tbuckley/cabot-search huggingface dataset:
Nebulized Hypertonic Saline for Bronchiolitis
Authors: Susan Wu, Chris Baker, Michael E. Lang, Sheree M. Schrager, Fasha F. Liley, Carmel Papa, Valerie Mira, Ara Balkian, Wilbert H. Mason
Journal: JAMA Pediatrics (2014)

Bronchiolitis is one of the most common and costly respiratory diseases in infants and young children. Previous studies have shown a potential benefit of nebulized hypertonic saline; however, its effect in the emergency department (ED) setting is unclear.To compare the effect of nebulized 3% hypertonic saline vs 0.9% normal saline on admission rate and length of stay in infants with bronchiolitis.We conducted a double-blind, randomized clinical trial during 3 consecutive bronchiolitis seasons from March 1, 2008, through April 30, 2011. We recruited a convenience sample of patients younger than 24 months with a primary diagnosis of viral bronchiolitis presenting to the ED of 2 urban free-standing tertiary children's hospitals. We excluded patients who were premature (gestational age, <34 weeks) or who had chronic pulmonary disease, immune deficiency, cardiac disease, or previous episodes of wheezing or inhaled bronchodilator use. Of eligible patients who were approached, 161 (26.6%) declined to participate.Patients received 4 mL of 3% sodium chloride (hypertonic saline [HS group]) or 0.9% sodium chloride (normal saline [NS group]) inhaled as many as 3 times in the ED. Those admitted received the assigned medication every 8 hours until discharge. All treatment solutions were premedicated with albuterol sulfate.Hospital admission rate, length of stay for admitted patients, and Respiratory Distress Assessment Instrument score.A total of 197 patients were enrolled in the NS group and 211 in the HS group. Admission rate in the 3% HS group was 28.9% compared with 42.6% in the NS group (adjusted odds ratio from logistic regression, 0.49 [95% CI, 0.28-0.86]). Mean (SD) length of stay for hospitalized patients was 3.92 (5.24) days for the NS group and 3.16 (2.11) days for the HS group (P = .24). The Respiratory Distress Assessment Instrument score decreased after treatment in both groups; however, we found no significant difference between groups (P = .35).Hypertonic saline given to children with bronchiolitis in the ED decreases hospital admissions. We can detect no significant difference in Respiratory Distress Assessment Instrument score or length of stay between the HS and NS groups.clinicaltrials.gov Identifier: NCT00619918.
Occlusive Fibroelastosis of Coronary Arteries in the Newborn
Authors: H. EDWARD MACMAHON, P. C. TAYLOR DICKINSON
Journal: Circulation (1967)

A developmental anomaly in the form of occlusive fibroelastosis of the proximal segments of both coronary arteries, leading to progressive myocardial infarction and death, was found in the course of an autopsy on a 6-week-old infant. Congenital malformations of the coronary arteries are not uncommon, but a report of one such as this has not been found in the literature.
Tempo and mode of concerted evolution in the L1 repeat family of mice.
Authors: S L Martin, C F Voliva, S C Hardies, M H Edgell, C A Hutchison
Journal: Molecular Biology and Evolution (1985)

A 300-bp DNA sequence has been determined for 30 (10 from each of three species of mice) random isolates of a subset of the long interspersed repeat family L1. From these data we conclude that members of the L1 family are evolving in concert at the DNA sequence level in Mus domesticus, Mus caroli, and Mus platythrix. The mechanism responsible for this phenomenon may be either duplicative transposition, gene conversion, or a combination of the two. The amount of intraspecies divergence averages 4.4%, although between species base substitutions accumulate at the rate of approximately 0.85%/Myr to a maximum divergence of 9.1% between M. platythrix and both M. domesticus and M. caroli. Parsimony analysis reveals that the M. platythrix L1 family has evolved into a distinct clade in the 10-12 Myr since M. platythrix last shared a common ancestor with M. domesticus and M. caroli. The parsimony tree also provides a means to derive the average half-life of L1 sequences in the genome. The rates of gain and loss of individual copies of L1 were estimated to be approximately equal, such that approximately one-half of them turn over every 3.3 Myr.
Euthanasia and Depression: A Prospective Cohort Study Among Terminally Ill Cancer Patients
Authors: Marije L. van der Lee, Johanna G. van der Bom, Nikkie B. Swarte, A. Peter M. Heintz, Alexander de Graeff, Jan van den Bout
Journal: Journal of Clinical Oncology (2005)

