A Progenitor Cell Expressing Transcription Factor RORγt Generates All Human Innate Lymphoid Cell Subsets.

The current model of murine innate lymphoid cell (ILC) development holds that mouse ILCs are derived downstream of the common lymphoid progenitor through lineage-restricted progenitors. However, corresponding lineage-restricted progenitors in humans have yet to be discovered. Here we identified a progenitor population in human secondary lymphoid tissues (SLTs) that expressed the transcription factor RORγt and was unique in its ability to generate all known ILC subsets, including natural killer (NK) cells, but not other leukocyte populations. In contrast to murine fate-mapping data, which indicate that only ILC3s express Rorγt, these human progenitor cells as well as human peripheral blood NK cells and all mature ILC populations expressed RORγt. Thus, all human ILCs can be generated through an RORγt(+) developmental pathway from a common progenitor in SLTs. These findings help establish the developmental signals and pathways involved in human ILC development.

Enriched environment enhances NK cell maturation through hypothalamic BDNF in male mice.

Macroenvironmental factors, including a patient's physical and social environment, play a role in cancer risk and progression. Our previous preclinical studies have shown that the enriched environment (EE) confers anti-obesity and anti-cancer phenotypes that are associated with enhanced adaptive immunity and are mediated by brain-derived neurotrophic factor (BDNF). Natural killer (NK) cells have anti-cancer and anti-viral properties, and their absence or depletion is associated with inferior clinical outcomes. In this study, we investigated the effects of EE on NK cell maturation following their depletion. Mice living in EE displayed a higher proportion of NK cells in the spleen, bone marrow, and blood, compared to those living in the standard environment (SE). EE enhanced NK cell maturation in the spleen and was associated with upregulation of BDNF expression in the hypothalamus. Hypothalamic BDNF overexpression reproduced the EE effects on NK cell maturation in secondary lymphoid tissues. Conversely, hypothalamic BDNF knockdown blocked the EE modulation on NK cell maturation. Our results demonstrate that a bio-behavior intervention enhanced NK cell maturation and was mediated at least in part by hypothalamic BDNF.

Successful Neonatal, Intraoperative Neuromonitoring in the Surgical Correction of a Thoracic Dermal Sinus Tract: Technical Note.

INTRODUCTION: Intraoperative neuromonitoring (IONM) is commonly used during surgery of the spine and spinal cord for early surveillance of iatrogenic injury to the central and peripheral nervous system. However, for infants and young children under 3 years of age, the use of IONM is challenging due to incomplete central and peripheral myelination. CASE PRESENTATION: We report a case of a T4-T6 dermal sinus tract (DST) that was resected on day of life 23, with the successful use of IONM. CONCLUSION: To our knowledge, this is the youngest reported case of the use of IONM in the surgical correction of a DST in a neonatal patient. This case demonstrates the potential efficacy of IONM in neonatal spine surgery and the techniques used to adapt the technology to an immature nervous system.

Environmental activation of a hypothalamic BDNF-adipocyte IL-15 axis regulates adipose-natural killer cells.

Physical and social environments influence immune homeostasis within adipose tissue, yet the mechanisms remain poorly defined. We report that an enriched environment (EE) housing modulates the immune cell population in white adipose tissue of mice including an increase in the abundance of natural killer (NK) cells. EE upregulates the expression of IL-15 and its receptor IL-15Rα specifically within mature adipocytes. Mechanistically, we show that hypothalamic brain-derived neurotrophic factor (BDNF) upregulates IL-15 production in adipocytes via sympathetic ß-adrenergic signaling. Overexpressing BDNF mediated by recombinant adeno-associated virus (rAAV) vector in the hypothalamus expands adipose NK cells. Conversely, inhibition of hypothalamic BDNF signaling via gene transfer of a dominant negative TrkB receptor suppresses adipose NK cells. In white adipose tissue, overexpression of IL-15 using an adipocyte-specific rAAV vector stimulates adipose NK cells and inhibits the progression of subcutaneous melanoma, whereas local IL-15 knockdown blocks the EE effect. These results suggest that bio-behavioral factors regulate adipose NK cells via a hypothalamic BDNF-sympathoneural-adipocyte IL-15 axis. Targeting this pathway may have therapeutic significance for cancer.

