Integrative Systematics and Biogeography of the Hydrozoans (Leptothecata: Eirenidae) Eirene menoni Kramp, 1953 and Eirene lacteoides Kubota and Horita, 1992 from Japan and China with Comments on Pacific Ocean Distributions.

The hydrozoan family Eirenidae is known scientifically for its morphological plasticity and challenges in species identification. We used an integrative taxonomic approach based on morphological, molecular and life history evidence to systematically assess field-collected medusae of Eirene menoni Kramp 1953 and captive raised polyps of both E. menoni and E. lacteoides Kubota and Horita 1992. Following morphological review, we updated the genus description to include the presence of rudimentary bulbs (warts) on the ring canal in at least eight of the 24 valid Eirene species. We propose the potential for the mature E. menoni hydrotheca to develop into a gonotheca. However, this proposal will require additional study for verification. We provide validated distribution records from the Indo-Pacific Ocean for E. menoni,and updated collection records for E. lacteoides from the Yellow and East China Seas, and public aquaria-cultured specimens from Japan and Hawaii, using cytochrome c oxidase I (COI) sequences that we generated and compared with those from GenBank. The COI gene reliably separated four species, each forming a monophyletic clade with strong bootstrap support and low mean intraspecific molecular divergences (≤ 1%) within clades. However, some of the deeper nodes of the tree remained poorly resolved, and our analysis failed to demonstrate monophyly among eirenid genera Eirene and Tima. Our integrative taxonomic approach is essential in confirming species identity within the family Eirenidae and genus Eirene,and we have also identified a likely range expansion of E. lacteoides to Hawaii.

Periodic discharges plus fast activity on electroencephalogram predict worse outcomes in poststroke epilepsy.

OBJECTIVE: Postseizure functional decline is a concern in poststroke epilepsy (PSE). However, data on electroencephalogram (EEG) markers associated with functional decline are scarce. Thus, we investigated whether periodic discharges (PDs) and their specific characteristics are associated with functional decline in patients with PSE. METHODS: In this observational study, patients admitted with seizures of PSE and who had scalp EEGs were included. The association between the presence or absence of PDs and postseizure short-term functional decline lasting 7 days after admission was investigated. In patients with PD, EEG markers were explored for risk stratification of short-term functional decline, according to the American Clinical Neurophysiology Society's Standardized Critical Care EEG Terminology. The association between EEG markers and imaging findings and long-term functional decline at discharge and 6 months after discharge, defined as an increase in the modified Rankin Scale score compared with the baseline, was evaluated. RESULTS: In this study, 307 patients with PSE (median age = 75 years, range = 35-97 years, 64% males; hemorrhagic stroke, 47%) were enrolled. Compared with 247 patients without PDs, 60 patients with PDs were more likely to have short-term functional decline (12 [20%] vs. 8 [3.2%], p < .001), with an adjusted odds ratio (OR) of 4.26 (95% confidence interval [CI] = 1.44-12.6, p = .009). Patients with superimposed fast-activity PDs (PDs+F) had significantly more localized (rather than widespread) lesions (87% vs. 58%, p = .003), prolonged hyperperfusion (100% vs. 62%, p = .023), and a significantly higher risk of short-term functional decline than those with PDs without fast activity (adjusted OR = 22.0, 95% CI = 1.87-259.4, p = .014). Six months after discharge, PDs+F were significantly associated with long-term functional decline (adjusted OR = 4.21, 95% CI = 1.27-13.88, p = .018). SIGNIFICANCE: In PSE, PDs+F are associated with sustained neuronal excitation and hyperperfusion, which may be a predictor of postseizure short- and long-term functional decline.

Molecular Dynamics Simulations of High-Concentration Li[TFSA] Sulfone Solution: Effect of Easy Conformation Change of Sulfolane on Fast Diffusion of Li Ion.

