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.

A Practice Guide for Physical Therapists Prescribing Physical Exercise for Older Adults.

INTRODUCTION: Physical activity and exercise are protective factors for physical and cognitive decline in older adults, but recent studies reveal that a large percentage of this population do not practice exercise at the levels recommended by international guidelines. The frequency, intensity, type, time, volume, and progression (FITT-VP) principles are a widely used method for prescribing physical exercise, allowing the development of a personalized exercise program that meets the needs of each individual. OBJECTIVES: This masterclass is intended to serve as a professional application tool for physical therapists who prescribe physical exercise for older adults. We present a section for each FITT-VP principle to facilitate handling these principles individually when prescribing exercise for this population. METHODS: Review of the scientific literature and international guidelines on the prescription of physical exercises for older adults. RESULTS: Aerobic, mobility, resistance, balance, and flexibility exercises, as well as functional training, should be included in an exercise program for older adults, which should be progressed using different methods for each of the exercise modalities. CONCLUSIONS: An exercise program for older adults should integrate different exercise modalities. Exercise progression should be performed following the FITT-VP principles and some specific progression factors recommended for each exercise modality. SIGNIFICANCE: Considering the challenge faced by clinicians in designing a viable exercise program for older adults that responds to international recommendations, with this masterclass we hope to help physical therapists to plan an exercise program that is feasible and at the same time, responds to the expected needs of this population.

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.

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.

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.

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).

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.

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.

Systematic review and meta-analysis on the association between chronic low back pain and cognitive function.

This study aimed to identify and assess the evidence on the association between idiopathic chronic low back pain (LBP) and cognitive function in individuals with LBP. A secondary aim was to explore whether changes in cognitive function are associated with pain characteristics and psychological factors (eg, catastrophizing and fear of movement). Eleven studies were included in this systematic review, and four meta-analyses were conducted. Low to very low-quality evidence suggests impaired cognitive function in individuals with LBP compared to asymptomatic controls for problem solving (k = 5; d = 0.33; CI = 0.16-0.50; z = 3.85 p = 0.0001), speed of information processing (k = 5; d = 0.44; CI = 0.22-0.65; z = 4.02 p < 0.0001), working memory (k = 6; d = 0.50; CI = 0.34-0.66; z = 6.09 p < 0.0001), and delayed memory (k = 3; d = 0.34; CI = 0.07-0.6, z = 2.49 p = 0.02). The association between LBP intensity and psychological factors and cognitive function was inconclusive. More studies are needed to explore these associations and improve evidence in this field. The results of this study suggest that cognitive aspects should be considered during the rehabilitation process of patients with LBP and raise further questions, including whether individuals with LBP are at a greater risk of developing dementia or whether targeting cognitive function will increase the probability of success of LBP treatment. These questions should, also, be considered in future studies.

High-throughput phenotyping of physiological traits for wheat resilience to high temperature and drought stress.

Interannual and local fluctuations in wheat crop yield are mostly explained by abiotic constraints. Heatwaves and drought, which are among the top stressors, commonly co-occur, and their frequency is increasing with global climate change. High-throughput methods were optimized to phenotype wheat plants under controlled water deficit and high temperature, with the aim to identify phenotypic traits conferring adaptative stress responses. Wheat plants of 10 genotypes were grown in a fully automated plant facility under 25/18 °C day/night for 30 d, and then the temperature was increased for 7 d (38/31 °C day/night) while maintaining half of the plants well irrigated and half at 30% field capacity. Thermal and multispectral images and pot weights were registered twice daily. At the end of the experiment, key metabolites and enzyme activities from carbohydrate and antioxidant metabolism were quantified. Regression machine learning models were successfully established to predict plant biomass using image-extracted parameters. Evapotranspiration traits expressed significant genotype-environment interactions (G×E) when acclimatization to stress was continuously monitored. Consequently, transpiration efficiency was essential to maintain the balance between water-saving strategies and biomass production in wheat under water deficit and high temperature. Stress tolerance included changes in carbohydrate metabolism, particularly in the sucrolytic and glycolytic pathways, and in antioxidant metabolism. The observed genetic differences in sensitivity to high temperature and water deficit can be exploited in breeding programmes to improve wheat resilience to climate change.

Real-World Impact of Transferring the Dispensing of Hospital-Only Medicines to Community Pharmacies During the COVID-19 Pandemic.