Pseudarthrosis rate following anterior cervical discectomy with fusion using an allograft cellular bone matrix: a multi-institutional analysis.

OBJECTIVE: The use of osteobiologics, engineered materials designed to promote bone healing by enhancing bone growth, is becoming increasingly common for spinal fusion procedures, but the efficacy of some of these products is unclear. The authors performed a retrospective, multi-institutional study to investigate the clinical and radiographic characteristics of patients undergoing single-level anterior cervical discectomy with fusion performed using the osteobiologic agent Osteocel, an allograft mesenchymal stem cell matrix. METHODS: The medical records across 3 medical centers and 12 spine surgeons were retrospectively queried for patients undergoing single-level anterior cervical discectomy and fusion (ACDF) with the use of Osteocel. Pseudarthrosis was determined based on CT or radiographic imaging of the cervical spine. Patients were determined to have radiographic pseudarthrosis if they met any of the following criteria: 1) lack of bridging bone on CT obtained > 300 days postoperatively, 2) evidence of instrumentation failure, or 3) motion across the index level as seen on flexion-extension cervical spine radiographs. Univariate and multivariate analyses were then performed to identify independent preoperative or perioperative predictors of pseudarthrosis in this population. RESULTS: A total of 326 patients met the inclusion criteria; 43 (13.2%) patients met criteria for pseudarthrosis, of whom 15 (34.9%) underwent revision surgery. There were no significant differences between patients with and those without pseudarthrosis, respectively, for patient age (54.1 vs 53.8 years), sex (34.9% vs 47.4% male), race, prior cervical spine surgery (37.2% vs 33.6%), tobacco abuse (16.3% vs 14.5%), chronic kidney disease (2.3% vs 2.8%), and diabetes (18.6% vs 14.5%) (p > 0.05). Presence of osteopenia or osteoporosis (16.3% vs 3.5%) was associated with pseudarthrosis (p < 0.001). Implant type was also significantly associated with pseudarthrosis, with a 16.4% rate of pseudarthrosis for patients with polyetherethereketone (PEEK) implants versus 8.4% for patients with allograft implants (p = 0.04). Average lengths of follow-up were 27.6 and 23.8 months for patients with and those without pseudarthrosis, respectively. Multivariate analysis demonstrated osteopenia or osteoporosis (OR 4.97, 95% CI 1.51-16.4, p < 0.01) and usage of PEEK implant (OR 2.24, 95% CI 1.04-4.83, p = 0.04) as independent predictors of pseudarthrosis. CONCLUSIONS: In patients who underwent single-level ACDF, rates of pseudarthrosis associated with the use of the osteobiologic agent Osteocel are higher than the literature-reported rates associated with the use of alternative osteobiologics. This is especially true when Osteocel is combined with a PEEK implant.

Enriched environment regulates thymocyte development and alleviates experimental autoimmune encephalomyelitis in mice.

Environmental and social factors have profound impacts on immune homeostasis. Our work on environmental enrichment (EE) has revealed a novel anti-obesity and anticancer phenotype associated with enhanced activity of CD8+ cytotoxic T lymphocytes in secondary lymphoid tissues. Here we investigated how an EE modulated thymus and thymocyte development. EE decreased thymus mass and cellularity, decreased the double positive thymocyte population, increased the proportion of CD8+ T cells, reduced the CD4:CD8 ratio, and downregulated CD69 expression in T cells. In a model of multiple sclerosis: experimental autoimmune encephalomyelitis (EAE), EE alleviated symptoms, inhibited spinal cord inflammation through regulation of type 1 T-helper cells mediated by glucocorticoid receptor signaling, and prevented EAE-induced thymic disturbance. Our mechanistic studies demonstrated that hypothalamic BDNF activated a hypothalamic-pituitary-adrenal axis mediating the EE's thymic effects. Our results indicate that a lifestyle intervention links the nervous, endocrine, and adaptive immune system, allowing the body to adapt to internal and external environments.

