tbuckley/cabot-search huggingface dataset:
Hypoxia and Hypoxia/Reoxygenation Activate Raf-1, Mitogen-Activated Protein Kinase Kinase, Mitogen-Activated Protein Kinases, and S6 Kinase in Cultured Rat Cardiac Myocytes
Authors: Yoshinori Seko, Kazuyuki Tobe, Kohjiro Ueki, Takashi Kadowaki, Yoshio Yazaki
Journal: Circulation Research (1996)

Abstract In response to hypoxia and reoxygenation, mammalian cells are known to express a variety of genes to adapt to these external stresses or lead to further cell damage. We investigated the intracellular signaling cascades in cultured rat cardiac myocytes subjected to hypoxia or hypoxia followed by reoxygenation (hypoxia/reoxygenation). Here, we show that both hypoxia and hypoxia/reoxygenation caused rapid activation of the mitogen-activated protein kinase kinase kinase (MAPKKK) activity of Raf-1. This was followed by the sequential activation of mitogen-activated protein kinase kinase (MAPKK), mitogen-activated protein (MAP) kinases, and S6 kinase (p90 rsk ). Furthermore, hypoxia caused hyperphosphorylation of Raf-1. The maximal hyperphosphorylation of Raf-1 appeared to be accompanied by a significant decrease in MAPKKK activity. These results strongly suggest the following: (1) Intracellular signals initiated by both hypoxia and hypoxia/reoxygenation converge on Raf-1 and activate its MAPKKK activity. Then, Raf-1 activates downstream serine/threonine kinases including MAPKK, MAP kinases, and p90 rsk . (2) Raf-1 is not only located upstream from MAPKK and MAP kinases but also may be phosphorylated by MAP kinases directly or indirectly, and at least Raf-1 kinase activity may be downregulated by this feedback mechanism.
A Randomized, Dose-Escalation Study of Subconjunctival and Intravitreal Injections of Sirolimus in Patients with Diabetic Macular Edema
Authors: Pravin U. Dugel, Mark S. Blumenkranz, Julia A. Haller, George A. Williams, Wayne A. Solley, David M. Kleinman, Joel Naor
Journal: Ophthalmology (2011)
Plasmacytoid dendritic cell–specific receptor ILT7–FcεRIγ inhibits Toll-like receptor–induced interferon production
Authors: Wei Cao, David B. Rosen, Tomoki Ito, Laura Bover, Musheng Bao, Gokuran Watanabe, Zhengbin Yao, Li Zhang, Lewis L. Lanier, Yong-Jun Liu
Journal: The Journal of Experimental Medicine (2006)

Immunoglobulin-like transcripts are a family of inhibitory and stimulatory cell surface immune receptors. Transcripts for one member of this family, ILT7, are selectively expressed in human plasmacytoid dendritic cells (pDCs). We demonstrate here that ILT7 protein associates with the signal adapter protein FcεRIγ to form a receptor complex. Using an anti-ILT7 monoclonal antibody, we show that ILT7 is expressed specifically on human pDCs, but not on myeloid dendritic cells or other peripheral blood leukocytes. Cross-linking of ILT7 resulted in phosphorylation of Src family kinases and Syk kinase and induced a calcium influx in freshly isolated pDCs, which was blocked by Src family and Syk kinases inhibitors, thus indicating the activation of an immunoreceptor-based tyrosine activation motif–mediated signaling pathway. ILT7 cross-linking on CpG or influenza virus-stimulated primary pDCs inhibited the transcription and secretion of type I interferon and other cytokines. Therefore, the ILT7–FcεRIγ receptor complex negatively regulates the innate immune functions of human pDCs.
Monoclonal anti-human factor VII antibodies. Detection in plasma of a second protein antigenically and genetically related to factor VII.
Authors: G J Broze, S Hickman, J P Miletich
Journal: Journal of Clinical Investigation (1985)

