Optimizing Epoch Length and Activity Count Threshold Parameters in Accelerometry: Enhancing Upper Extremity Use Quantification in Cerebral Palsy.

Various accelerometry protocols have been used to quantify upper extremity (UE) activity, encompassing diverse epoch lengths and thresholding methods. However, there is no consensus on the most effective approach. The aim of this study was to delineate the optimal parameters for analyzing accelerometry data to quantify UE use in individuals with unilateral cerebral palsy (CP). METHODS: A group of adults with CP (n = 15) participated in six activities of daily living, while a group of children with CP (n = 14) underwent the Assisting Hand Assessment. Both groups performed the activities while wearing ActiGraph GT9X-BT devices on each wrist, with concurrent video recording. Use ratio (UR) derived from accelerometry and video analysis and accelerometer data were compared for different epoch lengths (1, 1.5, and 2 s) and activity count (AC) thresholds (between 2 and 150). RESULTS: In adults, results are comparable across epoch lengths, with the best AC thresholds being ≥ 100. In children, results are similar across epoch lengths of 1 and 1.5 (optimal AC threshold = 50), while the optimal threshold is higher with an epoch length of 2 (AC = 75). CONCLUSIONS: The combination of epoch length and AC thresholds should be chosen carefully as both influence the validity of the quantification of UE use.

The REHAB-LAB model for individualized assistive device co-creation and production.

Assistive devices are designed to enhance individuals with disabilities' functional abilities. The rise of 3D printing technology enabled the production of individualized assistive devices (IADs). A REHAB-LAB is intended for IAD provision involving technical referents and occupational therapists. This study aimed to develop the REHAB-LAB logic model; to explore its fidelity and desirability; and to explore the characteristics of arising initiatives of IAD production. The REHAB-LAB logic model development involved stakeholders throughout the research process. A pragmatic multimethod approach followed two phases 1) logic model development and 2) exploration of its fidelity and desirability. The REHAB-LAB logic model presented the resources (equipment, space, human) required to implement IAD provision in a rehabilitation center, and the expected deliverables (activities and outputs). The REHAB-LAB logic model highlights the interdisciplinarity of IAD provision including occupational therapists, doctors, engineers, managers, and technical referents and places the users at the center of the IAD production. Results confirmed the fidelity and desirability of the REHAB-LAB logic model. The REHAB-LAB logic model can be used as a reference for future healthcare organizations wishing to implement an IAD provision. This research highlighted the interest of IAD provision based on the REHAB-LAB model involving users and transdisciplinary practices.

Reliability of an observation-based scoring grid to assess bimanual performance during unstandardized tasks in adults living with cerebral palsy.

PURPOSE: Most activities of daily living (ADLs) require the use of both upper extremities. However, few assessments exist to assess bimanual performance, especially among adults living with cerebral palsy (CP). The aim of this preliminary study is to assess the interrater reliability and convergent validity of the Assisting Hand Assessment (AHA) scoring grid applied to unstandardized ADLs. MATERIALS AND METHODS: For this validation study, nineteen adults living with spastic unilateral CP were videotaped performing seven bimanual ADLs. Three raters assessed the videos independently using the 20-item grid of the AHA. Gwet's AC2 was used to assess interrater reliability. Kendall's Tau-b correlation was used between the observation-based scoring grid and Jebsen-Taylor Hand Function Test (JTHFT) scores to assess convergent validity. RESULTS: Interrater reliability was good (0.84, SD = 0.02). The correlation with the JTHFT was high (τb = -0.74; p < 0.001). CONCLUSION: The results show the potential of using an observation-based scoring grid with unstandardized ADLs to assess bimanual performance in adults living with CP, but further research on psychometric properties is needed. This method allows for an assessment that is occupation-oriented, ecological, and meaningful.

An observation-based scoring grid (Assisting Hand Assessment) can be applied in unstandardized activities of daily living to assess bimanual performance in adults with cerebral palsy.This method allows an occupation-oriented, ecological, and client-meaningful assessment.Although this approach is a pilot measure, it can be used by clinicians and researchers until further psychometric analyses are undertaken.