The parameters of the polarizable force field used for molecular dynamics simulations of Li diffusion in high-concentration lithium bis(trifluoromethanesulfonyl)amide (Li[TFSA]) sulfone (sulfolane, dimethylsulfone, ethylmethylsulfone, and ethyl-i-propylsulfone) solutions were refined. The densities of the solutions obtained by molecular dynamics simulations reproduced well the experimental values. The calculated concentration, temperature, and solvent dependencies of self-diffusion coefficients of ions and solvents in the mixtures well reproduce the experimentally observed dependencies. Ab initio calculations show that the intermolecular interactions between Li ions and four sulfones are not largely different. Conformational analyses show that sulfolane can change the conformation more easily owing to lower barrier height for pseudorotation compared to the rotational barrier heights of diethylsulfone and ethylmethylsulfone. Molecular dynamics simulations indicate that the easy conformation change of solvent affects the rotational relaxation of the solvent and the diffusion of Li ion in the mixture. The easy conformation change of sulfolane is one of the causes of faster diffusion of Li ion in the mixture of Li[TFSA] and sulfolane compared to the mixtures of smaller dimethylsulfone and ethylmethylsulfone.

Case Report: Postmortem brain and heart pathology unveiling the pathogenesis of coexisting acute ischemic stroke and electrocardiographic abnormality.

Electrocardiography abnormalities have been occasionally reported at the onset of stroke. Simultaneous electrocardiographic abnormalities and stroke require a rapid differentiated diagnosis among several diseases. However, direct causal relationships remain unclear. A 92-year-old woman presented to our emergency department in a sudden-onset coma. The patient suffered from huge acute ischemic stroke with bilateral internal carotid artery occlusion assessed by brain magnetic resonance imaging, and her electrocardiography showed ST-segment elevation at II, III, aVF and V4-6, and atrial fibrillation (AF). However, the etiology of the medical condition was clinically unknown. Eventually, the patient died on day 4 of hospitalization before the diagnosis could be completed. Therefore, an autopsy was performed to investigate pathological findings after obtaining informed consent from the family. A postmortem pathological evaluation demonstrated that fibrin mural thrombi in the left atrial appendage (LAA), and the cerebral and coronary arteries possessed CD31-positive endothelial cells, and CD68-positive and CD168-positive macrophages in a similar fashion, suggesting the fibrin thrombi observed in the three sites implicated to be identical. We concluded that nearly concurrent cerebral and coronary artery embolism because of the fibrin thrombi in LAA developed by AF. Simultaneous cerebral infarction and myocardial infarction are referred to as cardiocerebral infarction (CCI), a rare disorder for which clear pathomechanisms remain unknown, although several mechanisms of CCI have been proposed. We first revealed the clear pathology of CCI using the autopsy. Additional pathological studies are warranted to establish clear pathomechanisms and preventive strategies of CCI.

Hypertension, cerebral Amyloid, aGe Associated Known neuroimaging markers of cerebral small vessel disease Undertaken with stroke REgistry (HAGAKURE) prospective cohort study: Baseline characteristics and association of cerebral small vessel disease with prognosis in an ischemic stroke cohort.

Introduction: Cerebral small vessel disease (SVD) is one of the leading causes of stroke; each neuroimaging marker of SVD is correlated with vascular risk factors and associated with poor prognosis after stroke. However, longitudinal studies investigating the association between comprehensive SVD burden scoring system, "total SVD score" - which encompasses the established neuroimaging markers of lacunae, cerebral microbleeds (CMBs), white matter hyperintensities (WMH) including periventricular hyperintensities, and perivascular spaces in basal ganglia- and clinical outcomes are limited. The aim of this study is to determine the association between SVD burden and long-term prognosis in patients with ischemic stroke. Methods and design: This prospective, single-center, observational study enrolled patients with acute ischemic stroke, including cerebral infarction and transient ischemic attack. Magnetic resonance imaging scans were performed, and then total SVD score (range, 0-4) was calculated. We recorded baseline characteristics and evaluated the relationships of long-term outcomes to SVD neuroimaging markers and total SVD score. Stroke recurrence was thought as primary outcome. Hazard ratios (HRs) of events during follow-up were calculated using Cox proportional hazards modeling with adjustments for age, sex, hypertension, dyslipidemia, diabetes mellitus, atrial fibrillation, and smoking. Cumulative event rates were estimated using the Kaplan-Meier method. Results: Consecutive 564 acute ischemic stroke patients were enrolled according to inclusion and exclusion criteria. A total of 467 participants with first-ever ischemic stroke were analyzed (median age 75.0 [interquartile range, 64.0-83.0] years, 59.3% male). Total SVD score was 0 point in 47 individuals (12.0%), 1 point in 83 (21.2%), 2 points in 103 (26.3%), 3 points in 85 (21.7%), and 4 points in 73 (18.7%). Twenty-eight recurrent stroke events were identified during follow-up. Total SVD score ≥ 2, presence of CMBs, and moderate-to-severe WMH were associated with increased risk of recurrent stroke events (HR 9.31, 95% confidence interval [CI] 2.33-64.23; HR 2.81, 95% CI 1.08-7.30; HR 2.90, 95% CI 1.22-6.88, respectively). Conclusion: The accumulation of SVD biomarkers as determined by total SVD score offered a reliable predictor of stroke recurrence. This study established a firm understanding of SVD prognosis in clinical settings.

