Effective Epilepsy Surgery for Post-Traumatic West Syndrome Following Abusive Head Trauma.

West syndrome, an infantile developmental and epileptic encephalopathy with a deleterious impact on long-term development, requires early treatment to minimize developmental abnormality; in such cases, epilepsy surgery should be considered a powerful therapeutic option. We describe a 10-month-old female admitted with West syndrome associated with a hemispheric lesion following abusive head trauma. Her seizures were suppressed by hemispherotomy at 12 months of age, leading to developmental improvement. Surgical treatment of West syndrome following traumatic brain injury has not been reported previously but is worth considering as a treatment option, depending on patient age and brain plasticity.

[Settings and Decisions of Monitoring].

Since the beginning of the 21st century, as intraoperative monitoring has been steadily spreading in Japan and globally, the values of motor-evoked potentials, visual-evoked potentials, and cortical-evoked potentials have been described. There are a wide variety of monitoring methods; the diseases handled are not limited to brain lesions, but extend also to spinal cord and spinal lesions; and there are many problems that have not yet been solved. Possible precautions are indicated by means of a video of an actual case site. Considerations are presented regarding the setting of this monitoring method, utilized in relatively frequent diseases and associated intraoperative judgments.

A Case of a Solitary Cortical Tuber with No Other Manifestations of Tuberous Sclerosis Complex Mimicking Focal Cortical Dysplasia Type II with Calcification.

Cortical tubers are one of the typical intracranial manifestations of tuberous sclerosis complex (TSC). Multiple cortical tubers are easy to diagnose as TSC; however, a solitary cortical tuber without any other cutaneous or visceral organ manifestations can be confused with other conditions, particularly focal cortical dysplasia. We report a surgical case of refractory epilepsy caused by a solitary cortical tuber mimicking focal cortical dysplasia type II, and describe the radiological, electrophysiological, and histopathological findings of our case.

[Infections in Functional Neurosurgery:Focusing on Device-based Surgery].

Functional neurosurgery for epilepsy, movement disorders, and spasticity includes some device-based surgeries such as deep brain stimulation, subdural electrode placement, vagus nerve stimulation, and baclofen pump implantation. These surgeries have a higher risk of surgical site infection(SSI)than other general neurological surgeries. Furthermore, because device removal after infection can significantly impair patients'activities of daily living and quality of life, SSI in functional neurosurgery is a worrisome surgical complication. In this study, we conducted a mini-review of the risk of infection in each device-based surgery and described associated surgical procedures and preparations performed at our institution, with a focus on infection prevention.

Preoperative Risks of Cerebral Infarction in Pediatric Moyamoya Disease.

Background and Purpose: In pediatric moyamoya disease, there have been few reports of the risk factors for preoperative cerebral infarction, especially during the waiting period before surgery. The clinical and radiological findings of surgically treated pediatric moyamoya patients were evaluated to analyze the risk factors for cerebral infarction seen from onset to surgery. Methods: Between August 2003 and September 2019, 120 hemispheres of 71 patients under 18 years of age with moyamoya disease were surgically treated by direct and indirect bypass procedures. The mean age of all surgical hemispheres at diagnosis was 6.7±3.9 years (6 months­17 years). The potential risk factors for preoperative infarction were examined statistically. Results: Multivariate logistic regression analysis showed that risk factors for infarction at the time of diagnosis were age at diagnosis (odds ratio [OR], 0.68 [95% CI, 0.57­0.82]; P<0.0001) and the magnetic resonance angiography (MRA) score (OR, 2.29 [95% CI, 1.40­3.75]; P=0.001). Univariate analysis showed that risk factors for infarction while waiting for surgery were age at diagnosis (OR, 0.61 [95% CI, 0.46­0.80]; P<0.0001), the MRA score (OR, 1.75 [95% CI, 1.26­2.41]; P=0.0003), and onset of infarction (OR, 40.4 [95% CI, 5.08­322.3]; P<0.0001). Multiple comparisons showed that patients under 4 years of age were at a significantly high risk of infarction at the time of diagnosis and while waiting for surgery. Time from diagnosis to surgery of >2 months was a significant risk factor for infarction while waiting for surgery in patients under 6 years of age. Conclusions: Young age at diagnosis and a high MRA score may be associated with rapid disease progression and result in preoperative infarction. We recommend that surgery be performed within 2 months of diagnosis for the patients under 4 years of age with a high MRA score (>5) and cerebral infarction. Further study is needed to define the optimal timing of surgery.

