tbuckley/cabot-search huggingface dataset:
Modulation of oestrogenic effects by progesterone antagonists in the rat uterus
Authors: K Chwalisz
Journal: Human Reproduction Update (1998)

Antiprogestins can modulate oestrogenic effects in various oestrogen-dependent tissues, dependent on species, tissue, dose and duration of treatment. Enhanced oestrogenic responses to mifepristone and onapristone occur in vitro and in vivo. However, the antiprogestins mifepristone, onapristone, and ZK 137 316 can block the ability of oestradiol to increase endometrial growth in non-human primates. Our purposes were firstly, to decide whether mifepristone and onapristone had direct oestrogenic activity in vitro and in the uterus of spayed and immature rats, and secondly, to discover whether antiprogestins exhibit inhibitory effects on oestrogen action in the uterus in spayed, oestrogen-substituted rats. In transactivation assays, mifepristone induced oestrogenic response, whereas onapristone had only marginal effects on reporter gene transcription. In immature rats, onapristone and mifepristone markedly increased uterine weights, and onapristone, but not mifepristone significantly enhanced endometrial luminal epithelial height, a sensitive oestrogen parameter. Conversely, in spayed and adrenalectomized rats, neither onapristone nor mifepristone changed uterine weights or endometrial morphology, indicating that their effects in immature rats were indirect. In spayed, oestrogen-substituted rats, antiprogestins did not block oestradiol-stimulated endometrial growth and luminal and glandular epithelium were stimulated more after antiprogestin plus oestrogen, than after oestradiol alone. All compounds induced compaction of the uterine stroma. In spayed rats, onapristone and some other 13alpha-configured (type 1) antagonists (ZK 135 569, ZK 131 535) reduced oestradiol-stimulated myometrial proliferation and induced an overall uterine weight reduction in animals treated with oestrogen and antiprogestins, in comparison with oestradiol-treated controls. 13beta- configured (type II) antagonists, including mifepristone, lilopristone and ZK 112 993, were not effective. In the uteri of spayed rats, onapristone was also found to enhance the oestradiol-stimulatory effect on expression of the oestrogen-dependent proto-oncogene, c-fos. In conclusion, antiprogestins do not inhibit, but rather enhance, oestrogen-induced uterine glandular and luminal epithelium in spayed rats, contrary to their effects in primates. The rat model is unsuitable to study endometrial antiproliferative effects of antiprogestins in primate uteri.
Proteolysis by Neutrophils
Authors: Edward J. Campbell, Robert M. Senior, John A. McDonald, David L. Cox, Jeanne M. Greco, Jill A. Landis
Journal: Journal of Clinical Investigation (1982)

Polymorphonuclear leukocytes have been implicated in connective tissue injury in a variety of disease processes. To gain insight into mechanisms by which neutrophils might degrade connective tissue macromolecules in the presence of proteinase inhibitors, we have used a model system that allows neutrophils to be held in vitro under physiologic conditions in close proximity to a very proteinase-sensitive substrate, 125I-labeled fibronectin. We have found: (a) neutrophils spread rapidly on the fibronectin substrate; (b) fibronectin proteolysis by neutrophils is largely attributable to released elastase, and is linearly related to cell number over the range of 2,000 to 30,000 cells per assay; (c) oxidants released from neutrophils stimulated by opsonized zymosan or phorbol myristate acetate do not protect released elastase from inhibition by α1-proteinase inhibitor or α2-macroglobulin; (d) neutrophil myeloperoxidase and enzymatically generated superoxide anion render α1-proteinase inhibitor ineffective against fibronectin proteolysis when neutrophils are added 30 min later; and (e) α1-proteinase inhibitor and α2-macroglobulin incompletely inhibit fibronectin proteolysis by neutrophils (79.8±6.3 and 73.5±12.0%, respectively.) The data suggested that proteolysis due to neutrophils that are in contact with susceptible macromolecules may occur due to partial exclusion of inhibitors from the cell-substrate interface. Although confirming that α1-proteinase inhibitor is ineffective against neutrophil-derived proteolysis after exposure to oxidants, these studies did not support the hypothesis that oxidants released from stimulated neutrophils enhance activity of proteinases they release in the presence of α1-proteinase inhibitor. We anticipate that further studies with this test system will be helpful in defining conditions that modulate inflammatory connective tissue injury in diseases such as pulmonary emphysema and rheumatoid arthritis.
EphB2 activity plays a pivotal role in pediatric medulloblastoma cell adhesion and invasion
Authors: Arend H. Sikkema, Wilfred F.A. den Dunnen, Esther Hulleman, Dannis G. van Vuurden, Guillermo Garcia-Manero, Hui Yang, Frank J.G. Scherpen, Kim R. Kampen, Eelco W. Hoving, Willem A. Kamps, Sander H. Diks, Maikel P. Peppelenbosch, Eveline S.J.M. de Bont
Journal: Neuro-Oncology (2012)

