Enhanced Oral Bioavailability of ß-Caryophyllene in Healthy Subjects Using the VESIsorb® Formulation Technology, a Novel Self-Emulsifying Drug Delivery System (SEDDS).

ß-Caryophyllene (BCP), a common constituent of many spice and food plants, is gaining increased attention due to recent research identifying numerous potential health benefits. Due to limited oral bioavailability observed in preclinical models, the described benefits of BCP may be maximized by using a suitable delivery system. Additionally, human pharmacokinetics (PK) remain unknown. This study evaluates the relative oral bioavailability of BCP formulated in a self-emulsifying drug delivery system (SEDDS) based on VESIsorb® formulation technology (BCP-SEDDS) compared to BCP neat oil. Hence, a randomized, double-blind, cross-over design, single oral dose study (100 mg BCP) in 24 healthy subjects (12 men/12 women) was performed under fasting conditions. Pharmacokinetic parameters were analyzed from individual concentration-time curves. The data show that BCP-SEDDS resulted in a 2.2/2.0-fold increase in AUC0-12h/AUC0-24h and a 3.6-fold increase in Cmax compared to BCP neat oil. Moreover, BCP was absorbed faster from BCP-SEDDS (Tmax: 1.43 h) compared to BCP neat oil (Tmax: 3.07 h). Gender analysis revealed that there is no significant difference between men and women for both the investigated formulations and all investigated PK endpoints. In conclusion, BCP-SEDDS offers a well-tolerated and effective oral delivery system to significantly enhance the oral bioavailability of BCP in humans.

Conservative management of a cervical ligamentum flavum hematoma: Case report.

BACKGROUND: Spontaneous epidural hematoma arising from the ligamentum flavum is a rare cause of acute spinal cord compression. There are only four reports in the cervical spine literature, and all were managed with surgery. Here, we describe an acute case of a spontaneous epidural hematoma arising from the ligamentum flavum in the cervical spine successfully managed without surgery. CASE DESCRIPTION: A 69-year-old woman with a cervical spine epidural hematoma contained within the ligamentum flavum presented with paroxysmal neck pain and stiffness without a history of trauma. The magnetic resonance imaging (MRI) revealed a posterolateral epidural hematoma contained within the ligamentum flavum. As the patient was intact, she was managed conservatively with cervical orthosis. Three months later, she was symptom-free, and the hematoma resolved on the follow-up MRI study. CONCLUSION: Spontaneous epidural hematoma arising from ligamentum flavum is a rare cause of spinal cord compression. Previous reports have described success with surgical decompression. However, initial observation and conservative management may be successful as illustrated in this case.

The Quest to Model Chronic Traumatic Encephalopathy: A Multiple Model and Injury Paradigm Experience.

Chronic neurodegeneration following a history of neurotrauma is frequently associated with neuropsychiatric and cognitive symptoms. In order to enhance understanding about the underlying pathophysiology linking neurotrauma to neurodegeneration, a multi-model preclinical approach must be established to account for the different injury paradigms and pathophysiologic mechanisms. We investigated the development of tau pathology and behavioral changes using a multi-model and multi-institutional approach, comparing the preclinical results to tauopathy patterns seen in post-mortem human samples from athletes diagnosed with chronic traumatic encephalopathy (CTE). We utilized a scaled and validated blast-induced traumatic brain injury model in rats and a modified pneumatic closed-head impact model in mice. Tau hyperphosphorylation was evaluated by western blot and immunohistochemistry. Elevated-plus maze and Morris water maze were employed to measure impulsive-like behavior and cognitive deficits respectively. Animals exposed to single blast (~50 PSI reflected peak overpressure) exhibited elevated AT8 immunoreactivity in the contralateral hippocampus at 1 month compared to controls (q = 3.96, p < 0.05). Animals exposed to repeat blast (six blasts over 2 weeks) had increased AT8 (q = 8.12, p < 0.001) and AT270 (q = 4.03, p < 0.05) in the contralateral hippocampus at 1 month post-injury compared to controls. In the modified controlled closed-head impact mouse model, no significant difference in AT8 was seen at 7 days, however a significant elevation was detected at 1 month following injury in the ipsilateral hippocampus compared to control (q = 4.34, p < 0.05). Elevated-plus maze data revealed that rats exposed to single blast (q = 3.53, p < 0.05) and repeat blast (q = 4.21, p < 0.05) spent more time in seconds exploring the open arms compared to controls. Morris water maze testing revealed a significant difference between groups in acquisition times on days 22-27. During the probe trial, single blast (t = 6.44, p < 0.05) and repeat blast (t = 8.00, p < 0.05) rats spent less time in seconds exploring where the platform had been located compared to controls. This study provides a multi-model example of replicating tau and behavioral changes in animals and provides a foundation for future investigation of CTE disease pathophysiology and therapeutic development.

