An SNP Marker Predicts Colorectal Cancer Outcomes with 5-Fluorouracil-Based Adjuvant Chemotherapy Post-Resection.

Colorectal cancer (CRC) is a global health concern, necessitating adjuvant chemotherapy post-curative surgery to mitigate recurrence and enhance survival, particularly in intermediate-stage patients. However, existing therapeutic disparities highlight the need for biomarker-guided adjuvant chemotherapy to achieve better CRC inhibition. This study explores the molecular mechanisms underlying the inhibition of CRC through a genome-wide association study (GWAS) focused on 5-fluorouracil (5-FU)-based adjuvant therapy in intermediate-stage CRC patients, a domain previously unexplored. We retrospectively included 226 intermediate-stage CRC patients undergoing surgical resection followed by 5-FU-based adjuvant chemotherapy. The exploration cohort comprised 31 patients, and the validation cohort included 195 individuals. Genotyping was carried out using either Axiom Genome-Wide TWB 2.0 Array Plate-based or polymerase chain reaction-based methods on genomic DNA derived from collected tissue samples. Statistical analyses involved descriptive statistics, Kaplan-Meier analyses, and Cox proportional hazard analyses. From the GWAS, potential genetic predictors, GALNT14-rs62139523 and DNMBP-rs10786578 genotypes, of 5-FU-based adjuvant therapy following surgery in intermediate-stage CRC patients were identified. Validation in a larger cohort of 195 patients emphasized the predictive significance of GALNT14-rs62139523 genotypes, especially the "A/G" genotype, for improved overall and progression-free survival. This predictive association remained robust across various subgroups, with exceptions for specific demographic and clinical parameters such as age < 58 years old, CEA ≤ 2.5 ng/mL, tumor diameter > 44.0 mm, and tumor-free margin ≥ 50 mm. This study identifies that the GALNT14-rs62139523 "A/G" genotype modulates therapeutic outcomes, establishing it as a promising biomarker for predicting favorable responses to 5-FU-based adjuvant chemotherapy in intermediate-stage CRC patients, although further investigations are needed to detail these mechanisms.

Anticoagulant drugs with or without proton pump inhibitor and colorectal cancer risk: a population-based, case-control study.

BACKGROUND: Low-dose aspirin and clopidogrel have demonstrated potential chemoprevention for colorectal cancer (CRC). Proton-pump inhibitors (PPI) are commonly prescribed with anticoagulation drugs, but the relationship between PPI and CRC is unclear. Moreover, evidence of CRC risk under direct oral anticoagulant (DOAC) is limited. This study aimed to investigate the effects of anticoagulation drugs combined with or without PPI on the risks of CRC in Taiwan. METHODS: A retrospective case-control study of 1,024,227 cases based on the Chang Gung Research Database from 2010 to 2017 was performed. Clinical characteristics, indications, duration of anticoagulation and PPI use, and CRC occurrence data were collected. Logistic regression was employed to adjust for known confounders of CRC risk. RESULTS: Monotherapy of clopidogrel decreased the risk of CRC (AOR 0.70; 95% CI 0.60-0.83), while no protective effect was observed in aspirin alone or aspirin plus clopidogrel. DOAC did not affect CRC significantly. The risk of CRC increased in patients with PPI (AOR 1.38; 95% CI 1.28-1.49) and PPI plus DOAC (OR 3.91; 95% CI 1.49-10.27), while PPI plus aspirin decreased the risk of CRC (OR 0.48; 95% CI 0.32-0.73). PPI plus clopidogrel showed no significant effect on the CRC. CONCLUSION: This study suggests clopidogrel alone and PPI plus aspirin offer a preventative benefit against CRC in the Taiwanese population studied. The same effect was not observed in DOAC. Moreover, a significant increase in CRC was observed in patients on PPI monotherapy and PPI plus DOAC, suggesting a possible risk.

Functional Role of Mitochondrial DNA in Cancer Progression.

