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Mammalian cells utilize over 1000 different lipid species to maintain cell and organelle membrane properties, control cell signaling and processes, and store energy. Lipid synthesis and metabolism are mediated by highly interconnected and spatiotemporally regulated networks of lipid-metabolizing enzymes and supported by vesicle trafficking and lipid-transfer at membrane contact sites. However, the regulatory mechanisms that achieve lipid homeostasis are largely unknown. Phosphatidic acid (PA) serves as the central hub for phospholipid biosynthesis, acting as a key intermediate in both the Kennedy pathway and the CDP-DAG pathway. Additionally, PA is a potent signaling molecule involved in various cellular processes. This dual role of PA, both as a critical intermediate in lipid biosynthesis and as a significant signaling molecule, suggests that it is tightly regulated within cells. This minireview will summarize the functional diversity of PA molecules based on their acyl tail structures and subcellular localization, highlighting recent tools and findings that shed light on how the physical, chemical, and spatial properties of PA species contribute to their differential metabolic fates and functions. Dysfunctional effects of altered PA metabolism as well as the strategies cells employ to maintain PA regulation and homeostasis will also be discussed. Furthermore, this review will explore the differential regulation of PA metabolism across distinct subcellular membranes. Our recent proximity labeling studies highlight the possibility that substrate cycling between PA and DAG may be location-dependent and have functional significance in cell signaling and lipid homeostasis., (© 2024 The Author(s).)

Background: Extracranial carotid artery aneurysms (ECAAs) are rare, and treatment guidelines are lacking. Few reports on endovascular treatments performed for ECAAs exist., Observations: A 73-year-old woman with a left giant cervical internal carotid artery aneurysm was treated with overlapping closed-cell stents. The aneurysm regrew 1 year after the treatment, and then a covered stent was deployed. Angioscopy was performed to confirm neointimal development to determine the appropriate stent position before the retreatment, and it revealed that the stent struts were embedded in thick neointima for the most part but that the neointima was thin around the aneurysm neck. Multiple holes connecting to the aneurysm were observed between the stent struts. A covered stent overlapped inside the closed-cell stents, and blood flow into the aneurysm completely disappeared., Lessons: When deploying the covered stent for recurrent aneurysms, angioscopy is useful for confirming neointimal development and determining the appropriate stent length and position. Angioscopic observations suggest that using stents with a higher mesh density and smaller pore size can reduce the neck hole size of the aneurysm and may achieve complete occlusion of the aneurysm. https://thejns.org/doi/10.3171/CASE24383.

Introduction: In facial motor-evoked potential monitoring, efforts to reduce peripheral stimulation are necessary because it can cause false-negatives. The effects of peripheral stimulation on Cz-C3/C4 and C3-C4 montages were compared., Methods: Facial motor-evoked potentials were recorded from bilateral orbicularis oculi (Oculi) and oris (Oris) muscles. The double-train approach combining single-pulse and five-train pulse stimulation was used to determine the effect of peripheral stimulation. If the five-train pulse produced a significant waveform, it was defined as "total success." In total success cases, "true success" was defined as a case in which no waveform appeared after the single pulse at the threshold level of the five-train pulse. The total and true success rates and the threshold value of Oculi and Oris were compared between Cz-C3/C4 and C3-C4 montages., Results: Thirty-six muscles each of Oculi and Oris of 18 patients were used for the analysis. True success was more likely to be obtained by the Cz-C3/C4 montage than the C3-C4 montage in Oculi (42% vs. 22%, p = 0.039). Both Oculi and Oris had higher thresholds to elicit facial motor-evoked potentials with the Cz-C3/C4 montage (Oculi: 101.7 vs. 71.4 mA, p = 0.038; Oris: 94.8 vs. 73.1 mA, p = 0.016)., Conclusions: Cz-C3/4 montage is more effective at reducing peripheral stimulation compared with the C3-4 montage. This effect was primarily seen in the orbicularis oculi muscle. It should be noted that the Cz-C3/C4 montage has a higher threshold than the C3-C4 montage in facial muscles. In facial motor-evoked potential monitoring, the Cz-C3/C4 montage may be more suitable to eliminate peripheral stimulation., Competing Interests: The authors have no funding or conflicts of interest to disclose., (Copyright © 2023 by the American Clinical Neurophysiology Society.)

Background: A syringosubarachnoid (SS) shunt combined with keyhole hemilaminectomy is a beneficial procedure that can reduce the size of the skin incision and the risk of complications. However, ingenuity is needed to confirm the position of the syrinx during surgery. The authors present a case in which they treated syringomyelia in the upper thoracic spine using augmented reality (AR) to confirm syrinx formation, bone resection, and skin incision., Observations: Microscope-based AR was an appropriate and practical choice in this case. By placing the reference array at the Mayfield clamp, it was possible to use AR from the point of skin incision. Under AR navigation, an SS shunt tube can be placed in the short syrinx., Lessons: AR navigation enables pinpoint SS shunt tube insertion with minimal skin incision and bone resection. It is particularly useful for upper thoracic and small syrinx lesions. https://thejns.org/doi/10.3171/CASE24130.

The proper distribution of lipids within organelle membranes requires rapid interorganelle lipid transport, much of which occurs at membrane contact sites and is mediated by lipid transfer proteins (LTPs). Our current understanding of LTP mechanism and function is based largely on structural studies and in vitro reconstitution. Existing cellular assays for LTP function use indirect readouts, and it remains an open question as to whether substrate specificity and transport kinetics established in vitro are similar in cellular settings. Here, we harness bioorthogonal chemistry to develop tools for direct visualization of interorganelle transport of phospholipids between the plasma membrane (PM) and the endoplasmic reticulum (ER). Unnatural fluorescent phospholipid analogs generated by the transphosphatidylation activity of phospholipase D (PLD) at the PM are rapidly transported to the ER dependent in part upon extended synaptotagmins (E-Syts), a family of LTPs at ER-PM contact sites. Ectopic expression of an artificial E-Syt-based tether at ER-mitochondria contact sites results in fluorescent phospholipid accumulation in mitochondria. Finally, in vitro reconstitution assays demonstrate that the fluorescent lipids are bona fide E-Syt substrates. Thus, fluorescent lipids generated in situ via PLD activity and bioorthogonal chemical tagging can enable direct visualization of the activity of LTPs that mediate bulk phospholipid transport at ER-PM contact sites.

