On 2019/07/30.86853 UT, IceCube detected a high-energy astrophysical neutrino can-didate. The Flat Spectrum Radio Quasar PKS 1502+106 is located within the 50 percent uncertainty region of the event. ...Our analysis of 15 GHz Very Long Baseline Ar-ray (VLBA) and astrometric 8 GHz VLBA data, in a time span prior and after theIceCube event, reveals evidence for a radio ring structure which develops with time.Several arc-structures evolve perpendicular to the jet ridge line. We find evidence forprecession of a curved jet based on kinematic modelling and a periodicity analysis.An outflowing broad line region (BLR) based on the C IV line emission (Sloan Dig-ital Sky Survey, SDSS) is found. We attribute the atypical ring to an interaction ofthe precessing jet with the outflowing material.We discuss our findings in thecontext of a spine-sheath scenario where the ring reveals the sheath andits interaction with the surroundings (NLR clouds).We find that the radioemission is correlated with theγ-ray emission, with radio lagging theγ-rays. Basedon theγ-ray variability timescale, we constrain theγ-ray emission zone to the BLR(30-200rg) and within the jet launching region. We discuss that the outflowing BLRprovides the external radiation field forγ-ray production via external Compton scat-tering.The neutrino is most likely produced by proton-proton interactionin the blazar zone (beyond the BLR), enabled by episodic encounters ofthe jet with dense clouds, i.e. some molecular cloud in the NLR.
Stimulating active transport by encouraging replacement of short-distance car trips by active transport modes such as cycling or walking has become a popular policy strategy. It has been suggested ...that neighbourhoods, designed to facilitate healthy behaviour, can influence a person׳s behavioural choices such as transport choice. In the present study, we investigated the association between perceived accessibility of facilities and transport choice for three different trip purposes (shopping, going to public natural spaces, and going to sports facilities) in the Netherlands.
An online questionnaire (N=3663) was used to collect data concerning transport choice for the general Dutch population over a period of one calendar year starting July 2012. Logistic regression analyses were used to model the odds of cycling versus car use and to model the odds of walking versus car use.
When perceived accessibility by car is high, persons were less likely to use active transport modes (OR range: 0.09–0.66) and when perceived accessibility by active transport modes is high, persons were more likely to use the bicycle (OR range: 2.18–10.43) or walk (OR range: 2.97–11.22).
Our results showed a strong association between perceived accessibility and transport choice even after adjusting for personal and environmental characteristics. Our results suggest that perceived accessibility should be taken into account when stimulating a shift from car use to cycling or walking.
•Perceived accessibility was found to be strongly associated with transport choice.•When perceived accessibility by car is high, persons were less likely to use active modes.•Perceived accessibility should be taken into account when stimulating a mode shift.
The objectives of this study were to assess the safety, pharmacokinetics, and efficacy of pegylated interferon alfa-2b (PEG-Intron) plus ribavirin in patients with chronic hepatitis C. A total of 72 ...patients (35 men/37 women, age range 20-68 years) with clinically compensated chronic hepatitis C virus (HCV) were enrolled into this open-label, randomized, active controlled study. Patients received either PEG-Intron 0.35, 0.7, or 1.4 μg/kg subcutaneously weekly for 24 weeks alone, or in combination with ribavirin 600, 800, or 1,000 to 1,200 mg orally daily. Patients were evaluated during treatment and after a 24-week follow-up period for safety and efficacy. Detailed pharmacokinetic assessments were performed at weeks 1 and 4. PEG-Intron alone produced expected dose-related reductions in white cells, neutrophils and platelets. Addition of ribavirin reduced hemoglobin levels in a dose-related manner, did not further reduce PEG-Intron–induced decreases in neutrophil or white cell count, and increased platelet counts. Neutrophil function tests (C5a and FMLP migration, killing curves) were unaltered. Reported adverse events (flu-like symptoms, asthenia) were qualitatively similar in all dose groups. Anti-HCV activity, as measured by loss of detectable serum HCV RNA (i.e. <100 copies/mL) at the end of treatment (week 24) and after 24 weeks of follow-up (week 48) showed dose-response trends for PEG-Intron. At each PEG-Intron dose level, anti-HCV activity was higher in patients coadministered ribavirin than in patients treated with PEG-Intron monotherapy. There was no evidence of pharmacokinetic interactions with either drug. We conclude that the safety and tolerability of combined PEG-Intron/ribavirin and PEG-Intron alone were comparable. Combined PEG-Intron/ribavirin showed dose-related synergistic anti-HCV effects, which were numerically superior to those obtained with PEG-Intron monotherapy.
(Hepatology 2000;32:647-653.)