Mitochondrial DNA (mtDNA) has been identified as a significant genetic biomarker in disease, cancer and evolution. Mitochondria function as modulators for regulating cellular metabolism. In the clinic, mtDNA variations (mutations/single nucleotide polymorphisms) and dysregulation of mitochondria-encoded genes are associated with survival outcomes among cancer patients. On the other hand, nuclear-encoded genes have been found to regulate mitochondria-encoded gene expression, in turn regulating mitochondrial homeostasis. These observations suggest that the crosstalk between the nuclear genome and mitochondrial genome is important for cellular function. Therefore, this review summarizes the significant mechanisms and functional roles of mtDNA variations (DNA level) and mtDNA-encoded genes (RNA and protein levels) in cancers and discusses new mechanisms of crosstalk between mtDNA and the nuclear genome.

Albumin-Bilirubin Grade as a Novel Predictor of the Development and Short-Term Survival of Post-Banding Ulcer Bleeding Following Endoscopic Variceal Ligation in Cirrhotic Patients.

Background and Objectives: Endoscopic variceal ligation (EVL) is the primary and secondary treatment for acute esophageal variceal bleeding. Post-banding ulcer bleeding (PBUB) may lead to bleeding episodes following EVL, increasing mortality. The aim of this study was to evaluate the risk factors for PBUB and predict the 6-week mortality risk after PBUB. Materials and Methods: We retrospectively analyzed the data collected from cirrhotic patients with EVL from 2015 to 2017. The incidence of PBUB and the 6-week mortality rate were evaluated. Risk factors for PBUB and predictive factors for mortality after PBUB were analyzed. Results: A total of 713 patients were enrolled in this study. Among the studied subjects, the incidence of PBUB was 5.8% (N = 41). The 6-week mortality rate was 63.4% (26/41). In multivariate analysis, MELD score ≥20 (OR: 3.77, 95% CI: 1.94−7.33, p < 0.001), ALBI score of 3 (OR: 2.67, 95% CI: 1.34−5.3, p = 0.005) and the presence of gastric varices (OR: 2.1, 95% CI: 1.06−4.16, p = 0.03) were associated with the development of PBUB. Patients with ALBI grade 3 (OR: 4.8, 95% CI: 1.18−19.6, p = 0.029) and Child-Pugh scores B and C (OR: 16.67, 95% CI: 1.75−158.1, p = 0.014) were associated with 6-week mortality after PBUB. Conclusions: PBUB is a complication with low incidence but increased mortality following EVL. The ALBI grade is a useful score to predict not only the development of PBUB but also the 6-week mortality after PBUB.

Impact of an MT-RNR1 Gene Polymorphism on Hepatocellular Carcinoma Progression and Clinical Characteristics.

Mitochondrial DNA (mtDNA) mutations are highly associated with cancer progression. The poor prognosis of hepatocellular carcinoma (HCC) is largely due to high rates of tumor metastasis. This emphasizes the urgency of identifying these patients in advance and developing new therapeutic targets for successful intervention. However, the issue of whether mtDNA influences tumor metastasis in hepatoma remains unclear. In the current study, multiple mutations in mtDNA were identified by sequencing HCC samples. Among these mutations, mitochondrially encoded 12S rRNA (MT-RNR1) G709A was identified as a novel potential candidate. The MT-RNR1 G709A polymorphism was an independent risk factor for overall survival and distant metastasis-free survival. Subgroup analysis showed that in patients with cirrhosis, HBV-related HCC, α-fetoprotein ≥ 400 ng/mL, aspartate transaminase ≥ 31 IU/L, tumor number > 1, tumor size ≥ 5 cm, and histology grade 3-4, MT-RNR1 G709A was associated with both shorter overall survival and distant metastasis-free survival. Mechanistically, MT-RNR1 G709A was clearly associated with hexokinase 2 (HK2) expression and unfavorable prognosis in HCC patients. Our data collectively highlight that novel associations among MT-RNR1 G709A and HK2 are an important risk factor in HCC patients.

The effect of prophylactic hemoclip placement and risk factors of delayed post-polypectomy bleeding in polyps sized 6 to 20 millimeters: a propensity score matching analysis.

