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In the endoplasmic reticulum (ER), accumulation of abnormal proteins with malformed higher-order structures activates signaling pathways (inositol-requiring enzyme 1α (IRE1α)/X-box binding protein 1 (XBP-1) pathway, protein kinase RNA-activated-like endoplasmic reticulum kinase (PERK)/CCAAT/enhancer binding protein-homologous protein (CHOP) pathway and activating transcription factor 6α (ATF6α) pathway) that result in a cellular response suppressing the production of abnormal proteins or inducing apoptosis. These responses are collectively known as the unfolded protein response (UPR). Recently, it has been suggested that the UPR induced by saturated fatty acids in hepatocytes and pancreatic β cells is involved in the development of metabolic diseases such as diabetes. The effect of palmitate, a saturated fatty acid, on the UPR has also been investigated in adipocytes, which are associated with the development of metabolic disorders, but the results were inconclusive. Therefore, as the major saturated fatty acids present in the daily diet are palmitate and stearate, we examined the effects of these saturated fatty acids on UPR in adipocytes. Here, we show that saturated fatty acids caused limited activation of the UPR in adipocytes. Exposure to stearate for several hours elevated the ratio of spliced XBP-1 mRNA, and this effect was stronger than that of palmitate. Moreover, the phosphorylation level of IRE1α, upstream of XBP-1 and expression levels of its downstream targets such as DNAJB9 and Pdia6 were elevated in 3T3-L1 adipocytes exposed to stearate. On the other hand, stearate did not affect the phosphorylation of PERK, its activation of CHOP, or the cleavage of ATF6α. Thus, in adipocytes, exposure to stearate activates the UPR via the IRE1α/XBP-1 pathway, but not the PERK/CHOP and ATF6α pathway.

Water transport in the brain is tightly controlled by blood-brain-barrier (BBB) composed of capillary endothelial cells expressing AQP1/AQP11 and glial foot processes expressing AQP4. Here we examined each AQP mRNA expression in acute hyponatremic and hypernatremic mouse models of wild type (WT) and AQP11 KO mice (KO). The expressions of AQP1, AQP4 and AQP11 mRNAs were quantified by real-time qRT-PCR analysis of whole brain RNA. Acute hyponatremia enhanced AQP4 expression without changing AQP1 expression in KO, whereas it did not change the expression of all AQPs in WT. On the other hand, acute hypernatremia increased AQP4 but decreased AQP1 expression by half in KO, whereas it decreased AQP1 and AQP11 by half without changing AQP4 expression in WT. Enhanced AQP4 expression by osmotic challenges with sodium in KO seems to be a compensation for the loss of AQP11. A stronger hypertonic stimulation with mannitol decreased all AQPs by 30-80% in WT. Since AQP4 plays an important role in the regulation of brain edema at BBB, the results suggest that AQP11 may also be involved in the osmotic regulation of the brain.

The role of exogenous microRNAs (miRNAs) in renal fibrosis is poorly understood. Here, the effect of exogenous miRNAs on renal fibrosis was investigated using a renal fibrosis mouse model generated by unilateral ureteral obstruction (UUO). miRNA microarray analysis and quantitative reverse-transcription polymerase chain reaction showed that miR−122−5p was the most downregulated (0.28-fold) miRNA in the kidneys of UUO mice. The injection of an miR−122−5p mimic promoted renal fibrosis and upregulated COL1A2 and FN1, whereas an miR−122−5p inhibitor suppressed renal fibrosis and downregulated COL1A2 and FN1. The expression levels of fibrosis-related mRNAs, which were predicted targets of miR−122−5p, were evaluated. The expression level of TGFBR2, a pro-fibrotic mRNA, was upregulated by the miR−122−5p mimic, and the expression level of FOXO3, an anti−fibrotic mRNA, was upregulated by the miR−122−5p inhibitor. The protein expressions of TGFBR2 and FOXO3 were confirmed by immunohistochemistry. Additionally, the expression levels of LC3, downstream anti-fibrotic mRNAs of FOXO3, were upregulated by the miR−122−5p inhibitor. These results suggest that miR−122−5p has critical roles in renal fibrosis.