Macrophage-infectivity potentiator of Trypanosoma cruzi (TcMIP) is a new pro-type 1 immuno-stimulating protein for neonatal human cells and vaccines in mice.

This work identifies the protein "macrophage infectivity potentiator" of Trypanosoma cruzi trypomastigotes, as supporting a new property, namely a pro-type 1 immunostimulatory activity on neonatal cells. In its recombinant form (rTcMIP), this protein triggers the secretion of the chemokines CCL2 and CCL3 by human umbilical cord blood cells from healthy newborns, after 24h in vitro culture. Further stimulation for 72h results in secretion of IFN-γ, provided cultures are supplemented with IL-2 and IL-18. rTcMIP activity is totally abolished by protease treatment and is not associated with its peptidyl-prolyl cis-trans isomerase enzymatic activity. The ability of rTcMIP to act as adjuvant was studied in vivo in neonatal mouse immunization models, using acellular diphtheria-tetanus-pertussis-vaccine (DTPa) or ovalbumin, and compared to the classical alum adjuvant. As compared to the latter, rTcMIP increases the IgG antibody response towards several antigens meanwhile skewing antibody production towards the Th-1 dependent IgG2a isotype. The amplitude of the rTcMIP adjuvant effect varied depending on the antigen and the co-presence of alum. rTcMIP did by contrast not increase the IgE response to OVA combined with alum. The discovery of the rTcMIP immunostimulatory effect on neonatal cells opens new possibilities for potential use as pro-type 1 adjuvant for neonatal vaccines. This, in turn, may facilitate the development of more efficient vaccines that can be given at birth, reducing infection associated morbidity and mortality which are the highest in the first weeks after birth.

From maternal breath to infant's cells: Impact of maternal respiratory infections on infants 'immune responses.

In utero exposure to maternally-derived antigens following chronic infection is associated with modulation of infants 'immune response, differential susceptibility to post-natal infections and immune response toward vaccines. The maternal environment, both internal (microbiota) and external (exposure to environmental microbes) also modulates infant's immune response but also the clinical phenotype after birth. Vertical transmission of ubiquitous respiratory pathogens such as influenza and COVID-19 is uncommon. Evidence suggest that in utero exposure to maternal influenza and SARS-CoV-2 infections may have a significant impact on the developing immune system with activation of both innate and adaptive responses, possibly related to placental inflammation. Here in, we review how maternal respiratory infections, associated with airway, systemic and placental inflammation but also changes in maternal microbiota might impact infant's immune responses after birth. The clinical impact of immune modifications observed following maternal respiratory infections remains unexplored. Given the high frequencies of respiratory infections during pregnancy (COVID-19, influenza but also RSV and HMPV), the impact on global child health could be important.

Impact of hippotherapy on the life habits of children with disabilities: a systematic review.

PURPOSE: The aim was to document the effects of hippotherapy on the 12 life habits of children with various disabilities. MATERIALS AND METHODS: A systematic review using PRISMA guidelines was conducted to identify relevant studies. Five databases were consulted. Inclusion criteria were: 2-to-18 years old; therapy provided by a PT, OT or SLP/SLT; variables relevant to life habits as defined by the Human Development Model - Disability Creation Process. Quality was analyzed using a quantitative studies critical review form developed by the McMaster University Occupational Therapy Evidence-Based Practice Research Group. Levels of evidence were evaluated using the Oxford Centre for Evidence-Based Medicine guidelines. RESULTS: The investigations' overall quality ratings were excellent (n = 5 studies), acceptable (n = 10) and poor (n = 8); the evidence levels were 2/high (n = 2), 3/moderate (n = 3) and 4/low (n = 18). This systematic review suggests an observable connection between hippotherapy and improvements in three habits (mobility, communication, interpersonal relationships). CONCLUSION: The findings provide support for hippotherapy as a therapy with a positive impact on three categories of life habits. Further research is warranted for education, housing, nutrition, personal care and recreation (only 3 studies), as well as community and spiritual life, employment, physical fitness and psychological well-being and responsibility (no studies). Implications for rehabilitationOccupational, physical and speech language therapists must continue to intervene with children with developmental delays related to various diagnoses as demonstrated by 15 studies involving hippotherapy rated from acceptable to excellent quality.Given improvements, therapists should pursue hippotherapy in mobility, communication, interpersonal relationships, as established specifically by five studies with moderate to high evidence.Given three studies in hippotherapy, therapists are encouraged to document improvement in other life habits such as education, housing, nutrition, personal care and recreation.

