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Radiotherapy is one of the definitive treatments for head and neck squamous cell carcinoma, especially early-stage glottic squamous cell carcinoma. Although there are several studies on the initiation weekday of cancer treatment, there are very few studies in the radiotherapy field. Thus, the present study investigated whether the initiation weekday of radiotherapy affects the local control rate for stage 1 glottic squamous cell carcinoma. A total of 105 patients with stage 1 glottic squamous cell carcinoma underwent definitive radiotherapy alone between 2007 and 2021. The group in which radiotherapy was started between Monday and Wednesday was compared with the group in which radiotherapy was started on Thursday or Friday. Sixty-seven patients started radiotherapy between Monday and Wednesday and 38 on Thursday or Friday. The 5-year local control rate was 98% (95% confidence interval: 94-100%) in the Monday-Wednesday group and 83% (95% confidence interval: 71-96%) in the Thursday-Friday group, with a significant difference (P = 0.005). On multivariate analysis including age, overall administration time (days), fractionation, irradiation field size and initiation weekday of radiotherapy, no factors other than initiation weekday affecting local control were identified. Radiotherapy toxicity did not differ between the two groups. For stage 1 glottic squamous cell carcinoma, starting radiotherapy on Thursday or Friday is associated with a lower local control rate; therefore, radiotherapy should be started by Wednesday., (© The Author(s) 2024. Published by Oxford University Press on behalf of The Japanese Radiation Research Society and Japanese Society for Radiation Oncology.)

Background/aim: In prostate cancer, robotic total prostatectomy is a popular treatment modality. However, prostate-specific antigen (PSA) recurrence after prostate cancer surgery remains a concern. Salvage radiotherapy is commonly used to treat PSA recurrence, but the recurrence rate after salvage radiotherapy is high, highlighting the need for better predictive markers. This study aimed to retrospectively evaluate the association between cribriform pattern and PSA recurrence in patients receiving radiotherapy after radical prostatectomy., Patients and Methods: Data of 50 patients who underwent radiotherapy after total prostatectomy between January 2010 and May 2020 were retrospectively evaluated. The median age was 67 years. Among these patients, two cases involved postoperative irradiation, while 48 cases involved salvage irradiation after postoperative PSA recurrence. The median time from surgery to PSA recurrence was 38.3 months. The median radiation dose was 64 Gy in 32 fractions. Three-dimensional conformal radiation therapy was administered in 38 cases and intensity-modulated radiation therapy was used in 12 cases. Combined hormone therapy was administered in 21 cases. PSA levels were measured every 3 months after treatment. Statistical analysis between groups was performed by a t-test., Results: The median follow-up period after radiotherapy was 31 months. No local recurrences were observed at the prostate bed, and no deaths related to prostate cancer were recorded during follow-up. However, 18 patients (36.0%) had PSA recurrence. The PSA recurrence rate based on the cribriform pattern was 17.6% in the none to moderate group (34 patients) and 75.0% in the severe cribriform pattern group (16 patients). The PSA recurrence rate was significantly higher in patients with a severe invasive cribriform pattern (p=0.001). No significant differences were observed in other histopathological characteristics., Conclusion: The cribriform pattern in surgical pathology specimens was found to be a useful predictor of PSA recurrence after postoperative radiotherapy., Competing Interests: The Authors declare that there are no conflicts of interest., (©2024 The Author(s). Published by the International Institute of Anticancer Research.)

To investigate the precise mechanism of xenon (Xe), pharmacologically isolated AMPA/KA and NMDA receptor-mediated spontaneous (s) and evoked (e) excitatory postsynaptic currents (s/eEPSC AMPA/KA and s/eEPSC NMDA ) were recorded from mechanically isolated single spinal sacral dorsal commissural nucleus (SDCN) neurons attached with glutamatergic nerve endings (boutons) using conventional whole-cell patch-clamp technique. We analysed kinetic properties of both s/eEPSC AMPA/KA and s/eEPSC NMDA by focal single- and/or paired-pulse electrical stimulation to compare them. The s/eEPSC NMDA showed smaller amplitude, slower rise time, and slower 1/e decay time constant (τ Decay ) than those of s/eEPSC AMPA/KA . We previously examined how Xe modulates s/eEPSC AMPA/KA , therefore, examined the effects on s/eEPSC NMDA in the present study. Xe decreased the frequency and amplitude of sEPSC NMDA , and decreased the amplitude but increased the failure rate and paired-pulse ratio of eEPSC NMDA without affecting their τ Decay . It was concluded that Xe might suppress NMDA receptor-mediated synaptic transmission via both presynaptic and postsynaptic mechanisms., (Copyright © 2024. Published by Elsevier B.V.)