OBJECTIVES: In Portugal, the dispensing of most outpatient specialty medicines is performed exclusively through hospital pharmacies and totally financed by the National Health Service. During the COVID-19 first wave, the government allowed the transfer of the dispensing of hospital-only medicines (HOMs) to community pharmacies (CPs). This study aimed to measure the value generated by the intervention of CP in the dispensing of HOM. METHODS: A single-arm, before-and-after study with 3-month follow-up was conducted enrolling a randomly selected sample of patients or caregivers with at least 1 dispensation of HOM through CP. Data were collected by telephone interview. Main outcomes were patients' self-reported adherence (Measure Treatment Adherence), health-related quality of life (EQ-5D 3-Level), satisfaction with the service, and costs related to HOM access. RESULTS: Overall 603 subjects were recruited to participate in the study (males 50.6%) with mean 55 years old (SD = 16). The already high mean adherence score to therapy improved significantly (P < .0001), and no statistically significant change (P > .5757) was found in the mean EQ-5D score between baseline (0.7 ± 0.3) and 3-month follow-up (0.8 ± 0.3). Annual savings account for €262.1/person, arising from travel expenses and absenteeism reduction. Participants reported a significant increase in satisfaction levels in all evaluated domains-pharmacist's availability, opening hours, waiting time, privacy conditions, and overall experience. CONCLUSIONS: Changing the dispense setting to CP may promote better access and satisfaction. Moreover, it ensures the persistence of treatments, promotes savings for citizens, and reduces the burden of healthcare services, representing a crucial public health measure.

Antileishmanial Drugs Modulate IL-12 Expression and Inflammasome Activation in Primary Human Cells.

Leishmaniases are neglected tropical diseases. The treatment of leishmaniasis relies exclusively on chemotherapy including amphotericin B (AmB), miltefosine (hexadecylphosphocholine), and pentamidine. Besides the fact that these molecules are harmful for patients, little is known about the impact of such antileishmanial drugs on primary human cells in relation to immune function. The present study demonstrates that all antileishmanial drugs inhibit CD4 and CD8 T cell proliferation at the doses that are not related to increased cell death. Our results highlight that antileishmanial drugs have an impact on monocytes by altering the expression of IL-12 induced by LPS, whereas only AmB induced IL-10 secretion; both cytokines are essential in regulating Th1 cell-mediated immunity. Interestingly, IL-12 and anti-IL-10 Abs improved T cell proliferation inhibited by AmB. Furthermore, our results show that in contrast to hexadecylphosphocholine and pentamidine, AmB induced gene expression of the inflammasome pathway. Thus, AmB induced IL-1ß and IL-18 secretions, which are reduced by specific inhibitors of caspase activation (Q-VD) and NLRP3 activation (MCC950). Our results reveal previously underestimated effects of antileishmanial drugs on primary human cells.

Predictors of pain persistence and disability in high-school students with chronic neck pain at 6-month follow-up.

BACKGROUND: Neck pain tends to persist for periods of 1 to 4 years of follow-up in adolescents, and a high percentage of them report disability. However, studies assessing the factors associated with persistent neck pain and disability in this age group are scarce. This study aimed to explore the association between psychosocial factors, sleep, and symptoms of central sensitization at baseline and the persistence of neck pain and disability at 6-month follow-up. METHODS: A total of 710 adolescents with chronic neck pain were assessed at baseline with an online questionnaire that collected information on sociodemographic data, presence of musculoskeletal pain, pain intensity, physical activity, functional disability, depression, anxiety, stress, quality of sleep, catastrophizing, kinesiophobia, self-efficacy, and symptoms of central sensitization. At 6-month follow-up, adolescents were reassessed for disability and pain intensity and categorized as recovered or reporting persistent neck pain. RESULTS: Of the 710 participants with neck pain at baseline, 334 were classified as having persistent neck pain and 375 adolescents as being recovered at 6-month follow-up. Multivariable analysis showed that female gender (OR 1.47; p = 0.04) and symptoms of central sensitization (OR 1.02; p = 0.001) at baseline were positively associated with the persistence of neck pain at 6-month follow-up. Similarly, higher levels of disability (ß = 0.41; p < 0.001) and symptoms of central sensitization (ß = 0.28; p < 0.001) at the baseline were positively associated with disability. CONCLUSIONS: Symptoms of central sensitization and disability at baseline should be considered in the assessment and design of interventions for adolescents with chronic neck pain as an attempt to minimize its future impact on pain persistence and disability.

Impact of Sex, Sleep, Symptoms of Central Sensitization, and Psychosocial Factors in Adolescents with Chronic Musculoskeletal Pain: An Exploratory Study.

