Novel Development of a Large Cerebral Cavernous Malformation in an Adolescent With a History of Familial Cerebral Cavernous Malformation Syndrome.

Cerebral cavernous malformations (CCM) are capillary vascular malformations of the central nervous system (CNS). These lesions can be either familial or sporadic. We present a case of a 16-year-old girl with familial CCM syndrome who presented with a six-month history of chronic headaches. A magnetic resonance imaging (MRI) scan revealed a large cavernoma in the right frontal lobe that had not been present on a prior scan performed eight years earlier. This case presentation demonstrates the possibility of significant novel cavernoma development further into adolescence.

Opportunities and challenges for robotic-assisted spine surgery: feasible indications for the MAZOR™ X Stealth Edition.

The clinical use of new technologies has several potential benefits including improved accuracy, precision and efficiency. Robotic assistance during surgery is one such technology and it is making its way into neurosurgical operating rooms with increasing frequency. The Mazor X™ Stealth robot was first used in Canada for spine surgery during July 2022 and since then multiple indications for its use have been identified and evaluated.The outcomes of robot-assisted spine surgery have been promising but there is a lack of supportive studies which would serve to refine indications, establish protocols and disseminate practical information. To begin filling this gap we gathered a list of use-cases for which this new technology was successfully employed. In combination with cases that took place in our Centre, we reviewed the existing reported uses of the Mazor X™ Stealth for spine surgery and recorded their respective procedures and outcomes for patients and surgeons.Through this review we identified common uses of the Mazor X™ Stealth for spine surgery. Usage of robotic-assisted technology had a net positive impact on outcomes for patients as well as surgeons (e.g., improved accuracy of pedicle screw placement and reduced radiation burden). This curation remains a dynamic list, and we foresee the addition of more indications in the future.Clinical Relevance- Enabling the use of technology including robotic systems has the potential to attract clinical research expertise, reduce resource usage and to improve surgical outcomes.

Dynamics of seizure termination in a non-human primate kindling model of mesial temporal lobe epilepsy.

Epilepsy is characterized by recurrent, unprovoked seizures which involve transient neuronal hyperexcitability or hypersynchrony. Focal seizures with impaired awareness (FIAS) are commonly related to mesial temporal lobe epilepsy (mTLE) with hippocampal sclerosis and potentially status epilepticus. How seizures terminate spontaneously remains an unanswered question fundamental to epileptology. To study seizure termination, we induced FIAS in a nonhuman primate (NHP) model with electrical kindling. Kindling stimulation was delivered to the basolateral amygdala once weekly for 30 weeks. Chronic linear microelectrode arrays were implanted in NHP mesial temporal lobe targets: the hippocampus, amygdala and entorhinal cortex. Daily electrophysiologic recordings were obtained from all targets before, during and after stimulation to monitor changes to local field potential activity. We detect prominent changes in electrophysiologic dynamics before after-discharge (AD; subclinical, electrographic seizures which begin after a stimulus) self-termination. Specifically, at seizure termination the power of the extra-focal theta rhythm increased, and the theta phase was shown to couple with the gamma rhythm within the seizure focus. The electrical current threshold for eliciting an after-discharge decreased from >700µA to 15µA. The refractory period, which prevents the induction of seizure events at threshold, was initially 3 minutes in duration. At 30 weeks after FIAS induction the refractory period increased to over 5 minutes in duration. Understanding the electrophysiologic dynamics that reflect endogenous seizure termination mechanisms may be a valuable consideration for refining intervention strategies for treatment of epilepsy. Clinical Relevance- Our findings provide further electrophysiologic description of the endogenous mechanisms behind seizure termination in a healthy brain. This work specifically highlights the importance of considering targets outside the epileptogenic zone for therapeutic intervention.

The Dostoyevsky effect: epileptogenesis and memory enhancement after kindling stimulation in the primate basolateral amygdala.