BACKGROUND: Delayed post-polypectomy bleeding (PPB) is a major complication of polypectomy. The effect of prophylactic hemoclipping on delayed PPB is uncertain. The aim of this study was to evaluate the effectiveness of prophylactic hemoclipping and identify the risk factors of delayed PPB. METHODS: Patients with polyps sized 6 to 20 mm underwent snare polypectomy from 2015 to 2017 were retrospectively reviewed. The patients with prophylactic hemoclipping for delayed PPB prevention were included in the clipping group, and those without prophylactic hemoclipping were included in the non-clipping group. The incidence of delayed PPB and time to bleeding were compared between the groups. Multivariate analysis was used to identify the risk factors of delayed PPB. Propensity score matching was used to minimize potential bias. RESULTS: After propensity score matching, 612 patients with 806 polyps were in the clipping group, and 576 patients with 806 polyps were in the non-clipping group. There were no significant differences in the incidence of delayed PPB and days to bleeding between two groups (0.8% vs 1.3%, p = 0.4; 3.4 ± 1.94 days vs 4.13 ± 3.39 days, p = 0.94). In the multivariate analysis, the polyp size [Odds ratio (OR):1.16, 95% confidence interval (CI):1.01-1.16, p = 0.03), multiple polypectomies (OR: 4.64, 95% CI:1.24-17.44, p = 0.02) and a history of anticoagulant use (OR:37.52, 95% CI:6.49-216.8, p < 0.001) were associated with delayed PPB. CONCLUSIONS: In polyps sized 6 to 20 mm, prophylactic hemoclip placement did not decrease the risk of delayed PPB. Patients without risk factors including multiple polypectomies and anticoagulant use are no need to performing prophylactic hemoclipping.

A prospective, multicenter, noninterventional study in Taiwan to evaluate the safety and tolerability of lacosamide as adjunctive therapy for epilepsy in clinical practice.

RATIONALE: Lacosamide (LCM) was initially approved in Taiwan in March 2014 for use as adjunctive therapy for focal impaired awareness seizures and secondarily generalized seizures (SGS) in patients with epilepsy ≥16 years of age. The efficacy and tolerability of adjunctive LCM for the treatment of patients with focal seizures have been demonstrated in randomized, placebo-controlled trials. However, the trials do not reflect a flexible dose setting. This study (EP0063) was conducted to assess the safety and tolerability of LCM in real-world clinical practice in Taiwan. Effectiveness of LCM was also assessed as an exploratory objective. METHODS: EP0063 was a multicenter, prospective, noninterventional study with an expected observation period of 12 months ±â€¯60 days. Eligible patients were ≥16 years of age, had focal impaired awareness seizures and/or SGS (in line with approved indication in Taiwan at the time of the study), were taking at least one concomitant antiseizure medication (ASM), and had at least one seizure in the 3 months before baseline. Patients were prescribed LCM by their treating physician in the course of routine clinical practice. The primary safety variable was treatment-emergent adverse events (TEAEs) spontaneously reported to, or observed by, the treating physician. Based on safety data from previous studies of LCM and known side effects of other ASMs, certain TEAEs (including but not limited to cardiac and electrocardiogram, suicidality, and rash related terms) were analyzed separately. Effectiveness variables included Clinical Global Impression of Change (CGIC) and change in 28-day seizure frequency from baseline to 12 months (or final visit), and freedom from focal seizures. RESULTS: A total of 171 patients were treated with LCM, of whom 139 (81.3%) completed the study. The Kaplan-Meier estimated 12-month retention was 82.9%. Patients had a mean (standard deviation [SD], range) age of 38.5 (14.0, 16-77) years, and 96 (56.1%) were male. Patients were taking a mean (SD, range) of 2.8 (1.1, 1-6) ASMs at baseline. Mean (SD, range) duration of LCM treatment was 288.7 (111.9, 2-414) days, and the mean (SD, range) daily dosage of LCM was 205.0 (82.7, 50.0-505.2) mg/day. Overall, 95 (55.6%) patients reported at least one TEAE, most commonly dizziness (33 [19.3%] patients). Drug-related TEAEs were reported in 74 (43.3%) patients, and drug-related TEAEs leading to discontinuation of LCM were reported in 14 (8.2%) patients. Two (1.2%) patients died during LCM treatment, which were considered not related to LCM. Two (1.2%) patients had suicidality-related TEAEs; these TEAEs were considered either not related to LCM or the relationship was not recorded. Rash-related TEAEs were reported in five (2.9%) patients (considered LCM-related in two patients). Based on the CGIC, at 12 months (or final visit), 109 (63.7%) patients were considered to have improved, 54 (31.6%) had no change, and the remaining eight (4.7%) were minimally worse. At 12 months (or final visit), the median percentage change in focal seizure frequency was -50.0. During the first 6 months of the study, 21 (12.3%) patients were free from focal seizures; 37 (21.6%) patients were free from focal seizures in the last 6 months of the study; and 14 (8.2%) were free from focal seizures for the full 12 months of the study. CONCLUSIONS: Results of this prospective, noninterventional study suggest that adjunctive LCM was generally safe and well tolerated in this patient group in real-world practice in Taiwan. Effectiveness was also favorable, with more than 60% of patients considered to be improved by their physician at 12 months (or final visit).