Cell encapsulation enhances antidepressant effect of the mesenchymal stem cells and counteracts depressive-like behavior of treatment-resistant depressed rats.

Despite the advances in pharmacological therapies, only the half of depressed patients respond to currently available treatment. Thus, the need for further investigation and development of effective therapies, especially those designed for treatment-resistant depression, has been sorely needed. Although antidepressant effects of mesenchymal stem cells (MSCs) have been reported, the potential benefit of this cell therapy on treatment-resistant depression is unknown. Cell encapsulation may enhance the survival rate of grafted cells, but the therapeutic effects and mechanisms mediating encapsulation of MSCs remain unexplored. Here, we showed that encapsulation enhanced the antidepressant effects of MSCs by attenuating depressive-like behavior of Wistar Kyoto (WKY) rats, which are considered as a promising animal model of treatment-resistant depression. The implantation of encapsulated MSCs (eMSCs) into the lateral ventricle counteracted depressive-like behavior and enhanced the endogenous neurogenesis in the subventricular zone (SVZ) and the dentate gyrus (DG) of the hippocampus, whereas the implantation of MSCs without encapsulation or the implantation of eMSCs into the striatum did not show such ameliorative effects. eMSCs displayed robust and stable secretion of vascular endothelial growth factor (VEGF), brain-derived neurotrophic factor, fibroblast growth factor-2, and ciliary neurotrophic factor (CNTF), and the implantation of eMSCs into the lateral ventricle activated relevant pathways associated with these growth factors. Additionally, eMSCs upregulated intrinsic expression of VEGF and CNTF and their receptors. This study suggests that the implantation of eMSCs into the lateral ventricle exerted antidepressant effects likely acting via neurogenic pathways, supporting their utility for depression treatment.

[What Is the Key Point for Intraoperative Monitoring in Cerebral Aneurysm Surgery?]

Intraoperative monitoring, which has advanced in the 21st century, consists of the motor evoked potential(MEP)and visual evoked potential(VEP). Transcranial stimulation has become the mainstream of MEP from cortical stimulation, and reports of MEP monitoring for the face and lower limbs are increasing. The biggest problem with VEP is poor reproducibility due to inhalation anesthetics. With the increase use of of MEP, total intravenous anesthesia has become common and reproducibility has improved, making it a clinically useful method. I will mention the key points of current intraoperative monitoring in cerebral aneurysm surgery. 1. Selection of type of intraoperative monitoring: Is MEP cortical stimulation or transcranial stimulation, upper limb or lower limb? What is VEP? What is somatosensory evoked potential? 2. What to do when the waveform deteriorates or disappears? Remove the clip after clipping. If the blood flow is temporarily occluded, release the occlusion as soon as possible. When the deterioration improves after this maneuver, it should be stopped until the waveform is restored. 3. Pitfall and coping method: Anesthesia method. Changes in the stimulation threshold of the transcranial stimulation MEPs. Deterioration/disappearance of MEP waveform after release of brain traction.

[Programing of Deep Brain Stimulation and Features of Devices].

Deep brain stimulation(DBS)is an effective therapy for conditions involving drug-resistant involuntary movements, such as Parkinson's disease, tremor, and dystonia. Programming of DBS, as well as strict surgical indications, appropriate target selection, and accurate electrode placement, is one of the most important factors in the success of DBS. To obtain effective stimulation for a long period, it is important to expand the therapeutic window and reduce side effects. Recent advances in DBS devices have dramatically expanded the variety of stimulus settings. While the indication criteria of DBS and surgical techniques have been established, the details of the programming algorithm are not yet unified. In this paper, we describe the features of each device, basic programming methods, management of DBS-related side effects, and advanced stimulus methods.

