Novel Potent and Selective Agonists of the GPR55 Receptor Based on the 3-Benzylquinolin-2(1H)-One Scaffold.

A growing body of evidence underlines the crucial role of GPR55 in physiological and pathological conditions. In fact, GPR55 has recently emerged as a therapeutic target for several diseases, including cancer and neurodegenerative and metabolic disorders. Several lines of evidence highlight GPR55's involvement in the regulation of microglia-mediated neuroinflammation, although the exact molecular mechanism has not been yet elucidated. Nevertheless, there are only a limited number of selective GPR55 ligands reported in the literature. In this work, we designed and synthesized a series of novel GPR55 ligands based on the 3-benzylquinolin-2(1H)-one scaffold, some of which showed excellent binding properties (with Ki values in the low nanomolar range) and almost complete selectivity over cannabinoid receptors. The full agonist profile of all the new derivatives was assessed using the p-ERK activation assay and a computational study was conducted to predict the key interactions with the binding site of the receptor. Our data outline a preliminary structure-activity relationship (SAR) for this class of molecules at GPR55. Some of our compounds are among the most potent GPR55 agonists developed to date and could be useful as tools to validate this receptor as a therapeutic target.

Neutrophil Count on Admission Predicts Acute Symptomatic Hydrocephalus After Aneurysmal Subarachnoid Hemorrhage.

OBJECTIVE: To investigate the association between immunologic counts on admission and acute symptomatic hydrocephalus after aneurysmal subarachnoid hemorrhage (aSAH). METHODS: We conducted a retrospective analysis of 143 consecutive patients with aSAH. Patient demographics, clinical parameters, laboratory values, and radiographic imaging were obtained. Univariate and multivariate logistic regression analyses were performed to investigate parameters independently associated with acute symptomatic hydrocephalus. Receiver operating characteristic (ROC) curve analysis determined the best threshold value of neutrophil count to differentiate patients with and without hydrocephalus. RESULTS: Overall, acute symptomatic hydrocephalus developed in 39.16% of patients. In an adjusted multivariate logistic regression model, Hunt and Hess grade 4-5 (odds ratio [OR]: 16.052, 95% confidence interval [CI]: 1.188-216.983; P = 0.037), modified Fisher score 3-4 (OR: 10.107, 95% CI: 1.715-59.572; P = 0.011), intraventricular hemorrhage (OR: 4.578, 95% CI: 1.417-14.788; P = 0.011), neutrophil count (OR: 1.183, 95% CI: 1.033-1.354; P = 0.015), and prior ischemic stroke (OR: 7.003, 95% CI: 1.293-37.929; P = 0.024) were significantly associated with hydrocephalus. ROC analysis for neutrophil count confirmed an acceptable area under the curve (AUC 0.780, 95% CI: 0.701-0.859; P < 0.001). The best threshold value of neutrophil count to predict hydrocephalus was ≥9.80 × 103/mL. Overall, 81.25% of patients who developed shunt dependence had a neutrophil count ≥9.80 × 103/mL on admission (P = 0.003). CONCLUSIONS: Neutrophil count ≥9.80 × 103/mL on admission predicts acute symptomatic hydrocephalus after aSAH in an adjusted multivariate logistic regression model. Moreover, shunt dependence was associated with higher neutrophil counts.

Socioeconomic Implications of Professional Relationships within Modern Care Delivery Systems.

No physician can successfully deliver high-value patient care in the modern-day health care system in isolation. Delivery of effective patient care requires integrated and collaborative systems that depend on dynamic professional relationships among members of the health care team. An overview of the socioeconomic implications of professional relationships within modern care delivery systems and potential employment models is presented.

In vivo Evidence for Brain Region-Specific Molecular Interactions Between Cannabinoid and Orexin Receptors.

