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Summary: The cochlea contains two extracellular fluids, perilymph and endolymph. Endolymph exhibits high potential of approximately +80 to +110 mV (depending on species), which sensitizes sensory hair cells. Other properties of this unique fluid remain elusive, owing to its minuscule volume in rodent cochlea. We therefore developed a technique to collect high-purity endolymph from mouse cochleae. Comprehensive proteomic analysis of sampled endolymph using liquid chromatography with mass spectrometry identified 301 proteins, dominated by molecules engaged in immunity and proteostasis. Approximately 30% of these proteins were undetectable in our perilymph. A combination of mass spectrometry and different approaches revealed that, compared to perilymph, endolymph was enriched with α2-macroglobulin, osteopontin, apolipoprotein D, apolipoprotein E, and apolipoprotein J/clusterin. In other cells or tissues, α2-macroglobulin, apolipoprotein E, and apolipoprotein J contribute to the clearance of degraded proteins from extracellular fluid. Altogether, with the proteins described here, endolymph may play a protective role in stabilizing cochlear homeostasis.

On-site monitoring of plasma drug concentrations is required for effective therapies. Recently developed handy biosensors are not yet popular owing to insufficient evaluation of accuracy on clinical samples and the necessity of complicated costly fabrication processes. Here, we approached these bottlenecks via a strategy involving engineeringly unmodified boron-doped diamond (BDD), a sustainable electrochemical material. A sensing system based on a ∼1 cm2 BDD chip, when analysing rat plasma spiked with a molecular-targeting anticancer drug, pazopanib, detected clinically relevant concentrations. The response was stable in 60 sequential measurements on the same chip. In a clinical study, data obtained with a BDD chip were consistent with liquid chromatography–mass spectrometry results. Finally, the portable system with a palm-sized sensor containing the chip analysed ∼40 μL of whole blood from dosed rats within ∼10 min. This approach with the ‘reusable’ sensor may improve point-of-monitoring systems and personalised medicine while reducing medical costs.

Summary: Mutations in the gene encoding the chromatin remodeler chromodomain helicase DNA-binding protein 8 (CHD8) are a highly penetrant risk factor for autism spectrum disorder (ASD). Although cerebellar abnormalities have long been thought to be related to ASD pathogenesis, it has remained largely unknown whether dysfunction of CHD8 in the cerebellum contributes to ASD phenotypes. We here show that cerebellar granule neuron progenitor (GNP)-specific deletion of Chd8 in mice impairs the proliferation and differentiation of these cells as well as gives rise to cerebellar hypoplasia and a motor coordination defect, but not to ASD-like behavioral abnormalities. CHD8 is found to regulate the expression of neuronal genes in GNPs. It also binds preferentially to promoter regions and modulates local chromatin accessibility of transcriptionally active genes in these cells. Our results have thus uncovered a key role for CHD8 in cerebellar development, with important implications for understanding the contribution of this brain region to ASD pathogenesis.

Schwann cells (SCs) myelinate peripheral neurons to promote the rapid conduction of action potentials, and the process of myelination is known to be regulated by signals from axons to SCs. Given that SC mitochondria are one of the potential regulators of myelination, we investigated whether SC mitochondria are regulated by axonal signaling. Here, we show a purinergic mechanism that sends information from neurons to SC mitochondria during myelination. Our results show that electrical stimulation of rat sciatic nerve increases extracellular ATP levels enough to activate purinergic receptors. Indeed, electrical stimulation of sciatic nerves induces Ca2+ increases in the cytosol and the mitochondrial matrix of surrounding SCs via purinergic receptor activation. Chronic suppression of this pathway during active myelination suppressed the longitudinal and radial development of myelinating SCs and caused hypomyelination. These results demonstrate a neuron-to-SC mitochondria signaling, which is likely to have an important role in proper myelination.