First-in-human phase I study of E7090, a novel selective fibroblast growth factor receptor inhibitor, in patients with advanced solid tumors.

Fibroblast growth factor receptors (FGFR) are a family of transmembrane receptor tyrosine kinases involved in regulating cellular processes. FGFR mutations are implicated in oncogenesis, representing therapeutic potential in the form of FGFR inhibitors. This phase I, first-in-human study in Japan evaluated safety and tolerability of E7090, a potent selective FGFR1-3 inhibitor, in patients with advanced solid tumors. Dose escalation (daily oral dose of 1-180 mg) was carried out to assess dose-limiting toxicity (DLT), maximum tolerated dose, and pharmacokinetics. Pharmacodynamic markers (serum phosphate, fibroblast growth factor 23, and 1,25-(OH)2 -vitamin D) were also evaluated. A total of 24 patients refractory to standard therapy or for whom no appropriate treatment was available were enrolled. No DLT were observed up to the 140-mg dose; one patient in the 180-mg cohort experienced a DLT (increased aspartate aminotransferase/alanine aminotransferase, grade 3). The maximum tolerated dose was not reached. Dose-dependent increases in the maximum concentration and area under the curve from time 0 to the last measurable concentration were observed up to 180 mg. Dose-dependent increases were observed in all pharmacodynamic markers and plateaued at 100-140 mg, indicating sufficient FGFR pathway inhibition at doses ≥100 mg. In conclusion, E7090 showed a manageable safety profile with no DLT at doses ≤140 mg. Maximum tolerated dose was not determined. The recommended dose for the follow-up expansion part, restricted to patients with tumors harboring FGFR alterations, was determined as 140 mg, once daily.

Paracrine CCL17 and CCL22 signaling regulates hematopoietic stem/progenitor cell migration and retention in mouse fetal liver.

Fetal liver (FL) is the major embryonic hematopoietic organ and a site where circulating hematopoietic stem/progenitor cells (HSPCs) reside. However, HSPC migration/retention mechanisms in FL remain unclear. A chemokine screen revealed that the CCR4 ligands CCL17 and CCL22 are highly expressed in mouse embryonic day (E) 12.5 FL. Flow cytometric analysis confirmed CCR4 expression in FL HSPCs. To identify sources of CCL17 and CCL22, we fractionated FL into various cell types and found that Ccl17 and Ccl22 were predominantly expressed in HPCs/matured HCs. In vitro cell migration analysis confirmed enhanced HSPC migration in the presence of HPCs/matured HCs. Furthermore, exo-utero injection of anti-CCR4 neutralizing antibody into pregnant mice significantly reduced the number of FL HSPCs in embryos. These data demonstrate a paracrine mechanism by which HSPC migration/retention is regulated by CCL17 and CCL22 secreted from HPCs or matured HCs in FL.

Study protocol of a Phase I/IIa clinical trial of Ad-SGE-REIC for treatment of recurrent malignant glioma.

Malignant glioma is one of the most common brain cancers in humans, which is very devastating. The expression of reduced expression in immortalized cells/Dickkopf-3 (REIC/Dkk-3) is decreased in various human cancers. Lately, we have developed a novel second-generation adenoviral vector that expresses REIC/Dkk-3 (Ad-SGE-REIC) and revealed its antiglioma efficacy. The present investigator-initiated clinical trial is a single-arm, prospective, nonrandomized, noncomparative, open-label, single-center trial performed at Okayama University Hospital, Okayama, Japan. The primary end points are dose-limiting toxicities and the incidence of adverse events. The secondary end points are the objective response rate and immunological assessment. Use of Ad-SGE-REIC will help to improve the prognosis of patients with malignant brain tumors.

The competitive advantage of institutional reward.

