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Sound localization in the front-back dimension is reported to be challenging, with individual differences. We investigated whether auditory discrimination processing in the brain differs based on front-back sound localization ability. This study conducted an auditory oddball task using speakers in front of and behind the participants. We used event-related brain potentials to examine the deviance detection process between groups that could and could not discriminate front-back sound localization. The results indicated that mismatch negativity (MMN) occurred during the deviance detection process, and P2 amplitude differed between standard and deviant locations in both groups. However, the latency of MMN was shorter in the group that could discriminate front-back sounds than in the group that could not. Additionally, N1 amplitude increased for deviant locations compared to standard ones only in the discriminating group. In conclusion, the sensory memories matching process based on traces of previously presented stimuli (MMN, P2) occurred regardless of discrimination ability. However, the response to changes in the physical properties of sounds (MMN latency, N1 amplitude) differed depending on the ability to discriminate front-back sounds. Our findings suggest that the brain may have different processing strategies for the two directions even without subjective recognition of the front-back direction of incoming sounds., Competing Interests: Declaration of competing interest None of the authors have potential conflicts of interest to be disclosed., (Copyright © 2024. Published by Elsevier B.V.)

Background: Computer programming, the process of designing, writing, and testing executable computer code, is an essential skill in numerous fields. A description of the neural structures engaged and modified during programming skill acquisition could help improve training programs and provide clues to the neural substrates underlying the acquisition of related skills., Methods: Fourteen female university students without prior computer programing experience were examined by functional magnetic resonance imaging (fMRI) during the early and late stages of a 5-month 'Computer Processing' course. Brain regions involved in task performance and learning were identified by comparing responses to programming and control tasks during the early and late stages., Results: The accuracy of performing a programming task was significantly improved during the late stage. Various regions of the frontal, temporal, parietal, and occipital cortex as well as several subcortical structures (caudate nuclei and cerebellum) were activated during programming tasks. Brain activity in the right inferior frontal gyrus was greater during the late stage and significantly correlated with improved task performance. Although the left inferior frontal gyrus was also highly active during the programming task, there were no learning-induced changes in activity or a significant correlation between activity and improved task performances., Conclusion: Computer programming learning among novices induces functional neuroplasticity within the right inferior frontal gyrus but not the left inferior gyrus (Broca's area)., (© 2023. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Aim: Extraction of the fetal body is typically performed immediately after delivery of the head in Western obstetric care. Reports justifying immediate extraction are few. Two-step delivery entails waiting for the next uterine contraction after delivery of the head. The present study evaluates neonatal asphyxia and respiratory impairment in two-step delivery using the head-to-body delivery interval., Methods: This prospective observational study performed at a single birth clinic used the data of 262 low-risk pregnant women with two-step delivery. We measured the time interval of head-to-body delivery and correlation analysis and simple linear regression analysis between the head-to-body delivery interval and umbilical artery pH. The women were divided into two groups according to the head-to-body delivery interval: ≤60 or >60 s. The prevalence of neonatal asphyxia and neonatal respiratory impairment was compared between the groups., Results: The mean head-to-body delivery interval was 88.9 ± 71.3 s. The umbilical artery pH tended to decrease with increasing head-to-body delivery interval; however, there was almost no correlation and the decline of pH was only 0.010 for every additional minute. Low Apgar score incidence at 5 min did not differ significantly between the groups. No cases of shoulder dystocia were reported, and tachypnea at 4 h after birth occurred in 3% of the births., Conclusions: A longer head-to-body delivery interval is not associated with negative outcomes in two-step delivery. We believe that two-step delivery could have some superior outcomes compared with one-step delivery outcomes, particularly as to improving fetal circulation and preventing shoulder dystocia., (© 2020 Japan Society of Obstetrics and Gynecology.)

While regulation of gene-enhancer interaction is intensively studied, its application remains limited. Here, we reconstituted arrays of CTCF-binding sites and devised a s ynthetic t opological i nsulator with t etO for ch romatin-engineering (STITCH). By coupling STITCH with tetR linked to the KRAB domain to induce heterochromatin and disable the insulation, we developed a drug-inducible system to control gene activation by enhancers. In human induced pluripotent stem cells, STITCH inserted between MYC and the enhancer down-regulated MYC. Progressive mutagenesis of STITCH led to a preferential escalation of the gene-enhancer interaction, corroborating the strong insulation ability of STITCH. STITCH also altered epigenetic states around MYC . Time-course analysis by drug induction uncovered deposition and removal of H3K27me3 repressive marks follows and reflects, but does not precede and determine, the expression change. Finally, STITCH inserted near NEUROG2 impaired the gene activation in differentiating neural progenitor cells. Thus, STITCH should be broadly useful for functional genetic studies., Competing Interests: TT, HO, KH An inventor on the Japanese patent application (2018-154577, filed on 21 August 2018) and the PCT international patent application (PCT/JP2019/032106, filed on 16 August 2019) in respect of the STITCH/KRAB system by Keio University. OT, MY, ES, MH, KH, TT, AT No competing interests declared, (© 2020, Tsujimura et al.)

In general, anxiety or nervousness in pregnant women increases the risk of dystocia. Pregnant women are easily susceptible to anxiousness or nervousness. To support a safe and healthy birthing process, childbirth educators, other health-care professionals, and pregnant women require an in-depth understanding about the disruptive effects of anxiety or nervousness on birth progress. Anxiety and nervousness are difficult to quantify and may be influenced by culture. Therefore, reports comparing anxiety or nervousness with dystocia must include various biases. It is difficult to find this issue by medical research. Here, we discuss links between anxiety or nervousness and disturbance in the progress of birth based on the adaptive standpoint of human behavioral evolutionary biology., (© Copyright 2019 Lamaze International.)