Bioremediation is a promising approach for mitigating commingled contaminations of chlorinated ethenes (CEs) and 1,4-dioxane (DX). However, aerobic bioremediation to simultaneously remove CEs and DX remains challenging. This study aimed to explore the ability of Pseudonocardia sp. D17 (D17) to aerobically degrade CEs and its applicability for concurrent removal of CEs and DX. Aerobic degradation experiments of individual CEs revealed that D17 could degrade trichloroethene (TCE), three isomers of dichloroethene (DCE), and vinyl chloride (VC), and the trend of its degradation ability was cis-1,2-DCE (cDCE) > VC > TCE > trans-1,2-DCE > 1,1-DCE. Notably, the CE-degrading activity of D17 was expressed even without any auxiliary substrates. Further, when TCE, cDCE, or VC was co-present with DX (each at 1 mg/L), D17 could degrade both compounds without any significant inhibition (for TCE and cDCE) or with only a transient and reversible suspension of its DX degradation ability (for VC). These findings indicated that D17 is a promising agent for the aerobic bioremediation of CEs and DX co-contamination and provide novel insights into the future development of efficient aerobic bioremediation strategies.

Purpose: Atovaquone is an alternative drug that is used for the prevention and treatment of Pneumocystis pneumonia when the first-line drug, sulfamethoxazole-trimethoprim (ST combination), cannot be used due to side effects. However, atovaquone is known to cause ocular side effects including oculomucocutaneous syndrome and vortex keratopathy. In this report, we describe a patient who developed bilateral white granular diffuse corneal opacity that extended from the corneal sub-epithelium to the stroma after continuous oral atovaquone administration for 14 months. Observations: The patient was a 15-year-old male with no prior ophthalmological or family medical history, but with a medical history of aplastic anemia treatment at our hospital's pediatric department. Examination showed bilateral diffuse white granular corneal opacity that extended from the sub-epithelium to the stroma, with no other abnormalities in the anterior and posterior segments of both eyes. Conclusions and importance: We encountered a rare case of bilateral corneal opacity resulting from oral atovaquone administration. Regular long-term ophthalmological examinations are necessary for patients taking atovaquone.

Purpose: Although good mid-term results of the first- and second-generation cementless stems have been reported, no study has compared outcomes between generations. This study aimed to compare the mid-term results of Accolade Ti–12Mo–6Zr–2Fe (TMZF) and Accolade II over a 5-year period. Methods: This retrospective, single-institution, single-surgeon observational study included patients who underwent primary total hip arthroplasty using the Accolade TMZF (n ​= ​71, group I) or Accolade II (n ​= ​73, group II) between January 2009 and July 2015. Revision and conversion cases were excluded. Functional evaluations were performed using the Japanese Orthopaedic Association hip (JOA) score. Radiographic evaluations were performed using anteroposterior radiographs. Spot welds, radiolucency, cortical hypertrophy, and stress shielding around the stem were assessed for each Gruen zone. Subsidence and stem alignment were evaluated. Results: The 5-year postoperative stem survival rate was 100% in both groups. The JOA score improved from 44.0 ​± ​10.2 to 90.6 ​± ​7.6 in group I and from 49.1 ​± ​10.1 to 91.7 ​± ​6.6 in group II. There were no significant differences in preoperative and postoperative JOA scores and subscale scores in either group. Significant spot welds were observed in group II in Gruen zones 3 and 5. Stress shielding progressed over time in both groups, and the prevalence of grade 3 shielding was significantly lower in group II (p ​= ​0.028). Conclusion: Both stems had a survival rate of 100%. The incidence of severe stress shielding seemed to be lower with Accolade II, but further investigations should be needed.

