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Patients with glioblastoma frequently suffer epileptic seizures and often require anticonvulsant therapy during the treatment course. The present study investigated four common antiepileptic drugs, perampanel, carbamazepine (CBZ), sodium valproate (VPA) and levetiracetam (LEV), which are expected to have antitumor effects, and determined the most beneficial drug for the treatment of malignant glioma by comparing antitumor effects such as inhibition of cell proliferation and suppression of migration and invasion (using Transwell assays). The inhibition of cell growth was investigated using six malignant glioma cell lines (A‑172, AM‑38, T98G, U‑138MG, U‑251MG and YH‑13). Significant inhibition of cell proliferation was observed in all six cell lines treated with perampanel, three cell lines treated with CBZ, four cell lines treated with VPA and two cell lines treated with LEV at the therapeutic blood concentration levels for the drugs to be used as antiepileptics. Further antitumor effects in combination with temozolomide were investigated using T98G and U‑251MG cell lines, and were confirmed in both cell lines with perampanel and in T98G cells with LEV, but not observed with CBZ and VPA. Cell migration was significantly suppressed in both T98G and U‑251MG cell lines with perampanel, but not with CBZ, VPA or LEV. To investigate the mechanisms by which perampanel suppresses the migration of malignant glioma cells, the expression of mRNA related to epithelial‑mesenchymal transition following perampanel treatment was analyzed using reverse transcription‑quantitative PCR in the T98G and U‑251MG cell lines. The expression of

Background Intracranial venous hypertension has been associated with a few cases of meningioma secondary to compression of the venous sinus. This is the rare case of small meningioma involving the sigmoid sinus leading to intracranial venous hypertension mimicking venous thrombosis. Case presentation A 39-year-old woman suffered visual dysfunction due to bilateral papilledema. Noncontrast head computed tomography (CT) showed no intracranial space-occupying lesions or hydrocephalus. Cerebrospinal fluid examination revealed high opening pressure. Various image inspections such as three-dimensional CT angiography, magnetic resonance imaging, and cerebral angiography demonstrated a small 2.5-cm lesion causing subtotal occlusion of the dominant right sigmoid sinus. No improvement of clinical manifestations was observed after medical treatment for 6 months, so right presigmoid craniectomy was performed. Operative findings revealed that the tumor was located predominantly involving the sigmoid sinus. The pathological diagnosis was fibrous meningioma. Postoperative fundoscopic examination showed improvement of bilateral papilledema. Conclusions We treated a patient presenting with intracranial hypertension due to a small meningioma involving the sigmoid sinus. This unusual case suggests that early surgical strategies should be undertaken to relieve the sinus obstruction.

BackgroundMeningiomas are the most common benign intracranial tumors, and commonly comprise high-vascularizing but slow-growing tumors. On the other hand, meningiomas arising from the ventricular system are of rare occurrence, and spontaneous hemorrhage is an infrequent event.Case presentationWe describe here the rare clinical manifestations of a 28-year-old female with acute intracranial hemorrhage located in the trigone of the lateral ventricle who was initially thought to have suffered an acute cerebrovascular accident, but was subsequently confirmed to have a benign intraventricular meningioma. To clarify the clinical features of such a rare course of meningioma, we also present a short literature review of acute intracranial hemorrhage caused by intraventricular meningioma.ConclusionsVentricular meningioma presenting with hemorrhage such as acute stroke is a rare event, but recognition of such a pathogenesis is important. Although further accumulation of clinical data is needed, we suggest that early surgery should be undertaken in patients with lateral ventricular meningioma, even if it is not so large or asymptomatic.

Iron deficiency anemia (IDA) due to malnutrition and/or blood loss is a common condition, especially in women of reproductive age. Intense exercise can induce anemia via an inflammatory response, but whether intense exercise affects the efficacy of iron supplementation to treat IDA is unclear. Here, we show in a mouse model of IDA that acute intense swimming increased IL-6 levels in the blood, but did not affect the maximum elevation of plasma iron following oral administration of 0.5 mg/kg Bw iron. However, compared with the control group without intense exercise, acute intense swimming was associated with a significant decrease in plasma iron 2 and 4 h after iron loading that could be attributed to rapid iron absorption in peripheral tissues. In the chronic experiment, IDA mice administered 0.36, 1.06, or 3.2 mg/kg Bw iron per day that were subjected to 11 intense swimming sessions over 3 weeks showed significantly decreased recovery levels for hemoglobin and red blood cell count during the early phase of the experimental period. At the end of the experimental period, significant, dose-dependent effects of iron, but not the main effect of intense exercise, were seen for recovery of hemoglobin and red blood cell counts, consistent with the acute exercise study. These results suggested that intense exercise in the presence of IDA does not inhibit iron absorption from the gastrointestinal tract and that iron supplementation can enhance the recovery process even after intense exercise.

