Summary
Background
Rare variants in the genes IL36RN, CARD14 and AP1S3 have been identified to cause or contribute to pustular skin diseases, primarily generalized pustular psoriasis (GPP).
...Objectives
To better understand the disease relevance of these genes, we screened our cohorts of patients with pustular skin diseases primarily GPP and palmoplantar pustular psoriasis (PPP) for coding changes in these three genes. Carriers of single heterozygous IL36RN mutations were screened for a second mutation in IL36RN.
Methods
Coding exons of IL36RN, CARD14 and AP1S3 were sequenced in 67 patients – 61 with GPP, two with acute generalized exanthematous pustulosis and four with acrodermatitis continua of Hallopeau. We screened IL36RN and AP1S3 for intragenic copy‐number variants and 258 patients with PPP for coding changes in AP1S3. Eleven heterozygous IL36RN mutations carriers were analysed for a second noncoding IL36RN mutation. Genotype–phenotype correlations in carriers/noncarriers of IL36RN mutations were assessed within the GPP cohort.
Results
The majority of patients (GPP, 64%) did not carry rare variants in any of the three genes. Biallelic and monoallelic IL36RN mutations were identified in 15 and five patients with GPP, respectively. Noncoding rare IL36RN variants were not identified in heterozygous carriers. The only significant genotype–phenotype correlation observed for IL36RN mutation carriers was early age at disease onset. Additional rare CARD14 or AP1S3 variants were identified in 15% of IL36RN mutation carriers.
Conclusions
The identification of IL36RN mutation carriers harbouring additional rare variants in CARD14 or AP1S3 indicates a more complex mode of inheritance of pustular psoriasis. Our results suggest that, in heterozygous IL36RN mutation carriers, there are additional disease‐causing genetic factors outside IL36RN.
What's already known about this topic?
The genes IL36RN, CARD14 and AP1S3 have been implicated in pustular skin disease with IL36RN having a major role.
Most studies have analysed variants in different genes separately.
Significant subsets of patients with a pustular skin disease carry a single heterozygous mutation in IL36RN, leaving unanswered whether and how the variant is disease‐contributing.
What does this study add?
Intragenic copy‐number variants or noncoding mutations in carriers of single IL36RN mutations were not found.
In total, 15% of patients with generalized pustular psoriasis (GPP) with IL36RN mutations carried variants in CARD14 or AP1S3, providing evidence for a complex inheritance.
Lack of causal /disease‐contributing variants in 64% of GPP patients suggests a role for other, not yet identified genes.
Genotype–phenotype correlation did not reveal significant correlations aside from the presence of IL36RN mutations with age at onset.
What is the translational message?
This study of three genes provides evidence that the inheritance of GPP is more complex than previously understood.
The role of known genes in GPP is rather limited, as almost two‐thirds of patients do not carry a variant in any of these genes.
In palmoplantar pustular psoriasis, the percentage of noncarriers is even lower.
Further genetic studies will reveal the diseases’ pathogenesis and provide a basis to use/develop more specific treatments.
Linked Comment: Capon. Br J Dermatol 2018; 178:589–590
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SAZU, SBCE, SBMB, UL, UM, UPUK
It is 30 yr since the British Journal of Anaesthesia published the first consensus protocol for the laboratory diagnosis of malignant hyperthermia susceptibility from the European Malignant ...Hyperthermia Group. This has subsequently been used in more than 10 000 individuals worldwide to inform use of anaesthetic drugs in these patients with increased risk of developing malignant hyperthermia during general anaesthesia, representing an early and successful example of stratified medicine. In 2001, our group also published a guideline for the use of DNA-based screening of malignant hyperthermia susceptibility. We now present an updated and complete guideline for the diagnostic pathway for patients potentially at increased risk of developing malignant hyperthermia. We introduce the new guideline with a narrative commentary that describes its development, the changes to previously published protocols and guidelines, and new sections, including recommendations for patient referral criteria and clinical interpretation of laboratory findings.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
ABSTRACT
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There is growing interest in the therapeutic utility of psychedelic substances, like psilocybin, for disorders characterized by distortions of the self-experience, like depression. Accumulating ...preclinical evidence emphasizes the role of the glutamate system in the acute action of the drug on brain and behavior; however this has never been tested in humans. Following a double-blind, placebo-controlled, parallel group design, we utilized an ultra-high field multimodal brain imaging approach and demonstrated that psilocybin (0.17 mg/kg) induced region-dependent alterations in glutamate, which predicted distortions in the subjective experience of one's self (ego dissolution). Whereas higher levels of medial prefrontal cortical glutamate were associated with negatively experienced ego dissolution, lower levels in hippocampal glutamate were associated with positively experienced ego dissolution. Such findings provide further insights into the underlying neurobiological mechanisms of the psychedelic, as well as the baseline, state. Importantly, they may also provide a neurochemical basis for therapeutic effects as witnessed in ongoing clinical trials.