Irritable bowel syndrome (IBS), a common gastrointestinal disorder, was reported to contribute to abdominal pain, decrease the quality of life and work productivity of affected individuals, and lead to cachexia and frailty. However, molecules that regulate irritable bowel syndrome have not been fully clarified. MicroRNAs (miRNAs) are small non-coding RNAs that inhibit the translation of target messenger RNAs. Previous studies have shown that miRNAs have critical roles in the regulation of the pathogenicity of irritable bowel syndrome. Therefore, this systematic review focused on miRNAs that regulate irritable bowel syndrome. PubMed and Web of Science were searched to retrieve reference lists of eligible articles and related reviews. Original articles and reviews that reported the utility of miRNAs as potential biomarkers or targets for specific therapies of IBS that were published in English from 2004 to 2021 were included. Among 78 identified studies, 22 eligible studies were included in this systematic review. These results suggest that miRNAs are potential biomarkers and targets of gene therapy for IBS. Further studies including clinical studies will be necessary to confirm the utility of miRNAs as biomarkers and targets for the gene therapy of IBS.

Background The relationship between uptake of amino acid tracer with positron emission tomography (PET) and glioma subtypes/gene status is still unclear. Objective To assess the relationship between uptake of [11C]methionine using PET and pathology, IDH (isocitrate dehydrogenase) mutation, 1p/19q codeletion, and TERT (telomerase reverse transcriptase) promoter status in gliomas. Methods The participants were 68 patients with newly diagnosed and untreated glioma who underwent surgical excision and preoperative [11C]methionine PET examination at Osaka City University Hospital between July 2011 and March 2018. Clinical and imaging studies were reviewed retrospectively based on the medical records at our institution. Results The mean lesion/contralateral normal brain tissue (L/N) ratio of diffuse astrocytomas was significantly lower than that of anaplastic astrocytomas (P = 0.00155), glioblastoma (P Conclusions Distinguishing glioma subtypes based on the revised 2016 World Health Organization classification of the central nervous system tumors on the basis of [11C]methionine PET alone seems to be difficult. However, [11C]methionine PET might be useful for predicting the IDH mutation status in newly diagnosed and untreated gliomas noninvasively before tumor resection.

MicroRNAs (miRNAs) are small, noncoding RNAs consisting of 21-25 bases. They are not translated into proteins but rather work to impede the functioning of their target messenger RNAs (mRNAs) by destabilizing them and disrupting their translation. Although the miRNA expression profiles in various mouse organs and tissues have been investigated, there have been no standard methods for purifying and quantifying mouse kidney and serum miRNAs. We have established an effective and reliable method for extracting and evaluating the miRNA expression in the serum and kidney of mice with age-dependent renal impairment. The method uses quantitative reverse-transcription-polymerase chain reaction (qRT-PCR), and the protocol requires six steps: (1) preparing senescence-accelerated mouse resistance 1 (SAMR1) mice and senescence-accelerated mouse prone (SAMP1) mice; (2) extracting serum samples from these mice; (3) extracting a kidney sample from each mouse; (4) extracting total RNA (including miRNA) from kidney and serum samples from each mouse; (5) the synthesis of complementary DNA (cDNA) with reverse transcription from the miRNA; (6) conducting a qRT-PCR using the cDNA obtained. This protocol was used to confirm that, compared to the controls, the expression of miRNA-7218-5p and miRNA-7219-5p was significantly changed in the kidney and serum of a mouse model of age-dependent renal impairment. This protocol also clarified the relationship between the kidney and serum of the mouse model of age-dependent renal impairment. This protocol can be used to determine miRNA expression in the kidney and serum of mice with age-dependent renal impairment.

Purpose: This study aimed whether the uptake of amino tracer positron emissiontomography (PET) can be used as an additional imaging biomarker to estimatethe prognosis of glioma.Methods: Participants comprised 56 adult patients with newly diagnosed and untreated World Health Organization (WHO) gradeⅡ-Ⅳ astrocytic glioma who underwent surgical excision and were evaluated by 11C-methionine PET prior to the surgical excision at Osaka City University Hospital from July 2011 to March 2018. Clinical and imaging studies were retrospectively reviewed based on medical records at our institution.Results: Preoperative Karnofsky Performance Status (KPS) only influenced progression-free survival (PFS) (hazard ratio [HR] 0.20; 95% confidence interval [CI] 0.10-0.41, pp=0.025; glioblastoma: HR 11.52, 95%CI 2.27-58.47, p=0.0032), preoperative KPS≥80 (HR 0.23, 95%CI 0.09-0.62, p=0.004), maximum lesion-to-contralateral normal brain tissue (LN max)≥4.03 (HR 0.24, 95%CI 0.08-0.71, p=0.01), and isocitrate dehydrogenase (IDH) status (HR 14.06, 95%CI 1.81-109.2, p=0.011) were factors influencing overall survival (OS) in multivariate Cox regression. OS was shorter in patients with LN max≥ 4.03 (29.3 months) than in patients with LN maxp=0.03). OS differed significantly between patients with IDH mutant/LN maxIDH mutant/LN max ≥4.03.Conclusions: LN max using 11C-methionine PET may be used in prognostic markers for newly identified and untreated WHO gradeⅡ-Ⅳ astrocytic glioma.