Background: Recurrent esophageal cancer (EC) has a poor prognosis. However, the recurrence patterns and therapeutic outcomes after definitive chemoradiotherapy (CRT) are not fully understood. We analyzed survival and prognostic factors associated with post-definitive CRT recurrent EC., Methods: We retrospectively reviewed 71 consecutive patients with post-definitive CRT EC recurrence between 2008 and 2021 at our institution. Recurrence was locoregional, distant, and combined in 42 (59%), 18 (25%), and 11 (16%) patients, respectively. The median time from definitive CRT to recurrence was 8.3 months. Treatment modalities included local therapy, systemic therapy, and palliative care. Overall survival (OS) after recurrence was analyzed using the Kaplan-Meier and Cox proportional hazards models., Results: The median follow-up time from recurrence was 7.1 months, and the median survival time (MST) was 12.5 months. In the univariate analysis, longer time to recurrence, earlier stage at initial treatment, surgical tolerance at initial diagnosis, treatment modalities, and oligo-recurrence were associated with a better prognosis. The MST of the local therapy, systemic therapy, and palliative care groups were not reached, 11.8 months and 4.1 months, respectively (P < 0.001). In the multivariate analysis, treatment modalities and oligo-recurrence emerged as independent prognostic factors (P < 0.001 and P = 0.009)., Conclusions: Aggressive local therapy should be considered to improve the prognosis for patients with oligo-recurrence and/or indication of local therapy to treat recurrent EC., (© 2024. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

The effects of a general anesthetic xenon (Xe) on spontaneous, miniature, electrically evoked synaptic transmissions were examined using the "synapse bouton preparation," with which we can clearly evaluate pure synaptic responses and accurately quantify pre- and postsynaptic transmissions. Glycinergic and glutamatergic transmissions were investigated in rat spinal sacral dorsal commissural nucleus and hippocampal CA3 neurons, respectively. Xe presynaptically inhibited spontaneous glycinergic transmission, the effect of which was resistant to tetrodotoxin, Cd 2+ , extracellular Ca 2+ , thapsigargin (a selective sarcoplasmic/endoplasmic reticulum Ca 2+ -ATPase inhibitor), SQ22536 (an adenylate cyclase inhibitor), 8-Br-cAMP (membrane-permeable cAMP analog), ZD7288 (an hyperpolarization-activated cyclic nucleotide-gated channel blocker), chelerythrine (a PKC inhibitor), and KN-93 (a CaMKII inhibitor) while being sensitive to PKA inhibitors (H-89, KT5720, and Rp-cAMPS). Moreover, Xe inhibited evoked glycinergic transmission, which was canceled by KT5720. Like glycinergic transmission, spontaneous and evoked glutamatergic transmissions were also inhibited by Xe in a KT5720-sensitive manner. Our results suggest that Xe decreases glycinergic and glutamatergic spontaneous and evoked transmissions at the presynaptic level in a PKA-dependent manner. These presynaptic responses are independent of Ca 2+ dynamics. We conclude that PKA can be the main molecular target of Xe in the inhibitory effects on both inhibitory and excitatory neurotransmitter release. SIGNIFICANCE STATEMENT: Spontaneous and evoked glycinergic and glutamatergic transmissions were investigated using the whole-cell patch clamp technique in rat spinal sacral dorsal commissural nucleus and hippocampal CA3 neurons, respectively. Xenon (Xe) significantly inhibited glycinergic and glutamatergic transmission presynaptically. As a signaling mechanism, protein kinase A was responsible for the inhibitory effects of Xe on both glycine and glutamate release. These results may help understand how Xe modulates neurotransmitter release and exerts its excellent anesthetic properties., (Copyright © 2023 by The American Society for Pharmacology and Experimental Therapeutics.)

