Antiepileptic drug treatment of generalized tonic-clonic seizures: An evaluation of regulatory data and five criteria for drug selection

BACKGROUND: A generalized tonic–clonic seizure (GTCS) is the most severe form of common epileptic seizure and carries the greatest risk of harm. The aim of this review is to provide an evidence-based guide for the selection of antiepileptic drugs (AEDs) for patients with GTCSs. Eight AEDs are approved in Europe and the USA for the treatment of both primarily GTCSs (PGTCSs) and secondarily GTCSs (SGTCSs) and are considered in this paper. METHODS: Each AED is evaluated using five criteria: (1) efficacy, by seizure type (a: PGTCSs and b: SGTCSs); (2) adverse effects; (3) interactions; (4) adherence and dosing; and (5) mechanism of action (MOA). To ensure the inclusions of robust data, only efficacy data accepted by regulatory authorities were considered, and data related to adverse effects, interactions, adherence, and MOA were all extracted from UK Summaries of Product Characteristics (SPCs). RESULTS: (1a) There is class 1 evidence of the efficacy of only four AEDs in controlling PGTCSs (lamotrigine, levetiracetam, perampanel, and topiramate). (1b) There is no class 1 evidence of the efficacy of any AED in SGTCSs although some evidence from pooled/subgroup analyses or meta-analyses supports the use of the four AEDs (levetiracetam, perampanel, topiramate, and with less robust data for lamotrigine). (2) AEDs are associated with different, but to some extent overlapping, common adverse effect profiles but have differing idiosyncratic adverse effects. (3) Pharmacokinetic interactions are seen with most, but not all, AEDs and are most common with carbamazepine and phenytoin. (4) Good adherence is important for seizure control and is influenced by frequency of dosing, among other factors. (5) Mechanism of action is also a consideration in rationalising AED selection when switching or combining AEDs. CONCLUSION: Ultimately, the choice of AED depends on all these factors but particularly on efficacy and adverse effects. Different patients will weigh the various factors differently, and the role of the treating physician is to provide accurate information to allow patients to make informed choices

Effects of larval growth condition and water availability on desiccation resistance and its physiological basis in adult Anopheles gambiae sensu stricto

<p>Abstract</p> <p>Background</p> <p>Natural populations of the malaria mosquito <it>Anopheles gambiae </it>s.s. are exposed to large seasonal and daily fluctuations in relative humidity and temperature, which makes coping with drought a crucial aspect of their ecology.</p> <p>Methods</p> <p>To better understand natural variation in desiccation resistance in this species, the effects of variation in larval food availability and access to water as an adult on subsequent phenotypic quality and desiccation resistance of adult females of the Mopti chromosomal form were tested experimentally.</p> <p>Results</p> <p>It was found that, under normal conditions, larval food availability and adult access to water had only small direct effects on female wet mass, dry mass, and water, glycogen and body lipid contents corrected for body size. In contrast, when females subsequently faced a strong desiccation challenge, larval food availability and adult access to water had strong carry-over effects on most measured physiological and metabolic parameters, and affected female survival. Glycogen and water content were the most used physiological reserves in relative terms, but their usage significantly depended on female phenotypic quality. Adult access to water significantly influenced the use of water and body lipid reserves, which subsequently affected desiccation resistance.</p> <p>Conclusions</p> <p>These results demonstrate the importance of growth conditions and water availability on adult physiological status and subsequent resistance to desiccation.</p

Focused Deterrence and the Prevention of Violent Gun Injuries: Practice, Theoretical Principles, and Scientific Evidence

Focused deterrence strategies are a relatively new addition to a growing portfolio of evidence-based violent gun injury prevention practices available to policy makers and practitioners. These strategies seek to change offender behavior by understanding the underlying violence-producing dynamics and conditions that sustain recurring violent gun injury problems and by implementing a blended strategy of law enforcement, community mobilization, and social service actions. Consistent with documented public health practice, the focused deterrence approach identifies underlying risk factors and causes of recurring violent gun injury problems, develops tailored responses to these underlying conditions, and measures the impact of implemented interventions. This article reviews the practice, theoretical principles, and evaluation evidence on focused deterrence strategies. Although more rigorous randomized studies are needed, the available empirical evidence suggests that these strategies generate noteworthy gun violence reduction impacts and should be part of a broader portfolio of violence prevention strategies available to policy makers and practitioners

Conglobation in the Pill Bug, Armadillidium vulgare, as a Water Conservation Mechanism

Water balance of the terrestrial isopod, Armadillidium vulgare, was investigated during conglobation (rolling-up behavior). Water loss and metabolic rates were measured at 18 ± 1°C in dry air using flow-through respirometry. Water-loss rates decreased 34.8% when specimens were in their conglobated form, while CO2 release decreased by 37.1%. Water loss was also measured gravimetrically at humidities ranging from 6 to 75 %RH. Conglobation was associated with a decrease in water-loss rates up to 53 %RH, but no significant differences were observed at higher humidities. Our findings suggest that conglobation behavior may help to conserve water, in addition to its demonstrated role in protection from predation

Widespread sex differences in gene expression and splicing in the adult human brain

