SARS-CoV-2 Omicron BA.2.75 Variant May Be Much More Infective than Preexisting Variants Based on In Silico Model.

Previously, we developed a mathematical model via molecular simulation analysis to predict the infectivity of six SARS-CoV-2 variants. In this report, we aimed to predict the relative risk of the recent new variants of SARS-CoV-2 based on our previous research. We subjected Omicron BA.4/5 and BA.2.75 variants of SARS-CoV-2 to the analysis to determine the evolutionary distance of the spike protein gene (S gene) of the variants from the Wuhan variant so as to appreciate the changes in the spike protein. We performed molecular docking simulation analyses of the spike proteins with human angiotensin-converting enzyme 2 (ACE2) to understand the docking affinities of these variants. We then compared the evolutionary distances and the docking affinities of these variants with those of the variants that we had analyzed in our previous research. As a result, BA.2.75 has both the highest docking affinity (ratio per Wuhan variant) and the longest evolutionary distance of the S gene from the Wuhan variant. These results suggest that BA.2.75 infection can spread farther than can infections of preexisting variants.

Prediction of infectivity of SARS-CoV2: Mathematical model with analysis of docking simulation for spike proteins and angiotensin-converting enzyme 2.

Objectives: Variants of a coronavirus (SARS-CoV-2) have been spreading in a global pandemic. Improved understanding of the infectivity of future new variants is important so that effective countermeasures against them can be quickly undertaken. In our research reported here, we aimed to predict the infectivity of SARS-CoV-2 by using a mathematical model with molecular simulation analysis, and we used phylogenetic analysis to determine the evolutionary distance of the spike protein gene (S gene) of SARS-CoV-2. Methods: We subjected the six variants and the wild type of spike protein and human angiotensin-converting enzyme 2 (ACE2) to molecular docking simulation analyses to understand the binding affinity of spike protein and ACE2. We then utilized regression analysis of the correlation coefficient of the mathematical model and the infectivity of SARS-CoV-2 to predict infectivity. Results: The evolutionary distance of the S gene correlated with the infectivity of SARS-CoV-2 variants. The calculated biding affinity for the mathematical model obtained with results of molecular docking simulation also correlated with the infectivity of SARS-CoV-2 variants. These results suggest that the data from the docking simulation for the receptor binding domain of variant spike proteins and human ACE2 were valuable for prediction of SARS-CoV-2 infectivity. Conclusion: We developed a mathematical model for prediction of SARS-CoV-2 variant infectivity by using binding affinity obtained via molecular docking and the evolutionary distance of the S gene.

Core body temperature changes in school-age children with circadian rhythm sleep-wake disorder.

OBJECTIVE/BACKGROUND: Core body temperature (CBT) is considered a valuable marker for circadian rhythm. This study aimed to investigate the changes in CBT that are associated with the symptoms of circadian rhythm sleep-wake disorder (CRSWD) post-treatment in children. PATIENTS/METHODS: Twenty-eight school-age children [10 boys and 18 girls; mean age (±standard deviation), 13.68 ± 0.93 years] who were admitted to our hospital with CRSWD underwent treatment for 6-8 weeks according to the following protocol: lights-out for sleep at 21:00; phototherapy for waking at 6:00 or 7:00; light exercise everyday (eg, a 20- to 30-min walk). CBT was continuously measured for 24 h on the first day of admission and on the first day after treatment. RESULTS: The mean time of sleep onset/offset (±standard deviation; in hours:minutes) 1 week before admission and 1 week after treatment were 23:53 ± 2:26/9:58 ± 2:15 and 21:17 ± 0:19/6:46 ± 0:32, respectively. The mean times of sleep onset and offset measured post-treatment were significantly earlier than those measured pre-treatment (p < 0.001). The mean CBT and mean minimum CBT during sleep were significantly lower on the first day post-treatment than on the first day of admission (p = 0.011 and p < 0.001, respectively). CONCLUSIONS: Symptom improvements in patients with CRSWD were associated with a decrease in CBT during sleep, suggesting that CBT may be a biomarker for improvements in CRSWD. These results help elucidate the cause of this sleep disorder.

