Group III metabotropic glutamate receptors inhibit startle-mediating giant neurons in the caudal pontine reticular nucleus but do not mediate synaptic depression/short-term habituation of startle

Short-term habituation is a basic form of learning that is analyzed in different species and using different behavioral models. Previous studies on mechanisms of short-term habituation yielded evidence for a potential role of group III metabotropic glutamate receptors (mGluRIIIs). Here we tested the hypothesis that mGluRIII mediate short-term habituation of startle in rats, combining electrophysiological experiments in vitro with behavioral studies in vivo. We applied different mGluRIII agonists and antagonists on rat brainstem slices while recording from startle-mediating neurons in the caudal pontine reticular nucleus (PnC) and monitoring synaptic depression presumably underlying habituation. Furthermore, we injected the mGluRIII antagonist (RS)-α-phosphonophenylglycine (MPPG) and the agonist L-(+)-2-amino-4- phosphonobutyric acid (L-AP4) into the PnC of rats in vivo and measured its effect on startle habituation. Our results show that activation of mGluRIIIs in the PnC strongly inhibits startle-mediating giant neurons in vitro. Accordingly, L-AP4 reduced startle responses in vivo. However, synaptic depression in the slice was not disrupted by mGluRIII antagonists or agonists. Correspondingly, the in vivo application of the mGluRIII antagonist MPPG failed to show any effect on short-term habituation of startle responses. We therefore conclude that mGluRs are expressed within the primary startle pathway and that they inhibit startle responses upon activation; however, this inhibition does not play any role in synaptic depression and short-term habituation of startle. This is in contrast to the role of mGluRIIIs in other forms of habituation and supports the notion that there are different mechanisms involved in habituation of sensory-evoked behaviors. Copyright © 2010 the authors

Synaptic depression and short-term habituation are located in the sensory part of the mammalian startle pathway

BACKGROUND: Short-term habituation of the startle response represents an elementary form of learning in mammals. The underlying mechanism is located within the primary startle pathway, presumably at sensory synapses on giant neurons in the caudal pontine reticular nucleus (PnC). Short trains of action potentials in sensory afferent fibers induce depression of synaptic responses in PnC giant neurons, a phenomenon that has been proposed to be the cellular correlate for short-term habituation. We address here the question whether both this synaptic depression and the short-term habituation of the startle response are localized at the presynaptic terminals of sensory afferents. If this is confirmed, it would imply that these processes take place prior to multimodal signal integration, rather than occurring at postsynaptic sites on PnC giant neurons that directly drive motor neurons. RESULTS: Patch-clamp recordings in vitro were combined with behavioral experiments; synaptic depression was specific for the input pathway stimulated and did not affect signals elicited by other sensory afferents. Concordant with this, short-term habituation of the acoustic startle response in behavioral experiments did not influence tactile startle response amplitudes and vice versa. Further electrophysiological analysis showed that the passive properties of the postsynaptic neuron were unchanged but revealed some alterations in short-term plasticity during depression. Moreover, depression was induced only by trains of presynaptic action potentials and not by single pulses. There was no evidence for transmitter receptor desensitization. In summary, the data indicates that the synaptic depression mechanism is located presynaptically. CONCLUSION: Our electrophysiological and behavioral data strongly indicate that synaptic depression in the PnC as well as short-term habituation are located in the sensory part of the startle pathway, namely at the axon terminals of sensory afferents in the PnC. Our results further corroborate the link between synaptic depression and short-term habituation of the startle response

Improving pediatric TB diagnosis in North Kivu (DR Congo), focusing on a clinical algorithm including targeted Xpert MTB/RIF on gastric aspirates

Background The incidence of tuberculosis (TB) in the Democratic Republic of the Congo (DRC) is 323/100,000. A context of civil conflict, internally displaced people and mining activities suggests a higher regional TB incidence in North Kivu. Medecins Sans Frontieres (MSF) supports the General Reference Hospital of Masisi, North Kivu, covering a population of 520,000, with an elevated rate of pediatric malnutrition. In July 2017, an adapted MSF pediatric TB diagnostic algorithm, including Xpert MTB/RIF on gastric aspirates (GAs), was implemented. The aim of this study was to evaluate whether the introduction of this clinical pediatric TB diagnostic algorithm influenced the number of children started on TB treatment. Methods We performed a retrospective analysis of pediatric TB cases started on treatment in the inpatient therapeutic feeding centre (ITFC) and the pediatric ward. We compared data collected in the second half (July to December) of 2016 (before introduction of the new diagnostic algorithm) and the second half of 2017. For the outcome variables the difference between the two years was calculated by a Pearson Chi-square test. Results In 2017, 94 GAs were performed, compared to none in 2016. Twelve percent (11/94) of samples were Xpert MTB/RIF positive. Sixty-eight children (2.9% of total exits) aged between 3 months and 15 years started TB treatment in 2017, compared to 19 (1.4% of total exits) in 2016 (p 0.002). The largest increase in pediatric TB diagnoses in 2017 occurred in patients with a negative Xpert MTB/RIF result, but clinically highly suggestive of TB according to the newly introduced diagnostic algorithm. Fifty-two (3.1%) children under five years old started treatment in 2017, as compared to 14 (1.3%) in 2016 (p 0.004). The increase was less pronounced and not statistically significant in older patients: sixteen children (2.6%) above 5 years old started TB treatment in 2017 as compared to five (1.3%) in 2016 (p 0.17). Conclusion After the introduction of an adapted clinical pediatric TB diagnostic algorithm, including Xpert MTB/RIF on gastric aspirates, we observed a significant increase in the number of children - especially under 5 years old - started on TB treatment, mostly on clinical grounds. Increased 'clinician awareness' of pediatric TB likely played an important role