Background: Nurses faced with multiple demands in hospitals are often compelled to prioritize nursing care. Knowledge of missed nursing care provides insight into whether necessary nursing care is delivered, what is missed, and the reasons for missed nursing care. This insight is essential to support evidence-based policy and practice to improve patient care, enhance nursing practice, and optimize the work environment. Research on factors influencing missed nursing care is imperative to implement targeted strategies. However, studies investigating work experience as a predictor are inconclusive, and no identified studies have examined how nurses' work experience is associated with different elements of missed nursing care., Objectives: To investigate the prevalence and reasons for missed nursing care and whether nurses' work experience was associated with missed nursing care., Design: The design was cross-sectional, using the Danish version of the MISSCARE survey., Setting: The study was conducted at a public Danish university hospital with 1,150 beds and approximately 10,350 employees., Participants: Across 34 surgical, medical, and mixed bed wards for adults, 1,241 nurses were invited by email to respond anonymously to the Danish MISSCARE survey. Of these nurses, 50.3% responded, and 42.6% fully completed the questionnaire., Methods: A total score mean and a mean score were calculated and then compared between experience (≤5 years/>5 years) in a linear regression model adjusting for unequally distributed variables., Results: More than two thirds of the nurses reported that emotional support, patient bathing, ambulation, mouth care, interdisciplinary conferences, documentation, and assessing effectiveness of medication were frequently missed elements of nursing care. The most significant reasons for missed nursing care were an inadequate number of nurses, an unexpected rise in patient volume, urgent patient situations, heavy admission, and discharge activity. Nurses with work experience of less than 5 years reported more missed nursing care, especially within fundamental care., Conclusions: Nursing elements to avoid potentially critical situations and nursing related to treatment observations were rarely missed, while nursing care elements visible only to the patient and the nurse were most often missed. By increasing transparency and explicitness within nursing care, the results enable critical evaluation of prioritization of nursing care elements. The number of staff not balancing the number and acuity of patients was the main reason for missed nursing care. The perception of missed nursing care was most pronounced in less experienced nurses. The study contributes to the global research community to achieve a broader understanding of missed nursing care., Tweetable Abstract: Nursing to avoid potentially critical situations and treatment observations are prioritized over fundamental care, perceived mainly by less experienced nurses., Competing Interests: The study has no conflicts of interest., (© 2024 The Authors.)

Background: Nonneuronal cells, including epithelial cells, can produce acetylcholine (ACh). Muscarinic ACh receptor antagonists are used clinically to treat asthma and other medical conditions; however, knowledge regarding the roles of ACh in type 2 immunity is limited., Objective: Our aim was to investigate the roles of epithelial ACh in allergic immune responses., Methods: Human bronchial epithelial (HBE) cells were cultured with allergen extracts, and their ACh production and IL-33 secretion were studied in vitro. To investigate immune responses in vivo, naive BALB/c mice were treated intranasally with different muscarinic ACh receptor antagonists and then exposed intranasally to allergens., Results: At steady state, HBE cells expressed cellular components necessary for ACh production, including choline acetyltransferase and organic cation transporters. Exposure to allergens caused HBE cells to rapidly release ACh into the extracellular medium. Pharmacologic or small-interfering RNA-based blocking of ACh production or autocrine action through the M3 muscarinic ACh receptors in HBE cells suppressed allergen-induced ATP release, calcium mobilization, and extracellular secretion of IL-33. When naive mice were exposed to allergens, ACh was quickly released into the airway lumen. A series of clinical M3 muscarinic ACh receptor antagonists inhibited allergen-induced IL-33 secretion and innate type 2 immune response in the mouse airways. In a preclinical murine model of asthma, an ACh receptor antagonist suppressed allergen-induced airway inflammation and airway hyperreactivity., Conclusions: ACh is released quickly by airway epithelial cells on allergen exposure, and it plays an important role in type 2 immunity. The epithelial ACh system can be considered a therapeutic target in allergic airway diseases., (Copyright © 2023 American Academy of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.)

Phosphatidic acid (PA) is a multifunctional lipid with important metabolic and signaling functions, and efforts to dissect its pleiotropy demand strategies for perturbing its levels with spatiotemporal precision. Previous membrane editing approaches for generating local PA pools used light-mediated induced proximity to recruit a PA-synthesizing enzyme, phospholipase D (PLD), from the cytosol to the target organelle membrane. Whereas these optogenetic PLDs exhibited high activity, their residual activity in the dark led to undesired chronic lipid production. Here, we report ultralow background membrane editors for PA wherein light directly controls PLD catalytic activity, as opposed to localization and access to substrates, exploiting a light-oxygen-voltage (LOV) domain-based conformational photoswitch inserted into the PLD sequence and enabling their stable and nonperturbative targeting to multiple organelle membranes. By coupling organelle-targeted LOVPLD activation to lipidomics analysis, we discovered different rates of metabolism for PA and its downstream products depending on the subcellular location of PA production. We also elucidated signaling roles for PA pools on different membranes in conferring local activation of AMP-activated protein kinase signaling. This work illustrates how membrane editors featuring acute, optogenetic conformational switches can provide new insights into organelle-selective lipid metabolic and signaling pathways., Competing Interests: The authors declare no competing financial interest., (© 2024 The Authors. Published by American Chemical Society.)

Background: Eagle jugular syndrome (EJS), recently identified as a cause of cerebrovascular disease (CVD) due to venous obstruction by an elongated styloid process (SP), is reported here alongside a case of concurrent de novo cerebral cavernous malformation (CCM). This study aims to explore the potential causal relationship between EJS and de novo CCM through a comprehensive literature review., Method: Systematic literature reviews, spanning from 1995 to 2023, focused on EJS cases with definitive signs and symptoms and de novo CCM cases with detailed clinical characteristics. Data on the pathophysiology and clinical manifestations of EJS, as well as potential risk factors preceding de novo CCM, were collected to assess the relationship between the two conditions., Result: Among 14 patients from 11 articles on EJS, the most common presentation was increased intracranial hypertension (IIH), observed in 10 patients (71.4%), followed by dural sinus thrombosis in four patients (28.6%). In contrast, 30 patients from 28 articles were identified with de novo CCM, involving 37 lesions. In these cases, 13 patients developed CCM subsequent to developmental venous anomalies (43%), seven following dural arteriovenous fistula (dAVF) (23%), and two after sinus thrombosis (6%). In a specific case of de novo brainstem CCM, the development of an enlarged condylar emissary vein, indicative of venous congestion due to IJV compression by the elongated SP, was noted before the emergence of CCM., Conclusion: This study underscores that venous congestion, a primary result of symptomatic EJS, might lead to the development of de novo CCM. Thus, EJS could potentially be an indicator of CCM development. Further epidemiological and pathophysiological investigations focusing on venous circulation are necessary to clarify the causal relationship between EJS and CCM., (© 2024. The Author(s), under exclusive licence to Springer-Verlag GmbH Austria, part of Springer Nature.)

Mitochondria are dynamic organelles regulated by fission and fusion processes. The fusion of membranes requires elaborative coordination of proteins and lipids and is particularly crucial for the function and quality control of mitochondria. Phosphatidic acid (PA) on the mitochondrial outer membrane generated by PLD6 facilitates the fusion of mitochondria. However, how PA promotes mitochondrial fusion remains unclear. Here, we show that a mitochondrial outer membrane protein, NME3, is required for PLD6-induced mitochondrial tethering or clustering. NME3 is enriched at the contact interface of two closely positioned mitochondria depending on PLD6, and NME3 binds directly to PA-exposed lipid packing defects via its N-terminal amphipathic helix. The PA binding function and hexamerization confer NME3 mitochondrial tethering activity. Importantly, nutrient starvation enhances the enrichment efficiency of NME3 at the mitochondrial contact interface, and the tethering ability of NME3 contributes to fusion efficiency. Together, our findings demonstrate NME3 as a tethering protein promoting selective fusion between PLD6-remodeled mitochondria for quality control., (© 2023 Su et al.)