Electrical cortical stimulation for treatment of intractable epilepsy originating from eloquent cortex: surgical accuracy and clinical efficacy.

BACKGROUND: Electrical cortical stimulation is shown effective in treating patients with drug-resistant epilepsy. We demonstrated how detailed procedures of pre- and intra-operative planning of cortical stimulation implantation may influence the results of seizure reduction rate. METHODS: To confirm the precision of subdural grids covering the epileptogenic foci in the eloquent regions, pre- and intra-operative video-electroencephalography (VEEG) were performed in patients with drug-resistant epilepsy during a 4-day 24-h monitoring. The localization of the grid was determined via 3D reconstruction imaging of subdural electrodes co-registered onto the patient's cortex. A final quadripolar lead in cyclic stimulation mode was then placed and secured on the target cortex area. Post-operative 3D CT ensured the accurate location of stimulation lead without any misplacement. Bipolar cyclic stimulation and post-implantation VEEG were performed for 7 days. Patients were discharged and followed up regularly for parameters adjustment and recording of seizure outcomes. RESULTS: Eight patients received chronic cortical stimulation implantations between February 2003 and December 2017. The mean age of these patients was 21.1 years old and the average post-operative follow-up was 77.3 months. Comparisons of their seizure frequency at baseline and during the postoperative period revealed a mean reduction in seizures of 60.4% at the first year and 65.6% at the second year. CONCLUSIONS: Pre-surgical planning enhanced the accuracy of electrode placement and led to a favorable seizure reduction rate. Our report confirms that electrical cortical stimulation with detailed implantation procedures is safe and effective for patients with drug-resistant epilepsy originating from eloquent cortex.

DHA Attenuates Cerebral Edema Following Traumatic Brain Injury via the Reduction in Blood-Brain Barrier Permeability.

Traumatic brain injury (TBI) could result in edema and cause an increase in intracranial pressure of the brain resulting in mortality and morbidity. Although there is hyperosmolarity therapy available for this pathophysiological event, it remains controversial. Recently, several groups have shown docosahexaenoic acid (DHA) to improve functional and histological outcomes following brain injury based on reduction of neuroinflammation and apoptosis. However, the effect of DHA on blood-brain barrier (BBB) dysfunction after brain injury has not been fully studied. Here, a controlled cortical impact rat model was used to test the effect of a single dose of DHA administered 30 min post injury. Modified neurological severity score (mNSS) and forelimb asymmetry were used to determine the functional outcomes. Neuroimaging and histology were used to characterize the edema and BBB dysfunction. The study showed that DHA-treated TBI rats had better mNSS and forelimb asymmetry score than vehicle-treated TBI rats. Temporal analysis of edema using MRI revealed a significant reduction in edema level with DHA treatment compared to vehicle in TBI rats. Histological analysis using immunoglobulin G (IgG) extravasation showed that there was less extravasation, which corresponded with a reduction in aquaporin 4 and astrocytic metalloprotease 9 expression, and greater endothelial occludin expression in the peri-contusional site of the TBI rat brain treated with DHA in comparison to vehicle treatment. In conclusion, the study shows that DHA can exert its functional improvement by prevention of the edema formation via prevention of BBB dysfunction after TBI.

Association Between Flow Acceleration in the Carotid Artery and Intracranial Aneurysms.