Several murine monoclonal anti-human Factor VII antibodies were produced using hybridoma technology. Two noncompetitive monoclonal antibodies were used to examine by Western blotting the Factor VII cross-reactive material (CRM) in normal human plasma and three commercially available congenitally Factor VII-deficient plasmas, and to construct a facile "sandwich" immunoassay for plasma Factor VII. A second, previously undescribed, form of Factor VII CRM was detected in human plasma, which on Western blotting stained with an apparent intensity 5-8% that of Factor VII. This glycoprotein, tentatively called VII*, has a molecular weight 4,500 D less than Factor VII, lacks detectable Factor VII functional activity, does not bind to barium citrate, and is not recognized by a monoclonal antibody that recognizes Factor VII but not alpha-chymotrypsin-treated Factor VII. VII* was not proteolytically produced from Factor VII during in vitro coagulation or after infusion of human Factor VII into rabbits. As determined by Western blotting, the human hepatoma cell line, HepG2, cultured in the presence of vitamin K, secreted relatively greater levels of VII* in proportion to VII (75%) than that found in human plasma. Warfarin treatment of HepG2 cells decreased the quantity of VII secreted by 77%, whereas it only inhibited the secretion of VII* by 14%. Immunologic studies of the plasmas from a patient on chronic warfarin therapy and an individual given a short course of high dose warfarin therapy corroborated the in vitro synthetic studies obtained with HepG2 cells. The data are consistent with the production of VII* by posttranslational, proteolytic, modification of VII, that, at least in the HepG2 cells studied, occurs intracellularly. However, other mechanisms for the production of VII*, in particular, alternative RNA splicing of the transcript from a single gene, cannot be excluded.
Cellular basis for the monophasic action potential. Which electrode is the recording electrode?
Authors: M KONDO
Journal: Cardiovascular Research (2004)

The cellular basis for the monophasic action potential (MAP) has long been a matter of debate. At the center of the controversy is the issue as to which of the two electrodes is the recording electrode and which is the indifferent electrode. The present study is designed to address this issue.Transmembrane action potentials (TAPs) and either intramural MAPs or contact (Franz-like) MAPs were recorded from adjacent sites in canine arterially perfused ventricular wedge preparations. Intramural MAPs were recorded using thin wire electrodes referenced to a KCl electrode.Local cooling or injection of ATX-II into the region subtending the inactivating (contact or KCl) electrode did not affect the MAP. Similar maneuvers at the site of the noninactivating electrode always prolonged the MAP. The intramural MAP always prolonged in proportion to the TAP, whereas the contact MAP did not, often displaying apparent early afterdepolarizations (EADs) or delayed afterdepolarizations (DADs) due to its much wider field of view, which captured activity from the region of prolonged repolarization as well as the remote normal regions.Our results suggest that (1) it is not the contact or MAP electrode that records the MAP, but rather the noninactivating "indifferent" electrode and (2) intramural MAPs provide more accurate recordings of local activity. The data provide compelling evidence in support of the hypothesis that the MAP represents the extracellular potential difference between active and inactive sites within the heart rather than injury currents flowing at the boundary of the active and inactive zone under the inactivating electrode.
Respiratory epithelial permeability is unrelated to bronchial reactivity and small airway function in young smokers and nonsmokers
Authors: RG Taylor, JE Agnew, RA Francis, D Pavia, SW Clarke
Journal: European Respiratory Journal (1988)

We studied eight young smokers and ten nonsmokers, to determine whether respiratory epithelial permeability to radiolabelled diethylenetriamine penta-acetate (99mTcDTPA) was related to small airway function or bronchial reactivity. Permeability was measured in inner (containing central airways) and outer lung zones by gamma camera. Lung-to-blood half-time (LB-T1/2) was corrected for blood background. Histamine was inhaled tidally (2 min inhalations) using doubling concentrations from 2 to 64 mg.ml-1. Results of small airway function tests, and of bronchial reactivity (expressed as the threshold concentration (reducing forced expiratory volume in one second (FEV1) by 2 SD), and as the percentage reduction in FEV1 after histamine 16 mg.ml-1) were similar in smokers and nonsmokers. LB-T1/2 was shorter in smokers than in nonsmokers in both inner (median (range) 21 (5.5-33) vs 63.5 (41-115) min; p less than 0.004) and outer (20.5 (5.5-30) vs 58.5 (39-105) min; p less than 0.004) zones. Neither inner nor outer zone LB-T1/2 was related to small airway function or bronchial reactivity. Bronchial reactivity and small airway tests may be abnormal in middle-aged smokers, but neither is related to the increased respiratory epithelial permeability of young smokers, in whom it appears too sensitive an index of airway integrity.
National Council on Aging Releases New Falls Prevention Action Plan
Authors: Julie A. Jacob
Journal: JAMA (2015)

The National Council on Aging (NCOA) has released the "Falls Free: 2015 National Falls Prevention Action Plan" (http://bit.ly/1E0ipno). The action plan builds on a 2005 NCOA report and incorporates recommendations and evidence-based strategies presented at the 2015 Falls Prevention Summit.
Familial Nephropathy and Multiple Exostoses With Exostosin-1 (EXT1) Gene Mutation
Authors: Ian S. D. Roberts, Jonathan M. Gleadle
Journal: Journal of the American Society of Nephrology (2008)