The endocannabinoid and orexin neuromodulatory systems serve key roles in many of the same biological functions such as sleep, appetite, pain processing, and emotional behaviors related to reward. The type 1 cannabinoid receptor (CB1R) and both subtypes of the orexin receptor, orexin receptor type 1 (OX1R) and orexin receptor type 2 (OX2R) are not only expressed in the same brain regions modulating these functions, but physically interact as heterodimers in recombinant and neuronal cell cultures. In the current study, male and female C57BL/6 mice were co-treated with the cannabinoid receptor agonist CP55,940 and either the OX2R antagonist TCS-OX2-29 or the dual orexin receptor antagonist (DORA) TCS-1102. Mice were then evaluated for catalepsy, body temperature, thermal anti-nociception, and locomotion, after which their brains were collected for receptor colocalization analysis. Combined treatment with the DORA TCS-1102 and CP55,940 potentiated catalepsy more than CP55,940 alone, but this effect was not observed for changes in body temperature, nociception, locomotion, or via selective OX2R antagonism. Co-treatment with CP55,940 and TCS-1102 also led to increased CB1R-OX1R colocalization in the ventral striatum. This was not seen following co-treatment with TCS-OX2-29, nor in CB1R-OX2R colocalization. The magnitude of effects following co-treatment with CP55,940 and either the DORA or OX2R-selective antagonist was greater in males than females. These data show that CB1R-OX1R colocalization in the ventral striatum underlies cataleptic additivity between CP55,940 and the DORA TCS-1102. Moreover, cannabinoid-orexin receptor interactions are sex-specific with regards to brain region and functionality. Physical or molecular interactions between these two systems may provide valuable insight into drug-drug interactions between cannabinoid and orexin drugs for the treatment of insomnia, pain, and other disorders.

Pineal Gland Metastasis From Poorly Differentiated Carcinoma of Unknown Primary Origin.

Pineal metastasis is an exceedingly rare finding in patients with systemic malignancies. Such lesions are typically the manifestation of a primary lung cancer; nonetheless, a variety of malignancies have been reported to disseminate to the pineal gland including gastrointestinal, endocrine, and skin cancers, among others. However, to our knowledge, pineal gland metastasis without a primary origin has yet to be described. Carcinoma of unknown primary origin is a heterogeneous group of cancers characterized by the presence of metastatic disease without an identifiable primary tumor on metastatic workup. Here, we present a case of a 65-year-old male found to have a heterogeneously enhancing lesion of the pineal gland as well as an enhancing lesion of the left cerebellar hemisphere. Comprehensive metastatic workup demonstrated multifocal metastatic adenopathy without an identifiable primary lesion. Stereotactic biopsy of the pineal lesion revealed poorly differentiated carcinoma with an immunophenotype most consistent with gastrointestinal origin. To our knowledge, this is the first case to describe a pineal gland metastasis without a primary origin. We discuss the relevant literature on pineal gland metastases as well as carcinoma of unknown primary origin.

Idiopathic fourth ventricular outlet obstruction misdiagnosed as normal pressure hydrocephalus: A cautionary case.

BACKGROUND: Fourth ventricular outlet obstruction is an infrequent but well-established cause of tetraventricular hydrocephalus characterized by marked dilatation of the ventricular system with ballooning of the foramina of Monro, Magendie, and Luschka. Multiple processes including inflammation, infection, hemorrhage, neoplasms, or congenital malformations are known to cause this pathological obstruction. However, true idiopathic fourth ventricular outlet obstruction is a rare phenomenon with only a limited number of cases reported in the literature. CASE DESCRIPTION: A 61-year-old female presented with several months of unsteady gait, intermittent headaches, confusion, and episodes of urinary incontinence. Conventional magnetic resonance imaging demonstrated tetraventricular hydrocephalus without transependymal flow, but with ventral displacement of the brainstem and dorsal displacement of the cerebellum without an obvious obstructive lesion on pre- or post-contrast imaging prompting a diagnosis of normal pressure hydrocephalus. However, constructive interference in steady state (CISS) and half-Fourier acquisition single-shot turbo spin echo (HASTE) sequences followed by fluoroscopic dynamic cisternography suggested encystment of the fourth ventricle with thin margins of arachnoid membrane extending through the foramina of Luschka bilaterally into the pontocerebellar cistern. Operative intervention was pursued with resection of an identified arachnoid web. Postoperative imaging demonstrated marked reduction in the size of ventricular system, especially of the fourth ventricle. The patient's symptomatology resolved a few days after the procedure. CONCLUSION: Here, we describe an idiopathic case initially misdiagnosed as normal pressure hydrocephalus. The present case emphasizes the necessity of CISS sequences and fluoroscopic dynamic cisternography for suspected cases of fourth ventricular outlet obstruction as these diagnostic tests may guide surgical management and lead to superior patient outcomes.

Factors affecting R01 grant funding among academic neurosurgeons over the last decade.