OBJECTIVES: In physiologic pulsatile flow, velocity acceleration is an independent factor determining wall shear stress experienced by the vascular endothelium. The purpose of this study was to evaluate Doppler indices of systolic velocity acceleration in extracranial cerebral vessels and the occurrence of intracranial aneurysms. METHODS: We reviewed medical records and 3.0-T brain magnetic resonance imaging with 3-dimensional time-of-flight magnetic resonance angiography of 1323 adults who underwent health checkups from June 2006 to November 2011, in whom 53 intracranial aneurysms were identified in 45 patients. Doppler ultrasound parameters of the carotid and vertebral arteries were analyzed in these 45 patients with aneurysms and compared with another 45 control participants matched for age and sex. We defined the maximum systolic acceleration (ACCmax ) as the maximum slope of the early phase of systolic acceleration on the Doppler waveform and the maximum acceleration index (AImax ) as the ratio of the ACCmax and peak systolic velocity. RESULTS: The Doppler analysis showed a significantly increased AImax and ACCmax in the common carotid artery (CCA), internal carotid artery, and vertebral artery in the aneurysm group. A cutoff 13.89 s-1 for the AImax of the CCA had sensitivity of 80% with a negative predictive value of 99% for intracranial aneurysms. CONCLUSIONS: This study suggests that the AImax of the CCA with a cutoff of 13.89 s-1 may be an alternative to 3-dimensional time-of-flight magnetic resonance angiography or computed tomographic angiography as a screening tool for intracranial aneurysms. Further prospective studies are needed to validate the diagnostic performance and cost-effectiveness of these indices for screening.

Clinical, Electroencephalographic Features and Prognostic Factors of Cefepime-Induced Neurotoxicity: A Retrospective Study.

BACKGROUND: The incidence of cefepime-induced neurotoxicity (CIN) has been previously underestimated, and there have only been sporadic reports from critical neurological settings. The present study aimed to investigate the potential factors associated with disease development, electroencephalography (EEG) sub-classification, and outcome measures. METHODS: The 10-year medical records of patients who underwent EEG between 2007 and 2016 at a tertiary medical center in Taiwan, and developed encephalopathy after cefepime therapy were retrospectively reviewed. Age- and sex-matched controls were included for further analysis. Demographic data, the occurrence of clinical seizures, non-convulsive status epilepticus (NCSE), use of antiepileptic drugs (AEDs), receiving maintenance or urgent hemodialysis, EEG findings, and functional outcomes were analyzed. The Chi-square test and a logistic regression model were applied to survey significant prognostic factors relating to mortality. RESULTS: A total of 42 CIN patients were identified, including 25 patients from wards and 17 from intensive care units; their mean age was 75.8 ± 11.8 years. Twenty-one patients (50%) had chronic kidney disease, and 18 (43%) had acute kidney injury. Among these patients, 32 (76%) received appropriate cefepime dose adjustment. Three patients had a normal renal function at the time of CIN onset. The logistic regression model suggested that maintenance hemodialysis and longer duration of cefepime use were independently associated with the development of CIN, with odds ratios of 3.8 and 1.2, respectively. NCSE was frequently noted in the CIN patients (64%). Generalized periodic discharge with or without triphasic morphology was the most common EEG pattern (38%), followed by generalized rhythmic delta activity and generalized spike-and-waves. AEDs were administered to 86% of the patients. A total of 17 patients (40%) did not survive to hospital discharge. Adequate cefepime dose adjustment and early cefepime discontinuation led to a better prognosis. CONCLUSIONS: CIN was associated with high mortality and morbidity rates. Neurotoxic symptoms could still occur when the cefepime dose was adjusted, or in patients with normal renal function. Patients with maintenance hemodialysis or a longer duration of cefepime therapy tended to develop CIN. Early recognition of abnormal EEG findings allowed for the withdrawal of the offending agent, resulting in clinical improvements and a better prognosis at discharge.

Efficacy and tolerability of perampanel in children and adolescents with pharmacoresistant epilepsy: The first real-world evaluation in Asian pediatric neurology clinics.