Using Augmented Reality Technology to Optimize Transfacet Lumbar Interbody Fusion: A Case Report.

The transfacet minimally invasive transforaminal lumbar interbody fusion (MIS-TLIF) is a novel approach available for the management of lumbar spondylolisthesis. It avoids the need to manipulate either of the exiting or traversing nerve roots, both protected by the bony boundaries of the approach. With the advancement in operative technologies such as navigation, mapping, segmentation, and augmented reality (AR), surgeons are prompted to utilize these technologies to enhance their surgical outcomes. A 36-year-old male patient was complaining of chronic progressive lower back pain. He was found to have grade 2 L4/5 spondylolisthesis. We studied the feasibility of a trans-Kambin or a transfacet MIS-TLIF, and decided to proceed with the latter given the wider corridor it provides. Preoperative trajectory planning and level segmentation in addition to intraoperative navigation and image merging were all utilized to provide an AR model to guide us through the surgery. The use of AR can build on the safety and learning of novel surgical approaches to spine pathologies. However, larger high-quality studies are needed to further objectively analyze its impact on surgical outcomes and to expand on its application.

Measuring Outcomes in Spinal Deformity Surgery.

Outcome assessment in adult spinal deformity has evolved from radiographic analysis of curve correction to patient-centered perception of health-related quality-of-life. Oswestry Disability Index and the Scoliosis Research Society-22 Patient Questionnaire are the predominantly used patient-reported outcome (PRO) measurements for deformity surgery. Correction of sagittal alignment correlates with improved PRO. Functional outcomes and accelerometer measurements represent newer methods of measuring outcomes but have not yet been widely adopted or validated. Further adoption of a minimum set of core outcome domains will help facilitate international comparisons and benchmarking, and ultimately enhance value-based healthcare.

Surgical technique of combined minimally invasive anterior column realignment at L1-L2 with open extension of prior fusion.

Surgical correction of fixed kyphotic deformity or severe sagittal imbalance traditionally involves three column osteotomies, which are associated with high morbidity rates. Anterior column realignment (ACR) has emerged as a minimally invasive alternative for restoring segmental lordosis. This technique involves a lateral approach and release of the anterior longitudinal ligament (ALL), followed by placement of a hyperlordotic interbody cage. In this study, we present a successful case of minimally invasive ACR for the treatment of flatback deformity and adjacent segment disease in a patient with prior L2-S1 fusion. Imaging revealed a flatback deformity, sagittal vertical axis elevation, and spinopelvic disharmony. The patient underwent a multistage procedure involving a lateral retropleural approach for ACR and interbody fusion, followed by open posterior instrumented fusion and vertebroplasties. Postoperatively, the patient experienced significant pain relief and improvement in lumbar lordosis, pelvic tilt, and pelvic incidence-lumbar lordosis mismatch. ACR combined with posterior release allows for manipulation of all three spinal columns, leading to spine reconstruction and improved spinopelvic harmony. We discuss the advantages of ACR, including its minimally invasive nature and potential benefits for patients with sagittal deformities. The presented surgical technique demonstrates the feasibility and efficacy of minimally invasive ACR in addressing flatback deformity and adjacent segment disease.

Osteoimmunology: Interactions With the Immune System in Spinal Fusion.

Spinal fusion is important for the clinical success of patients undergoing surgery, and the immune system plays an increasingly recognized role. Osteoimmunology is the study of the interactions between the immune system and bone. Inflammation impacts the osteogenic, osteoconductive, and osteoinductive properties of bone grafts and substitutes and ultimately influences the success of spinal fusion. Macrophages have emerged as important cells for coordinating the immune response following spinal fusion surgery, and macrophage-derived cytokines impact each phase of bone graft healing. This review explores the cellular and molecular immune processes that regulate bone homeostasis and healing during spinal fusion.