Modeling Chronic Traumatic Encephalopathy: The Way Forward for Future Discovery.

Despite the extensive media coverage associated with the diagnosis of chronic traumatic encephalopathy (CTE), our fundamental understanding of the disease pathophysiology remains in its infancy. Only recently have scientific laboratories and personnel begun to explore CTE pathophysiology through the use of preclinical models of neurotrauma. Some studies have shown the ability to recapitulate some aspects of CTE in rodent models, through the use of various neuropathological, biochemical, and/or behavioral assays. Many questions related to CTE development, however, remain unanswered. These include the role of impact severity, the time interval between impacts, the age at which impacts occur, and the total number of impacts sustained. Other important variables such as the location of impacts, character of impacts, and effect of environment/lifestyle and genetics also warrant further study. In this work, we attempt to address some of these questions by exploring work previously completed using single- and repetitive-injury paradigms. Despite some models producing some deficits similar to CTE symptoms, it is clear that further studies are required to understand the development of neuropathological and neurobehavioral features consistent with CTE-like features in rodents. Specifically, acute and chronic studies are needed that characterize the development of tau-based pathology.

Models of mild traumatic brain injury: translation of physiological and anatomic injury.

Mild traumatic brain injury (TBI) has become a rising epidemic, affecting millions of people each year. Even though it is the most common type of brain injury, our understanding of the science underlying mild TBI is just in its infancy. There has been an explosion of basic science research interest in mild TBI, as emerging clinical evidence is suggestive that concussion and subconcussion may result in detrimental long-term neurological sequelae, particularly when occurring repetitively. Many animal models have been developed to study the different pathological mechanisms implicated in TBI, and more recently there has been a heightened focus on modeling mild TBI in the laboratory as well. The most widely used models of TBI have been adapted for experimental mild TBI research, although more work still remains. The ability to create improved diagnostic measures and treatment approaches for concussion depend on the development and characterization of clinically relevant models of mild TBI. This review aims to provide a broad general overview of the current efforts to model mild TBI in animals and the challenges and limitations that exist in translating this behavioral, physiological, and anatomic knowledge from the bench to the clinical arena.

Tree stand falls: A persistent cause of neurological injury in hunting.

AIM: To characterize and compare our current series of patients to prior reports in order to identify any changes in the incidence of neurological injury related to hunting accidents in Rochester, New York. METHODS: All tree stand-related injuries referred to our regional trauma center from September 2003 through November 2011 were reviewed. Information was obtained from the hospital's trauma registry and medical records were retrospectively reviewed for data pertaining to the injuries. RESULTS: Fifty-four patients were identified. Ninety-six percent of patients were male with a mean age of 47.9 years (range 15-69). The mean Injury Severity Score was 12.53 ± 1.17 (range 2-34). The average height of fall was 18.2 feet (range 4-40 feet). All patients fell to the ground with the exception of one who landed on rocks, and many hit the tree or branches on the way down. A reason for the fall was documented in only 13 patients, and included tree stand construction (3), loss of balance (3), falling asleep (3), structural failure (2), safety harness breakage (3) or light-headedness (1). The most common injuries were spinal fractures (54%), most commonly in the cervical spine (69%), followed by the thoracic (38%) and lumbar (21%) spine. Eight patients required operative repair. Head injuries occurred in 22%. Other systemic injuries include rib/clavicular fractures (47%), pelvic fractures (11%), solid organ injury (23%), and pneumothorax or hemothorax (19%). No patient deaths were reported. The average hospital length of stay was 6.56 ± 1.07 d. Most patients were discharged home without (72%) or with (11%) services and 17% required rehabilitation. CONCLUSION: Falls from hunting tree stands are still common, with a high rate of neurological injury. Compared to a decade ago we have made no progress in preventing these neurological injuries, despite an increase in safety advances. Neurosurgeons must continue to advocate for increased safety awareness and participate in leadership roles to improve outcomes for hunters.

