A Retrospective Review of Supratherapeutic Modafinil Exposures

Modafinil is a non-amphetamine wakefulness-promoting agent used for the treatment of various sleep disorders characterized by excessive daytime sleepiness. There is little information in the medical literature with respect to supratherapeutic doses of this medication. We performed a retrospective review of the California Poison Control System database for all cases of single-substance ingestion of modafinil with follow-up to a known outcome for the time period 1998–2008. Data collected included age, gender, dose ingested, clinical effects, and medical outcome. There were a total of 87 patients, 53 (61%) of which were female. Patient ages ranged from 1.25 to 72 years with a mean of 30 years; 17 (20%) patients were aged 6 years or less. Thirty-three (38%) were intentional overdoses. Most commonly reported effects were tachycardia (n = 23), agitation (n = 14), anxiety (n = 11), headache (n = 8), hypertension (n = 6), dystonia/tremor (n = 6), and dizziness (n = 5). Forty-nine patients (56%) were managed at home, and 38 (44%) were managed in a healthcare setting. Therapies administered included activated charcoal (n = 8), benzodiazepines (n = 7), antihistamines (n = 2), intravenous fluids (n = 2), haloperidol (n = 2), and beta-blockers (n = 1). Effects were classified as none (n = 22), minor (n = 54), and moderate (n = 11). No major effects and no deaths occurred. Effects of modafinil overdose appear to be mild in most cases, with tachycardia and CNS symptoms predominating. Clinically significant effects requiring treatment occurred in a small number of patients

Operational forecasting of daily summer maximum and minimum temperatures in the Valencia Region

Extreme-temperature events have a great impact on human society. Thus, knowledge of summer temperatures can be very useful both for the general public and for organizations whose workers operate in the open. An accurate forecasting of summer maximum and minimum temperatures could help to predict heatwave conditions and permit the implementation of strategies aimed at minimizing the negative effects that high temperatures have on human health. The objective of this work is to evaluate the skill of the regional atmospheric and modelling system (RAMS) model in determining daily summer maximum and minimum temperatures in the Valencia Region. For this, we have used the real-time configuration of this model currently running at the Centro de Estudios Ambientales de Mediterráneo Foundation. This operational system is run twice a day, and both runs have a 3-day forecast range. To carry out the verification of the model in this work, the information generated by the system has been broken into individual simulation days for a specific daily run of the model. Moreover, we have analysed the summer forecast period from 1 June to 31 August for 2007, 2008, 2009 and 2010. The results indicate good agreement between observed and simulated maximum temperatures, with RMSE in general near 2 °C both for coastal and inland stations. For this parameter, the model shows a negative bias around −1.5 °C in the coast, while the opposite trend is observed inland. In addition, RAMS also shows good results in forecasting minimum temperatures for coastal locations, with bias lower than 1 °C and RMSE below 2 °C. However, the model presents some difficulties for this parameter inland, where bias higher than 3 °C and RMSE of about 4 °C have been found. Besides, there is little difference in both temperatures forecasted within the two daily RAMS cycles and that RAMS is very stable in maintaining the forecast performance at least for three forecast days

CRL4 antagonizes SCFFbxo7-mediated turnover of cereblon and BK channel to regulate learning and memory

Intellectual disability (ID), one of the most common human developmental disorders, can be caused by genetic mutations in Cullin 4B (Cul4B) and cereblon (CRBN). CRBN is a substrate receptor for the Cul4A/B-DDB1 ubiquitin ligase (CRL4) and can target voltage- and calcium-activated BK channel for ER retention. Here we report that ID-associated CRL4CRBNmutations abolish the interaction of the BK channel with CRL4, and redirect the BK channel to the SCFFbxo7ubiquitin ligase for proteasomal degradation. Glioma cell lines harbouring CRBN mutations record density-dependent decrease of BK currents, which can be restored by blocking Cullin ubiquitin ligase activity. Importantly, mice with neuron-specific deletion of DDB1 or CRBN express reduced BK protein levels in the brain, and exhibit similar impairment in learning and memory, a deficit that can be partially rescued by activating the BK channel. Our results reveal a competitive targeting of the BK channel by two ubiquitin ligases to achieve exquisite control of its stability, and support changes in neuronal excitability as a common pathogenic mechanism underlying CRL4CRBN–associated ID

