Faculty Bibliography

INTRODUCTIONS:Excessive mechanical stress is closely associated with cell death in various conditions. Exposure of chondrocytes to excessive mechanical loading leads to a catabolic response as well as exaggerated cell death. Ferroptosis is a recently identified form of cell death during cell aging and degeneration. However, it's potential association with mechanical stress remains to be illustrated. OBJECTIVES:To identify whether excessive mechanical stress can cause ferroptosis. To explore the role of mechanical overloading in chondrocyte ferroptosis. METHODS:) mice OA model and chondrocytes cultured with high strain mechanical stress. Furthermore, the role of Piezo1 ion channel in chondrocyte ferroptosis and OA development was explored by using its inhibitor (GsMTx4) and agonist (Yoda1). Additionally, chondrocyte was cultured in calcium-free medium with mechanical stress, and ferroptosis phenotype was tested. RESULTS:Human cartilage and mouse chondrocyte experiments revealed that mechanical overloading can induce GPX4-associated ferroptosis. Conditional knockout of GPX4 in cartilage aggravated experimental OA process, while additional treatment with ferroptosis suppressor protein (FSP-1) and coenzyme Q10 (CoQ10) abated OA development in GPX4-CKO mice. In mouse OA model and chondrocyte experiments, inhibition of Piezo1 channel activity increased GPX4 expression, attenuated ferroptosis phenotype and reduced the severity of osteoarthritis. Additionally, high strain mechanical stress induced ferroptosis damage in chondrocyte was largely abolished by blocking calcium influx through calcium-free medium. CONCLUSIONS:Our findings show that mechanical overloading induces ferroptosis through Piezo1 activation and subsequent calcium influx in chondrocytes, which might provide a potential target for OA treatment.

BACKGROUND:Stroke mimics are non-vascular conditions that present with acute focal neurological deficits, simulating an acute ischemic stroke. Susumber berry (SB) toxicity is a rare cause of stroke mimic with limited case reports available in the literature. OBJECTIVES/OBJECTIVE:We report four new cases of SB toxicity presenting as stroke mimic, and we performed a systematic review. METHODS:MEDLINE/EMBASE/WoS were searched for "susumber berries," "susumber," or "solanum torvum." RESULTS:531 abstracts were screened after removal of duplicates; 5 articles and 2 conference abstracts were selected describing 13 patients. A total of 17 patients who ingested SB and became ill were identified, including our 4 patients. All but one presented with acute neurologic manifestation; 16 (94%) presented with dysarthria, 16 (94%) with unstable gait, 8 (47%) with nystagmus/gaze deviation, 10 (59%) with blurry vision, and 5 (29%) with autonomic symptoms. Six (35%) required ICU admission, and 3 (18%) were intubated. Fourteen (82%) had a rapid complete recovery, and 3 were hospitalized up to 1 month. CONCLUSIONS:SB toxicity can cause neurological symptoms that mimic an acute stroke typically with a posterior circulation symptom complex. Altered SB toxins (from post-harvest stressors or temperature changes) might stimulate muscarinic/nicotinic cholinergic receptors or inhibit acetylcholinesterase, causing gastrointestinal, neurological, and autonomic symptoms. In cases of multiple patients presenting simultaneously to the ED with stroke-like symptoms or when stroke-like symptoms fail to localize, a toxicological etiology (such as SB toxicity) should be considered.

BACKGROUND AND OBJECTIVES/OBJECTIVE:To report the tolerability and efficacy of olaparib with temozolomide (TMZ) for glioma. METHODS:Single-center retrospective series of patients with glioma treated with olaparib/TMZ from September 2018 to December 2021. RESULTS:-wildtype gliomas (0/3). Progression-free survival was 7.8, 1.3, and 2.0 months, respectively. DISCUSSION/CONCLUSIONS:-mutant grade 2-3 gliomas with encouraging progression-free survival and manageable toxicity. This supports a prospective trial of olaparib/TMZ for this population. CLASSIFICATION OF EVIDENCE/METHODS:This case series provides Class IV evidence that treatment with olaparib/TMZ may result in radiographic response in patients with glioma.

While several studies have attributed the development of tumour-associated seizures to an excitatory-inhibitory imbalance, we have yet to resolve the spatiotemporal interplay between different types of neuron in glioma-infiltrated cortex. Herein, we combined methods for single unit analysis of microelectrode array recordings with wide-field optical mapping of Thy1-GCaMP pyramidal cells in an ex vivo acute slice model of diffusely infiltrating glioma. This enabled simultaneous tracking of individual neurons from both excitatory and inhibitory populations throughout seizure-like events. Moreover, our approach allowed for observation of how the crosstalk between these neurons varied spatially, as we recorded across an extended region of glioma-infiltrated cortex. In tumour-bearing slices, we observed marked alterations in single units classified as putative fast-spiking interneurons, including reduced firing, activity concentrated within excitatory bursts and deficits in local inhibition. These results were correlated with increases in overall excitability. Mechanistic perturbation of this system with the mTOR inhibitor AZD8055 revealed increased firing of putative fast-spiking interneurons and restoration of local inhibition, with concomitant decreases in overall excitability. Altogether, our findings suggest that diffusely infiltrating glioma affect the interplay between excitatory and inhibitory neuronal populations in a reversible manner, highlighting a prominent role for functional mechanisms linked to mTOR activation.

