Do activities of cytochrome P450 (CYP)3A, CYP2D6 and P-glycoprotein differ between healthy volunteers and HIV-infected patients?

BACKGROUND: In inflammation and infection, cytochrome P450 (CYP) enzyme activities are down-regulated. Information on possible discrepancies in activities of CYP enzymes and drug transporters between HIV-infected patients and healthy people is limited. METHODS: We used midazolam, dextromethorphan and digoxin as in vivo phenotyping probes for CYP3A (CYP3A4/5), CYP2D6 and P-glycoprotein activities, respectively, and compared these activities between 12 healthy Caucasian volunteers and 30 treatment-naive HIV-infected patients. RESULTS: Among the HIV-infected patients, the overall CYP3A activity (apparent oral midazolam clearance) was approximately 50% of the activity observed in healthy volunteers (point estimate 0.490, 90% confidence interval [CI] 0.377-0.638). The CYP2D6 activity (plasma ratio area under the curve [AUC]; AUC(dextromethorphan)/AUC(dextrorphan)) was essentially unchanged (point estimate 1.289, 90% CI 0.778-2.136). P-glycoprotein activity was slightly lower in patients (digoxin maximum concentration point estimate 1.304, 90% CI 1.034-1.644). CONCLUSIONS: The overall CYP3A activity was approximately 50% lower in HIV-infected patients than in healthy volunteers. The CYP2D6 activity was highly variable, but, on average was not different between groups, whereas a marginally lower P-glycoprotein activity was observed in treatment-naive HIV-infected patients

Hydrogen atom moving across a strong magnetic field: analytical approximations

Analytical approximations are constructed for binding energies, quantum-mechanical sizes and oscillator strengths of main radiative transitions of hydrogen atoms arbitrarily moving in magnetic fields 10^{12}-10^{13} G. Examples of using the obtained approximations for determination of maximum transverse velocity of an atom and for evaluation of absorption spectra in magnetic neutron star atmospheres are presented.Comment: 17 pages, 3 figures, 5 tables, LaTeX with IOP style files (included). In v.2, Fig.1 and Table 5 have been corrected. In v.3, a misprint in the fit for oscillator strengths, Eq.(21), has been correcte

JOYS: MIRI/MRS spectroscopy of gas-phase molecules from the high-mass star-forming region IRAS 23385+6053

Space-based mid-IR spectroscopy provides tracers of warm gas in star-forming regions that are inaccessible from the ground. Past mid-IR spectra of bright high-mass protostars in the hot-core phase typically showed strong absorption features from molecules such as CO$_2$, C$_2$H$_2$, and HCN. However, little is known about their fainter counterparts at earlier stages. We thus aim to characterize the gas-phase molecular features in JWST MIRI/MRS observations of the young high-mass star-forming region IRAS 23385+6053. Spectra were extracted from two mid-IR sources and three H$_2$ bright outflow knots in the MIRI/MRS field of view. Rich molecular spectra with emission from CO, H$_2$, HD, H$_2$O, C$_2$H$_2$, HCN, CO$_2$, and OH are detected towards the two mid-IR sources. However, only CO and OH are seen towards the brightest H$_2$ knots, suggesting that the majority of the observed species are associated with disks or hot core regions rather than outflows. Simple Local thermodynamic equilibrium (LTE) slab models were used to fit the observed molecular features. The LTE model fits to $^{12}$CO$_{2}$, C$_{2}$H$_{2}$, and HCN emission suggest warm $120-200$ K emission arising from a disk surface around one or both protostars. Weak $\sim500$ K H$_2$O emission at $\sim$ 6-7 $\mu$m is detected towards one mid-IR source, whereas $250-1050$ K H$_2$O absorption is found in the other. The H$_2$O absorption may occur in the disk atmosphere due to strong accretion-heating of the midplane, or in a disk wind viewed at an ideal angle for absorption. CO emission may originate in the hot inner disk or outflow shocks. OH emission is likely excited in a non-LTE manner through water photodissociation or chemical formation. The observations are consistent with disks having already formed in the young IRAS 23385+6053 system, but further observations are needed to disentangle the effects of geometry and evolution.Comment: 21 Pages, 16 Figures. Accepted for publication in Astronomy and Astrophysic

JOYS: JWST Observations of Young protoStars: Outflows and accretion in the high-mass star-forming region IRAS23385+605