Kindling is an electrical stimulation technique used to lower the threshold for epileptogenic activity in the brain. It can also be used as a tool to investigate electrophysiologic alterations that occur as a result of seizures. Epileptiform activity, like seizures and after-discharges (AD; evoked epileptiform activity), commonly cause memory impairment but rarely, can elicit vivid memory retrieval. We kindled the basolateral amygdala of a non-human primate (NHP) once weekly and had him perform a spatial memory task in a 3D virtual environment before, during and after kindling. AD were associated with an initial average performance increase of 46.6%. The enhancement which followed AD persisted up to 2 days. Memory task performance enhancement was accompanied by significant resetting of hippocampal theta oscillations and robust hippocampal potentiation as measured by field evoked potentials. However, neither lasted throughout the duration of performance enhancement. Sharp-wave ripples (SWR), a local field event that supports episodic memory, were generated more often throughout the period of enhancement. SWR rate increased from 14.38 SWR per min before kindling to 24.22 SWR per min after kindling on average. Our results show that kindling can be associated with improved memory. Memory function appears to depend on the particular induction circuit and the resultant excitation/inhibition ratio of the mesial temporal lobe network. Investigating the electrophysiologic underpinnings of this observed memory enhancement is an important step towards understanding the network alterations that occur after seizures and stimulation.Clinical Relevance- Our findings provide new insight into the effects of kindling stimulation in the primate brain. Kindling can cause increase MTL synchrony and the frequency of spontaneous seizures in a primate. This work highlights important considerations for therapeutic deep brain stimulation.

A Kappa Opioid Receptor Agonist Blocks Bone Cancer Pain Without Altering Bone Loss, Tumor Size, or Cancer Cell Proliferation in a Mouse Model of Cancer-Induced Bone Pain.

Breast cancer metastasizes to bone, diminishing quality of life of patients because of pain, fracture, and limited mobility. Cancer-induced bone pain (CIBP) is characterized as moderate to severe ongoing pain, primarily managed by mu opioid agonists such as fentanyl. However, opioids are limited by escalating doses and serious side effects. One alternative may be kappa opioid receptor (KOR) agonists. There are few studies examining KOR efficacy on CIBP, whereas KOR agonists are efficacious in peripheral and inflammatory pain. We thus examined the effects of the KOR agonist U50,488 given twice daily across 7 days to block CIBP, tumor-induced bone loss, and tumor burden. U50,488 dose-dependently blocked tumor-induced spontaneous flinching and impaired limb use, without changing tactile hypersensitivity, and was fully reversed by the KOR antagonist nor-binaltorphimine. U50,488 treatment was higher in efficacy and duration of action at later time points. U50,488 blocked this pain without altering tumor-induced bone loss or tumor growth. Follow-up studies in human cancer cell lines confirmed that KOR agonists do not affect cancer cell proliferation. These studies suggest that KOR agonists could be a new target for cancer pain management that does not induce cancer cell proliferation or alter bone loss. PERSPECTIVE: This study demonstrates the efficacy of KOR agonists in the treatment of bone cancer-induced pain in mice, without changing tumor size or proliferation in cancer cell lines. This suggests that KOR agonists could be used to manage cancer pain without the drawbacks of mu opioid agonists and without worsening disease progression.

Synthesis and Investigation of Mixed µ-Opioid and δ-Opioid Agonists as Possible Bivalent Ligands for Treatment of Pain.

Several studies have suggested functional association between µ-opioid and δ-opioid receptors and showed that µ-activity could be modulated by δ-ligands. The general conclusion is that agonists for the δ-receptor can enhance the analgesic potency and efficacy of µ-agonists. Our preliminary investigations demonstrate that new bivalent ligands constructed from the µ-agonist fentanyl and the δ-agonist enkephalin-like peptides are promising entities for creation of new analgesics with reduced side effects for treatment of neuropathic pain. A new superposition of the mentioned pharmacophores led to novel µ-bivalent/δ-bivalent compounds that demonstrate both µ-opioid and δ-opioid receptor agonist activity and high efficacy in anti-inflammatory and neuropathic pain models with the potential of reduced unwanted side effects.

17-ß-Estradiol induces spreading depression and pain behavior in alert female rats.