Background: Cardiovascular events are one of the most serious complications that increase the risk of mortality and morbidity in pre-dialysis and on-dialysis chronic kidney disease (CKD) patients. Activation of the renin–angiotensin–aldosterone system (RAAS) is considered to contribute to the development of cardiovascular events in these populations. Therefore, several kinds of RAAS blockers have been frequently prescribed to prevent cardiovascular events in patients with CKD; however, their effectiveness remains controversial. This systematic review focuses on whether RAAS blockers prevent cardiovascular events in patients with CKD.Method: PubMed were searched to retrieve reference lists of eligible trials and related reviews. Randomized prospective controlled trials that investigated the effects on cardiovascular events in CKD patients that were published in English from 2010 to 2020 were included.Results: Among 167 identified studies, 11 eligible studies (n = 8,322 subjects) were included in the meta-analysis. The meta-analysis showed that RAAS blockers significantly reduced cardiovascular events in on-dialysis patients with CKD [three studies; odds ratio (OR), 0.52; 95% confidence interval (CI), 0.36 to 0.74; p = 0.0003], but there was no significant difference in pre-dialysis patients with CKD because of the heterogeneity in each study (eight studies). We also investigated the effects of each kind of RAAS blocker on cardiovascular events in CKD patients. Among the RAAS blockers, mineralocorticoid receptor antagonists significantly decreased cardiovascular events in pre-dialysis or on-dialysis patients with CKD (four studies; OR, 0.60; 95%CI, 0.50 to 0.73, p < 0.0001). However, angiotensin receptor blockers did not show significant effects (four studies; OR, 0.65; 95%CI, 0.42 to 1.01; p = 0.0529). The effects of angiotensin converting enzyme inhibitors and direct renin inhibitors on cardiovascular events in patients with CKD could not be analyzed because there were too few studies.Conclusion: Mineralocorticoid receptor antagonists may decrease cardiovascular events in pre-dialysis or on-dialysis patients with CKD.

The present study evaluated outcomes after preplanned partial surgical removal of a large vestibular schwannoma (VS) followed by low-dose Gamma Knife surgery (GKS).Between January 2000 and May 2015, 47 patients with a unilateral VS (median maximum diameter 32 mm) underwent preplanned partial tumor removal at our clinic. GKS for a residual lesion was done within a median time interval of 3 months. The median prescription dose was 12 Gy. The median length of subsequent follow-up was 74 months.The actuarial tumor growth control rates without a need for additional management at 3, 5, and 15 years after GKS were 92%, 86%, and 86%, respectively. At the time of the last follow-up, the function of the ipsilateral facial nerve corresponded to House-Brackmann grade I in 92% of patients. Significant improvement of ipsilateral hearing was noted in two patients after partial tumor removal and in one after GKS. Among 16 patients who presented with ipsilateral serviceable hearing, it was preserved immediately after surgery in 81% of cases and at the time of the last follow-up in 44%. Salvage surgical treatment was required in 9% of patients.Preplanned partial surgical removal followed by low-dose GKS provides a high level of functional preservation in patients with a large VS.

Purpose: This study aimed whether the uptake of amino tracer positron emission tomography (PET) can be used as an additional imaging biomarker to estimate the prognosis of glioma.Methods: Participants comprised 56 adult patients with newly diagnosed and untreated World Health Organization (WHO) gradeⅡ-Ⅳ astrocytic glioma who underwent surgical excision and were evaluated by 11C-methionine PET prior to the surgical excision at Osaka City University Hospital from July 2011 to March 2018. Clinical and imaging studies were retrospectively reviewed based on medical records at our institution.Results: Preoperative Karnofsky Performance Status (KPS) only influenced progression-free survival (PFS) (hazard ratio [HR] 0.20; 95% confidence interval [CI] 0.10-0.41, pp=0.025; glioblastoma: HR 11.52, 95%CI 2.27-58.47, p=0.0032), preoperative KPS≥80 (HR 0.23, 95%CI 0.09-0.62, p=0.004), maximum lesion-to-contralateral normal brain tissue (LN max)≥4.03 (HR 0.24, 95%CI 0.08-0.71, p=0.01), and isocitrate dehydrogenase (IDH) status (HR 14.06, 95%CI 1.81-109.2, p=0.011) were factors influencing overall survival (OS) in multivariate Cox regression. OS was shorter in patients with LN max≥ 4.03 (29.3 months) than in patients with LN maxp=0.03). OS differed significantly between patients with IDH mutant/LN maxIDH mutant/LN max ≥4.03.Conclusions: LN max using 11C-methionine PET may be used in prognostic markers for newly identified and untreated WHO gradeⅡ-Ⅳ astrocytic glioma.

