The p110δ isoform of the kinase PI(3)K controls the subcellular compartmentalization of TLR4 signaling and protects from endotoxic shock.

Lipopolysaccharide activates plasma-membrane signaling and endosomal signaling by Toll-like receptor 4 (TLR4) through the TIRAP-MyD88 and TRAM-TRIF adaptor complexes, respectively, but it is unclear how the signaling switch between these cell compartments is coordinated. In dendritic cells, we found that the p110δ isoform of phosphatidylinositol-3-OH kinase (PI(3)K) induced internalization of TLR4 and dissociation of TIRAP from the plasma membrane, followed by calpain-mediated degradation of TIRAP. Accordingly, inactivation of p110δ prolonged TIRAP-mediated signaling from the plasma membrane, which augmented proinflammatory cytokine production while decreasing TRAM-dependent endosomal signaling that generated anti-inflammatory cytokines (interleukin 10 and interferon-ß). In line with that altered signaling output, p110δ-deficient mice showed enhanced endotoxin-induced death. Thus, by controlling the 'topology' of TLR4 signaling complexes, p110δ balances overall homeostasis in the TLR4 pathway.

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.

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.

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.

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.

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.

IL-12p40/IL-10 Producing preCD8α/Clec9A+ Dendritic Cells Are Induced in Neonates upon Listeria monocytogenes Infection.

Infection by Listeria monocytogenes (Lm) causes serious sepsis and meningitis leading to mortality in neonates. This work explored the ability of CD11c(high) lineage DCs to induce CD8+ T-cell immune protection against Lm in mice before 7 days of life, a period symbolized by the absence of murine IL-12p70-producing CD11c(high)CD8α+ dendritic cells (DCs). We characterized a dominant functional Batf3-dependent precursor of CD11c(high) DCs that is Clec9A+CD205+CD24+ but CD8α- at 3 days of life. After Lm-OVA infection, these pre-DCs that cross-present Ag display the unique ability to produce high levels of IL-12p40 (not IL-12p70 nor IL-23), which enhances OVA-specific CD8+ T cell response, and regulatory IL-10 that limits OVA-specific CD8+ T cell response. Targeting these neonatal pre-DCs for the first time with a single treatment of anti-Clec9A-OVA antibody in combination with a DC activating agent such as poly(I:C) increased the protection against later exposure to the Lm-OVA strain. Poly(I:C) was shown to induce IL-12p40 production, but not IL-10 by neonatal pre-DCs. In conclusion, we identified a new biologically active precursor of Clec9A+ CD8α- DCs, endowed with regulatory properties in early life that represents a valuable target to augment memory responses to vaccines.

Elucidating the neural circuitry underlying planning of internally-guided voluntary action.

In an attempt to elucidate the neural circuitry of planning of internally guided voluntary action, Ariani et al. (2015) used a delayed-movement design and multivariate pattern analysis of functional MRI data and found areas decoding internally elicited action plans, stimulus-elicited action plans, and both types of plans. In interpreting their results in the context of a heuristic decision model of voluntary action, encompassing "what" action to perform, "when" to perform it, and "whether" to perform it at all, we highlight at least some neural dissociation of these components. More to that, we note that the exact neural circuitry of each component might vary depending on the performed action type, and finally, we underscore the importance of understanding the temporal specifics of such circuitries to further elucidate how they are involved and interact during voluntary action planning.

Forskolin Inhibits Lipopolysaccharide-Induced Modulation of MCP-1 and GPR120 in 3T3-L1 Adipocytes through an Inhibition of NFκB.

In an obese state, Toll-like receptor-4 (TLR-4) upregulates proinflammatory adipokines secretion including monocyte chemotactic protein-1 (MCP-1) in adipose tissue. In contrast, G-protein coupled receptor 120 (GPR120) mediates antiobesity effects. The aim of this study was to determine the signaling pathway by which Forskolin (FK), a cyclic adenosine monophosphate- (cAMP-) promoting agent causing positive changes in body composition in overweight and obese adult men, affects MCP-1 and GPR120 expression during an inflammatory response induced by lipopolysaccharide (LPS) in adipocytes, such as in an obese state. 3T3-L1 cells differentiated into adipocytes (DC) were stimulated with LPS in the absence or presence of FK and inhibitors of TLR-4 and inhibitor of kappa B (IκBα). In DC, LPS increased MCP-1, TLR-4, and nuclear factor-κB1 (NFκB1) mRNA levels, whereas it decreased GPR120 mRNA levels. In DC, FK inhibited the LPS-induced increase in MCP-1, TLR-4, and NFκB1 mRNA levels and the LPS-induced decrease in GPR120 mRNA. BAY11-7082 and CLI-095 abolished these LPS-induced effects. In conclusion, FK inhibits LPS-induced increase in MCP-1 mRNA levels and decrease in GPR120 mRNA levels in adipocytes and may be a potential treatment for inflammation in obesity. Furthermore, TLR-4-induced activation of NFκB may be involved in the LPS-induced regulation of these genes.

