The use of robot-assisted surgery for the unstable traumatic spine: A retrospective cohort study.

Background: Robotic assistance has been shown to increase instrumentation placement accuracy in open and minimally invasive spinal fusion. These gains have been achieved without increases in operative times, blood loss, or hospitalization duration. However, most work has been done in the degenerative population and little is known of the utility of robotic assistance when applied to spinal trauma. This is largely due to the uncertainty stemming from the disruption of normal anatomy by the traumatic injury. Since the robot depends upon registration for instrumentation guidance according to the fiducials it uses, trauma can introduce unique challenges. The present study sought to evaluate the safety and efficacy of robotic assistance in a consecutive cohort of spine trauma patients. Methods: All patients with Thoracolumbar Injury Classification and Severity Scale (TLICS) >4 who underwent robot-assisted spinal fusion using the Globus ExcelsiusGPS at a single tertiary care center for trauma between 2020 and 2022 were identified. Demographic, clinical, and surgical data were collected and analyzed; the primary endpoints were operative time, fluoroscopy time, estimated blood loss, postoperative complications, admission time, and 90-day readmission rate. The paired t-test was used to compare differences between mean values when looking at the number of surgical levels. Results: Forty-two patients undergoing robot-assisted spinal surgery were included (mean age 61.3±17.1 year; 47% female. Patients were stratified by the number of operative levels, 2 (n = 10), 3-4 (n = 11), 5 to 6 (n = 13), or >6 (n = 8). There appeared to be a positive correlation between number of levels instrumented and odds of postoperative complications, admission duration, fluoroscopy time, and estimated blood loss. There were no instances of screw malposition or breach. Conclusions: This initial experience suggests robotic assistance can be safely employed in the spine trauma population. Additional experiences in larger patient populations are necessary to delineate those traumatic pathologies most amenable to robotic assistance.

Staphylococcus schleiferi subspecies coagulans septic shock in an immunocompetent male following canine otitis externa.

Staphylococcus schleiferi bacteremia is an underappreciated cause of septic shock in the critical care department. Although nominally a coagulase variable Staphylococcus and associated with otitis externa infections in canine species, it has been associated with the metastatic infection including osteomyelitis, endocarditis, nephritis, and meningitis in humans. This report records a possible zoonotic case of S. schleiferi subspecies coagulans bacteremia following canine otitis externa associated with septic shock and endovascular infection precipitating intensive care admission for vasopressor support in an immunocompetent male.

TNFR-1 and GDF-15 Are Associated With Plasma Neurofilament Light Chain and Progranulin Among Community-Dwelling Older Adults: A Secondary Analysis of the MAPT Study.

There is growing evidence that cognitive decline can be affected by both nutritional aspects and inflammation. Plasma neurodegenerative biomarkers stand out as minimally invasive useful measures to monitor the potential risk of cognitive decline. This study aimed to investigate the associations between biomarkers of neurodegeneration, nutrition, and inflammation among community-dwelling older adults, and to verify if associations differed according to apolipoprotein E (APOE) ε4 status. This cross-sectional analysis included 475 participants ≥70 years old from the Multidomain Alzheimer Preventive Trial (MAPT), mean age 76.8 years (SD = 4.5), 59.4% women. Biomarkers of neurodegeneration (plasma amyloid-ß 42/40-Aß 42/40, neurofilament light chain-NfL, progranulin), nutrition (erythrocyte docosahexaenoic acid, eicosapentaenoic acid, omega-3 index; plasma homocysteine-Hcy, 25 hydroxyvitamin D), inflammation (plasma tumor necrosis factor receptor 1-TNFR-1, monocyte chemoattractant protein 1-MCP-1, interleukin 6-IL-6), and cellular stress (plasma growth differentiation factor 15-GDF-15) were assessed. Linear regression analyses were performed to investigate the associations between nutritional and inflammatory biomarkers (independent variables) and neurodegenerative biomarkers (dependent variables), with adjustments for age, sex, education, body mass index, physical activity, allocation to MAPT groups, and APOE ε4 status. After adjusting for confounders, Aß 42/40 was not associated with nutritional or inflammatory markers. NfL was positively associated with GDF-15, TNFR-1, IL-6, and Hcy. Progranulin was positively associated with GDF-15, TNFR-1, and MCP-1. Analyses restricted to APOE ε4 carriers (n = 116; 26.9%) or noncarriers were mostly similar. Our cross-sectional study with community-dwelling older adults corroborates previous evidence that inflammatory pathways are associated to plasma markers of neurodegeneration. Clinical Trials Registration Number: NCT00672685.

