tbuckley/cabot-search huggingface dataset:
Does Ischemic Preconditioning Trigger Translocation of Protein Kinase C in the Canine Model?
Authors: Karin Przyklenk, Mark A. Sussman, Boris Z. Simkhovich, Robert A. Kloner
Journal: Circulation (1995)

Background Brief episodes of ischemia protect or “precondition” the heart and reduce the size of infarcts caused by subsequent sustained coronary artery occlusion, yet the mechanisms responsible for this cardioprotection remain unresolved. We tested the theory that translocation of protein kinase C (PKC) to the myocyte membranes, initiated in response to brief preconditioning ischemia and manifest during the initial minutes of the sustained occlusion, mediates this phenomenon by attempting to (1) blunt the cardioprotective effects of preconditioning by administration of the PKC inhibitors H-7 and polymyxin B, (2) visualize by fluorescence staining and confocal microscopy changes in the amount or location of PKC, and (3) quantify by incorporation of 32 P into PKC-specific peptide changes in the subcellular distribution of PKC in preconditioned versus control hearts. Methods and Results In the first three limbs of this study, anesthetized open-chest dogs underwent four 5-minute episodes of preconditioning ischemia or a comparable control period before 1 hour of sustained occlusion and 4 to 5 hours of reperfusion. Collateral blood flow was assessed with radioactive microspheres; area at risk (AR) was delineated by injection of blue dye; and the area of necrosis (AN) was measured by tetrazolium staining. AN/AR was smaller in preconditioned versus control dogs that received no treatment (6±2% versus 19±3%, P &lt;.01), H-7 (2±2% versus 14±5%, P &lt;.02), or polymyxin B (10±3% versus 29±5%, P &lt;.01) during the preconditioning or control period. Additional dogs underwent four 5-minute episodes of ischemia, with biopsies obtained at baseline and after the first and fourth occlusions. Frozen sections were stained with a fluorescent probe for active PKC and viewed with confocal microscopy. No differences in the intensity or distribution of fluorescence staining were observed after brief ischemia compared with baseline. Finally, myocardial samples were obtained from dogs subjected to four 5-minute episodes of preconditioning ischemia and time-matched sham-operated controls. Incorporation of 32 P into PKC-specific peptide revealed no quantitative difference in the subcellular distribution of PKC between control and preconditioned cohorts. Conclusions H-7 and polymyxin B did not blunt the reduction in infarct size achieved with ischemic preconditioning. Neither fluorescence staining and confocal microscopy nor biochemical quantification revealed evidence of preconditioning-induced translocation of PKC to the cell membranes. These results fail to support the hypothesis that translocation of PKC, triggered by preconditioning ischemia, is an important mechanism for the reduction in infarct size seen with preconditioning in the dog model.
Screening for Lung Cancer: It Works, but Does It<i>Really</i>Work?
Authors: Gerard A. Silvestri
Journal: Annals of Internal Medicine (2011)

After the publication of the NLST (National Lung Screening Trial) results, physicians will be faced with whether to begin ordering low-dose computed tomography (LDCT) of the chest to screen for lung cancer in patients with a history of tobacco use. Despite the encouraging reduction in deaths observed by using LDCT in the NLST study population, recommending adoption of lung cancer screening in general practice is premature. Lessons learned from prostate and breast cancer screening should remind us that the reductions in deaths expected with screening are unfortunately not as readily achievable as initially believed. Furthermore, the potential harms of false-positive findings on chest computed tomography are very real. The morbidity and even mortality associated with invasive diagnostic testing and surgical resection due to false- and true-positive findings on computed tomography are likely to increase when the approach taken in the NLST is applied in non–specialty care settings and among the population at highest risk, namely, those with smoking-related comorbid conditions. Although the NLST results are perhaps encouraging, they do not tell us enough that we can be sure that patients who undergo LDCT in an attempt to find early-stage lung cancer will have more benefit than harm.
Hyperthyroidism enhances endothelium-dependent relaxation in the rat renal artery
Authors: E Büssemaker
Journal: Cardiovascular Research (2003)