Glomerular deposition of fibrillar collagen is a characteristic finding of genetically distinct conditions, including nail-patella syndrome and collagen type III glomerulopathy. A case of familial nephropathy in which steroid-sensitive nephrotic syndrome and glomerular deposits of fibrillar collagen are associated with multiple exostoses due to mutation of the EXT1 gene is described. This gene encodes a glycosyltransferase required for synthesis of heparan sulfate glycosaminoglycans. There is deficiency of heparan sulfate and perlecan, together with accumulation of collagens, in the matrix of EXT1-associated osteochondromas. Similar glomerular basement membrane abnormalities could offer an explanation for both the renal ultrastructural changes and steroid-sensitive nephrotic syndrome.
Combined Cardiac Resynchronization and Implantable Cardioversion Defibrillation in Advanced Chronic Heart Failure
Authors: James B. Young
Journal: JAMA (2003)

Cardiac resynchronization therapy (CRT) through biventricular pacing is an effective treatment for heart failure (HF) with a wide QRS; however, the outcomes of patients requiring CRT and implantable cardioverter defibrillator (ICD) therapy are unknown.To examine the efficacy and safety of combined CRT and ICD therapy in patients with New York Heart Association (NYHA) class III or IV congestive HF despite appropriate medical management.Randomized, double-blind, parallel-controlled trial conducted from October 1, 1999, to August 31, 2001, of 369 patients with left ventricular ejection fraction of 35% or less, QRS duration of 130 ms, at high risk of life-threatening ventricular arrhythmias, and in NYHA class III (n = 328) or IV (n = 41) despite optimized medical treatment.Of 369 randomized patients who received devices with combined CRT and ICD capabilities, 182 were controls (ICD activated, CRT off) and 187 were in the CRT group (ICD activated, CRT on).The primary double-blind study end points were changes between baseline and 6 months in quality of life, functional class, and distance covered during a 6-minute walk. Additional outcome measures included changes in exercise capacity, plasma neurohormones, left ventricular function, and overall HF status. Survival, incidence of ventricular arrhythmias, and rates of hospitalization were also compared.At 6 months, patients assigned to CRT had a greater improvement in median (95% confidence interval) quality of life score (-17.5 [-21 to -14] vs -11.0 [-16 to -7], P =.02) and functional class (-1 [-1 to -1] vs 0 [-1 to 0], P =.007) than controls but were no different in the change in distance walked in 6 minutes (55 m [44-79] vs 53 m [43-75], P =.36). Peak oxygen consumption increased by 1.1 mL/kg per minute (0.7-1.6) in the CRT group vs 0.1 mL/kg per minute (-0.1 to 0.8) in controls (P =.04), although treadmill exercise duration increased by 56 seconds (30-79) in the CRT group and decreased by 11 seconds (-55 to 12) in controls (P<.001). No significant differences were observed in changes in left ventricular size or function, overall HF status, survival, and rates of hospitalization. No proarrhythmia was observed and arrhythmia termination capabilities were not impaired.Cardiac resynchronization improved quality of life, functional status, and exercise capacity in patients with moderate to severe HF, a wide QRS interval, and life-threatening arrhythmias. These improvements occurred in the context of underlying appropriate medical management without proarrhythmia or compromised ICD function.
Advice on Statistical Analysis for Circulation Research
Authors: Hideo Kusuoka, Julien I.E. Hoffman
Journal: Circulation Research (2002)

Since the late 1970s when many journals published articles warning about the misuse of statistical methods in the analysis of data, researchers have become more careful about statistical analysis, but errors including low statistical power and inadequate analysis of repeated-measurement studies are still prevalent. In this review, several statistical methods are introduced that are not always familiar to basic and clinical cardiologists but may be useful for revealing the correct answer from the data. The aim of this review is not only to draw the attention of investigators to these tests but also to stress the conditions in which they are applicable. These methods are now generally available in statistical program packages. Researchers need not know how to calculate the statistics from the data but are required to select the correct method from the menu and interpret the statistical results accurately. With the choice of appropriate statistical programs, the issue is no longer how to do the test but when to do it.
Methotrexate Prevents Renal Injury in Experimental Diabetic Rats via Anti-Inflammatory Actions
Authors: Kosuke Yozai, Kenichi Shikata, Motofumi Sasaki, Atsuhiro Tone, Sakiko Ohga, Hitomi Usui, Shinichi Okada, Jun Wada, Ryo Nagase, Daisuke Ogawa, Yasushi Shikata, Hirofumi Makino
Journal: Journal of the American Society of Nephrology (2005)