In Silico Drug Repurposing by Structural Alteration after Induced Fit: Discovery of a Candidate Agent for Recovery of Nucleotide Excision Repair in Xeroderma Pigmentosum Group D Mutant (R683W).

Xeroderma pigmentosum complementation group D (XPD) is a UV-sensitive syndrome and a rare incurable genetic disease which is caused by the genetic mutation of the excision repair cross-complementation group 2 gene (ERCC2). Patients who harbor only XPD R683W mutant protein develop severe photosensitivity and progressive neurological symptoms. Cultured cells derived from patients with XPD (XPD R683W cells) demonstrate a reduced nucleotide excision repair (NER) ability. We hope to ameliorate clinical symptoms if we can identify candidate agents that would aid recovery of the cells' NER ability. To investigate such candidates, we created in silico methods of drug repurposing (in silico DR), a strategy that utilizes the recovery of ATP-binding in the XPD R683W protein after the induced fit. We chose 4E1RCat and aprepitant as the candidates for our in silico DR, and evaluated them by using the UV-induced unscheduled DNA synthesis (UDS) assay to verify the recovery of NER in XPD R683W cells. UDS values of the cells improved about 1.4-1.7 times after 4E1RCat treatment compared with solvent-only controls; aprepitant showed no positive effect. In this study, therefore, we succeeded in finding the candidate agent 4E1RCat for XPD R683W. We also demonstrated that our in silico DR method is a cost-effective approach for drug candidate discovery.

Establishment of the experimental procedure for prediction of conjugation capacity in mutant UGT1A1.

UDP-glucuronosyltransferase 1A1 (UGT1A1) is an enzyme that is found in the endoplasmic reticulum membrane and can reportedly have a large number of amino acid substitutions that result in the reduction of glucuronidation capacity. For example, adverse drug reactions when patients receive CPT-11 (irinotecan) such as in cancer chemotherapy are caused by amino acid substitutions in UGT1A1. We previously found that the extent of the docking when the hydroxyl residue of bilirubin was oriented toward UDP-glucuronic acid correlated with in vitro conjugation capacity. In this study, we analyzed the conformation of mutant UGT1A1s by means of structural optimization with water and lipid bilayers instead of the optimization in vacuo that we used in our previous study. We then derived a mathematical model that can predict the conjugation capacities of mutant UGT1A1s by using results of substrate docking in silico and results of in vitro analysis of glucuronidation of acetaminophen and 17ß-estradiol by UGT1A1s. This experimental procedure showed that the in silico conjugation capacities of other mutant UGT1A1s with bilirubin or SN-38 were similar to reported in vitro conjugation capacities. Our results suggest that this experimental procedure described herein can correctly predict the conjugation capacities of mutant UGT1A1s and any substrate.

Development of a Highly Sensitive Technique for Capturing Renal Cell Cancer Circulating Tumor Cells.

PURPOSE: Liquid biopsy is becoming increasingly important as a guide for selecting new drugs and determining their efficacy. In urological cancer, serum markers for renal cell and urothelial cancers has made the development of liquid biopsy for these cancers strongly desirable. Liquid biopsy is less invasive than conventional tissue biopsy is, enabling frequent biopsies and, therefore, is considered effective for monitoring the treatment course. Circulating tumor cells (CTCs) are a representative liquid biopsy specimen. In the present study, we focused on developing our novel technology for capturing renal cell cancer (RCC)-CTCs using an anti-G250 antibody combined with new devices. Basic experiments of our technology showed that it was possible to detect RCC-CTC with a fairly high accuracy of about 95%. Also, RCC-CTC was identified in the peripheral blood of actual RCC patients. Additionally, during the treatment course of the RCC patient, change in the number of RCC-CTC was confirmed in one case. We believe that the technology we developed will be useful for determining the treatment efficacy and drug selection for the treatment of renal cell cancer (RCC). In order to solve issues such as thresholds setting of this technology, large-scale clinical trials are expected.