Objective: Hyperthyroidism has pronounced effects on vascular function and endothelium-dependent relaxation. The aim of the present study was to identify mechanisms underlying hyperthyroidism-induced alterations in endothelial function in rats. Methods: Animals were subjected to either a single injection (36 h) or 8 weeks treatment with the thyroid hormone triiodothyronine (T3, i.p.). Vascular reactivity and agonist-induced hyperpolarization were studied in isolated renal arteries. Endothelial nitric oxide (NO) synthase expression and cyclic AMP accumulation were determined in aortic segments. Results: Endothelium-dependent relaxations to acetylcholine (ACh) were enhanced by T3 36 h after injection and after treatment for 8 weeks. Thirty-six hours after T3 application, relaxation mediated by the endothelium-derived hyperpolarizing factor (EDHF) and by endothelium-derived NO were significantly enhanced. After 8 weeks treatment with T3, however, EDHF-mediated relaxation was impaired, whereas NO-mediated relaxation remained enhanced. KCl- and ACh-induced hyperpolarizations were more pronounced in arteries from rats treated with T3 for 36 h compared to control, whereas in arteries from rats treated with T3 for 8 weeks both responses were attenuated. In rats treated for 36 h, vascular cyclic AMP levels were enhanced in the aorta and inhibition of protein kinase A attenuated EDHF-mediated relaxations of the renal artery without affecting responses in arteries from the control group. In the aorta from rats treated with T3 for 8 weeks, the expression of the endothelial NO synthase was markedly up-regulated (463±68%). Conclusions: These data indicate that short-term treatment with T3 increases endothelium-dependent relaxation, most probably by increasing vascular cyclic AMP content. Following treatment with T3 for 8 weeks, expression of the endothelial NO synthase was enhanced. During this phase, NO appears to be the predominant endothelium-derived vasodilator.
Lineage relationships, homeostasis, and recall capacities of central– and effector–memory CD8 T cells in vivo
Authors: Cécile Bouneaud, Zacarias Garcia, Philippe Kourilsky, Christophe Pannetier
Journal: The Journal of Experimental Medicine (2005)

The lineage relationships of central–memory T cells (TCM) cells and effector–memory T cells (TEM), as well as their homeostasis and recall capacities, are still controversial. We investigated these issues in a murine model using two complementary approaches: T cell receptor repertoire analysis and adoptive transfer experiments of purified H-Y–specific TCM and TEM populations. Repertoire studies showed that approximately two thirds of TCM and TEM clones derived from a common naive precursor, whereas the other third was distinct. Both approaches highlighted that TCM and TEM had drastically distinct behaviors in vivo, both in the absence of antigen or upon restimulation. TCM clones were stable in the absence of restimulation and mounted a potent and sustained recall response upon secondary challenge, giving rise to both TCM and TEM, although only a fraction of TCM generated TEM. In contrast, TEM persisted for only a short time in the absence of antigen and, although a fraction of them were able to express CD62L, they were unable to mount a proliferative response upon secondary challenge in this model.
How Quickly Do Systematic Reviews Go Out of Date? A Survival Analysis
Authors: Kaveh G. Shojania, Margaret Sampson, Mohammed T. Ansari, Jun Ji, Steve Doucette, David Moher
Journal: Annals of Internal Medicine (2007)

Background: Systematic reviews are often advocated as the best source of evidence to guide clinical decisions and health care policy, yet we know little about the extent to which they require updating. Objective: To estimate the average time to changes in evidence that are sufficiently important to warrant updating systematic reviews. Design: Survival analysis of 100 quantitative systematic reviews. Sample: Systematic reviews published from 1995 to 2005 and indexed in ACP Journal Club. Eligible reviews evaluated a specific drug or class of drug, device, or procedure and included only randomized or quasi-randomized, controlled trials. Measurements: Quantitative signals for updating were changes in statistical significance or relative changes in effect magnitude of at least 50% involving 1 of the primary outcomes of the original systematic review or any mortality outcome. Qualitative signals included substantial differences in characterizations of effectiveness, new information about harm, and caveats about the previously reported findings that would affect clinical decision making. Results: The cohort of 100 systematic reviews included a median of 13 studies and 2663 participants per review. A qualitative or quantitative signal for updating occurred for 57% of reviews (95% CI, 47% to 67%). Median duration of survival free of a signal for updating was 5.5 years (CI, 4.6 to 7.6 years). However, a signal occurred within 2 years for 23% of reviews and within 1 year for 15%. In 7%, a signal had already occurred at the time of publication. Only 4% of reviews had a signal within 1 year of the end of the reported search period; 11% had a signal within 2 years of the search. Shorter survival was associated with cardiovascular topics (hazard ratio, 2.70 [CI, 1.36 to 5.34]) and heterogeneity in the original review (hazard ratio, 2.15 [CI, 1.12 to 4.11]). Limitation: Judgments of the need for updating were made without involving content experts. Conclusion: In a cohort of high-quality systematic reviews directly relevant to clinical practice, signals for updating occurred frequently and within a relatively short time.
OCCURRENCE OF SURFACE IgM, IgD, AND FREE LIGHT CHAINS ON HUMAN LYMPHOCYTES
Authors: Shu Man Fu, Robert J. Winchester, Henry G. Kunkel
Journal: The Journal of Experimental Medicine (1974)

