VISTA Emerges as a Promising Target against Immune Evasion Mechanisms in Medulloblastoma.

BACKGROUND: Relapsed medulloblastoma (MB) poses a significant therapeutic challenge due to its highly immunosuppressive tumor microenvironment. Immune checkpoint inhibitors (ICIs) have struggled to mitigate this challenge, largely due to low T-cell infiltration and minimal PD-L1 expression. Identifying the mechanisms driving low T-cell infiltration is crucial for developing more effective immunotherapies. METHODS: We utilize a syngeneic mouse model to investigate the tumor immune microenvironment of MB and compare our findings to transcriptomic and proteomic data from human MB. RESULTS: Flow cytometry reveals a notable presence of CD45hi/CD11bhi macrophage-like and CD45int/CD11bint microglia-like tumor-associated macrophages (TAMs), alongside regulatory T-cells (Tregs), expressing high levels of the inhibitory checkpoint molecule VISTA. Compared to sham control mice, the CD45hi/CD11bhi compartment significantly expands in tumor-bearing mice and exhibits a myeloid-specific signature composed of VISTA, CD80, PD-L1, CTLA-4, MHCII, CD40, and CD68. These findings are corroborated by proteomic and transcriptomic analyses of human MB samples. Immunohistochemistry highlights an abundance of VISTA-expressing myeloid cells clustering at the tumor-cerebellar border, while T-cells are scarce and express FOXP3. Additionally, tumor cells exhibit immunosuppressive properties, inhibiting CD4 T-cell proliferation in vitro. Identification of VISTA's binding partner, VSIG8, on tumor cells, and its correlation with increased VISTA expression in human transcriptomic analyses suggests a potential therapeutic target. CONCLUSIONS: This study underscores the multifaceted mechanisms of immune evasion in MB and highlights the therapeutic potential of targeting the VISTA-VSIG axis to enhance anti-tumor responses.

A hidden infection: Racemose neurocysticercosis causing hydrocephalus; a case report.

INTRODUCTION AND IMPORTANCE: Neurocysticercosis (NCC) is the most common helminthic central nervous system infection (CNS) in the Western hemisphere and the most common cause of acquired epilepsy worldwide. Due to its relatively prolonged latent period and clinical similarity to other infectious diseases - including bacterial or viral meningitis and other helminthic infections - NCC may be difficult to diagnose, especially for clinicians who rarely encounter it. CASE PRESENTATION: This case report discusses a patient with obstructive hydrocephalus and eosinophilic meningitis secondary to racemose NCC. The diagnosis process was initially complicated by the patient's history of pork allergy and absence of radiographic evidence of helminthic CNS infection. Further investigation showed a 4th ventricle multi-cystic lesion causing hydrocephalus which prompted a surgical intervention with a ventriculoperitoneal shunt (VPS) in conjunction with anti-helminthic medical treatment. At 1-year follow-up, the patient has reported recurrence of VPS related complications. CLINICAL DISCUSSION: Larval cysts typically deposit within the brain parenchyma, making them easily detected on head computed tomography (CT) scans and leading to neurologic sequelae such as epilepsy. In this case, the absence of CT evidence of NCC and the patient's lifelong history of pork allergy slowed the diagnosis process. CONCLUSION: Racemose NCC is a rare subset of the disease in which cyst clusters occupy the extra parenchymal space, thereby changing the symptomatic profile and making the cysts more difficult to visualize in imaging studies. In this case, magnetic resonance imaging (MRI) was the best imaging modality to diagnosis extra parenchymal NCC and guide its surgical management.

Intra-articular MMP-1 in the spinal facet joint induces sustained pain and neuronal dysregulation in the DRG and spinal cord, and alters ligament kinematics under tensile loading.

Chronic joint pain is a major healthcare challenge with a staggering socioeconomic burden. Pain from synovial joints is mediated by the innervated collagenous capsular ligament that surrounds the joint and encodes nociceptive signals. The interstitial collagenase MMP-1 is elevated in painful joint pathologies and has many roles in collagen regulation and signal transduction. Yet, the role of MMP-1 in mediating nociception in painful joints remains poorly understood. The goal of this study was to determine whether exogenous intra-articular MMP-1 induces pain in the spinal facet joint and to investigate effects of MMP-1 on mediating the capsular ligament's collagen network, biomechanical response, and neuronal regulation. Intra-articular MMP-1 was administered into the cervical C6/C7 facet joints of rats. Mechanical hyperalgesia quantified behavioral sensitivity before, and for 28 days after, injection. On day 28, joint tissue structure was assessed using histology. Multiscale ligament kinematics were defined under tensile loading along with microstructural changes in the collagen network. The amount of degraded collagen in ligaments was quantified and substance P expression assayed in neural tissue since it is a regulatory of nociceptive signaling. Intra-articular MMP-1 induces behavioral sensitivity that is sustained for 28 days (p < 0.01), absent any significant effects on the structure of joint tissues. Yet, there are changes in the ligament's biomechanical and microstructural behavior under load. Ligaments from joints injected with MMP-1 exhibit greater displacement at yield (p = 0.04) and a step-like increase in the number of anomalous reorganization events of the collagen fibers during loading (p ≤ 0.02). Collagen hybridizing peptide, a metric of damaged collagen, is positively correlated with the spread of collagen fibers in the unloaded state after MMP-1 (p = 0.01) and that correlation is maintained throughout the sub-failure regime (p ≤ 0.03). MMP-1 injection increases substance P expression in dorsal root ganglia (p < 0.01) and spinal cord (p < 0.01) neurons. These findings suggest that MMP-1 is a likely mediator of neuronal signaling in joint pain and that MMP-1 presence in the joint space may predispose the capsular ligament to altered responses to loading. MMP-1-mediated pathways may be relevant targets for treating degenerative joint pain in cases with subtle or no evidence of structural degeneration.

