Newborn hearing screening failure and maternal factors during pregnancy.

OBJECTIVE: Temporary conductive hearing loss due to amniotic fluid accumulation in the middle ear cavity may lead to failure (false positive) in newborn hearing screening tests. The aim of this study was to identify whether amniotic fluid index has association with failure of the initial newborn otoacoustic emission (OAE) screening test. METHODS: A cohort study in a tertiary hospital center (Royal Victoria Hospital, Montréal) was constructed from 70 newborns that failed the OAE test, but passed a subsequent auditory brainstem response (ABR) test, and 75 randomly selected newborns that passed initial otoacoustic emission testing. Maternal (including the amniotic fluid index in the third trimester) and newborn clinical data were extracted from medical records. Statistical association models were built to determine variables that influenced hearing screen passage or failure. RESULTS: The two arms of the cohort had no significant differences in maternal or child clinical indices, including in amniotic fluid index. Calculated as individual odds ratios, maternal tobacco [95% CI of odds ratio: 0.04, 0.59, p = 0.0078], and drug use [95% CI of odds ratio: 0.0065, 0.72, p = 0.058] [borderline significance] were associated with failing the otoacoustic emission testing. CONCLUSIONS: Amniotic fluid index was not found to be associated with failure of otoacoustic emission screening in newborns. However, our study unveiled an interesting unexpected association of OAE failure with maternal smoking and/or drug use. This finding can help alleviate some of the time, cost and parental anxiety related to failed OAE screening. In selected cases of maternal smoking or drug use we might want to replace or add OAE to the ABR test in newborn hearing screening protocols, that don't perform both tests before discharge.

Corrigendum: Semaphorin 4C: A Novel Component of B-Cell Polarization in Th2-Driven Immune Responses.

[This corrects the article on p. 558 in vol. 7, PMID: 28003812.].

Peripherally Generated Foxp3+ Regulatory T Cells Mediate the Immunomodulatory Effects of IVIg in Allergic Airways Disease.

IVIg is widely used as an immunomodulatory therapy. We have recently demonstrated that IVIg protects against airway hyperresponsiveness (AHR) and inflammation in mouse models of allergic airways disease (AAD), associated with induction of Foxp3+ regulatory T cells (Treg). Using mice carrying a DTR/EGFP transgene under the control of the Foxp3 promoter (DEREG mice), we demonstrate in this study that IVIg generates a de novo population of peripheral Treg (pTreg) in the absence of endogenous Treg. IVIg-generated pTreg were sufficient for inhibition of OVA-induced AHR in an Ag-driven murine model of AAD. In the absence of endogenous Treg, IVIg failed to confer protection against AHR and airway inflammation. Adoptive transfer of purified IVIg-generated pTreg prior to Ag challenge effectively prevented airway inflammation and AHR in an Ag-specific manner. Microarray gene expression profiling of IVIg-generated pTreg revealed upregulation of genes associated with cell cycle, chromatin, cytoskeleton/motility, immunity, and apoptosis. These data demonstrate the importance of Treg in regulating AAD and show that IVIg-generated pTreg are necessary and sufficient for inhibition of allergen-induced AAD. The ability of IVIg to generate pure populations of highly Ag-specific pTreg represents a new avenue to study pTreg, the cross-talk between humoral and cellular immunity, and regulation of the inflammatory response to Ags.

Semaphorin 4C Protects against Allergic Inflammation: Requirement of Regulatory CD138+ Plasma Cells.

