113 research outputs found
Acute effects of intravenous nisoldipine on left ventricular function and coronary hemodynamics
The hemodynamic effects of nisoldipine were investigated in 16 patients with suspected coronary artery disease who underwent routine cardiac catheterization. Nisoldipine was given intravenously in a dose of 6 micrograms/kg over 3 minutes and measurements made before and after drug administration during spontaneous and matched atrial paced heart rate. During sinus rhythm, nisoldipine produced a significant increase in heart rate (19%, p less than 10(-5]. Left ventricular systolic pressure decreased 28% (p less than 10(-6) and left ventricular end-diastolic pressure did not change significantly (5%, difference not significant). Coronary sinus and great cardiac vein blood flow increased by 21% (p less than 0.02) and 25% (p less than 0.005), respectively, after nisoldipine administration. Simultaneously, mean aortic pressure decreased 33% (p less than 10(-6]; consequently, the global and regional coronary vascular resistances decreased by 50% (p less than 10(-4]. The decreases in global (-8%) and regional (-4%) myocardial oxygen consumption did not reach statistical significance. A 6% (not significant) increase in end-diastolic volume and an 11% (p less than 0.002) decrease in end-systolic volume resulted in an increase of 21% in stroke volume (p less than 10(-4] with a consistent increase in ejection fraction (+16%, p less than 10(-5]. Total systemic vascular resistance was reduced by 30% (p less than 0.0002). During spontaneous heart rate and matched atrial pacing, the time constant of isovolumic relaxation as assessed by a biexponential model, was significantly shortened.(ABSTRACT TRUNCATED AT 250 WORDS
Acute effects of intravenous nisoldipine on left ventricular function and coronary hemodynamics
The hemodynamic effects of nisoldipine were investigated in 16 patients with suspected coronary artery disease who underwent routine cardiac catheterization. Nisoldipine was given intravenously in a dose of 6 micrograms/kg over 3 minutes and measurements made before and after drug administration during spontaneous and matched atrial paced heart rate. During sinus rhythm, nisoldipine produced a significant increase in heart rate (19%, p less than 10(-5]. Left ventricular systolic pressure decreased 28% (p less than 10(-6) and left ventricular end-diastolic pressure did not change significantly (5%, difference not significant). Coronary sinus and great cardiac vein blood flow increased by 21% (p less than 0.02) and 25% (p less than 0.005), respectively, after nisoldipine administration. Simultaneously, mean aortic pressure decreased 33% (p less than 10(-6]; consequently, the global and regional coronary vascular resistances decreased by 50% (p less than 10(-4]. The decreases in global (-8%) and regional (-4%) myocardial oxygen consumption did not reach statistical significance. A 6% (not significant) increase in end-diastolic volume and an 11% (p less than 0.002) decrease in end-systolic volume resulted in an increase of 21% in stroke volume (p less than 10(-4] with a consistent increase in ejection fraction (+16%, p less than 10(-5]. Total systemic vascular resistance was reduced by 30% (p less than 0.0002). During spontaneous heart rate and matched atrial pacing, the time constant of isovolumic relaxation as assessed by a biexponential model, was significantly shortened.(ABSTRACT TRUNCATED AT 250 WORDS
The ÎČ3-integrin endothelial adhesome regulates microtubule-dependent cell migration
Integrin ÎČ3 is seen as a key anti-angiogenic target for cancer treatment due to its expression on neovasculature, but the role it plays in the process is complex; whether it is pro- or anti-angiogenic depends on the context in which it is expressed. To understand precisely ÎČ3's role in regulating integrin adhesion complexes in endothelial cells, we characterised, by mass spectrometry, the ÎČ3-dependent adhesome. We show that depletion of ÎČ3-integrin in this cell type leads to changes in microtubule behaviour that control cell migration. ÎČ3-integrin regulates microtubule stability in endothelial cells through Rcc2/Anxa2-driven control of active Rac1 localisation. Our findings reveal that angiogenic processes, both in vitro and in vivo, are more sensitive to microtubule targeting agents when ÎČ3-integrin levels are reduced
Prediction of long-term clinical outcome in a diverse chronic hepatitis B population: Role of the PAGE-B score