Cellular membranes contain numerous lipid species, and efforts to understand the biological functions of individual lipids have been stymied by a lack of approaches for controlled modulation of membrane composition in situ. Here we present a strategy for editing phospholipids, the most abundant lipids in biological membranes. Our membrane editor is based on a bacterial phospholipase D (PLD), which exchanges phospholipid head groups through hydrolysis or transphosphatidylation of phosphatidylcholine with water or exogenous alcohols. Exploiting activity-dependent directed enzyme evolution in mammalian cells, we have developed and structurally characterized a family of 'superPLDs' with up to a 100-fold enhancement in intracellular activity. We demonstrate the utility of superPLDs for both optogenetics-enabled editing of phospholipids within specific organelle membranes in live cells and biocatalytic synthesis of natural and unnatural designer phospholipids in vitro. Beyond the superPLDs, activity-based directed enzyme evolution in mammalian cells is a generalizable approach to engineer additional chemoenzymatic biomolecule editors., (© 2023. The Author(s), under exclusive licence to Springer Nature Limited.)

Background: Measuring missed nursing care in clinical settings may serve as an important indicator for improving patient safety and nursing staff retention. Internationally, several tools exist, with the MISSCARE Survey being the most frequently used and validated; however, no tools are available in the Danish language., Aim: This study aimed at translating the MISSCARE Survey from US English to Danish and evaluate its psychometric properties., Methods: The translation followed the recommended method, that is forward-and-backward translation, involving clinical experts and a professional, native English-speaking translator. The final version was approved by the survey's original developer. Face validity was tested among 10 nurses and 1 practical nurse. Nursing staff from 34 selected departments at Aarhus University Hospital's (n = 1241) were invited to participate in a pilot test in November 2020. The survey consisted of a demographic section, a section of 'nursing elements' (Part A) and section of 'reasons' (Part B). Acceptability was assessed on Part A and B. Reliability was tested by Cronbach's alpha, and psychometric properties were investigated using Confirmatory Factor Analysis (Part B)., Results: The face-validity test resulted in minor contextual changes and the addition of a 'not applicable' response option in Part A. The pilot test had a 42.6% response rate (n = 529). Acceptability was good, with 1-10 missing responses per item in Part A and 0-20 missing responses in Part B. The numbers of 'not applicable' responses ranged from 0 to 81. The overall Cronbach's alpha was 0.81. Factor-loading ranges were 0.62-0.48 for 'communication', 0.79-0.39 for 'materials and resources', and 0.50-0.35 for 'labour', suggesting an acceptable fit with the theoretical model., Conclusion: The MISSCARE Survey was successfully translated into Danish. The psychometric properties confirmed the questionnaire as a valid and reliable tool for measuring missed nursing care in Danish hospital settings., (© 2023 The Authors. Scandinavian Journal of Caring Sciences published by John Wiley & Sons Ltd on behalf of Nordic College of Caring Science.)

Lung group 2 innate lymphoid cells (ILC2s) control the nature of immune responses to airway allergens. Some microbial products, including those that stimulate interferons, block ILC2 activation, but whether this occurs after natural infections or causes durable ILC2 inhibition is unclear. In the present study, we cohoused laboratory and pet store mice as a model of physiological microbial exposure. Laboratory mice cohoused for 2 weeks had impaired ILC2 responses and reduced lung eosinophilia to intranasal allergens, whereas these responses were restored in mice cohoused for ≥2 months. ILC2 inhibition at 2 weeks correlated with increased interferon receptor signaling, which waned by 2 months of cohousing. Reinduction of interferons in 2-month cohoused mice blocked ILC2 activation. These findings suggest that ILC2s respond dynamically to environmental cues and that microbial exposures do not control long-term desensitization of innate type 2 responses to allergens., (© 2022. The Author(s), under exclusive licence to Springer Nature America, Inc.)

Background: Compared with several reports of cerebral vasospasm after clipping for unruptured cerebral aneurysm, only one study to date has reported cerebral vasospasm after coil embolization. Herein, the authors report a rare case of cerebral vasospasm after coil embolization for unruptured cerebral aneurysm., Observations: A 58-year-old woman with an unruptured anterior communicating artery aneurysm was referred to our department. Stent-assisted coil embolization was performed for the aneurysm, and no obvious adverse events were observed on cerebral angiography obtained immediately after the operation. However, the patient developed mild headache and slight restlessness soon after the operation and new-onset disorientation, left hemispatial neglect, and left hemiplegia the day after the operation. Emergency brain magnetic resonance imaging and cerebral angiography indicated vasospasm in the right middle cerebral artery, and intra-arterial injection of fasudil hydrochloride hydrate was performed to dilate the middle cerebral artery. Blood flow in the middle cerebral artery immediately improved, and she was discharged without neurological deficits 8 days after the operation., Lessons: Immediate intervention is necessary to prevent cerebral infarction in patients with cerebral vasospasm, which may occur even after coil embolization for unruptured cerebral aneurysm.

The simple structure of phosphatidic acid (PA) belies its complex biological functions as both a key phospholipid biosynthetic intermediate and a potent signaling molecule. In the latter role, PA controls processes including vesicle trafficking, actin dynamics, cell growth, and migration. However, experimental methods to decode the pleiotropy of PA are sorely lacking. Because PA metabolism and trafficking are rapid, approaches to accurately visualize and manipulate its levels require high spatiotemporal precision. Here, we describe recent efforts to create a suite of chemical tools that enable imaging and perturbation of PA signaling. First, we describe techniques to visualize PA production by phospholipase D (PLD) enzymes, which are major producers of PA, called Imaging Phospholipase D Activity with Clickable Alcohols via Transphosphatidylation (IMPACT). IMPACT harnesses the ability of endogenous PLD enzymes to accept bioorthogonally tagged alcohols in transphosphatidylation reactions to generate functionalized reporter lipids that are subsequently fluorescently tagged via click chemistry. Second, we describe two light-controlled approaches for precisely manipulating PA signaling. Optogenetic PLDs use light-mediated heterodimerization to recruit a bacterial PLD to desired organelle membranes, and photoswitchable PA analogs contain azobenzene photoswitches in their acyl tails, enabling molecular shape and bioactivity to be controlled by light. We highlight select applications of these tools for studying GPCR-G q signaling, discovering regulators of PLD signaling, tracking intracellular lipid transport pathways, and elucidating new oncogenic signaling roles for PA. We envision that these chemical tools hold promise for revealing many new insights into lipid signaling pathways., Competing Interests: Conflict of interest The authors declare that they no conflicts of interest with the contents of this article., (Copyright © 2022 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: Group 2 innate lymphoid cells (ILC2s) are involved in type 2 immune responses in mucosal organs and are associated with various allergic diseases in humans. Studies are needed to understand the molecules and pathways that control ILC2s., Objective: The aims of this study were to develop a mouse model that limits the innate type 2 immune response in the lung and to investigate the immunologic mechanisms involved in regulation of lung ILC2s., Methods: Naive BALB/c mice were administered various Toll-like receptor agonists and exposed intranasally to the fungal allergen Alternaria alternata. The mechanisms were investigated using gene knockout mice as well as cultures of lung cells and isolated lung ILC2s., Results: Polyinosinic-polycytidylic acid, or poly (I:C), effectively inhibited innate type 2 response to A alternata. Poly (I:C) promoted production of IFNα, -β, and -γ, and its inhibitory effects were dependent on the IFN-α/β receptor pathway. IFN-β was 100 times more potent than IFN-α at inhibiting type 2 cytokine production by lung ILC2s. Signal transducer and activator of transcription 5 (STAT5)-activating cytokines, including IL-2, IL-7, and thymic stromal lymphopoietin, but not IL-33, promoted survival and proliferation of lung ILC2s in vitro, while IFN-β blocked these effects. Expression of the transcription factor GATA3, which is critical for differentiation and maintenance of ILC2s, was inhibited by IFN-β., Conclusions: IFN-β blocks the effects of STAT5-activating cytokines on lung ILC2s and inhibits their survival and effector functions. Administration of IFN-β may provide a new strategy to treat diseases involving ILC2s., (Copyright © 2021 American Academy of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.)

