Disordered semantic representation in schizophrenic temporal cortex revealed by neuromagnetic response patterns

BACKGROUND: Loosening of associations and thought disruption are key features of schizophrenic psychopathology. Alterations in neural networks underlying this basic abnormality have not yet been sufficiently identified. Previously, we demonstrated that spatio-temporal clustering of magnetic brain responses to pictorial stimuli map categorical representations in temporal cortex. This result has opened the possibility to quantify associative strength within and across semantic categories in schizophrenic patients. We hypothesized that in contrast to controls, schizophrenic patients exhibit disordered representations of semantic categories. METHODS: The spatio-temporal clusters of brain magnetic activities elicited by object pictures related to super-ordinate (flowers, animals, furniture, clothes) and base-level (e.g. tulip, rose, orchid, sunflower) categories were analysed in the source space for the time epochs 170–210 and 210–450 ms following stimulus onset and were compared between 10 schizophrenic patients and 10 control subjects. RESULTS: Spatio-temporal correlations of responses elicited by base-level concepts and the difference of within vs. across super-ordinate categories were distinctly lower in patients than in controls. Additionally, in contrast to the well-defined categorical representation in control subjects, unsupervised clustering indicated poorly defined representation of semantic categories in patients. Within the patient group, distinctiveness of categorical representation in the temporal cortex was positively related to negative symptoms and tended to be inversely related to positive symptoms. CONCLUSION: Schizophrenic patients show a less organized representation of semantic categories in clusters of magnetic brain responses than healthy adults. This atypical neural network architecture may be a correlate of loosening of associations, promoting positive symptoms

State trust in middle childhood: an experimental manipulation of maternal support

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Unified treatment algorithm for the management of crotaline snakebite in the United States: results of an evidence-informed consensus workshop

<p>Abstract</p> <p>Background</p> <p>Envenomation by crotaline snakes (rattlesnake, cottonmouth, copperhead) is a complex, potentially lethal condition affecting thousands of people in the United States each year. Treatment of crotaline envenomation is not standardized, and significant variation in practice exists.</p> <p>Methods</p> <p>A geographically diverse panel of experts was convened for the purpose of deriving an evidence-informed unified treatment algorithm. Research staff analyzed the extant medical literature and performed targeted analyses of existing databases to inform specific clinical decisions. A trained external facilitator used modified Delphi and structured consensus methodology to achieve consensus on the final treatment algorithm.</p> <p>Results</p> <p>A unified treatment algorithm was produced and endorsed by all nine expert panel members. This algorithm provides guidance about clinical and laboratory observations, indications for and dosing of antivenom, adjunctive therapies, post-stabilization care, and management of complications from envenomation and therapy.</p> <p>Conclusions</p> <p>Clinical manifestations and ideal treatment of crotaline snakebite differ greatly, and can result in severe complications. Using a modified Delphi method, we provide evidence-informed treatment guidelines in an attempt to reduce variation in care and possibly improve clinical outcomes.</p

Commentary: mechanistic considerations for associations between formaldehyde exposure and nasopharyngeal carcinoma

Occupational exposure to formaldehyde has been linked to nasopharyngeal carcinoma. To date, mechanistic explanations for this association have primarily focused on formaldehyde-induced cytotoxicity, regenerative hyperplasia and DNA damage. However, recent studies broaden the potential mechanisms as it is now well established that formaldehyde dehydrogenase, identical to S-nitrosoglutathione reductase, is an important mediator of cGMP-independent nitric oxide signaling pathways. We have previously described mechanisms by which formaldehyde can influence nitrosothiol homeostasis thereby leading to changes in pulmonary physiology. Considering evidences that nitrosothiols govern the Epstein-Barr virus infection cycle, and that the virus is strongly implicated in the etiology of nasopharyngeal carcinoma, studies are needed to examine the potential for formaldehyde to reactivate the Epstein-Barr virus as well as additively or synergistically interact with the virus to potentiate epithelial cell transformation

Working with pain : sustainable work participation of workers with chronic nonspecific musculoskeletal pain