Multiple components of vascular alpha adrenergic responsiveness were investigated in twenty-four men with mild hypertension and eighteen age- and weight-matched normotensive controls. Arterial plasma ...norepinephrine (paNE), an index of sympathetic drive, was increased in hypertensives compared to normotensives (mean +/- SE), 199 +/- 24 vs. 134 +/- 11 pg/ml, P less than 0.02. The effective concentration of intra-arterial (iaNE) increasing forearm vascular resistance (FAVR) 30% (NE-EC30, an index of vascular alpha-receptor sensitivity) was similar in normotensives and hypertensives, 9 +/- 1 vs. 13 +/- 3 ng/100 ml per min, respectively, P greater than 0.3. The phentolamine induced reduction in FAVR, an index of vascular alpha-tone, was greater in hypertensives, -21.3 +/- 1.8 vs. normotensives, -14.9 +/- 1.2 U, P less than 0.02. We interpret these data as evidence for normal vascular alpha-receptor sensitivity to norepinephrine in mild hypertensives. Consequently, the increased sympathetic drive in mild hypertensives explains the elevated vascular alpha-tone. Although vascular alpha-receptor sensitivity to iaNE was normal, the FAVR responses at high doses (reactivity) were greater in hypertensives to regional infusion of both NE and angiotensin II. This "nonspecific" enhancement of vascular reactivity is probably explained by structural vascular changes in hypertensives.
Background: Peginterferon α-2b plus ribavirin therapy in previously untreated patients with chronic hepatitis C yields the highest sustained virological response rates of any treatment strategy but ...is expensive. Aims: To estimate the cost effectiveness of treatment with peginterferon α-2b plus ribavirin compared with interferon α-2b plus ribavirin for initial treatment of patients with chronic hepatitis C. Methods: Individual patient level data from a randomised clinical trial with peginterferon plus ribavirin were applied to a previously published and validated Markov model to project lifelong clinical outcomes. Quality of life and economic estimates were based on German patient data. We used a societal perspective and applied a 3% annual discount rate. Results: Compared with no antiviral therapy, peginterferon plus fixed or weight based dosing of ribavirin increased life expectancy by 4.2 and 4.7 years, respectively. Compared with standard interferon α-2b plus ribavirin, peginterferon plus fixed or weight based dosing of ribavirin increased life expectancy by 0.5 and by 1.0 years with incremental cost effectiveness ratios of 11 800 and 6600 per quality adjusted life year (QALY), respectively. Subgroup analyses by genotype, viral load, sex, and histology showed that peginterferon plus weight based ribavirin remained cost effective compared with other well accepted medical treatments. Conclusions: Peginterferon α-2b plus ribavirin should reduce the incidence of liver complications, prolong life, improve quality of life, and be cost effective for the initial treatment of chronic hepatitis C.
The percentage and the activity of natural killer (NK) cells are known to be decreased in HIV-infected patients. However, the mechanisms responsible for this NK deficiency are poorly understood. ...Because of the role of NK cells in the host defence against microbial infections, this defect contributes to the virus-induced immune deficiency. The aim of the present study was to better understand this defect in order to be able to restore NK function in HIV infection.
The expression of the cytolytic mediators perforin and granzyme A was analysed by flow cytometry, the lytic activity of peripheral blood NK cells of HIV-infected patients was analysed by cytotoxic assay, and the expression of perforin was followed during administration of interferon (IFN)alpha attached to polyethylene glycol (PEG)-IFNalpha.
The lytic activity and the expression of perforin and granzyme A was low in NK cells of infected individuals in comparison with normal control volunteers. In both groups NK cytotoxic capacity was linked to perforin expression. The low perforin expression in HIV-infected subjects negatively correlated with HIV RNA plasma level. administration of PEG-IFNalpha restored perforin expression even in patients whose viral load was not reduced by this treatment.
These results suggest that HIV-induced NK deficiency could be partly mediated by a defect in perforin and granzyme A expression, and that PEG-IFNalpha could be used in infected subjects to directly improve their natural immunity in addition to eventually reducing their viraemia.
Enfuvirtide (T-20) is the first of a novel class of human immunodeficiency virus (HIV) drugs that block gp41-mediated viral fusion to host cells. The objectives of this study were to develop a ...structural pharmacokinetic model that would adequately characterize the absorption and disposition of enfuvirtide pharmacokinetics after both intravenous and subcutaneous administration and to evaluate the dose proportionality of enfuvirtide pharmacokinetic parameters at a subcutaneous dose higher than that currently used in phase III studies.
Twelve patients with HIV infection received 4 single doses of enfuvirtide separated by a 1-week washout period in an open-label, randomized, 4-way crossover fashion. The doses studied were 90 mg (intravenous) and 45 mg, 90 mg, and 180 mg (subcutaneous). Serial blood samples were collected up to 48 hours after each dose. Plasma enfuvirtide concentrations were measured with use of a validated liquid chromatography-tandem mass spectrometry method.
