Discovery of 1,3,4-Oxadiazole Derivatives as Broad-Spectrum Antiparasitic Agents.

Vector-borne parasitic diseases (VBPDs) pose a significant threat to public health on a global scale. Collectively, Human African Trypanosomiasis (HAT), Leishmaniasis, and Malaria threaten millions of people, particularly in developing countries. Climate change might alter the transmission and spread of VBPDs, leading to a global burden of these diseases. Thus, novel agents are urgently needed to expand therapeutic options and limit the spread of drug-resistant parasites. Herein, we report the development of broad-spectrum antiparasitic agents by screening a known library of antileishmanial and antimalarial compounds toward Trypanosoma brucei (T. brucei) and identifying a 1,3,4-oxadiazole derivative (19) as anti-T. brucei hit with predicted blood-brain barrier permeability. Subsequently, extensive structure-activity-relationship studies around the lipophilic tail of 19 led to a potent antitrypanosomal and antimalarial compound (27), with moderate potency also toward Leishmania infantum (L. infantum) and Leishmania tropica. In addition, we discovered a pan-active antiparasitic molecule (24), showing low-micromolar IC50s toward T. brucei and Leishmania spp. promastigotes and amastigotes, and nanomolar IC50 against Plasmodium falciparum, together with high selectivity for the parasites over mammalian cells (THP-1). Early ADME-toxicity assays were used to assess the safety profile of the compounds. Overall, we characterized 24 and 27, bearing the 1,3,4-oxadiazole privileged scaffold, as broad-spectrum low-toxicity agents for the treatment of VBPDs. An alkyne-substituted chemical probe (30) was synthesized and will be utilized in proteomics experiments aimed at deconvoluting the mechanism of action in the T. brucei parasite.

Associations between pain intensity, pain sensitivity, demographics, psychological factors, disability, physical activity, pain phenotype and COVID-19 history in low back pain: An observational study.

BACKGROUND AND PURPOSE: Knowledge of the factors affecting pain intensity and pain sensitivity can inform treatment targets and strategies aimed at personalizing the intervention, conceivably increasing its positive impact on patients. Therefore, this study aimed to investigate the association between demographic factors (sex and age), body mass index (BMI), psychological factors (anxiety and depression, kinesiophobia and catastrophizing), self-reported physical activity, pain phenotype (symptoms of central sensitization, and nociceptive or neuropathic pain), history of COVID-19 and pain intensity and sensitivity in patients with chronic non-specific low back pain (LBP). METHODS: This was a cross-sectional secondary analysis with 83 participants with chronic non-specific LBP recruited from the community between August 2021 and April 2022. BMI, pain intensity (Visual Analog Scale), pain sensitivity at the lower back and at a distant point [pressure pain threshold], catastrophizing (Pain Catastrophizing Scale), kinesiophobia (Tampa Scale for Kinesiophobia), anxiety and depression (Hospital Anxiety and Depression Scale), pain phenotype (Central Sensitization Inventory and PainDetect Questionnaire), physical activity (International Physical Activity Questionnaire), and disability (Roland Morris Disability Questionnaire) were assessed. Multiple linear regression analyses with pain intensity and sensitivity as the dependent variables were used. RESULTS: The model for pain intensity explained 34% of its variance (Adjusted R2 = -0.343, p < 0.001), with depression and anxiety (p = 0.008) and disability (p = 0.035) reaching statistical significance. The model for pain sensitivity at the lower back, also explained 34% of its variance (Adjusted R2 = 0.344, p < 0.001) at the lower back with sex, BMI, and kinesiophobia reaching statistical significance (p < 0.05) and 15% of the variance at a distant body site (Adjusted R2 = 0.148, p = 0.018) with sex and BMI reaching statistical significance (p < 0.05). DISCUSSION: This study found that different factors are associated with pain intensity and pain sensitivity in individuals with LBP. Increased pain intensity was associated with higher levels of anxiety and depression and disability and increased pain sensitivity was associated with being a female, higher kinesiophobia, and lower BMI.

Leishmania and HIV co-infection: first naturally Leishmania strain presenting decreased susceptibility to miltefosine, recovered from a patient in Portugal.