To study the association between depression and the incidence of explicit requests for euthanasia in terminally ill cancer patients.A prospective cohort study was conducted on 138 consecutive cancer patients with an estimated life expectancy of 3 months or less, in the period between September 1999 and August 2003. At inclusion, participants completed the Hospital Anxiety and Depression Scale. To identify "depressed mood" we used a cutoff score of 20. Kaplan-Meier curves and Cox regression analyses were used to assess the association between depressed mood and the risk of a request for euthanasia.Of 138 patients, 32 patients had depressed mood at inclusion. Thirty patients (22%) made an explicit request for euthanasia. The risk to request euthanasia for patients with depressed mood was 4.1 times higher than that of patients without depressed mood at inclusion (95% CI, 2.0 to 8.5).Depression in cancer patients with an estimated life expectancy of less than 3 months is associated with a higher likelihood to request for euthanasia. The question of whether depressed mood can adequately be treated in this terminally ill population, and if so, whether it would lower the incidence of requests for euthanasia needs further investigation.
Role of Lipooligosaccharide in Opa-Independent Invasion of <i>Neisseria gonorrhoeae</i> into Human Epithelial Cells
Authors: Wenxia Song, Lang Ma, Ruiwu Chen, Daniel C. Stein
Journal: The Journal of Experimental Medicine (2000)

Lipooligosaccharide (LOS) has been implicated in the adhesion and invasion of host epithelial cells. We examined the adhesive and invasive abilities of isogenic gonococcal opacity-associated outer membrane protein-negative, pilus-positive (Opa-Pil+) Neisseria gonorrhoeae strains expressing genetically defined LOS. Strain F62 (Opa-Pil+), expressing the lacto-N-neotetraose and the galNac-lacto-N-neotetraose LOS, and its isogenic derivative that expressed only the lacto-N-neotetraose LOS (F62 Delta lgtD), adhered to, and invaded, to the same extent the human cervical epidermoid carcinoma cell line, ME180. While the adhesive abilities of Opa-Pil+ isogenic strains that express LOS molecules lacking the lacto-N-neotetraose structure were similar to that seen for F62, their invasive abilities were much lower than the strains expressing lacto-N-neotetraose. Fluorescence microscopy studies showed that the adherence of F62, but not the strains lacking lacto-N-neotetraose, induced the rearrangement of actin filaments under the adherent sites. Electron microscopy studies demonstrated that F62, but not the strains lacking lacto-N-neotetraose, formed extensive and intimate associations with epithelial cell membranes. Thus, in the absence of detectable Opa protein, the lacto-N-neotetraose LOS promotes gonococcal invasion into ME180 cells. The data also suggest that LOS is involved in the mobilization of actin filaments in host cells, and in the formation of a direct interaction between the bacterial outer membrane and the plasma membrane of ME180 cells.
Avascular necrosis of bone complicating corticosteroid replacement therapy.
Authors: P L Williams, M Corbett
Journal: Annals of the Rheumatic Diseases (1983)

Two patients who developed widespread severe avascular necrosis of bone while on steroid replacement therapy are described. One, a diabetic, underwent yttrium-90 pituitary ablation for retinopathy and developed avascular necrosis within 18 months of starting prednisolone. The other, who had Addison's disease, developed avascular necrosis within 14 months of starting cortisol replacement therapy. Both cases came to bilateral total hip replacement.
Extracellular matrix protein CCN1 regulates cardiomyocyte apoptosis in mice with stress-induced cardiac injury
Authors: P.-L. Hsu, B.-C. Su, Q.-Y. Kuok, F.-E. Mo
Journal: Cardiovascular Research (2013)

