91 research outputs found
A mathematical model for top-shelf vertigo: the role of sedimenting otoconia in BPPV
Benign Paroxysmal Positional Vertigo (BPPV) is a mechanical disorder of the
vestibular system in which calcite particles called otoconia interfere with the
mechanical functioning of the fluid-filled semicircular canals normally used to
sense rotation. Using hydrodynamic models, we examine the two mechanisms
proposed by the medical community for BPPV: cupulolithiasis, in which otoconia
attach directly to the cupula (a sensory membrane), and canalithiasis, in which
otoconia settle through the canals and exert a fluid pressure across the
cupula. We utilize known hydrodynamic calculations and make reasonable
geometric and physical approximations to derive an expression for the
transcupular pressure exerted by a settling solid particle in
canalithiasis. By tracking settling otoconia in a two-dimensional model
geometry, the cupular volume displacement and associated eye response
(nystagmus) can be calculated quantitatively. Several important features
emerge: 1) A pressure amplification occurs as otoconia enter a narrowing duct;
2) An average-sized otoconium requires approximately five seconds to settle
through the wide ampulla, where is not amplified, which suggests a
mechanism for the observed latency of BPPV; and 3) An average-sized otoconium
beginning below the center of the cupula can cause a volumetric cupular
displacement on the order of 30 pL, with nystagmus of order /s, which
is approximately the threshold for sensation. Larger cupular volume
displacement and nystagmus could result from larger and/or multiple otoconia.Comment: 15 pages, 5 Figures updated, to be published in J. Biomechanic
Bone Marrow Stromal Cell Transplantation Mitigates Radiation-Induced Gastrointestinal Syndrome in Mice
Nuclear accidents and terrorism presents a serious threat for mass casualty. While bone-marrow transplantation might mitigate hematopoietic syndrome, currently there are no approved medical countermeasures to alleviate radiation-induced gastrointestinal syndrome (RIGS), resulting from direct cytocidal effects on intestinal stem cells (ISC) and crypt stromal cells. We examined whether bone marrow-derived adherent stromal cell transplantation (BMSCT) could restitute irradiated intestinal stem cells niche and mitigate radiation-induced gastrointestinal syndrome.Autologous bone marrow was cultured in mesenchymal basal medium and adherent cells were harvested for transplantation to C57Bl6 mice, 24 and 72 hours after lethal whole body irradiation (10.4 Gy) or abdominal irradiation (16-20 Gy) in a single fraction. Mesenchymal, endothelial and myeloid population were characterized by flow cytometry. Intestinal crypt regeneration and absorptive function was assessed by histopathology and xylose absorption assay, respectively. In contrast to 100% mortality in irradiated controls, BMSCT mitigated RIGS and rescued mice from radiation lethality after 18 Gy of abdominal irradiation or 10.4 Gy whole body irradiation with 100% survival (p<0.0007 and p<0.0009 respectively) beyond 25 days. Transplantation of enriched myeloid and non-myeloid fractions failed to improve survival. BMASCT induced ISC regeneration, restitution of the ISC niche and xylose absorption. Serum levels of intestinal radioprotective factors, such as, R-Spondin1, KGF, PDGF and FGF2, and anti-inflammatory cytokines were elevated, while inflammatory cytokines were down regulated.Mitigation of lethal intestinal injury, following high doses of irradiation, can be achieved by intravenous transplantation of marrow-derived stromal cells, including mesenchymal, endothelial and macrophage cell population. BMASCT increases blood levels of intestinal growth factors and induces regeneration of the irradiated host ISC niche, thus providing a platform to discover potential radiation mitigators and protectors for acute radiation syndromes and chemo-radiation therapy of abdominal malignancies
Experimental concepts for toxicity prevention and tissue restoration after central nervous system irradiation
Several experimental strategies of radiation-induced central nervous system toxicity prevention have recently resulted in encouraging data. The present review summarizes the background for this research and the treatment results. It extends to the perspectives of tissue regeneration strategies, based for example on stem and progenitor cells. Preliminary data suggest a scenario with individually tailored strategies where patients with certain types of comorbidity, resulting in impaired regeneration reserve capacity, might be considered for toxicity prevention, while others might be "salvaged" by delayed interventions that circumvent the problem of normal tissue specificity. Given the complexity of radiation-induced changes, single target interventions might not suffice. Future interventions might vary with patient age, elapsed time from radiotherapy and toxicity type. Potential components include several drugs that interact with neurodegeneration, cell transplantation (into the CNS itself, the blood stream, or both) and creation of reparative signals and a permissive microenvironment, e.g., for cell homing. Without manipulation of the stem cell niche either by cell transfection or addition of appropriate chemokines and growth factors and by providing normal perfusion of the affected region, durable success of such cell-based approaches is hard to imagine
Mesenchymal stem cell therapy induces glucocorticoid synthesis in colonic mucosa and suppresses radiation-activated T cells New insights into MSC immunomodulation
International audienceNon-neoplastic tissues around an abdomino-pelvic tumor can be damaged by the radiotherapy protocol, leading to chronic gastrointestinal complications that affect the quality of life with substantial mortality. Stem cell-based approaches using immunosuppressive bone marrow mesenchymal stem cells (MSCs) are promising cell therapy tools. In a rat model of radiation proctitis, weevidenced that a singleMSCinjection reduces colonic mucosa damages induced by ionizing radiation with improvement of the re-epithelization process for up to 21 days. Immune cell infiltrate and inflammatory molecule expressions in the colonic mucosa were investigated. We report that MSC therapy specifically reduces T-cell infiltration and proliferation, and increases apoptosis of radiation-activated T cells. We assessed the underlying molecular mechanisms and found that interleukin-10 and regulatory T lymphocytes are not involved in the immunosuppressive process in this model. However, an increased level of corticosterone secretion and HSD11b1 (11b-hydroxysteroid dehydrogenase type 1)-steroidogenic enzyme expression was detected in colonic mucosa 21 days after MSC treatment. Moreover, blocking the glucocorticoid (GC) receptor using the RU486 molecule statistically enhances the allogenic lymphocyte proliferation inhibited by MSCs in vitro and abrogates the mucosal protection induced by MSC treatment in vivo. Using the irradiation model, we found evidence for a new MSC immunosuppressive mechanism involving GCs. © 2014 Society for Mucosal Immunology
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