59 research outputs found

    Serotonin and hallucinogens

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    This brief review traces the serotonin (5-HT) hypothesis of the action of hallucinogenic drugs from the early 1950s to the present day. There is now converging evidence from biochemical, electrophysiological, and behavioral studies that the two major classes of psychedelic hallucinogens, the indoleamines (e.g., LSD) and the phenethylamines (e.g., mescaline), have a common site of action as partial agonists at 5-HT 2A and other 5-HT 2 receptors in the central nervous system. The noradrenergic locus coeruleus and the cerebral cortex are among the regions where hallucinogens have prominent effects through their actions upon a 5-HT The accidental discovery in 1943 of the hallucinogenic properties of the synthetic ergoline compound LSD (dlysergic acid diethylamide) by the chemist Albert Hoffman is well known. Five years later, in 1948, serotonin (later determined to be 5-hydroxytryptamine or 5-HT) was found in bovine blood serum NEURONAL ACTIONS OF HALLUCINOGENIC DRUGS Effects of Hallucinogens on 5-HT Neurons of the Raphe Nuclei The identification of 5-HT as a neurotransmitter was not achieved until the mid-1960s, when monoaminergic neuronal pathways in the brain were discovered and mapped by histochemical fluorescence methods (Dähl-strom and Fuxe 1964). These maps, which revealed that 5-HT neuronal cell bodies were clustered in the raphe nuclei of the brainstem, provided the basis for singlecell electrophysiological recordings from identified 5-HT neurons. LSD was found to have a potent inhibitory effect upon the tonically firing 5-HT neurons of the dorsal raphe nucleus In subsequent years, the delineation of multiple 5-HT receptor subtypes by radiolabeled ligand binding and molecular methods (see Affinity for 5-HT 2 Receptors Correlates with Hallucinogenic Potency Glennon, Titeler, and their colleagues showed that there is an excellent correlation between the affinity of both indoleamine and phenethylamine hallucinogens for 5-HT 2 receptors and hallucinogenic potency in humans Actions at 5-HT 2C receptors, which have been associated with anxiogenic responses Hallucinogens Enhance Sensory Responses in the Locus Coeruleus via 5-HT 2A Receptors The locus coeruleus (LC) consists of two dense clusters of noradrenergic neurons located bilaterally in the upper pons at the lateral border of the 4th ventricle. The LC, which projects diffusely to virtually all regions of the neuraxis, receives an extraordinary convergence of somatic, visceral, and other sensory inputs from all regions of the body, has been likened to a novelty detector for salient external stimuli (Aston-Jones and Bloom 1981; Cedarbaum and Aghajanian 1978). In this context, it is of interest that the systemic administration of LSD, mescaline, or other psychedelic hallucinogens in anesthetized rats, although decreasing spontaneous activity, produces a paradoxical facilitation of the activation of LC neurons by sensory stimuli (Aghajanian 1980; Rasmussen and Aghajanian 1986); this effect is not through a direct action on LC cell bodies, because it cannot be mimicked by the local, microiontophoretic application of the drugs. The effects of hallucinogens on LC neurons can be reversed by low intravenous doses of selective 5-HT 2 antagonists, such as ritanserin (Rasmussen and Aghajanian 1986). Antipsychotic drugs are also able to reverse the actions of hallucinogens in the locus coeruleus at doses correlating with their affinity for 5-HT 2A but not dopamine and adrenergic receptors Because the effects of systemically administered hallucinogens are through an activation of afferent inputs rather than through a direct action upon LC cell bodies, the LC itself cannot be used as a model for studying the direct cellular actions of hallucinogens. Nevertheless, the effects of the hallucinogens upon the LC are of interest, because this nucleus receives such an extraordinarily widespread convergence of sensory information, both somatosensory and visceral, relaying this information to virtually all other parts of the neuraxis, including the cerebral cortex. 5-HT 2A Receptors Enhance Glutamate Release in Neocortex The ubiquitous effects of hallucinogens on such complex processes as cognition, perception, and mood suggest the involvement of the cerebral cortex. The direct, postsynaptic effect of 5-HT in the cortex are variable: depolarization, hyperpolarization, or no change, depending upon whether the effects of excitatory 5-HT 2 receptors or inhibitory 5-HT 1A receptors are predominant in any given layer V pyramidal cell Whole-cell patch clamp recordings have demonstrated that 5-HT induces a small, but significant, increase in the amplitude of spontaneous EPSCs, an effect that may involve a postsynaptic amplification mechanism (Aghajanian and Marek 1997). Such a postsynaptic effect is consistent with the finding of a high density of 5-HT 2A receptor immunoreactivity in the apical dendrites of cortical pyramidal cells (Jakab and GoldmanRakic 1998; A Focal Mechanism for 5-HT 2A -Induced Glutamate Release onto Apical Dendrites of Layer V Pyramidal Cells A novel mechanism, independent of impulse flow, seems to be involved in the increase in glutamate release induced by 5-HT 2A receptor activation. Blockade of 5-HT-induced EPSCs by bath application of the fast sodium channel blocker tetrodotoxin (TTX) or perfusion of the slice with a solution containing no added calcium ("0" calcium) would generally suggest that 5-HT had activated glutamatergic cells in the slice, leading to an impulse-flow-dependent release of glutamate. Several lines of evidence argue against this conventional interpretation. First, we rarely found any neurons induced to fire by bath application of 5-HT (unlike our experience in the piriform cortex, where we readily found GABAergic interneurons excited by 5-HT). Second, none of the pyramidal cells (a potential source of intracortical excitatory inputs) in our sample were depolarized by 5-HT sufficiently to reach threshold for firing. Third, EPSCs could be induced by the microiontophoresis of 5-HT onto the apical dendrites of layer V pyramidal cells, but no cell firing was detected while recording extracellularly through the microiontophoretic electrod