Background Pituitary apoplexy is an acute clinical syndrome caused by infarction and/or hemorrhage of pituitary adenoma, which typically presents with severe headache, visual deterioration, and endocrine abnormalities. However, temporal lobe seizure (and temporal lobe epilepsy) has not been viewed as a symptom of pituitary apoplexy in the literature. Case Description To elucidate further such a rare complication of temporal lobe seizure, we describe here the rare clinical manifestations of a 55-year-old previously healthy man with pituitary apoplexy harboring headache, combined palsies involving cranial nerves III to VI, endocrinologic disturbances, and temporal lobe seizure. In addition, we discuss the temporal lobe seizure (and temporal lobe epilepsy) associated with pituitary adenoma based on the literature. Conclusions Although further accumulation of clinical data is needed, we would like to emphasize the importance of recognition of temporal lobe seizure caused by pituitary apoplexy, and to suggest that early surgery could be considered as an option in patients displaying such a rare complication.

Recent research has revealed that glioblastoma (GBM) avoids the immune system via strong expression of indoleamine 2,3-dioxygenase 1 (IDO1). IDO1, an enzyme involved in tryptophan metabolism, is now proposed as a new target in GBM treatment, since several reports have demonstrated that IDO1 expression is related to GBM malignancy. On the other hand, it is well known that glioma stem cells (GSCs) are strongly related to the malignancy of GBM. However, there is as yet no report evaluating the relationship between GSCs and IDO1. We therefore examined the expression levels of IDO1 in GSCs in order to identify a new therapeutic target for GBM based on the immune systems of GSCs. In the present study, we employed human GBM cell lines (U-138MG, U-251MG) and patient-derived GSC model cell lines (0125-GSC, 0222-GSC). GSC model cell lines Rev-U-138MG and Rev-U-251MG were established by culturing U-138MG and U-251MG in serum-free media, while differentiated GBM model cell lines 0125-DGC and 0222-DGC were established by culturing 0125-GSC and 0222-GSC in serum-containing media. The expression levels of stem cell markers (Nanog, Nestin, Oct4 and Sox2) and IDO1 protein and mRNA were determined. Rev-U-138MG and Rev-U-251MG formed spheres and their expression levels of stem cell markers were increased as compared to U-138MG and U-251MG. On the other hand, 0125-DGC and 0222-DGC suffered breakdown of sphere formation, despite the original 0125-GSC and 0222-GSC forming spheres, and their expression levels of the markers were decreased. IDO1 expressions were strongly recognized in Rev-U-138MG, Rev-U-251MG, 0125-GSC and 0222-GSC as compared to U-138MG, U-251MG, 0125-DGC and 0222-DGC. These findings demonstrate that GSCs exhibit treatment resistance with immunosuppression via high expression levels of IDO1, and could represent a novel target for GBM treatment.

A 68-year-old female was admitted to our hospital with right-sided hemianopsia. Magnetic resonance imaging (MRI) demonstrated a well-enhanced tuberculum sellae region tumor. The patient underwent surgical tumor resection via an extended endoscopic endonasal trans-sphenoidal approach and the tumor was totally removed. The mass was extremely soft and there was no clear attachment between it and the dura mater. Furthermore, the histopathological findings obtained for the tumor during intra-operative rapid diagnosis were divergent from typical meningioma. We therefore diagnosed the tumor intra-operatively as a pituitary adenoma. However, the post-operative pathological diagnosis for the tumor was chordoid meningioma (CM). CM is a rare subtype of meningioma, and most of such tumors arise in the convexity. In the preoperative MRI in the present case, meningioma was suspected; however, since we did not consider CM for differential diagnosis, we failed to reach an accurate diagnosis during the operation. Tuberculum sellae CM is very rare, and only a few cases have been reported previously. The surgical strategy will differ greatly depending on whether the tumor is a meningioma or a pituitary adenoma, especially when treatment involves the dura mater. The pre and/or intra-operative diagnosis is thus very important for developing an accurate treatment strategy. We report here the details of our rare case and describe the intra-operative features of tuberculum sellae CM.

Chronic inflammation (CI) can contribute to muscle atrophy and sarcopenia. Resistance exercise (RE) promotes increased and/or maintenance of skeletal muscle mass, but the effects of RE in the presence of CI are unclear. In this study, we developed a novel animal model of CI-induced muscle atrophy and examined the effect of acute or chronic RE by electrical stimulation. CI was induced in young female Lewis rats by injection with peptidoglycan-polysaccharide (PG-PS). Extracellular signal-regulated kinase (ERK), p70S6 kinase (p70S6K), 4E binding protein 1 (4E-BP1), Akt, and Forkhead box O1 (FOXO1) phosphorylation levels increased in gastrocnemius (Gas) muscle from normal rats subjected to acute RE. After acute RE in CI rats, increased levels of phosphorylated ERK, p70S6K, and 4E-BP1, but not Akt or FOXO1, were observed. Chronic RE significantly increased the Gas weight in the exercised limb relative to the nontrained opposing limb in CI rats. Dietary supplementation with anti-inflammatory agents, eicosapentaenoic/docosahexaenoic acid and α-lactalbumin attenuated CI-induced muscle atrophy in the untrained Gas and could promote RE-induced inhibition of atrophy in the trained Gas. In the trained leg, significant negative correlations ( r ≤ −0.80) were seen between Gas weights and CI indices, including proinflammatory cytokines and white blood cell count. These results indicated that the anabolic effects of RE are effective for preventing CI-induced muscle atrophy but are partially attenuated by inflammatory molecules. The findings also suggested that anti-inflammatory treatment together with RE is an effective intervention for muscle atrophy induced by CI. Taken together, we conclude that systemic inflammation levels are associated with skeletal muscle protein metabolism and plasticity. NEW & NOTEWORTHY This study developed a novel chronic inflammation (CI) model rat demonstrating that resistance exercise (RE) induced activation of protein synthesis signaling pathways and mitigated skeletal muscle atrophy. These anabolic effects were partially abrogated likely through attenuation of Akt/Forkhead box O1 axis activity. The degree of skeletal muscle atrophy was related to inflammatory responses. Dietary supplementation with anti-inflammatory agents could enhance the anabolic effect of RE. Our findings provide insight for development of countermeasures for CI-related muscle atrophy, especially secondary sarcopenia.