Recent studies suggested the involvement of inflammatory processes in the pathogenesis of diabetic nephropathy. Methotrexate (MTX), a folic acid antagonist, is widely used for the treatment of inflammatory diseases. Recently, it has been shown that treatment with low-dose MTX reduces the cardiovascular mortality in patients with rheumatoid arthritis, suggesting that MTX has anti-atherosclerotic effects via its anti-inflammatory actions. This study was designed to determine the anti-inflammatory effects of this agent on diabetic nephropathy. Diabetes was induced in Sprague-Dawley rats with streptozotocin, and MTX (0.5 or 1.0 mg/kg) was administered once a week for 8 wk. Treatment with MTX reduced urinary albumin excretion, mesangial matrix expansion, macrophage infiltration, expression of TGF-beta and type IV collagen, and intercellular adhesion molecule-1 in glomeruli. MTX also reduced the high glucose-induced NF-kappaB activation in vitro and in vivo. The results indicate that intermittent administration of MTX prevented renal injuries without changes in blood glucose level and BP in experimental diabetic rats. The protective effects of MTX are suggested to be mediated by its anti-inflammatory actions through inhibition of NF-kappaB activation and consequent reduction of intercellular adhesion molecule-1 expression and macrophage infiltration. The results suggest that anti-inflammatory agents might be beneficial for the treatment of diabetic nephropathy.
The HPV-16 E7 oncoprotein induces centriole multiplication through deregulation of Polo-like kinase 4 expression
Authors: Nina Korzeniewski, Benjamin Treat, Stefan Duensing
Journal: Molecular Cancer (2011)

Abstract Background Infection with high-risk human papillomaviruses (HPVs) such as HPV-16 is intimately associated with squamous cell carcinomas (SCCs) of the anogenital tract and a subset of oropharyngeal carcinomas. Such lesions, including pre-invasive precursors, frequently show multipolar mitoses and aneuploidy. The high-risk HPV-16-encoded E7 oncoprotein has been shown to rapidly induce centrosome abnormalities thereby causing the formation of supernumerary mitotic spindle poles and increasing the risk for chromosome missegregation. HPV-16 E7 has been found to rapidly induce centriole overduplication, in part, through the simultaneous formation of more than one daughter centriole at single maternal centrioles (centriole multiplication). The precise molecular mechanism that underlies HPV-16 E7-induced centriole multiplication, however, remains poorly understood. Findings Here, we show that human keratinocytes engineered to stably express the HPV-16 E7 oncoprotein exhibit aberrant Polo-like kinase 4 (PLK4) protein expression at maternal centrioles. Real-time quantitative reverse transcriptase (qRT-PCR) analysis of these cells revealed an increase of PLK4 mRNA levels compared to control cells. Importantly, the ability of the HPV-16 E7 oncoprotein to induce centriole multiplication was found to correlate with its ability to activate the PLK4 promoter and to up-regulate PLK4 mRNA. Conclusions These results highlight the critical role of PLK4 transcriptional deregulation in centriole multiplication in HPV-16 E7-expressing cells. Our findings encourage further experiments to test transcriptional inhibitors or small molecules targeting PLK4 to prevent centriole abnormalities, mitotic infidelity and malignant progression in HPV-associated neoplasms and other tumors in which PLK4 regulation is disrupted.
Obesity and colorectal cancer risk in women
Authors: P D Terry, A B Miller, T E Rohan
Journal: Gut (2002)

<b>Background:</b> Several large studies of obesity and colorectal cancer risk have found no association among women but a reasonably consistent positive association among men. In women, a positive association that is stronger among, or limited to, those who are premenopausal has been suggested by studies that stratified analyses by age, although no previous study has examined the association by menopausal status. <b>Methods:</b> We used proportional hazards analyses to estimate hazard ratios relating obesity to colorectal cancer risk among 89 835 women aged 40–59 years at recruitment into the Canadian National Breast Screening Study, a multicentre randomised controlled trial of mammography screening for breast cancer. During an average 10.6 years of follow up (936 433 person years), a total of 527 women were diagnosed with incident colorectal cancer (363 colon and 164 rectal). <b>Results:</b> We found that obesity (body mass index ≥30 kg/m<sup>2</sup>) was associated with an approximately twofold increased risk of colorectal cancer among women who were premenopausal at baseline (hazard ratio 1.88, 95% confidence interval 1.24–2.86). There was no association among postmenopausal women (p for interaction=0.01), and there was only a weak positive association in the entire cohort. <b>Conclusions:</b> Our data suggest that obesity is associated with a twofold increased risk of colorectal cancer in premenopausal women but is not associated with altered risk in postmenopausal women. Effect modification by menopausal status may better explain the inconsistent or weak findings in previous studies than the presumed lack of an association among women.
A Large Subgroup of Mild-to-Moderate Asthma Is Persistently Noneosinophilic
Authors: Kelly Wong McGrath, Nikolina Icitovic, Homer A. Boushey, Stephen C. Lazarus, E. Rand Sutherland, Vernon M. Chinchilli, John V. Fahy
Journal: American Journal of Respiratory and Critical Care Medicine (2012)

