ER stress protein PERK promotes inappropriate innate immune responses and pathogenesis during RSV infection.

The activation of dendritic cells (DC) during respiratory viral infections is central to directing the immune response and the pathologic outcome. In these studies, the effect of RSV infection on development of ER stress responses and the impact on innate immunity was examined. The upregulation of ER stress was closely associated with the PERK pathway through the upregulation of CHOP in RSV infected DC. The inhibition of PERK corresponded with decreased EIF2a phosphorylation but had no significant effect on Nrf2 in DC, two primary pathways regulated by PERK. Subsequent studies identified that by blocking PERK activity in infected DC an altered ER stress response and innate cytokine profile was observed with the upregulation of IFNß and IL-12, coincident to the down regulation of IL-1ß. When mitochondria respiration was assessed in PERK deficient DC there were increased dysfunctional mitochondria after RSV infection that resulted in reduced oxygen consumption rates (OCR) and ATP production indicating altered cellular metabolism. Use of a CD11c targeted genetic deleted murine model, RSV infection was characterized by reduced inflammation and diminished mucus staining as well as reduced mucus-associated gene gob5 expression. The assessment of the cytokine responses showed decreased IL-13 and IL-17 along with diminished IL-1ß in the lungs of PERK deficient infected mice. When PERK-deficient animals were assessed in parallel for lung leukocyte numbers, animals displayed significantly reduced myeloid and activated CD4 and CD8 T cell numbers. Thus, the PERK activation pathway may provide a rational target for altering the severe outcome of an RSV infection through modifying immune responses.

Correction to: Is the new ASNM intraoperative neuromonitoring supervision "guideline" a trustworthy guideline? A commentary.

The article Is the new ASNM intraoperative neuromonitoring supervision "guideline" a trustworthy guideline? A commentary, written by Stanley A. Skinner, Elif Ilgaz Aydinlar, Lawrence F. Borges, Bob S. Carter, Bradford L. Currier, Vedran Deletis, Charles Dong, John Paul Dormans, Gea Drost, Isabel Fernandez­Conejero, E. Matthew Hoffman, Robert N. Holdefer, Paulo Andre Teixeira Kimaid, Antoun Koht, Karl F. Kothbauer, David B. MacDonald, John J. McAuliffe III, David E. Morledge, Susan H. Morris, Jonathan Norton, Klaus Novak, Kyung Seok Park, Joseph H. Perra, Julian Prell, David M. Rippe, Francesco Sala, Daniel M. Schwartz, Martín J. Segura, Kathleen Seidel, Christoph Seubert, Mirela V. Simon, Francisco Soto, Jeffrey A. Strommen, Andrea Szelenyi, Armando Tello, Sedat Ulkatan, Javier Urriza and Marshall Wilkinson, was originally published electronically on the publisher's internet portal (currently SpringerLink) on 05 January 2019 without open access. With the author(s)' decision to opt for Open Choice the copyright of the article changed on 30 January 2019 to © The Author(s) 2019 and the article is forthwith distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits use, duplication, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license and indicate if changes were made. The original article has been corrected.

Group 2 innate lymphoid cells (ILC2) are regulated by stem cell factor during chronic asthmatic disease.

Stem cell factor (SCF) binds to the receptor c-Kit that is expressed on a number of myeloid and lymphoid cell populations, including Type 2 innate lymphoid cells (ILC2). However the importance of the SCF/c-Kit interaction in ILC2 has not been studied. Here we investigate the role of a specific SCF isoform, SCF248, in the allergic asthmatic response and SCF/c-Kit in ILC2 activation during chronic allergy. We observed that mice treated with a monoclonal antibody specific for SCF248 attenuated the development of chronic asthmatic disease by decreasing the number of mast cells, ILC2 and eosinophils, as well as reducing the accompanying pathogenic cytokine responses. These data were supported using SCFfl/fl-Col1-Cre-ERT mice and W/Wv mice that demonstrated the importance of the stem cell factor/c-Kit activation during chronic allergy and the accumulation of c-kit+ cells. Finally, these data demonstrate for the first time that SCF could activate ILC2 cells in vitro for the production of key allergic cytokines. Together these findings indicate that SCF is a critical cytokine involved in the activation of ILC2 that lead to more severe outcomes during chronic allergy and that the SCF248 isoform could be an important therapeutic target to control the disease progression.

Comparison of Motor-Evoked Potentials Versus Somatosensory-Evoked Potentials as Early Indicators of Neural Compromise in Rat Model of Spinal Cord Compression.