Characteristics of patients who return to work after undergoing surgery for cervical spondylotic myelopathy: a Quality Outcomes Database study.

OBJECTIVE: Return to work (RTW) is an important surgical outcome for patients who are employed, yet a significant number of patients with cervical spondylotic myelopathy (CSM) who are employed undergo cervical spine surgery and fail to RTW. In this study, the authors investigated factors associated with failure to RTW in the CSM population who underwent cervical spine surgery and who were considered to have a good surgical outcome yet failed to RTW. METHODS: This study retrospectively analyzed prospectively collected data from the cervical myelopathy module of a national spine registry, the Quality Outcomes Database. The CSM data set of the Quality Outcomes Database was queried for patients who were employed at the time of surgery and planned to RTW postoperatively. Distinct multivariable logistic regression models were fitted with 3-month RTW as an outcome for the overall population to identify risk factors for failure to RTW. Good outcomes were defined as patients who had no adverse events (readmissions or complications), who had achieved 30% improvement in Neck Disability Index score, and who were satisfied (North American Spine Society satisfaction score of 1 or 2) at 3 months postsurgery. RESULTS: Of the 409 patients who underwent surgery, 80% (n = 327) did RTW at 3 months after surgery. At 3 months, 56.9% of patients met the criteria for a good surgical outcome, and patients with a good outcome were more likely to RTW (88.1% vs 69.2%, p < 0.01). Of patients with a good outcome, 11.9% failed to RTW at 3 months. Risk factors for failing to RTW despite a good outcome included preoperative short-term disability or leave status (OR 3.03 [95% CI 1.66-7.90], p = 0.02); a higher baseline Neck Disability Index score (OR 1.41 [95% CI 1.09-1.84], p < 0.01); and higher neck pain score at 3 months postoperatively (OR 0.81 [95% CI 0.66-0.99], p = 0.04). CONCLUSIONS: Most patients with CSM who undergo spine surgery reenter the workforce within 3 months from surgery, with RTW rates being higher among patients who experience good outcomes. Among patients with good outcomes who were employed, failure to RTW was associated with being on preoperative short-term disability or leave status prior to surgery as well as higher neck pain scores at baseline and at 3 months postoperatively.

Sacroiliac Joint Fusion Using Robotic Navigation: Technical Note and Case Series.

BACKGROUND: Patients undergoing sacroiliac (SI) fusion can oftentimes experience significant improvements in pain and quality of life. OBJECTIVE: To describe a novel application of robotic navigation to assist with minimally invasive SI joint fusion. METHODS: Patients undergoing stand-alone SI joint fusion with ExcelsiusGPS robotic navigation from July 2020 through June 2021 were retrospectively enrolled. Baseline demographic and perioperative variables including radiation exposure, postoperative pain scores, and narcotic requirements in the postanesthesia care unit (PACU) were recorded. Length of stay and any postoperative complications were also noted. RESULTS: A total of 10 patients (64.4 ± 8.2 years, body mass index 28.7 ± 4.8 kg/m2) met inclusion criteria. Seven patients (70.0%) were female, and there was a 6:4 split between left-sided and right-sided SI joint fusion. The total operative time was 54 ± 9 minutes, and the estimated blood loss was 21.0 ± 16.7 mL. The intraoperative radiation exposure was 13.7 ± 6.2 mGy, and there were no complications. The average pain score in PACU was 5.2 ± 1.0, and the average opioid administration in PACU was 27.6 ± 10.3 morphine equivalents. Length of stay was 0.4 ± 0.7 days, with 7 of 10 patients discharged on the same day as surgery. There were no readmissions. The average length of follow-up was 4.3 ± 2.5 months. At the last follow-up, patients reported an average of 73.1% ± 30.1% improvement in their preoperative pain. CONCLUSION: Robot-navigated SI joint fusion is a feasible and reproducible method for addressing refractory SI joint disease. Further investigation on clinical outcomes and long-term fusion rates is needed, as are studies comparing robot-navigated SI joint fusion with more traditional techniques.