Airway eosinophilia is typical of asthma, and many controller treatments target eosinophilic disease. Asthma is clinically heterogeneous, however, and a subgroup of people with asthma do not have airway eosinophilia. The size of this subgroup is uncertain because prior studies have not examined repeated measures of sputum cytology to determine when people with asthma have intermittent versus persistent sputum eosinophila and when they are persistently noneosinophilic.To determine the prevalence and clinical characteristics of the noneosinophilic asthma phenotype.We analyzed sputum cytology data from 995 subjects with asthma enrolled in clinical trials in the Asthma Clinical Research Network where they had undergone sputum induction and measures of sputum cytology, often repeatedly, and assessment of responses to standardized asthma treatments.In cross-sectional analyses, sputum eosinophilia (≥2% eosinophils) was found in only 36% of subjects with asthma not taking an inhaled corticosteroid (ICS) and 17% of ICS-treated subjects with asthma; an absence of eosinophilia was noted frequently, even in subjects with asthma whose disease was suboptimally controlled. In repeated measures analyses of people with asthma not taking an ICS, 22% of subjects had sputum eosinophilia on every occasion (persistent eosinophilia); 31% had eosinophilia on at least one occasion (intermittent eosinophilia); and 47% had no eosinophilia on every occasion (persistently noneosinophilic). Two weeks of combined antiinflammatory therapy caused significant improvements in airflow obstruction in eosinophilic asthma, but not in persistently noneosinophilic asthma. In contrast, bronchodilator responses to albuterol were similar in eosinophilic and noneosinophilic asthma.Approximately half of patients with mild-to-moderate asthma have persistently noneosinophilic disease, a disease phenotype that responds poorly to currently available antiinflammatory therapy.
Haemodynamic evaluation of pulmonary hypertension
Authors: D. Chemla, V. Castelain, P. Hervé, Y. Lecarpentier, S. Brimioulle
Journal: European Respiratory Journal (2002)

Pulmonary hypertension is characterised by the chronic elevation of pulmonary artery pressure (PAP) and pulmonary vascular resistance (PVR) leading to right ventricular enlargement and hypertrophy. Pulmonary hypertension may result from respiratory and cardiac diseases, the most severe forms occurring in thromboembolic and primary pulmonary hypertension. Pulmonary hypertension is most often defined as a mean PAP &gt;25 mmHg at rest or &gt;30 mmHg during exercise, the pressure being measured invasively with a pulmonary artery catheter. Doppler echocardiography allows serial, noninvasive follow-up of PAPs and right heart function. When the adaptive mechanisms of right ventricular dilatation and hypertrophy cannot compensate for the haemodynamic burden, right heart failure occurs and is associated with poor prognosis. The haemodynamic profile is the major determinant of prognosis. In both primary and secondary pulmonary hypertension, special attention must be paid to the assessment of pulmonary vascular resistance index (PVRI), right heart function and pulmonary vasodilatory reserve. Recent studies have stressed the prognostic values of exercise capacity (6-min walk test), right atrial pressure, stroke index and vasodilator challenge responses, as well as an interest in new imaging techniques and natriuretic peptide determinations. Overall, careful haemodynamic evaluation may optimise new diagnostic and therapeutic strategies in pulmonary hypertension.
Prelinguistic evolution in hominin mothers and babies: For cryin' out loud!
Authors: Dean Falk
Journal: Behavioral and Brain Sciences (2004)

Unlike chimpanzees, human infants engage in persistent adult-directed (AD) crying, and human mothers produce a special form of infant-directed vocalization, known as motherese. These complementary behaviors are hypothesized to have evolved initially in our hominin ancestors in conjunction with the evolution of bipedalism, and to represent prelinguistic substrates that paved the way for the eventual emergence of protolanguage.