Eph/ephrin signaling has been implicated in various types of key cancer-enhancing processes, like migration, proliferation, and angiogenesis. In medulloblastoma, invading tumor cells characteristically lead to early recurrence and a decreased prognosis. Based on kinase-activity profiling data published recently, we hypothesized a key role for the Eph/ephrin signaling system in medulloblastoma invasion. In primary medulloblastoma samples, a significantly higher expression of EphB2 and the ligand ephrin-B1 was observed compared with normal cerebellum. Furthermore, medulloblastoma cell lines showed high expression of EphA2, EphB2, and EphB4. Stimulation of medulloblastoma cells with ephrin-B1 resulted in a marked decrease in in vitro cell adhesion and an increase in the invasion capacity of cells expressing high levels of EphB2. The cell lines that showed an ephrin-B1–induced phenotype possessed increased levels of phosphorylated EphB2 and, to a lesser extent, EphB4 after stimulation. Knockdown of EphB2 expression by short hairpin RNA completely abolished ephrin ligand–induced effects on adhesion and migration. Analysis of signal transduction identified p38, Erk, and mTOR as downstream signaling mediators potentially inducing the ephrin-B1 phenotype. In conclusion, the observed deregulation of Eph/ephrin expression in medulloblastoma enhances the invasive phenotype, suggesting a potential role in local tumor cell invasion and the formation of metastases.
Neurodiagnostic Abnormalities in Patients with Acute Renal Failure
Authors: Jerry D. Cooper, Virginia C. Lazarowitz, Allen I. Arieff
Journal: Journal of Clinical Investigation (1978)

Neurological abnormalities are a major cause of morbidity in patients with renal failure. The pathophysiology of these neurological changes is unclear, and the effects on them of dialysis and return of renal function have not been well studied. Studies were done in 31 patients who had acute renal failure (ARF), all of whom were either treated with dialysis within 5 days or did not survive. Studies on these patients included the electroencephalogram (EEG), motor nerve conduction velocity, and plasma Ca++ and parathyroid hormone (PTH) levels. Studies were done at the time ARF was diagnosed, after stabilization on dialysis, during the diuretic phase of ARF, and 3 mo after recovery from ARF. In 16 patients with acute or chronic renal failure who did not survive and in nine patients without renal disease who died, measurements were made in brain of content of Na+, K+, Cl−, Ca++, Mg++, and water.
Cardiocirculatory and metabolic responses at different walking intensities
Authors: M Schwarz, A Urhausen, L Schwarz, T Meyer, W Kindermann
Journal: British Journal of Sports Medicine (2005)

