Relationship of the structure of mescaline and seven analogs to toxicity and behavior in five species of laboratory animals

The effect of mescaline and of 7 mescaline analogs (3,4-dimethoxy-[beta]-phenylethylamine; 3,4-methylenedioxy-[beta]-phenylethylamine; 3,4-methylenedioxy-[alpha]-methyl-[beta]-phenylethylamine; 3,4-methylenedioxy-[alpha]-ethyl-[beta]-phenylethylamine; 3,4-dimethoxy-[alpha]-methyl-[beta]-phenylethylamine; 3,4,5-trimethoxy-[alpha]-methyl-[beta]-phenylethylamine; and 3,4-methylenedioxy-N,[alpha]-dimethyl-[beta]-phenylethylamine) has been studied in the mouse, rat and guinea pig following ip administration and in the mongrel dog and rhesus monkey following iv administration. The LD50 value for each agent has been determined in each species. For 7 of the 8 drugs tested the LD50 value is significantly lower in the rat than in the mouse or guinea pig. A comparison of the observable signs of drug action in the dog and monkey shows the dog to be the preferred species for evaluating the effects of these agents. The relevant literature regarding the actions of the drugs has been reviewed. Modifications in the mescaline structure which are represented by the 7 analogs and which alter pharmacologic activity include: decreased potency following removal of the 5-methoxy group or N-demethylation, and increased potency following alpha substitution on the side chain or introduction of the 3,4-methylenedioxy group.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/33868/1/0000129.pd

Insulinopathies of the brain? Genetic overlap between somatic insulin-related and neuropsychiatric disorders

The prevalence of somatic insulinopathies, like metabolic syndrome (MetS), obesity, and type 2 diabetes mellitus (T2DM), is higher in Alzheimer’s disease (AD), autism spectrum disorder (ASD), and obsessive-compulsive disorder (OCD). Dysregulation of insulin signalling has been implicated in these neuropsychiatric disorders, and shared genetic factors might partly underlie this observed multimorbidity. We investigated the genetic overlap between AD, ASD, and OCD with MetS, obesity, and T2DM by estimating pairwise global genetic correlations using the summary statistics of the largest available genome-wide association studies for these phenotypes. Having tested these hypotheses, other potential brain “insulinopathies” were also explored by estimating the genetic relationship of six additional neuropsychiatric disorders with nine insulin-related diseases/traits. Stratified covariance analyses were then performed to investigate the contribution of insulin-related gene sets. Significant negative genetic correlations were found between OCD and MetS (rg = −0.315, p = 3.9 × 10−8), OCD and obesity (rg = −0.379, p = 3.4 × 10−5), and OCD and T2DM (rg = −0.172, p = 3 × 10−4). Significant genetic correlations with insulin-related phenotypes were also found for anorexia nervosa (AN), attention-deficit/hyperactivity disorder (ADHD), major depressive disorder, and schizophrenia (p < 6.17 × 10−4). Stratified analyses showed negative genetic covariances between AD, ASD, OCD, ADHD, AN, bipolar disorder, schizophrenia and somatic insulinopathies through gene sets related to insulin signalling and insulin receptor recycling, and positive genetic covariances between AN and T2DM, as well as ADHD and MetS through gene sets related to insulin processing/secretion (p < 2.06 × 10−4). Overall, our findings suggest the existence of two clusters of neuropsychiatric disorders, in which the genetics of insulin-related diseases/traits may exert divergent pleiotropic effects. These results represent a starting point for a new research line on “insulinopathies” of the brain

Investigating Shared Genetic Basis Across Tourette Syndrome and Comorbid Neurodevelopmental Disorders Along the Impulsivity-Compulsivity Spectrum