The regulatory properties of B cells have been studied in autoimmune diseases; however, their role in allergic diseases is poorly understood. We demonstrate that Semaphorin 4C (Sema4C), an axonal guidance molecule, plays a crucial role in B cell regulatory function. Mice deficient in Sema4C exhibited increased airway inflammation after allergen exposure, with massive eosinophilic lung infiltrates and increased Th2 cytokines. This phenotype was reproduced by mixed bone marrow chimeric mice with Sema4C deficient only in B cells, indicating that B lymphocytes were the key cells affected by the absence of Sema4C expression in allergic inflammation. We determined that Sema4C-deficient CD19+CD138+ cells exhibited decreased IL-10 and increased IL-4 expression in vivo and in vitro. Adoptive transfer of Sema4c-/- CD19+CD138+ cells induced marked pulmonary inflammation, eosinophilia, and increased bronchoalveolar lavage fluid IL-4 and IL-5, whereas adoptive transfer of wild-type CD19+CD138+IL-10+ cells dramatically decreased allergic airway inflammation in wild-type and Sema4c-/- mice. This study identifies a novel pathway by which Th2-mediated immune responses are regulated. It highlights the importance of plasma cells as regulatory cells in allergic inflammation and suggests that CD138+ B cells contribute to cytokine balance and are important for maintenance of immune homeostasis in allergic airways disease. Furthermore, we demonstrate that Sema4C is critical for optimal regulatory cytokine production in CD138+ B cells.

Semaphorin 4C: A Novel Component of B-Cell Polarization in Th2-Driven Immune Responses.

BACKGROUND: Semaphorins are important molecules in embryonic development and multiple semaphorins have been identified as having key roles in immune regulation. To date, there is little known about Semaphorin 4C (Sema4C) in immune biology. We report for the first time that Sema4C is inducible in human and murine B-cells and may be important for normal B-cell development. METHODS: Human tonsillar B-cells were studied following activation via anti-CD40 antibodies in the presence or absence of representative Th1, Th2, and regulatory cytokines. Murine B-cells from WT and Sema4C-/- mice were similarly stimulated. B-cell phenotyping in WT and Sema4C mutant mice was performed by flow cytometry and lymphoid architecture was studied by immunohistochemistry. Sema4C expression and synapse formation were analyzed by confocal microscopy. RESULTS: Gene array studies performed on human tonsillar B-cells stimulated to produce IgE revealed that Sema4C was among the top genes expressed at 24 h, and the only semaphorin to be increased under Th2 conditions. Validation studies demonstrated that human and murine B-cells expressed Sema4C under similar conditions. Sema4C-/- mice had impaired maturation of B-cell follicles in spleens and associated decreases in follicular and marginal zone B-cells as well as impaired IgG and IgA production. In keeping with a potential role in maturation of B-cells, Sema4C was expressed predominantly on CD27+ human B-cells. Within 72 h of B-cell activation, Sema4C was localized to one pole in a synapse-like structure, in association with F-actin, B-cell receptor, and Plexin-B2. Cell polarization was impaired in Sema4C-/- mice. CONCLUSION: We have identified a novel immune semaphorin induced in human and murine B-cells under Th2 conditions. Sema4C appears to be a marker for human memory B-cells. It may be important for B-cell polarization and for the formation of normal splenic follicles.

Induction of Regulatory T Cells by Intravenous Immunoglobulin: A Bridge between Adaptive and Innate Immunity.

Intravenous immunoglobulin (IVIg) is a polyclonal immunoglobulin G preparation with potent immunomodulatory properties. The mode of action of IVIg has been investigated in multiple disease states, with various mechanisms described to account for its benefits. Recent data indicate that IVIg increases both the number and the suppressive capacity of regulatory T cells, a subpopulation of T cells that are essential for immune homeostasis. IVIg alters dendritic cell function, cytokine and chemokine networks, and T lymphocytes, leading to development of regulatory T cells. The ability of IVIg to influence Treg induction has been shown both in animal models and in human diseases. In this review, we discuss data on the potential mechanisms contributing to the interaction between IVIg and the regulatory T-cell compartment.

Microarray expression profiling identifies genes with altered expression in Adolescent Idiopathic Scoliosis.