Deficiency of the frontotemporal dementia gene GRN results in gangliosidosis.

Haploinsufficiency of GRN causes frontotemporal dementia (FTD). The GRN locus produces progranulin (PGRN), which is cleaved to lysosomal granulin polypeptides. The function of lysosomal granulins and why their absence causes neurodegeneration are unclear. Here we discover that PGRN-deficient human cells and murine brains, as well as human frontal lobes from GRN-mutation FTD patients have increased levels of gangliosides, glycosphingolipids that contain sialic acid. In these cells and tissues, levels of lysosomal enzymes that catabolize gangliosides were normal, but levels of bis(monoacylglycero)phosphates (BMP), lipids required for ganglioside catabolism, were reduced with PGRN deficiency. Our findings indicate that granulins are required to maintain BMP levels to support ganglioside catabolism, and that PGRN deficiency in lysosomes leads to gangliosidosis. Lysosomal ganglioside accumulation may contribute to neuroinflammation and neurodegeneration susceptibility observed in FTD due to PGRN deficiency and other neurodegenerative diseases.

Prone-lateral access to the lumbar spine: single-level corpectomy with approach discussion.

The lateral lumbar interbody fusion has evolved as newly envisioned access corridors become feasible with technological advances. Prone lateral access has evolved as a single-access approach to combine the benefits of minimally invasive surgery with direct and indirect decompression of the neural elements with synergistic anterior and posterior column correction. In this video, the authors discuss the pearls, pitfalls, and adjuvant technologies they use in a high-volume prone lateral center via case demonstration of a prone lateral corpectomy. The video can be found here: https://stream.cadmore.media/r10.3171/2022.3.FOCVID2216.

Serum neurofilament light levels are predictive of all-cause mortality in late middle-aged individuals.

BACKGROUND: Blood biomarkers can offer valuable and easily accessible indicators of normal biological processes, pathogenic conditions, and responses to therapeutic interventions. Recent studies found that levels of neurofilament light chain (NfL) in the blood are associated with mortality in three European cohorts of older adults (median ages 73, 93, and 100 years). Whether similar associations exist in younger adults and in other ethnic groups is currently not known. METHODS: We utilized a cohort study that included 294 African Americans (baseline ages 49-65). Serum NfL levels were measured using a Meso Scale Discovery-based assay. Vital status was determined by matching through the National Death Index. FINDINGS: Seventy-two participants (24.5%) died during the 14-15 years of follow up (2000-2014). Baseline serum NfL levels were significantly higher in the decedent group (86.1±65.7 pg/ml vs. 50.1±28.0 pg/ml, p < 0·001). In binomial logistic regression models adjusted for age, gender, education, baseline smoking status, BMI, and total comorbidities (0-11), serum NfL levels remained a strong predictor of all-cause mortality, and sensitivity analyses employing multiple additional covariates did not substantively change the relationship. Further, Kaplan-Meier curves based on serum NfL quartiles showed reduced survival in groups with higher serum NfL levels. INTERPRETATION: This study found a positive association between serum NfL levels and mortality in late middle-aged and older individuals. While our findings support that serum NfL levels may be a useful biomarker for all-cause mortality, further studies are needed to understand the biological mechanisms underlying this association. FUNDING: National Institute on Aging, Saint Louis University.

Chronic social isolation signals starvation and reduces sleep in Drosophila.

Social isolation and loneliness have potent effects on public health1-4. Research in social psychology suggests that compromised sleep quality is a key factor that links persistent loneliness to adverse health conditions5,6. Although experimental manipulations have been widely applied to studying the control of sleep and wakefulness in animal models, how normal sleep is perturbed by social isolation is unknown. Here we report that chronic, but not acute, social isolation reduces sleep in Drosophila. We use quantitative behavioural analysis and transcriptome profiling to differentiate between brain states associated with acute and chronic social isolation. Although the flies had uninterrupted access to food, chronic social isolation altered the expression of metabolic genes and induced a brain state that signals starvation. Chronically isolated animals exhibit sleep loss accompanied by overconsumption of food, which resonates with anecdotal findings of loneliness-associated hyperphagia in humans. Chronic social isolation reduces sleep and promotes feeding through neural activities in the peptidergic fan-shaped body columnar neurons of the fly. Artificial activation of these neurons causes misperception of acute social isolation as chronic social isolation and thereby results in sleep loss and increased feeding. These results present a mechanistic link between chronic social isolation, metabolism, and sleep, addressing a long-standing call for animal models focused on loneliness7.

Serum progranulin levels are associated with frailty in middle-aged individuals.