The history of neurosurgery at the University of Rochester.

The Department of Neurosurgery at the University of Rochester has a long legacy of excellent patient care and innovation in the neurosciences. The department's founder, Dr. William Van Wagenen, was a direct pupil of Harvey Cushing and the first president of the Harvey Cushing Society. His successor, Dr. Frank P. Smith, was also a leader in organized neurosurgery and helped to permanently memorialize his mentor with an endowed fellowship that today is one of the most prestigious training awards in neurosurgery. The first 2 chiefs are honored every year by the department with memorial invited lectureships in their names. The department is home to a thriving multidisciplinary research program that fulfills the lifelong vision of its founder, Dr. Van Wagenen.

Neurologic injury in snowmobiling.

BACKGROUND: Snowmobiles are increasingly popular recreational, all-terrain utility vehicles that require skill and physical strength to operate given their inherent maneuverability, acceleration, and top speed capabilities. These same characteristics increase the risk of injury with the operation of these vehicles, particularly neurological injury. We characterize our series of 107 patients involved in snowmobiling accidents. METHODS: From January 2004 to January 2012, all snowmobiling-related injuries referred to our regional trauma center were reviewed. Information had been recorded in the hospital's trauma registry and medical records were retrospectively reviewed for data pertaining to the injuries, with particular emphasis on neurological injuries and any associated details. RESULTS: A total of 107 patients were identified. Ninety percent of injured riders were male. The mean age was 34.4 years (range 10-70), with 7% younger than age 16. The mean Injury Severity Score was 12.0 ± 0.69 (range 1-34). Although not documented in all patients, alcohol use was found in 7.5% of the patients and drug use found in one patient. Documentation of helmet use was available for only 31 of the patients; of which 13% were not helmeted. Causes included being thrown, flipped, or roll-over (33%), striking a stationary object (27%), being struck by a snowmobile (9%), striking another snowmobile (5.5%) or a car, train, or truck (5.5%), being injured by the machine itself (9%), other (2%) or unspecified (18%). Head injuries occurred in 35% patients, including concussion, subarachnoid hemorrhage, subdural hematoma, contusion, and facial/skull fracture. Spinal fractures occurred in 21% of the patients. Fractures to the thoracic spine were the most common (50%), followed by the cervical (41%) and lumbar (36%) spine. There were also three brachial plexus injuries, one tibial nerve injury, and one internal carotid artery dissection. Average length of stay was 4.98 ± 0.56 days. Disposition was home (78%), home with services (12%), rehabilitation placement (9%), and one death. Details regarding other systemic injuries will also be reviewed. CONCLUSIONS: Snowmobiles are a significant source of multi-trauma, particularly neurological injury. Neurosurgeons can play key roles in advocating for neurological safety in snowmobiling.

Cumulative effects of repetitive mild traumatic brain injury.

The majority of traumatic brain injuries (TBI) in the USA are mild in severity. Sports, particularly American football, and military experience are especially associated with repetitive, mild TBI (mTBI). The consequences of repetitive brain injury have garnered increasing scientific and public attention following reports of altered mood and behavior, as well as progressive neurological dysfunction many years after injury. This report provides an up-to-date review of the clinical, pathological, and pathophysiological changes associated with repetitive mTBI, and their potential for cumulative effects in certain individuals.