Lipids are highly dynamic molecules that, due to their hydrophobicity, are spatially confined to membrane environments. From these locations, certain privileged lipids serve as signaling molecules. For understanding the biological functions of subcellular pools of signaling lipids, induced proximity tools have been invaluable. These methods involve controlled heterodimerization, by either small-molecule or light triggers, of functional proteins. In the arena of lipid signaling, induced proximity tools can recruit lipid-metabolizing enzymes to manipulate lipid signaling and create artificial tethers between organelle membranes to control lipid trafficking pathways at membrane contact sites. Here, we review recent advances in methodology development and biological application of chemical-induced and light-induced proximity tools for manipulating lipid metabolism, trafficking, and signaling., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Enzymes that produce second messengers are highly regulated. Revealing the mechanisms underlying such regulation is critical to understanding both how cells achieve specific signaling outcomes and return to homeostasis following a particular stimulus. Pooled genome-wide CRISPR screens are powerful unbiased approaches to elucidate regulatory networks, their principal limitation being the choice of phenotype selection. Here, we merge advances in bioorthogonal fluorescent labeling and CRISPR screening technologies to discover regulators of phospholipase D (PLD) signaling, which generates the potent lipid second messenger phosphatidic acid. Our results reveal glycogen synthase kinase 3 as a positive regulator of protein kinase C and PLD signaling. More generally, this work demonstrates how bioorthogonal, activity-based fluorescent tagging can expand the power of CRISPR screening to uncover mechanisms regulating specific enzyme-driven signaling pathways in mammalian cells., Competing Interests: The authors declare no competing interest.

Phosphatidic acids (PAs) are glycerophospholipids that regulate key cell signaling pathways governing cell growth and proliferation, including the mTOR and Hippo pathways. Their acyl chains vary in tail length and degree of saturation, leading to marked differences in the signaling functions of different PA species. For example, in mTOR signaling, saturated forms of PA are inhibitory, whereas unsaturated forms are activating. To enable rapid control over PA signaling, we describe here the development of photoswitchable analogues of PA, termed AzoPA and dAzoPA , that contain azobenzene groups in one or both lipid tails, respectively. These photolipids enable optical control of their tail structure and can be reversibly switched between a straight trans form and a relatively bent cis form. We found that cis - dAzoPA selectively activates mTOR signaling, mimicking the bioactivity of unsaturated forms of PA. Further, in the context of Hippo signaling, whose growth-suppressing activity is blocked by PA, we found that the cis forms of both AzoPA and dAzoPA selectively inhibit this pathway. Collectively, these photoswitchable PA analogues enable optical control of mTOR and Hippo signaling, and we envision future applications of these probes to dissect the pleiotropic effects of physiological and pathological PA signaling., Competing Interests: The authors declare no competing financial interest., (© 2021 The Authors. Published by American Chemical Society.)

Eukaryotic cells are compartmentalized into organelles by intracellular membranes. While the organelles are distinct, many of them make intimate contact with one another. These contacts were first observed in the 1950s, but only recently have the functions of these contact sites begun to be understood. In yeast, the endoplasmic reticulum (ER) makes extensive intermembrane contacts with the plasma membrane (PM), covering ∼40% of the PM. Many functions of ER-PM contacts have been proposed, including nonvesicular lipid trafficking, ion transfer, and as signaling hubs. Surprisingly, cells that lack ER-PM contacts grow well, indicating that alternative pathways may be compensating for the loss of ER-PM contact. To better understand the function of ER-PM contact sites we used saturating transposon mutagenesis to identify synthetic lethal mutants in a yeast strain lacking ER-PM contact sites. The strongest hits were components of the ESCRT complexes. The synthetic lethal mutants have low levels of some lipid species but accumulate free fatty acids and lipid droplets. We found that only ESCRT-III components are synthetic lethal, indicating that Vps4 and other ESCRT complexes do not function in this pathway. These data suggest that ESCRT-III proteins and ER-PM contact sites act in independent pathways to maintain lipid homeostasis.

Background: Full-endoscopic spine surgery (FESS) necessitates the use of X-ray fluoroscopy for intraoperative guidance and orientation. However, the two-dimensional X-ray fluoroscopic images do not provide real-time guidance. The authors developed a new real-time three-dimensional (3D) navigation technique for FESS that entails the use of intraoperative cone beam computed tomography (CBCT) in a hybrid operating room (OR)., Methods: A total of 23 patients undergoing FESS using real-time 3D navigation system were enrolled. Preoperative and intraoperative CBCT data were registered in the navigation system. The 3D navigation was used to intraoperatively determine the trajectory and obtain position information. The feasibility and usefulness of the navigation system were retrospectively analyzed., Results: Twenty patients had lumbar spine disease, whereas three patients had cervical spine disease. The 3D navigation was successfully used for intraoperative guidance and provided accurate information in all patients. X-ray fluoroscopy was not required in any of the patients. No complications associated with the use of 3D navigation system were encountered., Conclusions: The use of real-time 3D navigation system in the hybrid OR was found to be safe and effective in providing intraoperative guidance for FESS., Competing Interests: Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at http://dx.doi.org/10.21037/jss-2019-fess-19). The series “Full-endoscopic Spine Surgery” was commissioned by the editorial office without any funding or sponsorship. The authors have no other conflicts of interest to declare., (2020 Journal of Spine Surgery. All rights reserved.)