Co-precipitation molecules hemopexin and transferrin may be key molecules for fibrillogenesis in TTR V30M amyloidogenesis.

The disease model of familial amyloidotic polyneuropathy-7.2-hMet30 mice-manifests amyloid deposition that consists of a human amyloidogenic mutant transthyretin (TTR) (TTR V30M). Our previous study found amyloid deposits in 14 of 27 7.2-hMet30 mice at 21-24 months of age. In addition, non-fibrillar TTR deposits were found in amyloid-negative 7.2hMet30 mice. These results suggested that TTR amyloidogenesis required not only mutant TTR but also an additional factor (or factors) as an etiologic molecule. To determine the differences in serum proteome in amyloid-positive and amyloid-negative mice in the 7.2-hMet30 model, we used proteomic analyses and studied serum samples obtained from these mice. Hemopexin (HPX) and transferrin (Tf) were detected in the serum samples from amyloid-positive mice and were also found in amyloid deposits via immunohistochemistry, but serum samples from amyloid-negative mice did not contain HPX and Tf. These two proteins were also not detected in non-fibrillar TTR deposits. In addition, in silico analyses suggested that HPX and Tf facilitate destabilization of TTR secondary structures and misfolding of TTR. These results suggest that HPX and Tf may be associated with TTR amyloidogenesis after fibrillogenesis in vivo.

Docking analysis and the possibility of prediction efficacy for an anti-IL-13 biopharmaceutical treatment with tralokinumab and lebrikizumab for bronchial asthma.

Interleukin-13 (IL-13) is associated with allergic airway inflammation and airway remodeling. Our group found a variant with a single nucleotide polymorphism in the IL13 gene at position +2044G>A (rs20541) that was expected to result in the non-conservative replacement of a positively charged arginine (R) with a neutral glutamine (Q) at position 144. IL-13Q144 was associated with augmented allergic airway inflammation and bronchial asthma remodeling. There is some indication that anti-IL-13 monoclonal antibodies can demonstrate a positive effect on the clinical course of refractory asthmatic patients. To date, the binding stability of these agents for IL-13Q144 is unknown. The objective of this study was to investigate the prediction efficacy of the anti-IL-13 monoclonal antibodies tralokinumab and lebrikizumab in asthmatic patients with IL-13R144 and IL-13Q144. The three-dimensional (3-D) structure of tralokinumab was obtained from the Protein Data Bank (PDB ID: 5L6Y), and the complete 3-D structure of lebrikizumab was built through homology modeling. For the binding stability analysis, we performed and analyzed docking simulations of IL-13 with tralokinumab or lebrikizumab. The tralokinumab and lebrikizumab structures changed after binding to IL-13 to facilitate binding with IL-13Q144. The stability analysis with tralokinumab and lebrikizumab demonstrated that IL-13Q144 was more stable than IL-13R144 for both the Rosetta energy score and for the free energy of binding. IL-13Q144 might be a promising predictor of responsiveness to tralokinumab and lebrikizumab treatment for bronchial asthma.

Efficacy of femtosecond lasers for application of acupuncture therapy.