Protein expression in human umbilical vein endothelial cells (HUVECs) is a useful indicator of maternal condition and the intrauterine environment during pregnancy. Therefore, we investigated protein expression in HUVECs obtained from patients with gestational diabetes mellitus (GDM). HUVECs were prepared from the umbilical cords of GDM patients and controls who underwent planned cesarean section between 2013 and 2014 at Teikyo University Hospital (Tokyo, Japan). There were no differences in blood glucose levels between the GDM patients and controls at admission. However, pre-pregnancy body mass index (BMI) was higher in GDM patients, although the changes in gestational BMI were smaller during hospitalization. To evaluate the state of the endothelium, we examined the protein expression levels of vascular adhesion molecule-1 (VCAM-1), intercellular adhesion molecule-1, thrombomodulin (TM), endothelial nitric oxide synthase, plasminogen activator inhibitor-1 (PAI-1), cyclooxygenase-2 (COX-2), and VE-cadherin, which are altered by various factors in endothelial tissue. VCAM-1, PAI-1, and COX-2 expression was higher in HUVECs from patients with GDM than the controls. Because the pre-pregnancy BMI was higher in GDM patients, we examined the relationship between BMI and protein expression. However, the expression levels of these proteins were not correlated with pre-pregnancy BMI and were higher in HUVECs from BMI-matched GDM patients than from BMI-matched controls. Intriguingly, TM expression was also higher in HUVECs from BMI-matched GDM patients. Thus, expression of VCAM-1, PAI-1, COX-2, and TM may reflect certain factors in the intrauterine environment that are altered in hospitalized GDM patients with controlled body weight.

Protein-tyrosine kinases transmit signals by phosphorylating their substrates in diverse cellular events. The receptor-type tyrosine kinase ErbB4, a member of the epidermal growth factor receptor subfamily, is activated and proteolytically cleaved upon ligand stimulation, and the cleaved ErbB4 intracellular domain (4ICD) is released into the cytoplasm and the nucleus. We previously showed that generation of nuclear 4ICD by neuregulin-1 (NRG-1) stimulation enhances the levels of trimethylation of histone H3 at lysine 9 (H3K9me3). However, it remains unclear how nuclear 4ICD enhances H3K9me3 levels. Here we show that the histone H3K9 methyltransferase SUV39H1 associates with NRG-1/ErbB4-mediated H3K9me3. Knockdown of SUV39H1 blocked NRG-1-mediated enhancement of the levels of H3K9me3. Nuclear 4ICD was found to phosphorylate SUV39H1 primarily at Tyr-297, -303, and −308 that are conserved among humans, mice, and flies. Furthermore, knockdown-rescue experiments showed that the unphosphorylatable SUV39H1 mutant (3 YF) was incapable of enhancing the levels of H3K9me3 upon NRG-1 stimulation. These results suggest that nuclear ErbB4 enhances H3K9me3 levels through tyrosine phosphorylation of SUV39H1 in NRG-1/ErbB4 signal-mediated chromatin remodeling.

