Correlation between blood and oral fluid psychoactive drug concentrations and cognitive impairment in driving under the influence of drugs

The effects of drugs on driving performance should be checked with drug concentration in the brain and at the same time with the evaluation of both the behavioural and neurophysiological effects. The best accessible indicator of this information is the concentration of the drug and/or metabolites in blood and, to a certain extent, oral fluid. We sought to review international studies on correlation between blood and oral fluid drug concentrations, neurological correlates and cognitive impairment in driving under the influence of drugs. Methods : Relevant scientific articles were identified from PubMed, Cochrane Central, Scopus, Web of Science, Science Direct, EMBASE up to April 2017. Results : Up to 2010, no epidemiological studies were available on this matter and International scientists suggested that even minimal amounts of parent drugs in blood and oral fluid could affect driving impairment. More recently, epidemiological data, systematic reviews and meta-analysis on drugged drivers allowed the suggestion of impairment concentration limits for the most common illicit drugs. These values were obtained comparing driving disability induced by psychotropic drugs with that of established blood alcohol limits. Differently from ethyl alcohol where both detection methods and concentration limits have been well established even with inhomogeneity of ranges within different countries, in case of drugs of abuse no official cut-offs have yet been established, nor any standardized analytical protocols. Conclusion : Multiple aspects of driving performance can be differently affected by illicit drugs, and even if for few of them some dose/concentration dependent impairment has been reported, a wider knowledge on concentration/impairment relationship is still missin

Molecular Insights of New Psychoactive Substances (NPS) 2.0

The New Psychoactive Substances (NPS) phenomenon represents an ever-changing global issue, with a number of new molecules entering the illicit market every year in response to international banning laws [...]

Early Science with the Large Millimeter Telescope: Exploring the Effect of AGN Activity on the Relationships Between Molecular Gas, Dust, and Star Formation

The molecular gas, H$_2$, that fuels star formation in galaxies is difficult to observe directly. As such, the ratio of $L_{\rm IR}$ to $L^\prime_{\rm CO}$ is an observational estimation of the star formation rate compared with the amount of molecular gas available to form stars, which is related to the star formation efficiency and the inverse of the gas consumption timescale. We test what effect an IR luminous AGN has on the ratio $L_{\rm IR}/L^\prime_{\rm CO}$ in a sample of 24 intermediate redshift galaxies from the 5 mJy Unbiased Spitzer Extragalactic Survey (5MUSES). We obtain new CO(1-0) observations with the Redshift Search Receiver on the Large Millimeter Telescope. We diagnose the presence and strength of an AGN using Spitzer IRS spectroscopy. We find that removing the AGN contribution to $L_{\rm IR}^{\rm tot}$ results in a mean $L_{\rm IR}^{\rm SF}/L^\prime_{\rm CO}$ for our entire sample consistent with the mean $L_{\rm IR}/L^\prime_{\rm CO}$ derived for a large sample of star forming galaxies from $z\sim0-3$. We also include in our comparison the relative amount of polycyclic aromatic hydrocarbon emission for our sample and a literature sample of local and high redshift Ultra Luminous Infrared Galaxies and find a consistent trend between $L_{6.2}/L_{\rm IR}^{\rm SF}$ and $L_{\rm IR}^{\rm SF}/L^\prime_{\rm CO}$, such that small dust grain emission decreases with increasing $L_{\rm IR}^{\rm SF}/L^\prime_{\rm CO}$ for both local and high redshift dusty galaxies.Comment: Accepted for publication in ApJ (to appear on December 10

A Bright Submillimeter Source in the Bullet Cluster (1E0657--56) Field Detected with BLAST

We present the 250, 350, and 500 micron detection of bright submillimeter emission in the direction of the Bullet Cluster measured by the Balloon-borne Large Aperture Submillimeter Telescope (BLAST). The 500 micron centroid is coincident with an AzTEC 1.1 mm point-source detection at a position close to the peak lensing magnification produced by the cluster. However, the 250 micron and 350 micron centroids are elongated and shifted toward the south with a differential shift between bands that cannot be explained by pointing uncertainties. We therefore conclude that the BLAST detection is likely contaminated by emission from foreground galaxies associated with the Bullet Cluster. The submillimeter redshift estimate based on 250-1100 micron photometry at the position of the AzTEC source is z_phot = 2.9 (+0.6 -0.3), consistent with the infrared color redshift estimation of the most likely IRAC counterpart. These flux densities indicate an apparent far-infrared luminosity of L_FIR = 2E13 Lsun. When the amplification due to the gravitational lensing of the cluster is removed, the intrinsic far-infrared luminosity of the source is found to be L_FIR <= 10^12 Lsun, consistent with typical luminous infrared galaxies.Comment: Accepted for publication in the Astrophysical Journal. Maps are available at http://blastexperiment.info