An abundance of noninvasive scores have been associated with fibrosis and hepatocellular carcinoma (HCC) development. We aimed to compare the prognostic ability of these scores in relation to liver histology in chronic hepatitis B (CHB) patients. Liver biopsies from treatment-naĂŻve CHB patients at one tertiary care centre were scored by a single hepato-pathologist. Laboratory values at liver biopsy were used to calculate the PAGE-B, REACH-B, GAG-HCC, CU-HCC and FIB-4 scores. Any clinical event was defined as HCC development, liver failure, transplantation and mortality. HCC and mortality data were obtained from national database registries. Of 557 patients, 40 developed a clinical event within a median follow-up of 10.1 (IQR 5.7-15.9) years. The PAGE-B score predicted any clinical event (C-statistic.86, 95% CI: 0.80-0.92), HCC development (C-statistic.91) and reduced transplant-free survival (C-statistic.83) with good accuracy, also when stratified by ethnicity, antiviral therapy after biopsy or advanced fibrosis. The C-statistics (95% CI) of the REACH-B, GAG-HCC, CU-HCC and FIB-4 scores for any event were.70 (0.59-0.81),.82 (0.75-0.89),.73 (0.63-0.84) and.79 (0.69-0.89), respectively. The PAGE-B event risk assessment improved modestly when combined with the Ishak fibrosis stage (C-statistic.87, 95% CI: 0.82-0.93). The PAGE-B score showed the best performance in assessing the likelihood of developing a clinical event among a diverse CHB population over 15Â years of follow-up. Additional liver histological characteristics did not appear to provide a clinically significant improvement
Close monitoring of hepatitis B surface antigen levels helps classify flares during peginterferon therapy and predicts treatment response
Background. Alanine aminotransferase (ALT) flares occur frequently during peginterferon (PEG-IFN) therapy. We related occurrence of flares to presence of precore (PC) and/or basal core promoter (BCP) mutants and studied kinetics of hepatitis B e antigen (HBeAg) and hepatitis B surface antigen (HBsAg) levels during flares.Methods. Fifty of 214 (23%) patients treated with PEG-IFN ± lamivudine for 52 weeks experienced flares. Flares were host-induced (ALT elevation followed by HBV DNA decline, n = 19), virus-induced (HBV DNA increase with subsequent ALT elevation, n = 17) or indeterminate (n = 14
Serum hepatitis B virus RNA predicts response to peginterferon treatment in HBeAg-positive chronic hepatitis B
Hepatitis B virus (HBV) RNA in serum is a novel biomarker that reflects cccDNA activity. We investigated whether HBV RNA can predict serological response to peginterferon (PEG-IFN) treatment. Serum HBV RNA levels were retrospectively measured at weeks 0, 12, 24 and 52 of therapy and after treatment discontinuation (week 78) in 266 HBeAg-positive chronic HBV patients who had participated in a global randomized controlled trial (HBV99-01 study). Patients received 52 weeks PEG-IFN monotherapy (n = 136) or PEG-IFN and lamivudine (n = 130). The primary end point was HBeAg loss 24 weeks after PEG-IFN discontinuation. At baseline, the mean serum level of HBV RNA was 6.8 (SD 1.2) log c/mL. HBV RNA levels declined to 4.7 (1.7) log c/mL after one year of PEG-IFN therapy alone and to 3.3 (1.2)log c/mL after combination therapy. From week 12 onward, HBV RNA level was significantly lower in patients who achieved HBeAg loss at the end of follow-up as compared to those who did not, regardless of treatment allocation (week 12:4.4 vs 5.1 log c/mL, P =.01; week 24:3.7 vs 4.9 log c/mL, P <.001). The performance of a multivariable model based on HBV RNA level was comparable at week 12 (AUC 0.68) and 24 (AUC 0.72) of therapy. HBV RNA level above 5.5 log c/mL at week 12 showed negative predictive values of 93/67/90/64% for HBV genotypes A/B/C/D for the prediction of HBeAg loss. In conclusion, HBV RNA in serum declines profoundly during PEG-IFN treatment. Early on-treatment HBV RNA level may be used to predict nonresponse
Evaluation of IL-28B Polymorphisms and Serum IP-10 in Hepatitis C Infected Chimpanzees
In humans, clearance of hepatitis C virus (HCV) infection is associated with genetic variation near the IL-28B gene and the induction of interferon-stimulated genes, like IP-10. Also in chimpanzees spontaneous clearance of HCV is observed. To study whether similar correlations exist in these animals, a direct comparison of IP-10 and IL-28B polymorphism between chimpanzees and patients was performed. All chimpanzees studied were monomorphic for the human IL-28B SNPs which are associated with spontaneous and treatment induced HCV clearance in humans. As a result, these particular SNPs cannot be used for clinical association studies in chimpanzees. Although these human SNPs were absent in chimpanzees, gene variation in this region was present however, no correlation was observed between different SNP-genotypes and HCV outcome. Strikingly, IP-10 levels in chimpanzees correlated with HCV-RNA load and ÎłGT, while such correlations were not observed in humans. The correlation between IP-10, ÎłGT and virus load in chimpanzees was not found in patients and may be due to the lack of lifestyle-related confounding factors in chimpanzees. Direct comparison of IP-10 and IL-28B polymorphism between chimpanzees and patients in relation to HCV infection, illustrates that the IFN-pathways are important during HCV infection in both species. The Genbank EMBL accession numbers assigned to chimpanzees specific sequences near the IL-28B gene are HE599784 and HE599785
ITPA polymorphisms are associated with hematological side effects during antiviral therapy for chronic HCV infection
