The competitive NMDA antagonist CPP protects substantia nigra neurons from MPTP-induced degeneration in primates

Degeneration of nigrostriatal dopaminergic neurons is the primary histopathological feature of Parkinson's disease. The neurotoxin MPTP (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine) induces a neurological syndrome in man and non-human primates very similar to idiopathic Parkinson's disease by selectively destroying dopaminergic nigrostriatal neurons. This gives rise to the hypothesis that Parkinson's disease may be caused by endogenous or environmental toxins. Endogenous excitatory amino acids (EAAs) such as L-glutamate could be involved in neurodegenerative disorders including Parkinson's disease. We report in this study that the competitive NMDA antagonist CPP (3-((+/-)-2-carboxypiperazin-4-yl)-propyl-1-phosphonic acid) protects nigral tyrosine hydroxylase (TH) positive neurons from degeneration induced by systemic treatment with MPTP in common marmosets. This indicates that EAAs are involved in the pathophysiological cascade of MPTP-induced neuronal cell death and that EAA antagonists may offer a neuroprotective therapy for Parkinson's disease

The Use of a Driving Simulator to Assess Senior Driver Performance: Increasing Situational Awareness Through Post-Drive One-on-One Advisement

Older drivers are over-represented in angled impact crashes and experience a higher fatality rate than their younger counterparts. Due to the gradual deterioration of the senses, diminished cognitive processing capabilities and decreased mobility and flexibility, it is more difficult for older drivers to gather and process information about their environment. This can lead older drivers to incorrectly perceive their driving environment as safe, when in reality it is not. The current study investigates whether post-drive feedback following a simulated drive can effectively change older drivers’ attitudes about their own driving ability and influence them to incorporate additional compensatory behaviors into their day-to-day driving

Palonosetron compared with ondansetron in pediatric cancer patients: multicycle analysis of a randomized Phase III study

Aim: To investigate across multiple cycles the efficacy and safety of palonosetron in the prevention of chemotherapy-induced nausea and vomiting in pediatric cancer patients receiving highly or moderately emetogenic chemotherapy (HEC/MEC). Patients & methods: Patients were randomly assigned to 10, 20 mu g/kg palonosetron or 3 x 150 mu g/kg ondansetron for up to four cycles of HEC/MEC. Results: In all on-study chemotherapy cycles, complete response rates were higher in patients in the 20 mu g/kg palonosetron group than the ondansetron group. Treatment-emergent adverse events were comparable between the palonosetron 20 mu g/kg and ondansetron groups. Conclusion: Over four cycles of HEC/MEC, 20 mu g/kg palonosetron was an efficacious and safe treatment for the prevention of chemotherapy-induced nausea and vomiting in pediatric cancer patients

Event-based knowledge elicitation of operating room management decision-making using scenarios adapted from information systems data

<p>Abstract</p> <p>Background</p> <p>No systematic process has previously been described for a needs assessment that identifies the operating room (OR) management decisions made by the anesthesiologists and nurse managers at a facility that do not maximize the efficiency of use of OR time. We evaluated whether event-based knowledge elicitation can be used practically for rapid assessment of OR management decision-making at facilities, whether scenarios can be adapted automatically from information systems data, and the usefulness of the approach.</p> <p>Methods</p> <p>A process of event-based knowledge elicitation was developed to assess OR management decision-making that may reduce the efficiency of use of OR time. Hypothetical scenarios addressing every OR management decision influencing OR efficiency were created from published examples. Scenarios are adapted, so that cues about conditions are accurate and appropriate for each facility (e.g., if OR 1 is used as an example in a scenario, the listed procedure is a type of procedure performed at the facility in OR 1). Adaptation is performed automatically using the facility's OR information system or anesthesia information management system (AIMS) data for most scenarios (43 of 45). Performing the needs assessment takes approximately 1 hour of local managers' time while they decide if their decisions are consistent with the described scenarios. A table of contents of the indexed scenarios is created automatically, providing a simple version of problem solving using case-based reasoning. For example, a new OR manager wanting to know the best way to decide whether to move a case can look in the chapter on "Moving Cases on the Day of Surgery" to find a scenario that describes the situation being encountered.</p> <p>Results</p> <p>Scenarios have been adapted and used at 22 hospitals. Few changes in decisions were needed to increase the efficiency of use of OR time. The few changes were heterogeneous among hospitals, showing the usefulness of individualized assessments.</p> <p>Conclusions</p> <p>Our technical advance is the development and use of automated event-based knowledge elicitation to identify suboptimal OR management decisions that decrease the efficiency of use of OR time. The adapted scenarios can be used in future decision-making.</p

prior shared experience and survival of spin-offs from restructured state enterprises