Mechanical design of a new device to assist eating in people with movement disorders.

Many people living with neurological disorders, such as cerebral palsy, stroke, muscular dystrophy or dystonia, experience upper limb impairments (muscle spasticity, loss of selective motor control, muscle weakness or tremors) and are unable to eat independently. This article presents the development of a new device to assist with eating, aimed at stabilizing the movement of people who have movement disorders. The design was guided by insights gathered through focus groups, with occupational therapists and engineers, about the challenges faced by individuals who have movement disorders and difficulty in eating autonomously. The proposed assistive device prototype is designed to be fixed on a table and to support a spoon. The mechanism is designed so that the spoon maintains a position parallel to the ground for the user. Dampers and inertia allow stabilizing the user's motion. A preliminary trial with five individuals living with cerebral palsy is presented to assess the prototype's performance and to guide future iterations of the prototype. Task completion time generally decreased and movement fluidity generally improved when using the assistive device prototype. The prototype showed good potential in stabilizing the spoon for the user and improving movement fluidity.

Measuring functional outcome in Dupuytren's disease: A systematic review of patient-reported outcome measures.

BACKGROUND: Functional impairments related to Dupuytren's disease (DD) can be assessed using patient-reported outcome measures (PROMs). A systematic review was published in 2013 on outcome measures for assessing treatment in individuals with DD; however, several articles have since been published on this matter. PURPOSE: To conduct a systematic review to analyze the quality and content of the evidence on the psychometric properties of PROMs used in individuals with DD. STUDY DESIGN: Systematic review. METHODS: CINAHL, EBM reviews, Embase, Medline, and Web of Science were searched to identify studies evaluating the psychometric properties of PROMs used with individuals with DD. All studies retained were appraised by two independent assessors using two validated critical appraisal tools. RESULTS: Fifteen articles on the psychometric properties of 10 PROMs were included. Construct validity and responsiveness were the most studied. Eighty percent of the studies were of good to very good methodological quality according to MacDermid's Critical appraisal checklist for psychometric articles, whereas 67% of the studies comported risks of bias according to the COSMIN checklist. Of the 10 PROMs, three were specifically developed for DD but remain mostly under-studied for their psychometric properties (≤ 2 studies for the SDSS and DIF-CHUM). The QuickDASH, MHQ, BriefMHQ, and URAM present moderate to good convergent validity. Test-retest reliability was found to be good for the MHQ, briefMHQ, URAM, SDSS, SF-36, and the multi-attribute of the HUI-3. The MHQ and BriefMHQ are highly responsive. CONCLUSION: There is a need for more psychometric studies on the PROMs used with individuals with DD. However, to date, the results included in this systematic review support that the MHQ and briefMHQ are the PROMs with the most acceptable psychometric properties.

Plexin-A4 Mediates Cytotoxic T-cell Trafficking and Exclusion in Cancer.