Intracranial Myeloid Sarcoma Mimicking Hypertensive Intracerebral Hemorrhage.

We herein report a case of intracranial myeloid sarcoma mimicking hypertensive intracerebral hemorrhage. A 71-year-old man with a history of acute myeloid leukemia was admitted with acute-onset dysarthria. A hematoma-like lesion was found on computed tomography in the left putamen. Magnetic resonance imaging (MRI) and cerebrospinal fluid cytology confirmed the diagnosis of intracranial myeloid sarcoma. The patient showed a favorable response to chemotherapy, and follow-up MRI revealed shrinkage of the tumor. Since the computed tomography findings resemble those of intracerebral hemorrhage, it is important to suspect intracranial neoplasm, particularly in cases with a history of hematologic diseases.

Harboring Cnm-expressing Streptococcus mutans in the oral cavity relates to both deep and lobar cerebral microbleeds.

BACKGROUND: Cerebral microbleeds (CMBs) influence long-term prognoses of stroke patients. Streptococcus mutans expressing the collagen-binding protein Cnm induces cerebrovascular inflammation, impairing blood brain barrier integrity and causing cerebral bleeding. Here, we examine the association of Cnm-positive S. mutans with CMBs. METHODS: Acute stroke patients were selected from a single-center registry database. Oral carriage of Cnm-positive or Cnm-negative S. mutans was determined using polymerase chain reaction assays. The associations of Cnm-positive S. mutans with CMB number and specifically the presence of >10 CMBs were examined using quasi-Poisson and logistic regression models, respectively. RESULTS: This study included 3154 stroke patients, of which 428 patients (median [interquartile range] age, 73.0 [63.0-81.0] years; 269 men [62.9%]) underwent oral bacterial examinations. In total, 326 patients harbored S. mutans. After excluding four patients without imaging data, we compared patients with Cnm-positive (n = 72) and Cnm-negative (n = 250) S. mutans. Harboring Cnm-positive S. mutans was independently associated with the presence of >10 CMBs (adjusted odds ratio 2.20 [1.18-4.10]) and higher numbers of deep and lobar CMBs (adjusted risk ratio 1.61 [1.14-2.27] for deep; 5.14 [2.78-9.51] for lobar), but not infratentorial CMBs, after adjusting for age, sex, hypertension, stroke type, National Institutes of Health Stroke Scale score, and cerebral amyloid angiopathy. CONCLUSIONS: Harboring Cnm-positive S. mutans was independently associated with a higher number of CMBs in deep and lobar locations. Reducing Cnm-positive S. mutans in the oral cavity may serve as a novel therapeutic approach for stroke.

Association of Cortical Superficial Siderosis with Post-Stroke Epilepsy.

OBJECTIVE: To assess whether post-stroke epilepsy (PSE) is associated with neuroimaging findings of hemosiderin in a case-control study, and whether the addition of hemosiderin markers improves the risk stratification models of PSE. METHODS: We performed a post-hoc analysis of the PROgnosis of POST-Stroke Epilepsy study enrolling PSE patients at National Cerebral and Cardiovascular Center, Osaka, Japan, from November 2014 to September 2019. PSE was diagnosed when one unprovoked seizure was experienced >7 days after the index stroke, as proposed by the International League Against Epilepsy. As controls, consecutive acute stroke patients with no history or absence of any late seizure or continuing antiseizure medications at least 3 months after stroke were retrospectively enrolled during the same study period. We examined cortical microbleeds and cortical superficial siderosis (cSS) using gradient-echo T2*-weighted images. A logistic regression model with ridge penalties was tuned using 10-fold cross-validation. We added the item of cSS to the existing models (SeLECT and CAVE) for predicting PSE and evaluated performance of new models. RESULTS: The study included 180 patients with PSE (67 women; median age 74 years) and 1,183 controls (440 women; median age 74 years). The cSS frequency was higher in PSE than control groups (48.9% vs 5.7%, p < 0.0001). Compared with the existing models, the new models with cSS (SeLECT-S and CAVE-S) demonstrated significantly better predictive performance of PSE (net reclassification improvement 0.63 [p = 0.004] for SeLECT-S and 0.88 [p = 0.001] for CAVE-S at the testing data). INTERPRETATION: Cortical superficial siderosis was associated with PSE, stratifying stroke survivors at high risk of PSE. ANN NEUROL 2023;93:357-370.