Background: Contact domains of chromatin serve as a fundamental unit to regulate action of enhancers for target genes. Looping between a pair of CCCTC-binding factor (CTCF)-binding sites in convergent orientations underlies the formation of contact domains, while those in divergent orientations establish domain boundaries. However, every CTCF site is not necessarily engaged in loop or boundary structures, leaving functions of CTCF in varied genomic contexts still elusive. The locus containing Tfap2c and Bmp7 encompasses two contact domains separated by a region between the two genes, termed transition zone (TZ), characterized by two arrays of CTCF sites in divergent configuration. In this study, we created deletion and inversion alleles of these and other regions across the locus and investigated how they impinge on the conformation., Results: Deletion of the whole two CTCF arrays with the CRISPR/Cas9 system resulted in impairment of blocking of chromatin contacts by the TZ, as assessed by the circular chromatin conformation capture assay (4C-seq). Deletion and inversion of either of the two arrays similarly, but less pronouncedly, led to reduction in the blocking activity. Thus, the divergent configuration provides the TZ with the strong boundary activity. Uniquely, we show the TZ harbors a 50-kb region within one of the two arrays that contacts broadly with the both flanking intervals, regardless of the presence or orientation of the other CTCF array. Further, we show the boundary CTCF array has little impact on intra-domain folding; instead, locally associating CTCF sites greatly affect it., Conclusions: Our results show that the TZ not only separates the two domains, but also bears a wide interval that shows isotropic behavior of chromatin folding, indicating a potentially complex nature of actual boundaries in the genome. We also show that CTCF-binding sites inside a domain greatly contribute to the intra-domain folding of chromatin. Thus, the study reveals diverse and context-dependent roles of CTCF in organizing chromatin conformation at different levels.

Hypercalcemia and hyperparathyroidism in patients receiving maintenance hemodialysis (MHD) can cause the progression of cardiovascular diseases (CVD) and mineral bone disorders (MBD). The KDIGO recommends the dialysates with a calcium (Ca) concentration of 1.25-1.5 mmol/L for MHD treatments, but the optimal concentration remains controversial. Here, we conducted a systematic review and a meta-analysis of seven randomized controlled trials examining a total of 622 patients to investigate the optimal concentration for MHD for 6 months or longer. The dialysates with a low Ca concentration (1.125 or 1.25 mmol/L) significantly lowered the serum Ca and raised the intact parathyroid hormone levels by 0.52 mg/dL (95% confidence interval, 0.20-0.85) and 39.59 pg/mL (14.80-64.38), respectively, compared with a high Ca concentration (1.50 or 1.75 mmol/L). Three studies showed that a low concentration was preferred for lowering arterial calcifications or atherosclerosis in different arteries, but one study showed that coronary arterial calcifications increased with a low concentration. Two studies showed contradictory outcomes in terms of MBD. Our meta-analysis showed that a dialysate with a low Ca concentration lowered the serum Ca levels in patients receiving long-term MHD, but further studies are needed to determine the optimal Ca concentration in terms of CVD and MBD.

Uterine rupture, a complete disruption of uterine wall, is synonymously used of intrapartum uterine corpus injuries. However, uterine laceration, partial and minor myometrial tear, is not well characterized. A 35-year-old Japanese woman with unscarred uterus was delivered of a baby at 38 gestational weeks. Shortly after delivering the placenta, she complained of severe lower abdominal pain with shock vitals. Exploratory laparotomy revealed a partial and shallow myometrial and serosal tear with massive hemoperitoneum. Despite its shallow and minor nature of the injury, uterine laceration can cause a catastrophic massive hemoperitoneum and should be noted as a type of intrapartum uterine injury in clinical practice.

The Objectives: Continuous positive airway pressure (CPAP) by face mask is commonly performed in newborn resuscitation. We evaluated the effect of face mask CPAP on system dead space., Working Hypothesis: Face mask CPAP increases dead space., Study Design: A CPAP model study., Methodology: We estimated the volume of the inner space of the mask. We devised a face mask CPAP model, in which the outlet of the mask was covered with plastic; and three modified face mask CPAP models, in which holes were drilled near to the cushion of the covered face mask to alter the air exit. We passed a continuous flow of 21% oxygen through each model and we controlled the inner pressure to 5 cmH 2 O by adjusting the flow-relief valve. To evaluate the ventilation in the inner space of each model, we measured the oxygen concentration rise time, that is, the time needed for the oxygen concentration of each model to reach 35% after the oxygen concentration of the continuous flow was raised from 21% to 40%., Results: The volume of inner space of the face mask was 38.3 ml. Oxygen concentration rise time in the face mask CPAP model was significantly longer at various continuous flow rates and points of the inner space of the face mask compared with that of the modified face mask CPAP model., Conclusions: Our study indicates that face mask CPAP leads to an increase in dead space and a decrease in ventilation efficiency under certain circumstances. Pediatr Pulmonol. 2017;52:107-111. © 2016 Wiley Periodicals, Inc., (© 2016 Wiley Periodicals, Inc.)

The gene encoding bone morphogenetic protein-7 (Bmp7) is expressed in the developing kidney in embryos and also in the mature organ in adults. During kidney development, expression of Bmp7 is essential to determine the final number of nephrons in and proper size of the organ. The secreted BMP7 acts on the nephron progenitor cells to exert its dual functions: To maintain and expand the progenitor population and to provide them with competence to respond to differentiation cues, each relying on distinct signaling pathways. Intriguingly, in the adult organ, BMP7 has been implicated in protection against and regeneration from injury. Exogenous administration of recombinant BMP7 to animal models of kidney diseases has shown promising effects in counteracting inflammation, apoptosis and fibrosis evoked upon injury. Although the expression pattern of Bmp7 has been well described, the mechanisms by which it is regulated have remained elusive and the processes by which the secretion sites of BMP7 impinge upon its functions in kidney development and diseases have not yet been assessed. Understanding the regulatory mechanisms will pave the way towards gaining better insight into the roles of BMP7, and to achieving desired control of the gene expression as a therapeutic strategy for kidney diseases., Competing Interests: Conflict-of-interest statement: All authors declare no conflict-of-interest for this study.