Intra-articular collagenase in the spinal facet joint induces pain, DRG neuron dysregulation and increased MMP-1 absent evidence of joint destruction.

Degeneration is a hallmark of painful joint disease and is mediated by many proteases that degrade joint tissues, including collagenases. We hypothesized that purified bacterial collagenase would initiate nociceptive cascades in the joint by degrading the capsular ligament's matrix and activating innervating pain fibers. Intra-articular collagenase in the rat facet joint was investigated for its effects on behavioral sensitivity, joint degeneration, and nociceptive pathways in the peripheral and central nervous systems. In parallel, a co-culture collagen gel model of the ligament was used to evaluate effects of collagenase on microscale changes to the collagen fibers and embedded neurons. Collagenase induced sensitivity within one day, lasting for 3 weeks (p < 0.001) but did not alter ligament structure, cartilage health, or chondrocyte homeostasis. Yet, nociceptive mediators were increased in the periphery (substance P, pERK, and MMP-1; p ≤ 0.039) and spinal cord (substance P and MMP-1; p ≤ 0.041). The collagen loss (p = 0.008) induced by exposing co-cultures to collagenase was accompanied by altered neuronal activity (p = 0.002) and elevated neuronal MMP-1 (p < 0.001), suggesting microscale collagen degradation mediates sensitivity in vivo. The induction of sustained sensitivity and nociception without joint damage may explain the clinical disconnect in which symptomatic joint pain patients present without radiographic evidence of joint destruction.

Intra-articular etanercept attenuates pain and hypoxia from TMJ loading in the rat.

Mechanical overloading of the temporomandibular joint (TMJ) and biochemical changes, like inflammation and hypoxia, contribute to cartilage degeneration and pain associated with osteoarthritis (OA). Yet, how overloading contributes to early dysregulation of chondrocytes is not understood, limiting the development of diagnostics and treatments for TMJ OA. Hypoxia-inducible factors (HIF)-1α/2α in chondrocytes were evaluated at Days 8 and 15 in a rat TMJ pain model induced by jaw loading (1 h/day for 7 days) using immunohistochemistry and compared between cases that induce persistent (3.5 N), acute (2 N), or no (0 N) sensitivity. Hypoxia was measured on Day 8 by immunolabeling of the tracer EF5 and 18 F-EF5 PET imaging. To assess the role of tumor necrosis factor (TNF) in painful TMJ loading, intra-articular etanercept was given before loading. Orofacial sensitivity was evaluated during and after loading. Facial grimace, TNF-α, HIF-2α, and hypoxia levels in the TMJ were measured after loading. HIF-2α was elevated (P = .03) after 3.5 N loading at Day 8, but HIF-1α was unchanged. EF5 uptake increased on Day 8 in the 3.5 N group (P < .048) by tissue assay and 18 F-EF5 PET. At Day 8, both HIF-2α (P = .01) and EF5 uptake (P = .005) were correlated with loading magnitude. Etanercept attenuated sensitivity (P < .01) and the facial grimace on Day 7 (P = .01). It also reduced (P < .01) HIF-2α and EF5 uptake on Day 8; but TNF-α levels were not different from controls at that time. Findings suggest that TMJ loading that induces persistent sensitivity upregulates the catabolic factor HIF-2α and reduces oxygen levels in the cartilage, which may be TNF-driven.

Remote Virtual Spinal Evaluation in the Era of COVID-19.

