and apoptosis,8 and it is already enabling us to understand the operation of functional gene networks.

Although a number of microarray platforms have been developed, microarrays come in two basic formats. Complementary DNA (cDNA) arrays usually contain polymerase chain reaction (PCR) products generated from cDNA libraries or clone collections, spotted onto glass slides or nylon membranes. Expression values are based on the competitive hybridisation of two samples being directly …
Analysis of GABA<sub>A</sub> Receptor Function and Dissection of the Pharmacology of Benzodiazepines and General Anesthetics Through Mouse Genetics
Authors: Uwe Rudolph, Hanns Möhler
Journal: The Annual Review of Pharmacology and Toxicology (2004)

GABAA receptors are molecular substrates for the regulation of vigilance, anxiety, muscle tension, epileptogenic activity, and memory functions, and the enhancement of GABAA receptor-mediated fast synaptic inhibition is the basis for the pharmacotherapy of various neurological and psychiatric disorders. Two kinds of GABAA receptor-targeted mutant mice have been generated: (a) knockout mice that lack individual GABAA receptor subunits (alpha1, alpha5, alpha6, beta2, beta3, gamma2, delta, and rho1) and (b) knockin mice that carry point mutations affecting the action of modulatory drugs [alpha1(H101R), alpha2(H101R), alpha3(H126R), alpha5(H105R), and beta3(N265M)]. Whereas the knockout mice have provided information primarily with respect to the regulation of subunit gene transcription, receptor assembly, and some physiological functions of individual receptor subtypes, the point-mutated knockin mice in which specific GABAA receptor subtypes are insensitive to diazepam or some general anesthetics have revealed the specific contribution of individual receptor subtypes to the pharmacological spectrum of diazepam and general anesthetics.
Cetuximab in combination with weekly 5-fluorouracil/folinic acid and oxaliplatin (FUFOX) in untreated patients with advanced colorectal cancer: a phase Ib/II study of the AIO GI Group
Authors: D. Arnold, T. Höhler, C. Dittrich, F. Lordick, T. Seufferlein, J. Riemann, E. Wöll, T. Herrmann, A. Zubel, H.-J. Schmoll
Journal: Annals of Oncology (2008)