Sustaining cooperation among unrelated individuals is a fundamental challenge in biology and the social sciences. In human society, this problem can be solved by establishing incentive institutions that reward cooperators and punish free-riders. Most of the previous studies have focused on which incentives promote cooperation best. However, a higher cooperation level does not always imply higher group fitness, and only incentives that lead to higher fitness can survive in social evolution. In this paper, we compare the efficiencies of three types of institutional incentives, namely, reward, punishment, and a mixture of reward and punishment, by analysing the group fitness at the stable equilibria of evolutionary dynamics. We find that the optimal institutional incentive is sensitive to decision errors. When there is no error, a mixture of reward and punishment can lead to high levels of cooperation and fitness. However, for intermediate and large errors, reward performs best, and one should avoid punishment. The failure of punishment is caused by two reasons. First, punishment cannot maintain a high cooperation level. Second, punishing defectors almost always reduces the group fitness. Our findings highlight the role of reward in human cooperation. In an uncertain world, the institutional reward is not only effective but also efficient.

A Phase II study of the safety and efficacy of lenvatinib in patients with advanced thyroid cancer.

AIM: To investigate the safety and efficacy of lenvatinib in advanced thyroid cancer. PATIENTS/METHODS: In this Phase II study, 51 Japanese patients with radioiodine-refractory differentiated thyroid cancer (RR-DTC), medullary thyroid cancer (MTC) or anaplastic thyroid cancer (ATC) received once-daily lenvatinib 24 mg. The primary end point was safety. RESULTS: All patients experienced ≥1 adverse event (AE); only one patient experienced an AE leading to discontinuation. The most common any-grade AEs were hypertension, decreased appetite, palmar-plantar erythrodysesthesia, fatigue and proteinuria. Response rates for RR-DTC: 68%; MTC: 22%; ATC: 24%. Median progression-free survival for RR-DTC: 25.8 months; MTC: 9.2 months; ATC: 7.4 months. CONCLUSION: Lenvatinib demonstrated a manageable safety profile, proven antitumor activity in RR-DTC and promising efficacy in MTC and ATC. CLINICAL TRIAL REGISTRATION: clinicaltrials.gov NCT01728623.

Quantitative Analysis of Zigzag and Armchair Edges on Carbon Materials with and without Pentagons Using Infrared Spectroscopy.

Edge structures of carbon materials such as zigzag and armchair edges are known to affect their chemical and electronic properties. Although infrared spectroscopy (IR) has been known to be capable of identifying such edge structures, quantitative analysis using IR spectra has been conducted using only out-of-plane sp2C-H bending vibration, and the estimation of the percentage of edges is still challenging. In this work, a novel two-dimensional method to quantify edge structures of carbon materials with and without pentagons was developed by analyzing both out-of-plane sp2C-H bending and in-plane sp2C-H stretching vibration. Calibration factors of sp2C-H on each type of edge were obtained from experimental and simulated IR spectra of various reference compounds. Using the calibration factors, the edge structures of carbonized aromatic compounds with zigzag edges such as tetracene, armchair edges such as chrysene, and zigzag-like edges such as coronene were estimated quantitatively. From tetracene carbonized at 893 K, chrysene carbonized at 933 K, and coronene carbonized at 873 K, carbon materials with 20% of zigzag edges, 38% of armchair edges, and 67% of others edges were prepared, respectively. This method can be utilized as a quantitative analysis to determine edge structures of various carbon materials prepared below 933 K at the lowest.

Electrical Stimulation Enhances Migratory Ability of Transplanted Bone Marrow Stromal Cells in a Rodent Ischemic Stroke Model.