BACKGROUND: Recent studies have reported a gender and medical degree disparity for those receiving Research Project Grants in surgical specialties. The aim of the present study is to analyze factors among academics neurosurgeons that correlate to higher amounts of R01 grant monies awarded. MATERIALS AND METHODS: The National Institutes of Health Research Portfolio Online Reporting Tools Expenditures and Results database was queried for neurosurgery funding between 2008 and 2018. Grant recipients were categorized among type of degree, secondary degree(s), professorship, gender, and h - index. Statistical analysis was performed. RESULTS: The National Institutes of Health awarded 480 R01 grants totaling $182,482,644 to 81 allopathic neurosurgeons between 2008 and 2018. No osteopathic neurosurgeons were awarded an R01 grant during this timeframe. There was a significant difference for type of professorship on the total awarded amount at the p < 0.05 level for the three types of professorship [F (2,78) = 4.85, p < 0.01)]. There was a significant difference for magnitude of h - index on total R01 monies (p < 0.00001). Males accounted for the majority of R01 monies (93.99%); however, no significant difference between average amount awarded and gender was identified (p = 0.86). A secondary degree was without significant difference for R01 amount awarded (p = 0.75). CONCLUSIONS: The present study establishes a medical degree disparity for academic neurosurgeons who receive an R01 grant. Statistically significant factors found to affect amount of R01 grant monies awarded were limited to type of professorship and magnitude of h - index.

Ruptured Distal Superior Cerebellar Artery Aneurysm After Gamma Knife Radiosurgery for Trigeminal Neuralgia: A Case Report and Review of the Literature.

BACKGROUND: Intracranial aneurysm formation after Gamma Knife radiosurgery (GKRS) is a rare complication that has only recently been reported in the literature. We report the case of a fatal distal superior cerebellar artery (SCA) aneurysm rupture in a woman treated twice with GKRS for trigeminal neuralgia along with a review of the literature regarding radiation-induced aneurysms. CASE DESCRIPTION: A 77-year-old white woman with a history of refractory right-sided trigeminal neuralgia treated with GKRS in 2001, and again in 2006 after a relapse, presented to our emergency department with complaints of a sudden-onset severe headache associated with vomiting, right eye vision loss, left-sided facial droop, and left-sided weakness with no history of hypertension or smoking prior to presentation. Initial head computed tomography scan without contrast demonstrated an intraparenchymal hemorrhage centered in the right middle cerebellar peduncle with subarachnoid hemorrhage in the basal cisterns and extension into the fourth ventricle causing early hydrocephalus. Head computed tomography angiography (CTA) demonstrated a distal right SCA aneurysm adjacent to the hemorrhage. The patient's mental status deteriorated into coma after suspected rerupture during the CTA requiring immediate intubation, external ventricular drain placement, and emergent cerebral angiogram with coil embolization. Ultimately, the patient never recovered despite medical and surgical management; therefore, care was withdrawn in accordance with her known wishes. CONCLUSIONS: The pathophysiologic association of aneurysm formation after GKRS remains to be elucidated, but given the potentially fatal consequences of aneurysm rupture, we advocate for further research and propose serial vascular imaging during the postradiosurgery follow-up period for iatrogenic aneurysm formation surveillance.

Distal Cauda equina syndrome: A case report of lumbosacral disc pathology and review of literature.

BACKGROUND: Cauda equina syndrome (CES) is an uncommon entity that presents acutely with all or some of the following symptoms; urinary incontinence from retention, fecal incontinence from loss of sphincter tone, saddle area hypoesthesia or anesthesia, and acute or progressive weakness in one or both lower extremities. The protean symptomatology is often mixed and is vulnerable to confounding comorbidities making the accurate and timely diagnosis of this syndrome uniquely challenging. Here, we present the case of a man who developed isolated sacral nerve dysfunction from CES in the midst of a diabetic crisis. CASE DESCRIPTION: A 53-year-old male with a long history of uncontrolled Type 2 diabetes presented with acute-onset urinary and fecal incontinence, scrotal anesthesia, and a 3-day history of lower back pain with intermittent bilateral leg pain. This patient displayed no objective changes in leg strength, sensation, or reflexes. In addition, the patient tested positive for cocaine and had a blood glucose level of 800 mg/dL which confounded his clinical picture. The patient underwent bilateral laminectomies from L4-S1 with the removal of a large sequestered disc fragment from the S1-S2 disc space within 8 h of presentation with reasonable recovery. CONCLUSION: Highly variable presentations often confound the accurate and timely diagnosis of CES with severe implications on quality of life. Despite the limited functional recovery seen after surgical decompression, urgent or emergent intervention is paramount for treatment. Our patient's presenting symptomatology and comorbidities highlight the need for practitioners to maintain a high index of suspicion in anyone with incontinence and back pain, regardless of distractors and even in the absence of other anticipated motor or sensory findings.