Design and synthesis of aryl-piperidine derivatives as potent and selective PET tracers for cholesterol 24-hydroxylase (CH24H).

Cholesterol 24-hydroxylase (CH24H, CYP46A1) is a cytochrome P450 family enzyme that maintains the homeostasis of brain cholesterol. Soticlestat, a potent and selective CH24H inhibitor, is in development as a therapeutic agent for Dravet syndrome and Lennox-Gastaut syndrome. Herein, we report the discovery of aryl-piperidine derivatives as potent and selective CH24H positron emission tomography (PET) tracers which can be used for dose guidance of a clinical CH24H inhibitor and as a diagnostic tool for CH24H-related pathology. Starting from compound 1 (IC50 = 16 nM, logD = 1.7), which was reported as a CH24H inhibitor with lower lipophilicity, a18F-labeling site (3-fluoroazetidine) was incorporated by structure-based drug design (SBDD) utilizing the co-crystal structure of a compound 1 analog. Subsequent optimization to adjust key parameters for PET tracers, such as potency, lipophilicity, brain penetration, and unbound plasma protein binding, enabled compounds 3f (IC50 = 8.8 nM) and 3g (IC50 = 8.7 nM) as PET imaging candidates. Selectivity of these compounds for CH24H was validated by a brain distribution study using CH24H-WT and KO mice. In non-human primate PET imaging, [18F]3f and [18F]3g showed similar regional uptake in the brain, indicating that these tracers were specific to the CH24H-expressed regions and validated the expression of CH24H in the living brain by different tracers.

Risk Assessment of Cnm-Positive Streptococcus mutans in Stroke Survivors (RAMESSES): Protocol for a Multicenter Prospective Cohort Study.

Introduction: The role of commensal microbiota in systemic diseases, including brain diseases, has attracted increasing attention. Oral infectious diseases, such as dental caries and periodontitis, are also involved in cerebrovascular diseases and cognitive impairment. Cerebral microbleeds (CMBs) and intracerebral hemorrhage due to small vessel disease (SVD), are presumably associated with a high risk of vascular cognitive impairment and stroke. We previously reported that Streptococcus mutans (S. mutans, the main pathogen of dental caries), harboring the cnm gene that encodes the collagen-binding protein Cnm, is associated with the development of hypertensive intracerebral hemorrhage and aggravation of CMBs. We also proposed a mechanism by which the circulating Cnm-expressing S. mutans causes intracerebral hemorrhage or CMBs; it binds to denuded basement membranes mainly composed of collagen IV through damaged tight junctions or it directly invades endothelial cells, resulting in blood-brain barrier injury. In November 2018, we initiated a multicenter, prospective cohort study (RAMESSES: Risk Assessment of Cnm-positive S. mutans in Stroke Survivors; UMIN Clinical Trials Registry: UMIN000045559) to explore the longitudinal association between Cnm-positive S. mutans and CMBs with comprehensive dental findings, which should determine the effect of Cnm-positive S. mutans in the oral cavity on the risk of CMB development and cognitive decline. Methods: Fifteen domestic institutes will be enlisted to enroll 230 patients who have at least one CMB in the deep brain area and develop a stroke within the past year. The prevalence of Cnm-positive S. mutans based on oral specimens and dental hygiene will be examined. The primary outcome is the number of newly developed deep CMBs. The secondary outcomes include the new development of lobar, subtentorial, or any type of CMBs; symptomatic intracerebral hemorrhage or ischemic stroke; changes in cognitive function or frailty; major bleeding; all-cause mortality; and antibody titers against periodontal pathogens. The observation period will be 2 years. Discussion: The 2-year longitudinal prospective cohort study is expected to establish the role of Cnm-positive S. mutans in SVD including CMBs and intracerebral hemorrhage from the perspective of the "brain-oral axis" and provide guidance for novel prophylactic strategies against Cnm-positive S. mutans-induced SVD.