Expression of extracellular matrix protein CCN1 is induced in end-stage ischaemic cardiomyopathy in humans, and after cardiac ischaemia and reperfusion in experimental animal models. Despite its well-documented angiogenic activities, CCN1 increases the cytotoxicities of the tumour necrosis factor family cytokines, which promotes apoptosis in fibroblasts. We aimed to determine the physiological function of CCN1 in an injured heart.To assess the function of CCN1 in vivo, knock-in mice carrying the apoptosis-defective mutant allele Ccn1-dm were tested in an isoproterenol (ISO)-induced myocardial injury model (100 mg/kg/day of sc injected ISO for 5 days). Compared with wild-type mice, Ccn1(dm/dm) mice were remarkably resistant to ISO-induced cardiac injury; they showed no post-treatment cardiomyocyte apoptosis or myocardial tissue damage. ISO cardiotoxicity was dependent on Fas ligand (FasL) and its downstream signalling. Using primary cultures of cardiomyocytes isolated from rats, we demonstrated that CCN1 sensitized FasL-mediated apoptosis by engaging its cell-surface receptor integrin α6β1 and up-regulating intracellular reactive oxygen species (ROS), which activated mitogen-activated protein kinase p38, and increased cell-surface Fas expression.CCN1 is a critical pathophysiological regulator that mediates cardiomyocyte apoptosis during work-overload-induced cardiac injury. CCN1 increases cellular susceptibility to Fas-induced apoptosis by increasing ROS and cell-surface Fas expression.
The Cavβ subunit prevents RFP2-mediated ubiquitination and proteasomal degradation of L-type channels
Authors: Christophe Altier, Agustin Garcia-Caballero, Brett Simms, Haitao You, Lina Chen, Jan Walcher, H William Tedford, Tamara Hermosilla, Gerald W Zamponi
Journal: Nature Neuroscience (2010)
Utility and appropriateness of the fatty liver inhibition of progression (FLIP) algorithm and steatosis, activity, and fibrosis (SAF) score in the evaluation of biopsies of nonalcoholic fatty liver disease
Authors: Pierre Bedossa
Journal: Hepatology (2014)

Biopsy is still the gold standard for the diagnosis of nonalcoholic steatohepatitis but the definition may vary among pathologists, a drawback especially in evaluation of biopsies for clinical trials. We previously developed a scoring system (steatosis, activity, fibrosis [SAF]) allowing the use of an algorithm (fatty liver inhibition of progression [FLIP]) for the classification of liver injury in morbid obesity. The aim of this study was to determine whether the use of the SAF score and FLIP algorithm can decrease interobserver variations among pathologists. In a first session, pathologists categorized 40 liver biopsies of patients with nonalcoholic fatty liver disease (NAFLD) according to their own experience. In a second reading session, each pathologist reclassified the same slides by using the FLIP algorithm and SAF score, blinded to their first evaluation. The experiment was repeated with two different groups of pathologists at varying levels of training in liver pathology. The percentage of biopsy interpretation concordant with reference evaluation increased from 77% to 97% in Group 1 and from 42% to 75% in Group 2 after the use of the SAF score and FLIP algorithm. The strength of concordance in classification increased in Group 1 from moderate (κ = 0.54) to substantial (κ = 0.66) and from fair (κ = 0.35) to substantial (κ = 0.61) in Group 2 with application of the algorithm. With regard to the SAF score, concordance was substantial in Group 1 for steatosis (κ = 0.61), activity (κ = 0.75), and almost perfect for fibrosis (κ = 0.83 after pooling 1a, 1b, and 1c together into a single score F1). Similar trends were observed in Group 2 (κ = 0.54 for S, κ = 0.68 for A, and κ = 0.72 for F). Conclusion : The FLIP algorithm based on the SAF score should decrease interobserver variations among pathologists and are likely to be implemented in pathology practice. (Hepatology 2014;60:565–575)
High salt reduces the activation of IL-4– and IL-13–stimulated macrophages
Authors: Katrina J. Binger, Matthias Gebhardt, Matthias Heinig, Carola Rintisch, Agnes Schroeder, Wolfgang Neuhofer, Karl Hilgers, Arndt Manzel, Christian Schwartz, Markus Kleinewietfeld, Jakob Voelkl, Valentin Schatz, Ralf A. Linker, Florian Lang, David Voehringer, Mark D. Wright, Norbert Hubner, Ralf Dechend, Jonathan Jantsch, Jens Titze, Dominik N. Müller
Journal: Journal of Clinical Investigation (2015)

A high intake of dietary salt (NaCl) has been implicated in the development of hypertension, chronic inflammation, and autoimmune diseases. We have recently shown that salt has a proinflammatory effect and boosts the activation of Th17 cells and the activation of classical, LPS-induced macrophages (M1). Here, we examined how the activation of alternative (M2) macrophages is affected by salt. In stark contrast to Th17 cells and M1 macrophages, high salt blunted the alternative activation of BM-derived mouse macrophages stimulated with IL-4 and IL-13, M(IL-4+IL-13) macrophages. Salt-induced reduction of M(IL-4+IL-13) activation was not associated with increased polarization toward a proinflammatory M1 phenotype. In vitro, high salt decreased the ability of M(IL-4+IL-13) macrophages to suppress effector T cell proliferation. Moreover, mice fed a high salt diet exhibited reduced M2 activation following chitin injection and delayed wound healing compared with control animals. We further identified a high salt-induced reduction in glycolysis and mitochondrial metabolic output, coupled with blunted AKT and mTOR signaling, which indicates a mechanism by which NaCl inhibits full M2 macrophage activation. Collectively, this study provides evidence that high salt reduces noninflammatory innate immune cell activation and may thus lead to an overall imbalance in immune homeostasis.
Characteristics of flow-mediated brachial artery vasodilation in human subjects.
Authors: L I Sinoway, C Hendrickson, W R Davidson, S Prophet, R Zelis
Journal: Circulation Research (1989)