BACKGROUND AND OBJECTIVE: A recent study identified progranulin as a candidate biomarker for frailty, based on gene expression databases. In the present study, we investigated associations between serum progranulin levels and frailty in a population-based sample of late middle-age and older adults. METHODS: We utilized a cohort study that included 358 African Americans (baseline ages 49-65). Frailty was assessed by three established methods: the interview-based FRAIL scale, the Cardiovascular Health Study (CHS) frailty scale that includes performance-based measurements, and the Frailty Index (FI) that is based on cumulative deficits. Serum levels of the following proteins and metabolites were measured: progranulin, cystatin C, fructosamine, soluble cytokine receptors (interleukin-2 and -6, tumor necrosis factor α-1 and -2), and C-reactive protein. Sarcopenia was assessed using the SARC-F index. Vital status was determined by matching through the National Death Index (NDI). RESULTS: Serum progranulin levels were associated with frailty for all indices (FRAIL, CHS, and FI) but not with sarcopenia. Inflammatory markers indicated by soluble cytokine receptors (sIL-2R, sIL-6R, sTNFR1, sTNFR2) were positively associated serum progranulin. Increased serum progranulin levels at baseline predicted poorer outcomes including future frailty as measured by the FRAIL scale and 15-year all-cause mortality independent of age, gender, and frailty. CONCLUSIONS: Our findings suggest that serum progranulin levels may be a candidate biomarker for physical frailty, independent of sarcopenia. Further studies are needed to validate this association and assess the utility of serum progranulin levels as a potential biomarker for prevalent frailty, for risk for developing incident frailty, and for mortality risk over and above the effect of baseline frailty.

Radiotherapy patterns of care for stage I and II non-small cell lung cancer in Sydney, Australia.

INTRODUCTION: Curative radiotherapy is guideline treatment for inoperable patients of good performance status with Stage I & II Non-Small Cell Lung Cancer (NSCLC). The aim of this study was to evaluate radiotherapy patterns of care in these patients, the reasons for palliative treatment and the proportion of patients suitable for curative stereotactic ablative body radiotherapy (SABR). METHODS: Electronic oncology databases at three institutions were queried to retrieve data on patients with inoperable Stage I & II NSCLC seen in radiation oncology clinics between 1/1/2008 and 31/12/2014. Suitability for SABR was defined as peripheral tumours less than 5 cm in size. Factors associated with curative treatment were determined using univariate and multivariate analyses. RESULTS: Three-hundred-and-twelve patients were identified of whom 178 (57%) received curative radiotherapy, 58 (19%) palliative radiotherapy and 76 (24%) no radiotherapy. The main reason for receiving palliative rather than curative treatment was COPD or poor pulmonary function (26%). Method of diagnosis (P = 0.031), Simplified Comorbidity Score (P = 0.003), ECOG performance status (P = 0.016), FEV1% (P = 0.040), treating institution (P < 0.0001) and time period (P = 0.016) were associated with curative radiotherapy on multivariate analysis. In patients with T1-2N0M0 NSCLC, 19 (31%) who did not receive treatment and 7 (21%) who underwent palliative radiotherapy were technically and clinically suitable for SABR. CONCLUSION: Only 57% of patients with Stage I-II NSCLC were treated with curative radiotherapy. Patient factors were the predominant reason for palliative treatment, however, treating institution also played a role. A considerable proportion of patients who underwent palliative or no radiotherapy were suitable for SABR treatment.

Progranulin in the hematopoietic compartment protects mice from atherosclerosis.

BACKGROUND AND AIMS: Progranulin is a circulating protein that modulates inflammation and is found in atherosclerotic lesions. Here we determined whether inflammatory cell-derived progranulin impacts atherosclerosis development. METHODS: Ldlr-/- mice were transplanted with bone marrow from wild-type (WT) or Grn-/- (progranulin KO) mice (referred to as Tx-WT and Tx-KO, respectively). RESULTS: After 10 weeks of high-fat diet feeding, both groups displayed similarly elevated plasma levels of cholesterol and triglycerides. Despite abundant circulating levels of progranulin, the size of atherosclerotic lesions in Tx-KO mice was increased by 47% in aortic roots and by 62% in whole aortas. Aortic root lesions in Tx-KO mice had increased macrophage content and larger necrotic cores, consistent with more advanced lesions. Progranulin staining was markedly reduced in the lesions of Tx-KO mice, indicating little or no uptake of circulating progranulin. Mechanistically, cultured progranulin-deficient macrophages exhibited increased lysosome-mediated exophagy of aggregated low-density lipoproteins resulting in increased cholesterol uptake and foam cell formation. CONCLUSIONS: We conclude that hematopoietic progranulin deficiency promotes diet-induced atherosclerosis in Ldlr-/- mice, possibly due to increased exophagy-mediated cholesterol uptake. Circulating progranulin was unable to prevent the increased lesion development, consistent with the importance of progranulin acting via cell-autonomous or local effects.