Aims: The JWST program JOYS (JWST Observations of Young protoStars) aims at characterizing the physical and chemical properties of young high- and low-mass star-forming regions, in particular the unique mid-infrared diagnostics of the warmer gas and solid-state components. We present early results from the high-mass star formation region IRAS23385+6053. Methods: The JOYS program uses the MIRI MRS with its IFU to investigate a sample of high- and low-mass star-forming protostellar systems. Results: The 5 to 28mum MIRI spectrum of IRAS23385+6053 shows a plethora of features. While the general spectrum is typical for an embedded protostar, we see many atomic and molecular gas lines boosted by the higher spectral resolution and sensitivity compared to previous space missions. Furthermore, ice and dust absorption features are also present. Here, we focus on the continuum emission, outflow tracers like the H2, [FeII] and [NeII] lines as well as the potential accretion tracer Humphreys alpha HI(7--6). The short-wavelength MIRI data resolve two continuum sources A and B, where mid-infrared source A is associated with the main mm continuum peak. The combination of mid-infrared and mm data reveals a young cluster in its making. Combining the mid-infrared outflow tracer H2, [FeII] and [NeII] with mm SiO data shows a complex interplay of at least three molecular outflows driven by protostars in the forming cluster. Furthermore, the Humphreys alpha line is detected at a 3-4sigma level towards the mid-infrared sources A and B. Following Rigliaco et al. (2015), one can roughly estimate accretion luminosities and corresponding accretion rates between ~2.6x10^-6 and ~0.9x10^-4 M_sun/yr. This is discussed in the context of the observed outflow rates. Conclusions: The analysis of the MIRI MRS observations for this young high-mass star-forming region reveals connected outflow and accretion signatures.Comment: 12 pages, 9 figures, accepted for Astronomy & Astrophysics, the paper is also available at https://www2.mpia-hd.mpg.de/homes/beuther/papers.htm

Activation of Autophagy in a Rat Model of Retinal Ischemia following High Intraocular Pressure

Acute primary open angle glaucoma is an optic neuropathy characterized by the elevation of intraocular pressure, which causes retinal ischemia and neuronal death. Rat ischemia/reperfusion enhances endocytosis of both horseradish peroxidase (HRP) or fluorescent dextran into ganglion cell layer (GCL) neurons 24 h after the insult. We investigated the activation of autophagy in GCL-neurons following ischemia/reperfusion, using acid phosphatase (AP) histochemistry and immunofluorescence against LC3 and LAMP1. Retinal I/R lead to the appearance of AP-positive granules and LAMP1-positive vesicles 12 and 24 h after the insult, and LC3 labelling at 24 h, and induced a consistent retinal neuron death. At 48 h the retina was negative for autophagic markers. In addition, Western Blot analysis revealed an increase of LC3 levels after damage: the increase in the conjugated, LC3-II isoform is suggestive of autophagic activity. Inhibition of autophagy by 3-methyladenine partially prevented death of neurons and reduces apoptotic markers, 24 h post-lesion. The number of neurons in the GCL decreased significantly following I/R (I/R 12.21±1.13 vs controls 19.23±1.12 cells/500 µm); this decrease was partially prevented by 3-methyladenine (17.08±1.42 cells/500 µm), which potently inhibits maturation of autophagosomes. Treatment also prevented the increase in glial fibrillary acid protein immunoreactivity elicited by I/R. Therefore, targeting autophagy could represent a novel and promising treatment for glaucoma and retinal ischemia

Outflows from the youngest stars are mostly molecular

The formation of stars and planets is accompanied not only by the build-up of matter, namely accretion, but also by its expulsion in the form of highly supersonic jets that can stretch for several parsecs 1,2. As accretion and jet activity are correlated and because young stars acquire most of their mass rapidly early on, the most powerful jets are associated with the youngest protostars 3. This period, however, coincides with the time when the protostar and its surroundings are hidden behind many magnitudes of visual extinction. Millimetre interferometers can probe this stage but only for the coolest components 3. No information is provided on the hottest (greater than 1,000 K) constituents of the jet, that is, the atomic, ionized and high-temperature molecular gases that are thought to make up the jet’s backbone. Detecting such a spine relies on observing in the infrared that can penetrate through the shroud of dust. Here we report near-infrared observations of Herbig-Haro 211 from the James Webb Space Telescope, an outflow from an analogue of our Sun when it was, at most, a few times 104 years old. These observations\ua0reveal copious emission from hot molecules, explaining the origin of the ‘green fuzzies’ 4–7 discovered nearly two decades ago by the Spitzer Space Telescope 8. This outflow is found to be propagating slowly in comparison to its more evolved counterparts and, surprisingly, almost no trace of atomic or ionized emission is seen, suggesting its spine is almost purely molecular

Complex organic molecules in low-mass protostars on Solar System scales -- II. Nitrogen-bearing species

The chemical inventory of planets is determined by the physical and chemical processes that govern the early phases of star formation. The aim is to investigate N-bearing complex organic molecules towards two Class 0 protostars (B1-c and S68N) at millimetre wavelengths with ALMA. Next, the results of the detected N-bearing species are compared with those of O-bearing species for the same and other sources. ALMA observations in Band 6 ($\sim$ 1 mm) and Band 5 ($\sim$ 2 mm) are studied at $\sim$ 0.5" resolution, complemented by Band 3 ($\sim$ 3 mm) data in a $\sim$ 2.5" beam. NH2CHO, C2H5CN, HNCO, HN13CO, DNCO, CH3CN, CH2DCN, and CHD2CN are identified towards the investigated sources. Their abundances relative to CH3OH and HNCO are similar for the two sources, with column densities that are typically an order of magnitude lower than those of O-bearing species. The largest variations, of an order of magnitude, are seen for NH2CHO abundance ratios with respect to HNCO and CH3OH and do not correlate with the protostellar luminosity. In addition, within uncertainties, the N-bearing species have similar excitation temperatures to those of O-bearing species ($\sim$ 100 $\sim$ 300 K). The similarity of most abundances with respect to HNCO, including those of CH2DCN and CHD2CN, hints at a shared chemical history, especially the high D/H ratio in cold regions prior to star formation. However, some of the variations in abundances may reflect the sensitivity of the chemistry to local conditions such as temperature (e.g. NH2CHO), while others may arise from differences in the emitting areas of the molecules linked to their different binding energies in the ice. The two sources discussed here add to the small number of sources with such a detailed chemical analysis on Solar System scales. Future JWST data will allow a direct comparison between the ice and gas abundances of N-bearing species.Comment: Accepted to A&A, 41 pages, 37 figure