OBJECTIVE: This study aimed to explore and compare the associations of psychosocial factors, sleep, and central sensitization with chronic neck, back, limb, and multiregional pain and disability. METHODS: One thousand seven hundred thirty (n = 1,730) adolescents responded to an online questionnaire containing questions about sociodemographic data, as well as the Nordic Musculoskeletal Questionnaire; the International Physical Activity Questionnaire; the Functional Disability Inventory; the Depression, Anxiety, and Stress Scale; the Basic Scale on Insomnia Complaints and Quality of Sleep; the Pain Catastrophizing Scale; the Tampa Scale of Kinesiophobia; the Child Self-Efficacy Scale; and the Central Sensitization Inventory. Univariable and multivariable regression analysis were used to assess the associations between these variables and pain and disability. RESULTS: Groups were categorized into those with neck (n = 54), back (n = 80), upper limb (n = 52), lower limb (n = 109), or multiregional (n = 1,140) pain. Multivariable analysis showed that symptoms of central sensitization increased the odds of neck, back, and multiregional pain; depression, anxiety and stress, and physical activity increased the odds of multiregional pain; and fear of movement increased the odds of lower limb pain. Female gender increased the odds of pain in all groups, except in the lower limb group. Depression, anxiety, and stress also remained associated with disability in neck, back, upper limb, and multiregional pain; poorer sleep remained associated with disability in neck, upper limb, and multiregional pain; catastrophizing remained associated with back and multiregional pain; and fear of movement and symptoms of central sensitization were associated with disability only in multiregional pain. CONCLUSIONS: There are similar but also different variables associated with the presence of pain and disability in the neck, back, limbs, and multiregional pain.

Toward Chemical Validation of Leishmania infantum Ribose 5-Phosphate Isomerase as a Drug Target.

Neglected tropical diseases caused by kinetoplastid parasites (Trypanosoma brucei, Trypanosoma cruzi, and Leishmania spp.) place a significant health and economic burden on developing nations worldwide. Current therapies are largely outdated, inadequate, and face mounting drug resistance from the causative parasites. Thus, there is an urgent need for drug discovery and development. Target-led drug discovery approaches have focused on the identification of parasite enzymes catalyzing essential biochemical processes, which significantly differ from equivalent proteins found in humans, thereby providing potentially exploitable therapeutic windows. One such target is ribose 5-phosphate isomerase B (RpiB), an enzyme involved in the nonoxidative branch of the pentose phosphate pathway, which catalyzes the interconversion of d-ribose 5-phosphate and d-ribulose 5-phosphate. Although protozoan RpiB has been the focus of numerous targeted studies, compounds capable of selectively inhibiting this parasite enzyme have not been identified. Here, we present the results of a fragment library screening against Leishmania infantum RpiB (LiRpiB), performed using thermal shift analysis. Hit fragments were shown to be effective inhibitors of LiRpiB in activity assays, and several fragments were capable of selectively inhibiting parasite growth in vitro. These results support the identification of LiRpiB as a validated therapeutic target. The X-ray crystal structure of apo LiRpiB was also solved, permitting docking studies to assess how hit fragments might interact with LiRpiB to inhibit its activity. Overall, this work will guide structure-based development of LiRpiB inhibitors as antileishmanial agents.

A role for hepcidin in the anemia caused by Trypanosoma brucei infection.

Trypanosomiasis is a parasitic disease affecting both humans and animals in the form of Human African Trypanosomiasis and Nagana disease, respectively. Anemia is one of the most common symptoms of trypanosomiasis, and if left unchecked can cause severe complications and even death. Several factors have been associated with the development of this anemia, including dysregulation of iron homeostasis, but little is known about the molecular mechanisms involved. Here, using murine models, we study the involvement of hepcidin, the key regulator of iron metabolism and an important player in the development of anemia of inflammation. Our data show two stages for the progression of anemia, to which hepcidin contributes a first stage when anemia develops, with a likely cytokine-mediated stimulation of hepcidin and subsequent limitation in iron availability and erythropoiesis, and a second stage of recovery, where the increase in hepcidin then declines due to the reduced inflammatory signal and increased production of erythroid regulators by the kidney, spleen and bone marrow, thus leading to an increase in iron release and availability, and enhanced erythropoiesis. In agreement with this, in hepcidin knockout mice, anemia is much milder and its recovery is complete, in contrast to wild-type animals which have not fully recovered from anemia after 21 days. Besides all other factors known to be involved in the development of anemia during trypanosomiasis, hepcidin clearly makes an important contribution to both its development and recovery.