Cytotoxic T cell (CTL) infiltration of the tumor carries the potential to limit cancer progression, but their exclusion by the immunosuppressive tumor microenvironment hampers the efficiency of immunotherapy. Here, we show that expression of the axon guidance molecule Plexin-A4 (Plxna4) in CTLs, especially in effector/memory CD8+ T cells, is induced upon T-cell activation, sustained in the circulation, but reduced when entering the tumor bed. Therefore, we deleted Plxna4 and observed that Plxna4-deficient CTLs acquired improved homing capacity to the lymph nodes and to the tumor, as well as increased proliferation, both achieved through enhanced Rac1 activation. Mice with stromal or hematopoietic Plxna4 deletion exhibited enhanced CTL infiltration and impaired tumor growth. In a melanoma model, adoptive transfer of CTLs lacking Plxna4 prolonged survival and improved therapeutic outcome, which was even stronger when combined with anti-programmed cell death protein 1 (PD-1) treatment. PLXNA4 abundance in circulating CTLs was augmented in melanoma patients versus healthy volunteers but decreased after the first cycle of anti-PD-1, alone or in combination with anti-cytotoxic T-Lymphocyte Associated Protein 4 (CTLA-4), in those patients showing complete or partial response to the treatment. Altogether, our data suggest that Plxna4 acts as a "checkpoint," negatively regulating CTL migration and proliferation through cell-autonomous mechanisms independent of the interaction with host-derived Plxna4 ligands, semaphorins. These findings pave the way toward Plxna4-centric immunotherapies and propose Plxna4 detection in circulating CTLs as a potential way to monitor the response to immune checkpoint blockade in patients with metastatic melanoma.

Maternal Lactobacillus rhamnosus administration impacts neonatal CD4 T-cell activation and prevents murine T helper 2-type allergic airways disease.

Gut microbiota plays a role in the neonatal immune education and could influence susceptibility to Th2-type immune disorders, such as allergies, the most prevalent chronic diseases in early childhood. We studied the impact of oral Lactobacillus rhamnosus (L.rhamnosus) supplementation to pregnant/breastfeeding C57BL/6 mice on the development of allergic airways disease in their offspring. We observed that mice, from L.rhamnosus-treated mothers, inoculated with ovalbumin (OVA)-Aluminium hydroxide (ALUM) at 3 days of life and challenged intranasally 4 weeks later showed decreased Th2-associated cytokines, IgE and IgG1, lung eosinophilia and airway hyper-reactivity compared to OVA-sensitized mice from untreated mothers. In that setting, the L.rhamnosus treatment increased the number and maturation of splenic neonatal type 1 conventional dendritic cells (cDC1) that remained largely dominant over the cDC2 and favored their OVA-specific Th1 differentiation. In response to inhaled house dust mite (HDM) allergen, the maternal L.rhamnosus supplementation increased the number of neonatal pulmonary cDC1 expressing lower amount of costimulatory molecules compared with no supplementation and decreased the number of cDC2 without affecting their costimulatory molecules expression. An HDM-specific Foxp3+RORγt+ Treg polarization was monitored in the lung draining lymph nodes. Finally, we confirmed the inhibitory effect of maternal L.rhamnosus treatment on all the measured features of the HDM allergic airways reaction in their offspring. We conclude that maternal L.rhamnosus administration prevents Th2-type allergic airways disease in their neonates by favoring splenic cDC1/Th1 responses against ALUM-adjuvanted OVA or by promoting a pulmonary Foxp3+RORγt+ Treg activation against inhaled HDM.

Aconitate decarboxylase 1 participates in the control of pulmonary Brucella infection in mice.

Brucellosis is one of the most widespread bacterial zoonoses worldwide. Here, our aim was to identify the effector mechanisms controlling the early stages of intranasal infection with Brucella in C57BL/6 mice. During the first 48 hours of infection, alveolar macrophages (AMs) are the main cells infected in the lungs. Using RNA sequencing, we identified the aconitate decarboxylase 1 gene (Acod1; also known as Immune responsive gene 1), as one of the genes most upregulated in murine AMs in response to B. melitensis infection at 24 hours post-infection. Upregulation of Acod1 was confirmed by RT-qPCR in lungs infected with B. melitensis and B. abortus. We observed that Acod1-/- C57BL/6 mice display a higher bacterial load in their lungs than wild-type (wt) mice following B. melitensis or B. abortus infection, demonstrating that Acod1 participates in the control of pulmonary Brucella infection. The ACOD1 enzyme is mostly produced in mitochondria of macrophages, and converts cis-aconitate, a metabolite in the Krebs cycle, into itaconate. Dimethyl itaconate (DMI), a chemically-modified membrane permeable form of itaconate, has a dose-dependent inhibitory effect on Brucella growth in vitro. Interestingly, structural analysis suggests the binding of itaconate into the binding site of B. abortus isocitrate lyase. DMI does not inhibit multiplication of the isocitrate lyase deletion mutant ΔaceA B. abortus in vitro. Finally, we observed that, unlike the wt strain, the ΔaceA B. abortus strain multiplies similarly in wt and Acod1-/- C57BL/6 mice. These data suggest that bacterial isocitrate lyase might be a target of itaconate in AMs.