BACKGROUND: In Europe, up to 70% of visceral leishmaniasis (VL) cases occurring in adults living with HIV. People living with HIV with VL co-infection often display persistent parasitemia, requiring chronic intermittent anti-Leishmania therapies. Consequently, frequent VL relapses and higher mortality rates are common in these individuals. As such, it is of paramount importance to understand the reasons for parasite persistence to improve infection management. METHODS: To outline possible causes for treatment failure in the context of HIV-VL, we followed a person living with HIV-VL co-infection for nine years in a 12-month period. We characterized: HIV-related clinicopathological alterations (CD4+ T counts and viremia) and Leishmania-specific seroreactivity, parasitemia, quantification of pro-inflammatory cytokines upon stimulation and studied a Leishmania clinical isolate recovered during this period. RESULTS: The subject presented controlled viremia and low CD4+ counts. The subject remained PCR positive for Leishmania and also seropositive. The cellular response to parasite antigens was erratic. The isolate was identified as the first Leishmania infantum case with evidence of decreased miltefosine susceptibility in Portugal. CONCLUSION: Treatment failure is a multifactorial process driven by host and parasite determinants. Still, the real-time determination of drug susceptibility profiles in clinical isolates is an unexplored resource in the monitoring of VL.

Predictors of improvement in community adolescents with chronic neck pain: A secondary analysis using different improvement criteria.

BACKGROUND: Interventions based on pain neuroscience education and exercise have emerged as effective in the management of chronic neck pain in adolescents. No studies have explored factors that might be associated with recovery in adolescents with neck pain. OBJECTIVE: To explore predictors of improvement after an intervention based on exercise and pain neuroscience education. DESIGN: Secondary analysis of a randomized trial. SETTING: Community. PARTICIPANTS: 127 community adolescents with neck pain. INTERVENTIONS: Blended-learning intervention based on exercise and pain neuroscience education. MAIN OUTCOME MEASURES: A set of variables including sociodemographic data, pain characteristics, physical activity, disability, sleep, catastrophizing, fear of movement, self-efficacy, symptoms of central sensitization, knowledge of pain neuroscience, pressure pain thresholds, and neck muscles endurance were used to predict a clinical response at 1 week after intervention and at 6-month follow-up. RESULTS: Different predictors of improvement and non-improvement to intervention were found, but common predictors were not found for all the improvement criteria explored and time points. CONCLUSIONS: These findings suggest that using different criteria to characterize adolescents with neck pain as improved and non-improved after pain neuroscience education and exercise have an effect on the variables associated with a response to the intervention.

The discovery of aryl-2-nitroethyl triamino pyrimidines as anti-Trypanosoma brucei agents.

Pteridine reductase 1 (PTR1) is a catalytic protein belonging to the folate metabolic pathway in Trypanosmatidic parasites. PTR1 is a known target for the medicinal chemistry development of antiparasitic agents against Trypanosomiasis and Leishmaniasis. In previous studies, new nitro derivatives were elaborated as PTR1 inhibitors. The compounds showing a diamino-pyrimidine core structure were previously developed but they showed limited efficacy. Therefore, a new class of phenyl-, heteroaryl- and benzyloxy-nitro derivatives based on the 2-nitroethyl-2,4,6-triaminopyrimidine scaffold were designed and tested. The compounds were assayed for their ability to inhibit T. brucei and L. major PTR1 enzymes and for their antiparasitic activity towards T. brucei and L. infantum parasites. To understand the structure-activity relationships of the compounds against TbPTR1, the X-ray crystallographic structure of the 2,4,6-triaminopyrimidine (TAP) was obtained and molecular modelling studies were performed. As a next step, only the most effective compounds against T. brucei were then tested against the amastigote cellular stage of T. cruzi, searching for a broad-spectrum antiprotozoal agent. An early ADME-Tox profile evaluation was performed. The early toxicity profile of this class of compounds was investigated by measuring their inhibition of hERG and five cytochrome P450 isoforms (CYP1A2, CYP2C9, CYP2C19, CYP2D6 and CYP3A4), cytotoxicity towards A549 cells and mitochondrial toxicity. Pharmacokinetic studies (SNAP-PK) were performed on selected compounds using hydroxypropyl-ß-cyclodextrins (50 % w/v) to preliminarily study their plasma concentration when administered per os at a dose of 20 mg/kg. Compound 1p, showed the best pharmacodynamic and pharmacokinetic properties, can be considered a good candidate for further bioavailability and efficacy studies.

