372 research outputs found
Chapter 8 – Beyond authors’ rights
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Zolpidem is a potent stoichiometry-selective modulator of α1β3 GABAA receptors : evidence of a novel benzodiazepine site in the α1-α1 interface
Zolpidem is not a typical GABAA receptor hypnotic. Unlike benzodiazepines, zolpidem modulates tonic GABA currents in the rat dorsal motor nucleus of the vagus, exhibits residual effects in mice lacking the benzodiazepine binding site, and improves speech, cognitive and motor function in human patients with severe brain injury. The receptor by which zolpidem mediates these effects is not known. In this study we evaluated binary α1β3 GABAA receptors in either the 3α1:2β3 or 2α1:3β3 subunit stoichiometry, which differ by the existence of either an α1-α1 interface, or a β3-β3 interface, respectively. Both receptor stoichiometries are readily expressed in Xenopus oocytes, distinguished from each other by using GABA, zolpidem, diazepam and Zn2+. At the 3α1:2β3 receptor, clinically relevant concentrations of zolpidem enhanced GABA in a flumazenil-sensitive manner. The efficacy of diazepam was significantly lower compared to zolpidem. No modulation by either zolpidem or diazepam was detected at the 2α1:3β3 receptor, indicating that the binding site for zolpidem is at the α1-α1 interface, a site mimicking the classical α1-γ2 benzodiazepine site. Activating α1β3 (3α1:2β3) receptors may, in part, mediate the physiological effects of zolpidem observed under distinct physiological and clinical conditions, constituting a potentially attractive drug target
What Sets the Initial Rotation Rates of Massive Stars?
The physical mechanisms that set the initial rotation rates in massive stars
are a crucial unknown in current star formation theory. Observations of young,
massive stars provide evidence that they form in a similar fashion to their
low-mass counterparts. The magnetic coupling between a star and its accretion
disk may be sufficient to spin down low-mass pre-main sequence (PMS) stars to
well below breakup at the end stage of their formation when the accretion rate
is low. However, we show that these magnetic torques are insufficient to spin
down massive PMS stars due to their short formation times and high accretion
rates. We develop a model for the angular momentum evolution of stars over a
wide range in mass, considering both magnetic and gravitational torques. We
find that magnetic torques are unable to spin down either low or high mass
stars during the main accretion phase, and that massive stars cannot be spun
down significantly by magnetic torques during the end stage of their formation
either. Spin-down occurs only if massive stars' disk lifetimes are
substantially longer or their magnetic fields are much stronger than current
observations suggest.Comment: 12 pages, 10 figures, Accepted for publication in Ap
Instability of LBV-stars against radial oscillations
In this study we consider the nonlinear radial oscillations exciting in
LBV--stars with effective temperatures 1.5e4 K <= Teff <= 3e4 K, bolometric
luminosities 1.2e6 L_odot <= L <= 1.9e6 L_odot and masses 35.7 M_odot <= M <=
49.1 M_odot. Hydrodynamic computations were carried out with initial conditions
obtained from evolutionary sequences of population I stars (X=0.7, Z=0.02) with
initial masses from 70M_odot to 90 M_odot. All hydrodynamical models show
instability against radial oscillations with amplitude growth time comparable
with dynamical time scale of the star. Radial oscillations exist in the form of
nonlinear running waves propagating from the boundary of the compact core to
the upper boundary of the hydrodynamical model. The velocity amplitude of outer
layers is of several hundreds of km/s while the bolometric light amplitude does
not exceed 0.2 mag. Stellar oscillations are not driven by the kappa-mechanism
and are due to the instability of the gas with adiabatic exponent close to the
critical value Gamma_1 = 4/3 due to the large contribution of radiation in the
total pressure. The range of the light variation periods (6 day <= P <= 31 day)
of hydrodynamical models agrees with periods of microvariability observed in
