Pharmacokinetic-pharmacodynamic modelling of the antinociceptive effect of a romifidine infusion in standing horses

OBJECTIVE To evaluate the effect of a romifidine infusion on antinociception and sedation, and to investigate its relationship with plasma concentration. STUDY DESIGN Prospective, experimental, nonrandomized trial. ANIMALS A total of 10 healthy adult warmblood horses. METHODS Romifidine (loading dose: 0.08 mg kg-1, infusion: 0.03 mg kg-1 hour-1) was administered intravenously over 120 minutes. Romifidine plasma concentrations were determined by capillary electrophoresis. Sedation quality and nociceptive thresholds were evaluated at regular time points before, during and after romifidine administration. The nociceptive withdrawal reflex was elicited by electrical stimulation at the thoracic limb using a dedicated threshold tracking algorithm and recorded by electromyography at the deltoid muscle. A pharmacokinetic-pharmacodynamic model was established and correlation between romifidine plasma concentration and main output variables tested. RESULTS A two compartmental model best described the romifidine pharmacokinetic profile. The nociceptive thresholds increased compared with baseline in all horses from 10 to 146 minutes after romifidine administration (p < 0.001). Peak effect reached 5.7 ± 2.3 times the baseline threshold (mean ± standard deviation). The effect/concentration relationship followed a counter-clockwise hysteresis loop. The mean plasma concentration was weakly correlated to nociceptive thresholds (p < 0.0071, r = 0.392). The sedative effects were significant until 160 minutes but variable, not correlated to plasma concentration (p = 0.067), and weakly correlated to nociceptive thresholds (p < 0.0001, r = 0.33). CONCLUSIONS AND CLINICAL RELEVANCE Romifidine elicited a marked antinociceptive effect. Romifidine-induced antinociception appeared with a delayed onset and lasted longer than sedation after discontinuing its administration

Clustering subspecies of Aeromonas salmonicida using IS630 typing.

BACKGROUND The insertion element IS630 found in Aeromonas salmonicida belongs to the IS630-Tc1-mariner superfamily of transposons. It is present in multiple copies and represents approximately half of the IS present in the genome of A. salmonicida subsp. salmonicida A449. RESULTS By using High Copy Number IS630 Restriction Fragment Length Polymorphism (HCN-IS630-RFLP), strains of various subspecies of Aeromonas salmonicida showed conserved or clustering patterns, thus allowing their differentiation from each other. Fingerprints of A. salmonicida subsp. salmonicida showed the highest homogeneity while 'atypical' A. salmonicida strains were more heterogeneous. IS630 typing also differentiated A. salmonicida from other Aeromonas species. The copy number of IS630 in Aeromonas salmonicida ranges from 8 to 35 and is much lower in other Aeromonas species. CONCLUSIONS HCN-IS630-RFLP is a powerful tool for subtyping of A. salmonicida. The high stability of IS630 insertions in A. salmonicida subsp. salmonicida indicates that it might have played a role in pathoadaptation of A. salmonicida which has reached an optimal configuration in the highly virulent and specific fish pathogen A. salmonicida subsp. salmonicida

Participatory land resources planning to promote sustainable landscape management in rainfed areas-Morocco

Land degradation and desertification affect around one-third of the land used for agriculture, undermining productivity, and farmers' livelihoods, and resilience. People in rainfed and dryland areas are the most vulnerable to the environmental and social impacts of degradation, yet opportunities to expand agricultural areas in order to meet the needs of an ever-growing population are limited and/or not feasible. On the bright side, there are opportunities to avoid, reduce and reverse land degradation (LD), however, it will require identifying areas that are suited to implement sustainable land management (SLM) practices and create an enabling environment that encourages such initiatives. In Morocco, latest available data from 2015 showed that 19 percent of its land over the total land area is degraded. In order to assess the level of degradation in rainfed landscapes of Morocco and identify the appropriate technological solutions in response to the driving forces and pressures, and to come up with a territorial planning strategy, analyses were carried out at different levels to identify the land degradation “hot spots” as well as the SLM “bright spots.” This paper sheds light on the decision support framework, co-developed with partners and applied in Morocco, the findings from national and subnational assessments of LD, as well as the process of participatory planning in selected communities of the Souss-Massa region for evaluation and scaling up of SLM good practices. The process led to the development of a “Territorial Planning Pact” as a tool for land use planning and a 3-year action plan to help decision-makers implement and mainstream SLM in the selected communities and guide similar processes throughout the region. The “Territorial Planning Pact” forms a base for planning and implementing the development program in the region led by key stakeholders. The paper presents the actions taken and concludes by highlighting the importance of integrating both biophysical and socio-economic information in a multi-level participatory process to identify the actions and responsibilities of various stakeholders and ensure sustainable management of limited natural resources and improved livelihoods for all

Decatransin, a novel natural product inhibiting protein translocation at the Sec61/SecY translocon