BACKGROUND Laparoscopic treatments of abdominal pregnancy have been reported; however, resection of an implanted gestational sac could lead to massive bleeding and treatment failure. Hemostasis of the resected stump is critical for the success of laparoscopic treatment. CASE REPORT A 32-year-old woman presented to the emergency department with severe abdominal pain. We suspected a ruptured ectopic pregnancy and performed urgent diagnostic laparoscopy. The gestational sac was implanted in the posterior wall of the uterus near the left uterosacral ligament, and bleeding from the gestational sac was noticed. We injected 3 ml of diluted vasopressin solution (0.4 U/ml) directly into the gestational sac and into the posterior uterine wall around the gestational sac. Thereafter, we could resect the gestational product using an ultrasonically activated scalpel. Additional hemostasis in the resected stump was not required. CONCLUSIONS We believe that a local injection of a diluted vasopressin solution helps in maintaining the hemostasis after the laparoscopic resection of the implanted gestational sac in cases of abdominal pregnancy.

Neutrophils are central players in the innate immune system. They generate neutrophil extracellular traps (NETs), which protect against invading pathogens but are also associated with the development of autoimmune and/or inflammatory diseases and thrombosis. Here, we report that lactoferrin, one of the components of NETs, translocated from the cytoplasm to the plasma membrane and markedly suppressed NETs release. Furthermore, exogenous lactoferrin shrunk the chromatin fibers found in released NETs, without affecting the generation of oxygen radicals, but this failed after chemical removal of the positive charge of lactoferrin, suggesting that charge-charge interactions between lactoferrin and NETs were required for this function. In a model of immune complex-induced NET formation in vivo, intravenous lactoferrin injection markedly reduced the extent of NET formation. These observations suggest that lactoferrin serves as an intrinsic inhibitor of NETs release into the circulation. Thus, lactoferrin may represent a therapeutic lead for controlling NETs release in autoimmune and/or inflammatory diseases., (Copyright © 2016 The Authors. Published by Elsevier B.V. All rights reserved.)

Background: The Japan Resuscitation Council (JRC) updated the guidelines for neonatal cardiopulmonary resuscitation in 2010, which recommended appropriate oxygen supplementation under the assessment of oximetry, with continuous positive airway pressure (CPAP) as a consideration in the delivery room. Whether this update has resulted in an improvement of respiratory stabilization in term neonates has not been well investigated to date., Objectives: The aim of this study is to evaluate the impact of the update of the JRC Guidelines in 2010 on the frequency of respiratory support for term neonates within 24 h of life in the nursery or neonatal intensive care unit (NICU)., Methods: We conducted a retrospective, single-center study using data of term neonates born between 2008 and 2009 (defined as 'group 1', before the update of the guidelines), and between 2011 and 2012 (defined as 'group 2', after the update of the guidelines). We compared resuscitation procedures in the delivery room and respiratory support in the nursery or NICU within 24 h of life between the two groups. Respiratory support included oxygen therapy, nasal CPAP and mechanical ventilation., Results: A total of 5,036 infants were analyzed. In group 2, oxygen administration in the delivery room was significantly decreased (38.9 vs. 22.1%, p < 0.001) and face mask CPAP in the delivery room increased (1.7 vs. 11.1%, p < 0.001). The prevalence of respiratory support within 24 h of life in the nursery or NICU increased significantly in group 2 (group 1, 6.8% vs. group 2, 16.6%, p < 0.001)., Conclusions: The update of the JRC Guidelines in 2010 resulted in an increase of respiratory support for term infants within 24 h of life., (© 2016 S. Karger AG, Basel.)

Epigenetic mechanisms may underlie the progression of diabetic kidney disease. Because the kidney is a heterogeneous organ with different cell types, we investigated DNA methylation status of the kidney in a cell type-specific manner. We first identified genes specifically demethylated in the normal proximal tubules obtained from control db/m mice, and next delineated the candidate disease-modifying genes bearing aberrant DNA methylation induced by diabetes using db/db mice. Genes involved in glucose metabolism, including Sglt2, Pck1, and G6pc, were selectively hypomethylated in the proximal tubules in control mice. Hnf4a, a transcription factor regulating transporters for reabsorption, was also selectively demethylated. In diabetic mice, aberrant hypomethylation of Agt, Abcc4, Cyp4a10, Glut5, and Met and hypermethylation of Kif20b, Cldn18, and Slco1a1 were observed. Time-dependent demethylation of Agt, a marker of diabetic kidney disease, was accompanied by histone modification changes. Furthermore, inhibition of DNA methyltransferase or histone deacetylase increased Agt mRNA in cultured human proximal tubular cells. Aberrant DNA methylation and concomitant changes in histone modifications and mRNA expression in the diabetic kidney were resistant to antidiabetic treatment with pioglitazone. These results suggest that an epigenetic switch involving aberrant DNA methylation causes persistent mRNA expression of select genes that may lead to phenotype changes of the proximal tubules in diabetic kidney disease., (Copyright © 2015 by the American Society of Nephrology.)

Objective: The Japan Resuscitation Council (JRC) Guidelines 2010 for neonatal resuscitation introduced continuous positive airway pressure (CPAP) in delivery room. The present study evaluated the effect of CPAP for pulmonary air leak at term birth., Design, Setting and Patients: This retrospective single-centre study used the data of term neonates who were born without major congenital anomalies at our centre between 2008 and 2009, and between 2011 and 2012., Interventions: Resuscitation according to the JRC Guidelines 2010., Main Outcome Measures: We examined the association between the JRC Guidelines 2010, CPAP by face mask and pulmonary air leak., Results: A total of 5038 infants were analysed. The frequency of CPAP by face mask increased after the update of the JRC Guidelines in 2010 (1.7% vs 11.1%; p<0.001). Pulmonary air leak increased at early term (37 weeks: 1.0% vs 3.5%, p=0.02; 38 weeks: 0.7% vs 2.2%, p=0.02). While adjusting for confounders, the JRC Guidelines 2010 was associated with pulmonary air leak in early-term neonates (37 weeks: adjusted OR (aOR) 4.37; 95% CI 1.40 to 17.45; 38 weeks: aOR 2.80; 95% CI 1.04 to 8.91), but this association disappeared while adjusting for face mask CPAP additionally (37 weeks: aOR 1.90; 95% CI 0.47 to 8.71; 38 weeks: aOR 1.66; 95% CI 0.54 to 5.77)., Conclusions: Following the update of the JRC guidelines on neonatal resuscitation, we observed an increased use of CPAP via face mask, which was associated with a higher prevalence of pulmonary air leak in early-term neonates in our centre., (Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://group.bmj.com/group/rights-licensing/permissions.)