Dit proefschrift is een van de eerste studies specifiek gericht op mensen die blijven werken met chronische pijn aan het bewegingsapparaat. Unieke kennis over duurzame arbeidsparticipatie van werknemers met chronische pijn werd vergaard. Doel van dit promotieonderzoek was meer inzicht te krijgen in de groep mensen die werkt met pijn en te achterhalen hoe zij in staat zijn ondanks hun klachten te blijven werken. In het proefschrift staan kenmerken en determinanten beschreven van werknemers die doorwerken met chronische pijn, waardoor een completer beeld is ontstaan van arbeidsparticipatie bij mensen met chronische pijn aan het bewegingsapparaat. Uit de vergelijking van mensen die doorwerken ondanks chronische pijn en mensen met arbeidsverzuim die in revalidatiebehandeling komen met chronische pijn blijkt dat deze groepen op diverse factoren significant verschillen. In het onderzoek werd onder andere aangetoond dat de motivatie voor werk, zelfmanagementvaardigheden en het belang dat wordt toegekend aan pijn, belangrijke factoren zijn die werken met chronische pijn faciliteren. Chronische pijn op zichzelf is vaak niet de reden voor arbeidsverzuim, maar meestal spelen persoonlijke- en omgevingsfactoren daarin een beslissende rol. Deze factoren kunnen dienen als aangrijpingspunt voor het verhogen van duurzame inzetbaarheid en preventie van arbeidsverzuim van mensen met chronische pijn aan het bewegingsapparaat. De effectieve manier waarop deelnemende werknemers in het onderzoek met hun pijn omgingen en productief bleven, kan anderen inspireren aan het werk te blijven. Daarnaast biedt het onderzoek een nieuw referentiekader voor de bedrijfs-, verzekerings-, en revalidatiegeneeskunde. This thesis was one of the first studies that focused specifically on people who continued work with chronic nonspecific musculoskeletal pain (CMP), and collected (identified) unique data concerning sustainable work participation of workers with CMP. It provides a large range of characteristics of workers with CMP who continued work despite pain, which has added to our understanding of sustainable work participation in people suffering from CMP. Comparison of workers who continued work with CMP with sick listed workers with CMP admitted for rehabilitation revealed that these groups differ significantly on several factors. In this thesis, evidence was found that the workers’ motivation to work, self-management skills, and the attributed importance of pain on their (working) lives are important factors to manage staying at work with CMP. It is recommended to be aware of the fact that CMP standing on itself is often not the reason for sick leave and disability, but regularly personal and environmental factors play an additional decisive role. Because these factors can be influenced, they offer opportunity to promote staying at work. In the process of guiding workers back to work, the results of the project ‘Working with pain’ may be used. The findings of this thesis potentially contribute to promotion of sustained work participation and prevention of sick-leave in workers with CMP. The effective way workers in this project coped with CMP and remained productive, may inspire others in their efforts to stay work. Finally, this thesis offers a new reference for rehabilitation-, occupational-,and insurance medicine.

Parps: Rapidly Evolving Weapons in the War against Viral Infection

Post-translational protein modifications such as phosphorylation and ubiquitinylation are common molecular targets of conflict between viruses and their hosts. However, the role of other post-translational modifications, such as ADP-ribosylation, in host-virus interactions is less well characterized. ADP-ribosylation is carried out by proteins encoded by the PARP (also called ARTD) gene family. The majority of the 17 human PARP genes are poorly characterized. However, one PARP protein, PARP13/ZAP, has broad antiviral activity and has evolved under positive (diversifying) selection in primates. Such evolution is typical of domains that are locked in antagonistic 'arms races' with viral factors. To identify additional PARP genes that may be involved in host-virus interactions, we performed evolutionary analyses on all primate PARP genes to search for signatures of rapid evolution. Contrary to expectations that most PARP genes are involved in 'housekeeping' functions, we found that nearly one-third of PARP genes are evolving under strong recurrent positive selection. We identified a >300 amino acid disordered region of PARP4, a component of cytoplasmic vault structures, to be rapidly evolving in several mammalian lineages, suggesting this region serves as an important host-pathogen specificity interface. We also found positive selection of PARP9, 14 and 15, the only three human genes that contain both PARP domains and macrodomains. Macrodomains uniquely recognize, and in some cases can reverse, protein mono-ADP-ribosylation, and we observed strong signatures of recurrent positive selection throughout the macro-PARP macrodomains. Furthermore, PARP14 and PARP15 have undergone repeated rounds of gene birth and loss during vertebrate evolution, consistent with recurrent gene innovation. Together with previous studies that implicated several PARPs in immunity, as well as those that demonstrated a role for virally encoded macrodomains in host immune evasion, our evolutionary analyses suggest that addition, recognition and removal of ADP-ribosylation is a critical, underappreciated currency in host-virus conflicts

Coherence and recurrency: maintenance, control and integration in working memory

Working memory (WM), including a ‘central executive’, is used to guide behavior by internal goals or intentions. We suggest that WM is best described as a set of three interdependent functions which are implemented in the prefrontal cortex (PFC). These functions are maintenance, control of attention and integration. A model for the maintenance function is presented, and we will argue that this model can be extended to incorporate the other functions as well. Maintenance is the capacity to briefly maintain information in the absence of corresponding input, and even in the face of distracting information. We will argue that maintenance is based on recurrent loops between PFC and posterior parts of the brain, and probably within PFC as well. In these loops information can be held temporarily in an active form. We show that a model based on these structural ideas is capable of maintaining a limited number of neural patterns. Not the size, but the coherence of patterns (i.e., a chunking principle based on synchronous firing of interconnected cell assemblies) determines the maintenance capacity. A mechanism that optimizes coherent pattern segregation, also poses a limit to the number of assemblies (about four) that can concurrently reverberate. Top-down attentional control (in perception, action and memory retrieval) can be modelled by the modulation and re-entry of top-down information to posterior parts of the brain. Hierarchically organized modules in PFC create the possibility for information integration. We argue that large-scale multimodal integration of information creates an ‘episodic buffer’, and may even suffice for implementing a central executive