Although walking is a common physical activity, scientifically based training guidelines using standardised tests have not been established. Therefore this explorative study investigated the cardiovascular and metabolic load resulting from different walking intensities derived from maximal velocity (Vmax) during an incremental treadmill walking test.Oxygen uptake, heart rate (HR), blood concentrations of lactate and catecholamines, and rating of perceived exertion were recorded in 16 recreational athletes (mean (SD) age 53 (9) years) during three 30 minute walking trials at 70%, 80%, and 90% of Vmax (V70, V80, and V90) attained during an incremental treadmill walking test.Mean (SD) oxygen uptake was 18.2 (2.3), 22.3 (3.1), and 29.3 (5.0) ml/min/kg at V70, V80, and V90 respectively (p<0.001). V70 led to a mean HR of 110 (9) beats/min (66% HRmax), V80 to 124 (9) beats/min (75% HRmax), and V90 to 152 (13) beats/min (93% HRmax) (p<0.001). Mean (SD) lactate concentrations were 1.1 (0.2), 1.8 (0.6), and 3.9 (2.0) mmol/l at V70, V80, and V90 respectively (p<0.001). There were no significant differences between catecholamine concentrations at the different intensities. Rating of perceived exertion was 10 (2) at V70, 12 (2) at V80, and 15 (2) at V90. Twelve subjects reported muscular complaints during exercise at V90 but not at V70 and V80.Intensity and heart rate prescriptions for walking training can be derived from an incremental treadmill walking test. The cardiovascular and metabolic reactions observed suggest that V80 is the most efficient workload for training in recreational athletes. Further studies are needed to confirm these findings.
Exhaled nitric oxide and the risk of wheezing in infancy: the Generation R Study
Authors: C. Gabriele, V. W. Jaddoe, E. van Mastrigt, L. R. Arends, A. Hofman, H. A. Moll, J. C. de Jongste
Journal: European Respiratory Journal (2011)

We assessed whether exhaled nitric oxide fraction (<i>F</i><sub>eNO</sub>), a marker of eosinophilic airway inflammation, at 6 months was associated with the risk of wheezing during the first 2 yrs of life. In the Generation R birth cohort, pre- and post-natal risk factors for respiratory morbidity and respiratory symptoms were assessed by questionnaires at 6 and 24 months. In 428 infants, off-line mixed oral/nasal <i>F</i><sub>eNO</sub> was successfully measured during tidal breathing at 6 months. Complete data on <i>F</i><sub>eNO</sub> and respiratory symptoms within the first 6 months of life were available for 294 infants. <i>F</i><sub>eNO</sub> was higher in males, was positively associated with age and was negatively associated with upper and lower respiratory symptoms within the first 6 months. Logistic regression analysis showed that for every ppb increase of <i>F</i><sub>eNO</sub> measured at 6 months, infants had a 1.06 (95% confidence interval 1.01–1.11)-fold increased risk of wheezing in the second year of life. High <i>F</i><sub>eNO</sub> (&gt;17.5 ppb) showed a limited added value in predicting wheezing in the second year. We conclude that <i>F</i><sub>eNO</sub> at 6 months is positively associated with the risk of wheezing, but has limited added value in predicting wheezing in the second year of life in individual children.
Bone-Density Testing Interval and Transition to Osteoporosis in Older Women
Authors: Margaret L. Gourlay, Jason P. Fine, John S. Preisser, Ryan C. May, Chenxi Li, Li-Yung Lui, David F. Ransohoff, Jane A. Cauley, Kristine E. Ensrud
Journal: New England Journal of Medicine (2012)

Although bone mineral density (BMD) testing to screen for osteoporosis (BMD T score, −2.50 or lower) is recommended for women 65 years of age or older, there are few data to guide decisions about the interval between BMD tests.
Primary and secondary risk factors for birth defects.
Authors: K L Yielding
Journal: Environmental Health Perspectives (1993)

Birth defects may be inherited in the germ line or may result primarily from a wide spectrum of predictable physical, chemical, and infectious processes that can operate in the mother, the father, or in the zygote. The systematic consideration of these mechanisms can lead to a fresh awareness of risk and possible strategies toward recognizing and avoiding such risks. Birth defects also depend heavily on secondary factors that may even be of greater concern than any single primary insult because they may simultaneously affect the consequences of more than one primary exposure. Under the influence of secondary factors, the frequency, timing, and intensity of developmental deficiencies can be quite varied. It is particularly interesting that expression can be delayed until quite late in life, and deficiencies may occur or be expressed only in response to the appropriate environmental stress or functional demand. Any discussion of teratogenic mechanisms, therefore, is not complete without taking into account the important concept of co-teratogenesis, or the operation of secondary risk mechanisms. The principle of secondary risk or co-teratogenesis has been demonstrated by means of enhancement of radiation-induced terata by the administration of drugs that inhibit DNA repair. An example of late-onset expression of prenatal damage was illustrated with postnatal retinal degeneration occurring after prenatal damage to the developing retina. It is suggested that a systematic consideration of primary and secondary risk mechanisms can lead to a better understanding of the problem of birth defects.
Surgeon-related variance: how much longer for its recognition?
Authors: L Peter Fielding, Roger Grace, Rosemary Hittinger
Journal: Gut (2012)