Photocontrollable NO donors enable precise spatiotemporal release of NO under physiological conditions. We designed and synthesized a novel dimethylnitrobenzene-type NO donor, Flu-DNB-DB, which contains a carbon-carbon double bond in place of the amide bond of previously reported Flu-DNB. Flu-DNB-DB releases NO in response to one-photon activation in the blue wavelength region, and shows a greatly increased two-photon cross-section (δu) at 720 nm (Flu-DNB: 0.12 GM, Flu-DNB-DB: 0.98 GM). We show that Flu-DNB-DB enables precisely controlled intracellular release of NO in response to 950 nm pulse laser irradiation for as little as 1s. This near-infrared-light-controllable NO source should be a valuable tool for studies on the biological roles of NO., (Copyright © 2015 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Human pluripotent cells are promising for treatment for kidney diseases, but the protocols for derivation of kidney cell types are still controversial. Kidney tissue regeneration is well confirmed in several lower vertebrates such as fish, and the repair of nephrons after tubular damages is commonly observed after renal injury. Even in adult mammal kidney, renal progenitor cell or system is reportedly presents suggesting that adult stem-like cells in kidney can be practical clinical targets for kidney diseases. However, it is still unclear if kidney stem cells or stem-like cells exist or not. In general, stemness is defined by several factors such as self-renewal capacity, multi-lineage potency and characteristic gene expression profiles. The definite use of stemness may be obstacle to understand kidney regeneration, and here we describe the recent broad findings of kidney regeneration and the cells that contribute regeneration.

Immunoglobulin (Ig) A nephropathy is a prevalent form of primary glomerulonephritis, which leads to end-stage renal failure in a significant proportion of patients. Immunotherapy, including steroid use, is widely used to induce disease remission; however, it can cause serious side effects. We herein report 3 cases of progressive IgA nephropathy and their successful treatment with a combination of aspirin and eicosapentaenoic acid (EPA) without the use of steroids. The precise mechanism responsible for the combination therapy is still unknown; however, aspirin may potentiate the production of anti-inflammatory lipid mediators derived from EPA. Further clinical trials are required to substantiate this treatment regimen.

Nitric oxide (NO) is a well-known free-radical molecule which is endogenously biosynthesised and shows various functions in mammals. To investigate NO functions, photocontrollable NO donors, compounds which release NO in response to light, are expected to be potentially useful. However, most of the conventional NO donors require harmful ultra-violet light for NO release. In this study, two dimethylnitrobenzene derivatives conjugated with coumarins were designed, synthesized and evaluated as photocontrollable NO donors. The optical properties and efficiency of photo-induced NO release were dependent upon the nature of the conjugation system. One of these compounds, Bhc-DNB (1), showed spatiotemporally well-controlled NO release in cultured cells upon exposure to light in the less-cytotoxic visible wavelength range (400-430 nm)., (Copyright © 2014 Elsevier Ltd. All rights reserved.)

Small-vessel vasculitis is a life-threatening autoimmune disease that is frequently associated with anti-neutrophil cytoplasmic antibodies (ANCAs). Conventional immunotherapy including steroids and cyclophosphamide can cause serious adverse events, limiting the efficacy and safety of treatment. Eicosapentaenoic acid (EPA), a key component of fish oil, is an omega-3 polyunsaturated fatty acid widely known to be cardioprotective and beneficial for vascular function. We report two elderly patients with systemic ANCA-associated vasculitis (AAV) in whom the administration of EPA in concert with steroids safely induced and maintained remission, without the use of additioal immunosuppressants. To explore the mechanisms by which EPA enhances the treatment of AAV, we employed SCG/Kj mice as a spontaneous murine model of AAV. Dietary enrichment with EPA significantly delayed the onset of crescentic glomerulonephritis and prolonged the overall survival. EPA-derived anti-inflammatory lipid mediators and their precursors were present in the kidney, plasma, spleen, and lungs in the EPA-treated mice. Furthermore, a decrease in ANCA production and CD4/CD8-double negative T cells, and an increase in Foxp3(+) regulatory T cells in the lymph nodes of the kidney were observed in the EPA-treated mice. These clinical and experimental observations suggest that EPA can safely support and augment conventional therapy for treating autoimmune small-vessel vasculitis.

Two-photon-excitation release of nitric oxide (NO) from our recently synthesized photolabile NO donor, Flu-DNB, was confirmed to allow fine spatial and temporal control of NO release at the subcellular level in vitro. We then evaluated in vivo applications. Femtosecond near-infrared pulse laser irradiation of predefined regions of interest in living mouse brain treated with Flu-DNB induced NO-release-dependent, transient vasodilation specifically at the irradiated site. Photoirradiation in the absence of Flu-DNB had no effect. Further, NO release from Flu-DNB by pulse laser irradiation was shown to cause chemoattraction of microglial processes to the irradiated area in living mouse brain. To our knowledge, this is the first demonstration of induction of biological responses in vitro and in vivo by means of precisely controlled, two-photon-mediated release of NO.