Short- and Long-Term Geriatric Mortality After Acute Traumatic Subdural Hemorrhage.

BACKGROUND: Acute subdural hemorrhage often occurs in those ≥65 years of age after trauma and tends to yield poor clinical outcomes. Previous studies have demonstrated a propensity toward high in-hospital mortality rates in this population; however, postdischarge mortality data are limited. The objective of the present study was to analyze short- and long-term mortality data after acute traumatic subdural hemorrhage in the geriatric population as well as review the impact of associated clinical variables including mechanism of injury, pre-morbid antithrombotic use, and need for surgical decompression on mortality rates. METHODS: We retrospectively reviewed 455 patients who presented with an isolated traumatic acute subdural hemorrhage to our level-1 trauma center over a 5 year period using our data registry. Patients were then cross-referenced in the National Social Security Death Index for postdischarge mortality rates. United States life tables were used for peer-controlled actuarial comparisons. RESULTS: Acute traumatic subdural hemorrhage is often a fatal injury in the geriatric population, especially if taking antithrombotics or requiring surgical decompression. Specifically, they have greater in-hospital mortality rates than adults with similar injuries and have significantly lower survival rates for several years following discharge compared with their peer-matched controls. CONCLUSIONS: Here, we found that age is a significant predictor of both short- and long-term survival after acute traumatic subdural hemorrhage. Moreover, the present study corroborates that the need for surgical decompression or the use of pre-morbid antithrombotic medications is associated with increased overall mortality.

Repetitive Diffuse Mild Traumatic Brain Injury Causes an Atypical Astrocyte Response and Spontaneous Recurrent Seizures.

Focal traumatic brain injury (TBI) induces astrogliosis, a process essential to protecting uninjured brain areas from secondary damage. However, astrogliosis can cause loss of astrocyte homeostatic functions and possibly contributes to comorbidities such as posttraumatic epilepsy (PTE). Scar-forming astrocytes seal focal injuries off from healthy brain tissue. It is these glial scars that are associated with epilepsy originating in the cerebral cortex and hippocampus. However, the vast majority of human TBIs also present with diffuse brain injury caused by acceleration-deceleration forces leading to tissue shearing. The resulting diffuse tissue damage may be intrinsically different from focal lesions that would trigger glial scar formation. Here, we used mice of both sexes in a model of repetitive mild/concussive closed-head TBI, which only induced diffuse injury, to test the hypothesis that astrocytes respond uniquely to diffuse TBI and that diffuse TBI is sufficient to cause PTE. Astrocytes did not form scars and classic astrogliosis characterized by upregulation of glial fibrillary acidic protein was limited. Surprisingly, an unrelated population of atypical reactive astrocytes was characterized by the lack of glial fibrillary acidic protein expression, rapid and sustained downregulation of homeostatic proteins and impaired astrocyte coupling. After a latency period, a subset of mice developed spontaneous recurrent seizures reminiscent of PTE in human TBI patients. Seizing mice had larger areas of atypical astrocytes compared with nonseizing mice, suggesting that these atypical astrocytes might contribute to epileptogenesis after diffuse TBI.SIGNIFICANCE STATEMENT Traumatic brain injury (TBI) is a leading cause of acquired epilepsies. Reactive astrocytes have long been associated with seizures and epilepsy in patients, particularly after focal/lesional brain injury. However, most TBIs also include nonfocal, diffuse injuries. Here, we showed that repetitive diffuse TBI is sufficient for the development of spontaneous recurrent seizures in a subset of mice. We identified an atypical response of astrocytes induced by diffuse TBI characterized by the rapid loss of homeostatic proteins and lack of astrocyte coupling while reactive astrocyte markers or glial scar formation was absent. Areas with atypical astrocytes were larger in animals that later developed seizures suggesting that this response may be one root cause of epileptogenesis after diffuse TBI.

