Dimethyl Fumarate Mediates Sustained Vascular Smooth Muscle Cell Remodeling in a Mouse Model of Cerebral Aneurysm.

Cerebral aneurysms (CA) are a type of vascular disease that causes significant morbidity and mortality with rupture. Dysfunction of the vascular smooth muscle cells (VSMCs) from circle of Willis (CoW) vessels mediates CA formation, as they are the major cell type of the arterial wall and play a role in maintaining vessel integrity. Dimethyl fumarate (DMF), a first-line oral treatment for relapsing-remitting multiple sclerosis, has been shown to inhibit VSMC proliferation and reduce CA formation in a mouse model. Potential unwanted side effects of DMF on VSMC function have not been investigated yet. The present study characterizes the impact of DMF on VSMC using single-cell RNA-sequencing (scRNA-seq) in CoW vessels following CA induction and further explores its role in mitochondrial function using in vitro VSMC cultures. Two weeks of DMF treatment following CA induction impaired the transcription of the glutathione redox system and downregulated mitochondrial respiration genes in VSMCs. In vitro, DMF treatment increased lactate formation and enhanced the mitochondrial production of reactive oxygen species (ROS). These effects rendered VSMCs vulnerable to oxidative stress and led to mitochondrial dysfunction and enhancement of apoptosis. Taken together, our data support the concept that the DMF-mediated antiproliferative effect on VSMCs is linked to disturbed antioxidative functions resulting in altered mitochondrial metabolism. This negative impact of DMF treatment on VSMCs may be linked to preexisting alterations of cerebrovascular function due to renal hypertension. Therefore, before severe adverse effects emerge, it would be clinically relevant to develop indices or biomarkers linked to this disturbed antioxidative function to monitor patients undergoing DMF treatment.

Utility of Decremental Triggered Electromyogram for Intraoperative Neuromonitoring to Identify Midline in Posterior Myelotomy for Spinal Cord Intramedullary Lesions: Technical Note of a Novel Method.

BACKGROUND AND IMPORTANCE: Intramedullary spinal cord lesions are eloquent lesions that are surgically resected via posterior midline myelotomy (PMM). This treatment method carries the risk of postoperative neurological deficits. Various intraoperative neuromonitoring techniques have been used to address this concern. Our study aimed to highlight a newly developed monitoring technique (decremental-triggered electromyogram [dtEMG]) as a novel method to identify the spinal cord midline during PMM. CLINICAL PRESENTATION: Seven patients in prone position underwent PMM for an intramedullary lesion using dtEMG for neuromonitoring. dtEMG was used to determine the threshold amplitude (ie, the lowest amplitude to elicit an EMG response) as well as a silent zone, which was determined to be the midline. The age range was 26-73 years. dtEMG detected a silent zone in 6/7 patients. The only patient in whom dtEMG was not useful was a patient with complete paraplegia and sensory loss before surgery. There were no motor evoked or somatosensory evoked potential changes related to PMM in these patients. DISCUSSION: Although the commonly used neuromonitoring techniques, including motor and sensory evoked potentials and free-run electromyograms are of utmost importance in spinal cord surgery, they lack the potential to identify midline in such cases. The currently available tools, including dorsal column mapping, are more cumbersome to use. CONCLUSION: The newly proposed dtEMG technique can safely and efficiently identify the midline when used as an intraoperative neuromonitoring technique in PMM for spinal cord intramedullary lesion resection.

Predicting the Need for Surgery in Patients with Lumbar Disc Herniation: A New Internally Validated Scoring System.