Modelling optimal location for pre-hospital helicopter emergency medical services

<p>Abstract</p> <p>Background</p> <p>Increasing the range and scope of early activation/auto launch helicopter emergency medical services (HEMS) may alleviate unnecessary injury mortality that disproportionately affects rural populations. To date, attempts to develop a quantitative framework for the optimal location of HEMS facilities have been absent.</p> <p>Methods</p> <p>Our analysis used five years of critical care data from tertiary health care facilities, spatial data on origin of transport and accurate road travel time catchments for tertiary centres. A location optimization model was developed to identify where the expansion of HEMS would cover the greatest population among those currently underserved. The protocol was developed using geographic information systems (GIS) to measure populations, distances and accessibility to services.</p> <p>Results</p> <p>Our model determined Royal Inland Hospital (RIH) was the optimal site for an expanded HEMS – based on denominator population, distance to services and historical usage patterns.</p> <p>Conclusion</p> <p>GIS based protocols for location of emergency medical resources can provide supportive evidence for allocation decisions – especially when resources are limited. In this study, we were able to demonstrate conclusively that a logical choice exists for location of additional HEMS. This protocol could be extended to location analysis for other emergency and health services.</p

Enhancing protective microglial activities with a dual function TREM2 antibody to the stalk region

Triggering receptor expressed on myeloid cells 2 (TREM2) is essential for the transition of homeostatic microglia to a disease‐associated microglial state. To enhance TREM2 activity, we sought to selectively increase the full‐length protein on the cell surface via reducing its proteolytic shedding by A Disintegrin And Metalloproteinase (i.e., α‐secretase) 10/17. We screened a panel of monoclonal antibodies against TREM2, with the aim to selectively compete for α‐secretase‐mediated shedding. Monoclonal antibody 4D9, which has a stalk region epitope close to the cleavage site, demonstrated dual mechanisms of action by stabilizing TREM2 on the cell surface and reducing its shedding, and concomitantly activating phospho‐SYK signaling. 4D9 stimulated survival of macrophages and increased microglial uptake of myelin debris and amyloid β‐peptide in vitro. In vivo target engagement was demonstrated in cerebrospinal fluid, where nearly all oluble TREM2 was 4D9‐bound. Moreover, in a mouse model for Alzheimer's disease‐related pathology, 4D9 reduced amyloidogenesis, enhanced microglial TREM2 expression, and reduced a homeostatic marker, suggesting a protective function by driving microglia toward a disease‐associated state

Update of the international HerniaSurge guidelines for groin hernia management

Background: Groin hernia repair is one of the most common operations performed globally, with more than 20 million procedures per year. The last guidelines on groin hernia management were published in 2018 by the HerniaSurge Group. The aim of this project was to assess new evidence and update the guidelines. The guideline is intended for general and abdominal wall surgeons treating adult patients with groin hernias. Method: A working group of 30 international groin hernia experts and all involved stakeholders was formed and examined all new literature on groin hernia management, available until April 2022. Articles were screened for eligibility and assessed according to GRADE methodologies. New evidence was included, and chapters were rewritten. Statements and recommendations were updated or newly formulated as necessary. Results: Ten chapters of the original HerniaSurge inguinal hernia guidelines were updated. In total, 39 new statements and 32 recommendations were formulated (16 strong recommendations). A modified Delphi method was used to reach consensus on all statements and recommendations among the groin hernia experts and at the European Hernia Society meeting in Manchester on October 21, 2022. Conclusion: The HerniaSurge Collaboration has updated the international guidelines for groin hernia management. The updated guidelines provide an overview of the best available evidence on groin hernia management and include evidence-based statements and recommendations for daily practice. Future guideline development will change according to emerging guideline methodology