Improvements in Upper Extremity Function Following Intensive Training Are Independent of Corticospinal Tract Organization in Children With Unilateral Spastic Cerebral Palsy: A Clinical Randomized Trial.

Background/Objectives: Intensive training of the more affected upper extremity (UE) has been shown to be effective for children with unilateral spastic cerebral palsy (USCP). Two types of UE training have been particularly successful: Constraint-Induced Movement Therapy (CIMT) and Bimanual training. Reorganization of the corticospinal tract (CST) early during development often occurs in USCP. Prior studies have suggested that children with an ipsilateral CST controlling the affected UE may improve less following CIMT than children with a contralateral CST. We tested the hypothesis that improvements in UE function after intensive training depend on CST laterality. Study Participants and Setting: Eighty-two children with USCP, age 5 years 10 months to 17 years, University laboratory setting. Materials/Methods: Single-pulse transcranial magnetic stimulation (TMS) was used to determine each child's CST connectivity pattern. Children were stratified by age, sex, baseline hand function and CST connectivity pattern, and randomized to receive either CIMT or Bimanual training, each of which were provided in a day-camp setting (90 h). Hand function was tested before, immediately and 6 months after the intervention with the Jebsen-Taylor Test of Hand Function, the Assisting Hand Assessment, the Box and Block Test, and ABILHAND-Kids. The Canadian Occupational Performance Measure was used to track goal achievement and the Pediatric Evaluation of Disability Inventory was used to assess functioning in daily living activities at home. Results: In contrast to our hypothesis, participants had statistically similar improvements for both CIMT and Bimanual training for all measures independent of their CST connectivity pattern (contralateral, ipsilateral, or bilateral) (p < 0.05 in all cases). Conclusions/Significance: The efficacy of CIMT and Bimanual training is independent of CST connectivity pattern. Children with an ipsilateral CST, previously thought to be maladaptive, have the capacity to improve as well as children with a contralateral or bilateral CST following intensive CIMT or Bimanual training. Clinical Trial Registration: www.ClinicalTrials.gov, identifier NCT02918890.

Very early-life exposure to microbiota-induced TNF drives the maturation of neonatal pre-cDC1.

OBJECTIVE: Induction of immune protection against pathogens is particularly crucial during the neonatal period dominated by anti-inflammatory and tolerance immunity. The preclinical study was carried out to determine whether environmental factors such as microbiota may influence early life immunity by impacting the development and the functional maturation of precursors of type 1 conventional dendritic cells (pre-cDC1), endowed with regulatory properties. DESIGN: Pre-cDC1 phenotype and cytokine expression in the spleen of neonates from antibiotic-treated mothers were established. The role of myeloid-derived tumour necrosis factor (TNF) was tested in vitro and in vivo. RNA sequencing analysis on neonatal sorted pre-cDC1 was performed. The early life protective CD8+ T-cell response against Listeria monocytogenes was monitored. RESULTS: We observed that first exposure to microbiota promotes TNF secretion by monocytes and macrophages shortly after birth. We demonstrated that this myeloid-derived inflammatory cytokine is crucial to induce the maturation of these neonatal regulatory pre-cDC1. Myeloid TNF signalling acts on C1q and ß-catenin pathway and modifies the fatty acid metabolism in neonatal pre-cDC1. Furthermore, we showed that during neonatal L. monocytogenes infection, microbiota-associated myeloid TNF promotes the capacity of these pre-cDC1 to induce protective CD8+ T-cell responses, by modulating their ability to secrete interleukin-10 (IL-10) and IL-12p40. CONCLUSION: Our findings emphasise the role of microbiota-derived TNF to kick-start the differentiation and the functional maturation of the neonatal splenic pre-cDC1 compartment. They bring a better understanding of potential mechanisms underlying some microbiota-linked immune dysfunction in early life.