In an effort to determine whether arterial conductance vessels dilate in response to increased blood flow stimuli, brachial artery area (cm2) and diameter (cm) were derived by simultaneous measurement of forearm blood flow (ml/min.100 ml) and brachial artery blood flow velocity (cm/sec) following the release of arterial occlusion. Measurements were made at rest and at the time of maximal flow after the release of graded periods of forearm arterial occlusion (20 seconds to 10 minutes). These studies showed a graded large vessel dilation following occlusions of up to 1 minute (baseline diameter, 0.33 +/- 0.01; after 1 minute occlusion, 0.45 +/- 0.02 cm; p less than 0.05) after which time diameter plateaued (after 10 minutes of occlusion, 0.48 +/- 0.02 cm). In addition, the time course of diameter and flow changes after 3 minutes of arterial occlusion were examined. Flow was maximal at 5 seconds but diameter was maximal at 15-30 seconds after release. Furthermore, the half time for the return of diameter to baseline was longer than that for blood flow. We also measured the diameter after forearm heating (42 degrees C) and noted a substantial increase in diameter (before heating, 0.32 +/- 0.01; after heating, 0.39 +/- 0.02 cm; p less than 0.05). Finally, we applied pressure to the venous side of arteriovenous fistulae in five hemodialysis patients. This maneuver was associated with large reductions in forearm blood flow (baseline flow, 63.3 +/- 10.6; venous compression flow, 36.0 +/- 4.4 ml/min.100 ml; p less than 0.05) and a decrease in brachial artery size (baseline diameter, 0.63 +/- 0.07; venous compression diameter, 0.58 +/- 0.06 cm; p less than 0.05). We conclude that 1) the human brachial artery size changes in response to changes in blood flow, and 2) the maximal dilation occurs after maximal flow is noted. Although alternate explanations are possible for each of our observations, our results are most consistent with a flow-mediated, localized vasodilating process.
A case of primary cutaneous CD30+ T-cell lymphoproliferative disorder with features of granulomatous slack skin disease
Authors: K. Wada, C. Maesawa, T. Satoh, T. Akasaka, T. Masuda
Journal: British Journal of Dermatology (2002)

We present a patient with primary CD30+ cutaneous T-cell lymphoma whose histological and clinical features overlapped with those of granulomatous slack skin disease (GSSD). A 26-year-old woman had infiltrative erythema on the abdominal wall and an incurable ulcerative lesion on the left knee. Her skin progressively became atrophic and pendulous, showing a hyperpigmented appearance over almost the whole body. Histopathologically, a dense lymphoid cell infiltrate accompanying numerous macrophages and multinucleated giant cells (MGC) extended into the subcutaneous tissue. Most lymphoid cells were small and positive for T-cell markers. Some relatively large atypical cells were scattered in the lesion, most of which (60%) were positive for CD30. T-cell receptor-beta gene rearrangement was confirmed in the abdominal lesion. MGC infiltrated more dominantly into a deeeper layer of the skin with the elastic fibres there almost completely disappearing. Immunoreactivity for CD30 of MGC was negative and overexpression of elastolytic metalloproteinases was observed. The association between primary cutaneous CD30+ lym- phoproliferative disorders and GSSD has not previously been reported. Overexpression of elastolytic metalloproteinases in MGC contributes to the disappearance of the elastic fibres and enhances the severity of the clinical course.
Vitamin B6 deficiency in chronic liver disease--evidence for increased degradation of pyridoxal-5'-phosphate.
Authors: D Labadarios, J E Rossouw, J B McConnell, M Davis, R Williams
Journal: Gut (1977)