    Generalised quantum weakest preconditions

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    Generalisation of the quantum weakest precondition result of D'Hondt and Panangaden is presented. In particular the most general notion of quantum predicate as positive operator valued measure (POVM) is introduced. The previously known quantum weakest precondition result has been extended to cover the case of POVM playing the role of a quantum predicate. Additionally, our result is valid in infinite dimension case and also holds for a quantum programs defined as a positive but not necessary completely positive transformations of a quantum states.Comment: 7 pages, no figures, added references, changed conten

    A European spectrum of pharmacogenomic biomarkers: Implications for clinical pharmacogenomics

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    Pharmacogenomics aims to correlate inter-individual differences of drug efficacy and/or toxicity with the underlying genetic composition, particularly in genes encoding for protein factors and enzymes involved in drug metabolism and transport. In several European populations, particularly in countries with lower income, information related to the prevalence of pharmacogenomic biomarkers is incomplete or lacking. Here, we have implemented the microattribution approach to assess the pharmacogenomic biomarkers allelic spectrum in 18 European populations, mostly from developing European countries, by analyzing 1,931 pharmacogenomics biomarkers in 231 genes. Our data show significant interpopulation pharmacogenomic biomarker allele frequency differences, particularly in 7 clinically actionable pharmacogenomic biomarkers in 7 European populations, affecting drug efficacy and/or toxicity of 51 medication treatment modalities. These data also reflect on the differences observed in the prevalence of high-risk genotypes in these populations, as far as common markers in the CYP2C9, CYP2C19, CYP3A5, VKORC1, SLCO1B1 and TPMT pharmacogenes are concerned. Also, our data demonstrate notable differences in predicted genotype-based warfarin dosing among these populations. Our findings can be exploited not only to develop guidelines for medical prioritization, but most importantly to facilitate integration of pharmacogenomics and to support pre-emptive pharmacogenomic testing. This may subsequently contribute towards significant cost-savings in the overall healthcare expenditure in the participating countries, where pharmacogenomics implementation proves to be cost-effective

    Global trends of hand and wrist trauma: A systematic analysis of fracture and digit amputation using the Global Burden of Disease 2017 Study

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    Background: As global rates of mortality decrease, rates of non-fatal injury have increased, particularly in low Socio-demographic Index (SDI) nations. We hypothesised this global pattern of non-fatal injury would be demonstrated in regard to bony hand and wrist trauma over the 27-year study period. Methods: The Global Burden of Diseases, Injuries, and Risk Factors Study 2017 was used to estimate prevalence, age-standardised incidence and years lived with disability for hand trauma in 195 countries from 1990 to 2017. Individual injuries included hand and wrist fractures, thumb amputations and non-thumb digit amputations. Results: The global incidence of hand trauma has only modestly decreased since 1990. In 2017, t

    Variation in neurosurgical management of traumatic brain injury

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    Background: Neurosurgical management of traumatic brain injury (TBI) is challenging, with only low-quality evidence. We aimed to explore differences in neurosurgical strategies for TBI across Europe. Methods: A survey was sent to 68 centers participating in the Collaborative European Neurotrauma Effectiveness Research in Traumatic Brain Injury (CENTER-TBI) study. The questionnaire contained 21 questions, including the decision when to operate (or not) on traumatic acute subdural hematoma (ASDH) and intracerebral hematoma (ICH), and when to perform a decompressive craniectomy (DC) in raised intracranial pressure (ICP). Results: The survey was completed by 68 centers (100%). On average, 10 neurosurgeons work in each trauma center. In all centers, a neurosurgeon was available within 30 min. Forty percent of responders reported a thickness or volume threshold for evacuation of an ASDH. Most responders (78%) decide on a primary DC in evacuating an ASDH during the operation, when swelling is present. For ICH, 3% would perform an evacuation directly to prevent secondary deterioration and 66% only in case of clinical deterioration. Most respondents (91%) reported to consider a DC for refractory high ICP. The reported cut-off ICP for DC in refractory high ICP, however, differed: 60% uses 25 mmHg, 18% 30 mmHg, and 17% 20 mmHg. Treatment strategies varied substantially between regions, specifically for the threshold for ASDH surgery and DC for refractory raised ICP. Also within center variation was present: 31% reported variation within the hospital for inserting an ICP monitor and 43% for evacuating mass lesions. Conclusion: Despite a homogeneous organization, considerable practice variation exists of neurosurgical strategies for TBI in Europe. These results provide an incentive for comparative effectiveness research to determine elements of effective neurosurgical care

    Performance measures for lower gastrointestinal endoscopy: a European Society of Gastrointestinal Endoscopy (ESGE) quality improvement initiative

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    The European Society of Gastrointestinal Endoscopy and United European Gastroenterology present a short list of key performance measures for lower gastrointestinal endoscopy. We recommend that endoscopy services across Europe adopt the following seven key performance measures for lower gastrointestinal endoscopy for measurement and evaluation in daily practice at a center and endoscopist level: 1 rate of adequate bowel preparation (minimum standard 90%); 2 cecal intubation rate (minimum standard 90%); 3 adenoma detection rate (minimum standard 25%); 4 appropriate polypectomy technique (minimum standard 80%); 5 complication rate (minimum standard not set); 6 patient experience (minimum standard not set); 7 appropriate post-polypectomy surveillance recommendations (minimum standard not set). Other identified performance measures have been listed as less relevant based on an assessment of their importance, scientific acceptability, feasibility,
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