Many organizations, especially in emerging economies, trace their origins to restructured state enterprises, and this study explores the implications of such origins for organizational adaptation to changing environmental conditions. We compare the activity choices and survival chances of spin-offs from restructured state enterprises with those of de novo organizations. We argue that prior shared experience of spin-offs’ managers and employees facilitates the redeployment of routines developed in parent state enterprises. This should predispose spin-offs to pursue familiar activities, but this choice is not completely predetermined, and its survival implications depend on the environmental conditions. Our empirical findings suggest that spin-offs from restructured state enterprises are less likely to engage in new activities than de novo organizations. However, those restructuring spin-offs that do engage in new activities before the regulatory regime shift significantly improve their survival chances after the shift. Moreover, we find that the detrimental effect of the regulatory regime shift and the beneficial effect of engaging in new activities are stronger for spin-offs from restructured state enterprises than for de novo organizations.authorsversionpublishe

Inhomogeneous Phases in a Double-Exchange Magnet with Long Range Coulomb Interactions

We consider a model with competing double-exchange (ferromagnetic) and super-exchange (anti-ferromagnetic) interactions in the regime where phase separation takes place. The presence of a long range Coulomb interaction frustrates a macroscopic phase separation, and favors microscopically inhomogeneous configurations. We use the variational Hartree-Fock approach, in conjunction with Monte-Carlo simulations to study the geometry of such configurations in a two-dimensional system. We find that an array of diamond shaped ferromagnetic droplets is the preferred configuration at low electronic densities, while alternating ferromagnetic and anti-ferromagnetic diagonal stripes emerge at higher densities. These findings are expected to be relevant for thin films of colossal magneto-resistive manganates.Comment: 15 pages, 9 figures. Journal Ref. added, errors correcte

Miswired Enhancer Logic Drives a Cancer of the Muscle Lineage

Core regulatory transcription factors (CR TFs) establish enhancers with logical ordering during embryogenesis and development. Here we report that in fusion-positive rhabdomyosarcoma, a cancer of the muscle lineage, the chief oncogene PAX3-FOXO1 is driven by a translocated FOXO1 super enhancer (SE) restricted to a late stage of myogenesis. Using chromatin conformation capture techniques, we demonstrate that the extensive FOXO1 cis-regulatory domain interacts with PAX3. Furthermore, RNA sequencing and chromatin immunoprecipitation sequencing data in tumors bearing rare PAX translocations implicate enhancer miswiring across all fusion-positive tumors. HiChIP of H3K27ac showed connectivity between the FOXO1 SE, additional intra-domain enhancers, and the PAX3 promoter. We show that PAX3-FOXO1 transcription is diminished when this network of enhancers is ablated by CRISPR. Our data reveal a hijacked enhancer network that disrupts the stepwise CR TF logic of normal skeletal muscle development (PAX3 to MYOD to MYOG), replacing it with an "infinite loop" enhancer logic that locks rhabdomyosarcoma in an undifferentiated stage

Negative emotional stimuli reduce contextual cueing but not response times in inefficient search

In visual search, previous work has shown that negative stimuli narrow the focus of attention and speed reaction times (RTs). This paper investigates these two effects by first asking whether negative emotional stimuli narrow the focus of attention to reduce the learning of a display context in a contextual cueing task and, second, whether exposure to negative stimuli also reduces RTs in inefficient search tasks. In Experiment 1, participants viewed either negative or neutral images (faces or scenes) prior to a contextual cueing task. In a typical contextual cueing experiment, RTs are reduced if displays are repeated across the experiment compared with novel displays that are not repeated. The results showed that a smaller contextual cueing effect was obtained after participants viewed negative stimuli than when they viewed neutral stimuli. However, in contrast to previous work, overall search RTs were not faster after viewing negative stimuli (Experiments 2 to 4). The findings are discussed in terms of the impact of emotional content on visual processing and the ability to use scene context to help facilitate search