Impact of different CRPS phenotypes and diagnostic criteria on quantitative sensory testing outcomes: systematic review and meta-analysis.

OBJECTIVES: This review and meta-analysis evaluated the impact of diagnostic criteria and clinical phenotypes on quantitative sensory testing (QST) outcomes in patients with complex regional pain syndrome (CRPS). METHODS: Eight databases were searched based on a previously published protocol. Forty studies comparing QST outcomes between CRPS-I vs II, warm vs cold CRPS, upper vs lower limb CRPS, males vs females, or using Budapest vs older IASP criteria were included. RESULTS: Studies investigating QST differences between CRPS-I vs II (n = 4), between males vs females (n = 2), and between upper and lower limb CRPS (n = 2) showed no significant differences. Four studies compared QST outcomes in warm vs cold CRPS, showing heat hyperalgesia in warm CRPS, with thermal and mechanical sensory loss in cold CRPS. Although CRPS diagnosed using the Budapest criteria (24 studies) vs 1994 IASP criteria (13 studies) showed similar sensory profiles, there was significant heterogeneity and low quality of evidence in the latter. CONCLUSIONS: Based on the findings of this review, classifying CRPS according to presence or absence of nerve lesion into CRPS-I and II, location (upper or lower limb) or according to sex might not be clinically relevant as all appear to have comparable sensory profiles that might suggest similar underlying mechanisms. In contrast, warm vs cold phenotypes exhibited clear differences in their associated QST sensory profiles. To the extent that differences in underlying mechanisms might lead to differential treatment responsiveness, it appears unlikely that CRPS-I vs II, CRPS location, or patient sex would prove useful in guiding clinical management.

Effectiveness of Neural Mobilisation on Pain Intensity, Functional Status, and Physical Performance in Adults with Musculoskeletal Pain - A Systematic Review with Meta-Analysis.

OBJECTIVE: To investigate up-to-date evidence of the effectiveness of neural mobilisation techniques compared with any type of comparator in improving pain, function, and physical performance in people with musculoskeletal pain. DATA SOURCES: The following sources were consulted: PubMed, Web of Science, CENTRAL, CINAHL, Scopus, and PEDro databases; scientific repositories; and clinical trial registers. The last search was performed on 01/06/2023. METHODS: Two reviewers independently assessed the studies for inclusion. We included randomised, quasi-randomised, and crossover trials on musculoskeletal pain in which at least one group received neural mobilisation (alone or as part of multimodal interventions). Meta-analyses were performed where possible. The RoB 2 and the Grading of Recommendations Assessment, Development and Evaluation tools were used to assess risk of bias and to rate the certainty of evidence, respectively. RESULTS: Thirty-nine trials were identified. There was a significant effect favouring neural mobilisation for pain and function in people with low back pain, but not for flexibility. For neck pain, there was a significant effect favouring neural mobilisation as part of multimodal interventions for pain, but not for function and range of motion. Regarding other musculoskeletal conditions, it was not possible to conclude whether neural mobilisation is effective in improving pain and function. There was very low confidence for all effect estimates. CONCLUSIONS: Neural mobilisation as part of multimodal interventions appears to have a positive effect on pain for patients with low back pain and neck pain and on function in people with low back pain. For the other musculoskeletal conditions, results are inconclusive.