Background: It is known that patients on hemodialysis (HD) are prone to developing zinc deficiency due to removal of zinc by HD, inadequate dietary intake, and reduced gastrointestinal zinc absorption. However, the prevalence of zinc deficiency in patients on peritoneal dialysis (PD) has not been well established., Methods: Serum zinc levels were compared between 47 patients on PD and 47 patients on HD matched for age, sex, and duration of dialysis. A serum zinc level < 60 μg/dL was defined as clinical zinc deficiency and a level of 60-80 μg/dL as subclinical zinc deficiency. The prevalence of zinc deficiency and associated clinical factors were determined in both groups., Results: Clinical zinc deficiency was found in 59.6% of the PD group and 70.2% of the HD group ( p = 0.391). Subclinical zinc deficiency was found in 40.4% of the PD group and 29.8% of the HD group. Age, body mass index, and serum albumin level were identified as independent predictors of zinc deficiency in the PD group by multivariate analysis., Conclusions: A higher prevalence of clinical and subclinical zinc deficiency was found in patients on PD. The rates were comparable between patients on PD and those on HD after adjustment for confounding factors.

Phosphatidic acid (PA) is both a central phospholipid biosynthetic intermediate and a multifunctional lipid second messenger produced at several discrete subcellular locations. Organelle-specific PA pools are believed to play distinct physiological roles, but tools with high spatiotemporal control are lacking for unraveling these pleiotropic functions. Here, we present an approach to precisely generate PA on demand on specific organelle membranes. We exploited a microbial phospholipase D (PLD), which produces PA by phosphatidylcholine hydrolysis, and the CRY2-CIBN light-mediated heterodimerization system to create an optogenetic PLD (optoPLD). Directed evolution of PLD using yeast membrane display and IMPACT, a chemoenzymatic method for visualizing cellular PLD activity, yielded a panel of optoPLDs whose range of catalytic activities enables mimicry of endogenous, physiological PLD signaling. Finally, we applied optoPLD to elucidate that plasma membrane, but not intracellular, pools of PA can attenuate the oncogenic Hippo signaling pathway. OptoPLD represents a powerful and precise approach for revealing spatiotemporally defined physiological functions of PA., (© 2020 Tei and Baskin.)

Background: We evaluated the erythropoietic effects of canagliflozin, a sodium-glucose cotransporter 2 inhibitor, in type 2 diabetes patients with anemia of chronic kidney disease. Methods: Nine diabetes patients were enrolled and administered 100 mg canagliflozin once a day for 12 weeks. The patients received fixed doses of conventional antidiabetic drugs and renin-angiotensin system inhibitors for 8 weeks before enrollment; these drugs were continued during the study. Endpoints were changes in erythropoiesis parameters, including erythrocyte and reticulocyte count, hemoglobin, hematocrit, and serum erythropoietin (EPO) concentration from baseline to 12 weeks. All variables were measured every 2 weeks. Results: Serum EPO concentration increased by 38 [15-62]% ( P  = 0.043) between baseline and 2 and 4 weeks. Reticulocyte count transiently increased at 2 weeks. Erythropoiesis occurred after 2 weeks of canagliflozin treatment. Erythrocyte count (from 386 ± 36 × 10 4 /μL to 421 ± 36 × 10 4 /μL; P  = 0.0009), hemoglobin (from 11.8 ± 0.6 g/dL to 12.9 ± 1.1 g/dL; P  = 0.0049), and hematocrit (from 37.1 ± 2.3% to 40.4 ± 3.2%; P  = 0.002) increased from baseline to study completion. Although there were no significant changes in transferrin saturation, serum ferritin levels were decreased ( P  = 0.003). Conclusions: Canagliflozin treatment led to an improvement in erythropoiesis in patients with impaired kidney function. The effect on erythropoiesis appeared to be due to an EPO production-mediated mechanism and might be independent of glycemic control; however, further studies are needed to clarify this since the present study had a small sample size and no comparator group.

Background: Carnitine deficiency is common in patients on dialysis. Serum free carnitine concentration is significantly lower in patients on hemodialysis (HD) than in healthy individuals. However, there are few reports on serum free carnitine concentration in patients on peritoneal dialysis (PD)., Methods: We examined serum concentrations of total, free, and acylcarnitine and the acylcarnitine/free carnitine ratio in 34 PD and 34 age-, sex-, and dialysis duration-matched HD patients. We investigated the prevalence of carnitine deficiency and clinical factors associated with carnitine deficiency in the PD group., Results: Prevalence of carnitine deficiency was 8.8% in the PD group and 17.7% in the HD group ( p = 0.283). High risk of carnitine deficiency was found in 73.5% of the PD group and 76.4% of the HD group ( p = 0.604). Carnitine insufficiency was found in 82.3% of the PD group and 88.2% of HD group ( p = 0.733). Multivariate analysis revealed that duration of dialysis and age were independent predictors of serum free carnitine level in the PD group., Conclusions: The prevalence of carnitine deficiency, high risk of carnitine deficiency, and carnitine insufficiency in PD patients was 8.8%, 73.5%, and 82.3%, respectively. These rates were comparable to those in patients on HD.

The fidelity of signal transduction requires spatiotemporal control of the production of signaling agents. Phosphatidic acid (PA) is a pleiotropic lipid second messenger whose modes of action differ based on upstream stimulus, biosynthetic source, and site of production. How cells regulate the local production of PA to effect diverse signaling outcomes remains elusive. Unlike other second messengers, sites of PA biosynthesis cannot be accurately visualized with subcellular precision. Here, we describe a rapid, chemoenzymatic approach for imaging physiological PA production by phospholipase D (PLD) enzymes. Our method capitalizes on the remarkable discovery that bulky, hydrophilic trans -cyclooctene-containing primary alcohols can supplant water as the nucleophile in the PLD active site in a transphosphatidylation reaction of PLD's lipid substrate, phosphatidylcholine. The resultant trans -cyclooctene-containing lipids are tagged with a fluorogenic tetrazine reagent via a no-rinse, inverse electron-demand Diels-Alder (IEDDA) reaction, enabling their immediate visualization by confocal microscopy in real time. Strikingly, the fluorescent reporter lipids initially produced at the plasma membrane (PM) induced by phorbol ester stimulation of PLD were rapidly internalized via apparent nonvesicular pathways rather than endocytosis, suggesting applications of this activity-based imaging toolset for probing mechanisms of intracellular phospholipid transport. By instead focusing on the initial 10 s of the IEDDA reaction, we precisely pinpointed the subcellular locations of endogenous PLD activity as elicited by physiological agonists of G protein-coupled receptor and receptor tyrosine kinase signaling. These tools hold promise to shed light on both lipid trafficking pathways and physiological and pathological effects of localized PLD signaling., Competing Interests: The authors declare no conflict of interest.

