Terguride stimulates locomotor activity at 2 months but not 10 months after 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine treatment of common marmosets

The mixed dopamine (DA) agonist/antagonist terguride acts as a DA antagonist on normosensitive receptors but shows DA agonistic properties at supersensitive DA receptors. Such a compound could offer an alternative to the treatment of Parkinson's disease with indirect or direct DA agonists. The present study compares the actions of terguride, 4-12 mg/kg i.p., in naive common marmosets with its effects in animals rendered parkinsonian by administration of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), 2 months or 10 months previously, in order to test its antiparkinsonian efficacy. Terguride reduced locomotor activity in naive common marmosets, similar to its effects in rodents and in line with the DA antagonistic activity of the compound. In marmosets treated with MPTP 2 months previously and exhibiting pronounced behavioural motor deficits, terguride stimulated locomotor activity, showing DA agonistic properties under these conditions. In contrast, the locomotor activity of animals that had recovered from MPTP treatment 10 months previously was not altered by terguride. It is concluded that terguride has anti-akinetic efficacy in this primate model of Parkinson's disease. In addition, terguride offers a unique opportunity to differentiate, pharmacologically, the extent of dopaminergic recovery from MPTP treatment in this primate species

Use of the wound healing trajectory as an outcome determinant for acute wound healing

Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/72454/1/j.1524-475x.2000.00511.x.pd

Some recent radio talks.

Myxomatosis is losing its punch - By A. R. TOMLINSON, Chief Vermin Control Officer The results of the testing of field strains of myxomatosis just released by the Australian National University are of vital importance to every farmer in Western Australia. They show clearly that the predicted decline in the effectiveness of myxomatosis has occurred. Worse still, they reveal that the decline has been more rapid in some areas than observers anticipated. The importance of good seed in vegetable production. - By T. WACHTEL, Vegetable Adviser, Horticultural Division The seed is the foundation of the crop that eventually is to be harvested. As an American textbook on vegetable vegetable growing puts it: Within the seed coat may be locked up the key to future success or failure. A vegetable crop can be much poorer than the seed, but it cannot be better. Water conservation on the farm - By J. W. LEWIS, Irrigation Adviser, Bunbury Water conservation on the farm is becoming increasingly important in this State, and on most properties in the South-West water can be conserved easily and economically. Coupled with the use of modern spray irrigation systems, this trend may well revolutionise farming methods in years to come and lead the way to greater agricultural prosperity. Itch mite in sheep - By C. R. TOOP, Chief Veterinary Surgeon During the past 12 months there has been a sharp rise in the incidence of itch mite and many cases have been reported both from sheep markets and individual properties. The symptoms of itch mite infestation are very similar to those produced by hce but, unlike the sheep louse, the itch mite is invisible to the naked eye and the microscopic examination of scrapings taken from the skin after the wool has been closely clipped is necessary for its detection. Orchard irrigation - By J. CRIPPS, Horticultural Adviser There are no fruits grown in Western Australia which do not give larger crops if irrigated, although the majority of fruit growers do not have irrigation installations. Powdery mildew diseases in the home garden - By OLGA M. GOSS, B.Sc. Hons., Plant Pathologist Most of you will be only too familiar with the powdery mildew diseases which occur so frequently during the warmer months in your gardens. The most common plants badly affected by these diseases are grape vines, roses, hydrangeas, delphinium, Iagerstroemia and melons of various types. Cat Flu - A matter of serious concern - By J. SHILKIN, B.V.Sc, Veterinary Surgeon The importance of cats in the community is not generally realised by the public, yet severe epidemics among the feline population should be a matter of considerable concern. The presence of a reasonably large cat population in our cities is most important in keeping rat and mice numbers down to a low level, and their importance on farming properties is too well known to need any comment. Rat-borne diseases do occur m man in Australia and rats are always a potential danger as carriers and spreaders of some extremely serious diseases of man. Even good farmers can cause erosion. - By BRIAN MARSH, B.Sc. (Agric), Soil Conservation Adviser The particular aspects of soil conservation I am to discuss has not been publicised before, and the suggestions contained in this talk may be of use to you during seeding operations this year. It is often asked, Will the use of clover really prevent erosion

European Paediatric Formulation Initiative (EuPFI)-Formulating Ideas for Better Medicines for Children.

