MicroRNA‐204‐5p: A novel candidate urinary biomarker of Xp11.2 translocation renal cell carcinoma

Xp11.2 translocation renal cell carcinoma (Xp11 tRCC) is a rare sporadic pediatric kidney cancer caused by constitutively active TFE3 fusion proteins. Tumors in patients with Xp11 tRCC tend to recur and undergo frequent metastasis, in part due to lack of methods available to detect early‐stage disease. Here we generated transgenic (Tg) mice overexpressing the human PRCC‐TFE3 fusion gene in renal tubular epithelial cells, as an Xp11 tRCC mouse model. At 20 weeks of age, mice showed no histological abnormalities in kidney but by 40 weeks showed Xp11 tRCC development and related morphological and histological changes. MicroRNA (miR)‐204‐5p levels in urinary exosomes of 40‐week‐old Tg mice showing tRCC were significantly elevated compared with levels in control mice. MicroRNA‐204‐5p expression also significantly increased in primary renal cell carcinoma cell lines established both from Tg mouse tumors and from tumor tissue from 2 Xp11 tRCC patients. All of these lines secreted miR‐204‐5p‐containing exosomes. Notably, we also observed increased miR‐204‐5p levels in urinary exosomes in 20‐week‐old renal PRCC‐TFE3 Tg mice prior to tRCC development, and those levels were equivalent to those in 40‐week‐old Tg mice, suggesting that miR‐204‐5p increases follow expression of constitutively active TFE3 fusion proteins in renal tubular epithelial cells prior to overt tRCC development. Finally, we confirmed that miR‐204‐5p expression significantly increases in noncancerous human kidney cells after overexpression of a PRCC‐TFE3 fusion gene. These findings suggest that miR‐204‐5p in urinary exosomes could be a useful biomarker for early diagnosis of patients with Xp11 tRCC.     

Spatiotemporal and anatomical analyses of P2X receptor-mediated neuronal and glial processing of sensory signals in the rat dorsal horn

Extracellularly released adenosine triphosphate (ATP) modulates sensory signaling in the spinal cord. We analyzed the spatiotemporal profiles of P2X receptor-mediated neuronal and glial processing of sensory signals and the distribution of P2X receptor subunits in the rat dorsal horn. Voltage imaging of spinal cord slices revealed that extracellularly applied ATP (5-500 μM), which was degraded to adenosine and acting on P1 receptors, inhibited depolarizing signals and that it also enhanced long-lasting slow depolarization, which was potentiated after ATP was washed out. This post-ATP rebound potentiation was mediated by P2X receptors and was more prominent in the deep than in the superficial layer. Patch clamp recording of neurons in the superficial layer revealed long-lasting enhancement of depolarization by ATP through P2X receptors during the slow repolarization phase at a single neuron level. This depolarization pattern was different from that in voltage imaging, which reflects both neuronal and glial activities. By immunohistochemistry, P2X₁ and P2X₃ subunits were detected in neuropils in the superficial layer. The P2X₅ subunit was found in neuronal somata. The P2X₆ subunit was widely expressed in neuropils in the whole gray matter except for the dorsal superficial layer. Astrocytes expressed the P2X₇ subunit. These findings indicate that extracellular ATP is degraded into adenosine and prevents overexcitation of the sensory system, and that ATP acts on pre- and partly on postsynaptic neuronal P2X receptors and enhances synaptic transmission, predominantly in the deep layer. Astrocytes are involved in sensitization of sensory network activity more importantly in the superficial than in the deep layer.     