Straight from the horse's mouth: neurological injury in equestrian sports.

OBJECTIVES: Equestrian sports can result in a variety of injuries to the nervous system due to many factors. We describe our series of 80 patients with injuries sustained during participation in equestrian sports. METHODS AND RESULTS: All patients seen at the regional trauma center with injuries associated with equestrian sports between 2003 and 2011 were reviewed; 80 patients were identified. Fifty-four per cent were female and the average age was 37 years (2·2-79·3). The mean injury severity score (ISS) was 9·9 ± 0·7. Only two patients had documented helmet use. Glasgow coma score (GCS) was 15 in 93% of patients. The most common neurosurgical injuries were to the cranial vault (28%), including concussions, intracranial hematomas and hemorrhages, and skull, facial, and spine fractures (10%), with the majority (63%) being transverse process fractures. The mechanisms of injury varied: 55% were kicked or stepped on, 28% were thrown or fell off, and 21% were injured by the horse falling on them. The causes ranged from carelessness and lack of attention to animal factors including inadequate training of horses and animal fear. Fourteen per cent required surgery. There were no mortalities and average length of stay was 3·7 ± 0·35 days. All patients were discharged home with 95% requiring no services. DISCUSSION: Equestrian sports convey special risks for its participants. With proper protection and precautions, a decrease in the incidence of central nervous system injuries may be achieved. Neurosurgeons can play key roles in advocating for neurologic safety in equestrian sports.

The spectrum of neurobehavioral sequelae after repetitive mild traumatic brain injury: a novel mouse model of chronic traumatic encephalopathy.

There has been an increased focus on the neurological sequelae of repetitive mild traumatic brain injury (TBI), particularly neurodegenerative syndromes, such as chronic traumatic encephalopathy (CTE); however, no animal model exists that captures the behavioral spectrum of this phenomenon. We sought to develop an animal model of CTE. Our novel model is a modification and fusion of two of the most popular models of TBI and allows for controlled closed-head impacts to unanesthetized mice. Two-hundred and eighty 12-week-old mice were divided into control, single mild TBI (mTBI), and repetitive mTBI groups. Repetitive mTBI mice received six concussive impacts daily for 7 days. Behavior was assessed at various time points. Neurological Severity Score (NSS) was computed and vestibulomotor function tested with the wire grip test (WGT). Cognitive function was assessed with the Morris water maze (MWM), anxiety/risk-taking behavior with the elevated plus maze, and depression-like behavior with the forced swim/tail suspension tests. Sleep electroencephalogram/electromyography studies were performed at 1 month. NSS was elevated, compared to controls, in both TBI groups and improved over time. Repetitive mTBI mice demonstrated transient vestibulomotor deficits on WGT. Repetitive mTBI mice also demonstrated deficits in MWM testing. Both mTBI groups demonstrated increased anxiety at 2 weeks, but repetitive mTBI mice developed increased risk-taking behaviors at 1 month that persist at 6 months. Repetitive mTBI mice exhibit depression-like behavior at 1 month. Both groups demonstrate sleep disturbances. We describe the neurological sequelae of repetitive mTBI in a novel mouse model, which resemble several of the neuropsychiatric behaviors observed clinically in patients sustaining repetitive mild head injury.

The pathophysiology underlying repetitive mild traumatic brain injury in a novel mouse model of chronic traumatic encephalopathy.