Background/Objective Genetic polymorphisms in the inosine triphosphatase (ITPA) gene have been associated with the protection from early ribavirin(RBV)-induced hemolytic anemia among patients with chronic hepatitis C virus (HCV) infection. The aim of the present study was to investigate the association between the functional ITPA variants and hematological side effects during antiviral therapy with pegylated interferon (PegIFN) and RBV. Patients and Methods This cohort study included all consecutive Caucasian patients treated for chronic HCV infection with PegIFN and RBV between 2000 and 2009 for whom a serum sample was available for genetic testing. The predicted inosine triphosphate pyrophosphatase (ITPase) activity was based on the genotypes of the SNPs rs1127354 and rs7270101. Decline in hemoglobin (Hb) during antiviral therapy, as well as dose reductions, blood transfusions and use of erythropoietin were assessed. Results In total, 213 patients were included. The predicted ITPase activity was normal among 152 (71%) patients; 61 (29%) patients had ITPase deficiency. By multivariable linear regression, RBV dose in mg per kilogram (Beta 0.09, 95%CI 0.04-0.13, p<0.001) and normal ITPase activity (Beta 0.89, 95%CI 0.64-1.14, p<0.001) were associated with more Hb decline at week 4 of treatment. Patients with normal ITPase activity underwent more dose adjustments of RBV than patients with ITPase deficiency (19(13%) vs 1(2%),p = 0.014) and received erythropoietin more frequently (12 (8%) vs 0 (0%),p = 0.024). Conclusion Genetic variants in the ITPA gene protected against RBV treatment-induced anemia among Caucasian patients with chronic HCV infection. Patients with normal ITPase activity underwent more dose reductions of RBV and received erythropoietin more frequently
Gravitational radiation from gamma-ray bursts as observational opportunities for LIGO and VIRGO
Gamma-ray bursts are believed to originate in core-collapse of massive stars.
This produces an active nucleus containing a rapidly rotating Kerr black hole
surrounded by a uniformly magnetized torus represented by two counter-oriented
current rings. We quantify black hole spin-interactions with the torus and
charged particles along open magnetic flux-tubes subtended by the event
horizon. A major output of Egw=4e53 erg is radiated in gravitational waves of
frequency fgw=500 Hz by a quadrupole mass-moment in the torus. Consistent with
GRB-SNe, we find (i) Ts=90s (tens of s, Kouveliotou et al. 1993), (ii)
aspherical SNe of kinetic energy Esn=2e51 erg (2e51 erg in SN1998bw, Hoeflich
et al. 1999) and (iii) GRB-energies Egamma=2e50 erg (3e50erg in Frail et al.
2001). GRB-SNe occur perhaps about once a year within D=100Mpc. Correlating
LIGO/Virgo detectors enables searches for nearby events and their spectral
closure density 6e-9 around 250Hz in the stochastic background radiation in
gravitational waves. At current sensitivity, LIGO-Hanford may place an upper
bound around 150MSolar in GRB030329. Detection of Egw thus provides a method
for identifying Kerr black holes by calorimetry.Comment: to appear in PRD, 49
Low hepatitis B surface antigen and HBV DNA levels predict response to the addition of pegylated interferon to entecavir in hepatitis B e antigen positive chronic hepatitis B
Background: Various treatment combinations of peginterferon (PEGâIFN) and
nucleos(t)ide analogues have been evaluated for chronic hepatitis B (CHB), but the
optimal regimen remains unclear.
Aims: To study whether PEGâIFN addâon increases response compared to entecavir
(ETV) monotherapy, and whether the duration of ETV pretreatment influences
response.
Methods: Response was evaluated in HBeAg positive patients previously treated in
two randomized controlled trials. Patients received ETV pretreatment for at least
24 weeks and were then allocated to 24â48 weeks of ETV+PEGâIFN addâon, or
continued ETV monotherapy. Response was defined as HBeAg loss combined with
HBV DNA <200 IU/mL 48 weeks after discontinuing PEGâIFN.
Results: Of 234 patients, 118 were assigned PEGâIFN addâon and 116 continued
ETV monotherapy. Response was observed in 38/118 (33%) patients treated with
addâon therapy and in 23/116 (20%) with monotherapy (P = 0.03). The highest
response to addâon therapy compared to monotherapy was observed in PEGâIFN
naive patients with HBsAg levels below 4000 IU/mL and HBV DNA levels below
50 IU/mL at randomization (70% vs 34%; P = 0.01). Above the cutâoff levels,
response was low and not significantly different between treatment groups. Duration of ETV pretreatment was associated with HBsAg and HBV DNA levels (both
P < 0.005), but not with response (P = 0.82).
Conclusions: PEGâIFN addâon to ETV therapy was associated with higher response
compared to ETV monotherapy in patients with HBeAg positive CHB. Response
doubled in PEGâIFN naive patients with HBsAg below 4000 IU/mL and HBV DNA
below 50 IU/mL, and therefore identifies them as the best candidates for PEGâIFN
addâon (Identifiers: NCT00877760, NCT01532843)
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