ORIGINAL ARTICLE: Detection of early amnestic mild cognitive impairment without significantly objective memory impairment: a case‐controlled study

Background: We encountered eight early amnestic mild cognitive impairment (aMCI) patients (early MCI group) who did not fulfill the diagnostic criteria for aMCI. We compared the scores of neuropsychological examinations as well as the cerebral metabolic rate for glucose consumption (CMRglc) decrease on ¹⁸F‐FDG PET examination between the early MCI group and 10 aMCI patients (MCI group) or six normal elderly subjects (normal group), to examine whether the current diagnostic criteria can detect early‐stage aMCI. Methods: The three groups underwent Mini‐Mental State Examination (MMSE), Wechsler Adult Intelligence Scale – Third Edition (WAIS‐III), Wechsler Memory Scale Revised (WMS‐R), magnetic resonance imaging and 18F‐fluorodeoxyglucose positron emission tomography (¹⁸F‐FDG PET) examinations. Results: The early MCI group did not show significant memory impairment of 1.0 SD or other cognitive dysfunctions on neuropsychological examinations, and did not fulfill the diagnostic criteria of aMCI. With one‐way anova and Tukey's HSD post‐hoc test, the early MCI group showed the highest scores for WAIS‐III, whereas the MCI group showed the lowest scores for WMS‐R, although there were no significant differences between the early MCI and normal groups. In order to show a discrepancy in scores between WAIS‐III and WMS‐R, we subtracted the scores of WMS‐R from WAIS‐III. Consequently, the normal group showed significantly smaller differences in scores than the other groups, although there were no significant differences between the early MCI and MCI groups. ¹⁸F‐FDG PET recognized a CMRglc decrease in the posterior cingulate gyrus and/or part of the parietotemporal area in both the MCI and early MCI groups, of which the extent and magnitude were weaker in the early MCI group. The normal group did not show a significant CMRglc. Conclusions: The early MCI group should be included in aMCI not only based on the discrepancy between intelligence and memory scores, but also based on the ¹⁸F‐FDG PET findings. The combination of these examinations would make it possible to diagnose early‐stage aMCI.     

Up-regulation of endogenous PML induced by a combination of interferon-beta and temozolomide enhances p73/YAP-mediated apoptosis in glioblastoma

Interferon-beta (IFN-β) is reported to augment anti-tumor effects by temozolomide in glioblastoma via down-regulation of MGMT. Promyelocytic leukemia (PML), a gene induced by IFN-β, is a tumor suppressor. Here, we report for the first time that in combination therapy, an IFN-β-induced increase in endogenous PML contributes to anti-tumor effects in p53 wild- and mutant glioma cells in a xenograft mice model. The increased PML promoted the accumulation of p73, a structural and functional homolog of p53, to fuse the coactivator Yes-associated-protein in the PML nuclear bodies. The adjuvant therapy targeted at PML may be a promising therapeutic strategy for glioblastoma.     

Superoxide dismutase in psoriasis, squamous cell carcinoma and basal cell epithelioma: an immunohistochemical study

Monoclonal antibodies against human Cu,Zn-superoxide dismutase (SOD) and Mn-SOD were used to stain frozen sections of normal and abnormal human skin. In normal human epidermis, the Cu,Zn-SOD antibody almost exclusively stained the basal cells. Mn-SOD antibody weakly stained the whole of the epidermis but more predominantly the basal cell layer. In psoriasis, Cu,Zn-SOD antibody mainly stained the basal cells of the lowest parts of the elongated rete ridges. Basal cells corresponding to the tip of the dermal papillae were weakly stained. Mn-SOD staining was considerably decreased in the psoriatic epidermis. In squamous cell carcinoma, staining with both Cu,Zn-SOD and Mn-SOD antibodies was decreased, and single cells positive for Cu,Zn-SOD were scattered throughout the tumour nests. In basal cell epithelioma, Cu,Zn-SOD staining was intense and diffusely distributed throughout the tumour nests, while Mn-SOD staining was absent.     

