Pharmacological analysis of the increases in heart rate and diastolic blood pressure produced by (S)-isometheptene and (R)-isometheptene in pithed rats

Background: Isometheptene is a sympathomimetic drug effective in acute migraine treatment. It is composed of two enantiomers with diverse pharmacological properties. This study investigated in pithed rats the cardiovascular effects of (S)- isometheptene and (R)-isometheptene, and the pharmacological profile of the more potent enantiomer. Methods: The effects of i.v. bolus injections (0.03, 0.1, 0.3, 1 and 3 mg/kg) of isometheptene racemate, (S)-isometheptene or (R)-isometheptene on heart rate and blood pressure were analyzed in control experiments. The enantiomer producing more pronounced tachycardic and/or vasopressor responses was further analyzed in rats receiving i.v. injections of prazosin (0.1 mg/kg), rauwolscine (0.3 mg/kg), propranolol (1 mg/kg) or intraperitoneal reserpine (5 mg/kg, -24 h). Results: Compared to (R)-isometheptene, (S)-isometheptene produced greater vasopressor responses, whilst both compounds equipotently increased heart rate. The tachycardic responses to (S)-isometheptene were abolished after propranolol, but remained unaffected by the other antagonists. In contrast, the vasopressor responses to (S)-isometheptene were practically abolished after prazosin. Interestingly, after reserpine, the tachycardic responses to (S)-isometheptene were abolished, whereas its vasopressor responses were attenuated and subsequently abolished by prazosin. Conclusions: The different cardiovascular effects of the isometheptene enantiomers are probably due to differences in their mechanism of action, namely: (i) a mixed sympathomimetic action for (S)-isometheptene (a tyramine-like action and a direct stimulation of α1-adrenoceptors); and (ii) exclusively a tyramine like action for (R)-isometheptene. Thus, (R)-isometheptene may represent a superior therapeutic benefit as an antimigraine agent

The genome sequencing of an albino Western lowland gorilla reveals inbreeding in the wild

Background The only known albino gorilla, named Snowflake, was a male wild born individual from Equatorial Guinea who lived at the Barcelona Zoo for almost 40 years. He was diagnosed with non-syndromic oculocutaneous albinism, i.e. white hair, light eyes, pink skin, photophobia and reduced visual acuity. Despite previous efforts to explain the genetic cause, this is still unknown. Here, we study the genetic cause of his albinism and making use of whole genome sequencing data we find a higher inbreeding coefficient compared to other gorillas. Results We successfully identified the causal genetic variant for Snowflake¿s albinism, a non-synonymous single nucleotide variant located in a transmembrane region of SLC45A2. This transporter is known to be involved in oculocutaneous albinism type 4 (OCA4) in humans. We provide experimental evidence that shows that this amino acid replacement alters the membrane spanning capability of this transmembrane region. Finally, we provide a comprehensive study of genome-wide patterns of autozygogosity revealing that Snowflake¿s parents were related, being this the first report of inbreeding in a wild born Western lowland gorilla. Conclusions In this study we demonstrate how the use of whole genome sequencing can be extended to link genotype and phenotype in non-model organisms and it can be a powerful tool in conservation genetics (e.g., inbreeding and genetic diversity) with the expected decrease in sequencing cost. Keywords: Gorilla; Albinism; Inbreeding; Genome; Conservatio

Multiplicity dependence of jet-like two-particle correlations in p-Pb collisions at sNN\sqrt{s_{NN}} = 5.02 TeV

Two-particle angular correlations between unidentified charged trigger and associated particles are measured by the ALICE detector in p-Pb collisions at a nucleon-nucleon centre-of-mass energy of 5.02 TeV. The transverse-momentum range 0.7 $< p_{\rm{T}, assoc} < p_{\rm{T}, trig} <$ 5.0 GeV/$c$ is examined, to include correlations induced by jets originating from low momen\-tum-transfer scatterings (minijets). The correlations expressed as associated yield per trigger particle are obtained in the pseudorapidity range $|\eta|<0.9$. The near-side long-range pseudorapidity correlations observed in high-multiplicity p-Pb collisions are subtracted from both near-side short-range and away-side correlations in order to remove the non-jet-like components. The yields in the jet-like peaks are found to be invariant with event multiplicity with the exception of events with low multiplicity. This invariance is consistent with the particles being produced via the incoherent fragmentation of multiple parton--parton scatterings, while the yield related to the previously observed ridge structures is not jet-related. The number of uncorrelated sources of particle production is found to increase linearly with multiplicity, suggesting no saturation of the number of multi-parton interactions even in the highest multiplicity p-Pb collisions. Further, the number scales in the intermediate multiplicity region with the number of binary nucleon-nucleon collisions estimated with a Glauber Monte-Carlo simulation.Comment: 23 pages, 6 captioned figures, 1 table, authors from page 17, published version, figures at http://aliceinfo.cern.ch/ArtSubmission/node/161

Multi-particle azimuthal correlations in p-Pb and Pb-Pb collisions at the CERN Large Hadron Collider