This study aimed to clarify the natural course of positional plagiocephaly using a three-dimensional (3D) scanner and investigate the effectiveness of cranial helmet therapy (CHT). One hundred infants with severe plagiocephaly who visited our institutions between April 2020 and March 2021 were included. Cranial shape was measured using an Artec Eva 3D scanner. A cranial asymmetry (CA) >12 mm was diagnosed as severe plagiocephaly. An infant whose CA subsided to 12 mm on the initial evaluation.

There is ongoing debate as to whether or not α-hydroxyisocaproic acid (HICA) positively regulates skeletal muscle protein synthesis resulting in the gain or maintenance of skeletal muscle. We investigated the effects of HICA on mouse C2C12 myotubes under normal conditions and during cachexia induced by co-exposure to TNFα and IFNγ. The phosphorylation of AMPK or ERK1/2 was significantly altered 30 min after HICA treatment under normal conditions. The basal protein synthesis rates measured by a deuterium-labeling method were significantly lowered by the HICA treatment under normal and cachexic conditions. Conversely, myotube atrophy induced by TNFα/IFNγ co-exposure was significantly improved by the HICA pretreatment, and this improvement was accompanied by the inhibition of iNOS expression and IL-6 production. Moreover, HICA also suppressed the TNFα/IFNγ co-exposure-induced secretion of 3-methylhistidine. These results demonstrated that HICA decreases basal protein synthesis under normal or cachexic conditions, however, HICA might attenuate skeletal muscle atrophy via maintaining a low level of protein degradation under cachexic conditions.

The prognosis of gioblastoma, the standard chemotherapy agent for which is temozolomide (TMZ), remains poor despite recent advances in multimodal treatments. Therefore, it is necessary to identify and develop novel therapeutics for this malignant disease. Ribavirin, an anti-viral agent which is one of the standard agents for treatment of chronic hepatitis C in combination with interferon (IFN), was recently revealed to have an antitumor potential towards various tumor cells, including malignant glioma cells. The aim of the present study was to examine the antitumor effect of ribavirin in combination with TMZ and IFN-β on glioma cells and to evaluate the possibility that such combinations might represent a novel candidate for glioblastoma therapy. The combination of ribavirin with TMZ and IFN-β displayed a significant cell growth inhibitory effect with a ribavirin dose-dependency, including a relatively low concentration of ribavirin, on not only TMZ-sensitive but also TMZ-resistant malignant glioma cells. The antitumor efficacy of such a combination further indicated a synergistic interaction when assessed by the Chou-Talalay method. Furthermore, flow cytometry analysis suggested that apoptosis induction was one of the possible biological processes underlying the synergistic antitumor effect of these triple combination treatments. Therefore, such combinations may be potentially important in the clinical setting for glioblastoma treatment, although further detailed studies, e.g. on the adverse effects, are required.

NEW FINDINGS What is the central question of this study? Is stretch-shortening contraction effective to attenuate skeletal muscle atrophy and hepatic dysfunction in a rat model of peptidoglycan-polysaccharide (PG-PS)-induced inflammation (PG-PS rat)? What are the main findings and their importance? Stretch-shortening contraction attenuates skeletal muscle atrophy in the trained leg and increases circulating interleukin-10 in PG-PS rats. Stretch-shortening contraction also ameliorates liver dysfunction in PG-PS rats, possibly via increased blood interleukin-10. These findings are important because they suggest that stretch-shortening contraction is effective to maintain liver function in addition to exercised skeletal muscle mass. ABSTRACT Stretch-shortening contraction (SSC) is an effective modality to improve skeletal muscle mass. However, the beneficial effects of SSC in the presence of chronic inflammation remain unclear. Here, we imposed five SSC sessions unilaterally on the triceps surae in young female Lewis rats. Rats were injected with vehicle or peptidoglycan-polysaccharide (PG-PS) to induce long-lasting inflammation. The PG-PS reduced gastrocnemius muscle mass in both legs, but that of the SSC-trained leg was significantly greater than that of the contralateral leg. Circulating pro-inflammatory cytokines, such as IL-1β, were significantly increased by PG-PS injection, even if carrying out SSC. The circulating anti-inflammatory cytokine IL-10 increased with SSC in both healthy and inflammatory conditions. Stretch-shortening contraction also prevented increases in serum aspartate aminotransferase activity and plasma free phenylalanine concentration induced by PG-PS, in comparison to the control resistance exercise consisting of isometric contractions. Moreover, aspartate aminotransferase and phenylalanine concentrations demonstrated a significant and negative correlation with IL-10/IL-1β values (r = -0.61, P = 0.017, and r = -0.66, P = 0.008, respectively). These results suggest that SSC training is effective to reduce both muscle atrophy and the hepatic dysfunction induced by PG-PS, mediated, at least in part, through an increase in circulating IL-10.