Postexercise Death Due to Hemorrhagic Colloid Cyst of Third Ventricle: Case Report and Literature Review.

BACKGROUND: Colloid cysts of the third ventricle are rare, slow-growing lesions of neuroepithelial origin. Although histopathologically benign, third ventricular colloid cysts are a well-known cause of sudden, unexpected coma and death. Several theories have been proposed to describe the rare, sudden onset of severe symptomatology and rapid clinical decline due to colloid cysts. Moreover, there is currently no clear consensus regarding the most suitable neurosurgical technique or the most effective approach for resection, nor do guidelines or standardized clinical indications exist to recommend observation versus intervention and/or resection in the asymptomatic patient. To highlight this conundrum, we present a clinical case of a hemorrhagic colloid cyst that resulted in fatality and discuss the relevant literature. CASE DESCRIPTION: A 21-year-old male presented to an outside hospital with an acute onset of a severe headache, nausea, and vomiting, which started while jogging. A few hours later, he precipitously declined into a comatose state. Radiographic imaging demonstrated a hemorrhagic third ventricular colloid cyst causing acute obstructive hydrocephalus, severe increased intracranial pressure, and downward herniation. He was then transferred to our institution for neurosurgical intervention. Despite aggressive cerebrospinal fluid drainage and medical management, he was declared brain dead several days later. CONCLUSIONS: To our knowledge, this is the only case report to describe sudden-onset coma and death due to a hemorrhagic third ventricular colloid cyst occurring after exercising. We review the literature on fatal colloid cysts emphasizing the proposed mechanisms of sudden death and current neurosurgical management in both asymptomatic and symptomatic patients.

ACTA2 Cerebral Arteriopathy: Not Just a Puff of Smoke.

BACKGROUND: Missense mutations in the gene that codes for smooth muscle actin, ACTA2, cause diffuse smooth muscle dysfunction and a distinct cerebral arteriopathy collectively known as multisystemic smooth muscle dysfunction syndrome (MSMDS). Until recently, ACTA2 cerebral arteriopathy was considered to be a variant of moyamoya disease. However, recent basic science and clinical data have demonstrated that the cerebral arteriopathy caused by mutant ACTA2 exhibits genetic loci, histopathology, neurological sequelae, and radiographic findings unique from moyamoya disease. We conducted a literature review to provide insight into the history, clinical significance, and neurosurgical management of this recently described novel cerebral arteriopathy. SUMMARY: We performed a literature search using PubMed with the key words "ACTA2 mutation," "ACTA2 cerebral arteriopathy," and "multisystemic smooth muscle dysfunction syndrome." Case reports with confirmed ACTA2 mutations and cerebral arteriopathy were included in our review. Our literature search revealed 15 articles (58 cases) of confirmed ACTA2 cerebral arteriopathy. Distinctive features of this arteriopathy included an aberrant internal carotid circulation with dilatation of the proximal segments, occlusive disease at the distal segments, and dolichoectasia. As such, mutant ACTA2 predisposed patients to ischemic strokes as children. Direct and indirect cerebral revascularization procedures are the mainstay treatment options with varying degrees of success. Key Messages: ACTA2 cerebral arteriopathy is a recently described novel cerebrovascular disease seen in patients with MSMDS. Patients currently diagnosed with moyamoya disease who also have dysfunction of smooth muscle organs may benefit from reevaluation by a medical geneticist and ACTA2 genotyping.

Vaccine-Based Immunotherapeutics for the Treatment of Glioblastoma: Advances, Challenges, and Future Perspectives.

Glioblastoma is a highly aggressive neoplasm with an extremely poor prognosis. Despite maximal gross resection and chemoradiotherapy, these grade IV astrocytomas consistently recur. Glioblastoma cells exhibit numerous pathogenic mechanisms to decrease tumor immunogenicity while promoting gliomagenesis, which manifests clinically as a median survival of less than 2 years and few long-term survivors. Recent clinical trials of vaccine-based immunotherapeutics against glioblastoma have demonstrated encouraging results in prolonging progression-free survival and overall survival. Several vaccine-based treatments have been trialed, such as peptide and heat-shock proteins, dendritic cell-based vaccines, and viral-based immunotherapy. In this literature review, we discuss the immunobiology of glioblastoma, significant current and completed vaccine-based immunotherapy clinical trials, and broad clinical challenges and future directions of glioblastoma vaccine-based immunotherapeutics.