Crop Updates 2005 - Geraldton

This session covers seventeen papers from different authors 2005 Seasonal Outlook, David Stephens and Nicola Telcik, Department of Agriculture Horses for Courses – using the best tools to manage climate risk, Cameron Weeks, Mingenew-Irwin Group / Planfarm and Richard Quinlan, Planfarm Agronomy Global influences driving Australian agriculture, Tony Harman, Australian Government Department of Agriculture, Fisheries and Forestry Wheat yield and quality improvements – where have they come from and can we have more? Wal Anderson, Department of Agriculture Rotations for nematode management, Vivien A. Vanstone, Sean J. Kelly, Helen F. Hunter and Mena C. Gilchrist, Department of Agriculture Integrate strategies to manage stripe rust risk, Ciara Beard, Geoff Thomas, Robert Loughman, Kith Jayasena and Manisha Shenkar, Department of Agriculture Frequency of herbicide resistance in wild radish populations across the WA wheatbelt, Dr Michael Walsh, Mechelle Owen and Prof. Stephen Powels, University of Western Australia The incidence and severity of wild radish resistance in the NAR – results from an in-situ survey, Rob Grima and Andrew Blake, Elders Limited Stubble management: the pros and cons of different methods, Bill Bowden, Department of Agriculture, Mike Collins WANTFA Effectiveness of Zinc Application Methods in Wheat, Luigi Moreschi, CSBP Know your Mo, Douglas Hamilton, Department of Agriculture Atrazine contamination of groundwater in the agricultural region of Western Australia, Russell Speed1, Neil Rothnie2, John Simons1, Ted Spadek2, and John Moore1, 1Department of Agriculture, 2Chemistry Centre (W.A.) Comparison of canola varieties in the Northern Agricultural Region in 2004, Graham Walton Department of Agriculture Pasture rotations are a promising option for sandplain production, Nadine Eva, Department of Agriculture Zone management can improve profit on sandplain, Bindi Webb, Damian Shepherd, Department of Agriculture, David Forrester, Davejeff Farms, casuarinas via Geraldton, Peter Tozer, Department of Agriculture Crop leftovers: what’s in stubble for sheep? Roy Butler and Keith Croker, Department of Agriculture Realising Rural Equity, Nathan Windebank, Australian Agricultural Contracts Limite

Effect of angiotensin-converting enzyme inhibitor and angiotensin receptor blocker initiation on organ support-free days in patients hospitalized with COVID-19

IMPORTANCE Overactivation of the renin-angiotensin system (RAS) may contribute to poor clinical outcomes in patients with COVID-19. Objective To determine whether angiotensin-converting enzyme (ACE) inhibitor or angiotensin receptor blocker (ARB) initiation improves outcomes in patients hospitalized for COVID-19. DESIGN, SETTING, AND PARTICIPANTS In an ongoing, adaptive platform randomized clinical trial, 721 critically ill and 58 non–critically ill hospitalized adults were randomized to receive an RAS inhibitor or control between March 16, 2021, and February 25, 2022, at 69 sites in 7 countries (final follow-up on June 1, 2022). INTERVENTIONS Patients were randomized to receive open-label initiation of an ACE inhibitor (n = 257), ARB (n = 248), ARB in combination with DMX-200 (a chemokine receptor-2 inhibitor; n = 10), or no RAS inhibitor (control; n = 264) for up to 10 days. MAIN OUTCOMES AND MEASURES The primary outcome was organ support–free days, a composite of hospital survival and days alive without cardiovascular or respiratory organ support through 21 days. The primary analysis was a bayesian cumulative logistic model. Odds ratios (ORs) greater than 1 represent improved outcomes. RESULTS On February 25, 2022, enrollment was discontinued due to safety concerns. Among 679 critically ill patients with available primary outcome data, the median age was 56 years and 239 participants (35.2%) were women. Median (IQR) organ support–free days among critically ill patients was 10 (–1 to 16) in the ACE inhibitor group (n = 231), 8 (–1 to 17) in the ARB group (n = 217), and 12 (0 to 17) in the control group (n = 231) (median adjusted odds ratios of 0.77 [95% bayesian credible interval, 0.58-1.06] for improvement for ACE inhibitor and 0.76 [95% credible interval, 0.56-1.05] for ARB compared with control). The posterior probabilities that ACE inhibitors and ARBs worsened organ support–free days compared with control were 94.9% and 95.4%, respectively. Hospital survival occurred in 166 of 231 critically ill participants (71.9%) in the ACE inhibitor group, 152 of 217 (70.0%) in the ARB group, and 182 of 231 (78.8%) in the control group (posterior probabilities that ACE inhibitor and ARB worsened hospital survival compared with control were 95.3% and 98.1%, respectively). CONCLUSIONS AND RELEVANCE In this trial, among critically ill adults with COVID-19, initiation of an ACE inhibitor or ARB did not improve, and likely worsened, clinical outcomes. TRIAL REGISTRATION ClinicalTrials.gov Identifier: NCT0273570