ALMA reveals a stable rotating gas disk in a paradoxical low-mass, ultra-dusty galaxy at z = 4.274

We report ALMA detections of [CII] and dust continuum in Az9, a multiply-imaged galaxy behind the Frontier Field cluster MACSJ0717.5+3745. The bright [CII] emission line provides a spectroscopic redshift of z = 4.274. This strongly lensed (mu = 7 +/- 1) galaxy has an intrinsic stellar mass of only 2e9 Msun and a total star formation rate of 26 Msun/yr (~80% of which is dust obscured). Using public magnification maps, we reconstruct the [CII] emission in the source plane to reveal a stable, rotation-dominated disk with V/sigma = 5.3, which is > 2x higher than predicted from simulations for similarly high-redshift, low-mass galaxies. In the source plane, the [CII] disk has a half-light radius of 1.8 kpc and, along with the dust, is spatially offset from the peak of the stellar light by 1.4 kpc. Az9 is not deficient in [CII]; L[CII]/LIR = 0.0027 consistent with local and high redshift normal star forming galaxies. While dust-obscured star formation is expected to dominate in higher mass galaxies, such a large reservoir of dust and gas in a lower mass disk galaxy 1.4 Gyr after the Big Bang challenges our picture of early galaxy evolution. Furthermore, the prevalence of such low-mass dusty galaxies has important implications for the selection of the highest redshift dropout galaxies with JWST. As one of the lowest stellar mass galaxies at z > 4 to be detected in dust continuum and [CII], Az9 is an excellent laboratory in which to study early dust enrichment in the interstellar medium.Comment: Accepted for publication in ApJ Letter

Glycosylation-dependent circuits synchronize the pro-angiogenic and immunoregulatory functions of myeloid-derived suppressor cells in cancer