Efficacy of ultrasound-guided infiltration with levobupivacaine and triamcinolone for myofascial pain syndrome of the quadratus lumborum: a retrospective observational study

Abstract Introduction and objectives: Myofascial Pain Syndrome (MPS) of the Quadratus Lumborum muscle (QL) is a frequent cause of chronic low back pain. With this study, we aimed to assess the efficacy of ultrasound-guided infiltration with 0.25% levobupivacaine and 40 mg triamcinolone for MPS of the QL. Methods: Observational and retrospective study of participants submitted to ultrasound-guided infiltration of the QL muscle from January 1, 2015 to June 31, 2019. Pain intensity was assessed using the five-point pain Numeric Rating Scale (NRS): pre-intervention, at 72 hours, 1 month, 3 months and 6 months post-intervention. Additional data collected were demographic characteristics, opioid consumption, and adverse effects. Results: We assessed 90 participants with mean age of 55.2 years. Sixty-eight percent of participants were female. Compared to the pre-intervention assessment, there was an improvement in pain at 72 hours (Mean Difference [MD = 3.085]; 95% CI: 2.200-3.970, p < 0.05), at the 1st month (MD = 2.644; 95% CI: 1.667-3.621, p < 0.05), at the 3rdmonth (MD = 2.017; 95% CI: 0.202-2.729, p < 0.05) and at the 6th month (MD = 1.339; 95% CI 0.378-2.300, p < 0.05), post-intervention. No statistically significant differences in opioid consumption were observed. No adverse effects associated with the technique were reported. Conclusions: Ultrasound-guided infiltration of the QL muscle is a safe and effective procedure for the treatment of pain in the QL MPS within 6 months post-intervention.

A single session of action observation therapy versus observing a natural landscape in adults with chronic neck pain - a randomized controlled trial.

BACKGROUND: Action observation (AO) has emerged as a potential neurorehabilitation therapy for patients with neck pain (NP), but evidence of its effectiveness is scarce. This study aims to assess the effect of a single session of AO when compared to observing a natural landscape on NP intensity, fear of movement, fear-avoidance beliefs, neck muscles' strength, pressure pain threshold, and tactile acuity. METHODS: Sixty participants with NP were randomly allocated to the AO group (n = 30) or control group (n = 30). Both groups watched an 11-minute video: the AO group watched a video of a person matched for age and sex performing neck exercises, while the control group watched a video of natural landscapes. Neck pain intensity, fear of movement, fear-avoidance beliefs, tactile acuity, pressure pain thresholds, and neck muscle strength were assessed both at baseline and post-intervention. General linear models of repeated measures (ANCOVA of two factors) were used to explore between-group differences at post-intervention. RESULTS: There was a significant main effect of time for pain intensity (p = 0.02; η2p = 0.09; within-group mean change and 95% CI: AO=-1.44 (-2.28, -0.59); control=-1.90 (-2.74, -1.06), but no time versus group interaction (p = 0.46). A time versus group significant interaction was found for one out of the six measurement sites of two-point discrimination and the neck flexors strength (p < 0.05) favoring the control group. No other statistically significant differences were found for the remaining variables). CONCLUSIONS: Results suggest a similar acute benefit for both a single session of AO and observing natural landscapes for promoting hypoalgesia, but no impact on kinesiophobia, fear-avoidance beliefs, or pressure pain thresholds. Also, AO had no positive effect on two-point discrimination and muscle strength. Further research is needed, with longer interventions. TRIAL REGISTRATION: Clinialtrials.gov (NCT05078489).

High-Throughput Phenotypic Screening and Machine Learning Methods Enabled the Selection of Broad-Spectrum Low-Toxicity Antitrypanosomatidic Agents.

Broad-spectrum anti-infective chemotherapy agents with activity against Trypanosomes, Leishmania, and Mycobacterium tuberculosis species were identified from a high-throughput phenotypic screening program of the 456 compounds belonging to the Ty-Box, an in-house industry database. Compound characterization using machine learning approaches enabled the identification and synthesis of 44 compounds with broad-spectrum antiparasitic activity and minimal toxicity against Trypanosoma brucei, Leishmania Infantum, and Trypanosoma cruzi. In vitro studies confirmed the predictive models identified in compound 40 which emerged as a new lead, featured by an innovative N-(5-pyrimidinyl)benzenesulfonamide scaffold and promising low micromolar activity against two parasites and low toxicity. Given the volume and complexity of data generated by the diverse high-throughput screening assays performed on the compounds of the Ty-Box library, the chemoinformatic and machine learning tools enabled the selection of compounds eligible for further evaluation of their biological and toxicological activities and aided in the decision-making process toward the design and optimization of the identified lead.