Patient: Female, 36 FINAL DIAGNOSIS: Pregnancy - placenta increta Symptoms: -, Medication: - Clinical Procedure: Cesarean hysterectomy Specialty: Obstetrics and Gynecology., Objective: Unusual clinical course., Background: The generally accepted treatment for placenta percreta is cesarean hysterectomy without attempts to detach the placenta. Preoperative internal iliac artery balloon occlusion (IIABO) has been widely performed to minimize blood loss during cesarean hysterectomy for an abnormal attachment of the placenta. Our case is the first reported case of common iliac artery balloon occlusion (CIABO) being more effective than IIABO for reducing blood loss during a cesarean hysterectomy in the same patient., Case Report: We performed cesarean hysterectomy with IIABO in a 36-year-old Japanese female who had placenta percreta. However, there was still a large amount of blood loss. We immediately changed the balloon from the internal iliac artery to the common iliac artery, which visibly reduced the amount of blood loss. We finally achieved cesarean hysterectomy., Conclusions: CIABO was found to be more effective than IIABO for reducing blood loss during cesarean hysterectomy. Failure of IIABO can be explained by the presence of extensive anastomoses in the pelvic vasculature.

MyoR was originally identified as a transcriptional repressor in embryonic skeletal muscle precursors, but its function in adult kidney has not been clarified. In this study, we tried to clarify the functional role of MyoR using MyoR(-/-) mice. Cisplatin induced a significantly higher degree of severe renal dysfunction, tubular injury, and mortality in MyoR(-/-) mice than in wild-type mice. The injection of cisplatin significantly increased the number of apoptotic cells in the kidney tissues of MyoR(-/-) mice, compared with that in wild-type mice. To clarify the mechanism of severe cisplatin-induced damage and apoptosis in MyoR(-/-) mice, we focused on the p53 signaling pathway and bone morphogenic protein-7 (BMP-7). Treatment with cisplatin significantly activated p53 signaling in cultured renal proximal tubular epithelial cells (RTECs) in both wild-type and MyoR(-/-) mice, but no significant difference between the groups was observed. The injection of cisplatin significantly increased the expression of BMP-7 in the kidney tissues of wild-type mice, but no increase was observed in the MyoR(-/-) mice. Treatment with cisplatin significantly increased the expression of BMP-7 in cultured RTECs from wild-type mice but not in those from MyoR(-/-) mice. Moreover, treatment with recombinant BMP-7 rescued the cisplatin-induced apoptosis in RTECs from MyoR(-/-) mice. Taken together, our results demonstrate a new protective role of MyoR in adult kidneys that acts through the regulation of BMP-7.

This study aimed to evaluate the possibility of performing radical prostatectomy (RP) alone to achieve radical cure of prostate cancer in a high-risk group. Between August 1998 and December 2008, 436 Japanese patients underwent antegrade RP following the exclusion of 139 patients. According to the D'Amico criteria, the low-, intermediate- and high-risk groups comprised 63, 122 and 112 patients, respectively. Twenty-five patients who were classified into the high-risk group based only on T2c stage, were evaluated as a separate intermediate/high-risk group. Results of the multivariate analysis revealed that of the preoperative characteristics only a biopsy Gleason score was a significant predictor in patients with and without PSA failure (P=0.017). After a median follow-up period of 60 months, the PSA failure-free rates in the low-, intermediate-, high- and intermediate/high-risk groups were 96.5, 92.2, 76.8 and 95.0%, respectively. No statistically significant difference was detected in the high- and intermediate/high-risk groups (P=0.064). Thus, patients classified into the high-risk group based on cT2 stage only, are considered to be potentially eligible for radical treatment by surgery alone, and should not be evaluated as high-risk patients.

NF-κB signaling plays an essential role in maintaining the undifferentiated state of embryonic stem (ES) cells. However, opposing roles of NF-κB have been reported in mouse and human ES cells, and the role of NF-κB in human induced pluripotent stem (iPS) cells has not yet been clarified. Here, we report the role of NF-κB signaling in maintaining the undifferentiated state of human iPS cells. Compared with differentiated cells, undifferentiated human iPS cells showed an augmentation of NF-κB activity. During differentiation induced by the removal of feeder cells and FGF2, we observed a reduction in NF-κB activity, the expression of the undifferentiation markers Oct3/4 and Nanog, and the up-regulation of the differentiated markers WT-1 and Pax-2. The specific knockdown of NF-κB signaling using p65 siRNA also reduced the expression of Oct3/4 and Nanog and up-regulated WT-1 and Pax-2 but did not change the ES-like colony formation. Our results show that the augmentation of NF-κB signaling maintains the undifferentiated state of human iPS and suggest the importance of this signaling pathway in maintenance of human iPS cells.

Cutaneous ureterostomy cannot be carried out by the retroperitoneal method in cases showing an insufficient length of the available ureter. We therefore proposed and carried out cutaneous ureterostomy transperitoneally on a ureter of minimum length using the transverse mesocolon. The right and left ureters are drawn from the retroperitoneum into the peritoneal cavity in the renal hilus area. The right ureter is then led from the root of the transverse mesocolon to the area attached to the transverse colon under the subserous part of the transverse mesocolon, and penetrates the gastrocolic ligament. The left ureter is led to the area attached to the transverse mesocolon under the subserous part of the transverse mesocolon, and penetrates the transverse mesocolon, bursa omentalis and gastrocolic ligament. Next, both the right and left ureters are drawn up to the abdominal wall and a ureterstoma is constructed. The transverse mesocolon can be used as supporting tissue for the ureter. Furthermore, this also ensures blood flow in the ureter., (© 2011 The Japanese Urological Association.)