BACKGROUND: With the COVID-19 pandemic disrupting many facets of our society, physicians and patients have begun using telemedicine as a platform for the delivery of health care. One of the challenges in implementing telemedicine for the spine care provider is completing a comprehensive spinal examination. Currently, there is no standardized methodology to complete a full spinal examination through telemedicine. METHODS: We propose a novel, remote spinal examination methodology that is easily implemented through telemedicine, where the patient is an active participant in the successful completion of his or her examination. This type of examination has been validated in a neurology setting. To facilitate the telemedicine visit, we propose that video instruction be shared with the patient prior to the telemedicine visit to increase the efficacy of the examination. RESULTS: Since the issuance of stay-at-home order across the states, many spine practices around the country have rapidly adopted and increased their telemedicine program to continue provide care for patients during COVID-19 pandemic. At a tertiary academic center in a busy metropolitan area, nearly 700 telemedicine visits were successfully conducted during a 4-week period. There were no remote visits being done prior to the shutdown. CONCLUSIONS: Implementation of our proposed remote spinal examination has the potential to serve as a guideline for the spine care provider to efficiently assess patients with spine disease using telemedicine. Because these are only suggestions, providers should tailor examination to each individual patient's needs. LEVEL OF EVIDENCE: V. CLINICAL RELEVANCE: It is likely that physicians will incorporate telemedicine into health care delivery services even after the COVID-19 pandemic subsides because of telemedicine's efficiency in meeting patient needs. Using the standard maneuvers provided in our study, spine care providers can perform a nearly comprehensive spine examination through telemedicine. Further studies will be needed to validate the reproducibility and reliability of our methodology.

Email as an Encumbrance to Physician-patient Communication.

Physician-patient interaction through email poses several concerns regarding the security, efficiency, and misinterpretation of critical information. Incoming emails received by a single university-based physician in 2013 were analyzed in order to determine whether a general non-patient specific email is appropriate for patient use. Emails received were divided into seven categories: Informational, Academic, Advertisement, Organization/Department/ University, Mission Critical, Personal, and Patient. A total of 9,102 emails were received and read by the physician, with an average of 25 emails per day, out of which 823 (9%) emails were directly sent by patients. The total time spent reading emails was five days, seven hours, and 24 minutes. General email is not an effective means of streamlining physician-patient communication. Non-essential emails, which represent a majority of incoming messages, decrease the productivity of physicians and prevent them from responding to urgent messages in a timely manner. Additionally, this creates the chance for critical patient information getting lost with the volume of received emails. This could be detrimental to patient care and satisfaction. Recently, an online portal was instated to provide a method of secure communication, and less than five patient emails were received in the physician's personal email since then.

A Prospective Detailed Time Analysis Study of 18 Patients Undergoing Elective Single-Level Open Lumbar Microdiscectomy Spinal Surgery Compared with Centers for Medicare and Medicaid Services Reimbursement Guidelines.

BACKGROUND: Single-level open lumbar microdiscectomy surgery is one of the most straightforward and effective spinal surgeries performed by spinal surgeons today to treat disk herniation. Although a common operation, little in the literature is reported on the exact overall time, cost, and effort associated with the performance of this surgery. The consistency of this operation across institutions and disciplines makes it a good starting point to accurately track the total time and effort of all phases of the surgical intervention. METHODS: Eighteen patients undergoing elective single-level open lumbar microdiscectomy surgery were prospectively enrolled in this study. The time spent interacting with each patient by every member of the surgical team was tracked and recorded along will every phone call and e-mail. All perioperative times associated with the surgery were tracked and analyzed. Each patient was followed from their first interaction through surgery and for the first 3 months postoperatively. RESULTS: The advanced practice providers spent the most time with the patient both pre- and postoperatively followed by the surgeon and resident. A total of 2.98 hours was spent with the patient preoperatively in clinic and 1.69 hours postoperatively. The total time commitment of an institution treating this condition was 12.56 hours. CONCLUSIONS: Comparing our results with the Centers for Medicare and Medicaid Services data, a significant discrepancy and underestimation was observed. As such, we hope our results enable health care providers to more accurately allocate resources for the provision of high-quality medical care to patients with this increasingly common condition.

Grading facial expression is a sensitive means to detect grimace differences in orofacial pain in a rat model.

Although pre-clinical models of pain are useful for defining relationships between biological mechanisms and pain, common methods testing peripheral sensitivity do not translate to the human pain experience. Facial grimace scales evaluate affective pain levels in rodent models by capturing and scoring spontaneous facial expression. But, the Rat Grimace Scale (RGS) has not assessed the common disorder of temporomandibular joint (TMJ) pain. A rat model of TMJ pain induced by jaw loading (1 hr/day for 7 days) was used to investigate the time course of RGS scores and compare them between different loading magnitudes with distinct peripheral sensitivity profiles (0N-no sensitivity, 2N-acute sensitivity, 3.5N-persistent sensitivity). In the 3.5N group, RGS is elevated over baseline during the loading period and one day after loading and is correlated with peripheral sensitivity (ρ = -0.48, p = 0.002). However, RGS is not elevated later when that group exhibits peripheral sensitivity and moderate TMJ condylar cartilage degeneration. Acutely, RGS is elevated in the 3.5N loading group over the other loading groups (p < 0.001). These findings suggest that RGS is an effective tool for detecting spontaneous TMJ pain and that spontaneous pain is detectable in rats that develop persistent TMJ sensitivity, but not in rats with acute resolving sensitivity.