Synthesis and Evaluation of Marine-Inspired Compounds Result in Hybrids with Antitrypanosomal and Antileishmanial Activities.

Natural products are a very rich source for obtaining new compounds with therapeutic potential. In the search for new antiparasitic and antimicrobial agents, molecular hybrids were designed based on the structures of antimicrobial marine quinazolinones and eugenol, a natural phenolic compound. Following reports of the therapeutic potential of quinazolinones and eugenol derivatives, it was expected that the union of these pharmacophores could generate biologically relevant substances. The designed compounds were obtained by classical synthetic procedures and were characterized by routine spectrometric techniques. Nine intermediates and final products were then evaluated in vitro against Trypanosoma brucei and Leishmania infantum. Antifungal and antibacterial activity were also evaluated. Six compounds (9b, 9c, 9d, 10b, 10c, and 14) showed mild activity against T. brucei with IC50 in the range of 11.17-31.68 µM. Additionally, intermediate 9c showed anti-Leishmania activity (IC50 7.54 µM) and was six times less cytotoxic against THP-1 cells. In conclusion, novel derivatives with a simple quinazolinone scaffold showing selectivity against parasites without antibacterial and antifungal activities were disclosed, paving the way for new antitrypanosomal agents.

Intramacrophage lipid accumulation compromises T cell responses and is associated with impaired drug therapy against visceral leishmaniasis.

Under perturbing conditions such as infection with Leishmania, a protozoan parasite living within the phagosomes in mammalian macrophages, cellular and organellar structures, and metabolism are dynamically regulated for neutralizing the pressure of parasitism. However, how modulations of the host cell metabolic pathways support Leishmania infection remains unknown. Herein, we report that lipid accumulation heightens the susceptibility of mice to L. donovani infection and promotes resistance to first-line anti-leishmanial drugs. Despite being pro-inflammatory, the in vitro generated uninfected lipid-laden macrophages (LLMs) or adipose-tissue macrophages (ATMs) display lower levels of reactive oxygen and nitrogen species. Upon infection, LLMs secrete higher IL-10 and lower IL-12p70 cytokines, inhibiting CD4+ T cell activation and Th1 response suggesting a key modulatory role for intramacrophage lipid accumulation in anti-leishmanial host defence. We, therefore, examined this causal relationship between lipids and immunomodulation using an in vivo high-fat diet (HFD) mouse model. HFD increased the susceptibility to L. donovani infection accompanied by a defective CD4+ Th1 and CD8+ T cell response. The white adipose tissue of HFD mice displays increased susceptibility to L. donovani infection with the preferential infection of F4/80+ CD11b+ CD11c+ macrophages with higher levels of neutral lipids reserve. The HFD increased resistance to a first-line anti-leishmanial drug associated with a defective adaptive immune response. These data demonstrate that the accumulation of neutral lipids contributes to susceptibility to visceral leishmaniasis hindering host-protective immune response and reducing the efficacy of antiparasitic drug therapies.

Pain intensity and pain sensitivity are not increased by a single session of high-intensity interval aerobic exercise in individuals with chronic low back pain: A randomized and controlled trial.

BACKGROUND: Evidence on the acute impact of high-intensity interval aerobic exercise on pain is scarce. This type of exercise might be perceived as increasing pain intensity and pain sensitivity negatively impacting adherence. More evidence on the acute effects of high-intensity interval aerobic exercise in individuals with low back pain (LBP) is needed. OBJECTIVES: To compare the acute effects of a single session of high-intensity interval aerobic exercise, continuous moderate-intensity aerobic exercise, and no exercise on pain intensity and pain sensitivity in patients with chronic non-specific LBP. DESIGN: Randomized controlled trial with three arms. METHOD: Participants were randomly assigned to one of three groups (i) continuous moderate-intensity aerobic exercise, ii) high-intensity interval aerobic exercise, and iii) no intervention. Measures of pain intensity and pressure pain threshold (PPT) at the lower back and at a distant body site (upper limb) were taken before and after 15 min of exercise. RESULTS: Sixty-nine participants were randomized. A significant main effect of time was found for pain intensity (p = 0.011; η2p = 0.095) and for PPT at the lower back (p < 0.001; η2p = 0.280), but not a time versus group interaction (p > 0.05). For PPT at the upper limb, no main effect of time or interaction was found (p > 0.5). CONCLUSIONS: Fifteen minutes of high-intensity interval aerobic exercise does not increase pain intensity or pain sensitivity compared to both moderate-intensity continuous aerobic exercise and no exercise, suggesting that high-intensity interval aerobic exercise can be used in clinical practice and patients reassured that it is unlikely to increase pain.