Intracranial hemorrhage associated with lower grade glioma is unusual. Furthermore, pleomorphic xanthoastrocytoma (PXA) with intracranial hemorrhage, especially in a children, is extremely rare. We report here a rare case of child PXA with intracranial hemorrhage. An 11-year-old girl was admitted with headache and convulsions. A computed tomography scan demonstrated intracranial hemorrhage in the right temporal lobe. An angiogram revealed no vascular disease including arteriovenous malformation, angioma or aneurysm. Magnetic resonance (MR) imaging demonstrated no enhanced or cystic mass to suggest tumor presence. A follow-up study by MR imaging at 6 months after onset of the intracranial hemorrhage revealed a cystic mass lesion, with gadolinium-enhancement, in the right temporal lobe. This mass lesion was removed by surgery and diagnosed as PXA. Areas of tumor lesion could not be diagnosed immediately after the intracranial hemorrhage since bleeding lesion was prominent. Lower grade gliomas, including PXAs, should therefore be taken into consideration in the differential diagnosis of pediatric intracranial hemorrhage cases, separately from vascular disease and/or malignant brain tumor.

We previously reported a patient who had developed 2 glioblastomas at the age of 54 and 64 years, respectively. The first glioblastoma in the right frontal lobe was treated with surgery and radiotherapy. Ten years later, the patient developed a second, left frontal glioblastoma. Discordant patterns of TP53 and PTEN mutations suggested that the second tumor was not a recurrence but an independently developed glioblastoma. To determine the molecular mechanism underlying this enigmatic case with 10-year survival, we performed whole-exome sequencing. We found that both tumors were IDH-wildtype, excluding the possibility of secondary glioblastomas that developed from a less malignant astrocytic precursor lesion. We here report that the patient carried a heterozygous germline mutation [c.3305_3306insT; p.1102-fs-insT(Gly1105/TrpfsX3)] in the MSH6 mismatch repair gene. Further sequencing revealed that in addition to the germline MSH6 mutation, the first glioblastoma showed loss of the MSH6 wild-type allele, and the second glioblastoma carried a somatic MSH6 mutation [c.1403G>A; p.Arg468His]. Our results indicate that both glioblastomas had 2 hits in the MSH6 gene, and that loss of MSH6 function was the key event in the pathogenesis of these 2 independent primary glioblastomas.

We report a novel CASP9 germline mutation that may increase susceptibility to the development of brain tumors. We identified this mutation in a family in which three brain tumors had developed within three generations, including two anaplastic astrocytomas occurring in cousins. The cousins were diagnosed at similar ages (29 and 31 years), and their tumors showed similar histological features. Genetic analysis revealed somatic IDH1 and TP53 mutations in both tumors. However, no germline TP53 mutations were detected, despite the fact that this family fulfills the criteria of Li-Fraumeni-like syndrome. Whole exome sequencing revealed a germline stop-gain mutation (R65X) in the CASP9 gene, which encodes caspase-9, a key molecule for the p53-dependent mitochondrial death pathway. This mutation was also detected in DNA extracted from blood samples from the two siblings who were each a parent of one of the affected cousins. Caspase-9 immunohistochemistry showed the absence of caspase-9 immunoreactivity in the anaplastic astrocytomas and normal brain tissues of the cousins. These observations suggest that CASP9 germline mutations may have played a role at least in part to the susceptibility of development of gliomas in this Li-Fraumeni-like family lacking a TP53 germline mutation.

Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL), a member of the tumor necrosis factor (TNF) family, induces apoptosis in cancer cells by binding to its receptors, death receptor 4 (DR4) and DR5, without affecting normal cells, and is therefore considered to be a promising antitumor agent for use in cancer treatment. However, several studies have indicated that most glioma cell lines display resistance to TRAIL-induced apoptosis. To overcome such resistance and to improve the efficacy of TRAIL-based therapies, identification of ideal agents for combinational treatment is important for achieving rational clinical treatment in glioblastoma patients. The main aim of this study was to investigate whether interferon-β (IFN-β) (with its pleiotropic antitumor activities) could sensitize malignant glioma cells to TRAIL-induced apoptosis using glioma cell lines. TRAIL exhibited a dose-dependent antitumor effect in all of the 7 types of malignant glioma cell lines, although the intensity of the effect varied among the cell lines. In addition, combined treatment with TRAIL (low clinical dose: 1 ng/ml) and IFN-β (clinically relevant concentration: 10 IU/ml) in A-172, AM-38, T98G, U-138MG and U-251MG demonstrated a more marked antitumor effect than TRAIL alone. Furthermore, the antitumor effect of the combined treatment with TRAIL and IFN-β may be enhanced via an extrinsic apoptotic system, and upregulation of DR5 was revealed to play an important role in this process in U-138MG cells. These findings provide an experimental basis to suggest that combined treatment with TRAIL and IFN-β may offer a new therapeutic strategy for malignant gliomas.