Myeloid tumor necrosis factor and heme oxygenase-1 regulate the progression of colorectal liver metastases during hepatic ischemia-reperfusion.

The liver ischemia-reperfusion (IR) injury that occurs consequently to hepatic resection performed in patients with metastases can lead to tumor relapse for not fully understood reasons. We assessed the effects of liver IR on tumor growth and the innate immune response in a mouse model of colorectal (CR) liver metastasis. Mice subjected to liver ischemia 2 days after intrasplenic injection of CR carcinoma cells displayed a higher metastatic load in the liver, correlating with Kupffer cells (KC) death through the activation of receptor-interating protein 3 kinase (RIPK3) and caspase-1 and a recruitment of monocytes. Interestingly, the immunoregulatory mediators, tumor necrosis factor-α (TNF-α) and heme oxygenase-1 (HO-1) were strongly upregulated in recruited monocytes and were also expressed in the surviving KC following IR. Using TNFflox/flox LysMcre/wt mice, we showed that TNF deficiency in macrophages and monocytes favors tumor progression after IR. The antitumor effect of myeloid cell-derived TNF involved direct tumor cell apoptosis and a reduced expression of immunosuppressive molecules such as transforming growth factor-ß, interleukin (IL)-10, inducible nitric oxyde synthase (iNOS), IL-33 and HO-1. Conversely, a monocyte/macrophage-specific deficiency in HO-1 (HO-1flox/flox LysMcre/wt ) or the blockade of HO-1 function led to the control of tumor progression post-liver IR. Importantly, host cell RIPK3 deficiency maintains the KC number upon IR, inhibits the IR-induced innate cell recruitment, increases the TNF level, decreases the HO-1 level and suppresses the tumor outgrowth. In conclusion, tumor recurrence in host undergoing liver IR is associated with the death of antitumoral KC and the recruitment of monocytes endowed with immunosuppressive properties. In both of which HO-1 inhibition would reinforce their antitumoral activity.

Hepatocarcinoma Induces a Tumor Necrosis Factor-Dependent Kupffer Cell Death Pathway That Favors Its Proliferation Upon Partial Hepatectomy.

Partial hepatectomy (PH) is the main treatment for early-stage hepatocellular carcinoma (HCC). Yet, a significant number of patients undergo recursion of the disease that could be linked to the fate of innate immune cells during the liver regeneration process. In this study, using a murine model, we investigated the impact of PH on HCC development by bioluminescence imaging and flow cytometry. While non-resected mice were able to control and reject orthotopic implanted Hepa1-6 hepatocarcinoma cells, resected liver underwent an increased tumoral proliferation. This phenomenon was associated with a PH-induced reduction in the number of liver-resident macrophages, i.e., Kupffer cells (KC). Using a conditional ablation model, KC were proved to participate in Hepa1-6 rejection. We demonstrated that in the absence of Hepa1-6, PH-induced KC number reduction was dependent on tumor necrosis factor-alpha (TNF-α), receptor-interacting protein kinase (RIPK) 3, and caspase-8 activation, whereas interleukin (IL)-6 acted as a KC pro-survival signal. In mice with previous Hepa1-6 encounter, the KC reduction switched toward a TNF-α-RIPK3-caspase-1 activation. Moreover, KC disappearance associated with caspase-1 activity induced the recruitment of monocyte-derived cells that are beneficial for tumor growth, while caspase-8-dependent reduction did not. In conclusion, our study highlights the importance of the TNF-α-dependent death pathway induced in liver macrophages following partial hepatectomy in regulating the antitumoral immune responses.

Anatomical and Functional Characterization in Children With Unilateral Cerebral Palsy: An Atlas-Based Analysis.