BACKGROUND/AIMS: Bone marrow stromal cells (BMSCs) transplantation is an important strategy for the treatment of ischemic stroke. Currently, there are no effective methods to guide BMSCs toward the targeted site. In this study, we investigated the effect of electrical stimulation on BMSCs migration in an ischemic model of rats. METHODS: Adult male Wistar rats weighing 200 to 250 g received right middle cerebral artery occlusion (MCAO) for 90 minutes. BMSCs (2.5×105 cells/ 4 µl PBS) were stereotaxically injected into the left corpus callosum at 1 day after MCAO. After BMSCs injection, a plate electrode with a diameter of 3 mm connected to an implantable electrical stimulator was placed on the right frontal epidural space and a counter electrode was placed in the extra-cranial space. Electrical stimulation at preset current (100 µA) and frequency (100 Hz) was performed for two weeks. Behavioral tests were performed at 1, 4, 8, and 15 days after MCAO using the modified Neurological Severity Score (mNSS) and cylinder test. Rats were euthanized at 15 days after MCAO for evaluation of infarction area and the migration distance and area of BMSCs found in the brain tissue. After evaluating cell migration, we proceeded to explore the mechanisms guiding these observations. MCAO rats without BMSCs transplantation were stimulated with same current and frequency. At 1 and 2 weeks after MCAO, rats were euthanized to evaluate stromal cell-derived factor 1 alpha (SDF-1α) level of brain tissues in the bilateral cortex and striatum. RESULTS: Behavioral tests at 4, 8, and 15 days after MCAO revealed that stimulation group displayed significant amelioration in mNSS and cylinder test compared to control group (p<0.05). Similarly, the infarction areas of stroke rats in stimulation group were significantly decreased compared to control group (p<0.05). Migration distance and area of transplanted BMSCs were significantly longer and wider respectively in stimulation group. An increased concentration gradient of SDF-1α in stimulation group accompanied this enhanced migration of transplanted cells. CONCLUSIONS: These results suggest that electrical stimulation enhances migratory ability of transplanted BMSCs in ischemic stroke model of rats. If we can direct the implanted BMSCs to the site of interest, it may lead to a greater therapeutic effect.

A solution for private assessment in indirect reciprocity using solitary observation.

Although indirect reciprocity is a fundamental mechanism in the evolution of human cooperation, most studies assume public assessment in which individuals are not permitted to obtain private assessments of others. Existing studies on private assessment have used individual-based simulations because of the analytical difficulty involved. Here, we develop an analytical method using solitary observation to solve private assessment in indirect reciprocity problem without any approximation. In this study, we formulate a model of solitary observation and calculate the replicator dynamics systems of five leading norms of indirect reciprocity. Indirect reciprocity in private assessment provides a different result to that in public assessment. According to the existence proofs of cooperative evolutionarily stable (CES) points in the system, strict norms (stern judging and shunning) have no CES point in private assessment, while they do in public assessment. Image scoring does not change the system regardless of the assessment types because it does not use second-order information. In tolerant norms (simple standing and staying), the CES points move to co-existence of norms and unconditional cooperators. Despite the fact that there is no central coercive assessment system in private assessment, the average cooperation rate at the CES points in private assessment is greater than that in public assessment. This is because private assessment gives unconditional cooperators a role. Our results also show the superiority of the staying norm. Compared with simple standing, staying has three advantages in private assessment: a higher cooperation rate, easiness of invasion into defectors, and robustness to maintain cooperative evolutionarily stable situations. Our results are applicable to general social dilemmas in relation to private information. Under some dilemmas, norms or assessment rules should be carefully chosen to enable cooperation to evolve.

Significance of High-frequency Electrical Brain Activity.

　Electroencephalogram (EEG) data include broadband electrical brain activity ranging from infra-slow bands (< 0.1 Hz) to traditional frequency bands (e.g., the approx. 10 Hz alpha rhythm) to high-frequency bands of up to 500 Hz. High-frequency oscillations (HFOs) including ripple and fast ripple oscillations (80-200 Hz and>200 / 250 Hz, respectively) are particularly of note due to their very close relationship to epileptogenicity, with the possibility that they could function as a surrogate biomarker of epileptogenicity. In contrast, physiological high-frequency activity plays an important role in higher brain functions, and the differentiation between pathological / epileptic and physiological HFOs is a critical issue, especially in epilepsy surgery. HFOs were initially recorded with intracranial electrodes in patients with intractable epilepsy as part of a long-term invasive seizure monitoring study. However, fast oscillations (FOs) in the ripple and gamma bands (40-80 Hz) are now noninvasively detected by scalp EEG and magnetoencephalography, and thus the scope of studies on HFOs /FOs is rapidly expanding.