STUDY DESIGN: Prospective study. PURPOSE: To propose a scoring system for predicting the need for surgery in patients with lumbar disc herniation (LDH). OVERVIEW OF LITERATURE: The indications for surgery in patients with LDH are well established. However, the exact timing of surgery is not. According to surgeons, patients with failed conservative treatment who underwent delayed surgery, often after 6 months postsymptom initiation, have poor functional recovery and outcome. METHODS: The current study included patients with symptomatic LDH. Patients with an indication for emergent surgery such as profound or progressive motor deficit, cauda equina syndrome, and diagnoses other than single-level LDH were excluded from the analysis. All patients followed a conservative treatment regimen (a combination of physical therapy, pain medications, and/or spinal epidural steroid injections). Surgery was indicated for patients who continuously experienced pain despite maximal conservative therapy. RESULTS: In total, 134 patients met the inclusion and exclusion criteria. Among them, 108 (80.6%) responded to conservative management, and 26 (19.4%) underwent unilateral laminotomy and microdiscectomy. The symptom duration, disc degeneration grade on magnetic resonance imaging (Pfirrmann disc grade), herniated disc location and type, fragment size, and thecal sac diameter significantly differed between patients who responded to conservative treatment and those requiring surgery. The area under the receiver operating characteristic curve of the scoring system based on the anteroposterior size of the herniated disc fragment and herniated disc location and type was 0.81. CONCLUSIONS: A scoring system based on herniated disc/fragment size, location, and type can be applied to predict the need for surgery in patients with LDH. In the future, this tool can be used to prevent unnecessarily prolonged conservative management (>4-8 weeks).

Prevalence, Laterality, and Classification of Ossified Petroclival Ligaments: An Anatomical and Histological Study With Application to Skull Base Surgery.

Background The petroclival ligament (PL) forms the roof of Dorello's canal (DC). In humans, partial and complete ossification of this ligament have been reported. When completely ossified, DC is transformed into a bony foramen for the abducens nerve and accompanying vascular structures. As this osteological finding might have an impact on skull base surgery, this anatomical study was performed. Methodology Using 100 adult human skulls, the presence of an ossified PL was noted and classified. The diameter of the resultant bony foramen and laterality were documented. Additionally, PL was evaluated histologically in 10 heads. Results Overall, 8% of the sides were found to have partial or complete ossification of the PL. Partial ossification (type I) was noted on 3% of the sides. Completely ossified PL was identified on 5% of the sides. Some ossified ligaments (2.5%) were seen as an ossified bridge (type II), and others (2.5%) were converted into small foramina (type III). Three skulls (3%) were found to have a completely ossified ligament bilaterally. The mean diameter of the underlying DC was 0.8 mm. Partially ossified ligaments were statistically more likely to be on the right sides, and the diameter of the underlying DC was statistically smaller in type III. Histologically, the PL was found to have bone within it on three skull sides. Conclusions An ossified ligament can be found on imaging of the skull base. Moreover, during surgical approaches to the petroclival region and, specifically, DC, skull base surgeons should be cognizant of this anatomical variation.

Granular Foveolae in the Groove of the Sigmoid Sinus: An Anatomical Study.

Background Granular foveolae in the groove of the sigmoid sinus have rarely been reported in the literature compared to numerous published reports on the granular foveolae near the superior sagittal sinus and its sulcus on the internal aspect of the calvaria. The present study was performed to better elucidate their prevalence and locations. Materials and methods One hundred and ten adult dry skulls (220 sides) were analyzed for the presence of granular foveolae within the groove of the sigmoid sinus. The exact position of the foveolae was documented, and the diameter of the granular foveola was measured. Results Granular foveolae were found in the groove of the sigmoid sinus on 3.6% of the sides. These were at or within a mean of 1.3 cm inferior to the transverse-sigmoid junction. When a mastoid foramen was noted in the groove, it was always located inferior to the granular foveolae when present. The mean diameters of the granular foveolae of the left groove of the sigmoid sinus were 2.8 mm and 4 mm for the right grooves. The mean depth of the granular foveolae in the left groove of the sigmoid sinus was 2.7 mm and 3.5 mm for the right grooves. Granular foveolae were statistically larger and deeper on the right versus left sides (p<0.05). Conclusions Granular foveolae of the groove of the sigmoid sinus were identified most commonly on the right sides and 3.6% on all sides. If identified on medical imaging, these uncommon structures at the skull base should be considered normal anatomical variations.

Morphology of the groove of the inferior petrosal sinus: application to better understanding variations and surgery of the skull base.

