Pharmaceuticals and personal care products in the environment: What are the big questions?

Background: Over the past 10-15 years, a substantial amount of work has been done by the scientific, regulatory, and business communities to elucidate the effects and risks of pharmaceuticals and personal care products (PPCPs) in the environment. Objective: This review was undertaken to identify key outstanding issues regarding the effects of PPCPs on human and ecological health in order to ensure that future resources will be focused on the most important areas. Data sources: To better understand and manage the risks of PPCPs in the environment, we used the "key question" approach to identify the principle issues that need to be addressed. Initially, questions were solicited from academic, government, and business communities around the world. A list of 101 questions was then discussed at an international expert workshop, and a top-20 list was developed. Following the workshop, workshop attendees ranked the 20 questions by importance. Data synthesis: The top 20 priority questions fell into seven categories: a) prioritization of substances for assessment, b) pathways of exposure, c) bioavailability and uptake, d) effects characterization, e) risk and relative risk, f) antibiotic resistance, and g) risk management. Conclusions: A large body of information is now available on PPCPs in the environment. This exercise prioritized the most critical questions to aid in development of future research programs on the topic.Centro de Investigaciones del Medioambient

Childhood Obstructive Sleep Apnea Associates with Neuropsychological Deficits and Neuronal Brain Injury

BACKGROUND: Childhood obstructive sleep apnea (OSA) is associated with neuropsychological deficits of memory, learning, and executive function. There is no evidence of neuronal brain injury in children with OSA. We hypothesized that childhood OSA is associated with neuropsychological performance dysfunction, and with neuronal metabolite alterations in the brain, indicative of neuronal injury in areas corresponding to neuropsychological function. METHODS AND FINDINGS: We conducted a cross-sectional study of 31 children (19 with OSA and 12 healthy controls, aged 6–16 y) group-matched by age, ethnicity, gender, and socioeconomic status. Participants underwent polysomnography and neuropsychological assessments. Proton magnetic resonance spectroscopic imaging was performed on a subset of children with OSA and on matched controls. Neuropsychological test scores and mean neuronal metabolite ratios of target brain areas were compared. Relative to controls, children with severe OSA had significant deficits in IQ and executive functions (verbal working memory and verbal fluency). Children with OSA demonstrated decreases of the mean neuronal metabolite ratio N-acetyl aspartate/choline in the left hippocampus (controls: 1.29, standard deviation [SD] 0.21; OSA: 0.91, SD 0.05; p = 0.001) and right frontal cortex (controls: 2.2, SD 0.4; OSA: 1.6, SD 0.4; p = 0.03). CONCLUSIONS: Childhood OSA is associated with deficits of IQ and executive function and also with possible neuronal injury in the hippocampus and frontal cortex. We speculate that untreated childhood OSA could permanently alter a developing child's cognitive potential

Transcriptional analysis of rat piriform cortex following exposure to the organophosphonate anticholinesterase sarin and induction of seizures

Abstract Background Organophosphorus nerve agents irreversibly inhibit acetylcholinesterase, causing a toxic buildup of acetylcholine at muscarinic and nicotinic receptors. Current medical countermeasures to nerve agent intoxication increase survival if administered within a short period of time following exposure but may not fully prevent neurological damage. Therefore, there is a need to discover drug treatments that are effective when administered after the onset of seizures and secondary responses that lead to brain injury. Methods To determine potential therapeutic targets for such treatments, we analyzed gene expression changes in the rat piriform cortex following sarin (O-isopropyl methylphosphonofluoridate)-induced seizure. Male Sprague-Dawley rats were challenged with 1 × LD50 sarin and subsequently treated with atropine sulfate, 2-pyridine aldoxime methylchloride (2-PAM), and the anticonvulsant diazepam. Control animals received an equivalent volume of vehicle and drug treatments. The piriform cortex, a brain region particularly sensitive to neural damage from sarin-induced seizures, was extracted at 0.25, 1, 3, 6, and 24 h after seizure onset, and total RNA was processed for microarray analysis. Principal component analysis identified sarin-induced seizure occurrence and time point following seizure onset as major sources of variability within the dataset. Based on these variables, the dataset was filtered and analysis of variance was used to determine genes significantly changed in seizing animals at each time point. The calculated p-value and geometric fold change for each probeset identifier were subsequently used for gene ontology analysis to identify canonical pathways, biological functions, and networks of genes significantly affected by sarin-induced seizure over the 24-h time course. Results A multitude of biological functions and pathways were identified as being significantly altered following sarin-induced seizure. Inflammatory response and signaling pathways associated with inflammation were among the most significantly altered across the five time points examined. Conclusions This analysis of gene expression changes in the rat brain following sarin-induced seizure and the molecular pathways involved in sarin-induced neurodegeneration will facilitate the identification of potential therapeutic targets for the development of effective neuroprotectants to treat nerve agent exposure.</p