AIMS: Test the putative contribution of 17-ß-estradiol in the development of spreading depression (SD) events and head pain in awake, non-restrained rats. MAIN METHODS: Female, Sprague-Dawley rats were intact or underwent ovariectomy followed one week later by surgery to place electrodes onto the dura to detect epidural electroencephalographic activity (dEEG). dEEG activity was recorded two days later for 12 hours after systemic administration of 17-ß-estradiol (180 µg/kg, i.p.). A separate set of rats were observed for changes in exploratory, ambulatory, fine, and rearing behaviors; periorbital allodynia was also assessed. KEY FINDINGS: A bolus of 17-ß-estradiol significantly elevated serum estrogen levels, increased SD episodes over a 12-hour recording period and decreased rearing behaviors in ovariectomized rats. Pre-administration of ICI 182,780, an estrogen receptor antagonist, blocked 17-ß-estradiol-evoked SD events and pain behaviors; similar results were observed when the antimigraine therapeutic sumatriptan was used. SIGNIFICANCE: These data indicate that an estrogen receptor-mediated mechanism contributes to SD events in ovariectomized rats and pain behaviors in both ovariectomized -and intact- rats. This suggests that estrogen plays a different role in each phenomenon of migraine where intense fluctuations in concentration may influence SD susceptibility. This is the first study to relate estrogen peaks to SD development and pain behaviors in awake, freely moving female rats, establishing a framework for future preclinical migraine studies.

Structure-Activity Relationships of [des-Arg7]Dynorphin A Analogues at the κ Opioid Receptor.

Dynorphin A (Dyn A) is an endogenous ligand for the opioid receptors with preference for the κ opioid receptor (KOR), and its structure-activity relationship (SAR) has been extensively studied at the KOR to develop selective potent agonists and antagonists. Numerous SAR studies have revealed that the Arg7 residue is essential for KOR activity. In contrast, our systematic SAR studies on [des-Arg7]Dyn A analogues found that Arg7 is not a key residue and even deletion of the residue does not affect biological activities at the KOR. In addition, it was also found that [des-Arg7]Dyn A(1-9)-NH2 is a minimum pharmacophore and its modification at the N-terminus leads to selective KOR antagonists. A lead ligand, 14, with high affinity and antagonist activity showed improved metabolic stability and could block antinociceptive effects of a KOR selective agonist, FE200665, in vivo, indicating high potential to treat KOR mediated disorders such as stress-induced relapse.

Determination of the active and inactive metabolites of prasugrel in human plasma by liquid chromatography/tandem mass spectrometry.

Two fast and sensitive liquid chromatography/tandem mass spectrometry (LC/MS/MS)-based bioanalytical assays were developed and validated to quantify the active and three inactive metabolites of prasugrel. Prasugrel is a novel thienopyridine prodrug that is metabolized to the pharmacologically active metabolite in addition to three inactive metabolites, which directly relate to the formation and elimination of the active metabolite. After extraction and separation, the analytes were detected and quantified using a triple quadrupole mass spectrometer using positive electrospray ionization. The validated concentration range for the inactive metabolites assay was from 1 to 500 ng/mL for each of the three analytes. Additionally, a 5x dilution factor was validated. The interday accuracy ranged from -10.5% to 12.5% and the precision ranged from 2.4% to 6.6% for all three analytes. All results showed accuracy and precision within +/-20% at the lower limit of quantification and +/-15% at other levels. The validated concentration range for the active metabolite assay was from 0.5 to 250 ng/mL. Additionally, a 10x dilution factor was validated. The interbatch accuracy ranged from -7.00% to 5.98%, while the precision ranged from 0.98% to 3.39%. Derivatization of the active metabolite in blood with 2-bromo-3'-methoxyacetophenone immediately after collection was essential to ensure the stability of the metabolite during sample processing and storage. These methods have been applied to determine the concentrations of the active and inactive metabolites of prasugrel in human plasma.

Perceived racial/ethnic bias in healthcare in Durham County, North Carolina: a comparison of community and national samples.

BACKGROUND: We sought to compare findings of a national survey of perceptions of racial/ethnic discrimination in healthcare to those of a community survey, with emphasis on the perceptions of Latinos. METHODS: Responses from a national survey were compared to a telephone survey of residents of Durham County, North Carolina. RESULTS: Black respondents in the Durham sample were more likely than those in the national sample to feel that a healthcare provider had treated them with disrespect because of health insurance status (28% vs 14%; P < 0.001). Approximately one third of Durham Latinos and 14% of Latinos in the national sample felt they had been treated with disrespect because of their English-language ability (P < 0.01). Compared to a national sample of white participants, white respondents in Durham were more likely to believe that black persons are worse off in terms of receiving routine medical care (40% vs 27%; P < 0.01) and having health insurance (58% vs 43%; P < 0.01). As compared to their national counterparts, there was a similar trend for how white respondents in Durham perceived how Latinos fared (P < 0.001 for all comparisons). CONCLUSIONS: Overall the perception of bias in healthcare was greater among Durham residents, especially among newly immigrated Latinos, than among their national counterparts.