Consensus on the Terms and Procedures for Planning and Reporting a Usability Evaluation of Health-Related Digital Solutions: Delphi Study and a Resulting Checklist.

BACKGROUND: Usability evaluation both by experts and target users is an integral part of the process of developing and assessing digital solutions. Usability evaluation improves the probability of having digital solutions that are easier, safer, more efficient, and more pleasant to use. However, despite the widespread recognition of the importance of usability evaluation, there is a lack of research and consensus on related concepts and reporting standards. OBJECTIVE: The aim of the study is to generate consensus on terms and procedures that should be considered when planning and reporting a study on a usability evaluation of health-related digital solutions both by users and experts and provide a checklist that can easily be used by researchers when conducting their usability studies. METHODS: A Delphi study with 2 rounds was conducted with a panel of international participants experienced in usability evaluation. In the first round, they were asked to comment on definitions, rate the importance of preidentified methodological procedures using a 9-item Likert scale, and suggest additional procedures. In the second round, experienced participants were asked to reappraise the relevance of each procedure informed by round 1 results. Consensus on the relevance of each item was defined a priori when at least 70% or more experienced participants scored an item 7 to 9 and less than 15% of participants scored the same item 1 to 3. RESULTS: A total of 30 participants (n=20 females) from 11 different countries entered the Delphi study with a mean age of 37.2 (SD 7.7) years. Agreement was achieved on the definitions for all usability evaluation-related terms proposed (usability assessment moderator, participant, usability evaluation method, usability evaluation technique, tasks, usability evaluation environment, usability evaluator, and domain evaluator). A total of 38 procedures related to usability evaluation planning and reporting were identified across rounds (28 were related to usability evaluation involving users and 10 related to usability evaluation involving experts). Consensus on the relevance was achieved for 23 (82%) of the procedures related to usability evaluation involving users and for 7 (70%) of the usability evaluation procedures involving experts. A checklist was proposed that can guide authors when designing and reporting usability studies. CONCLUSIONS: This study proposes a set of terms and respective definitions as well as a checklist to guide the planning and reporting of usability evaluation studies, constituting an important step toward a more standardized approach in the field of usability evaluation that may contribute to enhancing the quality of planning and reporting usability studies. Future studies can contribute to further validating this study work by refining the definitions, assessing the practical applicability of the checklist, or assessing whether using this checklist results in higher-quality digital solutions.

Design, synthesis and biological evaluation of antiparasitic dinitroaniline-ether phospholipid hybrids.