Histochemical localisation of versican, aggrecan and hyaluronan in the developing condylar cartilage of the fetal rat mandible

We investigated the histochemical localisation of versican, aggrecan and hyaluronan in the developing condylar cartilage of the fetal rat mandible at d 15–17 of gestation. At d 15 of gestation, immunostaining for versican was detected in the anlage of the future condylar process (condylar anlage), although the staining intensity showed a considerable regional variation. At d 16 of gestation, a metachromatically stained matrix firstly appeared in the condylar anlage. Aggrecan, hyaluronan and versican were simultaneously detected in this newly formed condylar cartilage. At d 17 of gestation, immunostaining for versican became restricted to the perichondrium and was barely detected in the cartilage. Colocalisation of versican and aggrecan was also seen in the cranial base cartilage at d 14 of gestation. These results indicate that although versican is replaced by aggrecan during the transition from prechondrogenic tissue to cartilage, both molecules were temporally colocalised in the newly formed cartilage. A hyaluronan-rich, low-versican area was identified in the posterior end of the condylar anlage during d 15–17 of gestation. The existence of this area is a unique structural feature of the developing condylar cartilage.     

Combined Strategy of Burr Hole Surgery and Elective Craniotomy under Intracranial Pressure Monitoring for Severe Acute Subdural Hematoma

Burr hole surgery in the emergency room can be lifesaving for patients with acute subdural hematoma (ASDH). In the first part of this study, a strategy of combined burr hole surgery, a period of intracranial pressure (ICP) monitoring, and then craniotomy was examined for safe and effective treatment of ASDH. Since 2012, 16 patients with severe ASDH with indications for burr hole surgery were admitted to Kenwakai Otemachi Hospital. From 2012 to 2016, craniotomy was performed immediately after burr hole surgery (emergency [EM] group, n = 10). From 2017, an ICP sensor was placed before burr hole surgery. After a period for correction of traumatic coagulopathy, craniotomy was performed when ICP increased (elective [EL] group, n = 6). Patient background, bleeding tendency, intraoperative blood transfusion, and outcomes were compared between the groups. In the second part of the study, ICP was measured before and after burr hole surgery in seven patients (including two of the six in the EL group) to assess the effect of this surgery. Activated partial thromboplastin time (APTT) and prothrombin time-international normalized ratio (PT-INR) were significantly prolonged after craniotomy in the EM group, but not in the EL group, and the EM group tended to require a higher intraoperative transfusion volume. The rate of good outcomes was significantly higher in the EL group, and ICP was significantly decreased after burr hole surgery. These results suggest the value of burr hole surgery followed by ICP monitoring in patients with severe ASDH. Craniotomy can be performed safely using this method, and this may contribute to improved outcomes.     

Carbamazepine-exacerbated epilepsy with multifocal shifting independent epileptiform discharges on electroencephalogram: A case report

Abstract A 7 year old girl with epilepsy and spastic quadriplegia secondary to an episode of status epilepticus at 4 months of age is reported. At the age of 6 years, she began to experience increased generalized myoclonic and tonic seizures during treatment with carbamazepine (CBZ) 200 mg/day and clonazepam 1.5 mg/day. When the CBZ was increased to 400 mg/day, the seizures increased dramatically in frequency. Following discontinuation of CBZ, the seizure frequency decreased to a level less than that prior to starting CBZ. Serial electroencephalograms displayed multifocal independent epileptiform discharges (MIED) characterized by shifting localization, which could be one of the risk factors for exacerbation by CBZ. In this case MIED may indicate widespread rather than localized cerebral dysfunction.     

A clinical case of neuro-Behçet syndrome without mucocutaneo-ocular symptoms: Relationship with brain stem encephalitis

Abstract The case of a 50 year old man with personality changes, dementia, and brain stem symptoms is presented. Magnetic resonance imaging (MRI) disclosed high signal areas mainly in the brain stem. Both a positive skin prick test and an HLA-B51 were demonstrated. These clinical findings were suggestive of neuro-Behçet syndrome, although there were no mucocutaneo-ocular symptoms characteristically associated with this disease. The relationship between neuro-Behçet syndrome and brain stem encephalitis, including a discrimination from multiple sclerosis, is discussed.