A 67-year-old man with abdominal pain and vomiting was referred to our hospital for the treatment of ileus. Enhanced computed tomography (CT) showed marked dilatation of the ileum and a presumed cecal tumor. After the intestinal decompression using nasogastric tube, a colonoscopy showed a type 3 tumor in the cecum. Endoscopic biopsy pathologically showed atypical cells growing in a cribriform fashion, leading to the diagnosis of cecal cancer. Staging CT showed multiple lung nodules either in a solid or a cavity-forming fashion and a presumed peritoneal disseminating lesion. Smaller lung nodules tended to show a solid pattern and larger ones a cavity-forming pattern. On diagnostic laparoscopic operation, a frozen section of the resected peritoneal lesion proved peritoneal dissemination. The patient, therefore, underwent palliative colectomy with functional anastomosis followed by thoracoscopic resection of one cavity-forming lung nodule for the accurate evaluation of the disease spread. Pathologic study showed marked tumor tip deciduation of cecal cancer and interminglement of necrotic tissue and exfoliated cancer cell clusters in the cavity of the metastatic lung tumor. Oncologists should note that ulcer-forming colon cancer can develop metastatic lung tumors in a cavity-forming fashion. Co-presence of small solid nodules and large cavity-forming ones suggests metastatic lung tumors from ulcer-forming colon cancer.

An 82-year-old man developed a hypervascular renal tumor, 2 cm in size, and multiple liver tumors. Liver tumors had obscured tumor margins on ultrasonography. Positron emission tomography/computed tomography (PET/CT) showed no areas of avid radiotracer uptake in the liver. Routine pathological examination failed to demonstrate tumor cells in 9 tissue samples obtained from repeated core needle biopsies. Even a frozen section of the liver segment 8 tumor further failed to prove malignant cells, and an additive frozen section of the liver section 2 tumor finally proved atypical cells growing in tubular and solid fashions with eosinophilic cytoplasm. Tumors showed expansive growth patterns, were in direct contact with normal liver cells, had abundant micro-vessels, had only sparse hyalinized septa, and had no pale cells. Immunostaining revealed the tumor cells to be positive for CD10, CD117, and E-cadherin and negative for CK7, and PAX8, leading to the diagnosis of metastatic chromophobe renal cell carcinoma (chRCC) in the liver. Arginase-1 immunostaining clearly demarcated the boundary between the chRCC cells and normal hepatic cells. Diagnostic physicians should note that chRCCs are of low-grade malignancy despite their abundant intra-tumoral blood flow and can often pose imaging and pathologic diagnostic difficulties.

Background: Sulcal hyperintensity on magnetic resonance images with fluid-attenuated inversion recovery sequences (FLAIR) can occur in patients without apparent cerebrospinal fluid (CSF) abnormalities. Taoka et al. speculated that pathological increases of the blood pool to CSF ratio within the sulcus, which could be caused by alterations in regional hemodynamics including venous congestion, do not suppress water signals on FLAIR images. However, few previous reports have described sulcal hyperintensity in patients with chronic subdural hematoma (CSDH). Methods: To demonstrate the pathophysiological mechanism and clinical significance of sulcal hyperintensity in CSDH, we retrospectively reviewed the chronological changes in clinical, electroencephalographic (EEG), and neuroradiological findings, including arterial spin labeling perfusion magnetic resonance imaging (ASL) with dual post-labeling delays (PLDs) of 1.5 and 2.5 s, of three patients who had sulcal hyperintensity. Results: In all three cases, sulcal hyperintensity was observed just below the CSDH with mass effect, and became more prominent as it went to the vertex. In patients 1 and 2, ASL with dual PLDs showed a prolonged arterial transit time (ATT) in the region with sulcal hyperintensity, and the sulcal hyperintensity disappeared along with the improvement of the prolonged ATT. In patient 3, in whom the degree of sulcal hyperintensity was mild, the prolongation of ATT was also very mild. In patient 2, a coinciding ictal EEG and ASL hyperperfusion findings were present in the cortex showing sulcal hyperintensity. In patients 1 and 3, the laterality of the sulcal hyperintensity was consistent with that of the epileptic symptoms, which were controlled by the administration of antiepileptic drugs. Conclusion: Although further studies with a larger number of patients are needed, the pathophysiological mechanism of sulcal hyperintensity in CSDH could be explained by the idea proposed by Taoka et al. Our findings also indicate that sulcal hyperintensity has a possible relationship with the development of epilepsy in the perioperative period of CSDH.