Background. Variability in hand function among children with unilateral cerebral palsy (UCP) might reflect the type of brain injury and resulting anatomical sequelae. Objective. We used atlas-based analysis of structural images to determine whether children with periventricular (PV) versus middle cerebral artery (MCA) injuries might exhibit unique anatomical characteristics that account for differences in hand function. Methods. Forty children with UCP underwent structural brain imaging using 3-T magnetic resonance imaging. Brain lesions were classified as PV or MCA. A group of 40 typically developing (TD) children served as comparison controls. Whole brains were parcellated into 198 structures (regions of interest) to obtain volume estimates. Dexterity and bimanual hand function were assessed. Unbiased, differential expression analysis was performed to determine volumetric differences between PV and MCA groups. Principal component analysis (PCA) was performed and the top 3 components were extracted to perform regression on hand function. Results. Children with PV had significantly better hand function than children with MCA. Multidimensional scaling analysis of volumetric data revealed separate clustering of children with MCA, PV, and TD children. PCA extracted anatomical components that comprised the 2 types of brain injury. In the MCA group, reductions of volume were concentrated in sensorimotor structures of the injured hemisphere. Models using PCA predicted hand function with greater accuracy than models based on qualitative brain injury type. Conclusions. Our results highlight unique quantitative differences in children with UCP that also predict differences in hand function. The systematic discrimination between groups found in our study reveals future questions about the potential prognostic utility of this approach.

Donor-Derived Myeloid Heme Oxygenase-1 Controls the Development of Graft-Versus-Host Disease.

Graft-versus-host disease (GVHD) remains a major clinical drawback of allogeneic hematopoietic stem cell transplantation (HSCT). Here, we investigated how the stress responsive heme catabolizing enzyme heme oxygenase-1 (HO-1, encoded by HMOX1) regulates GVHD in response to allogeneic hematopoietic stem cell transplantation in mice and humans. We found that deletion of the Hmox1 allele, specifically in the myeloid compartment of mouse donor bone marrow, promotes the development of aggressive GVHD after allogeneic transplantation. The mechanism driving GVHD in mice transplanted with allogeneic bone marrow lacking HO-1 expression in the myeloid compartment involves enhanced T cell alloreactivity. The clinical relevance of these observations was validated in two independent cohorts of HSCT patients. Individuals transplanted with hematopoietic stem cells from donors carrying a long homozygous (GT)n repeat polymorphism (L/L) in the HMOX1 promoter, which is associated with lower HO-1 expression, were at higher risk of developing severe acute GVHD as compared to donors carrying a short (GT)n repeat (S/L or S/S) polymorphism associated with higher HO-1 expression. In this study, we showed the unique importance of donor-derived myeloid HO-1 in the prevention of lethal experimental GVHD and we corroborated this observation by demonstrating the association between human HMOX1 (GT)n microsatellite polymorphisms and the incidence of severe acute GVHD in two independent HSCT patient cohorts. Donor-derived myeloid HO-1 constitutes a potential therapeutic target for HSCT patients and large-scale prospective studies in HSCT patients are necessary to validate the HO-1 L/L genotype as an independent risk factor for developing severe acute GVHD.

HO-1 mitigates acute kidney injury and subsequent kidney-lung cross-talk.

Ischemia-reperfusion injury (IRI) is a leading cause of acute kidney injury (AKI), which contributes to the development of chronic kidney disease (CKD). IRI-induced AKI releases proinflammatory cytokines (e.g. IL-1ß, TNF-α, IL-6) that induce a systemic inflammatory response, resulting in proinflammatory cells recruitment and remote organ damage. AKI is associated with poor outcomes, particularly when extrarenal complications or distant organ injuries occur. Acute lung injury (ALI) is a major remote organ dysfunction associated with AKI. Hence, kidney-lung cross-talk remains a clinical challenge, especially in critically ill population. The stress-responsive enzyme, heme oxygenase-1 (HO-1) is largely known to protect against renal IRI and may be preventively induced using hemin prior to renal insult. However, the use of hemin-induced HO-1 to prevent AKI-induced ALI remains poorly investigated. Mice received an intraperitoneal injection of hemin or sterile saline 1 day prior to surgery. Twenty-four hours later, mice underwent bilateral renal IRI for 26 min or sham surgery. After 4 or 24 h of reperfusion, mice were sacrificed. Hemin-induced HO-1 improved renal outcomes after IRI (i.e. fewer renal damage, renal inflammation, and oxidative stress). This protective effect was associated with a dampened systemic inflammation (i.e. IL-6 and KC). Subsequently, mitigated lung inflammation was found in hemin-treated mice (i.e. neutrophils influx and lung KC). The present study demonstrates that hemin-induced HO-1 controls the magnitude of renal IRI and the subsequent AKI-induced ALI. Therefore, targeting HO-1 represents a promising approach to prevent the impact of renal IRI on distant organs, such as lung.