Interferon gamma mediates the reduction of adipose tissue regulatory T cells in human obesity.

Decreased adipose tissue regulatory T cells contribute to insulin resistance in obese mice, however, little is known about the mechanisms regulating adipose tissue regulatory T cells numbers in humans. Here we obtain adipose tissue from obese and lean volunteers. Regulatory T cell abundance is lower in obese vs. lean visceral and subcutaneous adipose tissue and associates with reduced insulin sensitivity and altered adipocyte metabolic gene expression. Regulatory T cells numbers decline following high-fat diet induction in lean volunteers. We see alteration in major histocompatibility complex II pathway in adipocytes from obese patients and after high fat ingestion, which increases T helper 1 cell numbers and decreases regulatory T cell differentiation. We also observe increased expression of inhibitory co-receptors including programmed cell death protein 1 and OX40 in visceral adipose tissue regulatory T cells from patients with obesity. In human obesity, these global effects of interferon gamma to reduce regulatory T cells and diminish their function appear to instigate adipose inflammation and suppress adipocyte metabolism, leading to insulin resistance.

Perioperative Assessment of Cerebellar Masses and the Potential for Cerebellar Cognitive Affective Syndrome.

The cerebellum was long perceived to be a region of limited importance with primary functions in the regulation of motor control. A degree of its functional topography in motor modulation has been traditionally appreciated. However, an evolving body of evidence supports its role in a range of cognitive processes, including executive decision making, language, emotional processing, and working memory. To this end, numerous studies of cerebellar stroke syndromes as well as investigations with functional magnetic resonance imaging and diffusion tensor imaging have given clinicians a better model of the functional topography within the cerebellum and the essential lanes of communication with the cerebrum. With this deeper understanding, neurosurgeons should integrate these domains into the perioperative evaluation and postoperative rehabilitation of patients with cerebellar tumors. This review aims to discuss these understandings and identify valuable tools for implementation into clinical practice.

Ablation of the Brca1-Palb2 Interaction Phenocopies Fanconi Anemia in Mice.

Heterozygous mutations in the BRCA1 gene predispose women to breast and ovarian cancer, while biallelic BRCA1 mutations are a cause of Fanconi anemia (FA), a rare genetic disorder characterized by developmental abnormalities, early-onset bone marrow failure, increased risk of cancers, and hypersensitivity to DNA-crosslinking agents. BRCA1 is critical for homologous recombination of DNA double-strand breaks (DSB). Through its coiled-coil domain, BRCA1 interacts with an essential partner, PALB2, recruiting BRCA2 and RAD51 to sites of DNA damage. Missense mutations within the coiled-coil domain of BRCA1 (e.g., L1407P) that affect the interaction with PALB2 have been reported in familial breast cancer. We hypothesized that if PALB2 regulates or mediates BRCA1 tumor suppressor function, ablation of the BRCA1-PALB2 interaction may also elicit genomic instability and tumor susceptibility. We generated mice defective for the Brca1-Palb2 interaction (Brca1 L1363P in mice) and established MEF cells from these mice. Brca1 L1363P/L1363P MEF exhibited hypersensitivity to DNA-damaging agents and failed to recruit Rad51 to DSB. Brca1 L1363P/L1363P mice were viable but exhibited various FA symptoms including growth retardation, hyperpigmentation, skeletal abnormalities, and male/female infertility. Furthermore, all Brca1 L1363P/L1363P mice exhibited macrocytosis and died due to bone marrow failure or lymphoblastic lymphoma/leukemia with activating Notch1 mutations. These phenotypes closely recapitulate clinical features observed in patients with FA. Collectively, this model effectively demonstrates the significance of the BRCA1-PALB2 interaction in genome integrity and provides an FA model to investigate hematopoietic stem cells for mechanisms underlying progressive failure of hematopoiesis and associated development of leukemia/lymphoma, and other FA phenotypes. SIGNIFICANCE: A new Brca1 mouse model for Fanconi anemia (FA) complementation group S provides a system in which to study phenotypes observed in human FA patients including bone marrow failure.See related commentary by Her and Bunting, p. 4044.