The Pathway to Detangle a Scrambled Gene

Programmed DNA elimination and reorganization frequently occur during cellular differentiation. Development of the somatic macronucleus in some ciliates presents an extreme case, involving excision of internal eliminated sequences (IESs) that interrupt coding DNA segments (macronuclear destined sequences, MDSs), as well as removal of transposon-like elements and extensive genome fragmentation, leading to 98% genome reduction in Stylonychia lemnae. Approximately 20-30% of the genes are estimated to be scrambled in the germline micronucleus, with coding segment order permuted and present in either orientation on micronuclear chromosomes. Massive genome rearrangements are therefore critical for development.To understand the process of DNA deletion and reorganization during macronuclear development, we examined the population of DNA molecules during assembly of different scrambled genes in two related organisms in a developmental time-course by PCR. The data suggest that removal of conventional IESs usually occurs first, accompanied by a surprising level of error at this step. The complex events of inversion and translocation seem to occur after repair and excision of all conventional IESs and via multiple pathways.This study reveals a temporal order of DNA rearrangements during the processing of a scrambled gene, with simpler events usually preceding more complex ones. The surprising observation of a hidden layer of errors, absent from the mature macronucleus but present during development, also underscores the need for repair or screening of incorrectly-assembled DNA molecules

piggyBac is an effective tool for functional analysis of the Plasmodium falciparum genome

<p>Abstract</p> <p>Background</p> <p>Much of the <it>Plasmodium falciparum </it>genome encodes hypothetical proteins with limited homology to other organisms. A lack of robust tools for genetic manipulation of the parasite limits functional analysis of these hypothetical proteins and other aspects of the <it>Plasmodium </it>genome. Transposon mutagenesis has been used widely to identify gene functions in many organisms and would be extremely valuable for functional analysis of the <it>Plasmodium </it>genome.</p> <p>Results</p> <p>In this study, we investigated the lepidopteran transposon, <it>piggyBac</it>, as a molecular genetic tool for functional characterization of the <it>Plasmodium falciparum </it>genome. Through multiple transfections, we generated 177 unique <it>P. falciparum </it>mutant clones with mostly single <it>piggyBac </it>insertions in their genomes. Analysis of <it>piggyBac </it>insertion sites revealed random insertions into the <it>P. falciparum </it>genome, in regards to gene expression in parasite life cycle stages and functional categories. We further explored the possibility of forward genetic studies in <it>P. falciparum </it>with a phenotypic screen for attenuated growth, which identified several parasite genes and pathways critical for intra-erythrocytic development.</p> <p>Conclusion</p> <p>Our results clearly demonstrate that <it>piggyBac </it>is a novel, indispensable tool for forward functional genomics in <it>P. falciparum </it>that will help better understand parasite biology and accelerate drug and vaccine development.</p

Comorbid mental disorders in substance users from a single catchment area - a clinical study