A new cyclic decadepsipeptide was isolated from Chaetosphaeria tulasneorum with potent bioactivity on mammalian and yeast cells. Chemogenomic profiling in S. cerevisiae indicated that the Sec61 translocon, the machinery for protein translocation and membrane insertion at the endoplasmic reticulum, is the target. The profiles were similar to those of cyclic heptadepsipeptides of a distinct chemotype (HUN-7293/cotransin) that had previously been shown to inhibit cotranslational translocation at the mammalian Sec61 translocon. Unbiased, genome-wide mutagenesis followed by full-genome sequencing in both fungal and mammalian cells identified dominant mutations in Sec61p/Sec61α1 to confer resistance. Most, but not all, of these mutations affected inhibition by both chemotypes, despite an absence of structural similarity. Biochemical analysis confirmed inhibition of protein translocation into the endoplasmic reticulum of both co- and posttranslationally translocated substrates by both chemotypes, demonstrating a mechanism independent of a translating ribosome. Most interestingly, both chemotypes were found to also inhibit SecYEG, the bacterial Sec61 homolog. We suggest "decatransin" as the name for this novel decadepsipeptide translocation inhibitor

Down regulation of E-Cadherin (ECAD) - a predictor for occult metastatic disease in sentinel node biopsy of early squamous cell carcinomas of the oral cavity and oropharynx

<p>Abstract</p> <p>Background</p> <p>Prognostic factors in predicting occult lymph node metastasis in patients with head and neck squamous-cell carcinoma (HNSCC) are necessary to improve the results of the sentinel lymph node procedure in this tumour type. The E-Cadherin glycoprotein is an intercellular adhesion molecule in epithelial cells, which plays an important role in establishing and maintaining intercellular connections.</p> <p>Objectives</p> <p>To determine the value of the molecular marker E-Cadherin in predicting regional metastatic disease.</p> <p>Methods</p> <p>E-Cadherin expression in tumour tissue of 120 patients with HNSCC of the oral cavity and oropharynx were evaluated using the tissue microarray technique. 110 tumours were located in the oral cavity (91.7%; mostly tongue), 10 tumours in the oropharynx (8.3%). Intensity of E-Cadherin expression was quantified by the Intensity Reactivity Score (IRS). These results were correlated with the lymph node status of biopsied sentinel lymph nodes. Univariate and multivariate analysis was used to determine statistical significance.</p> <p>Results</p> <p>pT-stage, gender, tumour side and location did not correlate with lymph node metastasis. Differentiation grade (<it>p </it>= 0.018) and down regulation of E-Cadherin expression significantly correlate with positive lymph node status (<it>p </it>= 0.005) in univariate and multivariate analysis.</p> <p>Conclusion</p> <p>These data suggest that loss of E-cadherin expression is associated with increased lymhogeneous metastasis of HNSCC. E-cadherin immunohistochemistry may be used as a predictor for lymph node metastasis in squamous cell carcinoma of the oral cavity and oropharynx.</p> <p><b>Level of evidence: 2b</b></p

The SIB Swiss Institute of Bioinformatics' resources: focus on curated databases

The SIB Swiss Institute of Bioinformatics (www.isb-sib.ch) provides world-class bioinformatics databases, software tools, services and training to the international life science community in academia and industry. These solutions allow life scientists to turn the exponentially growing amount of data into knowledge. Here, we provide an overview of SIB's resources and competence areas, with a strong focus on curated databases and SIB's most popular and widely used resources. In particular, SIB's Bioinformatics resource portal ExPASy features over 150 resources, including UniProtKB/Swiss-Prot, ENZYME, PROSITE, neXtProt, STRING, UniCarbKB, SugarBindDB, SwissRegulon, EPD, arrayMap, Bgee, SWISS-MODEL Repository, OMA, OrthoDB and other databases, which are briefly described in this article

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

Diffusion and Change in Early Middle English: Methodological and Theoretical Implications from the LAEME Corpus of Tagged Texts

The present study examines the diffusion of three linguistic variables in Early Middle English with special focus on the East versus West Midlands divide, namely the reduction from four to three stems in the gradation of strong verbs, variation between Middle English and and the decline of the dual forms of the personal pronoun. The data is retrieved from version 2.1 of the corpus of tagged texts of the Linguistic Atlas of Early Middle English (LAEME) (Laing and Lass 2008–), in which two thirds of the 167 semi-diplomatically transcribed corpus files are localized, permitting innovative approaches to Early Middle English dialectology, such as investigations into spatial diffusion phenomena. The present study offers suggestions as to how modern diffusion models can be adjusted and applied to historical data. It also discusses the usability of LAEME for this specific purpose and develops a set of plausible hypotheses on spatial diffusion patterns in Early Middle English. At the same time, the study addresses the main issues of studying medieval manuscripts and of working with historical corpora, and it illustrates how maps prove to be a useful tool in the visual representation of linguistic change across time and space