Fish oil containing n-3 polyunsaturated fatty acids such as eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) is well known to prevent the progression of IgA nephropathy. However, the mechanism through which fish oil prevents the progression of renal injury remains uncertain. We tried to clarify the effects of EPA on tubulointerstitial injury in the kidney both in vivo and in vitro. We examined the effects of EPA, especially to focus on nuclear factor kappa B (NF-κB), using Thy-1 nephritis models. Also the mechanism of EPA was investigated using small-interfering RNA (siRNA) in lipopolysaccharide (LPS)-stimulated proximal tubular epithelial cells (PTECs). In Thy-1 nephritis models, EPA significantly inhibited tubulointerstitial injury and the infiltration of macrophages into tubulointerstitial lesions except severe glomerular injury at early stage. Compared with control animals, NF-κB activation was significantly augmented in the Thy-1 nephritic kidney. However, treatment with EPA significantly reduced NF-κB activation, down-regulated the expressions of NF-κB-dependent molecules. Also in LPS-stimulated PTECs, LPS augmented NF-κB activation and the expression of NF-κB-dependent molecules. As in the case with the Thy-1 nephritis models, treatment with EPA inhibited them, prevented the degradation of IκBα in LPS-stimulated PTECs. Pre-treatment with siRNA for IκBα abolished the inhibitory effect of EPA on LPS-induced NF-κB activation, suggesting that EPA inhibited NF-κB activation by regulating IκBα. Our results indicate that EPA prevents the early progression of tubulointerstitial injury in Thy-1 nephritis models, and the inhibitory effect of EPA on the expression of inflammatory molecules via the regulation of IκBα in cultured cells may explain this mechanism., (Copyright © 2011 Elsevier B.V. All rights reserved.)

Nitric oxide (NO) is a key molecule in blood pressure regulation, neuromodulation, and biodefense. Since it is an unstable gas under ambient conditions, various NO donors have been developed and employed for biological studies as an alternative to direct NO application. However, many of them release NO via spontaneous decomposition, so that it is difficult to control the NO release. Therefore, NO donors from which NO release can be temporally and spatially well-controlled by means of photoexcitation offer considerable advantages. Various NO donors from which NO release is activated by photoirradiation have been reported. However, the maximum absorption of these NO donors is generally limited to the UV or short-wavelength visible light range, which does not adequately penetrate living tissues. To overcome this limitation, NO donors working via two-photon excitation (TPE) were developed by Ford and Prasad, based on NO release from Fe-nitrosyl complex. We have also developed TPE-type NO donors based on our photo-controllable 2,6-dimethylnitrobenzene derivatives, and investigated their NO-releasing properties. Here, we present an overview of photocontrollable NO donors and discuss their properties in relation to biological applications.

To investigate the metastatic pathways from the primary organs to the ovaries, we examined the microscopic findings from 18 original and 18 metastatic ovarian tumors carefully. In addition, we examined the immunohistochemical findings (Victoria blue stain for vascular invasion and D2-40 expression for lymphangio invasion) of metastatic ovarian tumors carefully. There were 4 (57%) ovarian lymphangio invasion cases in the 7 gastric cancers, but there were no cases in the 6 colorectal cancers (P < 0.05). There were 4 (67%) ovarian vascular invasion cases and one (17%) liver metastasis case in the 6 colorectal cancers, while there were no ovarian vascular invasions (P < 0.05) or no liver metastases in the 7 gastric cancers. The patients with metastatic ovarian tumors originating from distant organs who were treated at the same time as the original cancers had a significantly poorer prognosis than the patients with ovarian tumors treated later (P < 0.05). The rate of lymphatic metastasis from the stomach to the ovary was significantly higher than from the colon to the ovary. In addition we hypothesized that the rate of intravascular metastasis from the colorectum to the ovary was relatively higher than from the stomach to the ovary.

Histone deacetylase (HDAC) inhibitors have recently been reported to have possible reno-protective effects in the last few years. In this study, we found that tricostatin A (TSA), an HDAC inhibitor, prevented transforming growth factor beta1 (TGF-beta1)-induced apoptosis in cultured human renal proximal tubular epithelial cells (RPTECs). TGF-beta1-induced apoptosis via the activation of both caspase-8 and caspase-9 but did not activate the Fas receptor and did not alter Bcl-2 or Bax protein expression. TSA prevented TGF-beta1-induced apoptosis and the activation of caspase-8 and caspase-9 in RPTECs but did not inhibit the TGF-beta1-induced phosphorylation of Smad3 and p38 mitogen-activated protein kinase (MAPK). However, TSA inhibited the TGF-beta1-induced phosphorylation of extracellular signal regulated kinase (ERK), and the MAPK/ERK kinase inhibitor U0126, which specifically inhibits ERK, also prevented TGF-beta1-induced apoptosis. Our results show, for the first time, that TSA inhibits TGF-beta1-induced ERK activation and overrides pro-apoptotic signals like Smad3 and p38 in human RPTECs., (Copyright (c) 2010 Elsevier B.V. All rights reserved.)

Side population (SP) cells are an enriched population of stem, and the existence of SP cells has been reported in human cancer cell lines. In this study, we performed an SP analysis using 11 human cancer cell lines and confirmed the presence of SP cells in an embryonic carcinoma cell line, NEC8. NEC8 SP cells showed characteristics of cancer stem cells, such as high growth rate, chemoresistance and high invasiveness. To further characterize the NEC8 SP cells, we used DNA microarrays. Among 38,500 genes, we identified 12 genes that were over-expressed in SP cells and 1 gene that was over-expressed in non-SP cells. Among these 13 genes, we focused on GADD45b. GADD45b was over-expressed in non-SP cells, but the inhibition of GADD45b had no effect on non-SP cells. Paradoxically, the inhibition of GADD45b significantly reduced the viability of NEC8 SP cells. The inhibition of ABCG2, which determines the SP phenotype, had no effect on the invasiveness of NEC8 SP cells, but the inhibition of GADD45b significantly reduced invasiveness. These results suggest that GADD45b, but not ABCG2, might determine the cancer stem cell-like phenotype, such as chemoresistance and the high invasiveness of NEC8 SP cells, and might be a good therapeutic target.

