tbuckley/cabot-search huggingface dataset:
EFFECT OF SPLENECTOMY ON THE SUSCEPTIBILITY OF MICE INOCULATED WITH DIPLOCOCCUS PNEUMONIAE
Authors: Henry R. Shinefield, Charles R. Steinberg, Donald Kaye
Journal: The Journal of Experimental Medicine (1966)

An experimental model is described which demonstrated increased susceptibility of mice to infection with D. pneumoniae following splenectomy. It was necessary to use small numbers of a particular strain of pneumococcus (D. pneumoniae type 6), intravenous infection and a particular strain of mouse (pathogen-free NCS strain). The increase in susceptibility persisted for at least 4 months after splenectomy. With modifications in experimental design such as use of large numbers of organisms, a different strain of pneumococcus, the intraperitoneal route of infection or a different mouse strain no increase or a much less impressive increase in susceptibility was demonstrated. Following intravenous injection of small numbers of D. pneumoniae Type 6 bacteremia tended to persist in all NCS mice. Multiplication of pneumococci subsequently occurred in a higher proportion of mice with splenectomy and at a more rapid rate than in control animals. Mice with splenectomy usually had more D. pneumoniae per ml of blood than per gram of any tissue. This suggested that in these mice multiplication of microorganisms occurs primarily in blood. In control mice higher concentrations of bacteria were present in spleen than in blood, and higher concentrations were found in blood than in other tissues. These results suggested that in normal mice infected intravenously with small numbers of D. pneumoniae Type 6, the spleen protects by removing and killing small but critical numbers of D. pneumoniae which are circulating in the blood. No evidence was found to suggest that the altered susceptibility is mediated by an effect of splenectomy on numbers of circulating leukocytes or on the antibacterial activity of mouse blood.
The door handle sign
Authors: John Williams
Journal: BMJ (2004)

Future challengesThe relatively fluid process of patient management often does not match the rigidity of most electronic health records systems.Medicine is far from a factual science, and patient management requires a tentative, evolving reinterpretation of previous data in the light of new information.Most interaction between clinicians comprises narrative (free text).Narrative contains more information than isolated or coded words.Most electronic records, however, rely on structured data entry.The drawbacks of this approach have been summarised by Powsner 12 and de Lusignan and colleagues. 26Read codes are less accurate at capturing general practice concepts. 27 There is great pressure to reduce patients' length of stay in hospital.At the time of discharge, computer generated summaries can be produced more quickly than dictated summaries and so improve communication with primary care. 28The pace of modern practice dictates the use of technology, but the lack of direct clinical input in the development and procurement of information technology has been cited as a major factor in the failure of many clinical information systems.Replacing paper with electronic records will change medical practice, including relationships between doctors and nurses, responsibilities, and work distribution.Clinicians need to be closely involved in ensuring that software for documenting patient encounters complements the way they work.Patients already have the right of full access to their electronic records for "any or no reason," says Goss; his article provides an interesting view of the difficulties associated with patients' access to health records. 29By June 2004, some patients should have "direct" access to their electronic records in hospitals and in primary care. 30From the clinician's perspective, however, the words of Scott McNealy of Sun Microsystems ring true: "You have zero privacy anyway.Get over it.
Cardiovascular magnetic resonance and single-photon emission computed tomography for diagnosis of coronary heart disease (CE-MARC): a prospective trial
Authors: John P Greenwood, Neil Maredia, John F Younger, Julia M Brown, Jane Nixon, Colin C Everett, Petra Bijsterveld, John P Ridgway, Aleksandra Radjenovic, Catherine J Dickinson, Stephen G Ball, Sven Plein
Journal: The Lancet (2011)
Pulmonary Vein Denervation Enhances Long-Term Benefit After Circumferential Ablation for Paroxysmal Atrial Fibrillation
Authors: Carlo Pappone, Vincenzo Santinelli, Francesco Manguso, Gabriele Vicedomini, Filippo Gugliotta, Giuseppe Augello, Patrizio Mazzone, Valter Tortoriello, Giovanni Landoni, Alberto Zangrillo, Christopher Lang, Takeshi Tomita, Cézar Mesas, Elio Mastella, Ottavio Alfieri
Journal: Circulation (2004)