Measurements of multi-particle azimuthal correlations (cumulants) for charged particles in p-Pb and Pb-Pb collisions are presented. They help address the question of whether there is evidence for global, flow-like, azimuthal correlations in the p-Pb system. Comparisons are made to measurements from the larger Pb-Pb system, where such evidence is established. In particular, the second harmonic two-particle cumulants are found to decrease with multiplicity, characteristic of a dominance of few-particle correlations in p-Pb collisions. However, when a $|\Delta \eta|$ gap is placed to suppress such correlations, the two-particle cumulants begin to rise at high-multiplicity, indicating the presence of global azimuthal correlations. The Pb-Pb values are higher than the p-Pb values at similar multiplicities. In both systems, the second harmonic four-particle cumulants exhibit a transition from positive to negative values when the multiplicity increases. The negative values allow for a measurement of $v_{2}\{4\}$ to be made, which is found to be higher in Pb-Pb collisions at similar multiplicities. The second harmonic six-particle cumulants are also found to be higher in Pb-Pb collisions. In Pb-Pb collisions, we generally find $v_{2}\{4\} \simeq v_{2}\{6\}\neq 0$ which is indicative of a Bessel-Gaussian function for the $v_{2}$ distribution. For very high-multiplicity Pb-Pb collisions, we observe that the four- and six-particle cumulants become consistent with 0. Finally, third harmonic two-particle cumulants in p-Pb and Pb-Pb are measured. These are found to be similar for overlapping multiplicities, when a $|\Delta\eta| > 1.4$ gap is placed.Comment: 25 pages, 11 captioned figures, 3 tables, authors from page 20, published version, figures at http://aliceinfo.cern.ch/ArtSubmission/node/87

A922 Sequential measurement of 1 hour creatinine clearance (1-CRCL) in critically ill patients at risk of acute kidney injury (AKI)

Meeting abstrac

Erratum to: 36th International Symposium on Intensive Care and Emergency Medicine

[This corrects the article DOI: 10.1186/s13054-016-1208-6.]

Alignment of the ALICE Inner Tracking System with cosmic-ray tracks

37 pages, 15 figures, revised version, accepted by JINSTALICE (A Large Ion Collider Experiment) is the LHC (Large Hadron Collider) experiment devoted to investigating the strongly interacting matter created in nucleus-nucleus collisions at the LHC energies. The ALICE ITS, Inner Tracking System, consists of six cylindrical layers of silicon detectors with three different technologies; in the outward direction: two layers of pixel detectors, two layers each of drift, and strip detectors. The number of parameters to be determined in the spatial alignment of the 2198 sensor modules of the ITS is about 13,000. The target alignment precision is well below 10 micron in some cases (pixels). The sources of alignment information include survey measurements, and the reconstructed tracks from cosmic rays and from proton-proton collisions. The main track-based alignment method uses the Millepede global approach. An iterative local method was developed and used as well. We present the results obtained for the ITS alignment using about 10^5 charged tracks from cosmic rays that have been collected during summer 2008, with the ALICE solenoidal magnet switched off.Peer reviewe

Week 48 resistance analyses of the once-daily, single-tablet regimen darunavir/cobicistat/emtricitabine/tenofovir alafenamide (D/C/F/TAF) in adults living with HIV-1 from the Phase III Randomized AMBER and EMERALD Trials

Darunavir/cobicistat/emtricitabine/tenofovir alafenamide (D/C/F/TAF) 800/150/200/10 mg is being investigated in two Phase III trials, AMBER (NCT02431247; treatment-naive adults) and EMERALD (NCT02269917; treatment-experienced, virologically suppressed adults). Week 48 AMBER and EMERALD resistance analyses are presented. Postbaseline samples for genotyping/phenotyping were analyzed from protocol-defined virologic failures (PDVFs) with viral load (VL) >= 400 copies/mL at failure/later time points. Post hoc analyses were deep sequencing in AMBER, and HIV-1 proviral DNA from baseline samples (VL = 3 thymidine analog-associated mutations (24% not fully susceptible to tenofovir) detected at screening. All achieved VL <50 copies/mL at week 48 or prior discontinuation. D/C/F/TAF has a high genetic barrier to resistance; no darunavir, primary PI, or tenofovir RAMs were observed through 48 weeks in AMBER and EMERALD. Only one postbaseline M184I/V RAM was observed in HIV-1 of an AMBER participant. In EMERALD, baseline archived RAMs to darunavir, emtricitabine, and tenofovir in participants with prior VF did not preclude virologic response

A population-based controlled experiment assessing the epidemiological impact of digital contact tracing

While Digital contact tracing (DCT) has been argued to be a valuable complement to manual tracing in the containment of COVID-19, no empirical evidence of its effectiveness is available to date. Here, we report the results of a 4-week population-based controlled experiment that took place in La Gomera (Canary Islands, Spain) between June and July 2020, where we assessed the epidemiological impact of the Spanish DCT app Radar Covid. After a substantial communication campaign, we estimate that at least 33% of the population adopted the technology and further showed relatively high adherence and compliance as well as a quick turnaround time. The app detects about 6.3 close-contacts per primary simulated infection, a significant percentage being contacts with strangers, although the spontaneous follow-up rate of these notified cases is low. Overall, these results provide experimental evidence of the potential usefulness of DCT during an epidemic outbreak in a real population