Identification of novel Coxiella burnetii genotypes from Ethiopian ticks

Background: Coxiella burnetii , the etiologic agent of Q fever, is a highly infectious zoonotic bacterium. Genetic information about the strains of this worldwide distributed agent circulating on the African continent is limited. The aim of the present study was the genetic characterization of C. burnetii DNA samples detected in ticks collected from Ethiopian cattle and their comparison with other genotypes found previously in other parts of the world. Methodology/Principal Findings: A total of 296 tick samples were screened by real-time PCR targeting the IS 1111 region of C. burnetii genome and from the 32 positive samples, 8 cases with sufficient C. burnetii DNA load ( Amblyomma cohaerens ,n 5 6; A. variegatum ,n 5 2) were characterized by multispacer sequence typing (MST) and multiple-locus variable-number tandem repeat analysis (MLVA). One novel sequence type (ST), the proposed ST52, was identified by MST. The MLVA-6 discriminated the proposed ST52 into two newly identified MLVA genotypes: type 24 or AH was detected in both Amblyomma species while type 26 or AI was found only in A. cohaerens . Conclusions/Significance: Both the MST and MLVA genotypes of the present work are closely related to previously described genotypes found primarily in cattle samples from different parts of the globe. This finding is congruent with the source hosts of the analyzed Ethiopian ticks, as these were also collected from cattle. The present study provides genotype information of C. burnetii from this seldom studied East-African region as well as further evidence for the presumed host-specific adaptation of this agent

Observations of the planetary nebula SMP LMC 058 with the JWST MIRI medium resolution spectrometer

During the commissioning of JWST, the medium-resolution spectrometer (MRS) on the mid-infrared instrument (MIRI) observed the planetary nebula SMP LMC 058 in the Large Magellanic Cloud. The MRS was designed to provide medium resolution (R = λ/Δλ) 3D spectroscopy in the whole MIRI range. SMP LMC 058 is the only source observed in JWST commissioning that is both spatially and spectrally unresolved by the MRS and is a good test of JWST's capabilities. The new MRS spectra reveal a wealth of emission lines not previously detected in this planetary nebula. From these lines, the spectral resolving power (λ/Δλ) of the MRS is confirmed to be in the range R = 4000-1500, depending on the MRS spectral sub-band. In addition, the spectra confirm that the carbon-rich dust emission is from complex hydrocarbons and SiC grains and that there is little to no time evolution of the SiC dust and emission line strengths over a 17-yr epoch. These commissioning data reveal the great potential of the MIRI MRS for the study of circumstellar and interstellar material.</p

No relationship between left ventricular radial wall motion and longitudinal velocity and the extent and severity of noncompaction cardiomyopathy

<p>Abstract</p> <p>Background</p> <p>Noncompaction cardiomyopathy (NCCM) is characterized by a prominent trabecular meshwork and deep intertrabecular recesses. Although systolic dysfunction is common, limited information is available on differences in wall motion of the normal compacted and noncompacted segments. The purpose of this study was to assess radial wall motion and longitudinal wall velocity in patients with NCCM, according to the extent and severity of noncompaction.</p> <p>Methods</p> <p>The study comprised 29 patients in sinus rhythm (age 41 ± 15 years, 15 men), who fulfilled stringent diagnostic criteria for NCCM and compared to 29 age and gender matched healthy controls. Segmental radial wall motion of all compacted and noncompacted segments was assessed with the standard visual wall motion score index and longitudinal systolic (Sm) wall velocity with tissue Doppler imaging of the mitral annulus. For each LV wall a normalized Sm value was calculated. The extent and severity of NC in each LV segment was assessed both in a qualitative and quantitative manner.</p> <p>Results</p> <p>Heart failure was the primary clinical presentation in half of the patients. NCCM patients had a wall motion score index of 1.68 ± 0.43 and a normalized Sm of 82 ± 20%. The total and maximal noncompaction scores were not related to the wall motion score index and the normalized Sm. NCCM patients with and without heart failure had similar total and maximal noncompaction scores.</p> <p>Conclusions</p> <p>In NCCM patient's radial wall motion and longitudinal LV wall velocity is impaired but not related to the extent or severity of noncompaction.</p