In vitro metabolism of ferroquine (SSR97193) in animal and human hepatic models and antimalarial activity of major metabolites on Plasmodium falciparum.

Ferroquine (SSR97193) has been shown to be a promising antimalarial, both on laboratory clones and on field isolates. So far, no resistance was documented in Plasmodium falciparum. In the present work, the metabolic pathway of ferroquine, based on experiments using animal and human hepatic models, is proposed. Ferroquine is metabolized mainly via an oxidative pathway into the major metabolite mono-N-demethyl ferroquine and then into di-N,N-demethyl ferroquine. Some other minor metabolic pathways were also identified. Cytochrome P450 isoforms 2C9, 2C19, and 3A4 and, possibly in some patients, isoform 2D6, are mainly involved in ferroquine oxidation. The metabolites were synthesized and tested against the 3D7 (chloroquine-sensitive) and W2 (chloroquine-resistant) P. falciparum strains. According to the results, the activity of the two main metabolites decreased compared with that of ferroquine; however, the activity of the mono-N-demethyl derivative is significantly higher than that of chloroquine on both strains, and the di-N-demethyl derivative remains more active than chloroquine on the chloroquine-resistant strain. These results further support the potential use of ferroquine against human malaria.     

Modulatory effect of substance P to the brain stem locomotor command in lampreys

Substance P initiates locomotion when injected in the brain stem of mammals. This study examined the possible role of this peptide on the supraspinal locomotor command system in lampreys. Substance P was bath applied or locally injected into an in vitro isolated brain stem, and the effects of the drug were examined on reticulospinal cells and on the occurrence of swimming in a semi-intact preparation. Bath applications of substance P induced sustained depolarizations occurring rhythmically in intracellularly recorded reticulospinal cells. Spiking activity was superimposed on the depolarizations and swimming was induced. The sustained depolarizations were abolished by tetrodotoxin, and substance P did not affect the membrane resistance of reticulospinal cells nor their firing properties, suggesting that it did not directly effect reticulospinal cells. To establish where the effects were exerted, successive lesions of the brain stem were made as well as local applications of the drug in the brain stem. Removing the mesencephalon abolished the sustained depolarizations, whereas large ejections of the drug in the mesencephalon excited reticulospinal cells and elicited bouts of swimming. More local injections into the mesencephalic locomotor region (MLR) also elicited swimming. After an injection of substance P, the current threshold needed to induce locomotion by MLR stimulation was decreased, and the size of the postsynaptic responses of reticulospinal cells to MLR stimulation was increased. Substance P also reduced the frequency of miniature spontaneous postsynaptic currents in reticulospinal cells. Taken together, these results suggest that substance P plays a neuromodulatory role on the brain stem locomotor networks of lampreys.     

A Web-Based Interactive Patient-Provider Software Platform Does Not Increase Patient Satisfaction or Decrease Hospital Resource Utilization in Total Knee and Hip Arthroplasty Patients in a Single Large Hospital System

BackgroundWeb-based platforms used to enhance patient-provider communication are being explored to improve patient satisfaction and care delivery, and decrease cost. This study tested a web-based interactive patient-provider software platform (IPSP), JointCOACH, which enabled patient communication with their care team and preparatory/recovery guidance. The aims of this study are to compare (1) patient satisfaction and (2) healthcare resource utilization by patients who underwent total knee and hip replacements and added IPSP to standard of care (SOC).MethodsThis study is a prospective, randomized clinical trial at a single large academic healthcare system. Between May 2018 and March 2020, 399 patients undergoing elective total hip or knee arthroplasty were randomized to SOC arm (n = 204) or SOC + IPSP arm (n = 195). Patient demographics, surgical details, and comorbidities were collected. Patient satisfaction was assessed using Visual Analog Scale and the Picker Patient Experience-15. Healthcare utilization was measured using length of stay, emergency department and office visits, office calls, readmissions, and reoperations at 30 and 90 days after surgery.ResultsNo difference was found in length of stay between SOC and SOC + IPSP. No differences were found in 30-day or 90-day satisfaction or in healthcare resource utilization (P > .05) including number of office and emergency department visits, phone calls, and readmissions.ConclusionStatistical differences were not found in satisfaction and healthcare utilization with the addition of IPSP to SOC. IPSP can be used to reinforce patient education and communication between the patient and provider, and should be evaluated as an element of virtual care rather than supplementing traditional in-office follow-up.Clinicaltrials.govMore information on this study can be found at clinicaltrials.gov NCT03499028.     

