Effect of hemodiafiltration against radical stress in the course of blood purification

The involvement of radical stress has been suggested as a cause for complications in patients on dialysis, such as arteriosclerosis, dialysis-related amyloidosis, etc. It has been reported that the increase in radical stress is not only seen in renal failure, but that its amplified effect is also seen in the process of blood purification. Our group has reported on the radical stress-reducing effect of HDF. We performed four types of blood purification (HD; on-line HDF; pre, on-line HDF; post, P/P HDF) in patients on maintenance dialysis using the polysulfone (APS) dialyzer. The change in radical related markers such as pentosidine (total, free) and CML (total, free), and the CTL/Cr ratio, and the hydroperoxide radicals were studied. In HDF (post, pre), the amplification rate of hydroperoxide radicals was significantly low, whereas the reduction rate of CTL/Cr ratio as index for hydroxy radicals was significantly higher in on-line HDF than in HD. Both the total CML and T-pentosidine increased in HD but showed a decrease in HDF. As HDF uses large amounts of replacement solution, the following effects can be expected: (a) suppression of the amplification of hydroperoxide radicals and suppression of the amplification of hydroxy radicals, and (b) suppression of fat oxidation by AGEs themselves. These antiradical stress effects are presumed to be exerted by effective removal of radical carrier protein, denatured protein, and complement protein in HDF, by dilution of radicals by massive use of replacement solution, and by the sequential reduction of the excitation and amplification effects.     

E‐cadherin interactions are required for Langerhans cell differentiation

Human skin contains the following two distinct DC subsets: (i) Langerhans cells (LCs), expressing Langerin but not DC‐specific intercellular adhesion molecule‐3‐grabbing nonintegrin (DC‐SIGN), are predominantly localized in the epidermis; and (ii) dermal DCs, expressing DC‐SIGN but not Langerin, are observed mainly in the dermis. It is not known whether localization in the epidermis provides cues for LC differentiation. Here, we show that E‐cadherin expressed by epidermal keratinocytes (KCs) is crucial for differentiation of LCs. Monocytes differentiated into LC‐like cells in presence of IL‐4, GM‐CSF, and TGF‐β1. However, these LC‐like cells expressed not only Langerin but also DC‐SIGN. Notably, co‐culturing of these LC‐like cells with KCs expressing E‐cadherin or recombinant E‐cadherin strongly decreased expression of DC‐SIGN and further induced a phenotype similar to purified epidermal LCs. Moreover, pretreatment of LC‐like cells with anti‐E‐cadherin‐specific antibody completely abolished their Langerin expression, indicating the requirement of E‐cadherin–E‐cadherin interactions for the differentiation into Langerin⁺ cells. These findings suggest that E‐cadherin expressed by KCs provide environmental cues that induce differentiation of LCs in the epidermis.     

ATP1A3 variants and slowly progressive cerebellar ataxia without paroxysmal or episodic symptoms in children

A heterogeneous spectrum of clinical manifestations caused by mutations in ATP1A3 have been previously described. Here we report two cases of infantile‐onset cerebellar ataxia, due to two different ATP1A3 variants. Both patients showed slowly progressive cerebellar ataxia without paroxysmal or episodic symptoms. Brain magnetic resonance imaging revealed mild cerebellar cortical atrophy in both patients. Whole exome sequencing revealed a de novo heterozygous variant in ATP1A3 in both patients. One patient had the c.460A>G (p.Met154Val) variant, while the other carried the c.1050C>A (p.Asp350Lys) variant. This phenotype was characterized by a slowly progressive cerebellar ataxia since the infantile period, which has not been previously described in association with ATP1A3 variants or in ATP1A3‐related clinical conditions. Our report contributes to extend the phenotypic spectrum of ATP1A3 mutations, showing paediatric slowly progressive cerebellar ataxia with mild cerebellar atrophy alone as an additional clinical presentation of ATP1A3‐related neurological disorders.     

Temporal Prediction Signals for Periodic Sensory Events in the Primate Central Thalamus