Plasma levels of pyridoxal-5'-phosphate (PLP), the active coenzyme form of vitamin B6, were found to be significantly lower than normal in 22 out of 31 patients with decompensated cirrhosis or subacute hepatic necrosis. There was no significant difference in plasma PLP levels between those with liver disease due to alcohol and those with other varieties. When intravenous supplements with pyridoxine hydrochloride were given only 33% responded with an increase in plasma PLP. In contrast, all patients given PLP responded, although peak plasma levels were variable, the response being significantly less than that found in normal control subjects. After supplementation with pyridoxine hydrochloride, and with PLP, the urinary excretion of 4-pyridoxic acid, which is derived from the degradation of PLP, was higher in patients who showed the least increase in plasma PLP levels. Although impaired phosphorylation of pyridoxine hydrochloride may be one factor, the most likely explanation for these findings is an increased rate of PLP degradation which may be important in the pathogenesis of vitamin B6 deficiency in patients with severe liver disease.
RKI-1447 Is a Potent Inhibitor of the Rho-Associated ROCK Kinases with Anti-Invasive and Antitumor Activities in Breast Cancer
Authors: Ronil A. Patel, Kara D. Forinash, Roberta Pireddu, Ying Sun, Nan Sun, Mathew P. Martin, Ernst Schönbrunn, Nicholas J. Lawrence, Saïd M. Sebti
Journal: Cancer Research (2012)

Abstract The Rho-associated kinases ROCK1 and ROCK2 are critical for cancer cell migration and invasion, suggesting they may be useful therapeutic targets. In this study, we describe the discovery and development of RKI-1447, a potent small molecule inhibitor of ROCK1 and ROCK2. Crystal structures of the RKI-1447/ROCK1 complex revealed that RKI-1447 is a Type I kinase inhibitor that binds the ATP binding site through interactions with the hinge region and the DFG motif. RKI-1447 suppressed phosphorylation of the ROCK substrates MLC-2 and MYPT-1 in human cancer cells, but had no effect on the phosphorylation levels of the AKT, MEK, and S6 kinase at concentrations as high as 10 μmol/L. RKI-1447 was also highly selective at inhibiting ROCK-mediated cytoskeleton re-organization (actin stress fiber formation) following LPA stimulation, but does not affect PAK-meditated lamellipodia and filopodia formation following PDGF and Bradykinin stimulation, respectively. RKI-1447 inhibited migration, invasion and anchorage-independent tumor growth of breast cancer cells. In contrast, RKI-1313, a much weaker analog in vitro, had little effect on the phosphorylation levels of ROCK substrates, migration, invasion or anchorage-independent growth. Finally, RKI-1447 was highly effective at inhibiting the outgrowth of mammary tumors in a transgenic mouse model. In summary, our findings establish RKI-1447 as a potent and selective ROCK inhibitor with significant anti-invasive and antitumor activities and offer a preclinical proof-of-concept that justify further examination of RKI-1447 suitability as a potential clinical candidate. Cancer Res; 72(19); 5025–34. ©2012 AACR.
Sputum eosinophilia is more closely associated with airway responsiveness to bradykinin than methacholine in asthma
Authors: R Polosa, L Renaud, R Cacciola, G Prosperini, N Crimi, R Djukanovic
Journal: European Respiratory Journal (1998)

Hyperresponsiveness of the airways to various spasmogenic stimuli is a characteristic feature of bronchial asthma. However, the association between the different stimuli to which asthmatic airways are hyperresponsive and airways inflammation is not completely understood. We have investigated the relationship between airway inflammation and airway hyperresponsiveness in asthma, as assessed by bronchoprovocation tests to methacholine and bradykinin, two well defined bronchoconstrictor agonists. Sputum induction by hypertonic saline and methacholine and bradykinin challenges were performed in 14 nonsmoking subjects with mild-to-moderate asthma. Airway responsiveness to either agonist did not correlate with sputum neutrophils, lymphocytes, and macrophages. Whilst the absolute number of eosinophilia failed to be significantly related to methacholine responsiveness (r=-0.47; p=0.09), it correlated markedly and significantly with provocative concentration of methacholine causing a 20% fall in forced expiratory volume in one second (r=0.72; p&lt;0.01). When expressed as % of total cell counts, sputum eosinophils correlated with both types of responsiveness (r=-056; p=0.04 and r=-0.76, p&lt;0.001, respectively). Although the concentration of eosinophil cationic protein (ECP) in the sputum correlated with the absolute numbers of eosinophils (r=0.62; p&lt;0.02), no correlation was found between ECP levels and the airway responsiveness to any of the agonists tested. In subjects with mild-to-moderate asthma, airway responsiveness to bradykinin is more strongly associated with the magnitude of eosinophilic inflammation in the airways than methacholine. This finding underlines the selectivity of diverse agonists in assessing airway hyperresponsiveness and cellular inflammation in asthma.