In this study, the region between the prostate and the rectum was examined. We reviewed, macroscopically, the clinical anatomy of the perioperative regions and excised specimens. Moreover, using fixed specimens from three cases of total pelvic exenteration, we histologically reviewed the regions between the prostate and rectum. Following bladder neck transection, the deferent duct was observed in connective tissues that continued to Denonvilliers' fascia. When the prostate was pulled ventrally, this connective tissue was identified as a sheet of membrane that traversed from the anterior prostate to the dorsal rectum. The dorsal surface of the specimen appeared to be covered with a thin membrane, and the regions that continued from this thin membrane were judged macroscopically as a stump. Between the prostate and the rectum, intricate connective tissue was present in the fixed specimen that was removed via a total pelvic exenteration. This connective tissue continued to the connective tissue surrounding the seminal vesicles and prostate. The complex connective tissue was present anatomically between the prostate and rectum. As a result of the surgical procedures, this connective tissue was identified surgically as Denonvilliers' fascia.

Histone deacetylase (HDAC) regulates gene expression by modifying chromatin structure. Although changes in the expression and activities of HDAC may affect the course of kidney disease, the role of HDAC in tubulointerstitial injury has not been explored. We therefore investigated the alterations in HDAC expression and determined the effects of HDAC inhibition on the tubulointerstitial injury induced by unilateral ureteral obstruction. The induction of HDAC1 and HDAC2, accompanied by a decrease in histone acetylation was observed in kidneys injured by ureteral obstruction. Immunohistochemical analysis revealed that HDAC1 and HDAC2 were induced in renal tubular cells. Treatment with an HDAC inhibitor, trichostatin A (TSA), attenuated macrophage infiltration and fibrotic changes in tubulointerstitial injury induced by ureteral obstruction. The induction of colony-stimulating factor-1 (CSF-1), a chemokine known to be involved in macrophage infiltration in tubulointerstitial injury, was reduced in injured kidneys from mice treated with TSA. TSA, valproate, and the knockdown of HDAC1 or HDAC2 significantly reduced CSF-1 induced by TNF-alpha in renal tubular cells. These results suggest that tubular HDAC1 and HDAC2, induced in response to injury, may contribute to the induction of CSF-1 and the initiation of macrophage infiltration and profibrotic responses. These findings suggest a potential of HDAC inhibition therapy aimed at reducing inflammation and fibrosis in tubulointerstitial injury.

Four novel nitric oxide (NO) releasers working via two-photon excitation (TPE), based on an acceptor-donor-acceptor (A-D-A) molecular design, were synthesized. Their decomposition and NO release in response to one-photon excitation, and their decomposition in response to two-photon excitation were examined. Their photoinduced decomposition characteristics are discussed., (Copyright 2009 Elsevier Ltd. All rights reserved.)

Background: Inflammation and thrombosis coexist in several disorders. Although it is recognized that leukocytes may induce a procoagulant state at sites of inflammation, the critical molecular determinants of this process remain largely unknown., Methods and Results: To examine mechanisms of inflammation-induced thrombosis, we developed a murine model of thrombotic glomerulonephritis (TGN), a known cause of acute renal failure in patients. This model, induced by lipopolysaccharide and antibody to the glomerular basement membrane, led to rapid glomerular neutrophil recruitment, thrombotic glomerular lesions with endothelial cell injury, and renal dysfunction. In mice immunodepleted of neutrophils or lacking the leukocyte-specific integrin Mac-1, neutrophil recruitment, endothelial injury, glomerular thrombosis, and acute renal failure were markedly attenuated despite the robust generation of renal cytokines. Neutrophil elastase is a likely effector of Mac-1 because its activity was reduced in Mac-1-deficient mice and the phenotype in mice deficient in Mac-1 or neutrophil elastase was similar. Platelets accumulated in glomerular capillaries within 4 hours of TGN before evidence of thrombosis. Platelet immunodepletion before TGN markedly exacerbated hematuria (hemorrhage), inflammation, and injury, whereas thrombocytopenic Mac-1-deficient mice remained resistant to disease, indicating that initial glomerular platelet deposition protects the vessel wall from neutrophil-mediated sequelae. The subsequent thrombosis relied on the interaction of Mac-1 on recruited neutrophils with glycoprotein Ibalpha on platelets as antibody-mediated disruption of this interaction attenuated TGN without affecting renal neutrophil accumulation., Conclusions: These observations establish Mac-1 on neutrophils as a critical molecular link between inflammation and thrombosis and suggest it as an attractive target for antithrombotic therapy.

Here, we demonstrated photoinduced NO generation from a 2,6-dimethylnitrobenzene-based compound (Flu-DNB) via a two-photon excitation (TPE) process. After pulse laser irradiation to a solution of Flu-DNB, oxidation products of NO were observed. This is the first account of a non-nitrosyl-chelated metal ion containing NO donor which can be controlled by the TPE technique.

Objectives: To assess the effectiveness, perioperative safety and invasiveness of the Tissue Fixation System (TFS) sling operation when used for repair of uterovaginal prolapse with uterine preservation., Methods: Operations using the TFS anchor system were performed on 25 women aged between 44 and 84 years (average 65) for grade 3 or 4 uterine prolapse with or without urinary incontinence. Details of the procedures were as follows: midurethral sling (n=2); posterior sling of the uterosacral ligaments (n=25); U-sling for lateral/central anterior vaginal wall defects (n=24). The defect of the perineal body and rectovaginal fascia were repaired in all cases., Results: All patients were followed up for a minimum of 3 months. The mean +/- standard deviation of the operating time and loss of blood were 94.2 (+/-19.3) minutes and 98.1 (+/-129.6) mL, respectively. Twelve patients (48%) were discharged on the same day of surgery and 13 patients (52%) on the following day, with a return to normal activities within 1-7 days. There were no intra- or postoperative complications. At the 3-month follow up, cure rates of symptoms due to pelvic laxity were: urinary frequency 85.7% (n=14); nocturia 66.6% (n=12); urgency 93.3% (n=15); and dragging pain 100% (n=6). There was one recurrent uterovaginal prolapse and one recurrent cystocele., Conclusion: The TFS procedure delivers satisfactory results for uterine prolapse repair with uterine preservation. The procedure is useful because of the short duration of the operation, the short term of recovery, its safety profile and minimal invasiveness. There is a significant improvement in the quality of life, especially for older women. However, long-term results are currently unknown.