Progranulin: at the interface of neurodegenerative and metabolic diseases.

Progranulin is a widely expressed, cysteine-rich, secreted glycoprotein originally discovered for its growth factor-like properties. Its subsequent identification as a causative gene for frontotemporal dementia (FTD), a devastating early-onset neurodegenerative disease, has catalyzed a surge of new discoveries about progranulin function in the brain. More recently, progranulin was recognized as an adipokine involved in diet-induced obesity and insulin resistance, revealing its metabolic function. We review here progranulin biology in both neurodegenerative and metabolic diseases. In particular, we highlight the growth factor-like, trophic, and anti-inflammatory properties of progranulin as potential unifying themes in these seemingly divergent conditions. We also discuss potential therapeutic options for raising progranulin levels to treat progranulin-deficient FTD, as well as the possible consequences of such treatment.

Secreted progranulin is a homodimer and is not a component of high density lipoproteins (HDL).

Progranulin is a secreted glycoprotein, and the GRN gene is mutated in some cases of frontotemporal dementia. Progranulin has also been implicated in cell growth, wound healing, inflammation, and cancer. We investigated the molecular nature of secreted progranulin and provide evidence that progranulin exists as a homodimer. Although recombinant progranulin has a molecular mass of ∼85 kDa by SDS-PAGE, it elutes in fractions corresponding to ∼170-180 kDa by gel-filtration chromatography. Additionally, recombinant progranulin can be intermolecularly cross-linked, yielding a complex corresponding to a dimer (∼180 kDa), and progranulins containing different epitope tags physically interact. In plasma, progranulin similarly forms complexes of ∼180-190 kDa. Although progranulin partially co-fractionated with high density lipoproteins (HDL) by gel-filtration chromatography, we found no evidence that progranulin in mouse or human plasma is a component of HDL either by ultracentrifugation or by lipid binding assays. We conclude that circulating progranulin exists as a dimer and is not likely a component of HDL.

A single spinal lesion arising from an intradural meningioma contiguous with an extradural lymphoma.

The authors describe here a unique case of contiguous, synchronous meningioma and lymphoma in the spinal column. Both tumors were present at the same vertebral level, one intradural and the other extradural. A patient presented with bilateral leg pain, acute weakness, and sensory loss in the lower extremities. Magnetic resonance imaging revealed an intradural mass at T6-7 with ambiguous boundaries relative to the thecal sac and compressing the spinal cord. The patient underwent resection of the epidural and intradural mass at T6-7. Histopathology revealed the epidural specimen to be a double-hit B-cell lymphoma and the intradural mass to be a transitional meningioma. Postoperatively, the patient did well, with an immediate return of strength and sensation. A postoperative MR image showed complete resection of the intradural mass. The authors suggest that biopsy may be prudent in patients with known systemic lymphoma presenting with a spinal lesion that has unclear boundaries relative to the thecal sac prior to commencing radiation and chemotherapy.

Lipopolysaccharide and tumor necrosis factor regulate Parkin expression via nuclear factor-kappa B.

Inflammation and oxidative stress have been implicated in the pathophysiology of Parkinson's disease (PD) and inhibition of microglial activation attenuates degeneration of dopaminergic (DA) neurons in animal models of PD. Loss-of-function mutations in the parkin gene, which encodes an E3 ubiquitin ligase, cause autosomal recessive parkinsonism. While most studies on Parkin have focused on its function in neurons, here we demonstrate that Parkin mRNA and protein is detectable in brain-resident microglia and peripheral macrophages. Using pharmacologic and genetic approaches, we found that Parkin levels are regulated by inflammatory signaling. Specifically, exposure to LPS or Tumor Necrosis Factor (TNF) induced a transient and dose-dependent decrease in Parkin mRNA and protein in microglia, macrophages and neuronal cells blockable by inhibitors of Nuclear Factor-Kappa B (NF-κB) signaling and not observed in MyD88-null cells. Moreover, using luciferase reporter assays, we identified an NF-κB response element in the mouse parkin promoter responsible for mediating the transcriptional repression, which was abrogated when the consensus sequence was mutated. Functionally, activated macrophages from Parkin-null mice displayed increased levels of TNF, IL-1ß, and iNOS mRNA compared to wild type macrophages but no difference in levels of Nrf2, HO-1, or NQO1. One implication of our findings is that chronic inflammatory conditions may reduce Parkin levels and phenocopy parkin loss-of-function mutations, thereby increasing the vulnerability for degeneration of the nigrostriatal pathway and development of PD.