Background: Carnitine deficiency is common in patients on hemodialysis. However, the efficacy of L-carnitine supplementation for improving lean body mass (LBM) and physical function has not yet been evaluated., Methods: In this multicenter, prospective, parallel, randomized, controlled trial, 91 patients on hemodialysis who developed carnitine deficiency were randomly assigned to receive injections of 1,000 mg L-carnitine 3 times per week after each hemodialysis session (L-carnitine group) or no injections (control group) with monitoring for 12 months., Results: The data for 84 of the 91 patients were available for analysis (L-carnitine group, n = 42; control group, n = 42). Dry weight and body mass index did not significantly change in the L-carnitine group, but significantly decreased in the control group. Arm muscle area (AMA) did not change significantly in the L-carnitine group but decreased significantly in the control group; the difference in mean AMA between the groups was 6.22% (95% confidence interval [CI] 1.90-10.5; P = 0.037). Hand grip strength did not change significantly in the L-carnitine group, but decreased significantly in the control group. The difference in change in hand grip strength between the groups was 4.27% (95% CI 0.42-8.12; P = 0.030). Furthermore, LBM did not change significantly in the L-carnitine group but decreased significantly in the control group; the difference in mean LBM between the groups was 2.92 % (95% CI 1.28-4.61; P = 0.0007)., Conclusions: L-carnitine supplementation is useful in patients who develop carnitine deficiency on hemodialysis because it maintains physical function and LBM.

Background: Patients on hemodialysis (HD) are known to be at risk of carnitine deficiency. The aims of this study were to investigate the prevalence of carnitine deficiency in patients on dialysis and to compare the likelihood of a reduction in the serum carnitine level on HD with that on hemodiafiltration (HDF)., Methods: The prevalence of carnitine deficiency, defined as a serum free carnitine level < 20 μmol/L, and that of carnitine insufficiency, defined as an acyl/free carnitine ratio > 0.4, was investigated in 150 patients on dialysis. The reduction rate of serum carnitine was then compared between HD and HDF., Results: The prevalence of carnitine deficiency and that of carnitine insufficiency was 25.3 and 86.7%, respectively. Patients at high risk of carnitine deficiency accounted for 64.7%. Multivariate regression identified an association of duration of dialysis with the free serum carnitine level. The reduction rates of serum free carnitine in HD and HDF were 64 ± 4 and 75 ± 7%, respectively (p < 0.0001)., Conclusion: The prevalence rates of carnitine deficiency and carnitine insufficiency were high in patients on dialysis. The serum carnitine reduction rate was greater with HDF than with HD., (© 2019 S. Karger AG, Basel.)

Background: To evaluate the renoprotective effects of canagliflozin, we assessed the albuminuria-lowering effect in Japanese type 2 diabetes patients with chronic kidney disease (CKD)., Methods: In this prospective, open-label, parallel-group study, type 2 diabetes patients with CKD were randomized to receive either oral canagliflozin (100 mg/day) or usual care (control group) for 52 weeks. Endpoints included changes in urinary albumin-to-creatinine ratio (UACR), other urinary biomarkers, laboratory parameters, and adverse events., Results: Both groups included 20 patients in the analysis. Mean changes in UACR was -83 (-266 to -31) mg/gCr and 27 (-11 to 131) mg/gCr, in the canagliflozin and control groups, respectively ( p = 0.004). Urinary liver-type free acid binding protein, N-acetyl-β-d-glucosaminidase, and β 2 -microglobulin levels were also significantly decreased in the canagliflozin group, but not in the control group. Mean change in estimated glomerular filtration rate at the end of the study was 0.7 and -3.4 mL/min/1.73 m 2 in the canagliflozin and control group, respectively ( p = 0.024). Canagliflozin treatment led to improvement of glycaemic control and reduction in body weight, blood pressure, and liver transaminase. There were no adverse events associated with canagliflozin., Conclusion: Canagliflozin was associated with slower progression of kidney disease and reduction in albuminuria and tubulointerstitial markers in diabetes patients with CKD.

Endothelial cells (EC) are involved in regulating several aspects of lipid metabolism, with recent research revealing the clinicopathological significance of interactions between EC and lipids. Induced pluripotent stem cells (iPSC) have various possible medical uses, so understanding the metabolism of these cells is important. In this study, endothelial phenotype cells generated from human iPSC formed cell networks in co-culture with fibroblasts. Changes of plasmalogen lipids and sphingomyelins in endothelial phenotype cells generated from human iPSC were investigated by reverse-phase ultra-high-pressure liquid chromatography mass spectrometry (UHPLC-MS/MS) analysis. The levels of plasmalogen phosphatidylethanolamines (38:5) and (38:4) increased during differentiation of EC, while sphingomyelin levels decreased transiently. These changes of plasmalogen lipids and sphingomyelins may have physiological significance for EC and could be used as markers of differentiation.

Background: Intelectin-1 (ITLN-1) is secreted by intestinal goblet cells and detectable in blood. Its expression is increased in IL-13-overexpressing mouse airways. However, its expression and function in human airways is poorly understood., Methods: Distal and proximal bronchial epithelial cells (BECs) were isolated from bronchoscopic brushings of disease control (D-CON), COPD, inhaled corticosteroid-treated asthma (ST-Asthma) and inhaled corticosteroid-naïve asthma (SN-Asthma) patients. ITLN - 1 mRNA expression in freshly isolated BECs, primary cultured BECs with or without IL-13 and inhibition effects of mometasone furoate (MF) were investigated by quantitative real-time PCR (qPCR). Correlations between ITLN - 1 mRNA and Type-2 related parameters (e.g. FeNO, IgE, iNOS, CCL26, periostin and DPP4 mRNA) were analyzed. ITLN-1 protein distribution in asthmatic airway tissue was assessed by immunohistochemistry. Bronchial alveolar lavage (BAL) and serum ITLN-1 protein were measured by ELISA. The effect of recombinant human (rh) ITLN-1 on stimulated production of CXCL10 and phospho(p)-STAT1 expression examined in lung fibroblasts., Results: ITLN - 1 mRNA was expressed in freshly isolated BECs and was correlated with Type-2 related parameters. ITLN-1 protein was increased in goblet cells in SN-Asthmatics and increased in SN-Asthmatic BAL fluid. There were no any differences in serum ITLN-1 concentration between ST and SN-Asthma. IL-13 enhanced ITLN-1 expression and inhibited by MF from BECs in vitro, while rhITLN-1 inhibited CXCL10 production and p-STAT1 expression in HFL-1 cells., Conclusion: ITLN-1 is induced by IL-13 and expressed mainly in goblet cells in untreated asthma where its levels correlate with known Type-2 related parameters. Further, ITLN-1 inhibits Type-1 chemokine expression.

Carney complex syndrome is an autosomal dominant familial tumor syndrome first described by Carney et al. in 1985. The diagnostic criteria include endocrine hyperactivity and spotty skin pigmentation. A 73-year-old woman with cerebral infarction was referred to our department because her brain magnetic resonance imaging(MRI)revealed a pituitary tumor. Her blood tests revealed elevated levels of growth hormone(GH), thyroid stimulating hormone(TSH), and insulin-like growth factor-1(IGF-1). We suspected the presence of a GH-secreting tumor and performed the operation. The pathological finding was a TSH-positive pituitary adenoma. Her cervical computed tomography(CT)revealed a thyroid tumor and the tumor removal was performed. The pathological diagnosis was papillary carcinoma. She had skin pigmentation bilaterally on her face, forearms, hands, and legs. We diagnosed this case as Carney complex syndrome based on these findings.