Background and Aims As the brain edema influences the outcomes of many edematous brain diseases due to the limited intracranial space, the role of aquaporins (AQPs) in brain edema needs to be clarified to advance its treatment especially in increasing ischemic brain diseases. Although the importance of AQP4 at the Blood Brain Barrier (BBB) has been well characterized, the roles of other AQPs is still unknown, especially a relatively new AQP11. As AQP11 is expressed in the brain capillary (Koike S et al. Int J Mol Sci. 17:861, 2016), AQP11 may also be important for the regulation of brain edema. The aim of the present study is to clarify the role of AQP11 in cerebral ischemic model to identify new treatment of cerebral edema. Method AQP expression in the brain was examined by RT-PCR. Common cervical artery was ligated for 15 min to produce ischemic-reperfusion model of brain infarction to induce brain edema. As the first step to study the involvement of AQPs in this process, the mRNA expression of AQP1, AQP4, AQP11 and GFAP were monitored after reperfusion which are expressed at BBB. As mannitol is often employed for the treatment of brain edema, the effects of single or twice doses of 1.1M mannitol 0.1 mL/g body weight i.p. on the expression of AQP1, AQP4 and AQP11 mRNA were examined after 6 h in control mice. Furthermore, hypertonic 2M NaCl was also challenged to simulate the osmotic effect: a single or twice doses of 2M NaCl 0.16 mL/g body weight were administered intraperitoneally, i.p. Results The expression of AQP1 mRNA increased by 20% one and two hours after 15-min ligation, while the expression of AQP4 mRNA decreased transiently just after the ligation but increased at 24 h by 10%. On the other hand, the expression of AQP11 mRNA started to decrease from 30 min after the ligation to continue decreasing up to 24h by 40% in wild mice, while the decrease of AQP11 mRNA only observed at 24h by 20% in AQP11 heterogenous KO mice. A single mannitol i.p. did not change serum osmolality from 320 to 317 mOsm, while twice i.p. in 6 h interval increased serum osmolality to 328 mOsm. Both procedures similarly decreased the expression of all AQPs: AQP1 by 80%, AQP4 by 40%, and AQP11 by 50%. Similar studies were conducted with 2M NaCl. A single dose of 2M NaCl increased serum Na/Osm from 151/319 to 154/322 mEq/mOsm, which decreased AQP1 by 50%, AQP11 by 35% and no change of AQP4. On the other hand, twice doses in 3 h interval increased serum Na/Osm to 208/435 mEq/Osm, which did not change all AQP expressions. Conclusion As AQP4 KO mice survive longer in brain edema models, decrease of AQP4 by mannitol will be beneficial as brain infarction increased AQP4 expression in our study. However, further decrease of AQP11 by mannitol will be detrimental as AQP11 was already decreased in brain infarction. As AQP11 KO mice die within a month due to polycystic kidneys, the studies on brain infarction in brain capillary specific AQP11 conditionaly KO mice are currently underway.

Objective: The present study evaluated outcomes after preplanned partial surgical removal of a large vestibular schwannoma (VS) followed by low-dose Gamma Knife surgery (GKS).

The relationship between uptake of amino acid tracer with positron emission tomography (PET) and glioma subtypes/gene status is still unclear.To assess the relationship between uptake of [The participants were 68 patients with newly diagnosed and untreated glioma who underwent surgical excision and preoperative [The mean lesion/contralateral normal brain tissue (L/N) ratio of diffuse astrocytomas was significantly lower than that of anaplastic astrocytomas (P = 0.00155), glioblastoma (P0.001), and oligodendrogliomas (P = 0.0157). The mean L/N ratio of IDH mutant gliomas was significantly lower than that of IDH wild-type gliomas (median 1.75 vs. 2.61; P = 0.00162). A mean L/N ratio of 2.05 provided the best sensitivity and specificity for distinguishing between IDH mutant and IDH wild-type gliomas (69.2% and 76.2%, respectively). The mean L/N ratio of TERT promoter mutant gliomas was significantly higher than that of TERT promoter wild-type gliomas (P = 0.0147). Multiple regression analysis showed that pathologic diagnosis was the only influential factor on L/N ratio.Distinguishing glioma subtypes based on the revised 2016 World Health Organization classification of the central nervous system tumors on the basis of [

Diabetic nephropathy is one of the major complications of diabetes mellitus and is the leading cause of end-stage renal disease worldwide. Podocyte injury contributes to the development of diabetic nephropathy. However, the molecules that regulate podocyte injury in diabetic nephropathy have not been fully clarified. MicroRNAs (miRNAs) are small non-coding RNAs that can inhibit the translation of target messenger RNAs. Previous reports have described alteration of the expression levels of many miRNAs in cultured podocyte cells stimulated with a high glucose concentration and podocytes in rodent models of diabetic nephropathy. The associations between podocyte injury and miRNA expression levels in blood, urine, and kidney in patients with diabetic nephropathy have also been reported. Moreover, modulation of the expression of several miRNAs has been shown to have protective effects against podocyte injury in diabetic nephropathy in cultured podocyte cells in vitro and in rodent models of diabetic nephropathy in vivo. Therefore, this review focuses on miRNAs in podocyte injury in diabetic nephropathy, with regard to their potential as biomarkers and miRNA modulation as a therapeutic option.