Transcriptional responses of the nerve agent-sensitive brain regions amygdala, hippocampus, piriform cortex, septum, and thalamus following exposure to the organophosphonate anticholinesterase sarin

Abstract Background Although the acute toxicity of organophosphorus nerve agents is known to result from acetylcholinesterase inhibition, the molecular mechanisms involved in the development of neuropathology following nerve agent-induced seizure are not well understood. To help determine these pathways, we previously used microarray analysis to identify gene expression changes in the rat piriform cortex, a region of the rat brain sensitive to nerve agent exposure, over a 24-h time period following sarin-induced seizure. We found significant differences in gene expression profiles and identified secondary responses that potentially lead to brain injury and cell death. To advance our understanding of the molecular mechanisms involved in sarin-induced toxicity, we analyzed gene expression changes in four other areas of the rat brain known to be affected by nerve agent-induced seizure (amygdala, hippocampus, septum, and thalamus). Methods We compared the transcriptional response of these four brain regions to sarin-induced seizure with the response previously characterized in the piriform cortex. In this study, rats were challenged with 1.0 × LD50 sarin and subsequently treated with atropine sulfate, 2-pyridine aldoxime methylchloride, and diazepam. The four brain regions were collected at 0.25, 1, 3, 6, and 24 h after seizure onset, and total RNA was processed for microarray analysis. Results Principal component analysis identified brain region and time following seizure onset as major sources of variability within the dataset. Analysis of variance identified genes significantly changed following sarin-induced seizure, and gene ontology analysis identified biological pathways, functions, and networks of genes significantly affected by sarin-induced seizure over the 24-h time course. Many of the molecular functions and pathways identified as being most significant across all of the brain regions were indicative of an inflammatory response. There were also a number of molecular responses that were unique for each brain region, with the thalamus having the most distinct response to nerve agent-induced seizure. Conclusions Identifying the molecular mechanisms involved in sarin-induced neurotoxicity in these sensitive brain regions will facilitate the development of novel therapeutics that can potentially provide broad-spectrum protection in five areas of the central nervous system known to be damaged by nerve agent-induced seizure.</p

Robust Emotional Stressed Speech Detection Using Weighted Frequency Subbands

License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. The problem of detecting psychological stress from speech is challenging due to differences in how speakers convey stress. Changes in speech production due to speaker state are not linearly dependent on changes in stress. Research is further complicated by the existence of different stress types and the lack of metrics capable of discriminating stress levels. This study addresses the problem of automatic detection of speech under stress using a previously developed feature extraction scheme based on the Teager Energy Operator (TEO). To improve detection performance a (i) selected sub-band frequency partitioned weighting scheme and (ii) weighting scheme for all frequency bands are proposed. Using the traditional TEO-based feature vector with a closed-speaker Hidden Markov Model-trained stressed speech classifier, error rates of 22.5/13.0 % for stress/neutral speech are obtained. With the new weighted sub-band detection scheme, closed-speaker error rates are reduced to 4.7/4.6 % for stress/neutral detection, with a relative error reduction of 79.1/64.6%, respectively. For the open-speaker case, stress/neutral speech detection error rates of 69.7/16.2 % using traditional features are used to 13.1/4.0 % (a relative 81.3/75.4 % reduction) with the proposed automatic frequency sub-band weighting scheme. Finally, issues related to speaker dependent/independent scenarios, vowel duration, and mismatched vowel type on stress detection performance are discussed. 1

Lipoic acid pretreatment attenuates ferric chloride-induced seizures in the rat

Traumatic brain injury (TBI) is often complicated by the occurrence of seizures, which adversely affect clinical outcome. The risk of seizures increases to the extent that the injury is associated with sub-arachnoid hemorrhage and hematoma. A likely mechanism of seizure development post-TBI is decompartmentalization of iron from extravasated hemoglobin (Hb). It is well known that iron can catalyze formation of reactive oxygen species (ROS). Based on this proposed mechanism, a descriptive model of TBI-induced seizures, using intracortical injection of iron salts, was developed by Willmore. We have added modifications to enhance the quantifiability of seizure activity and have used the model to examine the therapeutic efficacy of lipoic acids (ROS-scavenging antioxidants). Male SD rats were pretreated with alpha-lipoic acid (ALA) and dihydrolipoic acid (DHLA) or appropriate vehicles. Under anesthesia, unilateral intracortical infusions of ferric chloride were performed stereotaxically. EEG was recorded via extradural electrodes. EEG was sampled for 10 s of every 60-s interval over a 24-h period following injection of ferric chloride. We measured the number of seconds of epileptiform discharges or seizure activity in every 10-s EEG sample during the 24 h. The EEGs of rats pretreated with ALA and DHLA exhibited 55% less seizure activity than vehicle-treated ferric chloride-injected animals, suggesting that lipoic acids may be of use in preventing or attenuating TBI-induced seizures