Kidneys damaged by ischemia have the potential to regenerate through a mechanism involving intrarenal induction of protective factors, including bone morphogenetic protein-7 (BMP7). Epigenetic changes, such as alterations in histone modifications, have also been shown to play a role in various pathologic conditions, but their involvement in ischemic injury and regeneration remains unknown. This study investigated whether changes in histone acetylation, regulated by histone acetyltransferase and histone deacetylase (HDAC), are induced by renal ischemia and involved in the regenerative response. Ischemia/reperfusion of the mouse kidney induced a transient decrease in histone acetylation in proximal tubular cells, likely as a result of a decrease in histone acetyltransferase activity as suggested by experiments with energy-depleted renal epithelial cells in culture. During recovery after transient energy depletion in epithelial cells, the HDAC isozyme HDAC5 was selectively downregulated in parallel with the return of acetylated histone. Knockdown of HDAC5 by RNAi significantly increased histone acetylation and BMP7 expression. BMP7 induction and HDAC5 downregulation in the recovery phase were also observed in proximal tubular cells in vivo after transient ischemia. These data indicate that ischemia induces dynamic epigenetic changes involving HDAC5 downregulation, which contributes to histone re-acetylation and BMP7 induction in the recovery phase. This highlights HDAC5 as a modulator of the regenerative response after ischemia and suggests HDAC5 inhibition may be a therapeutic strategy to enhance BMP7 expression.

Background: A close correlation has been shown between tubulointerstitial (TI) injury and the outcome of renal dysfunction, and nuclear factor-kappaB (NFkappaB) has been shown to play a key role in proteinuria-induced TI injury. To explore the molecular mechanisms of the proteinuria-induced TI injury further, we have analyzed renal gene expression with DNA microarrays, with and without specific inhibition of NF-kappaB in the proximal tubules., Methods: Unilaterally nephrectomized rats loaded with bovine serum albumin (BSA) were used as a model of proteinuric renal injury. Renal NF-kappaB activation was inhibited by gene transfer of the truncated form of IkappaBalpha (inhibitor of NF-kappaB) via the injection of a recombinant adenovirus vector into the renal artery, an method established in a previous study. Total RNA was extracted from the kidney and analyzed with a DNA microarrays containing 1081 genes., Results: Renal NF-kappaB activation and TI injury in BSA-loaded proteinuric rats were inhibited by the gene transfer of the truncated form of IkappaBalpha. DNA microarray analysis revealed 45 up-regulated genes and six down-regulated genes in the proteinuric rats, and expression of 23 of these 51 genes was significantly altered by NF-kappaB inhibition. Among these 23 genes, we focused on clusterin and confirmed the results of microarray analysis by Western blotting and PCR., Conclusion: In this study, 23 genes of 51 proteinuria-related genes were regulated by NF-kappaB activation, suggesting that some of these genes may serve as target molecules for the treatment of progressive TI injury.

Functional recovery in acute renal failure is well known, and the adult kidney is generally recognized to have the capacity to regenerate and repair. Several groups have reported the contribution of bone marrow-derived cells in this process, and others have confirmed the existence of adult stem cells in the kidney, including label retaining cells, slow-cycling cells, side population cells, and rKS506 cells. However, recent data demonstrated that in vivo differentiation of bone marrow-derived cells into renal tubular cells may not occur at all, or is at most a minor component of the repair process. Moreover, it is now generally accepted that stem cells and multipotent cells contribute to the regenerative process by producing protective and regenerative factors rather than by directly differentiating to replace damaged cells. This review will focus on current understanding of kidney regeneration.

The existence of adult stem-like cells such as side population (SP) cells is reported in various kinds of animal tissues, and we recently reported that mice kidney SP cells differentiate into multilineage. However, there has thus far been no report about human kidney SP cells. In the present study, we examined the existence of SP cells in human kidney tissue by using Hoechst 33342 staining and fluorescence-activated cell sorting analysis. We used porcine kidney tissue to optimize the analysis conditions for human tissue, and found that the SP population in human kidney was 1.3%. The existence of SP cells in human kidney suggests that the cells could be good targets for clinical renal regenerative medicine.

Infusion of renal side population (SP) cells, enriched with adult stem-like cells, can ameliorate acute renal failure. We investigated the effects of an angiotensin II type 1 (AT(1)) receptor antagonist, valsartan on SP cell changes in renal injury by ureteral obstruction. Renal SP fraction was reduced by 38%, and the number of cells expressing CD45, a marker of hematopoietic system, in renal SP cells was increased in obstructed kidneys. Valsartan attenuated renal injury and the associated SP profile changes. Angiotensin AT(1) receptor blockade may exert regenerative effect by preserving adult stem-like cells such as SP cells in the kidney.

Bone morphogenic protein (BMP)-7 is expressed in the adult kidney and reverses chronic renal injury when given exogenously. Here, we report that a histone deacetylase inhibitor, trichostatin A (TSA), attenuates chronic renal injury, in part, by augmenting the expression of BMP-7 in kidney side population (SP) cells. We induced accelerated nephrotoxic serum nephritis (NTN) in C57BL/6 mice and treated them with TSA for 3 weeks. Compared with vehicle-treated NTN mice, treatment with TSA prevented the progression of proteinuria, glomerulosclerosis, interstitial fibrosis, and loss of kidney SP cells. Basal gene expression of renoprotective factors such as BMP-7, vascular endothelial growth factor, and hepatocyte growth factor was significantly higher in kidney SP cells as compared with non-SP cells. Treatment with TSA significantly upregulated the expression of BMP-7 in SP cells but not in non-SP cells. Moreover, initiation of treatment with TSA after 3 weeks of NTN (for 3 weeks, until 6 weeks) partially but significantly reversed renal dysfunction. Our results indicate an important role of SP cells in the kidney as one of the possible generator cells of BMP-7 and TSA as a stimulator of the cells in reversing chronic renal disease. Disclosure of potential conflicts of interest is found at the end of this article.