PURPOSE: Adolescent Idiopathic Scoliosis (AIS) is considered a complex genetic disease, in which malfunctioning or dysregulation of one or more genes has been proposed to be responsible for the expressed phenotype. However, to date, no disease causing genes has been identified and the pathogenesis of AIS remains unknown. The aim of this study is, therefore, to identify specific molecules with differing expression patterns in AIS compared to healthy individuals. METHODS: Microarray analysis and quantitative RT-PCR have examined differences in the gene transcription profile between primary osteoblasts derived from spinal vertebrae of AIS patients and those of healthy individuals. RESULTS: There are 145 genes differentially expressed in AIS osteoblasts. A drastic and significant change has been noted particularly in the expression levels of Homeobox genes (HOXB8, HOXB7, HOXA13, HOXA10), ZIC2, FAM101A, COMP and PITX1 in AIS compared to controls. Clustering analysis revealed the interaction of these genes in biological pathways crucial for bone development, in particular in the differentiation of skeletal elements and structural integrity of the vertebrae. CONCLUSIONS: This study reports on the expression of molecules that have not been described previously in AIS. We also provide for the first time gene interaction pathways in AIS pathogenesis. These genes are involved in various bone regulatory and developmental pathways and many of them can be grouped into clusters to participate in a particular biological pathway. Further studies can be built on our findings to further elucidate the association between different biological pathways and the pathogenesis of AIS.

Mesenchymal stem cell transplantation to promote bone healing.

An overall decline in the availability of osteogenic precursor cells and growth factors in the bone marrow microenvironment have been associated with impaired bone formation and osteopenia in humans. The objective of the current study was to determine if transplantation of mesenchymal stromal cells (MSC) from a healthy, young donor mouse into an osteopenic recipient mouse could enhance osseointegration of a femoral implant. MSC harvested from normal young adult mice differentiated into bone forming osteoblasts when cultured on implant grade titanium surfaces ex vivo and promoted bone formation around titanium-coated rods implanted in the femoral canal of osteopenic recipient mice. Micro computed tomographic imaging and histological analyses showed more, better quality, bone in the femur that received the MSC transplant compared with the contra-lateral control femur that received carrier alone. These results provide pre-clinical evidence that MSC transplantation promotes peri-implant bone regeneration and suggest the approach could be used in a clinical setting to enhance bone regeneration and healing in patients with poor quality bone.

Nociceptive tolerance is improved by bradykinin receptor B1 antagonism and joint morphology is protected by both endothelin type A and bradykinin receptor B1 antagonism in a surgical model of osteoarthritis.

INTRODUCTION: Endothelin-1, a vasoconstrictor peptide, influences cartilage metabolism mainly via endothelin receptor type A (ETA). Along with the inflammatory nonapeptide vasodilator bradykinin (BK), which acts via bradykinin receptor B1 (BKB1) in chronic inflammatory conditions, these vasoactive factors potentiate joint pain and inflammation. We describe a preclinical study of the efficacy of treatment of surgically induced osteoarthritis with ETA and/or BKB1 specific peptide antagonists. We hypothesize that antagonism of both receptors will diminish osteoarthritis progress and articular nociception in a synergistic manner. METHODS: Osteoarthritis was surgically induced in male rats by transection of the right anterior cruciate ligament. Animals were subsequently treated with weekly intra-articular injections of specific peptide antagonists of ETA and/or BKB1. Hind limb nociception was measured by static weight bearing biweekly for two months post-operatively. Post-mortem, right knee joints were analyzed radiologically by X-ray and magnetic resonance, and histologically by the OARSI histopathology assessment system. RESULTS: Single local BKB1 antagonist treatment diminished overall hind limb nociception, and accelerated post-operative recovery after disease induction. Both ETA and/or BKB1 antagonist treatments protected joint radiomorphology and histomorphology. Dual ETA/BKB1 antagonism was slightly more protective, as measured by radiology and histology. CONCLUSIONS: BKB1 antagonism improves nociceptive tolerance, and both ETA and/or BKB1 antagonism prevents joint cartilage degradation in a surgical model of osteoarthritis. Therefore, they represent a novel therapeutic strategy: specific receptor antagonism may prove beneficial in disease management.