There are no data to evaluate the relationship between autonomic nerve function modification and recurrent atrial fibrillation (AF) after circumferential pulmonary vein ablation (CPVA). This study assesses the incremental benefit of vagal denervation by radiofrequency in preventing recurrent AF in a large series of patients undergoing CPVA for paroxysmal AF.Data were collected on 297 patients undergoing CPVA for paroxysmal AF. Abolition of all evoked vagal reflexes around all pulmonary vein ostia was defined as complete vagal denervation (CVD) and was obtained in 34.3% of patients. Follow-up ended at 12 months. Heart rate variability attenuation, consistent with vagal withdrawal, was detectable for up to 3 months after CPVA, particularly in patients with reflexes and CVD, who were less likely to have recurrent AF than those without reflexes (P=0.0002, log-rank test). Only the percentage area of left atrial isolation and CVD were predictors of AF recurrence after CPVA (P<0.001 and P=0.025, respectively).This study suggests that adjunctive CVD during CPVA significantly reduces recurrence of AF at 12 months.
Additive Effects of Late Preconditioning Produced By Monophosphoryl Lipid A and the Early Preconditioning Mediated By Adenosine Receptors and K <sub>ATP</sub> Channel
Authors: Kristyne Stambaugh, Gary T. Elliott, Kenneth A. Jacobson, Bruce T. Liang
Journal: Circulation (1999)

Background —The cardioprotective effect of preconditioning can be exerted within 1 to 2 hours after initial ischemia, termed classical or early preconditioning, or can reappear 24 hours later as second window or late preconditioning. The objective of this study was to study the interaction between late and early preconditioning and to determine the potential underlying mechanism. Methods and Results —Adenosine receptor agonists and a K ATP channel opener were used to achieve early preconditioning, and Monophosphoryl lipid A (MLA) was used to induce late preconditioning. Cultured chick ventricular myocytes were used as a myocyte model of simulated ischemia and preconditioning. Prior treatment of the myocyte with MLA caused a dose-dependent decrease in the ischemia-induced myocyte injury 24 hours later, consistent with a late preconditioning effect. L-NMMA, glibenclamide, or 5-hydroxydecanoic acid administered during the ischemia blocked the MLA effect. Twenty four hours after MLA treatment, a 5-minute exposure to ischemia, adenosine, adenosine A 1 agonist CCPA, or A 3 agonist resulted in less myocyte injury during the subsequent prolonged ischemia, as compared with cells pretreated with the vehicle and subsequently exposed to the same early preconditioning stimuli. In addition to its ability to enhance the early preconditioning effect by A 1 and A 3 agonists, MLA pretreatment also increased the phorbol ester- and pinacidil-mediated early preconditioning effect. Conclusions —This study defined a novel interaction in which the cardioprotective effect of early preconditioning is additive to that of late preconditioning and raised the possibility that both agents can be used as combined therapy in the treatment of ischemic heart disease.
Skin exposure promotes a Th2-dependent sensitization to peanut allergens
Authors: Leticia Tordesillas, Ritobrata Goswami, Sara Benedé, Galina Grishina, David Dunkin, Kirsi M. Järvinen, Soheila J. Maleki, Hugh A. Sampson, M. Cecilia Berin
Journal: Journal of Clinical Investigation (2014)

Sensitization to foods often occurs in infancy, without a known prior oral exposure, suggesting that alternative exposure routes contribute to food allergy. Here, we tested the hypothesis that peanut proteins activate innate immune pathways in the skin that promote sensitization. We exposed mice to peanut protein extract on undamaged areas of skin and observed that repeated topical exposure to peanut allergens led to sensitization and anaphylaxis upon rechallenge. In mice, this epicutaneous peanut exposure induced sensitization to the peanut components Ara h 1 and Ara h 2, which is also observed in human peanut allergy. Both crude peanut extract and Ara h 2 alone served as adjuvants, as both induced a bystander sensitization that was similar to that induced by the atopic dermatitis-associated staphylococcal enterotoxin B. In cultured human keratinocytes and in murine skin, peanut extract directly induced cytokine expression. Moreover, topical peanut extract application induced an alteration dependent on the IL-33 receptor ST2 in skin-draining DCs, resulting in Th2 cytokine production from T cells. Together, our data support the hypothesis that peanuts are allergenic due to inherent adjuvant activity and suggest that skin exposure to food allergens contributes to sensitization to foods in early life.
Influences of Corticosteroids on Cardiac Glycogen Concentration in the Rat
Authors: J. CHARLES DAW, Allan M. Lefer, Robert M. Berne
Journal: Circulation Research (1968)