We read with interest the paper by Morris et al , which looked at 30-day postoperative mortality after colorectal cancer surgery in England.1 In 1978, using the data from the large bowel cancer (LBC) project2 we made the case for looking at ‘surgeon’ as a highly significant variable in the context of randomised control trials. Each surgeon was given a random number independent of their institution to protect their confidentiality The results in the LBC project showed a wide variance in 30-day mortality between 0% and 5% up to 21% and for clinical anastomotic leak, the …
ADAM15 regulates endothelial permeability and neutrophil migration via Src/ERK1/2 signalling
Authors: C. Sun, M. H. Wu, M. Guo, M. L. Day, E. S. Lee, S. Y. Yuan
Journal: Cardiovascular Research (2010)

Endothelial barrier dysfunction is a key event in the pathogenesis of vascular diseases associated with inflammation. ADAM (a disintegrin and metalloprotease) 15 has been shown to contribute to the development of vascular inflammation. However, its role in regulating endothelial barrier function is unknown. The aim of this study was to examine the effect of ADAM15 on endothelial permeability and its underlying mechanisms.By measuring albumin transendothelial flux and transendothelial electric resistance in cultured human umbilical vein endothelial cell monolayers, we found that depletion of ADAM15 expression via siRNA decreased endothelial permeability and attenuated thrombin-induced barrier dysfunction. In contrast, endothelial cells overexpressing either wild-type or catalytically dead mutant ADAM15 displayed a higher basal permeability and augmented hyperpermeability in response to thrombin. In addition, ADAM15 knockdown inhibited whereas ADAM15 overexpression promoted neutrophil transendothelial migration. Further molecular assays revealed that ADAM15 did not cleave vascular endothelial-cadherin or cause its degradation. However, overexpression of ADAM15 promoted extracellular signal-regulated kinase (ERK)1/2 phosphorylation in both non-stimulated and thrombin-stimulated endothelial cells in a protease activity-independent manner. Pharmacological inhibition of Src kinase or ERK activation reversed ADAM15-induced hyperpermeability and neutrophil transmigration.The data provide evidence for a novel function of ADAM15 in regulating endothelial barrier properties. The mechanisms of ADAM15-induced hyperpermeability involve Src/ERK1/2 signalling independent of junction molecule shedding.
Effect of antiviral treatment on evolution of liver steatosis in patients with chronic hepatitis C: indirect evidence of a role of hepatitis C virus genotype 3 in steatosis
Authors: L Castera
Journal: Gut (2004)