Background : Pituitary apoplexy is an acute clinical syndrome caused by infarction and/or hemorrhage of pituitary adenoma, which typically presents with severe headache, visual deterioration, and endocrine abnormalities. However, temporal lobe epileptic seizure has not been viewed as a symptom of pituitary apoplexy in the literature. Case presentation : To elucidate further such a rare complication of temporal lobe epilepsy-like seizure, we describe here the rare clinical manifestations of a 55-year-old previously healthy male with pituitary apoplexy harboring headache, combined palsies involving cranial nerves III to VI, endocrinologic disturbances, and temporal lobe epilepsy-like seizure. In addition, we discuss the temporal lobe epilepsy associated with pituitary adenoma based on the literature. Conclusion : Although further accumulation of clinical data is needed, we would like to emphasize the importance of recognition of temporal lobe epilepsy-like seizure due to pituitary apoplexy, and to suggest that early surgery should be considered as an option in patients displaying such a rare complication.

Glioblastoma is a malignant brain tumor exhibiting highly aggressive proliferation and invasion capacities. Despite treatment by aggressive surgical resection and adjuvant therapy including temozolomide and radiation therapy, patient prognosis remains poor. Lenalidomide, a derivative of thalidomide, is known to be an immunomodulatory agent that has been used to treat hematopoietic malignancies. There are numerous studies revealing an antitumor effect of lenalidomide in hematopoietic cells, but not in glioma cells. The present study aimed to demonstrate the antitumor effect of lenalidomide on malignant glioma cell lines. The growth inhibition of malignant glioma cells (A-172, AM-38, T98G, U-138MG, U-251MG, and YH-13) by lenalidomide was assessed using a Coulter counter. The mechanism of the antitumor effect of lenalidomide was examined employing a fluorescence-activated cell sorter, western blot analysis, and quantitative real-time reverse transcriptional polymerase chain reaction (RT-qPCR) in malignant glioma cell lines (A-172, AM-38). The results revealed that the number of malignant glioma cells was decreased in a concentration-dependent manner by lenalidomide. DNA flow cytometric analysis demonstrated an increase in the ratio of cells at the G0/G1 phase following lenalidomide treatment. Western blot analysis and RT-qPCR revealed that p53 activation and the expression of p21 were increased in glioma cells treated with lenalidomide. Western blot analysis revealed that cleavage of PARP did not occur; however, increased expression of Bax protein, cleavage of caspase-9 and cleavage of caspase-3 were confirmed. Analysis by FACS also supported the conclusion that little apoptosis induction occurred following lenalidomide treatment of malignant glioma cell lines. In conclusion, lenalidomide exerts an antitumor effect on glioma cells due to alterations in cell cycle distribution.

BACKGROUND The brain tumor has a highest mortality rate among childhood malignant tumors. Development of peripheral blood stem cell transplant combined chemotherapy and radiation therapy improved the survival rate of patients with pediatric brain tumor drastically late years. Because of its complicated treatment plan, neurosurgeons cannot readily manage these aggressive therapies which require minute whole body control including prevention of lethal infection due to bone marrow suppression. Even if such treatment is effective and patient survives, the aftereffects may reduce patient’s QOL. PURPOSE We report outcomes of the patients with CNS tumor after multimodality treatment. In addition, we introduce the activity contents by the in-hospital children brain tumor multi-disciplinary medical treatment team organized in March 2016. METHODS We retrospectively reviewed 29 patients (under 15 years old) diagnosed as CNS tumors with total of 43 tumor surgeries between January 2001 and December 2019. RESULTS The histopathological diagnoses were 7 germ cell tumor, 7 astrocytic tumor, 4 ependymal tumor, 4 medulloblastoma, 2 craniopharyngioma, 2 AT/RT and 3 others. The mean age at first surgery was 7.4 y.o. (range: 0.3–14.8). Both chemotherapy and radiation therapy were performed in 22 cases out of 29. There were 15 survivors (11 ambulant, 3 W/C, 1 bedridden), 12 deaths, 2 lost follow-ups. Mean follow-up period was 66 months (range: 1–206). CONCLUSION To improve outcomes, we hold on a regular basis of team meeting, discuss treatment plan, and share information. Recently, we also care issues of the patients, such as fertility and palliative medicine.