Background and Aims Some aquaporins transport not only water but also small non-ionic molecules such as glycerol. In fact, aquaporin-9 (AQP9) has been shown to transport glycerol which is critical to support memory T cell survival through metabolic fitness (Cui G et al. Cell. 161:750, 2015). As AQP11 is widely expressed and transport glycerol as well as water, AQP11 may also play a role in immunological system, which will expand the repertoire of the aquaporin research field. Method The AQP11 expression in the thymus was examined by RT-PCR, Western blot and immunohistochemistry in mice. Phenotypic analysis and microarray analysis of the thymus were conducted in wild and AQP11 null mice at 21 day old before the development of uremia due to polycystic kidneys. Results Both mRNA and protein expressions of AQP11 in the thymus were higher than those of the kidney by RT-PCR and Western blot. Interestingly, the size of the thymus from AQP11 null mice was smaller than that of the wild mice: 28mg vs. 56mg, even after the correction by the body weight: 0.59 % vs. 0.82 %, as the body size of AQP11 null mice was smaller. The vacuolated medullary epithelial cells were observed in the thymus of AQP11 null mice with narrowed cortex. The immunohistochemical analysis revealed the AQP11 expression at the stromal-epithelial cells in the thymus. The microarray analysis of the gene expression in the thymus was compared between the wild and AQP11 null thymus by the annotation analysis based on the David Bioinformatics Resources 6.8 (beta). The up-regulated 66 genes more than 1.5 folds in AQP11 null thymus are mainly related to the PI3K/Akt signaling pathway to promote metabolism, proliferation, cell survival, growth and angiogenesis. On the other hand, the down-regulated 55 genes less than half in AQP11 null thymus are related to energy production and the peroxisome proliferator-activated receptor (PPAR) signaling pathway. Further RT-qPCR analysis confirmed the enhanced expression of Egfr (Epidermal Growth Factor Receptor), Itgb4 (Integrin beta-4) and Il2ra (interleukin 2 receptor alpha) and the diminished expression of aquaglyceroporin AQP7, Pck1 (Phosphoenolpyruvate carboxy-kinase 1) and Ucp1 (Mitochondrial uncoupling protein 1). The up-regulated genes for growth signaling was unexpected with the smaller thymus but may support the survival of the hypoplastic thymus as a compensation. On the other hand, the down-regulated genes may compromise fat-glucose-energy metabolism in the thymus leading to the smaller thymus, which may be aggravated by the decreased expression of AQP7, another glycerol channel. Conclusion AQP11 may play an important role in the metabolic control of the developing thymus possibly through its glycerol transport. The smaller thymus with narrower cortex in AQP11 null mice may lead to immunological dysfunction, which is currently under study.

Study design Clinical case series. Objective To present a surgical technique and results of posterior direct reduction of lateral atlantoaxial joints for rigid pediatric atlantoaxial subluxation (AAS) using a fulcrum lever technique. Summary of background data The surgical treatment of pediatric rigid AAS is still technically challenging. Several factors contribute to the surgical difficulty, such as small vertebrae, incomplete bone formation, dysplasia, the difficulty of reduction and external fixation are considered as a surgical daunting challenge. Herein, the surgical technique of posterior direct reduction of lateral atlantoaxial joints for rigid pediatric AAS using a fulcrum lever technique is presented. Methods This retrospective study included 10 pediatric patients with rigid AAS who underwent posterior direct reduction of bilateral C1/2 facet joints via a fulcrum lever technique. The indication for surgery was the presence of neurological symptoms and spinal cord atrophy with an intramedullary high signal at the C1 level on T2-weighted magnetic resonance (MR) images. The surgical procedure consisted of three steps: (1) opening and distraction of the C1/2 facet joints and placement of tricortical bone as a spacer and fulcrum; (2) placement of C1 and C2 screws; and finally, (3) compression between the C1 posterior arch and C2 lamina and constructing C1/2 fusion. All patients underwent the neurological and radiological evaluations before and after surgery. Results Eight of 10 patients demonstrated genetic disorders, either Down syndrome or chondrodysplasia punctate. Besides, all cases documented congenital anomaly of the odontoid process. Bilateral C1 lateral mass screws were successfully placed in all cases. No evidence of postoperative neurovascular complications. Radiological evaluation showed the corrections and bony fusions of C1/2 facet joint in all cases. Conclusion The fulcrum lever technique for rigid pediatric AAS can be one of the effective surgical solutions to this challenging pediatric spinal disorder. Level of evidence 4.