Management of hydrocephalus in infants with severe hemophilia A: report of 2 cases.

The authors report on the clinical course of two infants with severe hemophilia A (HA) and concomitant progressive hydrocephalus that required management with a ventriculoperitoneal shunt. The first child, with known HA, presented with a spontaneous intracranial hemorrhage and acquired hydrocephalus. He underwent cerebrospinal fluid diversion with a temporary external ventricular drain, followed by placement of a ventriculoperitoneal shunt. The second child had hydrocephalus secondary to a Dandy-Walker malformation and was diagnosed with severe HA during preoperative evaluation. He underwent placement of a ventriculoperitoneal shunt after progression of the hydrocephalus. The authors also review the treatment of hydrocephalus in patients with HA and describe the perioperative protocols used in their two cases. Treatment of hydrocephalus in infants with HA requires unique perioperative management to avoid complications.

Environmental and Genetic Activation of Hypothalamic BDNF Modulates T-cell Immunity to Exert an Anticancer Phenotype.

Macroenvironmental factors, including a patient's physical and social environment, play a role in cancer risk and progression. Our previous studies show that living in an enriched environment (EE) providing complex stimuli confers an anticancer phenotype in mice mediated, in part by a specific neuroendocrine axis, with brain-derived neurotrophic factor (BDNF) as the key brain mediator. Here, we investigated how an EE modulated T-cell immunity and its role in the EE-induced anticancer effects. Our data demonstrated that CD8 T cells were required to mediate the anticancer effects of an EE in an orthotropic model of melanoma. In secondary lymphoid tissue (SLT), an EE induced early changes in the phenotype of T-cell populations, characterized by a decrease in the ratio of CD4 T helper to CD8 cytotoxic T lymphocytes (CTL). Overexpression of hypothalamic BDNF reproduced EE-induced T-cell phenotypes in SLT, whereas knockdown of hypothalamic BDNF inhibited EE-induced immune modulation in SLT. Both propranolol and mifepristone blocked the EE-associated modulation of CTLs in SLT, suggesting that both the sympathetic nervous system and the hypothalamic-pituitary-adrenal axis were involved. Our results demonstrated that enhanced anticancer effect of an EE was mediated at least in part through modulation of T-cell immunity and provided support to the emerging concept of manipulating a single gene in the brain to improve cancer immunotherapy. Cancer Immunol Res; 4(6); 488-97. ©2016 AACR.

The effect of nanowire length and diameter on the properties of transparent, conducting nanowire films.

This article describes how the dimensions of nanowires affect the transmittance and sheet resistance of a random nanowire network. Silver nanowires with independently controlled lengths and diameters were synthesized with a gram-scale polyol synthesis by controlling the reaction temperature and time. Characterization of films composed of nanowires of different lengths but the same diameter enabled the quantification of the effect of length on the conductance and transmittance of silver nanowire films. Finite-difference time-domain calculations were used to determine the effect of nanowire diameter, overlap, and hole size on the transmittance of a nanowire network. For individual nanowires with diameters greater than 50 nm, increasing diameter increases the electrical conductance to optical extinction ratio, but the opposite is true for nanowires with diameters less than this size. Calculations and experimental data show that for a random network of nanowires, decreasing nanowire diameter increases the number density of nanowires at a given transmittance, leading to improved connectivity and conductivity at high transmittance (>90%). This information will facilitate the design of transparent, conducting nanowire films for flexible displays, organic light emitting diodes and thin-film solar cells.