Effect of manual hyperinflation on recurrent atelectasis in a ventilator-dependent C3 complete spinal cord injury patient: A case report.

CLINICAL CASE: We present here the case of a ventilator-dependent 76-year-old man with C3 complete spinal cord injury (SCI) who presented with recurrent left lung atelectasis managed with manual hyperinflation (MH). Atelectasis was primarily assessed with chest X-ray (CXR). Additional monitoring included blood gas analysis, serum procalcitonin, and the Modified Borg Dyspnea Scale (MBS), as an objective measure of reported dyspnea. We found that MH successfully reversed the radiographic appearance of atelectasis after the first treatment and maintained this effect for the duration of the 2-week intervention period as well as at 2 weeks of follow-up post-intervention. Furthermore, MH decreased the patient's oxygen requirements and was associated with a decrease in serum procalcitonin. Clinically, the patient reported reduced subjective dyspnea post-MH, which was reflected as an improvement on the MBS. We conclude that MH may represent a therapeutic modality for consideration in the routine management of recurrent atelectasis in mechanically ventilated patients.

BCG immunomodulation: From the 'hygiene hypothesis' to COVID-19.

The century-old tuberculosis vaccine BCG has been the focus of renewed interest due to its well-documented ability to protect against various non-TB pathogens. Much of these broad spectrum protective effects are attributed to trained immunity, the epigenetic and metabolic reprogramming of innate immune cells. As BCG vaccine is safe, cheap, widely available, amendable to use as a recombinant vector, and immunogenic, it has immense potential for use as an immunotherapeutic agent for various conditions including autoimmune, allergic, neurodegenerative, and neoplastic diseases as well as a preventive measure against infectious agents. Of particular interest is the use of BCG vaccination to counteract the increasing prevalence of autoimmune and allergic conditions in industrialized countries attributable to reduced infectious burden as described by the 'hygiene hypothesis.' Furthermore, BCG vaccination has been proposed as a potential therapy to mitigate spread and disease burden of COVID-19 as a bridge to development of a specific vaccine and recombinant BCG expression vectors may prove useful for the introduction of SARS-CoV-2 antigens (rBCG-SARS-CoV-2) to induce long-term immunity. Understanding the immunomodulatory effects of BCG vaccine in these disease contexts is therefore critical. To that end, we review here BCG-induced immunomodulation focusing specifically on BCG-induced trained immunity and how it relates to the 'hygiene hypothesis' and COVID-19.

Factors Within the Endoneurial Microenvironment Act to Suppress Tumorigenesis of MPNST.

Background: Deciphering avenues to adequately control malignancies in the peripheral nerve will reduce the need for current, largely-ineffective, standards of care which includes the use of invasive, nerve-damaging, resection surgery. By avoiding the need for en bloc resection surgery, the likelihood of retained function or efficient nerve regeneration following the control of tumor growth is greater, which has several implications for long-term health and well-being of cancer survivors. Nerve tumors can arise as malignant peripheral nerve sheath tumors (MPNST) that result in a highly-aggressive form of soft tissue sarcoma. Although the precise cause of MPNST remains unknown, studies suggest that dysregulation of Schwann cells, mediated by the microenvironment, plays a key role in tumor progression. This study aimed to further characterize the role of local microenvironment on tumor progression, with an emphasis on identifying factors within tumor suppressive environments that have potential for therapeutic application. Methods: We created GFP-tagged adult induced tumorigenic Schwann cell lines (iSCs) and transplanted them into various in vivo microenvironments. We used immunohistochemistry to document the response of iSCs and performed proteomics analysis to identify local factors that might modulate divergent iSC behaviors. Results: Following transplant into the skin, spinal cord or epineurial compartment of the nerve, iSCs formed tumors closely resembling MPNST. In contrast, transplantation into the endoneurial compartment of the nerve significantly suppressed iSC proliferation. Proteomics analysis revealed a battery of factors enriched within the endoneurial compartment, of which one growth factor of interest, ciliary neurotrophic factor (CNTF) was capable of preventing iSCs proliferation in vitro. Conclusions: This dataset describes a novel approach for identifying biologically relevant therapeutic targets, such as CNTF, and highlights the complex relationship that tumor cells have with their local microenvironment. This study has significant implications for the development of future therapeutic strategies to fight MPNSTs, and, consequently, improve peripheral nerve regeneration and nerve function.

Adult skin-derived precursor Schwann cell grafts form growths in the injured spinal cord of Fischer rats.

In this study, GFP+ skin-derived precursor Schwann cells (SKP-SCs) from adult rats were grafted into the injured spinal cord of immunosuppressed rats. Our goal was to improve grafted cell survival in the injured spinal cord, which is typically low. Cells were grafted in hyaluronan-methylcellulose hydrogel (HAMC) or hyaluronan-methylcellulose modified with laminin- and fibronectin-derived peptide sequences (eHAMC). The criteria for selection of hyaluronan was for its shear-thinning properties, making the hydrogel easy to inject, methylcellulose for its inverse thermal gelation, helping to keep grafted cells in situ, and fibronectin and laminin to improve cell attachment and, thus, prevent cell death due to dissociation from substrate molecules (i.e., anoikis). Post-mortem examination revealed large masses of GFP+ SKP-SCs in the spinal cords of rats that received cells in HAMC (5 out of n = 8) and eHAMC (6 out of n = 8). Cell transplantation in eHAMC caused significantly greater spinal lesions compared to lesion and eHAMC only control groups. A parallel study showed similar masses in the contused spinal cord of rats after transplantation of adult GFP+ SKP-SCs without a hydrogel or immunosuppression. These findings suggest that adult GFP+ SKP-SCs, cultured/transplanted under the conditions described here, have a capacity for uncontrolled proliferation. Growth-formation in pre-clinical research has also been documented after transplantation of: human induced pluripotent stem cell-derived neural stem cells (Itakura et al 2015 PLoS One 10 e0116413), embryonic stem cells and embryonic stem cell-derived neurons (Brederlau et al 2006 Stem Cells 24 1433-40; Dressel et al 2008 PLoS One 3 e2622), bone marrow derived mesenchymal stem cells (Jeong et al 2011 Circ. Res. 108 1340-47) and rat nerve-derived SCs following in vitro expansion for >11 passages (Funk et al 2007 Eur. J. Cell Biol. 86 207-19; Langford et al 1988 J. Neurocytology 17 521-9; Morrissey et al 1991 J. Neurosci. 11 2433-42). It is of upmost importance to define the precise culture/transplantation parameters for maintenance of normal cell function and safe and effective use of cell therapy.