The dietary intake of elaidate (elaidic acid), a trans-fatty acid, is associated with the development of various diseases. Since elaidate is a C18 unsaturated fatty acid with a steric structure similar to that of a C18 saturated fatty acid (stearate), we previously revealed that insulin-dependent glucose uptake was impaired in adipocytes exposed to elaidate prior to and during differentiation similar to stearate. However, it is still unknown whether the mechanism of impairment of insulin-dependent glucose uptake due to elaidate is similar to that of stearate. Here, we indicate that persistent exposure to elaidate has particular effects on insulin signaling and GLUT4 dynamics. Insulin-induced accumulation of Akt at the plasma membrane (PM) and elevations of phosphorylated Akt and AS160 levels in whole cells were suppressed in adipocytes persistently exposed to 50 μM elaidate. Interestingly, persistent exposure to the same concentration of stearate has no effect on the phosphorylated Akt and AS160 levels. When cells were exposed to these fatty acids, elaidate suppressed insulin-induced fusion, but not translocation, of GLUT4 storage vesicles in the PM, whereas stearate did not suppress the fusion and translocation of GLUT4 storage, indicating that elaidate has suppressive effects on the accumulation of Akt and fusion of GLUT4 storage vesicles and that both elaidate and stearate vary in the mechanisms by which they impair insulin-dependent glucose uptake.

Aquaporins (AQPs) belong to a transmembrane protein superfamily composed of an internal repeat of a three membrane-spanning domain and each has a highly conserved NPA box. Based on the more variable carboxyl-terminal NPA box, AQPs can be divided into three subfamilies: (1) glycerol-channel aquaglyceroporin (gAQP) (2) water-selective AQP (wAQP), and (3) deviated superaquaporin (sAQP) in the order of passible evolution. This classification has functional and localization relevance: most wAQPs transports water selectively whereas gAQPs and sAQPs also transport small molecules with sAQPs mostly localized inside the cell. As this classification is not based on the function, some wAQPs functioning as glycerol channels will not be included in gAQPs. AQP ancestors may have first originated in eubacteria as gAQPs to transport small molecules such as glycerol. Later some of them may have acquired a water-selective filter to become wAQPs. Although AQPs are absent in many bacteria, especially in archaea, both gAQPs and wAQPs may have been carried over to eukaryotes or horizontally transferred. Finally, multicellular organisms have obtained new sAQPs, which are curiously absent in fungi and plants. Interestingly, both plants and higher insects independently have lost gAQPs, whose functions, however, have been taken over by functionally modified wAQPs partly obtained by horizontal gene transfers from bacteria. This evolutionary viewpoints on AQPs will facilitate further functional analysis of AQP-like sequences and expand our viewpoints on AQP superfamily.

Aquaporins (AQPs) belong to a transmembrane protein superfamily composed of an internal repeat of a three membrane-spanning domain and each has a highly conserved NPA box. Based on the more variable carboxyl-terminal NPA box, AQPs can be divided into three subfamilies: (1) glycerol-channel aquaglyceroporin (gAQP) (2) water-selective AQP (wAQP), and (3) deviated superaquaporin (sAQP) in the order of passible evolution. This classification has functional and localization relevance: most wAQPs transports water selectively whereas gAQPs and sAQPs also transport small molecules with sAQPs mostly localized inside the cell. As this classification is not based on the function, some wAQPs functioning as glycerol channels will not be included in gAQPs. AQP ancestors may have first originated in eubacteria as gAQPs to transport small molecules such as glycerol. Later some of them may have acquired a water-selective filter to become wAQPs. Although AQPs are absent in many bacteria, especially in archaea, both gAQPs and wAQPs may have been carried over to eukaryotes or horizontally transferred. Finally, multicellular organisms have obtained new sAQPs, which are curiously absent in fungi and plants. Interestingly, both plants and higher insects independently have lost gAQPs, whose functions, however, have been taken over by functionally modified wAQPs partly obtained by horizontal gene transfers from bacteria. This evolutionary viewpoints on AQPs will facilitate further functional analysis of AQP-like sequences and expand our viewpoints on AQP superfamily.