AIM: This study investigated the efficacy and safety of perampanel (PER) adjunctive therapy in pediatric patients with epilepsy whose seizures are pharmacoresistant to existing antiepileptic drugs. METHODS: A clinical retrospective study was conducted from 2016 to 2017 in the pediatric neurology clinic at a tertiary children's hospital. We reviewed the data obtained from 66 children whose seizures were pharmacoresistant to more than two antiepileptic drugs, and could be followed up for a minimum of 3 months after PER adjunctive therapy initiation. The efficacy was estimated by the PER response rate at 3-, 6-, and 12-month follow-up evaluations, and adverse events were also recorded. RESULTS: The rate of seizure reduction of >50% was 30.3%, 37.5%, and 34.7% for all seizure types at 3, 6, and 12 months, in which 7.6%, 8.9%, and 14.3% of the patients became seizure-free at these time points, respectively. No significant differences were found between enzyme-inducing and nonenzyme-inducing antiepileptic drugs in combination with PER with regard to the responder rate. Five patients with Dravet syndrome were included in the study. Four of them (80%) exhibited 50% seizure reduction at the last visit, at which point, two patients (40.0%) were seizure-free. The retention rate was 51% at 12 months. Adverse events were documented in 25 patients (35.7%) and led to PER discontinuation in eight patients (12.1%). The most common adverse events comprised irritability, skin rash, dizziness, and somnolence; however, all were transient and successfully managed after PER dose reduction or discontinuation. CONCLUSION: The current data support the value of adjunctive PER in child and adolescent patients with pharmacoresistant epilepsy in daily clinical practice. Perampanel was efficacious and generally well-tolerated as an add-on treatment for epilepsy.

Evaluation of cerebral blood flow in acute ischemic stroke patients with atrial fibrillation: A sonographic study.

BACKGROUND/PURPOSE: Although cerebral emboli are a frequent cause of cardiogenic stroke, the possibility of a reduction in cerebral perfusion consequent to arrhythmia or impaired cardiac function should be considered in patients with atrial fibrillation (AF). METHODS: We reviewed sonographic studies and clinical features of patients with acute ischemic stroke. A total of 144 patients with AF and 144 age- and sex-matched patients with small vessel occlusion but without AF were included. RESULTS: Patients with AF had significantly lower peak systolic velocity (PSV), mean velocity, flow volume (p < 0.001), and end-diastolic velocity (p = 0.035) of the internal carotid artery (ICA); significantly lower cerebral blood flow (p < 0.001); and lower flow velocities of the middle cerebral artery (p < 0.01) than patients with small vessel occlusion but without AF. In patients with AF, there was an inverse linear correlation between ICA end-diastolic velocity, mean velocity (p < 0.001), flow volume (p = 0.025), middle cerebral artery flow velocities (p < 0.05), and age. Cardiac ejection fraction had a positive linear correlation with ICA PSV (p = 0.016) but an inverse correlation with the heart rate (p = 0.009). There was a significant decline in PSV (p = 0.002), resistance index (p < 0.001), and flow volume (p = 0.0121) of the ICA as well as cerebral blood flow (p = 0.009) as the heart rate increased. CONCLUSION: Cerebral blood flow is markedly reduced in ischemic stroke patients with AF as compared with that in patients with small vessel disease but without AF.

Extracranial Carotid Artery Disease: Risk Factors and Outcomes in Patients With Acute Critical Hemispheric Ischemic Stroke.

OBJECTIVES: The prevalence of carotid disease in stroke patients has been underestimated because most stroke patients who receive carotid sonography have already survived the acute event. Little is known about the extracranial carotid arteries of patients with acute stroke who need intensive care. This study reviewed color-coded carotid duplex sonographic examinations of the extracranial carotid arteries of patients with acute critical hemispheric ischemic stroke. METHODS: We retrospectively reviewed 30 consecutive patients who had acute critical hemispheric ischemic stroke and received color-coded carotid duplex sonography in the intensive care unit. The presence of occlusive carotid artery disease was correlated with clinical features, vascular risk factors, and outcomes. RESULTS: Overall, 57% of the patients (17 of 30) had an occlusive internal carotid artery, and 44% of patients with atrial fibrillation (7 of 16) also had occlusive carotid disease. Eventually, 73% of the patients (21 of 30) had poor outcomes, and 57% (17 of 30) died. The contributing factors to a poor outcome were older age, an initial conscious disturbance, endotracheal intubation, and occlusive carotid disease, with the most significant factor being older age (P = .022; odds ratio, 27.76). The factors contributing to death were endotracheal intubation, occlusive carotid disease, and reversed ophthalmic flow, with the most significant factor being occlusive carotid disease (P = .014; odds ratio, 11.38). Soft homogeneously echogenic thrombi filling the lumen of the internal carotid artery and moving forward and backward with the carotid pulse were found in 3 patients. A small segment of ruptured plaque that was floating forward and backward with pulsation was found in 1 patient. CONCLUSIONS: Occlusive carotid artery disease is not uncommon among Chinese patients who have had an acute critical hemispheric infarction. Older age is the factor most significantly correlated with a poor outcome, and occlusive carotid disease is the factor most significantly correlated with death.