First of all, the background of this project is that in recent years, the birthrate in Japan has been declining and the population is aging, and more and more young people are migrating to urban areas. Therefore, we thought it was necessary to create a system using drones that would allow urban families to check on the health of elderly people in rural areas. In this time, assuming that the drone was able to follow a person, we fixed the drone in an environment similar to that situation, had the subject walk on a running machine, and processed the images from the video. In this paper, we evaluate the results.

Purpose: To report three cases of acute sterile corneal melt after cataract surgery. Observations: Case 1 was a 21-year-old male presenting with a corneal perforation of his right eye at 10 days after cataract surgery. Case 2 was a 67-year-old male who developed a corneal melt in his left eye at 15 days after cataract surgery. Case 3 was a 70-year-old female with a corneal melt of her left eye at 7 days after cataract surgery. None of the cases exhibited any signs of infection. Topical nonsteroidal anti-inflammatory drug use, dry eye, systemic autoimmune diseases, and/or a combination of these were present in patients who developed corneal melt after cataract surgery. Conclusions and Importance: Corneal melt cases can occur early after cataract surgery, thereby leading to corneal thinning and perforation. Keywords: Corneal melt, Corneal perforation, Nonsteroidal anti-inflammatory drugs, Dry eye, Autoimmune disease

Combination therapy of active vitamin D3 with some bisphosphonates (BPs) has been reported to be clinically beneficial. However, combination therapy of eldecalcitol (ELD) with BP has to date not been validated as to whether it is beneficial in the clinical setting. Preclinical studies suggested that simultaneous treatment with ELD and some BPs is more effective than monotherapy. However, the relative potency of various BPs, when used in combination with ELD, is completely unknown. In this study, we examined and compared the effects of risedronate (RIS), alendronate (ALN), and minodronate (MIN) alone or in combination with ELD on bone mass, microarchitecture, strength, and material properties in ovariectomized Sprague-Dawley rats aged 13 weeks. RIS, ALN, MIN, and ELD were administered five times weekly for 16 weeks. Micro-computed tomography analysis, compression test, and Fourier transform infrared (FTIR) imaging analysis were performed 16 weeks after treatment initiation. Trabecular and cortical bone mineral density (BMD) in the fourth lumbar vertebra (L4) significantly increased in the RIS + ELD, ALN + ELD, and MIN + ELD groups compared with the vehicle group. Moreover, the bone microarchitecture of L4 in all the BP + ELD groups also significantly improved. On mechanical testing of L4, the maximum load was significantly increased in the RIS + ELD and ALN + ELD groups. FTIR analysis revealed that the mineral-to-collagen ratio of trabecular bone in L3 of all the BP + ELD groups was significantly increased compared with the vehicle group. By contrast, the carbonate-to-phosphate ratio, a parameter of mineral immaturity, was significantly decreased in the RIS + ELD and ALN + ELD groups. BP + ELD improved the BMD and structural properties of the bone to a similar extent. RIS + ELD and ALN + ELD also improved bone strength. Furthermore, treatment with BP + ELD improved the bone material. These results suggest that the combination therapy of BP and ELD is beneficial and warrants further clinical trials.