Insig-mediated, sterol-accelerated degradation of the membrane domain of hamster 3-hydroxy-3-methylglutaryl-coenzyme A reductase in insect cells.

Sterol-accelerated degradation of the enzyme 3-hydroxy-3-methylglutaryl-coenzyme A reductase is one of several mechanisms through which cholesterol synthesis is controlled in mammalian cells. This degradation results from sterol-induced binding of the membrane domain of reductase to endoplasmic reticulum membrane proteins called Insig-1 and Insig-2, which are carriers of a ubiquitin ligase called gp78. The ensuing gp78-mediated ubiquitination of reductase is a prerequisite for its rapid, 26 S proteasome-mediated degradation from endoplasmic reticulum membranes, a reaction that slows a rate-limiting step in cholesterol synthesis. Here, we report that the membrane domain of hamster reductase is subject to sterol-accelerated degradation in Drosophila S2 cells, but only when mammalian Insig-1 or Insig-2 are co-expressed. This degradation mimics the reaction that occurs in mammalian cells with regard to its absolute requirement for the action of Insigs, sensitivity to proteasome inhibition, augmentation by nonsterol isoprenoids, and sterol specificity. RNA interference studies reveal that this degradation requires the Drosophila Hrd1 ubiquitin ligase and several other proteins, including a putative substrate selector, which associate with the enzyme in yeast and mammalian systems. These studies define Insigs as the minimal requirement for sterol-accelerated degradation of the membrane domain of reductase in Drosophila S2 cells.

Bone marrow-derived cells require a functional glucose 6-phosphate transporter for normal myeloid functions.

Glycogen storage disease type Ib (GSD-Ib) is caused by a deficiency in the ubiquitously expressed glucose 6-phosphate transporter (Glc-6-PT). Glc-6-PT activity has been shown to be critical in the liver and kidney where a deficiency disrupts glucose homeostasis. GSD-Ib patients also have defects in the neutrophil respiratory burst, chemotaxis, and calcium flux. They also manifest neutropenia, but whether Glc-6-PT deficiency in the bone marrow underlies myeloid dysfunctions in GSD-Ib remains controversial. To address this, we transferred bone marrow from Glc-6-PT-deficient (Glc-6-PT(-/-)) mice to wild-type mice to generate chimeric mice (BM-Glc-6-PT(-/-)). As a control, we also transferred bone marrow between wild-type mice (BM-Glc-6-PT(+/+)). While BM-Glc-6-PT(+/+) mice have normal myeloid functions, BM-Glc-6-PT(-/-) mice manifest myeloid abnormalities characteristic of Glc-6-PT(-/-) mice. Both have impairments in their neutrophil respiratory burst, chemotaxis response, and calcium flux activities and exhibit neutropenia. In the bone marrow of BM-Glc-6-PT(-/-) and Glc-6-PT(-/-) mice, the numbers of myeloid progenitor cells are increased, while in the serum there is an increase in granulocyte colony-stimulating factor and chemokine KC levels. Moreover, in an experimental model of peritoneal inflammation, local production of KC and the related chemokine macrophage inflammatory protein-2 is decreased in both BM-Glc-6-PT(-/-) and Glc-6-PT(-/-) mice along with depressed peritoneal neutrophil accumulation. The neutrophil recruitment defect was less severe in BM-Glc-6-PT(-/-) mice than in Glc-6-PT(-/-) mice. These findings demonstrate that Glc-6-PT expression in bone marrow and neutrophils is required for normal myeloid functions and that non-marrow Glc-6-PT activity also influences some myeloid functions.

Increased cellular cholesterol efflux in glycogen storage disease type Ia mice: a potential mechanism that protects against premature atherosclerosis.

Glycogen storage disease type Ia (GSD-Ia) patients manifest a pro-atherogenic lipid profile but are not at elevated risk for developing atherosclerosis. Serum phospholipid, which correlates positively with the scavenger receptor class B type I (SR-BI)-mediated cholesterol efflux, and apolipoprotein A-IV and E, acceptors for ATP-binding cassette transporter A1 (ABCA1)-mediated cholesterol transport, are increased in GSD-Ia mice. Importantly, sera from GSD-Ia mice are more efficient than sera from control littermates in promoting SR-BI- and ABCA1-mediated cholesterol effluxes. As the first step in reverse cholesterol transport, essential for cholesterol homeostasis, these observations provide one explanation why GSD-Ia patients are apparently protected against premature atherosclerosis.