Clinical and imaging features of nonmotor onset seizure in poststroke epilepsy.

OBJECTIVE: Motivated by the challenges raised by diagnosing poststroke epilepsy (PSE), especially in nonmotor onset seizure (non-MOS), we aimed to investigate the features of non-MOS, including seizure sequences, patient characteristics, and electrophysiological and imaging findings in PSE. METHODS: This observational cohort study enrolled patients with PSE whose seizure onset was witnessed. According to the International League Against Epilepsy (ILAE) 2017 seizure classification, we classified seizure-onset symptoms into the non-MOS and MOS groups. We compared the different clinical characteristics between the two groups. RESULTS: Between 2011 and 2018, we enrolled 225 patients with PSE (median age, 75 years), consisting of 97 (43%) with non-MOS and 128 (57%) with MOS. Overall, 65 (67%) of the patients without MOS had no subsequent convulsions. Multivariable logistic regression analysis showed significant associations of non-MOS with absence of poststroke hemiparesis (adjusted odds ratio [OR], 1.88; 95% confidence interval [CI], 1.03-3.42), frontal stroke lobe lesions (OR, 2.11; 95% CI, 1.14-3.91), and putaminal stroke lesions (OR, 2.51; 95% CI, 1.22-5.18) as negative indicators. Postictal single-photon emission computed tomography (SPECT) detected prolonged hyperperfusion in the temporal lobe more frequently in the non-MOS than in the MOS group (48% vs 31%; p = .02). The detection rate was higher than spikes/sharp waves in scalp electroencephalography, both in the non-MOS group (72% vs 33%; p < .001) and the MOS group (68% vs 29%; p < .001). SIGNIFICANCE: This study provides the clinical features of non-MOS in patients with PSE. Compared with the patients with MOS, patients with non-MOS showed less likely subsequent convulsive seizures, highlighting the clinical challenges. Postictal perfusion imaging and negative indicators of the non-MOS type may help diagnose and stratify PSE.

Discovery of Novel 3-Piperidinyl Pyridine Derivatives as Highly Potent and Selective Cholesterol 24-Hydroxylase (CH24H) Inhibitors.

Cholesterol 24-hydroxylase (CH24H or CYP46A1) is a brain-specific cytochrome P450 enzyme that metabolizes cholesterol into 24S-hydroxycholesterol (24HC) for regulating brain cholesterol homeostasis. For the development of a novel and potent CH24H inhibitor, we designed and synthesized 3,4-disubstituted pyridine derivatives using a structure-based drug design approach starting from compounds 1 (soticlestat) and 2 (thioperamide). Optimization of this series by focusing on ligand-lipophilicity efficiency value resulted in the discovery of 4-(4-methyl-1-pyrazolyl)pyridine derivative 17 (IC50 = 8.5 nM) as a potent and highly selective CH24H inhibitor. The X-ray crystal structure of CH24H in complex with compound 17 revealed a unique binding mode. Both blood-brain barrier penetration and reduction of 24HC levels (26% reduction) in the mouse brain were confirmed by oral administration of 17 at 30 mg/kg, indicating that 17 is a promising tool for the novel and selective inhibition of CH24H.

Preclinical characterization of [18F]T-008, a novel PET imaging radioligand for cholesterol 24-hydroxylase.