Background Tourette syndrome (TS) is often found comorbid with other neurodevelopmental disorders across the impulsivity-compulsivity spectrum, with attention-deficit/hyperactivity disorder (ADHD), autism spectrum disorder (ASD), and obsessive-compulsive disorder (OCD) as most prevalent. This points to the possibility of a common etiological thread along an impulsivity-compulsivity continuum. Methods Investigating the shared genetic basis across TS, ADHD, ASD, and OCD, we undertook an evaluation of cross-disorder genetic architecture and systematic meta-analysis, integrating summary statistics from the latest genome-wide association studies (93,294 individuals, 6,788,510 markers). Results As previously identified, a common unifying factor connects TS, ADHD, and ASD, while TS and OCD show the highest genetic correlation in pairwise testing among these disorders. Thanks to a more homogeneous set of disorders and a targeted approach that is guided by genetic correlations, we were able to identify multiple novel hits and regions that seem to play a pleiotropic role for the specific disorders analyzed here and could not be identified through previous studies. In the TS-ADHD-ASD genome-wide association study single nucleotide polymorphism–based and gene-based meta-analysis, we uncovered 13 genome-wide significant regions that host single nucleotide polymorphisms with a high posterior probability for association with all three studied disorders (m-value > 0.9), 11 of which were not identified in previous cross-disorder analysis. In contrast, we also identified two additional pleiotropic regions in the TS-OCD meta-analysis. Through conditional analysis, we highlighted genes and genetic regions that play a specific role in a TS-ADHD-ASD genetic factor versus TS-OCD. Cross-disorder tissue specificity analysis implicated the hypothalamus-pituitary-adrenal gland axis in TS-ADHD-ASD. Conclusions Our work underlines the value of redefining the framework for research across traditional diagnostic categories.publishedVersio

Why Does the Giant Panda Eat Bamboo? A Comparative Analysis of Appetite-Reward-Related Genes among Mammals

Background: The giant panda has an interesting bamboo diet unlike the other species in the order of Carnivora. The umami taste receptor gene T1R1 has been identified as a pseudogene during its genome sequencing project and confirmed using a different giant panda sample. The estimated mutation time for this gene is about 4.2 Myr. Such mutation coincided with the giant panda’s dietary change and also reinforced its herbivorous life style. However, as this gene is preserved in herbivores such as cow and horse, we need to look for other reasons behind the giant panda’s diet switch. Methodology/Principal Findings: Since taste is part of the reward properties of food related to its energy and nutrition contents, we did a systematic analysis on those genes involved in the appetite-reward system for the giant panda. We extracted the giant panda sequence information for those genes and compared with the human sequence first and then with seven other species including chimpanzee, mouse, rat, dog, cat, horse, and cow. Orthologs in panda were further analyzed based on the coding region, Kozak consensus sequence, and potential microRNA binding of those genes. Conclusions/Significance: Our results revealed an interesting dopamine metabolic involvement in the panda’s food choice

Exome chip analyses in adult attention deficit hyperactivity disorder

Attention-deficit/hyperactivity disorder (ADHD) is a highly heritable childhood-onset neuropsychiatric condition, often persisting into adulthood. The genetic architecture of ADHD, particularly in adults, is largely unknown. We performed an exome-wide scan of adult ADHD using the Illumina Human Exome Bead Chip, which interrogates over 250 000 common and rare variants. Participants were recruited by the International Multicenter persistent ADHD CollaboraTion (IMpACT). Statistical analyses were divided into 3 steps: (1) gene-level analysis of rare variants (minor allele frequency (MAF)<1%); (2) single marker association tests of common variants (MAFgreater than or equal to1%), with replication of the top signals; and (3) pathway analyses. In total, 9365 individuals (1846 cases and 7519 controls) were examined. Replication of the most associated common variants was attempted in 9847 individuals (2077 cases and 7770 controls) using fixed-effects inverse variance meta-analysis. With a Bonferroni-corrected significance level of 1.82E−06, our analyses of rare coding variants revealed four study-wide significant loci: 6q22.1 locus (P=4.46E−08), where NT5DC1 and COL10A1 reside; the SEC23IP locus (P=6.47E−07); the PSD locus (P=7.58E−08) and ZCCHC4 locus (P=1.79E−06). No genome-wide significant association was observed among the common variants. The strongest signal was noted at rs9325032 in PPP2R2B (odds ratio=0.81, P=1.61E−05). Taken together, our data add to the growing evidence of general signal transduction molecules (NT5DC1, PSD, SEC23IP and ZCCHC4) having an important role in the etiology of ADHD. Although the biological implications of these findings need to be further explored, they highlight the possible role of cellular communication as a potential core component in the development of both adult and childhood forms of ADHD