An analysis was made of the immunoglobulin surface markers of the cells of patients with chronic lymphatic leukemia (CLL) in view of previous evidence of their monoclonal B-cell character. The simultaneous presence of IgM and IgD on the surface of the majority of lymphocytes was demonstrated by both immunofluorescence and hemagglutination inhibition in most cases. However, cases were observed with surface IgM without IgD as well as cases with IgD without IgM. IgG and IgA were absent. Studies of the light chains indicated only a single class in a given case. In addition to bound light chains, free light chains were readily demonstrated in most cases through the use of antisera specific for "free chain" determinants. It thus appeared that there are three major types of surface Ig on CLL lymphocytes, IgM, IgD, and free light chains.
Availability of PSC833, a substrate and inhibitor of P-glycoproteins, in various concentrations of serum
Authors: A. J. Smith, U. Mayer, A. H. Schinkel, P. Borst
Journal: JNCI Journal of the National Cancer Institute (1998)

Background : P-glycoproteins are membrane- associated transporters that can render cells resistant to a variety of chemotherapeutic drugs. Reversal agents are (preferably nontoxic) drugs that can inhibit these P-glycoproteins and thereby overcome multidrug resistance. PSC833, a cyclosporin A analog, is a reversal agent that has shown potential in in vitro experiments and in clinical trials. We tested PSC833 to determine whether it is a transported substrate of human and murine Pglycoproteins associated with multidrug resistance (encoded by the human MDR1 gene and its murine homolog, mdr1a) and whether it can completely inhibit these P-glycoproteins under simulated in vivo conditions. Methods : Monolayers of polarized LLC-PK1 pig kidney cells transfected with complementary DNA containing either MDR1 or mdr1a sequences were used to measure the directional transport of Pglycoprotein substrates under various serum conditions. Results : In contrast to two previous studies, we found that PSC833 is transported by both the MDR1 and the mdr1a P-glycoproteins, albeit at a low rate. PSC833 has a very high affinity for the MDR1 Pglycoprotein, and its Michaelis constant (K m ) for transport is 50 n M , fourfold lower than for cyclosporin A. Inhibition of drug transport by PSC833 is approximately eightfold less effective in 100% fetal bovine serum than in tissue culture medium containing 10% serum. The concentration of PSC833 necessary to fully inhibit transport of digoxin and paclitaxel (Taxol) under complete (i.e., 100%) serum conditions is higher than the plasma concentrations achieved in clinical trials. Conclusions : Although PSC833 binds efficiently to the MDR1 P-glycoprotein and is released only sluggishly, the high concentrations of PSC833 necessary to inhibit this P-glycoprotein under complete serum conditions in our in vitro system suggest that it may be difficult for PSC833 alone to produce total inhibition of P-glycoprotein activity in patients. [J Natl Cancer Inst 1998;90: 1161–6]
P85 Hiv-related Acute Respiratory Admissions - Good Outcomes And An Opportunity For Testing
Authors: P. Howlett, D. Lux, R. Kulasegaram, R. Breen
Journal: Thorax (2014)