Recent studies suggest that liver steatosis in chronic hepatitis C may be the expression of a direct cytopathic effect of hepatitis C virus (HCV), particularly in patients infected with genotype 3. To investigate this hypothesis, we studied the relationship between steatosis evolution and HCV clearance after antiviral treatment in patients with chronic hepatitis C and paired liver biopsies.A total of 151 patients (37 with HCV genotype 3; 114 with HCV non-3 genotypes) were selected according to the following criteria: presence of steatosis at initial biopsy; no antiviral treatment prior to the first biopsy; antiviral treatment received between the two biopsies; body mass index (BMI) <28 kg/m(2); absence of excessive alcohol intake; no serum hepatitis B surface antigen or human immunodeficiency virus antibodies; and absence of diabetes mellitus. Evolution of steatosis was examined by comparing steatosis grades between the two biopsies.Twenty five patients (16.5%) were sustained virological responders (SVR) to antiviral treatment. Steatosis evolution after antiviral treatment was as follows: improvement in 36% of cases; stability in 51%; and worsening in 13%. Steatosis improvement was significantly more frequent in SVR than in non-responders (NR) (64% v 31%; p<0.004). This significant difference occurred in patients infected with genotype 3 (91% v 19%; p<0.0001) but not in those infected with non-3 genotypes (43% v 34%; NS). Among the 25 SVR, improvement in steatosis was significantly more frequent in patients infected with genotype 3 than in those infected with non-3 genotypes (91% v 43%; p<0.04) whereas in NR, improvement in steatosis did not differ between those infected with genotype 3 and non-3 genotypes (19% v 34%; NS). In multivariate analysis, four factors were independently associated with steatosis improvement: sustained virological response to antiviral therapy (odds ratio (OR) 6.06 (95% confidence interval (CI) 1.61-22.9); p = 0.01), severe steatosis (OR 5.50 (95% CI 1.54-19.6); p = 0.01), HCV genotype 3 (OR 2.90 (95% CI 0.85-10.0); p = 0.07), and BMI >25 kg/m(2) (OR 0.24 (95% CI 0.08-0.73); p = 0.02).Our results showed significant improvement in steatosis in patients infected with HCV genotype 3, who achieved sustained viral clearance. This provides further evidence for direct involvement of HCV genotype 3 in the pathogenesis of hepatic steatosis.
Genetic modifiers in carriers of repeat expansions in the C9ORF72 gene
Authors: Marka van Blitterswijk, Bianca Mullen, Aleksandra Wojtas, Michael G Heckman, Nancy N Diehl, Matthew C Baker, Mariely DeJesus-Hernandez, Patricia H Brown, Melissa E Murray, Ging-Yuek R Hsiung, Heather Stewart, Anna M Karydas, Elizabeth Finger, Andrew Kertesz, Eileen H Bigio, Sandra Weintraub, Marsel Mesulam, Kimmo J Hatanpaa, Charles L White, Manuela Neumann, Michael J Strong, Thomas G Beach, Zbigniew K Wszolek, Carol Lippa, Richard Caselli, Leonard Petrucelli, Keith A Josephs, Joseph E Parisi, David S Knopman, Ronald C Petersen, Ian R Mackenzie, William W Seeley, Lea T Grinberg, Bruce L Miller, Kevin B Boylan, Neill R Graff-Radford, Bradley F Boeve, Dennis W Dickson, Rosa Rademakers
Journal: Molecular Neurodegeneration (2014)

Hexanucleotide repeat expansions in chromosome 9 open reading frame 72 (C9ORF72) are causative for frontotemporal dementia (FTD) and motor neuron disease (MND). Substantial phenotypic heterogeneity has been described in patients with these expansions. We set out to identify genetic modifiers of disease risk, age at onset, and survival after onset that may contribute to this clinical variability. We examined a cohort of 330 C9ORF72 expansion carriers and 374 controls. In these individuals, we assessed variants previously implicated in FTD and/or MND; 36 variants were included in our analysis. After adjustment for multiple testing, our analysis revealed three variants significantly associated with age at onset (rs7018487 [UBAP1; p-value = 0.003], rs6052771 [PRNP; p-value = 0.003], and rs7403881 [MT-Ie; p-value = 0.003]), and six variants significantly associated with survival after onset (rs5848 [GRN; p-value = 0.001], rs7403881 [MT-Ie; p-value = 0.001], rs13268953 [ELP3; p-value = 0.003], the epsilon 4 allele [APOE; p-value = 0.004], rs12608932 [UNC13A; p-value = 0.003], and rs1800435 [ALAD; p-value = 0.003]). Variants identified through this study were previously reported to be involved in FTD and/or MND, but we are the first to describe their effects as potential disease modifiers in the presence of a clear pathogenic mutation (i.e. C9ORF72 repeat expansion). Although validation of our findings is necessary, these variants highlight the importance of protein degradation, antioxidant defense and RNA-processing pathways, and additionally, they are promising targets for the development of therapeutic strategies and prognostic tests.
Inaccuracy of tidal volume delivered by home mechanical ventilators
Authors: F Lofaso, R. Fodil, H. Lorino, K. Leroux, A Quintel, A Leroy, A Harf
Journal: European Respiratory Journal (2000)

Ideally, the inspired (tidal) volume (V(T)) provided by a volume-controlled ventilation device should not change when the pressure imposed on the ventilator varies. A bench study evaluation of V(T) versus pressure was performed on 10 commercially available devices. The difference between the desired V(T) and the observed V(T) reached 100 mL for some devices when inspiratory resistance was at its lowest, rising to 150 mL when inspiratory resistance was increased to obtain peak airway pressure of 60 cmH2O. The present data indicate that some home ventilators are inaccurate in delivering the preset tidal volume when the pressure imposed on the ventilator is increased to simulate high airway resistance.