The Effects of Acute Δ⁹-Tetrahydrocannabinol on Striatal Glutamatergic Function: A Proton Magnetic Resonance Spectroscopy Study

Background: Cannabis and its main psychoactive component, Δ9-tetrahydrocannabinol (THC), can elicit transient psychotic symptoms. A key candidate biological mechanism of how THC induces psychotic symptoms is the modulation of glutamate in the brain. We sought to investigate the effects of acute THC administration on striatal glutamate levels and its relationship to the induction of psychotic symptoms. Methods: We used proton magnetic resonance spectroscopy to measure glutamate levels in the striatum in 20 healthy participants after THC (15 mg, oral) and matched placebo administration in a randomized, double-blind, placebo-controlled design. Psychotic symptoms were measured using the Psychotomimetic States Inventory. Results: We found that THC administration did not significantly change glutamate (glutamate plus glutamine relative to creatine) concentration in the striatum (p = .58; scaled Jeffreys-Zellner-Siow Bayes factor = 4.29). THC increased psychotic symptoms, but the severity of these symptoms was not correlated with striatal glutamate levels. Conclusions: These findings suggest that oral administration of 15 mg of THC does not result in altered striatal glutamate levels. Further work is needed to clarify the effects of THC on striatal glutamate

Full Genome Characterization of the Culicoides-Borne Marsupial Orbiviruses: Wallal Virus, Mudjinbarry Virus and Warrego Viruses

Viruses belonging to the species Wallal virus and Warrego virus of the genus Orbivirus were identified as causative agents of blindness in marsupials in Australia during 1994/5. Recent comparisons of nucleotide (nt) and amino acid (aa) sequences have provided a basis for the grouping and classification of orbivirus isolates. However, full-genome sequence data are not available for representatives of all Orbivirus species. We report full-genome sequence data for three additional orbiviruses: Wallal virus (WALV); Mudjinabarry virus (MUDV) and Warrego virus (WARV). Comparisons of conserved polymerase (Pol), sub-core-shell 'T2' and core-surface 'T13' proteins show that these viruses group with other Culicoides borne orbiviruses, clustering with Eubenangee virus (EUBV), another orbivirus infecting marsupials. WARV shares <70% aa identity in all three conserved proteins (Pol, T2 and T13) with other orbiviruses, consistent with its classification within a distinct Orbivirus species. Although WALV and MUDV share <72.86%/67.93% aa/nt identity with other orbiviruses in Pol, T2 and T13, they share >99%/90% aa/nt identities with each other (consistent with membership of the same virus species - Wallal virus). However, WALV and MUDV share <68% aa identity in their larger outer capsid protein VP2(OC1), consistent with membership of different serotypes within the species - WALV-1 and WALV-2 respectively

Survival of Influenza A(H1N1) on Materials Found in Households: Implications for Infection Control

The majority of influenza transmission occurs in homes, schools and workplaces, where many frequently touched communal items are situated. However the importance of transmission via fomites is unclear since few data exist on the survival of virus on commonly touched surfaces. We therefore measured the viability over time of two H1N1 influenza strains applied to a variety of materials commonly found in households and workplaces.Influenza A/PuertoRico/8/34 (PR8) or A/Cambridge/AHO4/2009 (pandemic H1N1) viruses were inoculated onto a wide range of surfaces used in home and work environments, then sampled at set times following incubation at stabilised temperature and humidity. Virus genome was measured by RT-PCR; plaque assay (for PR8) or fluorescent focus formation (for pandemic H1N1) was used to assess the survival of viable virus.The genome of either virus could be detected on most surfaces 24 h after application with relatively little drop in copy number, with the exception of unsealed wood surfaces. In contrast, virus viability dropped much more rapidly. Live virus was recovered from most surfaces tested four hours after application and from some non-porous materials after nine hours, but had fallen below the level of detection from all surfaces at 24 h. We conclude that influenza A transmission via fomites is possible but unlikely to occur for long periods after surface contamination (unless re-inoculation occurs). In situations involving a high probability of influenza transmission, our data suggest a hierarchy of priorities for surface decontamination in the multi-surface environments of home and hospitals

The prognostic value of nestin expression in newly diagnosed glioblastoma: Report from the Radiation Therapy Oncology Group