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EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Creativity is an essential cognitive ability linked to all areas of our everyday functioning. Thus, finding a way to enhance it is of broad interest. A large number of anecdotal reports suggest that ...the consumption of psychedelic drugs can enhance creative thinking; however, scientific evidence is lacking. Following a double-blind, placebo-controlled, parallel-group design, we demonstrated that psilocybin (0.17 mg/kg) induced a time- and construct-related differentiation of effects on creative thinking. Acutely, psilocybin increased ratings of (spontaneous) creative insights, while decreasing (deliberate) task-based creativity. Seven days after psilocybin, number of novel ideas increased. Furthermore, we utilized an ultrahigh field multimodal brain imaging approach, and found that acute and persisting effects were predicted by within- and between-network connectivity of the default mode network. Findings add some support to historical claims that psychedelics can influence aspects of the creative process, potentially indicating them as a tool to investigate creativity and subsequent underlying neural mechanisms. Trial NL6007; psilocybin as a tool for enhanced cognitive flexibility; https://www.trialregister.nl/trial/6007 .
Increased use and improved methodology of carbonate clumped isotope thermometry has greatly enhanced our ability to interrogate a suite of Earth‐system processes. However, interlaboratory ...discrepancies in quantifying carbonate clumped isotope (Δ47) measurements persist, and their specific sources remain unclear. To address interlaboratory differences, we first provide consensus values from the clumped isotope community for four carbonate standards relative to heated and equilibrated gases with 1,819 individual analyses from 10 laboratories. Then we analyzed the four carbonate standards along with three additional standards, spanning a broad range of δ47 and Δ47 values, for a total of 5,329 analyses on 25 individual mass spectrometers from 22 different laboratories. Treating three of the materials as known standards and the other four as unknowns, we find that the use of carbonate reference materials is a robust method for standardization that yields interlaboratory discrepancies entirely consistent with intralaboratory analytical uncertainties. Carbonate reference materials, along with measurement and data processing practices described herein, provide the carbonate clumped isotope community with a robust approach to achieve interlaboratory agreement as we continue to use and improve this powerful geochemical tool. We propose that carbonate clumped isotope data normalized to the carbonate reference materials described in this publication should be reported as Δ47 (I‐CDES) values for Intercarb‐Carbon Dioxide Equilibrium Scale.
Key Points
The exclusive use of carbonate reference materials is a robust method for the standardization of clumped isotope measurements
Measurements using different acid temperatures, designs of preparation lines, and mass spectrometers are statistically indistinguishable
We propose new consensus values for a set of seven carbonate reference materials and updated guidelines to report clumped isotope measurements
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FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SAZU, SBCE, SBMB, UL, UM, UPUK
The oxygen-bearing molecular ions OH+, H2O+, and H3O+ are key species that probe the ionization rate of (partially) molecular gas that is ionized by X-rays and cosmic-rays permeating the interstellar ...medium. We report Herschel far-infrared and submillimeter spectroscopic observations of OH+ in Mrk 231, showing both ground-state P-Cygni profiles, and excited line profiles with blueshifted absorption wings extending up to 1000 km s−1. In addition, OH+ probes an excited component peaking at central velocities, likely arising from the torus probed by the OH centimeter-wave megamaser. Four lines of H2O+ are also detected at systemic velocities, but H3O+ is undetected. Based on our earlier OH studies, we estimate an abundance ratio of for the outflowing components and 20 for the torus, and an OH+ abundance relative to H nuclei of 10−7. We also find high OH+/H2O+ and OH+/H3O+ ratios; both are 4 in the torus and 10-20 in the outflowing gas components. Chemical models indicate that these high OH+ abundances relative to OH, H2O+, and H3O+ are characteristic of gas with a high ionization rate per unit density, cm3 s−1 and ∼(1-2) × 10−16 cm3 s−1 for the above components, respectively, an ionization rate of ζ ∼ (0.5-2) × 10−12 s−1, and a low molecular fraction, . X-rays appear to be unable to explain the inferred ionization rate, and thus we suggest that low-energy (10-400 MeV) cosmic-rays are primarily responsible for the ionization, with M yr−1 and erg s−1; the latter corresponds to ∼1% of the luminosity of the active galactic nucleus and is similar to the energetics of the molecular outflow. We suggest that cosmic-rays accelerated in the forward shock associated with the molecular outflow are responsible for the ionization, as they diffuse through the outflowing molecular phase downstream.
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