Photoprotection and optimization of sucrose usage contribute to faster recovery of photosynthesis after water deficit at high temperatures in wheat.

Plants are increasingly exposed to events of elevated temperature and water deficit, which threaten crop productivity. Understanding the ability to rapidly recover from abiotic stress, restoring carbon assimilation and biomass production, is important to unravel crop climate resilience. This study compared the photosynthetic performance of two Triticum aestivum L. cultivars, Sokoll and Paragon, adapted to the climate of Mexico and UK, respectively, exposed to 1-week water deficit and high temperatures, in isolation or combination. Measurements included photosynthetic assimilation rate, stomatal conductance, in vitro activities of Rubisco (EC 4.1.1.39) and invertase (INV, EC 3.2.1.26), antioxidant capacity and chlorophyll a fluorescence. In both genotypes, under elevated temperatures and water deficit (WD38°C), the photosynthetic limitations were mainly due to stomatal restrictions and to a decrease in the electron transport rate. Chlorophyll a fluorescence parameters clearly indicate differences between the two genotypes in the photoprotection when subjected to WD38°C and showed faster recovery of Paragon after stress relief. The activity of the cytosolic invertase (CytINV) under these stress conditions was strongly related to the fast photosynthesis recovery of Paragon. Taken together, the results suggest that optimal sucrose export/utilization and increased photoprotection of the electron transport machinery are important components to limit yield fluctuations due to water shortage and elevated temperatures.

Design, Synthesis and Antiparasitic Evaluation of Click Phospholipids.

A library of seventeen novel ether phospholipid analogues, containing 5-membered heterocyclic rings (1,2,3-triazolyl, isoxazolyl, 1,3,4-oxadiazolyl and 1,2,4-oxadiazolyl) in the lipid portion were designed and synthesized aiming to identify optimised miltefosine analogues. The compounds were evaluated for their in vitro antiparasitic activity against Leishmania infantum and Leishmania donovani intracellular amastigotes, against Trypanosoma brucei brucei and against different developmental stages of Trypanosoma cruzi. The nature of the substituents of the heterocyclic ring (tail) and the oligomethylene spacer between the head group and the heterocyclic ring was found to affect the activity and toxicity of these compounds leading to a significantly improved understanding of their structure-activity relationships. The early ADMET profile of the new derivatives did not reveal major liabilities for the potent compounds. The 1,2,3-triazole derivative 27 substituted by a decyl tail, an undecyl spacer and a choline head group exhibited broad spectrum antiparasitic activity. It possessed low micromolar activity against the intracellular amastigotes of two L. infantum strains and T. cruzi Y strain epimastigotes, intracellular amastigotes and trypomastigotes, while its cytotoxicity concentration (CC50) against THP-1 macrophages ranged between 50 and 100 µM. Altogether, our work paves the way for the development of improved ether phospholipid derivatives to control neglected tropical diseases.

Neural Mobilization Short-Term Dose Effect on the Lower-Limb Flexibility and Performance in Basketball Athletes: A Randomized, Parallel, and Single-Blinded Study.

CONTEXT: Neural mobilization is commonly used in sports, and previous studies have suggested that it has a positive impact on lower-limb flexibility and performance. However, studies exploring the effect of neural mobilization dosage are almost nonexistent. OBJECTIVES: This study aimed to assess whether 2 distinct dosages of neural gliding mobilization (4 and 8 sets of 10 repetitions) impact the flexibility and performance of both the mobilized and nonmobilized lower limb in basketball athletes differently. DESIGN: Randomized, parallel, and single-blinded study. SETTING: Amateur and professional basketball clubs. PARTICIPANTS: Fifty-two basketball athletes (40 men and 12 women), who were distributed into 2 groups; one received 40 (n = 28) and the other 80 repetitions (n = 24) of neural gliding mobilization. INTERVENTION: Neural gliding mobilization applied to a single limb (the dominant limb). MAIN OUTCOME MEASURES: Knee extension angle for hamstring flexibility; hop tests and single-leg vertical jump for performance. RESULTS: There was a significant main effect of time (P < .001), a significant interaction between time and limb for flexibility (P = .003), and a significant interaction between time and limb for the single-leg hop test (P = .032). No other significant main effect for any of the remaining variables was found (P > .05). CONCLUSIONS: The application of both 40 repetitions and 80 of neural gliding significantly improved lower-limb flexibility, and one was not superior to the other. Neither one dosage nor the other positively or negatively impacted the lower-limb performance of basketball athletes.