Although adequate venous drainage from the cranium is imperative for maintaining normal intracranial pressure, the bony anatomy surrounding the inferior petrosal sinus and the potential for a compressive canal or tunnel has, to our knowledge, not been previously investigated. One hundred adult human skulls (200 sides) were observed and documented for the presence or absence of an inferior petrosal groove or canal. Measurements were made and a classification developed to help better understand their anatomy and discuss it in future reports. We identified an inferior petrosal sinus groove (IPSG) in the majority of specimens. The IPSG began anteriorly where the apex of the petrous part of the temporal bone articulated with the sphenoid part of the clivus, traveled posteriorly, in a slight medial to lateral course, primarily just medial to the petro-occipital fissure, and ended at the anteromedial aspect of the jugular foramen. When the IPSGs were grouped into five types. In type I specimens, no IPSG was identified (10.0%), in type II specimens, a partial IPSG was identified (6.5%), in type III specimens, a complete IPSG (80.0%) was identified, in type IV specimens, a partial IPS tunnel was identified (2.5%), and in type V specimens, a complete tunnel (1.0%) was identified. An improved knowledge of the bony pathways that the intracranial dural venous sinuses take as they exit the cranium is clinically useful. Radiological interpretation of such bony landmarks might improve patient diagnoses and surgically, such anatomy could decrease patient morbidity during approaches to the posterior cranial fossa.

Prevalence of Petrooccipital Fissure Fusion: Osteological Study with Application to Approaches to the Skull Base and Imaging Interpretation.

INTRODUCTION: The petrooccipital fissure (POF) has relevance to skull base approaches, various tumors and craniosynostoses, and some cases of age-related hearing loss. However, the prevalence of fusion and classification of such is rarely found in the extant medical literature. METHODS: One-hundred and 10 dry human skulls (220 sides) were used for this study. The skulls were evaluated for fusion of the POF. Both the endocranial and exocranial aspects of the POF were analyzed. A classification scheme was developed to better describe the location of POF fusion. RESULTS: A fused POF was identified on 36 sides (16.4%) and commonly found bilaterally (11%). Of these, 30 sides (83.3%) were completely fused (type I) and 6 sides (2.7%) were partially fused (types II and III). For the partially fused fissures, the fused part was on all but 2 sides with the most anterior portion of the petrous part of the temporal bone and adjacent clivus (type II). For the 2 sides (both right sides), the fusion was more posteriorly located between the petrous part of the temporal bone and lateral clivus (type III). Fusion of the POF was more often found in specimens with a partially or fully ossified petroclival ligament. Completely fused POF was positively correlated to sides with an intrajugular bony septum. CONCLUSIONS: A POF fusion was relatively common and associated with an ossified petroclival ligament and intrajugular bony septation. Such a prevalence is important for clinicians and skull base surgeons interpreting imaging of the skull base.

SARS-CoV-2-specific T cells are rapidly expanded for therapeutic use and target conserved regions of the membrane protein.

T-cell responses to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) have been described in recovered patients, and may be important for immunity following infection and vaccination as well as for the development of an adoptive immunotherapy for the treatment of immunocompromised individuals. In this report, we demonstrate that SARS-CoV-2-specific T cells can be expanded from convalescent donors and recognize immunodominant viral epitopes in conserved regions of membrane, spike, and nucleocapsid. Following in vitro expansion using a good manufacturing practice-compliant methodology (designed to allow the rapid translation of this novel SARS-CoV-2 T-cell therapy to the clinic), membrane, spike, and nucleocapsid peptides elicited interferon-γ production, in 27 (59%), 12 (26%), and 10 (22%) convalescent donors (respectively), as well as in 2 of 15 unexposed controls. We identified multiple polyfunctional CD4-restricted T-cell epitopes within a highly conserved region of membrane protein, which induced polyfunctional T-cell responses, which may be critical for the development of effective vaccine and T-cell therapies. Hence, our study shows that SARS-CoV-2 directed T-cell immunotherapy targeting structural proteins, most importantly membrane protein, should be feasible for the prevention or early treatment of SARS-CoV-2 infection in immunocompromised patients with blood disorders or after bone marrow transplantation to achieve antiviral control while mitigating uncontrolled inflammation.