Neonatal follicular Th cell responses are impaired and modulated by IL-4.

Newborns are characterized by poor responses to vaccines. Defective B cell responses and a Th2-type polarization can account for this impaired protection in early life. We in this study investigated the generation of follicular Th (TFH) cells, involved in the development of Ab response and germinal center reaction, upon vaccination in neonates. We showed that, compared with adults, Ab production, affinity maturation, and germinal center formation were reduced in neonates immunized with OVA-aluminum hydroxide. Although this vaccination induced CD4(+) CXCR5(+) PD-1(+) TFH cells in newborns, their frequency, as well as their Bcl6 expression and IL-21 and IL-4 mRNA induction, was decreased in early life. Moreover, neonatal TFH cells were mainly localized in interfollicular regions of lymphoid tissues. The prototypic Th2 cytokine IL-4 was found to promote the emergence and the localization in germinal centers of neonatal TFH cells, as well as the neonatal germinal center reaction itself. In addition, IL-4 dampened expression of Th17-related molecules in neonatal TFH cells, as TFH cells from immunized IL-4-deficient neonates displayed enhanced expression of RORγt and IL-17. This Th17-like profile correlated with an increased secretion of OVA-specific IgG2a. Our study thus suggests that defective humoral immunity in early life is associated with limited and IL-4-modulated TFH cell responses.

Interferon regulatory factor 3 deficiency leads to interleukin-17-mediated liver ischemia-reperfusion injury.

UNLABELLED: Interferon regulatory factor 3 (IRF3) is an important transcription factor in Toll-like receptor 4 (TLR4) signaling, a pathway that is known to play a critical role in liver ischemia-reperfusion injury. In order to decipher the involvement of IRF3 in this setting, we first compared the intensity of hepatic lesions in IRF3-deficient versus wildtype mice. We found increased levels of blood transaminases, enhanced liver necrosis, and more pronounced neutrophil infiltrates in IRF3-deficient mice. Neutrophil depletion by administration of anti-Ly6G monoclonal antibody indicated that neutrophils play a dominant role in the development of severe liver necrosis in IRF3-deficient mice. Quantification of cytokine genes expression revealed increased liver expression of interleukin (IL)-12/IL-23p40, IL-23p19 messenger RNA (mRNA), and IL-17A mRNA in IRF3-deficient versus wildtype (WT) mice, whereas IL-27p28 mRNA expression was diminished in the absence of IRF3. The increased IL-17 production in IRF3-deficient mice was functionally relevant, as IL-17 neutralization prevented the enhanced hepatocellular damages and liver inflammation in these animals. Evidence for enhanced production of IL-23 and decreased accumulation of IL-27 cytokine in M1 type macrophage from IRF3-deficient mice was also observed after treatment with lipopolysaccharide, a setting in which liver gamma-delta T cells and invariant natural killer T cells were found to be involved in IL-17A hyperproduction. CONCLUSION: IRF3-dependent events downstream of TLR4 control the IL-23/IL-17 axis in the liver and this regulatory role of IRF3 is relevant to liver ischemia-reperfusion injury.

Noninvasive and painless magnetic stimulation of nerves improved brain motor function and mobility in a cerebral palsy case.

Motor deficits in cerebral palsy disturb functional independence. This study tested whether noninvasive and painless repetitive peripheral magnetic stimulation could improve motor function in a 7-year-old boy with spastic hemiparetic cerebral palsy. Stimulation was applied over different nerves of the lower limbs for 5 sessions. We measured the concurrent aftereffects of this intervention on ankle motor control, gait (walking velocity, stride length, cadence, cycle duration), and function of brain motor pathways. We observed a decrease of ankle plantar flexors resistance to stretch, an increase of active dorsiflexion range of movement, and improvements of corticospinal control of ankle dorsiflexors. Joint mobility changes were still present 15 days after the end of stimulation, when all gait parameters were also improved. Resistance to stretch was still lower than prestimulation values 45 days after the end of stimulation. This case illustrates the sustained effects of repetitive peripheral magnetic stimulation on brain plasticity, motor function, and gait. It suggests a potential impact for physical rehabilitation in cerebral palsy.

[Neonatal tolerance to alloantigens]. / La tolérance néonatale aux allo-antigènes.

In early life, our immune system has the characteristics of tolerance to alloantigens. During this period, our adaptive immunity is not at rest. On the contrary, it is polarized so as to promote the activation of Th2-type T cell response at the expense of cytotoxic Th1- or Th17-type responses. This may explain the vulnerability of infants to aggression by pathogens, their increased sensitivity to develop allergic diseases or their poor responses to some vaccines. Exposure to environmental factors will modify that neonatal tolerance due to its control by other actors and will thus have potential repercussions on the subsequent onset of allergies or autoimmune diseases.

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.

Usability of mechanical assistive technologies for performing activities involving the upper extremities in individuals with impairments: a systematic review.