Acupuncture treatment utilizes the stimulation of metal acupuncture needles that are manually inserted into a living body. In the last decades, laser light has been used as an alternative to needles to stimulate acupuncture points. We previously reported suppression of myostatin (Mstn) gene expression in skeletal muscle by means of femtosecond laser (FL) irradiation, after electroacupuncture, in which acupuncture needles are stimulated with a low-frequency microcurrent. The purpose of the study here was to investigate the efficacy of FL irradiation in mouse skeletal muscle with regard to protein synthesis. After irradiation of the hindlimbs, we first analyzed Mstn gene expression and Mstn protein level in the skeletal muscle. We then evaluated phosphorylation of the mammalian target of rapamycin (mTOR) and its downstream target 70-kDa ribosomal protein S6 kinase (p70S6K). The results showed that FL irradiation significantly reduced the amount of Mstn protein and enhanced the phosphorylation of p70S6K in of the mTOR/S6K signaling pathway. We suggest that FL irradiation activated the protein synthetic pathway in the skeletal muscle. In conclusion, we determined that FL irradiation can serve as an alternative for acupuncture needles and has the potential of being a new non-invasive acupuncture treatment of skeletal muscle.

Analysis of a single-codon E746 deletion in exon 19 of the epidermal growth factor receptor.

PURPOSE: Epidermal growth factor receptor (EGFR) gene mutations are the most established genomic biomarkers for the efficacy of EGFR tyrosine kinase inhibitors (EGFR-TKIs). The most frequent deletion in exon 19 is delE746_750, followed by del747_753insS and del747_750insP. Since investigations of delE746 have not been reported previously, it is unclear if delE746 conveys sensitivity to TKI effect of TKI on EGFR delE746. The objective was to characterize delE746 of the EGFR gene and to explore the effects of TKIs on the delE746. METHODS: We assessed the ability of gefitinib to inhibit phosphorylation of clonal L929 cell lines expressing EGFR with delE746. 3-D structures of the EGFR proteins were also used to investigate the interaction with gefitinib. RESULTS: The delE746 mutant EGFR-expressing cells exhibited gefitinib-sensitive autophosphorylation, which altered the structure of the EGFR and increased the instances of docking during docking simulations of gefitinib with the EGFR-TK. This mutant revealed that it exhibited molecular conformation alterations, and more frequent binding with gefitinib compared to wild-type EGFR. We administered EGFR-TKI, gefitinib to a Japanese woman with lung cancer that contained delE746. The patient achieved partial response after a 5 month of treatment with gefitinib. CONCLUSION: Our study revealed biological, structural, and probably clinical features of the delE746 form of EGFR.

Shakuyaku-kanzo-to (Shao-Yao-Gan-Cao-Tang) as Treatment of Painful Muscle Cramps in Patients with Lumbar Spinal Stenosis and Its Minimum Effective Dose.

Shakuyaku-kanzo-to (Shao-Yao-Gan-Cao-Tang) is a Kampo medicine, which is known to be effective against muscle cramps as well as crampy pain in the gastrointestinal smooth muscle and skeletal muscle. However, glycyrrhizin in this medicine also causes adverse drug reactions such as hypokalemia, hypertension, and edema. We analyzed the therapeutic efficacy of Shakuyaku-kanzo-to for painful muscle cramps associated with lumbar spinal stenosis and clarified its minimum effective dose. 58 patients with lumbar spinal stenosis and painful muscle cramps were included. We evaluated the therapeutic efficacy of Shakuyaku-kanzo-to (n=16) comparing with eperisone hydrochloride (n=14). We then examined the minimum effective dose of Shakuyaku-kanzo-to in the remaining 28 patients. Shakuyaku-kanzo-to reduced the frequency of painful muscle cramps to less than 50% in 13 of 16 patients. However, eperisone hydrochloride reduced it to the same level in 4 of 14 patients. The onset of the maximum therapeutic effect of Shakuyaku-kanzo-to was less than 3 days from the start of treatment in 11 of 15 patients. Regarding the minimum effective dose for painful muscle cramps, 2.5 g of Shakuyaku-kanzo-to used as needed had a therapeutic effect that was equivalent to the regular use of 7.5 g/day (given in divided doses three times daily). Our data show that Shakuyaku-kanzo-to is effective for painful muscle cramps associated with lumbar spinal stenosis. The dosage of 2.5 g of Shakuyaku-kanzo-to as needed had a therapeutic effect that was equal to the regular use of 7.5 g/day.