<h3>Introduction</h3> The burden, changing pattern and outcome of HIV-associated lung disease following the introduction of anti-retroviral therapy (ART) remains to be defined. We sought to investigate these factors in an unselected cohort of individuals admitted acutely to our London teaching hospital. <h3>Methods</h3> Consecutive admissions were prospectively collected between June 2013 and May 2014. In those where the cause for admission was an acute respiratory illness, patient notes and electronic records were interrogated. Patients were allowed &gt;1 diagnoses and in-hospital outcomes only were reported. <h3>Results</h3> Fifty-three of 149 (35%) acute HIV admissions were with respiratory causes, (3 patients had 2 admissions &gt;30 days apart). Median age was 45 years and 28% (15) were female. Median CD4 count was 109 (range 3–867) cells/uL; 14 (26%) had fully suppressed HIV loads (VL &lt;20 copies/ml). 4 of 53 (8%) were admitted with non-infectious diagnoses: 2 with lung cancer, 1 non-infective COPD exacerbation and 1 non-specific interstitial pneumonia. The remainder had infections: 12 (23%) had culture-confirmed bacterial pneumonia, 11 (21%) were treated for PCP, 8 (15%) had culture-confirmed Mycobacterium tuberculosis (1 MDR), 4 had confirmed viral pneumonia (8%). 20 (38%) patients completed treatment for pneumonia with no specific laboratory confirmation. The most common bacterial isolates were streptococcus pneumoniae (4 cases), haemophilus influenzae (3), pseudomonas aureginosa (2) and klebsiella pneumoniae (2). In 11 of 53 (22%) a new diagnosis of HIV was made at the time of admission, 10 of whom presented as acute community acquired pneumonia (CAP). In 9 of 11 (82%) CD4 count was &lt;200 cells/uL and 6 of 11 (55%) required ICU care. In total 20 of 53 (38%) were admitted to ICU, and 8 (15%) required mechanical ventilation. Median length of stay in hospital was 9 (2–397) days. 1 of 53 (2%) patients died. <h3>Conclusions</h3> Acute respiratory illness remains a significant cause of HIV admissions, with opportunistic and non-opportunistic pathogens commonly identified. Outcomes were reassuringly good despite the frequent need for ICU support. We believe our data underlines the important opportunity that a presentation with acute respiratory illness provides to test for and diagnose HIV infection.
OPEN DOOR POLICY ON AN ADOLESCENT SERVICE IN A PSYCHIATRIC HOSPITAL
Authors: JAMES M. TOOLAN, GEORGE NICKLIN
Journal: American Journal of Psychiatry (1959)

A short description has been offered of the effects of opening the doors of the adolescent service of a psychiatric hospital. In view of the situation of the hospital and the type of patients involved, we feel that the program to date has been successful. While a slight increase in elopements did occur from the boys' ward, the benefits to the patients and staff have in our opinion more than compensated.
Hearing Aid for Vertebrates via Multiple Episodic Adaptive Events on Prestin Genes
Authors: Z. Liu, G.-H. Li, J.-F. Huang, R. W. Murphy, P. Shi
Journal: Molecular Biology and Evolution (2012)

Auditory detection is essential for survival and reproduction of vertebrates, yet the genetic changes underlying the evolution and diversity of hearing are poorly documented. Recent discoveries concerning prestin, which is responsible for cochlear amplification by electromotility, provide an opportunity to redress this situation. We identify prestin genes from the genomes of 14 vertebrates, including three fishes, one amphibian, one lizard, one bird, and eight mammals. An evolutionary analysis of these sequences and 34 previously known prestin genes reveals for the first time that this hearing gene was under positive selection in the most recent common ancestor (MRCA) of tetrapods. This discovery might document the genetic basis of enhanced high sound sensibility in tetrapods. An investigation of the adaptive gain and evolution of electromotility, an important evolutionary innovation for the highest hearing ability of mammals, detects evidence for positive selections on the MRCA of mammals, therians, and placentals, respectively. It is suggested that electromotility determined by prestin might initially appear in the MRCA of mammals, and its functional improvements might occur in the MRCA of therian and placental mammals. Our patch clamp experiments further support this hypothesis, revealing the functional divergence of voltage-dependent nonlinear capacitance of prestin from platypus, opossum, and gerbil. Moreover, structure-based cdocking analyses detect positively selected amino acids in the MRCA of placental mammals that are key residues in sulfate anion transport. This study provides new insights into the adaptation and functional diversity of hearing sensitivity in vertebrates by evolutionary and functional analysis of the hearing gene prestin.
Pulmonary oedema precipitated by cold water swimming
Authors: R Biswas, P K Shibu, C M James
Journal: British Journal of Sports Medicine (2004)

The case is reported of a physically fit man, who, while training for a triathlon, developed pulmonary oedema secondary to swimming in cold water. Pulmonary oedema is usually caused by a combination of exercise and cold water, resulting in an increase in cardiac preload and after load, which causes an increase in pulmonary capillary pressure. Most cases improve spontaneously and quickly with no recurrence of symptoms.
Elevated number of recently activated T cells in bone marrow of patients with rheumatoid arthritis: a role for interleukin 15?
Authors: E. Kuca-Warnawin, T. Burakowski, W. Kurowska, M. Prochorec-Sobieszek, A. Radzikowska, M. Chorazy-Massalska, P. Maldyk, E. Kontny, W. Maslinski
Journal: Annals of the Rheumatic Diseases (2010)