<p>Abstract</p> <p>Background</p> <p>Nestin is an intermediate filament protein that has been implicated in early stages of neuronal lineage commitment. Based on the heterogeneous expression of nestin in GBM and its potential to serve as a marker for a dedifferentiated, and perhaps more aggressive phenotype, the Radiation Therapy Oncology Group (RTOG) sought to determine the prognostic value of nestin expression in newly diagnosed GBM patients treated on prior prospective RTOG clinical trials.</p> <p>Methods</p> <p>Tissue microarrays were prepared from 156 patients enrolled in these trials. These specimens were stained using a mouse monoclonal antibody specific for nestin and expression was measured by computerized quantitative image analysis using the Ariol SL-50 system. The parameters measured included both staining intensity and the relative area of expression within a specimen. This resulted into 3 categories: low, intermediate, and high nestin expression, which was then correlated with clinical outcome.</p> <p>Results</p> <p>A total of 153 of the 156 samples were evaluable for this study. There were no statistically significant differences between pretreatment patient characteristics and nestin expression. There was no statistically significant difference in either overall survival or progression-free survival (PFS) demonstrated, although a trend in decreased PFS was observed with high nestin expression (p = 0.06).</p> <p>Conclusion</p> <p>Although the correlation of nestin expression and histologic grade in glioma is of considerable interest, the presented data does not support its prognostic value in newly diagnosed GBM. Further studies evaluating nestin expression may be more informative when studied in lower grade glioma, in the context of markers more specific to tumor stem cells, and using more recent specimens from patients treated with temozolomide in conjunction with radiation.</p

Changes in Channel Trafficking and Protein Stability Caused by LQT2 Mutations in the PAS Domain of the HERG Channel

Inherited human long-QT2 syndrome (LQTS) results from mutations in the gene encoding the HERG channel. Several LQT2-associated mutations have been mapped to the amino terminal cytoplasmic Per-Arnt-Sim (PAS) domain of the HERG1a channel subunit. Here we have characterized the trafficking properties of some LQT2-associated PAS domain mutants and analyzed rescue of the trafficking mutants by low temperature (27°C) or by the pore blocker drug E4031. We show that the LQT2-associated mutations in the PAS domain of the HERG channel display molecular properties that are distinct from the properties of LQT2-associated mutations in the trans-membrane region. Unlike the latter, many of the tested PAS domain LQT2-associated mutations do not result in trafficking deficiency of the channel. Moreover, the majority of the PAS domain mutations that cause trafficking deficiencies are not rescued by a pore blocking drug. We have also explored the in vitro folding stability properties of isolated mutant PAS domain proteins using a thermal unfolding fluorescence assay and a chemical unfolding assay

Flexible Cognitive Strategies during Motor Learning

Visuomotor rotation tasks have proven to be a powerful tool to study adaptation of the motor system. While adaptation in such tasks is seemingly automatic and incremental, participants may gain knowledge of the perturbation and invoke a compensatory strategy. When provided with an explicit strategy to counteract a rotation, participants are initially very accurate, even without on-line feedback. Surprisingly, with further testing, the angle of their reaching movements drifts in the direction of the strategy, producing an increase in endpoint errors. This drift is attributed to the gradual adaptation of an internal model that operates independently from the strategy, even at the cost of task accuracy. Here we identify constraints that influence this process, allowing us to explore models of the interaction between strategic and implicit changes during visuomotor adaptation. When the adaptation phase was extended, participants eventually modified their strategy to offset the rise in endpoint errors. Moreover, when we removed visual markers that provided external landmarks to support a strategy, the degree of drift was sharply attenuated. These effects are accounted for by a setpoint state-space model in which a strategy is flexibly adjusted to offset performance errors arising from the implicit adaptation of an internal model. More generally, these results suggest that strategic processes may operate in many studies of visuomotor adaptation, with participants arriving at a synergy between a strategic plan and the effects of sensorimotor adaptation

Bacteria are important dimethylsulfoniopropionate producers in marine aphotic and high-pressure environments