STUDY DESIGN: Randomized controlled study comparing the efficacy of intraoperative somatosensory-evoked potentials (SSEPs) versus transcranial motor-evoked potentials (TcMEPs) as early indicators of neural compromise and predictors of postoperative function in a rat model of spinal cord compression. OBJECTIVE: To compare the relative efficacy of SSEPs and TcMEPs to detect spinal cord compromise and predict postoperative functional deficit after spinal cord compression. SUMMARY OF BACKGROUND DATA: There is controversy regarding the efficacy of SSEPs versus TcMEPs to detect intraoperative spinal cord compromise and predict functional outcomes. Previous trials provide some guidance as to the role of each modality in spinal cord monitoring but randomized controlled trials, which are not feasible in humans, are lacking. METHODS: Twenty-four adult male Wistar rats were evenly divided into three experimental groups and one control group. The experimental groups were determined according to the length of time that 100% TcMEP signal loss was maintained: 0, 5, or 15 minutes. All animals had standardized preoperative functional testing. Spinal cord compromise was initiated utilizing a validated protocol, which involved compression via a balloon catheter introduced into the thoracic sublaminar space. Both SSEPs and TcMEPs were recorded during cord compression for each experimental group. Functional behavioral testing using two validated methods (tilt and modified Tarlov) was repeated 24 hours after termination of spinal cord compression. Post hoc, animals were redistributed into two functional subgroups, noncompromised and compromised, for statistical analysis. RESULTS: TcMEPs consistently detected spinal cord compromise either in advance of or at the same time as SSEPs; however, the delay in SSEP response was not significant for cases when compromised postoperative function resulted. Both SSEP and TcMEP amplitude recovery correlated well with postoperative functional scores. CONCLUSION: TcMEPs are more sensitive to spinal cord compromise than SSEPs, but the recovery profiles of both SSEP and TcMEP amplitudes are good predictors of postoperative function. LEVEL OF EVIDENCE: 2.

Validity of transcranial motor evoked potentials as early indicators of neural compromise in rat model of spinal cord compression.

STUDY DESIGN: Randomized controlled study of intraoperative transcranial motor evoked potentials (TcMEPs) as early indicators of neural compromise in a rat model of spinal cord compression. OBJECTIVE: To determine the temporal threshold at which a complete (100%) loss of intraoperative TcMEPs will result in significant postoperative functional deficits. SUMMARY OF BACKGROUND DATA: There is controversy about the best TcMEP alarm criteria for intraoperative spinal cord protection. Clinical trials provide some evidence, but randomized controlled trials, which are not feasible in humans, are lacking. METHODS: Twenty-four adult male Wistar rats were divided into 3 experimental groups according to the length of time that a 100% TcMEP signal loss was maintained; all animals had preoperative functional testing. After surgical placement of a balloon catheter in the thoracic sublaminar space, TcMEPs were recorded while the spinal cord was compressed by balloon inflation. The recordings were terminated after maintaining a 100% TcMEP loss for different time periods (0, 5, or 15 min). Functional behavioral testing was repeated after 24 hours. RESULTS: Only the groups wherein the catheter was left inflated for 5 or 15 minutes after a complete (100%) loss of TcMEP amplitude showed a significant deterioration in functional testing as compared with preoperative baseline values. Functional testing remained normal for both the control group and the group in which termination of spinal cord compression occurred immediately after a decrease of TcMEP amplitude to 100%. There was a strong correlation between TcMEP amplitude recovery postintervention and functional ability at 24 hours postsurgery. CONCLUSION: If a 100% loss of TcMEP signals is immediately recognized and reversed by rapid removal of the compressive force on the spinal cord, normal postoperative function was observed in this rat model. However, delaying intervention for even 5 minutes can result in significant postoperative functional deficits. LEVEL OF EVIDENCE: N/A.

Autophagy-inducing protein beclin-1 in dendritic cells regulates CD4 T cell responses and disease severity during respiratory syncytial virus infection.

Recent work demonstrated the importance of macroautophagy in dendritic cell (DC) maturation and innate cytokine production upon viral infection through delivery of cytoplasmic viral components to intracellular TLRs. To study the functional consequences of impaired autophagosome formation during a respiratory syncytial virus (RSV) infection, mice harboring significant autophagy defects due to Beclin-1 haploinsufficiency (Beclin-1(+/-)) were used. Upon RSV infection in vivo, lungs of Beclin-1(+/-) mice showed increased Th2 cytokine production, mucus secretion, and lung infiltration of eosinophils and inflammatory DCs. Although isolated airway epithelial cells from Beclin-1(+/-) mice demonstrated little change compared with wild-type mice, Beclin-1(+/-) pulmonary and bone marrow-derived DCs showed decreased expression of MHC class II and innate cytokine production upon RSV infection. Further examination indicated that Beclin-1(+/-) DCs stimulated less IFN-γ and IL-17 production by cocultured CD4(+) T cells and increased Th2 cytokine production in comparison with wild-type controls. Finally, adoptive transfer of RSV-infected Beclin-1(+/-) DCs into the airways of wild-type mice produced severe lung pathology and increased Th2 cytokine production upon subsequent RSV challenge compared with wild-type DC transfer controls. These results indicate a critical role for autophagy in DCs during pulmonary viral infection, facilitating appropriate antiviral adaptive immune responses.