Myeloid-derived suppressor cells (MDSCs) favor tumorprogression and therapy resistance by reprogramming antitumor immunity and promoting angiogenesis. To elucidatethe mechanisms that synchronize these functions, we investigated the role of glycosylation-dependent, galectin-1(Gal1)-driven circuits in coupling immunoregulatory andpro-angiogenic activities of MDSCs. Flow cytometry andHPLC-HILIC/WAX revealed an activation-dependent glycanprofile in monocytic and polymorphonuclear MDSCs (p=0.03)that controlled Gal1 binding and was more prominent in tumor microenvironments. Exposure to Gal1 led to concomitant activation of immunosuppression and angiogenesisprograms in bone marrow derived MDSCs. Flow cytometryof Gal1-conditioned MDSCs showed higher expression ofimmune checkpoint molecules, including programmed deathligand-1 (PD-L1) (p=0.005) and indoleamine 2,3-dioxygenase (IDO) (p=0.037) and greater production of reactive oxygen species (ROS) and nitric oxide (NO) (p=0.02). In vitro,Gal1-conditioned MDSCs showed greater T-cell suppressive capacity (p=0.03) and higher IL-10 (p=0.04) and IL-27(p=0.003) secretion. These effects were accompanied by enhanced endothelial cell migration, tube formation, 3D-sprouting and vascularization (p<0.05). In vivo, Gal1-conditionedMDSCs accelerated tumor growth (p=0.001) and fosteredimmune evasion and vascularization programs in Gal1-deficient colorectal tumors. Mechanistically, mass spectrometry,immunoblot and blocking assays identified the CD18/CD11b/CD177 complex as a bona fide Gal1 receptor and STAT3 asa key signaling pathway coupling these functions. Accordingly, a combined algorithm that integrates Gal1 expressionand MDSC phenotype, showed critical prognostic value bydelineating the immune landscape and clinical outcome ofhuman cancers. Thus, glycosylation-dependent Gal1-drivencircuits favor tumor progression by coupling immunoregulatory and pro-angiogenic programs of MDSCs via CD18- andSTAT3-dependent pathways.Fil: Blidner, Ada Gabriela. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Biología y Medicina Experimental. Fundación de Instituto de Biología y Medicina Experimental. Instituto de Biología y Medicina Experimental; ArgentinaFil: Bach, Camila Agustina. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Biología y Medicina Experimental. Fundación de Instituto de Biología y Medicina Experimental. Instituto de Biología y Medicina Experimental; ArgentinaFil: García, Pablo Alfredo. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Mendoza. Instituto de Histología y Embriología de Mendoza Dr. Mario H. Burgos. Universidad Nacional de Cuyo. Facultad de Ciencias Médicas. Instituto de Histología y Embriología de Mendoza Dr. Mario H. Burgos; ArgentinaFil: Cagnoni, Alejandro. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Biología y Medicina Experimental. Fundación de Instituto de Biología y Medicina Experimental. Instituto de Biología y Medicina Experimental; ArgentinaFil: Manselle Cocco, Montana Nicolle. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Biología y Medicina Experimental. Fundación de Instituto de Biología y Medicina Experimental. Instituto de Biología y Medicina Experimental; ArgentinaFil: Pinto, Nicolás Alejandro. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Biología y Medicina Experimental. Fundación de Instituto de Biología y Medicina Experimental. Instituto de Biología y Medicina Experimental; ArgentinaFil: Torres, Nicolás. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Biología y Medicina Experimental. Fundación de Instituto de Biología y Medicina Experimental. Instituto de Biología y Medicina Experimental; ArgentinaFil: Gatto, Sabrina Gisela. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Biología y Medicina Experimental. Fundación de Instituto de Biología y Medicina Experimental. Instituto de Biología y Medicina Experimental; ArgentinaFil: Sarrias, Luciana. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Química y Físico-Química Biológicas "Prof. Alejandro C. Paladini". Universidad de Buenos Aires. Facultad de Farmacia y Bioquímica. Instituto de Química y Físico-Química Biológicas; ArgentinaFil: Giribaldi, María Laura. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Biología y Medicina Experimental. Fundación de Instituto de Biología y Medicina Experimental. Instituto de Biología y Medicina Experimental; ArgentinaFil: Merlo, Joaquín Pedro. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Biología y Medicina Experimental. Fundación de Instituto de Biología y Medicina Experimental. Instituto de Biología y Medicina Experimental; ArgentinaFil: Pérez Sáez, Juan Manuel. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Biología y Medicina Experimental. Fundación de Instituto de Biología y Medicina Experimental. Instituto de Biología y Medicina Experimental; ArgentinaFil: Salatino, Mariana. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Biología y Medicina Experimental. Fundación de Instituto de Biología y Medicina Experimental. Instituto de Biología y Medicina Experimental; ArgentinaFil: Troncoso, María Fernanda. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Química y Físico-Química Biológicas "Prof. Alejandro C. Paladini". Universidad de Buenos Aires. Facultad de Farmacia y Bioquímica. Instituto de Química y Físico-Química Biológicas; ArgentinaFil: Mariño, Karina Valeria. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Biología y Medicina Experimental. Fundación de Instituto de Biología y Medicina Experimental. Instituto de Biología y Medicina Experimental; ArgentinaFil: Abba, Martín Carlos. Universidad Nacional de La Plata; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; ArgentinaFil: Croci, Diego O.. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Mendoza. Instituto de Histología y Embriología de Mendoza Dr. Mario H. Burgos. Universidad Nacional de Cuyo. Facultad de Ciencias Médicas. Instituto de Histología y Embriología de Mendoza Dr. Mario H. Burgos; ArgentinaFil: Rabinovich, Gabriel Adrián. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Biología y Medicina Experimental. Fundación de Instituto de Biología y Medicina Experimental. Instituto de Biología y Medicina Experimental; ArgentinaLXVI Annual Meeting of Sociedad Argentina de Investigación Clínica; LXIX Annual Meeting of Sociedad Argentina de Inmunología; LIII Annual Meeting of Asociación Argentina de Farmacología Experimental and XI Annual Meeting of Asociación Argentina de NanomedicinasArgentinaSociedad Argentina de Investigación ClínicaSociedad Argentina de InmunologíaAsociación Argentina de Farmacología ExperimentalAsociación Argentina de Nanomedicin

Omecamtiv mecarbil in chronic heart failure with reduced ejection fraction, GALACTIC‐HF: baseline characteristics and comparison with contemporary clinical trials