Low and High Frequency Hippocampal Stimulation for Drug-Resistant Mesial Temporal Lobe Epilepsy.

OBJECTIVE: Electrical stimulation of the hippocampus offers the possibility to treat patients with mesial temporal lobe epilepsy (MTLE) who are not surgical candidates. We report long-term follow-up results in five patients receiving low or high frequency hippocampal stimulation for drug-resistant MTLE. MATERIALS AND METHODS: The patients underwent stereotactic implantation of quadripolar stimulating electrodes in the hippocampus. Two of the patients received unilateral electrode implantation, while the other three received bilateral implantation. Stimulation of the hippocampal electrodes was turned ON immediately after the implantation of an implantable pulse generator, with initial stimulation parameters: 1 V, 90-150 µs, 5 or 145 Hz. The frequency of seizures was monitored and compared with preimplantation baseline data. RESULTS: Two men and three women, aged 27-61 years were studied, with a mean follow-up period of 38.4 months (range, 30-42 months). The baseline seizure frequency was 2.0-15.3/month. The five patients had an average 45% (range 22-72%) reduction in the frequency of seizures after hippocampal stimulation over the study period. Low frequency hippocampal stimulation decreased the frequency of seizures in two patients (by 54% and 72%, respectively). No implantation- or stimulation-related side effects were reported. CONCLUSIONS: Electrical stimulation of the hippocampus is a minimally invasive and reversible method that can improve seizure outcomes in patients with drug-resistant MTLE. The optimal frequency of stimulation varied from patient to patient and therefore required individual setting. These experimental results warrant further controlled studies with a large patient population to evaluate the long-term effect of hippocampal stimulation with different stimulation parameters.

Clinical Research into Central Nervous System Inflammatory Demyelinating Diseases Related to COVID-19 Vaccines.

Various vaccines have been developed in response to the SARS-CoV-2 pandemic, and the safety of vaccines has become an important issue. COVID-19 vaccine-related central nervous system inflammatory demyelinating diseases (CNS IDDs) have been reported recently. We present one case of AstraZeneca vaccine-related myelin oligodendrocyte glycoprotein (MOG) antibody-associated disease and a literature review of another 78 patients published from January 2020 to October 2022. Patients were divided into three vaccine types (viral vector, mRNA, and inactivated vaccines) for further analyses. Among 79 patients with COVID-19 vaccine-related CNS IDDs, 49 (62%) cases received viral vector vaccines, 20 (25.3%) received mRNA vaccines, and 10 (12.7%) received inactivated vaccines. Twenty-seven cases (34.2%) were confirmed with autoantibodies, including fifteen patients (19%) with anti-MOG, eleven (13.9%) with anti-aquaporin 4 (AQP4), and one (1.3%) with both antibodies. Significantly, more males developed CNS IDDs post viral vector vaccines compared to mRNA and inactivated vaccines. Patients receiving mRNA vaccines were older than those receiving other types. Furthermore, mRNA and inactivated vaccines correlated more with anti-AQP4 antibodies, while viral vector vaccines showed higher MOG positivity. This research suggests potential associations between COVID-19 vaccine-related CNS IDDs and gender, age, and autoantibodies, contingent on vaccine types. Protein sequence analysis implies similarities between the S protein and AQP4/MOG. Further studies may elucidate the mechanisms of CNS IDDs, aiding vaccine selection for specific types.

Therapeutic drug monitoring of perampanel: Clinical utility and impact of co-medication on pharmacokinetic variability.