Hsp12.6 expression is inducible by host immunity in adult worms of the parasitic nematode Nippostrongylus brasiliensis.

Heat shock proteins (Hsp) are a family of stress-inducible molecular chaperones that play multiple roles in a wide variety of animals. However, the roles of Hsps in parasitic nematodes remain largely unknown. To elucidate the roles of Hsps in the survival and longevity of nematodes, particularly at the 2 most critical stages in their lifecycle, the infective-L3 stage and adult stage, which is subjected to host-derived immunological pressure, we examined the temporal gene transcription patterns of Hsp12.6, Hsp20, Hsp70, and Hsp90 throughout the developmental course of the nematode Nippostrongylus brasiliensis by reverse transcriptase real-time PCR. Nb-Hsp70 and Nb-Hsp90 expression were observed throughout the nematode's lifecycle, while the expression of Nb-Hsp20 was restricted to adults. Interestingly, Nb-Hsp12.6 showed a biphasic temporal expression pattern; i.e., it was expressed in infective-L3 larvae and in adults during worm expulsion from immunocompetent rats. However, the activation of Nb-Hsp12.6 in adult worms was aborted when they infected permissive athymic-rnu/rnu rats and was only marginal when they infected mast-cell-deficient Ws/Ws rats, which exhibited a low response of rat mast cell protease (RMCP) II and resistin-like molecule (Relm)-ß expression compared to those observed in immunocompetent rats. Moreover, the activation of Nb-Hsp12.6 was reversed when adult worms were transplanted into the naive rat intestine. These features of Nb-Hsp12.6, the expression of which is not only stage-specific in infective-L3, but is also inducible by mucosal immunity in adults, have implications for the survival strategies of parasitic nematodes in deleterious environmental conditions both outside and inside the host.

Herbal Medicine Containing Licorice May Be Contraindicated for a Patient with an HSD11B2 Mutation.

Licorice ingestion, as well as mutations in the HSD11B2 gene, inhibits 11ß-hydroxysteroid dehydrogenase type 2 (11ßHSD2) enzyme activity, causing the syndrome of apparent mineral corticoid excess (AME). However, the combined effect of licorice ingestion and an HSD11B2 mutation has never been reported, until now. In this study, we demonstrated that licorice ingestion can produce overt hypertension in an individual without medical history of hypertension who is heterozygous for wild-type and mutant HSD11B2 genes. Our patient was a 51-year-old female with serious hypertension who had been taking herbal medicine containing licorice for more than one year. She was clinically diagnosed as having licorice intoxication, because she did not present with hypertension after ceasing the herbal medicine. Molecular analysis showed that she carried a missense mutation, c.40C>T, in HSD11B2. In conclusion, licorice ingestion is an environmental risk factor for hypertension or AME state in patients with a mutation in HSD11B2. Carrying a mutation in HSD11B2 is, conversely, a genetic risk factor for licorice-induced hypertension or AME state. Herbal medicine containing licorice may, therefore, be contraindicated in patients with an HSD11B2 mutation.

Full-length sequence of mouse acupuncture-induced 1-L (aig1l) gene including its transcriptional start site.

We have been investigating the molecular efficacy of electroacupuncture (EA), which is one type of acupuncture therapy. In our previous molecular biological study of acupuncture, we found an EA-induced gene, named acupuncture-induced 1-L (Aig1l), in mouse skeletal muscle. The aims of this study consisted of identification of the full-length cDNA sequence of Aig1l including the transcriptional start site, determination of the tissue distribution of Aig1l and analysis of the effect of EA on Aig1l gene expression. We determined the complete cDNA sequence including the transcriptional start site via cDNA cloning with the cap site hunting method. We then analyzed the tissue distribution of Aig1l by means of northern blot analysis and real-time quantitative polymerase chain reaction. We used the semiquantitative reverse transcriptase-polymerase chain reaction to examine the effect of EA on Aig1l gene expression. Our results showed that the complete cDNA sequence of Aig1l was 6073 bp long, and the putative protein consisted of 962 amino acids. All seven tissues that we analyzed expressed the Aig1l gene. In skeletal muscle, EA induced expression of the Aig1l gene, with high expression observed after 3 hours of EA. Our findings thus suggest that the Aig1l gene may play a key role in the molecular mechanisms of EA efficacy.