The Effect of Incentives and Meta-incentives on the Evolution of Cooperation.

Although positive incentives for cooperators and/or negative incentives for free-riders in social dilemmas play an important role in maintaining cooperation, there is still the outstanding issue of who should pay the cost of incentives. The second-order free-rider problem, in which players who do not provide the incentives dominate in a game, is a well-known academic challenge. In order to meet this challenge, we devise and analyze a meta-incentive game that integrates positive incentives (rewards) and negative incentives (punishments) with second-order incentives, which are incentives for other players' incentives. The critical assumption of our model is that players who tend to provide incentives to other players for their cooperative or non-cooperative behavior also tend to provide incentives to their incentive behaviors. In this paper, we solve the replicator dynamics for a simple version of the game and analytically categorize the game types into four groups. We find that the second-order free-rider problem is completely resolved without any third-order or higher (meta) incentive under the assumption. To do so, a second-order costly incentive, which is given individually (peer-to-peer) after playing donation games, is needed. The paper concludes that (1) second-order incentives for first-order reward are necessary for cooperative regimes, (2) a system without first-order rewards cannot maintain a cooperative regime, (3) a system with first-order rewards and no incentives for rewards is the worst because it never reaches cooperation, and (4) a system with rewards for incentives is more likely to be a cooperative regime than a system with punishments for incentives when the cost-effect ratio of incentives is sufficiently large. This solution is general and strong in the sense that the game does not need any centralized institution or proactive system for incentives.

Indirect reciprocity can overcome free-rider problems on costly moral assessment.

Indirect reciprocity is one of the major mechanisms of the evolution of cooperation. Because constant monitoring and accurate evaluation in moral assessments tend to be costly, indirect reciprocity can be exploited by cost evaders. A recent study crucially showed that a cooperative state achieved by indirect reciprocators is easily destabilized by cost evaders in the case with no supportive mechanism. Here, we present a simple and widely applicable solution that considers pre-assessment of cost evaders. In the pre-assessment, those who fail to pay for costly assessment systems are assigned a nasty image that leads to them being rejected by discriminators. We demonstrate that considering the pre-assessment can crucially stabilize reciprocal cooperation for a broad range of indirect reciprocity models. In particular for the most leading social norms, we analyse the conditions under which a prosocial state becomes locally stable.

The take-it-or-leave-it option allows small penalties to overcome social dilemmas.

Self-interest frequently causes individuals engaged in joint enterprises to choose actions that are counterproductive. Free-riders can invade a society of cooperators, causing a tragedy of the commons. Such social dilemmas can be overcome by positive or negative incentives. Even though an incentive-providing institution may protect a cooperative society from invasion by free-riders, it cannot always convert a society of free-riders to cooperation. In the latter case, both norms, cooperation and defection, are stable: To avoid a collapse to full defection, cooperators must be sufficiently numerous initially. A society of free-riders is then caught in a social trap, and the institution is unable to provide an escape, except at a high, possibly prohibitive cost. Here, we analyze the interplay of (a) incentives provided by institutions and (b) the effects of voluntary participation. We show that this combination fundamentally improves the efficiency of incentives. In particular, optional participation allows institutions punishing free-riders to overcome the social dilemma at a much lower cost, and to promote a globally stable regime of cooperation. This removes the social trap and implies that whenever a society of cooperators cannot be invaded by free-riders, it will necessarily become established in the long run, through social learning, irrespective of the initial number of cooperators. We also demonstrate that punishing provides a "lighter touch" than rewarding, guaranteeing full cooperation at considerably lower cost.