Background: There is no published report of ruptured cerebral aneurysm accompanied by target vessel occlusion. We present a case of ruptured basilar tip aneurysm with concomitant basilar artery (BA) occlusion., Case Description: A 53-year-old man presented to our emergency room with the acute onset of disturbance. Plain head computed tomography showed diffuse subarachnoid hemorrhage. Computed tomography angiography and digital subtraction angiography showed a BA tip aneurysm with BA trunk occlusion. Endovascular treatment with mechanical thrombectomy using a stent retriever and coil embolization was performed. Clinical and radiologic results were good. The patient was discharged 30 days after onset (modified Rankin Scale score = 1)., Conclusions: We were able to recanalize the BA trunk and perform coil embolization of the ruptured BA tip aneurysm. Our case is the first published report of a ruptured aneurysm with target large-vessel occlusion. Awareness of the issues raised in this case is required to determine the best treatment strategy, and preoperative consideration allows neurointerventionalists to avoid unpleasant surprises in the angiography suite., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Aims: Saxagliptin is a dipeptidyl peptidase-4 inhibitor that was approved in Japan for the treatment of type 2 diabetes in 2013. We examined its efficacy and safety in Japanese hemodialysis patients with diabetic nephropathy., Methods: In this prospective, open-label, parallel-group study, Japanese hemodialysis patients were randomized to receive either oral saxagliptin (2.5mg/day) or usual care (control group) for 24weeks. Before randomization, patients received fixed doses of conventional antidiabetic drugs (oral drugs and/or insulin) for 8weeks; these drugs were continued during the study. Endpoints included changes in glycated albumin (GA), hemoglobin A1c (HbA1c), postprandial plasma glucose (PPG), and adverse events., Results: Both groups included 41 patients. Mean GA, HbA1c, and PPG decreased significantly in the saxagliptin group (-3.4%, -0.6% [-7mmol/mol], and -38.3mg/dL, respectively; all P<0.0001) but not in the control group (0%, -0.1% [-1mmol/mol], and -3.7mg/dL, respectively) (P<0.0001, P<0.001, and P<0.0001, respectively). In saxagliptin-treated patients, the reduction in GA was significantly greater when saxagliptin was administered as monotherapy than in combination therapy (-4.2% vs. -3.0%, P=0.012) despite similar baseline values (24.5% vs. 23.3%). Reductions in GA, HbA1c, and PPG were greater in patients whose baseline values exceeded the median (23.8% for GA, 6.6% for HbA1c, and 180mg/dL for PPG). There were no adverse events associated with saxagliptin., Conclusions: Saxagliptin (2.5mg/day) was effective and well tolerated when used as monotherapy or combined with other antidiabetic drugs in Japanese hemodialysis patients with type 2 diabetes., Clinical Trial Registration Number: UMIN000018445., (Copyright © 2016 The Authors. Published by Elsevier Ireland Ltd.. All rights reserved.)

Continuous erythropoietin receptor activator (CERA) seems to maintain a stable hemoglobin (Hb) level because its half-life is longer than darbepoetin α (DA). Twenty chronic kidney disease (CKD) patients at the pre-dialysis stage who had been administered DA for over 24 weeks were randomly assigned to receive subcutaneous CERA or DA once every four weeks during 48 weeks. In both groups, the rate of achievement of target Hb level changed from 70% to 100% in weeks 0 to 48, with no significant difference between the groups. Compared with week 0, the Hb level was significantly increased from week 24 in the DA group and from week 8 in the CERA group. In addition, the reticulocyte count was significantly increased from week 4 in the CERA group compared with the DA group. There was no significant difference in the levels of estimated glomerular filtration rate and iron status between both groups. Because of the small number of patients in this study, only limited conclusions can be drawn. However, the results suggest that subcutaneous administration of DA or CERA once every four weeks to predialysis patients has similar effects on achievement of target Hb levels.

Background: In hemodialysis (HD) patients, zinc depletion caused by inadequate intake, malabsorption, and removal by HD treatment leads to erythropoiesis-stimulating agent (ESA) hyporesponsiveness. This study investigated the effects of zinc supplementation in HD patients with zinc deficiency on changes in the erythropoietin responsiveness index (ERI)., Methods: Patients on HD with low serum zinc levels (<65 μg/dL) were randomly assigned to two groups: The polaprezinc group (who received daily polaprezinc, containing 34 mg/day of zinc) (n = 35) and the control group (no supplementation) (n = 35) for 12 months. All the 70 patients had been taking epoetin alpha as treatment for renal anemia. ERI was measured with the following equation: Weekly ESA dose (units)/dry weight (kg)/hemoglobin (g/dL)., Results: There were no significant changes in hemoglobin levels within groups or between the control and polaprezinc groups during the study period. Although reticulocyte counts were increased immediately after zinc supplementation, this change was transient. Serum zinc levels were significantly increased and serum copper levels were significantly decreased in the polaprezinc group after three months; this persisted throughout the study period. Although there was no significant change in the serum iron or transferrin saturation levels in the polaprezinc group during the study period, serum ferritin levels significantly decreased following polaprezinc treatment. Further, in the polaprezinc group, ESA dosage and ERI were significantly decreased at 10 months and nine months, respectively, as compared with the baseline value. Multiple stepwise regression analysis revealed that the change in the serum zinc level was an independent predictor of lowered ERI., Conclusions: Zinc supplementation reduces ERI in patients undergoing HD and may be a novel therapeutic strategy for patients with renal anemia and low serum zinc levels.

Objective: The complement system and activated neutrophils are thought to play a major role in initiating some of the inflammatory events that occur in spinal cord injury. The aim of the present study was to assess the effects of C1 esterase inhibitor (C1-INH) on traumatic spinal cord injury (SCI) in the rat., Methods: Thirty-eight male Wistar rats were used. Just after SCI by a pneumatic impact device, C1-INH (n=16, C1-INH group) or saline (n=16, saline group) was administered. Sham operated animals (n=6, sham group) received only laminectomy. Eighteen (six from each group) rats were killed and an assessment of leukocyte infiltration by myeloperoxidase (MPO) activity and immunoreactivity of MPO were performed 24 hours after SCI. Twenty (ten from each of C1-INH and saline groups) rats were examined using behavioral function on post-operative days. They were also examined after 7 days by histologic analysis using Luxol fast blue for axons and myelin. Lesion volume was calculated by considering a lesion as being composed of two cones with juxtaposed bases. During the experiment, sequential changes in regional spinal cord blood flow (rSCBF) were measured using the laser Doppler (LD) scanning technique., Results: The recovery of motor function was better in the C1-INH group than in the saline group. In the C1-INH group, immunoreactivity of MPO showed a tendency to be smaller than that of the saline group. Lesion volume was significantly smaller in the C1-INH group than in the control group (p<0.01) and MPO activity was also significantly smaller in the C1-INH group than in the control group (p<0.01). After SCI, the rSCBF value decreased gradually and significantly in both injured groups. Significant differences were observed from 30 to 120 minutes after SCI (p<0.05)., Discussion: The results of this study provided the first evidence that C1-INH reduced accumulation of polymorphonuclear leukocytes (PMLs) and neuronal damage in acute stage after SCI. This protection was not related to an improvement in rSCBF.