© American Association of Pharmaceutical Scientists 2016, published by Springer US, available online at doi: https://doi.org/10.1208/s12249-016-0584-1The European Paediatric Formulation Initiative (EuPFI), founded in 2007, aims to promote and facilitate the preparation of better and safe medicines for children through linking research and information dissemination. It brings together the capabilities of the industry, academics, hospitals, and regulators within a common platform in order to scope the solid understanding of the major issues, which will underpin the progress towards the future of paediatric medicines we want.The EuPFI was formed in parallel to the adoption of regulations within the EU and USA and has served as a community that drives research and dissemination through publications and the organisation of annual conferences. The membership and reach of this group have grown since its inception in 2007 and continue to develop and evolve to meet the continuing needs and ambitions of research into and development of age appropriate medicines. Five diverse workstreams (age-appropriate medicines, Biopharmaceutics, Administration Devices, Excipients and Taste Assessment & Taste Masking (TATM)) direct specific workpackages on behalf of the EuPFI. Furthermore, EuPFI interacts with multiple diverse professional groups across the globe to ensure efficient working in the area of paediatric medicines. Strong commitment and active involvement of all EuPFI stakeholders have proved to be vital to effectively address knowledge gaps related to paediatric medicines, discuss potential areas for further research and identify issues that need more attention and analysis in the future.Peer reviewedFinal Accepted Versio

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

Discs large (Dlg1) complexes in lymphocyte activation

T cell antigen recognition involves the formation of a structured interface between antigen-presenting and T cells that facilitates the specific transmission of activating and desensitizing stimuli. The molecular machinery that organizes the signaling molecules and controls their disposition in response to activation remains poorly understood. We show here that in T cells Discs large (Dlg1), a PDZ domain-containing protein, is recruited upon activation to cortical actin and forms complexes with early participants in T cell activation. Transient overexpression of Dlg1 attenuates basal and Vav1-induced NFAT reporter activation. Reduction of Dlg1 expression by RNA interference enhances both CD3- and superantigen-mediated NFAT activation. Attenuation of antigen receptor signaling appears to be a complex, highly orchestrated event that involves the mutual segregation of important elements of the early signaling complex

Association of Long Term Antibiotic Use and Diagnosis of Chronic Disease

Background: There has recently been increasing interest in the role of the human microbiome in disease. Antibiotic use is known to disrupt the intestinal microbial environment and cause acute disease, for example pseudomembranous colitis. This study aimed to investigate the hypothesis that long-term antibiotic use is associated with the development of chronic diseases, i.e., Asthma, Rheumatoid Arthritis, Inflammatory Bowel Disease, Colorectal Cancer, and Dementia. Methods:The study is a retrospective observational study using ontologically defined cases recorded by primary care physicians covering the period 2004 to 2015 combined with prescribing data. The study is primary care based, utilizing records held by the Royal College of General Practitioners Research and Surveillance Centre (RCGP RSC) database, representative of all English General Practices, over the period 2004 to 2015 inclusive. All patients registered with practices subscribing to the RCGP RSC database, with 10 years of prescribing history and other full demographic information required for the study recorded, numbering 644,273 were utilized. All records were analyzed for demographic data, diagnoses of study, known risk factors, and prescribing history of antibiotics. Exclusion criteria included incomplete data for known risk factors or demographics. The main outcome measures are the odds ratios (OR) of being diagnosed with one of the diseases of the study per antibiotic prescription issued over the preceding decade before diagnosis, adjusted for demographics and known risk factors. Results: The OR (2.5% CI, 97.5% CI) of being diagnosed with Asthma was 1.004 (1.002, 1.006), Rheumatoid Arthritis 1.006 (1.003, 1.008), Inflammatory Bowel Disease 1.007 (1.006, 1.008), Colorectal Cancer 1.001 (0.999, 1.002), and Dementia 1.001 (0.998, 1.001). Conclusions: The long-term use of antibiotics is associated with a statistically significant dose related increase in the odds of being diagnosed with asthma, rheumatoid arthritis and inflammatory bowel disease, but not all forms of dementia or colorectal cancer. Potential mechanisms include chronic disruption of the microbiome. This finding has implications for practitioners who prescribe antibiotics, the pharmaceutical industry, policy makers, and researchers involved in studying chronic disease mechanisms

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