BACKGROUND: An animal model of chronic traumatic encephalopathy (CTE) is essential for further understanding the pathophysiological link between repetitive head injury and the development of chronic neurodegenerative disease. We previously described a model of repetitive mild traumatic brain injury (mTBI) in mice that encapsulates the neurobehavioral spectrum characteristic of patients with CTE. We aimed to study the pathophysiological mechanisms underlying this animal model. METHODS: Our previously described model allows for controlled, closed head impacts to unanesthetized mice. Briefly, 12-week-old mice were divided into three groups: Control, single, and repetitive mTBI. Repetitive mTBI mice received six concussive impacts daily, for 7 days. Mice were then subsequently sacrificed for macro- and micro-histopathologic analysis at 7 days, 1 month, and 6 months after the last TBI received. Brain sections were immunostained for glial fibrillary acidic protein (GFAP) for astrocytes, CD68 for activated microglia, and AT8 for phosphorylated tau protein. RESULTS: Brains from single and repetitive mTBI mice lacked macroscopic tissue damage at all time-points. Single mTBI resulted in an acute rea ctive astrocytosis at 7 days and increased phospho-tau immunoreactivity that was present acutely and at 1 month, but was not persistent at 6 months. Repetitive mTBI resulted in a more marked neuroinflammatory response, with persistent and widespread astrogliosis and microglial activation, as well as significantly elevated phospho-tau immunoreactivity to 6-months. CONCLUSIONS: The neuropathological findings in this new model of repetitive mTBI resemble some of the histopathological hallmarks of CTE, including increased astrogliosis, microglial activation, and hyperphosphorylated tau protein accumulation.

Role of subconcussion in repetitive mild traumatic brain injury.

Research now suggests that head impacts commonly occur during contact sports in which visible signs or symptoms of neurological dysfunction may not develop despite those impacts having the potential for neurological injury. Recent biophysics studies utilizing helmet accelerometers have indicated that athletes at the collegiate and high school levels sustain a surprisingly high number of head impacts ranging from several hundred to well over 1000 during the course of a season. The associated cumulative impact burdens over the course of a career are equally important. Clinical studies have also identified athletes with no readily observable symptoms but who exhibit functional impairment as measured by neuropsychological testing and functional MRI. Such findings have been corroborated by diffusion tensor imaging studies demonstrating axonal injury in asymptomatic athletes at the end of a season. Recent autopsy data have shown that there are subsets of athletes in contact sports who do not have a history of known or identified concussions but nonetheless have neurodegenerative pathology consistent with chronic traumatic encephalopathy. Finally, emerging laboratory data have demonstrated significant axonal injury, blood-brain barrier permeability, and evidence of neuroinflammation, all in the absence of behavioral changes. Such data suggest that subconcussive level impacts can lead to significant neurological alterations, especially if the blows are repetitive. The authors propose "subconcussion" as a significant emerging concept requiring thorough consideration of the potential role it plays in accruing sufficient anatomical and/or physiological damage in athletes and military personnel, such that the effects of these injuries are clinically expressed either contemporaneously or later in life.

William P. Van Wagenen (1897-1961): pupil, mentor, and neurosurgical pioneer.

William Perrine ("Van") Van Wagenen (1897-1961) was the first Chief of Neurosurgery at the University of Rochester Medical Center (URMC), serving from 1928 to 1954, and was a leading figure in 20th-century neurosurgery. He was a devoted pupil of Dr. Harvey Cushing and helped to found the Harvey Cushing Society (now the AANS) in honor of his mentor and was elected as its first President in 1932. He served as the 27th President of the Society of Neurological Surgeons in 1952. Upon his death in 1961 he bequeathed an endowment for the Van Wagenen Fellowship, which has advanced the education of many leaders in American neurosurgery. His legacy of operative skill, his commitment to resident education and research in neurological disease, his inspiration for the foundation of the Cushing Brain Tumor registry, and his contributions to organized neurosurgery form the foundation of the legacy of neurosurgery at URMC.

Outcomes after anterior cervical discectomy and fusion in professional athletes.