A 51-year-old woman presented with a rare completely intradural and extramedullary spinal ganglioneuroma associated with multiple hamartoma syndrome and manifesting as complaints of neck pain and dizziness persisting for 8 months. Magnetic resonance imaging of the spinal cord revealed an intradural extramedullary lesion at the C1 level. She underwent right suboccipital craniectomy and C1-2 hemilaminectomy to remove the tumor. Histological examination confirmed ganglioneuroma. She also suffered from multiple facial trichilemmomas, thyroid goiter, multiple polyposis of the gastrointestinal tract, and pulmonary hamartoma indicating multiple hamartoma syndrome. These benign neoplasms were treated conservatively.

A 52-year-old woman presented with an intraspinal extradural meningeal cyst in the thoracolumbar region manifesting as progressive sensory disturbance of the bilateral lower extremities. Magnetic resonance imaging and computed tomography myelography showed an extradural meningeal cyst extending from the T-12 to L-4 levels in the thoracolumbar region with a dural defect and a valve-like mechanism developed in the enlarging cyst. Operative findings revealed a dural defect that allowed communication between the extradural cyst cavity and the subarachnoid space. Surgical resection of the cyst wall and repair of the dural defect resolved the symptoms.

A 49-year-old female presented with a rare giant schwannoma arising from the dura mater of the middle fossa manifesting as loss of left visual acuity. Magnetic resonance imaging revealed a heterogeneously enhanced giant mass in the left middle fossa. Surgery via the transsylvian approach confirmed the origin of the tumor between the left internal carotid artery and the trigeminal nerve in the lateral wall of the cavernous sinus. Elongated abducens nerve was confirmed, but no tumor adhesion to the abducens nerve was found. The tumor was closely attached to the dura mater of the middle fossa and the lateral wall of the cavernous sinus. The histological diagnosis was schwannoma. Both left oculomotor and abducens nerve pareses occurred immediately after the operation but gradually resolved over 3 months. The operative findings indicated that this schwannoma may have arisen from the meningeal branch of the trigeminal nerve in the dura mater of the middle fossa.

Objective: The incidence of spinal infections has increased in recent years, and vertebral osteomyelitis and epidural abscess are issues of great concern for spine surgeons. We retrospectively reviewed our cases treated by two-stage management for vertebral osteomyelitis and epidural abscess., Methods: The series consisted of nine patients (five men and four women); their ages ranged from 49 to 77 years (mean age, 60.6 yr). Coexisting medical conditions were diabetes mellitus in one case and long-term steroid intake in another. Myelopathy or radicular pain was caused by osteomyelitis and an epidural abscess in all patients. Cervical, thoracic, and lumbar osteomyelitis was detected in three, four, and two patients, respectively; epidural abscess was pyogenic in four patients, tuberculous in three, and unknown in two patients. Our surgical strategy involved anterior debridement or drainage and application of an external orthosis postoperatively during the first stage. After clinical control of the infection by using organism-specific intravenous antibiotics as far as possible, as confirmed by normal erythrocyte sedimentation rate and/or C-reactive protein, second stage surgery was performed. This included complete debridement of all necrotic bone and soft tissues, and stable reconstruction with or without instrumentation (six and three patients, respectively)., Results: The postoperative course was uneventful with relief of the symptoms after the second surgery. No evidence of recurrence or residual infection was observed in any patient, as shown by erythrocyte sedimentation rate and/or C-reactive protein levels during a follow-up period averaging 26.6 months (range, 2-56 mo)., Conclusion: Without denying the efficacy of the single-stage surgery, two-stage management can be a reasonable alternative for carefully selected patients who have spinal infection.

Objective: Use of instrumentation in spinal osteomyelitis remains controversial because of the perceived risk of persistent infection related to a devitalized graft and spinal hardware. Particularly, limited information is available regarding the long-term follow-up of patients. We retrospectively reviewed the use of titanium mesh-bone graft composite after corpectomy in pyogenic spinal infection with a minimum 3-year follow-up outcome., Methods: Four patients, two men and two women, with cervical and thoracic myelopathy caused by cervical (two cases) and thoracic (two cases) osteomyelitis and epidural abscess, were treated. Their age ranged from 49 to 74 years (mean age 58 years). In one case, the coexisting medical condition was diabetes. Neurologic deficits caused by direct spinal cord compression due to epidural abscess, segmental deformity, and instability were observed in all cases. After infection was clinically controlled by intravenous antibiotics, anterior debridement and fusion using titanium mesh cage along with anterior plate were performed. Two-stage treatment was performed in two cases., Results: The postoperative course was uneventful; all patients experienced relief of symptoms. No evidence of recurrence or residual infection was observed in any patient during the average follow-up period of 42-56 months (average 49.0 months)., Conclusions: Once infection is clinically controlled, a titanium mesh-bone graft composite and plate in combination with aggressive debridement might provide an effective therapy for spinal osteomyelitis requiring surgery. Despite studying a small number of patients, we can conclude that titanium mesh reconstruction can be useful as a surgical method in selected low-risk patients with vertebral osteomyelitis.

Objectives: The evaluation of the spatial spread of ischemia following spinal cord injury (SCI) is important for planning therapeutic strategies for secondary injury. The purpose of this study was to investigate in detail the change in regional spinal cord blood flow (rSCBF) after SCI., Methods: Thirty-four male Wistar rats were used, for which laminectomies of the T11-13 vertebrae were performed. SCI was produced by a directed impact through a laminectomy site at the level of the Th12 using a pneumatic impact device. We measured the sequential and spatial changes of rSCBF using a laser Doppler scanning technique before and after SCI in rats not only at the injured myelomere but also at the circumferent myelomeres. SCBF mapping was carried out before and after SCI on each site., Results: After SCI, the rSCBF value gradually decreased for each site for the SCI group (n=26), while it globally decreased at the epicenter. Moreover, a decrease in SCBF was observed at the caudal and rostral sites. The mean value of the %SCBF 120 minutes after SCI for each site was 63.6+/-2.3% (Th11), 74.4+/-4.5% (Th12), 75.8+/-3.2% (Th13), and was significantly lower for the rostral site compared with the caudal site (p<0.05, one-way analysis of variance)., Discussion: This study found that SCBF is significantly decreased not only at the injured myelomere but also at the circumferent myelomeres. Circumferentially extending ischemia after SCI is related to secondary injury after SCI. The improvement in SCBF after SCI, therefore, can be attributed to the treatment of SCI.