Enfuvirtide plasma concentration-time data after subcutaneous administration were well described by an inverse Gaussian density function-input model linked to a 2-compartment open distribution model with first-order elimination from the central compartment. The model-derived mean pharmacokinetic parameters (+/-SD) were volume of distribution of the central compartment (3.8 +/- 0.8 L), volume of distribution of the peripheral compartment (1.7 +/- 0.6 L), total clearance (1.44 +/- 0.30 L/h), intercompartmental distribution (2.3 +/- 1.1 L/h), bioavailability (89% +/- 11%), and mean absorption time (7.26 hours, 8.65 hours, and 9.79 hours for the 45-mg, 90-mg, and 180-mg dose groups, respectively). The terminal half-life increased from 3.46 to 4.35 hours for the subcutaneous dose range from 45 to 180 mg.
An inverse Gaussian density function-input model linked to a 2-compartment open distribution model with first-order elimination from the central compartment was appropriate to describe complex absorption and disposition kinetics of enfuvirtide plasma concentration-time data after subcutaneous administration to patients with HIV infection. Enfuvirtide was nearly completely absorbed from subcutaneous depot, and pharmacokinetic parameters were linear up to a dose of 180 mg in this study.
An HPLC method with UV detection was developed for the analysis of ceftibuten (cis-isomer) and its metabolite (trans-isomer of ceftibuten) in plasma and urine. The detection was performed at 254 nm. ...The procedure for the plasma assay involves the addition of an internal standard (ceftazidime), followed by treatment of the samples with acetonitrile and dichloromethane. The urine samples, after dilution (10- to 40-fold), were analyzed by a column-switching technique without internal standard. The proposed technique is reproducible, selective, reliable, and sensitive. Linear detector responses were observed for the calibration curve standards in the ceftibuten conentration range of 0.10 to 20 mg/L for plasma and 0.10 to 50 mg/L for urine, and in the metabolite concentration range of 0.20 to 4 mg/L for plasma and 0.20 to 16 mg/L for urine. The limit of quantitation is 0.1 mg/L for ceftibuten and 0.2 mg/L for the transisomer in plasma and urine. The reproducibility of the analytical method according to the statistical coefficients is approximately 7%. The accuracy of the method is good; that is, the relative error is < 5%. The methods were applied to pharmacokinetic studies of ceftibuten after multiple oral administration (400 mg every 12 h for 8 days) to healthy volunteers.
The concentration-time profiles of specific metabolites of moxisylyte, an alpha-adrenoceptor blocking agent, in the plasma and urine from 18 healthy volunteers were investigated after intracavernous ...(IC) administrations at three dose levels (10, 20 and 30 mg).
Four metabolites, unconjugated desacetyl-moxisylyte (DAM), DAM glucuronide, and DAM and monodesmethylated DAM (MDAM) sulphates were found in plasma and urine. For all metabolites, t1/2 elimination was independent of the administered dose (1.19 h for unconjugated DAM; 1.51 h for DAM glucuronide; 1.51 h for DAM sulphate; and 2.17 h for MDAM sulphate). Cmax and AUC increased in direct proportion to dose, except for the inactive DAM glucuronide. Any the differences detected were small and equivalence of the three doses can be accepted.
The pharmacokinetics of moxisylyte in humans following intracavernous administration were linear in the dose range 10 to 30 mg.
The concentration-time profiles of metabolites of moxisylyte (or thymoxamine), an alpha-blocking agent, were investigated in 18 healthy volunteers after intravenous (i.v.) and intracavernous (i.c.) ...administrations with and without a tourniquet. Four metabolites, unconjugated desacetylmoxisylyte (DAM), DAM glucuronide, and DAM and monodesmethylated DAM (MDAM) sulfates, were found in plasma and urine. For all metabolites, tmax was significantly increased after i.c. administrations and Cmax was significantly decreased. Maximum plasma level of unconjugated DAM was lower after i.c. administration with (1.81-fold) and without (1.26-fold) a tourniquet than after i.v. administration (43.6 +/- 19.6 ng/ml). The elimination half-life of each metabolite showed no change between the three treatments. The difference of 19 min between the mean residence times of unconjugated DAM after i.c. administration with and without a tourniquet may be compared with the difference between the mean duration of the intumescence, that is, 19 min (73 and 54 min with and without a tourniquet, respectively). Total percentages of metabolites recovered in urine were 66.2 +/- 20.9, 61.4 +/- 12.2, and 58.7 +/- 9.1% after i.v. and i.c. administrations with and without a tourniquet, respectively. In conclusion, tourniquet placed before i.c. administration increased the mean residence time of unconjugated DAM of approximately 25% and seemed to increase the efficacy of the drug in healthy volunteers.
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