PURPOSE: Cholesterol 24-hydroxylase (CH24H) is a brain-specific enzyme that plays a major role in brain cholesterol homeostasis by converting cholesterol into 24S-hydroxycholesterol. The selective CH24H inhibitor soticlestat (TAK-935) is being pursued as a drug for treatment of seizures in developmental and epileptic encephalopathies. Herein, we describe the successful discovery and the preclinical validation of the novel radiolabeled CH24H ligand (3-[18F]fluoroazetidin-1-yl){1-[4-(4-fluorophenyl)pyrimidin-5-yl]piperidin-4-yl}methanone ([18F]T-008) and its tritiated analog, [3H]T-008. METHODS: In vitro autoradiography (ARG) studies in the CH24H wild-type (WT) and knockout (KO) mouse brain sections were conducted using [3H]T-008. PET imaging was conducted in two adult rhesus macaques using [18F]T-008. Each macaque received two test-retest baseline scans and a series of two blocking doses of soticlestat administered prior to [18F]T-008 to determine the CH24H enzyme occupancy. PET data were analyzed with Logan graphical analysis using plasma input. A Lassen plot was applied to estimate CH24H enzyme occupancy by soticlestat. RESULTS: In ARG studies, binding of [3H]T-008 was specific to CH24H in the mouse brain sections, which was not observed in CH24H KO or in wild-type mice after pretreatment with soticlestat. In rhesus PET studies, the rank order of [18F]T-008 uptake was striatum > cortical regions > cerebellum, which was consistent with CH24H distribution in the brain. Pre-blocking with soticlestat reduced the maximum uptake and increased the washout in all brain regions in a dose-dependent manner. Calculated global occupancy values for soticlestat at a dose of 0.89 mg/kg were 97-98%, indicating maximum occupancy. CONCLUSION: The preclinical in vitro and in vivo evaluation of labeled T-008 demonstrates that [18F]T-008 is suitable for imaging CH24H in the brain and warrants further studies in humans.

A Nationwide Multi-Center Questionnaire Survey on the Real-World State and Clinical Management of Poststroke Dementia in Japan.

BACKGROUND: Poststroke dementia (PSD) is a serious problem for stroke survivors. However, there is still limited data on the real-world state and clinical management of PSD worldwide, and several countries already have a super-aged society. OBJECTIVE: We conducted a nationwide questionnaire survey to examine the real-world state and management of PSD in Japan. METHODS: A survey was conducted in the top 500 Japanese hospitals regarding the number of stroke patients treated between July 2018 and August 2019. Thirteen questions regarding PSD were mailed to doctors responsible for stroke management. RESULTS: Responses were obtained from 251 hospitals (50.2%). The chief doctors responsible for stroke management answered the questionnaires. The median numbers of patients admitted annually with stroke in the departments of neurology and neurosurgery in the hospitals were 281.0 (interquartile range [IQR], 231.8-385.3) and 253.5 (IQR, 210.0-335.3), respectively, and most hospitals were acute care hospitals. Executive dysfunction was the most common cognitive dysfunction (10.9%), followed by amnesia (9.5%) and apathy (4.1%). Surprisingly, many stroke survivors lived alone at home (23.7%). Montreal Cognitive Assessment was significantly uncommon compared to Mini-Mental State Examination (p < 0.01). Furthermore, objective evaluation tests for behavioral and psychological symptoms of dementia were not often performed. Cognitive rehabilitation treatments were performed more often and earlier than drug treatments. The first drug of choice for PSD was predominantly donepezil (79.1%), followed by galantamine (6.1%), cilostazol (4.9%), memantine (2.5%), and rivastigmine (1.8%). CONCLUSION: Our study provides real-world evidence for the state of clinical practice related to PSD in Japan.

Tima nigroannulata (Cnidaria: Hydrozoa: Eirenidae), a New Species of Hydrozoan from Japan.

Tima nigroannulata sp. nov. is described from medusae collected in shallow waters of four prefectures on the Pacific coast of Japan (Miyagi, Fukushima, Kanagawa, and Miyazaki), as well as from cultures maintained at two aquaria (Enoshima Aquarium, Kanagawa Prefecture; Tsuruoka City Kamo Aquarium, Yamagata Prefecture). Adult medusae differ from those of other known species of the genus Tima Eschscholtz, 1829 in the following combination of characters: (1) umbrella usually hemispherical or higher, (2) marginal tentacles up to 50 or more in number; and (3) black pigment granules form a ring around the umbrella rim, and sometimes extend onto the tentacles and radial canals. Their hydroids, from aquarium cultures, have stolonal colonies with pedicels of varied length, vestigial hydrothecae, slender and vase- to club-shaped hydranths, and a whorl of about 20 filiform tentacles with an intertentacular web basally. Medusa buds develop singly within gonothecae that arise from the hydrothecal pedicels. The cnidomes of both hydroid and medusa stages comprise heteronemes, provisionally identified as microbasic mastigophores. Medusae of T. nigroannulata are confirmed as a unique, cohesive lineage by comparing mtDNA COI sequence fragments with those from two congeners, resulting in three well-supported reciprocally monophyletic clades, one representing each species. Records of the western Atlantic medusa Tima formosa L. Agassiz, 1862 from Japan overlap those of T. nigroannulata, and are believed to have been based on the new species described herein.