There is strong evidence to show that men and women differ in terms of neurodevelopment, neurochemistry and susceptibility to neurodegenerative and neuropsychiatric disease. The molecular basis of these differences remains unclear. Progress in this field has been hampered by the lack of genome-wide information on sex differences in gene expression and in particular splicing in the human brain. Here we address this issue by using post-mortem adult human brain and spinal cord samples originating from 137 neuropathologically confirmed control individuals to study whole-genome gene expression and splicing in 12 CNS regions. We show that sex differences in gene expression and splicing are widespread in adult human brain, being detectable in all major brain regions and involving 2.5% of all expressed genes. We give examples of genes where sex-biased expression is both disease-relevant and likely to have functional consequences, and provide evidence suggesting that sex biases in expression may reflect sex-biased gene regulatory structures

Identification of plasma lipid biomarkers for prostate cancer by lipidomics and bioinformatics

Background: Lipids have critical functions in cellular energy storage, structure and signaling. Many individual lipid molecules have been associated with the evolution of prostate cancer; however, none of them has been approved to be used as a biomarker. The aim of this study is to identify lipid molecules from hundreds plasma apparent lipid species as biomarkers for diagnosis of prostate cancer. Methodology/Principal Findings: Using lipidomics, lipid profiling of 390 individual apparent lipid species was performed on 141 plasma samples from 105 patients with prostate cancer and 36 male controls. High throughput data generated from lipidomics were analyzed using bioinformatic and statistical methods. From 390 apparent lipid species, 35 species were demonstrated to have potential in differentiation of prostate cancer. Within the 35 species, 12 were identified as individual plasma lipid biomarkers for diagnosis of prostate cancer with a sensitivity above 80%, specificity above 50% and accuracy above 80%. Using top 15 of 35 potential biomarkers together increased predictive power dramatically in diagnosis of prostate cancer with a sensitivity of 93.6%, specificity of 90.1% and accuracy of 97.3%. Principal component analysis (PCA) and hierarchical clustering analysis (HCA) demonstrated that patient and control populations were visually separated by identified lipid biomarkers. RandomForest and 10-fold cross validation analyses demonstrated that the identified lipid biomarkers were able to predict unknown populations accurately, and this was not influenced by patient's age and race. Three out of 13 lipid classes, phosphatidylethanolamine (PE), ether-linked phosphatidylethanolamine (ePE) and ether-linked phosphatidylcholine (ePC) could be considered as biomarkers in diagnosis of prostate cancer. Conclusions/Significance: Using lipidomics and bioinformatic and statistical methods, we have identified a few out of hundreds plasma apparent lipid molecular species as biomarkers for diagnosis of prostate cancer with a high sensitivity, specificity and accuracy

Retained Surgical Items and Minimally Invasive Surgery

A retained surgical item is a surgical patient safety problem. Early reports have focused on the epidemiology of retained-item cases and the identification of patient risk factors for retention. We now know that retention has very little to do with patient characteristics and everything to do with operating room culture. It is a perception that minimally invasive procedures are safer with regard to the risk of retention. Minimally invasive surgery is still an operation where an incision is made and surgical tools are placed inside of patients, so these cases are not immune to the problem of inadvertent retention. Retained surgical items occur because of problems with multi-stakeholder operating room practices and problems in communication. The prevention of retained surgical items will therefore require practice change, knowledge, and shared information between all perioperative personnel

Cysteinyl-tRNA Deacylation Can Be Uncoupled from Protein Synthesis

Aminoacyl-tRNA synthetases (ARSs) are critical components of protein translation, providing ribosomes with aminoacyl-tRNAs. In return, ribosomes release uncharged tRNAs as ARS substrates. Here, we show that tRNA deacylation can be uncoupled from protein synthesis in an amino acid specific manner. While tRNAs coupled to radiolabeled Met, Leu Lys, or Ser are stable in cells following translation inhibition with arsenite, radiolabeled Cys is released from tRNA at a high rate. We discuss possible translation independent functions for tRNACys

A Dominant Negative ERβ Splice Variant Determines the Effectiveness of Early or Late Estrogen Therapy after Ovariectomy in Rats

The molecular mechanisms for the discrepancy in outcome of initiating estrogen therapy (ET) around peri-menopause or several years after menopause in women are unknown. We hypothesize that the level of expression of a dominant negative estrogen receptor (ER) β variant, ERβ2, may be a key factor determining the effectiveness of ET in post-menopausal women. We tested this hypothesis in ovariectomized nine month-old (an age when irregular estrous cycles occur) female Sprague Dawley rats. Estradiol treatment was initiated either 6 days (Early ET, analogous to 4 months post-menopause in humans), or 180 days (Late ET, analogous to 11 years post-menopause in humans) after ovariectomy. Although ERβ2 expression increased in all OVX rats, neurogenic and neuroprotective responses to estradiol differed in Early and Late ET. Early ET reduced ERβ2 expression in both hippocampus and white blood cells, increased the hippocampal cell proliferation as assessed by Ki-67 expression, and improved mobility in the forced swim test. Late ET resulted in either no or modest effects on these parameters. There was a close correlation between the degree of ERβ2 expression and the preservation of neural effects by ET after OVX in rats, supporting the hypothesis that persistent elevated levels of ERβ2 are a molecular basis for the diminished effectiveness of ET in late post-menopausal women. The correlation between the expression of ERβ2 in circulating white blood cells and brain cells suggests that ERβ2 expression in peripheral blood cells may be an easily accessible marker to predict the effective window for ET in the brain