Background: Perampanel (PER) is a newly developed antiseizure medication (ASM). This study aimed to determine the utilization of therapeutic drug monitoring (TDM) for PER in a real-world clinical setting and investigate the influence of concomitant use of ASMs on the plasma concentration profile of PER. Method: We analyzed data from the Chang Gung Research Database, which is the largest multi-institutional electronic medical records database in Taiwan. The main outcomes were the comparisons of PER plasma concentration and the ratio of concentration to the weight-adjusted dose (C/D; [ng/mL]/[mg/kg/d]) among patients received TDM of different clinical indication and among different ASM co-medication subgroups. Results: Overall, 88 plasma samples were collected from 66 epilepsy patients treated with PER. The majority of patients (77.3 %) underwent PER TDM owing to poorly controlled seizures. There was a trend toward a higher plasma concentration and C/D ratio in those suspected of having PER toxicity owing to adverse events than of other indications. The PER concentration exhibited dose linearity. The mean PER plasma concentrations in patients co-medicated with enzyme-inducing ASMs were significantly lower than those in the patients who were not prescribed enzyme-inducing or enzyme-inhibiting ASMs, and co-medication with carbamazepine (CBZ) resulted in a significant reduction in the PER concentration. Conclusion: PER concentration exhibited a linear regression relationship with PER dose, and the plasma concentration of the drug was highly susceptible to the drug's interactions with enzyme-inducing ASMs. TDM with clear indication could help determine the influence of ASMs used concomitantly on PER concentrations and guide clinical adjustments.

Improved outcome after peripheral nerve injury in mice with increased levels of endogenous ω-3 polyunsaturated fatty acids.

Functional recovery after a peripheral nerve injury (PNI) is often poor. There is a need for therapies that protect neurons against injury and enhance regeneration. ω-3 polyunsaturated fatty acids (PUFAs) have been shown to have therapeutic potential in a variety of neurological disorders, including acute traumatic injury. The objective of this study was to assess the neuroprotective and pro-regenerative potential of ω-3 PUFAs in PNI. We investigated this in mice that express the fat-1 gene encoding for ω-3 fatty acid desaturase, which leads to an increase in endogenous ω-3 PUFAs and a concomitant decrease in ω-6 PUFAs. Dorsal root ganglion (DRG) neurons from wild-type or fat-1 mice were subjected to a mechanical strain or hypoxic injury, and cell death was assessed using ethidium homodimer-1 labeling. The fat-1 background appears to confer robust neuroprotection against both injuries. We then examined the early functional and morphological changes in wild-type and fat-1 mice after a sciatic nerve crush. An accelerated functional recovery 7 d after injury was seen in fat-1 mice when assessed using von Frey filaments and the sciatic nerve functional index. These observations were also mapped to changes in injury-related markers. The injury-induced expression of ATF-3 was decreased in the DRG of fat-1 mice, whereas the axons detected 6 mm distal to the crush were increased. Fat-1 animals also had some protection against muscle atrophy after injury. In conclusion, both in vitro and in vivo experiments support the idea that a higher endogenous ω-3 PUFA could lead to beneficial effects after a PNI.

Transgenic mice with high endogenous omega-3 fatty acids are protected from spinal cord injury.

Omega-3 polyunsaturated fatty acids have been shown to have therapeutic potential in a variety of neurological disorders, including acute traumatic injury of the spinal cord. We addressed the question whether the neuroprotective effect of these compounds after spinal cord injury could also be seen when their level is raised in tissues prophylactically, prior to injury. In this study we used transgenic fat-1 mice to examine whether enriching spinal cord tissue in endogenous omega-3 polyunsaturated fatty acids has an effect on the outcome after compression spinal cord injury. The results demonstrate that after thoracic compression spinal cord injury, fat-1 mice display better locomotor recovery compared with the wild-type mice on a high omega-6 diet (high omega-6 polyunsaturated fatty acids in tissues), and wild-type mice on a normal diet (controls). This is associated with a significant increase in neuronal and oligodendrocyte survival and a decrease in non-phosphorylated neurofilament loss. The protection from spinal cord injury in fat-1 mice was also correlated with a reduction in microglia/macrophage activation and in pro-inflammatory mediators. In vitro experiments in dorsal root ganglia primary sensory neurons further demonstrated that a fat-1 tissue background confers robust neuroprotection against a combined mechanical stretch and hypoxic injury. In conclusion, our studies support the hypothesis that a raised omega-3 polyunsaturated fatty acid level and an altered tissue omega-6/omega-3 ratio prior to injury leads to a much improved outcome after spinal cord injury.