LBV--stars.Comment: 14 pages, 5 figures, submitted to Astronomy Letter
The Missing Luminous Blue Variables and the Bistability Jump
We discuss an interesting feature of the distribution of luminous blue
variables on the H-R diagram, and we propose a connection with the bistability
jump in the winds of early-type supergiants. There appears to be a deficiency
of quiescent LBVs on the S Dor instability strip at luminosities between log
L/Lsun = 5.6 and 5.8. The upper boundary, is also where the
temperature-dependent S Dor instability strip intersects the bistability jump
at about 21,000 K. Due to increased opacity, winds of early-type supergiants
are slower and denser on the cool side of the bistability jump, and we
postulate that this may trigger optically-thick winds that inhibit quiescent
LBVs from residing there. We conduct numerical simulations of radiation-driven
winds for a range of temperatures, masses, and velocity laws at log L/Lsun=5.7
to see what effect the bistability jump should have. We find that for
relatively low stellar masses the increase in wind density at the bistability
jump leads to the formation of a modest to strong pseudo photosphere -- enough
to make an early B-type star appear as a yellow hypergiant. Thus, the proposed
mechanism will be most relevant for LBVs that are post-red supergiants. Yellow
hypergiants like IRC+10420 and rho Cas occupy the same luminosity range as the
``missing'' LBVs, and show apparent temperature variations at constant
luminosity. If these yellow hypergiants do eventually become Wolf-Rayet stars,
we speculate that they may skip the normal LBV phase, at least as far as their
apparent positions on the HR diagram are concerned.Comment: 20 pages, 4 figs, accepted by Ap
Subchondral Bone Trabecular Integrity Predicts and Changes Concurrently with Radiographic and MRI Determined Knee Osteoarthritis Progression
OBJECTIVE: To evaluate subchondral bone trabecular integrity (BTI) on radiographs as a predictor of knee osteoarthritis (OA) progression. METHODS: Longitudinal (baseline, 12-month, and 24-month) knee radiographs were available for 60 female subjects with knee OA. OA progression was defined by 12- and 24-month changes in radiographic medial compartment minimal joint space width (JSW) and medial joint space area (JSA), and by medial tibial and femoral cartilage volume on magnetic resonance imaging. BTI of the medial tibial plateau was analyzed by fractal signature analysis using commercially available software. Receiver operating characteristic (ROC) curves for BTI were used to predict a 5% change in OA progression parameters. RESULTS: Individual terms (linear and quadratic) of baseline BTI of vertical trabeculae predicted knee OA progression based on 12- and 24-month changes in JSA (P < 0.01 for 24 months), 24-month change in tibial (P < 0.05), but not femoral, cartilage volume, and 24-month change in JSW (P = 0.05). ROC curves using both terms of baseline BTI predicted a 5% change in the following OA progression parameters over 24 months with high accuracy, as reflected by the area under the curve measures: JSW 81%, JSA 85%, tibial cartilage volume 75%, and femoral cartilage volume 85%. Change in BTI was also significantly associated (P < 0.05) with concurrent change in JSA over 12 and 24 months and with change in tibial cartilage volume over 24 months. CONCLUSION: BTI predicts structural OA progression as determined by radiographic and MRI outcomes. BTI may therefore be worthy of study as an outcome measure for OA studies and clinical trials. Copyright 2013 by the American College of Rheumatology
Intrathoracic vs Cervical Anastomosis After Totally or Hybrid Minimally Invasive Esophagectomy for Esophageal Cancer A Randomized Clinical Trial