Bilateral adrenalectomy resulted in a decrease (4.97 to 2.79 mg/g) in cardiac glycogen concentration in pentobarbital-anesthetized rats. Similar differences were observed at 10 to 14 days and at 27 days after adrenalectomy. Sham-adrenalectomized rats had normal cardiac glycogen concentration (4.98 mg/g). Total phosphorylase and phosphorylase α activities and glucose-6-phosphate concentrations in hearts obtained from adrenalectomized rats were not significantly different from controls. Total glycogen transferase activity was decreased in adrenalectomized rats and for any given glycogen concentration, the percent of the glycogen transferase in the independent form (percent transferase I) was significantly lower in the adrenalectomized rats than in the intact controls. The glucocorticoid dexamethasone (40 µg/day) prevented the decreases in cardiac glycogen concentration and percent transferase I in adrenalectomized rats. In the intact rat dexamethasone (40 µg/day) increased cardiac glycogen concentration and total transferase activity to above control levels as did larger doses in both adrenalectomized and control rats. The mineralocorticoid deoxycorticosterone acetate (DOCA), had relatively little effect on cardiac glycogen concentration. Conclusion: glucocorticoids exert a regulatory role in cardiac glycogen metabolism.
Relation between lipopolysaccharide-induced endothelial cell injury and entry of macromolecules into the rat aorta in vivo.
Authors: M S Penn, G M Chisolm
Journal: Circulation Research (1991)

Lipopolysaccharide (LPS) causes endothelial cell injury both in vitro and in vivo. It is widely believed that this injury in vivo enhances the transport of macromolecules from plasma into the interstitial space of the underlying artery wall. A new technique was used in rats to obtain high resolution transmural profiles of macromolecules in vivo. We compared the time course of the macromolecular transport into the aortic tissue in vivo after LPS injection to that of LPS-induced endothelial cell death and the proliferative response of the endothelium to LPS injury. At a dose of 1 mg LPS/kg body wt, endothelial cell death reached a maximum by 36 hours after LPS injection and remained elevated for 96 hours; the peak of the S phase of endothelial cell proliferation was observed 48 hours after injection. To examine the effect of LPS on macromolecular accumulation, we measured aortic intimal and medial transmural concentration profiles of horseradish peroxidase (HRP) after circulation of HRP for 15 minutes. The data revealed a transient increase in total aortic accumulation (reflecting predominantly the media), which was maximal between 12 and 48 hours after LPS injection. Although total medial accumulation was found to return to near control levels by 72 hours after LPS injection, intimal accumulation remained elevated above control levels for 120 hours. When HRP was added to the perfusate of an in situ aorta preparation at a near zero transmural pressure gradient, the resulting transmural concentration profiles across aortas from control rats and from rats given LPS 24 hours previously were indistinguishable, whereas a pressure gradient of 60 mm Hg revealed LPS-altered concentration profiles analogous to those in vivo. This suggests that the accumulation of HRP observed in vivo was driven by increased convective transport. These results reveal that LPS enhances entry of macromolecules into the aorta wall in vivo. The changes in macromolecular transport do not, however, correlate temporally with endothelial cell death or proliferation. The results are consistent with an LPS-induced decrease in the endothelial barrier function, which precedes, and may be independent of, cell death and a transient increase in convective transport across the media due to alterations in the barrier function of the internal elastic lamina.
Current management and novel agents for malignant melanoma
Authors: Byung Lee, Nikhil Mukhi, Delong Liu
Journal: Journal of Hematology & Oncology (2012)

Abstract Advanced malignant melanoma remains a challenging cancer. Over the past year, there have been 3 agents approved for treatment of melanoma by Food and Drug Administration. These include pegylated interferon alpha-2b for stage III melanoma, vemurafenib for unresectable or metastatic melanoma with BRAF V600E mutation, and ipilimumab for treatment of unresectable or metastatic melanoma. This review will also update on the development of novel agents, including tyrosine kinase inhibitors and adoptive cellular therapy.
Output characteristics of DeVilbiss No. 40 hand-held jet nebulizers
Authors: KN Chan, MM Clay, M Silverman
Journal: European Respiratory Journal (1990)