A series of nine novel ether phospholipid-dinitroaniline hybrids were synthesized in an effort to deliver more potent antiparasitic agents with improved safety profile compared to miltefosine. The compounds were evaluated for their in vitro antiparasitic activity against L. infantum, L.donovani, L. amazonensis, L. major and L. tropica promastigotes, L. infantum and L. donovani intracellular amastigotes, Trypanosoma brucei brucei and against different developmental stages of Trypanosoma cruzi. The nature of the oligomethylene spacer between the dinitroaniline moiety and the phosphate group, the length of the side chain substituent on the dinitroaniline and the choline or homocholine head group were found to affect both the activity and toxicity of the hybrids. The early ADMET profile of the derivatives did not reveal major liabilities. Hybrid 3, bearing an 11-carbon oligomethylene spacer, a butyl side chain and a choline head group, was the most potent analogue of the series. It exhibited a broad spectrum antiparasitic profile against the promastigotes of New and Old World Leishmania spp., against intracellular amastigotes of two L. infantum strains and L. donovani, against T. brucei and against T. cruzi Y strain epimastigotes, intracellular amastigotes and trypomastigotes. The early toxicity studies revealed that hybrid 3 showed a safe toxicological profile while its cytotoxicity concentration (CC50) against THP-1 macrophages being >100 µM. Computational analysis of binding sites and docking indicated that the interaction of hybrid 3 with trypanosomatid α-tubulin may contribute to its mechanism of action. Furthermore, compound 3 was found to interfere with the cell cycle in T. cruzi epimastigotes, while ultrastructural studies using SEM and TEM in T. cruzi showed that compound 3 affects cellular processes that result in changes in the Golgi complex, the mitochondria and the parasite's plasma membrane. The snapshot pharmacokinetic studies showed low levels of 3 after 24 h following oral administration of 100 mg/Kg, while, its homocholine congener compound 9 presented a better pharmacokinetic profile.

Advances in Leishmania Research: From Basic Parasite Biology to Disease Control.

The genus Leishmania (Trypanosomatida: Trypanosomatidae) currently comprises just over 50 species, of which about 20 cause several syndromes in humans, collectively known as leishmaniasis or "leishmaniases" [...].

Characterization and Proteomic Analysis of Plasma EVs Recovered from Healthy and Diseased Dogs with Canine Leishmaniosis.

Dogs are highly valued companions and work animals that are susceptible to many life-threatening conditions such as canine leishmaniosis (CanL). Plasma-derived extracellular vesicles (EVs), exploited extensively in biomarker discovery, constitute a mostly untapped resource in veterinary sciences. Thus, the definition of proteins associated with plasma EVs recovered from healthy and diseased dogs with a relevant pathogen would be important for biomarker development. For this, we recovered, using size-exclusion chromatography (SEC), EVs from 19 healthy and 20 CanL dogs' plasma and performed proteomic analysis by LC-MS/MS to define their core proteomic composition and search for CanL-associated alterations. EVs-specific markers were identified in all preparations and also non-EVs proteins. Some EVs markers such as CD82 were specific to the healthy animals, while others, such as the Integrin beta 3 were identified in most samples. The EVs-enriched preparations allowed the identification of 529 canine proteins that were identified in both groups, while 465 and 154 were only identified in healthy or CanL samples, respectively. A GO enrichment analysis revealed few CanL-specific terms. Leishmania spp. protein identifications were also found, although with only one unique peptide. Ultimately, CanL-associated proteins of interest were identified and a core proteome was revealed that will be available for intra- and inter-species comparisons.

Biomechanical consequences of the intervertebral disc centre of rotation kinematics during lateral bending and axial rotation.

The location of the instantaneous centre of rotation (ICR) of a lumbar unit has a considerable clinical importance as a spinal health estimator. Consequently, many studies have been conducted to measure or estimate the ICR during rotations in the three anatomical planes; however the results reported are widely scattered. Even if some inter-subjects variability is to be expected, such inconsistencies are likely explained by the differences in methods and experiments. Therefore, in this paper we seek to model three behaviours of the ICR during lateral bending and axial rotation based on results published in the literature. In order to assess the metabolic and mechanical sensibility to the assumption made on the ICR kinematics, we used a previously validated three dimensional non-linear poroelastic model of a porcine intervertebral disc to simulate physiological lateral and axial rotations. The impact of the geometry was also briefly investigated by considering a 11[Formula: see text] wedge angle. From our simulations, it appears that the hypothesis made on the ICR location does not significantly affect the critical nutrients concentrations but gives disparate predictions of the intradiscal pressure at the centre of the disc (variation up to 0.7 MPa) and of the displacement fields (variation up to 0.4 mm). On the contrary, the wedge angle does not influence the estimated intradiscal pressure but leads to minimal oxygen concentration decreased up to 33% and increased maximal lactate concentration up to 13%. While we can not settle on which definition of the ICR is more accurate, this work suggests that patient-specific modeling of the ICR is required and brings new insights that can be useful for the development of new tools or the design of surgical material such as total lumbar disc prostheses.