OBJECTIVES/OBJECTIVE:Long-term video-electroencephalographic monitoring (LTVEM) represents the gold-standard method to evaluate whether events represent electrographic seizures, but limited work has evaluated the quality of inpatient event capture. We evaluated the frequency of audiovisual factors impairing the ideal electroclinical correlation of seizure-like episodes during LTVEM. METHODS:We retrospectively reviewed consecutive inpatient LTVEM studies (11/2019-12/2019) from three academic epilepsy centers. We evaluated all pushbutton events for audiovisual characteristics such as whether the event was narrated, whether the patient was blocked on camera, and what diagnostic challenges impaired the electroencephalographer's ability to understand either the reason the event button was pushed or clinical semiology ("electroclinical correlation"). We determined the percent of events and studies with each outcome. RESULTS:There were 154 studies with 520 pushbutton events. The pushbutton was most commonly activated by patients (41%), followed by nurses (31%) or family (17%). Twenty-nine percent of events represented electrographic seizures, and 78% occurred in the Epilepsy Monitoring Unit. The reason for the push was not stated in 45% of events, and inadequate narration impaired electroclinical correlation in 19% of events. At least one relevant part of the patient's body was blocked during 12% of events, but this impaired electroclinical correlation in only 1% of events. There was at least one factor impairing electroclinical correlation in 21% of events, most commonly due to incomplete narration (N = 99), lights off (N = 15), or blankets covering the patient (N = 15). At least one factor impaired electroclinical correlation for any event in 36% of studies. CONCLUSION/CONCLUSIONS:Audiovisual factors impairing the electroencephalographer's ability to render an electroclinical correlation were common, particularly related to inadequate narration from bedside observers to explain the reason for pushing the button or event semiology. Future efforts to develop targeted countermeasures should address narration challenges and improve inpatient seizure monitoring quality metrics.

Diffuse spinal cord gliomas (SCGs) are rare tumors associated with a high morbidity and mortality that affect both pediatric and adult populations. In this retrospective study, we sought to characterize the clinical, pathological, and molecular features of diffuse SCG in 22 patients with histological and molecular analyses. The median age of our cohort was 23.64 years (range 1-82) and the overall median survival was 397 days. K27M mutation was significantly more prevalent in males compared to females. Gross total resection and chemotherapy were associated with improved survival, compared to biopsy and no chemotherapy. While there was no association between tumor grade, K27M status (p = 0.366) or radiation (p = 0.772), and survival, males showed a trend toward shorter survival. K27M mutant tumors showed increased chromosomal instability and a distinct DNA methylation signature.

Early diagnosis of Alzheimer's disease plays a pivotal role in patient care and clinical trials. In this study, we have developed a new approach based on 3D deep convolutional neural networks to accurately differentiate mild Alzheimer's disease dementia from mild cognitive impairment and cognitively normal individuals using structural MRIs. For comparison, we have built a reference model based on the volumes and thickness of previously reported brain regions that are known to be implicated in disease progression. We validate both models on an internal held-out cohort from The Alzheimer's Disease Neuroimaging Initiative (ADNI) and on an external independent cohort from The National Alzheimer's Coordinating Center (NACC). The deep-learning model is accurate, achieved an area-under-the-curve (AUC) of 85.12 when distinguishing between cognitive normal subjects and subjects with either MCI or mild Alzheimer's dementia. In the more challenging task of detecting MCI, it achieves an AUC of 62.45. It is also significantly faster than the volume/thickness model in which the volumes and thickness need to be extracted beforehand. The model can also be used to forecast progression: subjects with mild cognitive impairment misclassified as having mild Alzheimer's disease dementia by the model were faster to progress to dementia over time. An analysis of the features learned by the proposed model shows that it relies on a wide range of regions associated with Alzheimer's disease. These findings suggest that deep neural networks can automatically learn to identify imaging biomarkers that are predictive of Alzheimer's disease, and leverage them to achieve accurate early detection of the disease.

BACKGROUND:Neurocysticercosis is one of the most common causes of acquired epilepsy worldwide. Caused by Taenia solium, the infection uses pigs as an intermediate host and thus is often associated with proximity to and consumption of pigs. OBJECTIVE:This review explores the epidemiology of neurocysticercosis in endemic regions across Africa, Asia, and Latin America and examines common risk factors in these areas. METHODS:A literature review was conducted using pubmed to search for articles with key words including neurocysticercosis, Taenia, solium, epidemiology, and the names of countries and continents in the regions of interest. FINDINGS:Multiple risk factors for neurocysticercosis were identified, including inadequate regulation of pig farms and food safety, poor sanitation, and water contamination. In addition, additional barriers to appropriate diagnosis and management were found, including resource limitations and poor health literacy. CONCLUSION:Despite its global prevalence, effective limitation of neurocysticercosis is still achievable through projects which address common risk factors.