DeVilbiss No. 40 hand-held nebulizers are widely used for quantifying airway responsiveness in large populations using pharmacological agents. We examined the aerosol characteristics of five nebulizers. Within each device, the aerosol output and droplet size were reasonably stable over a wide range of bulb pressures, although there were considerable differences in output characteristics between nebulizers. The droplet size was very large compared to conventional aerosol delivery systems, with a mass median diameter greater than 10 microns for three of the five devices. Between 28-50% of the output was in particles sufficiently small for airway deposition (less than 6.2 microns). A more vigorous compression of the bulb caused a small increase output and a reduction in droplet size, resulting in a much bigger variation in the output of the respirable aerosol (less than 6.2 microns) with changes in bulb pressure. The loss due to evaporation was about 3.5%, causing a similar rise in the osmolality of the nebulizer solution. In view of the variable nebulizer output and the marked between-operator variation in bulb pressure, the characteristics of individual DeVilbiss No. 40 nebulizers should be evaluated by individual operators before use in clinical practice or research.
Protective effect of pneumococcal vaccine against death by pneumonia in elderly subjects
Authors: A. Vila-Córcoles, O. Ochoa-Gondar, C. Llor, I. Hospital, T. Rodríguez, A. Gómez
Journal: European Respiratory Journal (2005)

The present study assessed the effectiveness of the 23-valent pneumococcal polysaccharide vaccine to prevent pneumonia and death in older adults in a first-time report between January and December 2002. A prospective cohort study was conducted including all individuals ≥65 yrs of age assigned to one of eight primary care centres in Tarragona, Spain (n = 11,241). The primary outcomes were community-acquired pneumonia (hospitalised or outpatient) and death from pneumonia. All pneumonias were validated by checking clinical records. The association between the pneumococcal vaccination and the risk of each outcome was evaluated by means of multivariate Cox proportional-hazard models, adjusted by age, sex, influenza vaccination status, comorbidity and immunological status. Pneumococcal vaccination did not alter the risk of hospitalisation from pneumonia (hazard ratio (HR): 0.80; 95% confidence interval (CI): 0.50–1.28) or overall pneumonia (HR: 0.86; 95% CI: 0.56–1.31), but the vaccine was associated with considerable reductions of death risk from pneumonia (HR: 0.28; 95% CI: 0.09–0.83). In conclusion, these results suggest that pneumococcal polysaccharide vaccine may not be effective in reducing the incidence of pneumonia, but may be able to diminish the severity of the infection. These findings support the effectiveness of the pneumococcal polysaccharide vaccine to prevent mortality caused by pneumonia in older adults, providing a new argument to recommend systematic vaccination in the elderly.
Significant linkage to chromosome 12q24.32-q24.33 and identification of SFRS8 as a possible asthma susceptibility gene
Authors: Charlotte Brasch-Andersen, Qihua Tan, Anders D Børglum, Annette Haagerup, Trine R Larsen, Jørgen Vestbo, Torben A Kruse
Journal: Thorax (2006)

Background: Asthma is a complex genetic disorder. Many studies have suggested that chromosome 12q harbours a susceptibility gene for asthma and atopy. Linkage on chromosome 12q24.21–q24.33 was investigated in 167 Danish families with asthma. Methods: A two step procedure was used: (1) a genome-wide scan in one set of families followed by (2) fine scale mapping in an independent set of families in candidate regions with a maximum likelihood score (MLS) of ⩾1.5 in the genome-wide scan. Polymorphisms in a candidate gene in the region on 12q24.33 were tested for association with asthma in a family based transmission disequilibrium test. Results: An MLS of 3.27 was obtained at 12q24.33. The significance of this result was tested by simulation, resulting in a significant empirical genome-wide p value of 0.018. To our Knowledge, this is the first significant evidence for linkage on chromosome 12q, and suggests a candidate region distal to most previously reported regions. Three single nucleotide polymorphisms in splicing factor, arginine/serine-rich 8 ( SFRS8 ) had an association with asthma (p⩽0.0020–0.050) in a sample of 136 asthmatic sib pairs. SFRS8 regulates the splicing of CD45, a protein which, through alternative splice variants, has an essential role in activating T cells. T cells are involved in the pathogenesis of atopic diseases such as asthma, so SFRS8 is a very interesting candidate gene in the region. Conclusions: Linkage and simulation studies show that the very distal part of chromosome 12q contains a gene that increases the susceptibility to asthma. SFRS8 could act as a weak predisposing gene for asthma in our sample.
Inhibition of Inducible Nitric Oxide Synthase Prevents Myocardial and Systemic Vascular Barrier Dysfunction During Early Cardiac Allograft Rejection
Authors: Neil K. Worrall, Kathy Chang, Gloria M. Suau, Wanda S. Allison, Thomas P. Misko, Patrick M. Sullivan, Ronald G. Tilton, Joseph R. Williamson, T. Bruce Ferguson
Journal: Circulation Research (1996)