Background: Magnetic resonance imaging (MRI), including perfusion MRI with three-dimensional pseudocontinuous arterial spin labeling (ASL) and diffusion-weighted imaging (DWI), are applied in the periictal (including ictal and postictal) detection of circulatory and metabolic consequences associated with epilepsy. Our previous report revealed that periictal hyperperfusion can firstly be detected on ASL, and cortical hyperintensity of cytotoxic edema secondarily obtained on DWI from an epileptically activated cortex. Although magnetic resonance angiography (MRA) using three-dimensional time-of-flight is widely used to evaluate arterial circulation, few MRA studies have investigated the detection of periictal hyperperfusion. Methods: To compare the ability of ASL and MRA to detect the periictal hyperperfusion on visual inspection, we retrospectively selected 23 patients who underwent ASL and MRA examination on both periictal and interictal periods. Patients were divided into the following three groups according to periictal ASL/DWI findings: positive ASL and DWI findings (n = 13, ASL+/DWI+ group), positive ASL and negative DWI findings (n = 5, ASL+/DWI- group), and negative ASL and DWI findings (n = 5, ASL-/DWI- group). Results: Periictal hyperperfusion on MRA was detected in 6 out of 13 patients (46.2%) in the ASL+/DWI+ group, but not in all patients in the ASL+/DWI- and ASL-/DWI- groups. Furthermore, in 5 out of these 6 patients, the diagnosis of periictal MRA hyperperfusion could not be made without referring to interictal MRA and/or periictal ASL findings, because the periictal MRA findings were so minute. Conclusion: The minimum requirement for the development of periictal MRA hyperperfusion is that its epileptic event is intense enough to induce the uncoupling between metabolism and circulation, with the induction of glutamate excitotoxity, and severe cytotoxic edema on DWI. ASL is vastly superior to MRA in the detection of periictal hyperperfusion.

Three-dimensional (3D) high-definition endoscopy is an innovative technical advancement that helps surgeons gain precise depth perception and spatial recognition during endoscopic surgery. Here, we describe a new dual optical channel 3D neuroendoscopic technique and its clinical application. We performed endoscopic endonasal surgery on 88 patients using 3D and two-dimensional (2D) endoscopes in conjunction. We evaluated the usefulness of stereoscopic images acquired by dual optical channel 3D endoscopy during endoscopic surgery and compared the image resolution between dual optical channel 3D endoscopy and 2D endoscopy. Additionally, we compared the stereoscopic images acquired by dual optical channel and Visionsense 3D endoscopy in three cases. Combination surgery using 3D and 2D endoscopy was found to be safe. Stereoscopic images were useful in several surgical steps, especially in recognition of complex bony structures, bone drilling, and suprasellar manipulation. The magnitude of binocular disparity was greater in dual optical channel 3D endoscopy than in Visionsense 3D endoscopy. Stereoscopic images acquired by dual optical channel 3D neuroendoscopy were of adequate quality and were useful for endoscopic endonasal surgery. In consideration of its lower image resolution compared to that of 2D high-definition endoscopy, dual optical channel 3D neuroendoscopy can be applied as an assistive technique in endoscopic endonasal surgery. The magnitude of binocular disparity is one of the key factors to be considered for evaluation of the clinical significance of 3D endoscopy.

Background: MicroRNAs are non-coding small RNAs that regulate expression of target genes by binding to 3′ untranslated regions. In this study, we used bronchial epithelial cells to investigate in vitro the role of the microRNA miR-155 in the expression of chemokines associated with airway inflammation. miR-155 has previously been reported to regulate allergic inflammation. Methods: BEAS-2B bronchial epithelial cells were cultured and transfected with mimic or inhibitor oligonucleotides to overexpress or downregulate miR-155, as confirmed by real-time PCR. Cells were then stimulated with tumor necrosis factor-alpha, interleukin-13 (IL-13), and a double stranded RNA that binds Toll-like receptor 3. Expression and secretion of the chemokines CCL5, CCL11, CCL26, CXCL8, and CXCL10 were then quantified by real-time PCR and ELISA, respectively. Phosphorylation of signal transducer and activator of transcription 6 (STAT6), a target of the IL-13 receptor, was analyzed by ELISA. Results: miR-155 overexpression significantly suppressed IL-13-induced secretion of CCL11 and CCL26. These effects were specific, and were not observed for other chemokines, nor in cells with downregulated miR-155. miR-155 overexpression also suppressed CCL11 and CCL26 mRNA, but did not affect expression of the IL-13 receptor or phosphorylation of STAT6. Conclusions: miR-155 specifically inhibits IL-13-induced expression of eosinophilic chemokines CCL11 and CCL26 in bronchial epithelial cells, even though the 3'-untranslated region of these genes do not contain a consensus binding site for miR-155.