To investigate whether supplementation with low-dose dairy protein plus micronutrients augments the effects of resistance exercise (RE) on muscle mass and physical performance compared with RE alone among older adults.Randomized controlled trial.Tokyo, Japan.Eighty-two community-dwelling older adults (mean age, 73.5 years) were randomly allocated to an RE plus dairy protein and micronutrient supplementation group or an RE only group (n = 41 each).The RE plus supplementation group participants ingested supplements with dairy protein (10.5 g/day) and micronutrients (8.0 mg zinc, 12 μg vitamin B12, 200 μg folic acid, 200 IU vitamin D, and others/day). Both groups performed the same twice-weekly RE program for 12 weeks.Whole-body, appendicular, and leg lean soft-tissue mass (WBLM, ALM, and LLM, respectively) with dual-energy X-ray absorptiometry, physical performance, biochemical characteristics, nutritional intake, and physical activity were measured before and after the intervention. Data were analyzed by using linear mixed-effects models.The groups exhibited similar significant improvements in maximum gait speed, Timed Up-and-Go, and 5-repetition and 30-s chair stand tests. As compared with RE only, RE plus supplementation significantly increased WBLM (0.63 kg, 95% confidence interval [CI]: 0.31-0.95), ALM (0.37 kg, 95% CI: 0.16-0.58), LLM (0.27 kg, 95% CI: 0.10-0.46), and serum concentrations of 25-hydroxyvitamin D (4.7 ng/mL, 95% CI: 1.6-7.9), vitamin B12 (72.4 pg/mL, 95% CI: 12.9-131.9), and folic acid (12.9 ng/mL, 95% CI: 10.3-15.5) (all P0.05 for group-by-time interactions). Changes over time in physical activity and nutritional intake excluding the supplemented nutrients were similar between groups.Low-dose dairy protein plus micronutrient supplementation during RE significantly increased muscle mass in older adults but did not further improve physical performance.

Object Holmes' tremor (HT) is generally considered to be a symptomatic tremor associated with lesions of the cerebellum, midbrain, or thalamus. Deep brain stimulation (DBS) therapy for essential tremor and parkinsonian tremor has proved quite successful. In contrast, surgical treatment outcomes for HT have often been disappointing. The use of 2 ipsilateral DBS electrodes implanted in parallel within the thalamus for severe essential tremor has been reported. Since dual-lead stimulation within a single target can cover a wider area than single-lead stimulation, it produces greater effects. On the other hand, DBS of the subthalamic area (SA) was recently reported to be effective for refractory tremor. Methods The authors implanted 2 DBS electrodes (one at the nucleus ventralis oralis/nucleus ventralis intermedius and the other at the SA) in 4 patients with HT. For more than 2 years after implantation, each patient's tremor was evaluated using a tremor rating scale under the following 4 conditions of stimulation: “on” for both thalamus and SA DBS; “off” for both thalamus and SA DBS; “on” for thalamus and “off” for SA DBS; and “on” for SA and “off” for thalamus DBS. Results The tremor in all patients was improved for more than 2 years (mean 25.8 ± 3.5 months). Stimulation with 2 electrodes exerted greater effect on the tremor than did 1-electrode stimulation. Interestingly, in all patients progressive effects were observed, and in one patient treated with DBS for 1 year, tremor did not appear even while stimulation was temporarily switched off, suggesting irreversible improvement effects. The presence of both resting and intentional/action tremor implies combined destruction of the pallidothalamic and cerebellothalamic pathways in HT. A larger stimulation area may thus be required for HT patients. Multitarget, dual-lead stimulation permits coverage of the wide area needed to suppress the tremor without adverse effects of stimulation. Some reorganization of the neural network may be involved in the development of HT because the tremor appears several months after the primary insult. The mechanism underlying the absence of tremor while stimulation was temporarily off remains unclear, but the DBS may have normalized the abnormal neural network. Conclusions The authors successfully treated patients with severe HT by using dual-electrode DBS over a long period. Such DBS may offer an effective and safe treatment modality for intractable HT.

Object The objective of this study was to evaluate the efficacy of chronic subthalamic nucleus (STN) stimulation for alleviating pain related to Parkinson disease (PD). Methods Among 163 consecutive patients undergoing STN stimulation, 69 were identified as experiencing pain preoperatively that was related to their PD. All 69 patients suffering from pain were followed up prospectively for 12 months after surgery. All patients described the severity of their pain according to a visual analog scale (VAS) preoperatively and at 2 weeks, 6 months, and 12 months postoperatively. Pain unrelated to PD was not studied. Results Several types of pain related to PD, the categories of which were based on a modification of 2 previous classifications (Ford and Honey), can occur in such patients: 1) musculoskeletal pain, 2) dystonic pain, 3) somatic pain exacerbated by PD, 4) radicular/peripheral neuropathic pain, and 5) central pain. The overall mean VAS score was significantly decreased postoperatively by 75% and 69% at 2 weeks and 6 months, respectively (p < 0.001). The mean VAS score at 12 months was also decreased by 80%, but 6 instances of pain (3 reports of somatic back pain and 3 reports of radicular/peripheral neuropathic pain) required additional spinal surgery to alleviate the pain severity. The results were analyzed using the Wilcoxon signed-rank test and demonstrated a significant reduction in VAS scores at all follow-up assessments (p < 0.001). Musculoskeletal pain and dystonic pain were well alleviated by STN stimulation. In contrast, somatic pain exacerbated by PD and peripheral neuropathic pain originating from lumbar spinal diseases, such as spondylosis deformans and/or canal stenosis, often deteriorated postoperatively despite attenuation of the patients' motor disability. Patients with central pain were poor responders. Conclusions This study found that STN stimulation produced significant improvement of overall pain related to PD in patients with advanced PD, and the efficacy continued for at least 1 year. The present results indicate that musculoskeletal pain and dystonic pain responded well to STN stimulation, but patients with back pain (somatic pain) and radicular/peripheral neuropathic pain originating from spinal disease have a potential risk for postoperative deterioration of their pain.