Early-Warning Signals of Individual Tree Mortality Based on Annual Radial Growth

Tree mortality is a key driver of forest dynamics and its occurrence is projected to increase in the future due to climate change. Despite recent advances in our understanding of the physiological mechanisms leading to death, we still lack robust indicators of mortality risk that could be applied at the individual tree scale. Here, we build on a previous contribution exploring the differences in growth level between trees that died and survived a given mortality event to assess whether changes in temporal autocorrelation, variance, and synchrony in time-series of annual radial growth data can be used as early warning signals of mortality risk. Taking advantage of a unique global ring-width database of 3065 dead trees and 4389 living trees growing together at 198 sites (belonging to 36 gymnosperm and angiosperm species), we analyzed temporal changes in autocorrelation, variance, and synchrony before tree death (diachronic analysis), and also compared these metrics between trees that died and trees that survived a given mortality event (synchronic analysis). Changes in autocorrelation were a poor indicator of mortality risk. However, we found a gradual increase in inter- annual growth variability and a decrease in growth synchrony in the last similar to 20 years before mortality of gymnosperms, irrespective of the cause of mortality. These changes could be associated with drought-induced alterations in carbon economy and allocation patterns. In angiosperms, we did not find any consistent changes in any metric. Such lack of any signal might be explained by the relatively high capacity of angiosperms to recover after a stress-induced growth decline. Our analysis provides a robust method for estimating early-warning signals of tree mortality based on annual growth data. In addition to the frequently reported decrease in growth rates, an increase in inter-annual growth variability and a decrease in growth synchrony may be powerful predictors of gymnosperm mortality risk, but not necessarily so for angiosperms.Peer reviewe

Assessment of ePrescription quality: an observational study at three mail-order pharmacies

<p>Abstract</p> <p>Background</p> <p>The introduction of electronic transfer of prescriptions (ETP) or ePrescriptions in ambulatory health care has been suggested to have a positive impact on the prescribing and dispensing processes. Thereby, implying that ePrescribing can improve safety, quality, efficiency, and cost-effectiveness. In December 2007, 68% of all new prescriptions were transferred electronically in Sweden. The aim of the present study was to assess the quality of ePrescriptions by comparing the proportions of ePrescriptions and non-electronic prescriptions necessitating a clarification contact (correction, completion or change) with the prescriber at the time of dispensing.</p> <p>Methods</p> <p>A direct observational study was performed at three Swedish mail-order pharmacies which were known to dispense a large proportion of ePrescriptions (38–75%). Data were gathered on all ePrescriptions dispensed at these pharmacies over a three week period in February 2006. All clarification contacts with prescribers were included in the study and were classified and assessed in comparison with all drug prescriptions dispensed at the same pharmacies over the specified period.</p> <p>Results</p> <p>Of the 31225 prescriptions dispensed during the study period, clarification contacts were made for 2.0% (147/7532) of new ePrescriptions and 1.2% (79/6833) of new non-electronic prescriptions. This represented a relative risk (RR) of 1.7 (95% CI 1.3–2.2) for new ePrescriptions compared to new non-electronic prescriptions. The increased RR was mainly due to 'Dosage and directions for use', which had an RR of 7.6 (95% CI 2.8–20.4) when compared to other clarification contacts. In all, 89.5% of the suggested pharmacist interventions were accepted by the prescriber, 77.7% (192/247) as suggested and an additional 11.7% (29/247) after a modification during contact with the prescriber.</p> <p>Conclusion</p> <p>The increased proportion of prescriptions necessitating a clarification contact for new ePrescriptions compared to new non-electronic prescriptions indicates the need for an increased focus on quality aspects in ePrescribing deployment. ETP technology should be developed towards a two-way communication between the prescriber and the pharmacist with automated checks of missing, inaccurate, or ambiguous information. This would enhance safety and quality for the patient and also improve efficiency and cost-effectiveness within the health care system.</p