Validity of somatosensory evoked potentials as early indicators of neural compromise in rat model of spinal cord compression.

OBJECTIVE: To determine the percentage change in somatosensory evoked potential amplitude and the duration of spinal cord compression that can be tolerated intraoperatively in a rat model before there are significant post-operative functional deficits. METHODS: Thirty two adult male Wistar rats were divided into four groups according to the percentage of induced SSEP signal loss; all animals had pre-operative functional testing. Following surgical placement of a balloon catheter in the thoracic sub-laminar space, SSEPs were recorded while the spinal cord was compressed by inflation of the balloon. The recordings were terminated after a different percentage loss of SSEP amplitude in each group. Functional behavioral testing was repeated after 24 h. RESULTS: Only the group wherein the catheter was left inflated for 15 min after a complete (100%) loss of SSEP amplitude showed a significant deterioration in functional testing as compared to pre-operative baseline values. Functional testing remained normal for the groups in which termination of spinal cord compression occurred immediately after a decrease of SSEP amplitude to 50% or 100%. CONCLUSIONS: SSEP loss of up to 100% can be tolerated in a rat model of spinal cord compression as long as the compression is terminated immediately after the SSEP decrease is detected. Prolonged spinal cord compression, with concomitant SSEP decrease, can result in post-operative functional deficits despite mitigating procedures to remove the compression. SIGNIFICANCE: This study is an important first step in providing basic science evidence for the establishment of acceptable "alarm criteria" during spinal surgery.

Sagittal Spinopelvic Parameters of Young Children With Scoliosis.

STUDY DESIGN: Retrospective, multicenter review of the spinopelvic parameters in young children with scoliosis. OBJECTIVES: To describe sagittal alignment of the spine and pelvis in young children with scoliosis. SUMMARY OF BACKGROUND DATA: The natural history of spinopelvic parameters has been defined for the first 10 years of life in normal children; however, they have not been described for children with scoliosis. Such information is important because these values can be used as a baseline for the assessment of radiographic outcomes after surgical intervention. METHODS: Seven measures of sagittal alignment were taken from standing lateral radiographs of 80 children with scoliosis (coronal Cobb angle greater than 50°) and compared with age-matched normal children described in the literature. Statistical analysis was performed using 2-tailed Student t tests (level of significance = .05) and Pearson correlation coefficient. RESULTS: Patients had a mean age of 4.8 years (range, 1-10 years) and a mean Cobb angle of 72.0° ± 16°. Mean sagittal spine parameters were sagittal balance (2.2 ± 4 cm), thoracic kyphosis (38.0° ± 20.8°), and lumbar lordosis (49.0° ± 16.6°). These values were similar to those of children without scoliosis. Mean sagittal pelvic parameters were: pelvic incidence (46.5° ± 15.8°), pelvic tilt (10.7° ± 13.6°), sacral slope (35.5° ± 12.1°), and pelvic radius (55.7° ± 21.3°). Pelvic incidence was not significantly different from that of age-matched normal children; however, pelvic tilt was significantly higher and sacral slope was significantly lower in children with scoliosis. CONCLUSIONS: Sagittal plane spine parameters and some pelvic parameters were similar for young children with scoliosis versus age-matched normal children; however, children with scoliosis showed signs of increased pelvic tilt and decreased sacral slope. These values can be used as a baseline for both the natural history and the assessment of radiographic outcomes after surgical intervention.

Successful use of extracorporeal life support in a hematopoietic stem cell transplant patient with diffuse alveolar hemorrhage.

OBJECTIVE: To describe the successful use of extracorporeal life support in a hematopoietic stem cell transplant patient with diffuse alveolar hemorrhage. DESIGN: Case report. SETTING: Pediatric intensive care unit in a freestanding quaternary children's hospital. PATIENT: A 20-mo-old male with Hurler syndrome who developed respiratory failure from diffuse alveolar hemorrhage after hematopoietic stem cell transplant and was managed successfully with extracorporeal life support. INTERVENTION: Placement on extracorporeal membrane oxygenation. MEASUREMENTS AND MAIN RESULTS: Diffuse alveolar hemorrhage is a well-known complication in hematopoietic stem cell transplant patients, with an even higher occurrence in those with Hurler syndrome. Extracorporeal membrane oxygenation has been contraindicated traditionally in both pulmonary hemorrhage and hematopoietic stem cell transplant patients. We report the successful use of extracorporeal membrane oxygenation and survival to hospital discharge in a hematopoietic stem cell transplant patient with diffuse alveolar hemorrhage. CONCLUSION: Although the reported survival of hematopoietic stem cell transplant patients on extracorporeal membrane oxygenation remains low, each patient must be evaluated for potential benefit of extracorporeal life support.