<p>Abstract</p> <p>Background</p> <p>The optimal treatment of patients with substance use disorders (SUDs) requires an awareness of their comorbid mental disorders and vice versa. The prevalence of comorbidity in first-time-admitted SUD patients has been insufficiently studied. Diagnosing comorbidity in substance users is complicated by symptom overlap, symptom fluctuations, and the limitations of the assessment methods. The aim of this study was to diagnose all mental disorders in substance users living in a single catchment area, without any history of treatment for addiction or psychiatric disorders, admitted consecutively to the specialist health services. The prevalence of substance-induced versus substance-independent disorders according to the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition (DSM-IV), in SUD patients will be described.</p> <p>Methods</p> <p>First-time consecutively admitted patients from a single catchment area, aged 16 years or older, admitted to addiction clinics or departments of psychiatry as outpatients or inpatients will be screened for substance-related problems using the Alcohol Use Disorder Identification Test and the Drug Use Disorder Identification Test. All patients with scores above the cutoff value will be asked to participate in the study. The patients included will be diagnosed for SUD and other axis I disorders by a psychiatrist using the Psychiatric Research Interview for Substance and Mental Disorders. This interview was designed for the diagnosis of primary and substance-induced disorders in substance users. Personality disorders will be assessed according to the Structured Clinical Interview for DSM-IV axis II disorders. The Symptom Checklist-90-Revised, the Inventory of Depressive Symptoms, the Montgomery Asberg Depression Rating Scale, the Young Mania Rating Scale, and the Angst Hypomania Check List will be used for additional diagnostic assessments. The sociodemographic data will be recorded with the Stanley Foundation's Network Entry Questionnaire. Biochemical assessments will reveal somatic diseases that may contribute to the patient's symptoms.</p> <p>Discussion</p> <p>This study is unique because the material represents a complete sample of first-time-admitted treatment seekers with SUD from a single catchment area. Earlier studies have not focused on first-time-admitted patients, so chronically ill patients, may have been overrepresented in those samples. This study will contribute new knowledge about mental disorders in first-time-admitted SUD patients.</p

The Science Performance of JWST as Characterized in Commissioning

This paper characterizes the actual science performance of the James Webb Space Telescope (JWST), as determined from the six month commissioning period. We summarize the performance of the spacecraft, telescope, science instruments, and ground system, with an emphasis on differences from pre-launch expectations. Commissioning has made clear that JWST is fully capable of achieving the discoveries for which it was built. Moreover, almost across the board, the science performance of JWST is better than expected; in most cases, JWST will go deeper faster than expected. The telescope and instrument suite have demonstrated the sensitivity, stability, image quality, and spectral range that are necessary to transform our understanding of the cosmos through observations spanning from near-earth asteroids to the most distant galaxies

New Pharmacological Agents to Aid Smoking Cessation and Tobacco Harm Reduction: What has been Investigated and What is in the Pipeline?

A wide range of support is available to help smokers to quit and aid attempts at harm reduction, including three first-line smoking cessation medications: nicotine replacement therapy, varenicline and bupropion. Despite the efficacy of these, there is a continual need to diversify the range of medications so that the needs of tobacco users are met. This paper compares the first-line smoking cessation medications to: 1) two variants of these existing products: new galenic formulations of varenicline and novel nicotine delivery devices; and 2) twenty-four alternative products: cytisine (novel outside of central and eastern Europe), nortriptyline, other tricyclic antidepressants, electronic cigarettes, clonidine (an anxiolytic), other anxiolytics (e.g. buspirone), selective 5-hydroxytryptamine (5-HT) reuptake inhibitors, supplements (e.g. St John’s wort), silver acetate, nicobrevin, modafinil, venlafaxine, monoamine oxidase inhibitors (MAOI), opioid antagonist, nicotinic acetylcholine receptors (nAChR) antagonists, glucose tablets, selective cannabinoid type 1 receptor antagonists, nicotine vaccines, drugs that affect gamma-aminobutyric acid (GABA) transmission, drugs that affect N-methyl-D-aspartate receptors (NMDA), dopamine agonists (e.g. levodopa), pioglitazone (Actos; OMS405), noradrenaline reuptake inhibitors, and the weight management drug lorcaserin. Six criteria are used: relative efficacy, relative safety, relative cost, relative use (overall impact of effective medication use), relative scope (ability to serve new groups of patients), and relative ease of use (ESCUSE). Many of these products are in the early stages of clinical trials, however, cytisine looks most promising in having established efficacy and safety and being of low cost. Electronic cigarettes have become very popular, appear to be efficacious and are safer than smoking, but issues of continued dependence and possible harms need to be considered