Antiseizure medications for post-stroke epilepsy: A real-world prospective cohort study.

BACKGROUND AND PURPOSE: The management of post-stroke epilepsy (PSE) should ideally include prevention of both seizure and adverse effects; however, an optimal antiseizure medications (ASM) regimen has yet been established. The purpose of this study is to assess seizure recurrence, retention, and tolerability of older-generation and newer-generation ASM for PSE. METHODS: This prospective multicenter cohort study (PROgnosis of Post-Stroke Epilepsy [PROPOSE] study) was conducted from November 2014 to September 2019 at eight hospitals. A total of 372 patients admitted and treated with ASM at discharge were recruited. Due to the non-interventional nature of the study, ASM regimen was not adjusted and followed standard hospital practices. The primary outcome was seizure recurrence in patients receiving older-generation and newer-generation ASM. The secondary outcomes were the retention and tolerability of ASM regimens. RESULTS: Of the 372 PSE patients with ASM at discharge (median [IQR] age, 73 [64-81] years; 139 women [37.4%]), 36 were treated with older-generation, 286 with newer-generation, and 50 with mixed-generation ASM. In older- and newer-generation ASM groups (n = 322), 98 patients (30.4%) had recurrent seizures and 91 patients (28.3%) switched ASM regimen during the follow-up (371 [347-420] days). Seizure recurrence was lower in newer-generation, compared with the older-generation, ASM (hazard ratio [HR], 0.42, 95%CI 0.27-0.70; p = .0013). ASM regimen withdrawal and change of dosages were lower in newer-generation ASM (HR, 0.34, 95% CI 0.21-0.56, p < .0001). CONCLUSIONS: Newer-generation ASM possess advantages over older-generation ASM for secondary prophylaxis of post-stroke seizures in clinical practice.

Design and Synthesis of Novel Spiro Derivatives as Potent and Reversible Monoacylglycerol Lipase (MAGL) Inhibitors: Bioisosteric Transformation from 3-Oxo-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl Moiety.

The therapeutic potential of monoacylglycerol lipase (MAGL) inhibitors in central nervous system-related diseases has attracted attention worldwide. However, the availability of reversible-type inhibitor is still limited to clarify the pharmacological effect. Herein, we report the discovery of novel spiro chemical series as potent and reversible MAGL inhibitors with a different binding mode to MAGL using Arg57 and His121. Starting from hit compound 1 and its co-crystal structure with MAGL, structure-based drug discovery (SBDD) approach enabled us to generate various spiro scaffolds like 2a (azetidine-lactam), 2b (cyclobutane-lactam), and 2d (cyclobutane-carbamate) as novel bioisosteres of 3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl moiety in 1 with higher lipophilic ligand efficiency (LLE). Optimization of the left hand side afforded 4f as a promising reversible MAGL inhibitor, which showed potent in vitro MAGL inhibitory activity (IC50 6.2 nM), good oral absorption, blood-brain barrier penetration, and significant pharmacodynamic changes (2-arachidonoylglycerol increase and arachidonic acid decrease) at 0.3-10 mg/kg, po. in mice.

Conversion from cilostazol to OPC-13015 linked to mitigation of cognitive impairment.

INTRODUCTION: Cilostazol may be a novel therapeutic agent for Alzheimer's disease. Its metabolite, OPC-13015, has a stronger inhibitory effect on type 3 phosphodiesterase than cilostazol. METHODS: We prospectively enrolled patients with mild cognitive impairment to whom cilostazol was newly prescribed. Patients underwent the Montreal Cognitive Assessment (MoCA) twice, at a 6-month interval. Plasma cilostazol, OPC-13015, OPC-13213, and OPC-13217 concentrations were determined using liquid chromatography-tandem mass spectrometry. RESULTS: MoCA score changes from baseline to the 6-month visit were positively correlated with ratios of OPC-13015 to cilostazol and total metabolites (n = 19, P = .005). Patients with higher ratios of OPC-13015 (≥0.18, median value; n = 10) had significantly higher MoCA scores (P = .036) than patients with lower ratios (the ratio <0.18, n = 9). The absolute value of OPC-13015 concentration in blood was also higher in patients with preserved cognitive function (P = .033). DISCUSSION: Blood OPC-13015 levels may be a predictive biomarker of cilostazol treatment for Alzheimer's disease.