Recent studies have indicated the importance of subcortical mapping of the corticospinal tract (CT) during tumor resection close to the primary motor area. It is substantial evidence that the corticospinal descending direct wave (D-wave) can be used as a guide for mapping of the primary motor cortex (M1) and for monitoring of the CT functional integrity. In the present study, the authors investigated the feasibility of D-wave recordings after subcortical stimulation. The authors examined 14 patients with brain tumors close to the M1 and/or CT, who exhibited no obvious motor deficit before surgery. Subcortical white matter was electrically stimulated in monopolar or bipolar fashion by recording the descending wave (D-wave) from the spinal epidural space using a catheter-type electrode. Subcortical D-wave was more clearly recorded after monopolar stimulation than after bipolar stimulation. The features of the subcortical D-wave, including its waveform, conduction velocity, and latency, were nearly identical to those of the corticospinal D-wave recorded after M1 stimulation. Subcortical D-wave amplitude was prone to change depending on the distance from the stimulation points to the CT. Changes in parameters of subcortical D-wave may provide valuable information to prevent postoperative motor deficit. Further studies are required to clarify the relationship between the distance from the stimulating point to the CT and the amplitude of the subcortically elicited D-wave.

Objective: The development of image-guided systems rendered it possible to perform frameless stereotactic surgery for deep brain stimulation (DBS). As well as stereotactic targeting, neurophysiological identification of the target is important. Multitract microrecording is an effective technique to identify the best placement of an electrode. This is a report of our experience of using the Nexframe frameless stereotaxy with Ben’s Gun multitract microrecording drive and our study of the accuracy, usefulness and disadvantages of the system. Methods: Five patients scheduled to undergo bilateral subthalamic nucleus (STN) DBS were examined. The Nexframe device was adjusted to the planned target, and electrodes were introduced using a microdrive for multitract microrecording. In addition to the Nexframe frameless system, we adopted the Leksell G frame to the same patients simultaneously to use a stereotactic X-ray system. This system consisted of a movable X-ray camera with a crossbar and was adopted to be always parallel to the frame with the X-ray film cassette. The distance between the expected and actual DBS electrode placements was measured on such a stereotactic X-ray system. In addition, the distance measured with this system was compared with that measured by conventional frame-based stereotaxy in 20 patients (40 sides). Results: The mean deviations from 10 planned targets were 1.3 ± 0.3 mm in the mediolateral (x) direction, 1.0 ± 0.9 mm in the anteroposterior (y) direction and 0.5 ± 0.6 mm in the superoposterior (z) direction. The data from the frame-based stereotaxy in our institute were 1.5 ± 0.9 mm in the mediolateral (x) direction, 1.1 ± 0.7 mm in the anteroposterior (y) direction and 0.8 ± 0.6 mm in the superoposterior (z) direction. Then, differences were not statistically significant in any direction (p > 0.05). The multitract microrecording procedure associated with the Nexframe was performed without any problems in all of the patients. None of these electrodes migrated during and/or after the surgery. However, the disadvantage of the system is the narrow surgical field for multiple electrode insertion. Coagulating the cortex and inserting multiple electrodes under such a narrow visual field were complicated. Conclusion: The Nexframe with multitract microrecording for STN DBS still has some problems that need to be resolved. Thus far, we do not consider that this technology in its present state can replace conventional frame-based stereotactic surgery. The accuracy of the system is similar to that of frame-based stereotaxy. However, the narrow surgical field is a disadvantage for multiple electrode insertion. Improvement on this point will enhance the usefulness of the system.

We report a case of hemorrhage from brainstem cavernous angioma that caused various symptoms including neurootological, gustatory and facial sensory disturbances. A man experienced nausea and numbness of his right ear. It was confirmed that the symptom were derived not from a peripheral lesion but from retrocochlear and brainstem impairment based upon the findings of the DPOAE, ABR, VEMP, caloric test, optokinetic nystagmus etc. We detected an area of retrocochlear lesion that was responsible for both the auditory and vestibular disturbances based upon detailed neurootological examination in addition to MRI findings, and showed that the impairment was improved one year later without specific treatment.

Introduction. Chronic thalamic stimulation has been confirmed as an effective treatment for tremor. The optimal target has been commonly accepted to be situated within the ventral thalamus, but a standard trajectory of the deep brain stimulation (DBS) electrode has not yet been established. Materials and Methods. A 53-year-old man with an 11-year history of essential tremor was treated by DBS of the thalamus. In this patient, we had a chance to compare the effects of different trajectory angles of the DBS electrode on tremor. Results. Intraoperative stimulation with the DBS electrode temporarily inserted at a high angle to the horizontal plane of the anterior commissure-posterior commissure (AC-PC) line to cover only the nucleus ventralis intermedius (Vim) was not effective. In contrast, stimulation with the DBS electrode permanently implanted at a low angle, covering a wide area extending from the nucleus ventralis oralis (Vo) to the Vim, reduced the tremor. Conclusion. We report on the case of a patient who showed different effects on tremor depending on the trajectory angle of the DBS electrode to the AC-PC line. The insertion trajectory of the DBS electrode may be an important factor for the treatment of tremor.