BACKGROUND: Significant controversy exists regarding when an athlete may return to contact sports after anterior cervical discectomy and fusion (ACDF). Return-to-play (RTP) recommendations are complicated due to a mix of medical factors, social pressures, and limited outcome data. OBJECTIVE: The aim of this study was to characterize our diagnostic and surgical criteria, intervention, postoperative imaging results, and rehabilitation and report RTP decisions and outcomes for professional athletes with cervical spine injuries. METHODS: Fifteen professional athletes who had undergone a 1-level ACDF by a single neurosurgeon were identified after a retrospective chart and radiographic review from 2003 to 2012. Patient records and imaging studies were recorded. RESULTS: Seven of the 15 athletes presented with neurapraxia, 8 with cervical radiculopathy, and 2 with hyperintensity of the spinal cord. Cervical stenosis with effacement of the cerebrospinal fluid signal was noted in 14 subjects. The operative level included C3-4 (4 patients), C4-5 (1 patient), C5-6 (8 patients), and C6-7 (2 patients). All athletes were cleared for RTP after a neurological examination with normal findings, and radiographic criteria for early fusion were confirmed. Thirteen of the 15 players returned to their sport between 2 and 12 months postoperatively (mean, 6 months), with 8 still participating. The RTP duration of the 5 who retired after full participation ranged from 1 to 3 years. All athletes remain asymptomatic for radicular or myelopathic symptoms or signs. CONCLUSION: After a single-level ACDF, an athlete may return to contact sports if there are normal findings on a neurological examination, full range of neck movement, and solid arthrodesis. There may be an increased risk of the development of adjacent segment disease above or below the level of fusion. Cord hyperintensity may not necessarily preclude RTP.

An overview of the basic science of concussion and subconcussion: where we are and where we are going.

There has been a growing interest in the diagnosis and management of mild traumatic brain injury (TBI), or concussion. Repetitive concussion and subconcussion have been linked to a spectrum of neurological sequelae, including postconcussion syndrome, chronic traumatic encephalopathy, mild cognitive impairment, and dementia pugilistica. A more common risk than chronic traumatic encephalopathy is the season-ending or career-ending effects of concussion or its mismanagement. To effectively prevent and treat the sequelae of concussion, it will be important to understand the basic processes involved. Reviewed in this paper are the forces behind the primary phase of injury in mild TBI, as well as the immediate and delayed cellular events responsible for the secondary phase of injury leading to neuronal dysfunction and possible cell death. Advanced neuroimaging sequences have recently been developed that have the potential to increase the sensitivity of standard MRI to detect both structural and functional abnormalities associated with concussion, and have provided further insight into the potential underlying pathophysiology. Also discussed are the potential long-term effects of repetitive mild TBI, particularly chronic traumatic encephalopathy. Much of the data regarding this syndrome is limited to postmortem analyses, and at present there is no animal model of chronic traumatic encephalopathy described in the literature. As this arena of TBI research continues to evolve, it will be imperative to appropriately model concussive and even subconcussive injuries in an attempt to understand, prevent, and treat the associated chronic neurodegenerative sequelae.

Bipartite atlas in a collegiate football player - Not necessarily a contraindication for return-to-play: A case report and review of the literature.

BACKGROUND: Congenital malformations of the posterior arch of the atlas are rare, occurring in 4% of the population. Anterior arch aplasia is extremely rare and often only coexists with posterior arch anomalies, resulting in a split or bipartite atlas. This congenital anomaly is believed to be present in only 0.1% of the population. CASE DESCRIPTION: A 19-year-old male collegiate football player presented with neck pain and upper extremity paresthesias after sustaining a tackle that forced neck hyperextension. Computed tomography revealed significant congenital bony anomalies of the cervical spine, with incomplete fusion of the anterior and posterior arches of the atlas; however, there was no evidence for of any acute traumatic injury or fracture. Magnetic resonance imaging revealed increased edema in pre-vertebral soft tissues around C1-C2, with a possible increase in signal within the fibrous ring of the anterior C1 ring. Flexion and extension imaging confirmed reduced range of motion and no instability. Patient was treated non-operatively, and was able to resume normal activity and training regimens, and continued to do well clinically. CONCLUSION: We describe a rare case of split or bipartite atlas in collegiate football athlete who sustained a neck injury during a tackle. The patient had no atlanto-axial instability or other clinical contraindications and was managed non-operatively, resuming full participation shortly thereafter with a full resolution of symptoms.