PURPOSE: To conduct a systematic review on the impacts of using mechanical assistive devices on function, performance in activities and participation of persons with upper extremity impairments, and to synthesize the strengths and limitations of these devices. METHOD: Three independent reviewers conducted systematic searches of articles published between 2003 and 2023 in Compendex, Inspec, Embase, PubMed/Medline, IEEE Xplore, and Web of Science, as well as manual searches on the RESNA website for conference papers over the same period. The methodological quality of articles was appraised using the QualSyst tool. RESULTS: From the 34 retained studies, 28 mechanical devices were identified and classified into two categories: (1) mobile arm supports (MASs) designed to perform multiple activities, and (2) devices used to assist with a specific activity of daily living (ADL). Overall, MASs helped users to perform manual activities in elevation and/or against gravity. Specific ADL devices allowed users to perform unique activities requiring fine motor skills such as opening a medicine container. Some of these devices have advantages like portability, adaptability, low cost, and ease of use. Limitations most often reported included interference or mobility restraints. CONCLUSION: This review synthesizes the impacts of mechanical devices on the three domains of the International Classification of Functioning, Disability and Health (ICF) for individuals with upper extremity impairments. Impacts regarding function and performance in activities were more often measured than participation. Future studies should include outcomes related to participation, as taking this aspect into account might favor successful continued use of assistive devices.

Mechanical mobile arm supports can compensate for upper extremity muscle weakness and help users to perform diverse activities against gravity, including self-care, productivity and leisure activities.Mechanical assistive devices designed for specific activities of daily living (ADLs) can increase users' ability to perform activities requiring manual dexterity and fine motor skills, such as eating, handwriting, performing personal care or playing a musical instrument.Portability, adaptability, low cost, and ease of use are most often reported as strengths of specific ADL devices, while interference and mobility restrictions are aspects that still need to be reduced with respect to mechanical mobile arm supports.

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.

Corticomotor control of deep abdominal muscles in chronic low back pain and anticipatory postural adjustments.

Contralateral transversus abdominis muscle (cTrA) is known to be anticipatory to rapid focal movement. The activation of ipsilateral TrA (iTrA) follows cTrA, but their anticipatory interaction in healthy subjects seems to be delayed in low back pain (LBP) patients. TrA delay in LBP is linked with reorganization of the primary motor cortex (M1), thus supporting that cortical changes underlie the altered postural control. Our study tested whether differences in postural adjustments were present in LBP for TrA onsets and co-activation, and whether these differences were paralleled by cortical motor changes. Thirteen chronic LBP patients and 9 healthy Controls were enrolled. Surface recordings of cTrA/internal oblique (IO) and iTrA/IO were collected during a rapid shoulder flexion task while standing. Transcranial magnetic stimulation of M1 tested TrA/IO corticospinal excitability, active motor threshold and short-interval intracortical inhibition (SICI). In LBP compared to Controls, iTrA/IO activation was delayed, co-activation was absent, timing between TrA/IO onsets was impaired, and SICI was missing. Between-outcomes correlations observed in one group were not significant in the other. Delay of iTrA/IO and the lacking co-activation were not explained by between-group differences of transcranial magnetic stimulation outcomes. TrA/IO co-activation is present during rapid focal movement in healthy subjects only. LBP patients displayed an important alteration of the control of spine stability that can be explained by altered mechanisms of M1 motor programming.

Regulation of Th2 responses and allergic inflammation through bystander activation of CD8+ T lymphocytes in early life.

Th2-biased immune responses characterizing neonates may influence the later onset of allergic disease. The contribution of regulatory T cell populations in the prevention of Th2-driven pathologies in early life is poorly documented. We investigated the potential of CD8(+) T cells stimulated at birth with alloantigens to modulate the development of allergic airway inflammation. Newborn mice were immunized with semiallogeneic splenocytes or dendritic cells (DCs) and exposed at the adult stage to OVA aeroallergens. DC-immunized animals displayed a strong Th1 and Tc1/Tc2 alloantigen-specific response and were protected against the development of the allergic reaction with reduced airway hyperresponsiveness, mucus production, eosinophilia, allergen-specific IgE and IgG(1), and reduction of lung IL-4, IL-5, IL-10, and IL-13 mRNA levels. By contrast, splenocyte-immunized mice displayed a Th2 and a weak Tc2 alloantigen-specific response and were more sensitive to the development of the allergen-specific inflammation compared with mice unexposed at birth to alloantigens. DC-immunized animals displayed an important increase in the percentage of IFN-gamma-producing CD8(+)CD44(high), CD8(+)CD62L(high), and CD8(+)CD25(+) subsets. Adoptive transfers of CD8(+) T cells from semiallogeneic DC-immunized animals to adult beta(2)m-deficient animals prevented the development of allergic response, in particular IgE, IL-4, and IL-13 mRNA production in an IFN-gamma-dependent manner, whereas transfers of CD8(+) T cells from semiallogeneic splenocyte-immunized mice intensified the lung IL-4 and IL-10 mRNA level and the allergen-specific IgE. These findings demonstrated that neonatal induction of regulatory CD8(+) T cells was able to modulate key parameters of later allergic sensitization in a bystander manner, without recognition of MHC class I molecules.