<h3>Objectives</h3> (1) To compare the absolute T-cell numbers in bone marrow (BM) isolated from patients with rheumatoid arthritis (RA) and osteoarthritis (OA); (2) to measure the levels of soluble interleukin 15 (IL-15) and IL-7; (3) to analyse the expression of activation markers on T cells; (4) to analyse influence of IL-15 stimulation on T-cell proliferation. <h3>Methods</h3> BM samples were obtained from patients undergoing joint replacement surgery. Concentrations of IL-15 and IL-7 were measured using specific ELISAs. The absolute number of T lymphocytes, their activation status and proliferation were evaluated by flow cytometry. <h3>Results</h3> BM from patients with RA contained double the number of CD3 T cells in comparison with OA (6.1 vs 2.7 × 10<sup>6</sup> cells/ml, p&lt;0.008). Ratio CD3CD4:CD3CD8 was increased in RA BM, clearly indicating accumulation of CD3CD4 cells. T cells obtained from patients with RA expressed higher level of early activation markers than from OA. Elevated levels of IL-15 were found in BM plasma from patients with RA in comparison with patients with OA (1304.5±956.3 pg/ml and 760±238.7 pg/ml respectively, p&lt;0.01). These data were confirmed by immunohistochemistry of RA BM from regions proximal and distal to the joint. Although both CD3CD4 and CD3CD8 cells proliferated after IL-15 stimulation in vitro, CD3CD4 cells from patients with RA proliferated more vigorously than those from patients with OA, reflecting the composition of T-cell subsets in BM. <h3>Conclusion</h3> These results suggest that locally overproduced IL-15 may be responsible for the activation and proliferation of T cells in situ, reflected by significantly increased number of activated T cells in RA BM, possibly contributing to the pathogenesis of RA.
Infant Mortality in Socially Vulnerable Populations
Authors: William S. Nersesian
Journal: Annual Review of Public Health (1988)

Studies have shown for decades that certain subpopulations of infants, for example, those in poverty and in certain minority groups, are at substantially higher risk for illness and death than the national average. If mothers and infants of these “vulnerable populations” were as healthy as their “nonvulnerable” counterparts, as many as one third (approximately 12,000 deaths) of all infant deaths in the United States might be avoided each year. This paper is intended to document which infants are vulnerable, to quantitate the degree of risk where possible, and to outline potential changes in public policy that may lead to improvements in the health of these infants.
Cardiac Grafting of Engineered Heart Tissue in Syngenic Rats
Authors: Wolfram-Hubertus Zimmermann, Michael Didié, Gerald H. Wasmeier, Uwe Nixdorff, Andreas Hess, Ivan Melnychenko, Oliver Boy, Winfried L. Neuhuber, Michael Weyand, Thomas Eschenhagen
Journal: Circulation (2002)

Cell grafting has emerged as a novel approach to treat heart diseases refractory to conventional therapy. We hypothesize that survival and functional and electrical integration of grafts may be improved by engineering cardiac tissue constructs in vitro before grafting.Engineered heart tissue (EHT) was reconstituted by mixing cardiac myocytes from neonatal Fischer 344 rats with liquid collagen type I, matrigel, and serum-containing culture medium. EHTs were designed in circular shape (inner/outer diameter: 8/10 mm; thickness: 1 mm) to fit around the circumference of hearts from syngenic rats. After 12 days in culture and before implantation on uninjured hearts, contractile function of EHT was measured under isometric conditions. Baseline twitch tension amounted to 0.34+/-0.03 mN (n=33) and was stimulated by Ca(2+) and isoprenaline to 200+/-12 and 185+/-10% of baseline values, respectively. Despite utilization of a syngenic model immunosuppression (mg/kg BW: azathioprine 2, cyclosporine A 5, methylprednisolone 2) was necessary for EHT survival in vivo. Echocardiography conducted 7, 14, and 28 days after implantation demonstrated no change in left ventricular function compared with pre-OP values (n=9). Fourteen days after implantation, EHTs were heavily vascularized and retained a well organized heart muscle structure as indicated by immunolabeling of actinin, connexin 43, and cadherins. Ultrastructural analysis demonstrated that implanted EHTs surpassed the degree of differentiation reached before implantation. Contractile function of EHT grafts was preserved in vivo.EHTs can be employed for tissue grafting approaches and might serve as graft material to repair diseased myocardium.