Prediction of periodic event timing is an important function for everyday activities, while the exact neural mechanism remains unclear. Previous studies in nonhuman primates have demonstrated that neurons in the cerebellar dentate nucleus and those in the caudate nucleus exhibit periodic firing modulation when the animals attempt to detect a single omission of isochronous repetitive audiovisual stimuli. To understand how these subcortical signals are sent and processed through the thalamocortical pathways, we examined single-neuron activities in the central thalamus of two macaque monkeys (one female and one male). We found that three types of neurons responded to each stimulus in the sequence in the absence of movements. Reactive-type neurons showed sensory adaptation and gradually waned the transient response to each stimulus. Predictive-type neurons steadily increased the magnitude of the suppressive response, similar to neurons previously reported in the cerebellum. Switch-type neurons initially showed a transient response, but after several cycles, the direction of firing modulation reversed and the activity decreased for each repetitive stimulus. The time course of Switch-type activity was well explained by the weighted sum of activities of the other types of neurons. Furthermore, for only Switch-type neurons the activity just before stimulus omission significantly correlated with behavioral latency, indicating that this type of neuron may carry a more advanced signal in the system detecting stimulus omission. These results suggest that the central thalamus may transmit integrated signals to the cerebral cortex for temporal information processing, which are necessary to accurately predict rhythmic event timing.SIGNIFICANCE STATEMENT Several cortical and subcortical regions are involved in temporal information processing, and the thalamus will play a role in functionally linking them. The present study aimed to clarify how the paralaminar part of the thalamus transmits and modifies signals for temporal prediction of rhythmic events. Three types of thalamic neurons exhibited periodic activity when monkeys attempted to detect a single omission of isochronous repetitive stimuli. The activity of one type of neuron correlated with the behavioral latency and appeared to be generated by integrating the signals carried by the other types of neurons. Our results revealed the neuronal signals in the thalamus for temporal prediction of sensory events, providing a clue to elucidate information processing in the thalamocortical pathways.     

Postoperative improvement of executive function and adaptive behavior in children with intractable epilepsy

IntroductionAn alteration in postoperative cognitive function varies according to the patients’ background characteristics, such as etiology, focus, and seizure duration. Accurate prediction and assessment of postoperative cognitive function is difficult in each patient. Adaptive behavior could describe the typical performance of daily activities and represents the ability to translate cognitive potential into real-world skills. We examined the relationship between alterations of executive function (EF) and adaptive behavior in school children undergoing surgery for intractable epilepsy.MethodologyWe enrolled 31 children with focal resection or corpus callosotomy for intractable epilepsy [mean age at surgery, 12.5 years; 16 boys; mean intellectual quotient, 73.3]. We surveyed answered questionnaires on attention-deficit hyperactivity disorder (ADHD), autism spectrum disorder (ASD), and adaptive behavior using the Vineland Adaptive Behavior Scale, 2nd edition (VABS-II), and performed continuous performance tests (CPTs) on children pre- and postoperatively.ResultADHD and ASD symptoms improved after epilepsy surgery. The omission error (OE) in the CPT variable improved after epilepsy surgery, especially in children with a shorter preoperative period. Improved ASD symptoms led to an increased score of the coping skills subdomain. The reduced OE observed after surgery also increased the score of the community skills subdomain.ConclusionImprovement in EF and ASD symptoms resulted in better adaptive behavior postoperatively. These results were important for the pre- and postoperative evaluation and re-evaluation of children with epilepsy requiring special education and related services.     

Intraosseous leiomyosarcoma arising in the epiphysis of the distal femur

Herein, we present a rare case of intraosseous leiomyosarcoma arising in the epiphysis of the distal femur and showing unusual radiographic features. A 44-year-old man presented with a pain in the left knee joint. Computed tomography revealed an intraosseous lesion with slightly increased attenuation and a thin marginal sclerotic rim in the femoral medial condyle. The signal of the lesion was hypointense on T1-weighted magnetic resonance (MR) images and hyperintense on fat-suppressed T2-weighted MR images. After gadolinium administration, the signal of the lesion was moderately and diffusely enhanced. The histological diagnosis of leiomyosarcoma was made based on a preoperative core biopsy specimen. Microscopic examination of the resected specimen revealed an ill-defined intraosseous tumor composed of proliferated atypical and mildly pleomorphic smooth muscle cells permeating among the bone trabeculae with only focal destruction of the bone trabeculae and low mitotic activity, indicating low grade leiomyosarcoma. The bone trabeculae at the periphery of the tumor were mildly thickened and anastomosed with a rim of an increased number of osteoblasts. Systemic examination showed no tumorous lesions in other anatomical sites. Leiomyosarcomas rarely present in the bone as a diffuse intertrabecular growth, even in low grade tumors.     

Correlation between number of renal cysts and aortic circumferences measured using autopsy material

Although the presence of renal cysts has been reported to be associated with aortic aneurysm or dissection by imaging studies, an autopsy study has not been performed. Therefore, in our institute, recent consecutive adult autopsy cases (n = 108, 64 males and 44 females) were reviewed. The circumferences and atherosclerosis ratios of both thoracic and abdominal aorta were individually measured and graded. The number of renal cysts was scored and graded. Age of subjects along with histories of smoking, hypertension, and diabetes mellitus were confirmed. Multiple linear regression analyses demonstrated that severity of atherosclerosis and the number of renal cysts were correlated with thoracic aortic circumference, while only the number of renal cysts was correlated with abdominal aortic circumference (p < 0.05), which was more predominant in female subjects (p < 0.05). Microscopically, significantly more dilated renal tubules (by Student's t-test, p < 0.05) along with decreased stainability of basement membrane by Periodic acid-Schiff staining and immunostaining of type IV collagen were noted in background renal tissues in cases with numerous renal cysts than in age- and sex-matched controls without renal cysts (n = 10 vs. 10). The present study suggests that a syndrome that affects both aorta and renal tubules may exist.