We report a novel CASP9 germline mutation that may increase susceptibility to the development of brain tumors. We identified this mutation in a family in which four brain tumors had developed within three generations, including two anaplastic astrocytomas occurring in cousins. The cousins were diagnosed at similar ages (29 and 31 years), and their tumors showed similar histological features. Genetic analysis revealed somatic IDH1 and TP53 mutations in both tumors. However, no germline TP53 mutations were detected, despite the fact that this family fulfills the criteria of Li-Fraumeni-like syndrome. Whole exome sequencing revealed a germline stop-gain mutation (R65X) in the CASP9 gene, which encodes caspase-9, a key molecule for the p53-dependent mitochondrial death pathway. This mutation was also detected in DNA extracted from blood samples from the two siblings who were each a parent of one of the affected cousins. Caspase-9 immunohistochemistry demonstrated the absence of caspase-9 immunoreactivity in the anaplastic astrocytomas and normal brain tissues of the cousins. These observations suggest that CASP9 germline mutations may have played a role at least in part to the susceptibility of development of gliomas in this Li-Fraumeni-like family lacking a TP53 germline mutation.

Extracellular signal-regulated kinase (ERK) is required for clenbuterol (CB)-dependent fast-type myofibril enlargement; however, its contribution to translation control is unclear. ERK mediates translational regulation through mammalian target of rapamycin complex 1 (mTORC1) activation and (or) mTORC1-independent pathways. In this study, we aimed to investigate the role of ERK in translational control during CB-induced muscular hypertrophy by measuring time-dependent changes in the phosphorylation statuses of ERK, p70 ribosomal S6 kinase (p70S6K; an indicator of mTORC1 activity), 4E-binding protein 1 (4E-BP1), eukaryotic elongation factor 2 (eEF2), and other related signaling molecules in rat gastrocnemius muscles. Five-day administration of CB induced phenotypes associated with muscular hypertrophy (significant increases in wet weight and isometric ankle flexion torque in the gastrocnemius muscle), but was not accompanied by elevated ERK or p70S6K phosphorylation. One-day administration of CB caused significant increases in the phosphorylation of ERK, p70S6K, and 4E-BP1. In contrast, 3-day administration of CB caused significant increases in the phosphorylation of ERK and 4E-BP1, but not p70S6K. In addition, positive correlations were observed between ERK and 4E-BP1 on days 1 and 3, whereas a correlation between ERK and p70S6K was only observed on day 1. eEF2 phosphorylation was unchanged on both days 1 and 3. These findings suggest that ERK accelerates the initiation of translation, but does not support the involvement of ERK in translational elongation. Furthermore, ERK may play a major role in promoting translational initiation by mediating the phosphorylation of 4E-BP1, and may contribute to the initial activation of mTORC1 during CB administration.

Holmes' tremor (HT) is generally considered to be a symptomatic tremor associated with lesions of the cerebellum, midbrain, or thalamus. Deep brain stimulation (DBS) therapy for essential tremor and parkinsonian tremor has proved quite successful. In contrast, surgical treatment outcomes for HT have often been disappointing. The use of 2 ipsilateral DBS electrodes implanted in parallel within the thalamus for severe essential tremor has been reported. Since dual-lead stimulation within a single target can cover a wider area than single-lead stimulation, it produces greater effects. On the other hand, DBS of the subthalamic area (SA) was recently reported to be effective for refractory tremor.The authors implanted 2 DBS electrodes (one at the nucleus ventralis oralis/nucleus ventralis intermedius and the other at the SA) in 4 patients with HT. For more than 2 years after implantation, each patient's tremor was evaluated using a tremor rating scale under the following 4 conditions of stimulation: "on" for both thalamus and SA DBS; "off" for both thalamus and SA DBS; "on" for thalamus and "off" for SA DBS; and "on" for SA and "off" for thalamus DBS.The tremor in all patients was improved for more than 2 years (mean 25.8 ± 3.5 months). Stimulation with 2 electrodes exerted greater effect on the tremor than did 1-electrode stimulation. Interestingly, in all patients progressive effects were observed, and in one patient treated with DBS for 1 year, tremor did not appear even while stimulation was temporarily switched off, suggesting irreversible improvement effects. The presence of both resting and intentional/action tremor implies combined destruction of the pallidothalamic and cerebellothalamic pathways in HT. A larger stimulation area may thus be required for HT patients. Multitarget, dual-lead stimulation permits coverage of the wide area needed to suppress the tremor without adverse effects of stimulation. Some reorganization of the neural network may be involved in the development of HT because the tremor appears several months after the primary insult. The mechanism underlying the absence of tremor while stimulation was temporarily off remains unclear, but the DBS may have normalized the abnormal neural network.The authors successfully treated patients with severe HT by using dual-electrode DBS over a long period. Such DBS may offer an effective and safe treatment modality for intractable HT.