Cardiovascular disease is one of the most important risk factors for mortality and morbidity in patients with Chronic Kidney Disease (CKD). This systematic review focuses on the protective effects of diuretics against the development of cardiovascular disease in patients with CKD. Among various kinds of diuretics, spironolactone, a mineralocorticoid receptor antagonist, has been shown to have protective effects against cardiovascular disease in patients with all stages of CKD, including predialysis, hemodialysis, and peritoneal dialysis. Low-dose loop diuretics have also been shown to have cardioprotective effects in patients with CKD during the pre-dialysis and hemodialysis stages; however, high-dose loop diuretics have failed to show these cardioprotective effects. The protective effects of other classes of diuretics, including thiazide and tolvaptan, against cardiovascular diseases in patients with CKD remain unclear.

Identification of genotypes is crucial for treatment of glioma. Here, we developed a method to predict tumor genotypes using a pretrained convolutional neural network (CNN) from magnetic resonance (MR) images and compared the accuracy to that of a diagnosis based on conventional radiomic features and patient age. Multisite preoperative MR images of 164 patients with grade II/III glioma were grouped by IDH and TERT promoter (pTERT) mutations as follows: (1) IDH wild type, (2) IDH and pTERT co-mutations, (3) IDH mutant and pTERT wild type. We applied a CNN (AlexNet) to four types of MR sequence and obtained the CNN texture features to classify the groups with a linear support vector machine. The classification was also performed using conventional radiomic features and/or patient age. Using all features, we succeeded in classifying patients with an accuracy of 63.1%, which was significantly higher than the accuracy obtained from using either the radiomic features or patient age alone. In particular, prediction of the pTERT mutation was significantly improved by the CNN texture features. In conclusion, the pretrained CNN texture features capture the information of IDH and TERT genotypes in grade II/III gliomas better than the conventional radiomic features.

Background Trigeminal neuralgia is a rare feature of basilar impression, a complication of osteochondrodysplasic disorders. Microvascular decompression is difficult in medically refractory cases. Gamma knife radiosurgery (GKS) is effective for classical trigeminal neuralgia, and we first applied this GKS for a patient suffering from trigeminal neuralgia with basilar impression complicated by osteogenesis imperfecta. Case Description An 18-year-old man with type I osteogenesis imperfecta presented with a 2-year history of typical left trigeminal neuralgia affecting the ophthalmic, maxillary, and mandibular nerves. His condition was poorly controlled by carbamazepine and pregabalin. Magnetic resonance imaging confirmed severe basilar impression and an elongated cisternal portion of the left trigeminal nerve. GKS was performed under local anesthesia. The middle part of the cisternal portion of the left trigeminal nerve was chosen as the radiosurgical target, despite the lack of neurovascular compression. The maximum radiosurgical dose was 85 Gy, using a single 4-mm collimator. The patient's trigeminal neuralgia improved by 1 month after GKS, and at 21 months after GKS he remained free of pain and medications. Conclusions We report a case of trigeminal neuralgia resulting from severe basilar impression. Conventional microvascular decompression would not have been an appropriate treatment for this patient, so GKS was used. GKS is a simple and effective option even in cases with severe cranial deformity.

Autosomal Dominant Polycystic Kidney Disease (ADPKD) is caused by the mutation of polycystins (PC-1 or PC-2), in which cysts start from the collecting duct to extend to all nephron segments with eventual end stage renal failure. The cyst development is attenuated by a vasopressin V2 receptor antagonist tolvaptan which, however, will not affect proximal tubule cysts devoid of V2 receptor. Aquaporin-11 (AQP11) is expressed selectively in the proximal tubule of the kidney and AQP11-null kidneys have a disruptive PC-1 trafficking to the plasma membrane to develop polycystic kidneys. Here, we analyzed AQP11-null kidneys at the beginning of cyst formation by quantitative proteomic analysis using Tandem Mass Tag (TMT). Among ~ 1200 identified proteins, 124 proteins were differently expressed by > 1.5 or < 0.8 fold change. A pancreatic stone inhibitor or a growth factor, lithostathine-1 (Reg1) was most enhanced by 5 folds which was confirmed by western blot, while mitochondria-related proteins were downregulated. The identified proteins will be new target molecules for the treatment of proximal tubular cysts and helpful to explore the functional roles of AQP11 in the kidney., Highlights • Proteomic analysis of the kidney from AQP11-null mice of proximal tubular specific ADPKD. • Among ~ 1200 identified proteins, 124 proteins were differently expressed by > 1.5 or < 0.8 fold change. • Mitochondrial proteins were downregulated reflecting a functional mitochondrial damage in cystic epithelia. • Reg1 protein was most enhanced by 5 folds which was confirmed by western blot.