Background: Transthoracic minimally invasive esophagectomy (MIE) is increasingly performed as part of curative multimodality treatment. There appears to be no robust evidence on the preferred location of the anastomosis after transthoracic MIE. Objective: To compare an intrathoracic with a cervical anastomosis in a randomized clinical trial. Design, Setting, and Participants: This open, multicenter randomized clinical superiority trial was performed at 9 Dutch high-volume hospitals. Patients with midesophageal to distal esophageal or gastroesophageal junction cancer planned for curative resection were included. Data collection occurred from April 2016 through February 2020. Intervention: Patients were randomly assigned (1:1) to transthoracic MIE with intrathoracic or cervical anastomosis. Main Outcomes and Measures: The primary end point was anastomotic leakage requiring endoscopic, radiologic, or surgical intervention. Secondary outcomes were overall anastomotic leak rate, other postoperative complications, length of stay, mortality, and quality of life. Results: Two hundred sixty-two patients were randomized, and 245 were eligible for analysis. Anastomotic leakage necessitating reintervention occurred in 15 of 122 patients with intrathoracic anastomosis (12.3%) and in 39 of 123 patients with cervical anastomosis (31.7%; risk difference, -19.4% [95% CI, -29.5% to -9.3%]). Overall anastomotic leak rate was 12.3% in the intrathoracic anastomosis group and 34.1% in the cervical anastomosis group (risk difference, -21.9% [95% CI, -32.1% to -11.6%]). Intensive care unit length of stay, mortality rates, and overall quality of life were comparable between groups, but intrathoracic anastomosis was associated with fewer severe complications (risk difference, -11.3% [-20.4% to -2.2%]), lower incidence of recurrent laryngeal nerve palsy (risk difference, -7.3% [95% CI, -12.1% to -2.5%]), and better quality of life in 3 subdomains (mean differences: dysphagia, -12.2 [95% CI, -19.6 to -4.7]; problems of choking when swallowing, -10.3 [95% CI, -16.4 to 4.2]; trouble with talking, -15.3 [95% CI, -22.9 to -7.7]). Conclusions and Relevance: In this randomized clinical trial, intrathoracic anastomosis resulted in better outcome for patients treated with transthoracic MIE for midesophageal to distal esophageal or gastroesophageal junction cancer. Trial Registration: Trialregister.nl Identifier: NL4183 (NTR4333)
A Population-based Study on Lymph Node Retrieval in Patients with Esophageal Cancer: Results from the Dutch Upper Gastrointestinal Cancer Audit
Background: For esophageal cancer, the number of retrieved lymph nodes (LNs) is often used as a quality indicator. The aim of this study is to analyze the number of retrieved LNs in The Netherlands, assess factors associated with LN yield, and explore the association with short-term outcomes. This is a population-based study on lymph node retrieval in patients with esophageal cancer, presenting results from the Dutch Upper Gastrointestinal Cancer Audit. Study Design: For this retrospective national cohort study, patients with esophageal carcinoma who underwent esophagectomy between 2011 and 2016 were included. The primary outcome was the number of retrieved LNs. Univariable and multivariable regression analyses were used to test for association with ≥ 15 LNs. Patients and Results: 3970 patients were included. Between 2011 and 2016, the median number of LNs increased from 15 to 20. Factors independently associated with ≥ 15 LNs were: 0–10 kg preoperative weight loss (versus: unknown weight loss, odds ratio [95% confidence interval]: 0.71 [0.57–0.88]), Charlson score 0 (versus: Charlson score 2: 0.76 [0.63–0.92]), cN2 category (reference: cN0, 1.32 [1.05–1.65]), no neoadjuvant therapy and neoadjuvant chemotherapy (reference: neoadjuvant chemoradiotherapy, 1.73 [1.29–2.32] and 2.15 [1.54–3.01]), minimally invasive transthoracic (reference: open transthoracic, 1.46 [1.15–1.85]), open transthoracic (versus open and minimally invasive transhiatal, 0.29 [0.23–0.36] and 0.43 [0.32–0.59]), hospital volume of 26–50 or > 50 resections/year (reference: 0–25, 1.94 [1.55–2.42] and 3.01 [2.36–3.83]), and year of surgery [reference: 2011, odds ratios (ORs) 1.48, 1.53, 2.28, 2.44, 2.54]. There was no association of ≥ 15 LNs with short-term outcomes. Conclusions: The number of LNs retrieved increased between 2011 and 2016. Weight loss, Charlson score, cN category, neoadjuvant therapy, surgical approach, year of resection, and hospital volume were all associated with increased LN yield. Retrieval of ≥ 15 LNs was not associated with increased postoperative morbidity/mortality
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