Dimethylsulfoniopropionate (DMSP) is an important marine osmolyte. Aphotic environments are only recently being considered as potential contributors to global DMSP production. Here, our Mariana Trench study reveals a typical seawater DMSP/dimethylsulfide (DMS) profile, with highest concentrations in the euphotic zone and decreased but consistent levels below. The genetic potential for bacterial DMSP synthesis via the dsyB gene and its transcription is greater in the deep ocean, and is highest in the sediment.s DMSP catabolic potential is present throughout the trench waters, but is less prominent below 8000 m, perhaps indicating a preference to store DMSP in the deep for stress protection. Deep ocean bacterial isolates show enhanced DMSP production under increased hydrostatic pressure. Furthermore, bacterial dsyB mutants are less tolerant of deep ocean pressures than wild-type strains. Thus, we propose a physiological function for DMSP in hydrostatic pressure protection, and that bacteria are key DMSP producers in deep seawater and sediment

How and why are communities of practice established in the healthcare sector? A systematic review of the literature

Background: Communities of Practice (CoPs) are promoted in the healthcare sector as a means of generating and sharing knowledge and improving organisational performance. However CoPs vary considerably in the way they are structured and operate in the sector. If CoPs are to be cultivated to benefit healthcare organisations, there is a need to examine and understand their application to date. To this end, a systematic review of the literature on CoPs was conducted, to examine how and why CoPs have been established and whether they have been shown to improve healthcare practice. Methods. Peer-reviewed empirical research papers on CoPs in the healthcare sector were identified by searching electronic health-databases. Information on the purpose of establishing CoPs, their composition, methods by which members communicate and share information or knowledge, and research methods used to examine effectiveness was extracted and reviewed. Also examined was evidence of whether or not CoPs led to a change in healthcare practice. Results: Thirty-one primary research papers and two systematic reviews were identified and reviewed in detail. There was a trend from descriptive to evaluative research. The focus of CoPs in earlier publications was on learning and exchanging information and knowledge, whereas in more recently published research, CoPs were used more as a tool to improve clinical practice and to facilitate the implementation of evidence-based practice. Means by which members communicated with each other varied, but in none of the primary research studies was the method of communication examined in terms of the CoP achieving its objectives. Researchers are increasing their efforts to assess the effectiveness of CoPs in healthcare, however the interventions have been complex and multifaceted, making it difficult to directly attribute the change to the CoP. Conclusions: In keeping with Wenger and colleagues' description, CoPs in the healthcare sector vary in form and purpose. While researchers are increasing their efforts to examine the impact of CoPs in healthcare, cultivating CoPs to improve healthcare performance requires a greater understanding of how to establish and support CoPs to maximise their potential to improve healthcare

Monitoring of Regulatory T Cell Frequencies and Expression of CTLA-4 on T Cells, before and after DC Vaccination, Can Predict Survival in GBM Patients

PURPOSE: Dendritic cell (DC) vaccines have recently emerged as an innovative therapeutic option for glioblastoma patients. To identify novel surrogates of anti-tumor immune responsiveness, we studied the dynamic expression of activation and inhibitory markers on peripheral blood lymphocyte (PBL) subsets in glioblastoma patients treated with DC vaccination at UCLA. EXPERIMENTAL DESIGN: Pre-treatment and post-treatment PBL from 24 patients enrolled in two Phase I clinical trials of dendritic cell immunotherapy were stained and analyzed using flow cytometry. A univariate Cox proportional hazards model was utilized to investigate the association between continuous immune monitoring variables and survival. Finally, the immune monitoring variables were dichotomized and a recursive partitioning survival tree was built to obtain cut-off values predictive of survival. RESULTS: The change in regulatory T cell (CD3(+)CD4(+)CD25(+)CD127(low)) frequency in PBL was significantly associated with survival (p = 0.0228; hazard ratio = 3.623) after DC vaccination. Furthermore, the dynamic expression of the negative co-stimulatory molecule, CTLA-4, was also significantly associated with survival on CD3(+)CD4(+) T cells (p = 0.0191; hazard ratio = 2.840) and CD3(+)CD8(+) T cells (p = 0.0273; hazard ratio = 2.690), while that of activation markers (CD25, CD69) was not. Finally, a recursive partitioning tree algorithm was utilized to dichotomize the post/pre fold change immune monitoring variables. The resultant cut-off values from these immune monitoring variables could effectively segregate these patients into groups with significantly different overall survival curves. CONCLUSIONS: Our results suggest that monitoring the change in regulatory T cell frequencies and dynamic expression of the negative co-stimulatory molecules on peripheral blood T cells, before and after DC vaccination, may predict survival. The cut-off point generated from these data can be utilized in future prospective immunotherapy trials to further evaluate its predictive validity