Relationship Between Peer Victimization and Posttraumatic Stress Among Primary School Children

Peer victimization is a common stressor experienced by children. Although peer victimization has been studied extensively, few studies have examined the potential link between peer victimization and posttraumatic stress disorder (PTSD), and no studies of which we are aware have examined this link among children in primary school. The paucity of studies examining the link between PTSD and peer victimization in primary school is surprising because peer victimization occurs more frequently and is more likely to be physical among 7‐ and 8‐year‐old children. This study assessed the relationship between peer victimization and PTSD in a sample of 358 elementary school children (ages 6–11 years). Results indicated that peer victimization accounted for 14.1% of PTSD symptom severity among boys and 10.1% among girls. Additionally, we found gender differences in the types of peer victimization that were most associated with PTSD symptom severity (d = 0.38). The long‐term developmental consequences that may be associated with peer victimization‐linked PTSD symptomatology are discussed.     

γδ T cells restrain extrathymic development of Foxp3+‐inducible regulatory T cells via IFN‐γ

Inducible Treg (iTreg) cells generated from Ag‐stimulated naïve CD4⁺ T cells in the periphery play an important role in regulating immune responses. TGF‐β is a key cytokine that promotes this conversion process; however, how this process is regulated in vivo remains unclear. Here, we report that γδ T cells play a crucial role in controlling iTreg generation and suppressor function. Ag‐induced iTreg generation was significantly enhanced in C57BL/6 mice in the absence of γδ T cells. Inhibition of iTreg conversion was mediated by IFN‐γ produced by activated γδ T cells but not by activated CD4⁺ T cells. BM chimera experiments further confirmed γδ‐derived IFN‐γ‐dependent mechanism in regulating iTreg generation in vivo. Lastly, human peripheral blood γδ T cells also interfere with iTreg conversion via IFN‐γ. Our results suggest a novel function of γδ T cells in limiting the generation of iTreg cells, potentially balancing immunity and tolerance.     

Reduced Expression of STOP/MAP6 in Mice Leads to Cognitive Deficits

Background: STOP/MAP6 null (KO) mice recapitulate behavioral abnormalities related to positive and negative symptoms and cognitive deficits of schizophrenia. Here, we investigated whether decreased expression of STOP/MAP6 proteins in heterozygous mice (only one allele expressed) would result in abnormal behavior related to those displayed by STOP null mice. Methods: Using a comprehensive test battery, we investigated the behavioral phenotype of STOP heterozygous (Het) mice compared with STOP KO and wild type (WT) mice on animals raised either in standard conditions (controls) or submitted to maternal deprivation. Results: Control Het mice displayed prominent deficits in social interaction and learning, resembling KO mice. In contrast, they exhibited short-lasting locomotor hyperreactivity to acute mild stress and no impaired locomotor response to amphetamine, much like WT mice. Additionally, perinatal stress deteriorated Het mouse phenotype by exacerbating alterations related to positive symptoms such as their locomotor reactivity to acute mild stress and psychostimulant challenge. Conclusion: Results show that the dosage of susceptibility genes modulates their putative phenotypic contribution and that STOP expression has a high penetrance on cognitive abilities. Hence, STOP Het mice might be useful to investigate cognitive defects related to those observed in mental diseases and ultimately might be a valuable experimental model to evaluate preventive treatments.Key words: schizophrenia, animal model, microtubule, neurodevelopment, behavioral phenotype, gene x environment interaction