Abstract NO is produced during cardiac allograft rejection by expression of inducible NO synthase (iNOS) in the rejecting heart. Recent evidence indicates that NO modulates vascular permeability under both physiological and pathophysiological conditions. The present study explored the effects of early acute cardiac allograft rejection, and specifically the effects of NO, on myocardial and systemic vascular barrier function using a quantitative double-tracer permeation method in a rat cardiac transplant model. Early allograft rejection increased albumin permeation twofold to fivefold in the allograft heart and systemic vasculature (brain, lung, sciatic nerve, diaphragm, retina, muscle, kidney, and uvea) compared with isografts and controls. There were no detectable differences in regional blood flow or hemodynamics, suggesting that increased albumin permeation resulted from increased vascular permeability. iNOS mRNA was expressed in the allograft heart and native lung and was associated with increased serum nitrite/nitrate levels. iNOS inhibition with aminoguanidine prevented or attenuated allograft heart and systemic vascular barrier dysfunction and reduced allograft serum nitrite/nitrate levels to isograft values. Aminoguanidine did not affect the mild histological changes of rejection present in allografts. These data demonstrate the novel observations that (1) endothelial barrier function is compromised in the systemic vasculature, particularly in the brain, remote from the site of allograft rejection; (2) allograft vascular barrier dysfunction is associated with increased NO production and iNOS mRNA expression in the affected tissues (eg, native lung and grafted heart); and (3) inhibition of NO production by iNOS prevents vascular barrier dysfunction in the allograft heart and systemic vasculature.
Hedgehog signaling and primary cilia are required for the formation of adult neural stem cells
Authors: Young-Goo Han, Nathalie Spassky, Miriam Romaguera-Ros, Jose-Manuel Garcia-Verdugo, Andrea Aguilar, Sylvie Schneider-Maunoury, Arturo Alvarez-Buylla
Journal: Nature Neuroscience (2008)
Endocardial Fibroelastosis Is Caused by Aberrant Endothelial to Mesenchymal Transition
Authors: Xingbo Xu, Ingeborg Friehs, Tachi Zhong Hu, Ivan Melnychenko, Björn Tampe, Fouzi Alnour, Maria Iascone, Raghu Kalluri, Michael Zeisberg, Pedro J. del Nido, Elisabeth M. Zeisberg
Journal: Circulation Research (2015)

Rationale: Endocardial fibroelastosis (EFE) is a unique form of fibrosis, which forms a de novo subendocardial tissue layer encapsulating the myocardium and stunting its growth, and which is typically associated with congenital heart diseases of heterogeneous origin, such as hypoplastic left heart syndrome. Relevance of EFE was only recently highlighted through the establishment of staged biventricular repair surgery in infant patients with hypoplastic left heart syndrome, where surgical removal of EFE tissue has resulted in improvement in the restrictive physiology leading to the growth of the left ventricle in parallel with somatic growth. However, pathomechanisms underlying EFE formation are still scarce, and specific therapeutic targets are not yet known. Objective: Here, we aimed to investigate the cellular origins of EFE tissue and to gain insights into the underlying molecular mechanisms to ultimately develop novel therapeutic strategies. Methods and Results: By utilizing a novel EFE model of heterotopic transplantation of hearts from newborn reporter mice and by analyzing human EFE tissue, we demonstrate for the first time that fibrogenic cells within EFE tissue originate from endocardial endothelial cells via aberrant endothelial to mesenchymal transition. We further demonstrate that such aberrant endothelial to mesenchymal transition involving endocardial endothelial cells is caused by dysregulated transforming growth factor beta/bone morphogenetic proteins signaling and that this imbalance is at least in part caused by aberrant promoter methylation and subsequent transcriptional suppression of bone morphogenetic proteins 5 and 7. Finally, we provide evidence that supplementation of exogenous recombinant bone morphogenetic proteins 7 effectively ameliorates endothelial to mesenchymal transition and experimental EFE in rats. Conclusions: In summary, our data point to aberrant endothelial to mesenchymal transition as a common denominator of infant EFE development in heterogeneous, congenital heart diseases, and to bone morphogenetic proteins 7 as an effective treatment for EFE and its restriction of heart growth.