Biological actions of green tea catechins on cardiac troponin C.

BACKGROUND AND PURPOSE: Catechins, biologically active polyphenols in green tea, are known to have a protective effect against cardiovascular diseases. In this study, we investigated direct actions of green tea catechins on cardiac muscle function to explore their uses as potential drugs for cardiac muscle disease. EXPERIMENTAL APPROACH: The effects of catechins were systematically investigated on the force-pCa relationship in skinned cardiac muscle fibres to determine their direct effects on cardiac myofilament contractility. The mechanisms of action of effective catechins were investigated using troponin exchange techniques, quartz crystal microbalance, nuclear magnetic resonance and a transgenic mouse model. KEY RESULTS: (-)-Epicatechin-3-gallate (ECg) and (-)-epigallocatechin-3-gallate (EGCg), but not their stereoismers (-)-catechin-3-gallate and (-)-gallocatechin-3-gallate, decreased cardiac myofilament Ca(2+) sensitivity probably through its interaction with cardiac troponin C. EGCg restored cardiac output in isolated working hearts by improving diastolic dysfunction caused by increased myofilament Ca(2+) sensitivity in a mouse model of hypertrophic cardiomyopathy. CONCLUSIONS AND IMPLICATIONS: The green tea catechins, ECg and EGCg, are Ca(2+) desensitizers acting through binding to cardiac troponin C. These compounds might be useful compounds for the development of therapeutic agents to treat the hypertrophic cardiomyopathy caused by increased Ca(2+) sensitivity of cardiac myofilaments.

Ligand orientation governs conjugation capacity of UDP-glucuronosyltransferase 1A1.

UDP-glucuronosyltransferase 1A1 (UGT1A1) is an endoplasmic reticulum membrane protein that catalyses glucuronidation. Mutant UGT1A1 possesses a different conjugation capacity, and the molecular mechanisms regulating these conjugation reactions are as yet unclear. To elucidate these molecular mechanisms, we simulated and analysed the glucuronidation of wild-type UGT1A1 and six UGT1A1 mutants, with bilirubin as the substrate. We found that only the orientation of the substrates correlated with the conjugation capacity in in vitro experiments. Inasmuch as glucuronidation is an intermolecular rearrangement reaction, we find that the conjugation reaction proceeds only when the hydroxyl group of the substrate is oriented towards the coenzyme, which allows the proton transfer to occur.

Efficacy of temozolomide treatment in patients with high-grade glioma.

BACKGROUND: Numerous studies have reported the clinical efficacy of temozolomide (TMZ) treatment for high-grade glioma, but information on Japanese populations has been limited. This study assessed the safety and early outcomes of TMZ treatment, with or without combination therapy. PATIENTS AND METHODS: The subjects comprised ten patients with high-grade glioma [glioblastoma multiforme (GBM), n=3, gliosarcoma (GS), n=1, anaplastic oligodendroglioma (AO), n=3, anaplastic mixed oligoastrocytoma (AOA), n=1, and anaplastic ependymoma (AE), n=2]. All the patients were initially treated with conventional radiotherapy following surgical resection with or without adjuvant chemotherapy. As second- or third-line chemotherapy, patients received TMZ for recurrence or tumor progression. As combination therapy, the local administration of tumor necrosis factor-alpha and the addition of carboplatin and etoposide were included for three patients during the course of oral TMZ treatment. RESULTS: Partial response (PR) to TMZ therapy was achieved by four out of the ten patients (objective response rate, 40%), while three patients displayed stable disease (SD) and three showed disease progression (PD). One of the patients receiving combination therapy has continued to show shrinkage of the relapsed tumor. Despite prior radio- and chemotherapy, most patients experienced only grade 1-2 hematotoxicity that was well-controlled by conservative therapy. CONCLUSION: TMZ chemotherapy is effective for the treatment of high-grade glioma in some patients without serious toxicity. Assessing the true efficacy of TMZ will require a larger study with comparison of long-term outcomes between other agents or combined therapeutic modalities.