Dual effect of hemin on renal ischemia-reperfusion injury.

Acute kidney injury (AKI) is a major public health concern, which is contributing to serious hospital complications, chronic kidney disease (CKD) and even death. Renal ischemia-reperfusion injury (IRI) remains a leading cause of AKI. The stress-responsive enzyme, heme oxygenase-1 (HO-1) mediates protection against renal IRI and may be preventively induced using hemin prior to renal insult. This HO-1 induction pathway called hemin preconditioning is largely known to be effective. Therefore, HO-1 might be an interesting therapeutic target in case of predictable AKI (e.g. partial nephrectomy or renal transplantation). However, the use of hemin to mitigate established AKI remains poorly characterized. Mice underwent bilateral renal IRI for 26 min or sham surgery. After surgical procedure, animals were injected either with hemin (5 mg/kg) or vehicle. Twenty-four hours later, mice were sacrificed. Despite strong HO-1 induction, hemin-treated mice exhibited significant renal damage and oxidative stress as compared to vehicle-treated mice. Interestingly, higher dose of hemin is associated with more severe IRI-induced AKI in a dose-dependent relation. To determine whether hemin preconditioning remains efficient to dampen postoperative hemin-amplified IRI-induced AKI, we pretreated mice either with hemin (5 mg/kg) or vehicle 24 h prior to surgical procedure. Then, all mice (hemin- and vehicle-pretreated) received postoperative injection of hemin (5 mg/kg) to amplify IRI-induced AKI. In comparison to vehicle, prior administration of hemin to renal IRI mitigated hemin-amplified IRI-induced AKI as attested by fewer renal damage, inflammation and oxidative stress. In conclusion, hemin may have a dual effect on renal IRI, protective or deleterious, depending on the timing of its administration.

Altered transcallosal inhibition evidenced by transcranial magnetic stimulation highlights neurophysiological consequences of premature birth in early adulthood.

BACKGROUND AND OBJECTIVE: A very preterm birth can induce deleterious neurophysiological consequences beyond childhood; alterations of the corpus callosum (CC) are reported in adolescents born very preterm along with cognitive impairments. The question remains whether neurophysiological alterations are still detectable in adulthood such as an alteration in CC inhibitory function. The aim of the present study was thus to examine transcallosal inhibition in young adults born very preterm compared to counterparts born at term. STUDY PARTICIPANTS & METHODS: Transcallosal inhibition was probed by measuring the ipsilateral silent period (iSP) using transcranial magnetic stimulation (TMS) in 13 young adults born at 33w of gestation or less (20 ±â€¯3. 2y) and 12 young adults born at term (22 ±â€¯1. 75y). Single high-intensity TMS were delivered to the primary motor cortex (M1) ipsilateral to the preactivated first dorsal interosseous (FDI) muscle. Occurrence, latency, and duration of iSP were measured in the FDI EMG activity, for both hemispheres alternatively (10-12 trials each) along with their resting motor threshold (RMT). RESULTS: In individuals born very preterm as compared to individuals born at term, ISP occurred less frequently (p < .0001), its latency was longer (p = .004), especially in the non-dominant hemisphere, its duration shorter (p < .0001), and RMT was higher in the non-dominant M1 than in the dominant. CONCLUSIONS: Impairment of transcallosal inhibition along with asymmetry of M1 excitability in young adults born very preterm as compared to those born at term underline that neurophysiological consequences of a preterm birth can still be detected in early adulthood.