Aims: The safety and efficacy of the novel selective cardiac myosin activator, omecamtiv mecarbil, in patients with heart failure with reduced ejection fraction (HFrEF) is tested in the Global Approach to Lowering Adverse Cardiac outcomes Through Improving Contractility in Heart Failure (GALACTIC‐HF) trial. Here we describe the baseline characteristics of participants in GALACTIC‐HF and how these compare with other contemporary trials. Methods and Results: Adults with established HFrEF, New York Heart Association functional class (NYHA) ≥ II, EF ≤35%, elevated natriuretic peptides and either current hospitalization for HF or history of hospitalization/ emergency department visit for HF within a year were randomized to either placebo or omecamtiv mecarbil (pharmacokinetic‐guided dosing: 25, 37.5 or 50 mg bid). 8256 patients [male (79%), non‐white (22%), mean age 65 years] were enrolled with a mean EF 27%, ischemic etiology in 54%, NYHA II 53% and III/IV 47%, and median NT‐proBNP 1971 pg/mL. HF therapies at baseline were among the most effectively employed in contemporary HF trials. GALACTIC‐HF randomized patients representative of recent HF registries and trials with substantial numbers of patients also having characteristics understudied in previous trials including more from North America (n = 1386), enrolled as inpatients (n = 2084), systolic blood pressure &lt; 100 mmHg (n = 1127), estimated glomerular filtration rate &lt; 30 mL/min/1.73 m2 (n = 528), and treated with sacubitril‐valsartan at baseline (n = 1594). Conclusions: GALACTIC‐HF enrolled a well‐treated, high‐risk population from both inpatient and outpatient settings, which will provide a definitive evaluation of the efficacy and safety of this novel therapy, as well as informing its potential future implementation

Synthetic Cathinones and Neurotoxicity Risks: A Systematic Review

According to the EU Early Warning System (EWS), synthetic cathinones (SCs) are the second largest new psychoactive substances (NPS) class, with 162 synthetic cathinones monitored by the EU EWS. They have a similar structure to cathinone, principally found in Catha Edulis; they have a phenethylamine related structure but also exhibit amphetamine-like stimulant effects. Illegal laboratories regularly develop new substances and place them on the market. For this reason, during the last decade this class of substances has presented a great challenge for public health and forensic toxicologists. Acting on different systems and with various mechanisms of action, the spectrum of side effects caused by the intake of these drugs of abuse is very broad. To date, most studies have focused on the substances' cardiac effects, and very few on their associated neurotoxicity. Specifically, synthetic cathinones appear to be involved in different neurological events, including increased alertness, mild agitation, severe psychosis, hyperthermia and death. A systematic literature search in PubMed and Scopus databases according to PRISMA guidelines was performed. A total of 515 studies published from 2005 to 2022 (350 articles from PubMed and 165 from Scopus) were initially screened for eligibility. The papers excluded, according to the criteria described in the Method Section (n = 401) and after full text analyses (n = 82), were 483 in total. The remaining 76 were included in the present review, as they met fully the inclusion criteria. The present work provides a comprehensive review on neurotoxic mechanisms of synthetic cathinones highlighting intoxication cases and fatalities in humans, as well as the toxic effects on animals (in particular rats, mice and zebrafish larvae). The reviewed studies showed brain-related adverse effects, including encephalopathy, coma and convulsions, and sympathomimetic and hallucinogenic toxidromes, together with the risk of developing excited/agitated delirium syndrome and serotonin syndrome

Correlation between Blood and Oral Fluid Psychoactive Drug Concentrations and Cognitive Impairment in Driving under the Influence of Drugs

Background: The effects of drugs on driving performance should be checked with drug concentration in the brain and at the same time with the evaluation of both the behavioural and neurophysiological effects. The best accessible indicator of this information is the concentration of the drug and/or metabolites in blood and, to a certain extent, oral fluid. We sought to review international studies on correlation between blood and oral fluid drug concentrations, neurological correlates and cognitive impairment in driving under the influence of drugs.Methods: Relevant scientific articles were identified from PubMed, Cochrane Central, Scopus, Web of Science, Science Direct, EMBASE up to April 2017.Results: Up to 2010, no epidemiological studies were available on this matter and International scientists suggested that even minimal amounts of parent drugs in blood and oral fluid could affect driving impairment. More recently, epidemiological data, systematic reviews and meta-analysis on drugged drivers allowed the suggestion of impairment concentration limits for the most common illicit drugs. These values were obtained comparing driving disability induced by psychotropic drugs with that of established blood alcohol limits. Differently from ethyl alcohol where both detection methods and concentration limits have been well established even with inhomogeneity of ranges within different countries, in case of drugs of abuse no official cut-offs have yet been established, nor any standardized analytical protocols.Conclusion: Multiple aspects of driving performance can be differently affected by illicit drugs, and even if for few of them some dose/concentration dependent impairment has been reported, a wider knowledge on concentration/impairment relationship is still missing