Two novel mutations in the ED1 gene in Japanese families with X-linked hypohidrotic ectodermal dysplasia.

X-linked hypohidrotic ectodermal dysplasia (XLHED), which is characterized by hypodontia, hypotrichosis, and hypohidrosis, is caused by mutations in ED1, the gene encoding ectodysplasin-A (EDA). This protein belongs to the tumor necrosis factor ligand superfamily. We analyzed ED1 in two Japanese patients with XLHED. In patient 1, we identified a 4-nucleotide insertion, c.119-120insTGTG, in exon 1, which led to a frameshift mutation starting from that point (p.L40fsX100). The patient's mother was heterozygous for this mutation. In patient 2, we identified a novel missense mutation, c.1141G>C, in exon 9, which led to a substitution of glycine with arginine in the TNFL domain of EDA (p.G381R). This patient's mother and siblings showed neither symptoms nor ED1 mutations, so this mutation was believed to be a de novo mutation in maternal germline cells. According to molecular simulation analysis of protein structure and electrostatic surface, p.G381R increases the distance between K375 in monomer A and K327 in monomer B, which suggests an alteration of overall structure of EDA. Thus, we identified two novel mutations, p.L40fsX100 and p.G381R, in ED1 of two XLHED patients. Simulation analysis suggested that the p.G381R mutation hampers binding of EDA to its receptor via alteration of overall EDA structure.

Ruptured tectal arteriovenous malformation demonstrated angiographically after removal of an unruptured occipital lobe arteriovenous malformation.

We report a case of ruptured tectal arteriovenous malformation (AVM) that was demonstrated angiographically only after removal of an unruptured occipital AVM. A 57-year-old man presented with sudden onset of diplopia and tinnitus. Computed tomography revealed a small hemorrhage in the right tectum mesencephali with intraventricular hemorrhage. Magnetic resonance imaging and angiography disclosed AVM in the right occipital lobe which was separate from the hemorrhagic lesion. Angiography demonstrated that the right occipital AVM was fed by the parieto-occipital artery and drained into the superior sagittal sinus and vein of Galen. However, no abnormal vascular lesion was detected near the tectum mesencephali. As venous hypertension was considered the reason for hemorrhage, the occipital AVM was completely resected. Postoperative angiography demonstrated disappearance of the occipital AVM, but it also disclosed a small tectal AVM fed by branches from the superior cerebellar artery, which had not been detected on preoperative angiography. This was considered the true cause of hemorrhage, and gamma knife surgery was accordingly performed. Even if an AVM is demonstrated, if the lesion does not correspond to the hemorrhage we recommend serial angiographical evaluation so that a small AVM is not missed.

Cavernous malformation of the ventral midbrain successfully removed via a transsylvian-transpeduncular approach: case report.

A 37-year-old woman presented with a rare cavernous malformation of the ventral midbrain with brainstem hemorrhage manifesting as sudden onset of headache and vomiting. The lesion was removed successfully through a transsylvian approach and a medial peduncular route. Postoperatively, her oculomotor nerve paresis worsened temporarily, but diplopia disappeared 2 months after surgery. We recommend the transsylvian-transpeduncular approach if the lesion is located in the ventral midbrain and faces the ventral surface of the brainstem, because of the effective access with minimal neurological deficits.