Background/aim: Accelerated hyperfractionation (AHF) is used in head and neck cancer to improve the local control (LC) rate, but reports of outcomes for early-stage GC are limited. The outcomes of radiotherapy (RT) for stage 1 glottic carcinoma (GC) were retrospectively analyzed, comparing AHF and once-daily fractionation (ODF) using 2.0-2.4 Gy., Patients and Methods: A total of 102 patients with stage 1 GC underwent RT alone between 2007 and 2021, with 43 in the AHF group and 59 in the ODF group. A p-value less than 0.05 was considered to indicate a significant difference., Results: The 5-year LC rate was 98% in the AHF group and 91% in the ODF group (p=0.19). During RT, significantly more patients in the AHF group required opioids due to mucositis than in the ODF group (74% vs. 25%, p<0.001), and the rate of aspiration pneumonia tended to be higher in the AHF group than in the ODF group (7% vs. 0%, p=0.072)., Conclusion: There was no difference in the LC rate between AHF and ODF for stage 1 GC. Moreover, the AHF group required opioids at a higher rate and tended to have a higher risk of developing aspiration pneumonia., (Copyright © 2023, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.)

In "synapse bouton preparation" of rat hippocampal CA3 neurons, we examined how Xe and N 2 O modulate N-methyl-D-aspartate (NMDA) receptor-mediated spontaneous and evoked excitatory post-synaptic currents (sEPSC NMDA and eEPSC NMDA ). This preparation is a mechanically isolated single neuron attached with nerve endings (boutons) preserving normal physiologic function and promoting the exact evaluation of sEPSC NMDA and eEPSC NMDA responses without influence of extrasynaptic, glial, and other neuronal tonic currents. These sEPSCs and eEPSCs are elicited by spontaneous glutamate release from many homologous glutamatergic boutons and by focal paired-pulse electric stimulation of a single bouton, respectively. The s/eEPSC AMPA/KA and s/eEPSC NMDA were isolated pharmacologically by their specific antagonists. Thus, independent contributions of pre- and postsynaptic responses could also be quantified. All kinetic properties of s/eEPSC AMPA/KA and s/eEPSC NMDA were detected clearly. The s/eEPSC NMDA showed smaller amplitude and slower rise and 1/e decay time constant ( τ Decay ) than s/eEPSC AMPA/KA Xe (70%) and N 2 O (70%) significantly decreased the frequency and amplitude without altering the τ Decay of sEPSC NMDA They also decreased the amplitude but increased the Rf and PPR without altering the τ Decay of the eEPSC NMDA These data show clearly that "synapse bouton preparation" can be an accurate model for evaluating s/eEPSC NMDA Such inhibitory effects of gas anesthetics are primarily due to presynaptic mechanisms. Present results may explain partially the powerful analgesic effects of Xe and N 2 O. SIGNIFICANCE STATEMENT: We could record pharmacologically isolated NMDA receptor-mediated spontaneous and (action potential-evoked) excitatory postsynaptic currents (sEPSC NMDA and eEPSC NMDA ) and clearly detect all kinetic parameters of sEPSC NMDA and eEPSC NMDA at synaptic levels by using "synapse bouton preparation" of rat hippocampal CA3 neurons. We found that Xe and N 2 O clearly suppressed both sEPSC NMDA and eEPSC NMDA . Different from previous studies, present results suggest that Xe and N 2 O predominantly inhibit the NMDA responses by presynaptic mechanisms., (Copyright © 2022 by The American Society for Pharmacology and Experimental Therapeutics.)

Background: Growing evidence supports the important role of persistent sodium currents (I NaP ) in the neuronal excitability of various central neurons. However, the role of tetrodotoxin-resistant (TTX-R) Na + channel-mediated I NaP in the neuronal excitability of nociceptive neurons remains poorly understood., Methods: We investigated the functional role of TTX-R I NaP in the excitability of C-type nociceptive dural afferent neurons, which was identified using a fluorescent dye, 1,1'-dioctadecyl-3,3,3',3'-tetramethylindocarbocyanine perchloride (DiI), and a whole-cell patch-clamp technique., Results: TTX-R I NaP were found in most DiI-positive neurons, but their density was proportional to neuronal size. Although the voltage dependence of TTX-R Na + channels did not differ among DiI-positive neurons, the extent of the onset of slow inactivation, recovery from inactivation, and use-dependent inhibition of these channels was highly correlated with neuronal size and, to a great extent, the density of TTX-R I NaP . In the presence of TTX, treatment with a specific I NaP inhibitor, riluzole, substantially decreased the number of action potentials generated by depolarizing current injection, suggesting that TTX-R I NaP are related to the excitability of dural afferent neurons. In animals treated chronically with inflammatory mediators, the density of TTX-R I NaP was significantly increased, and it was difficult to inactivate TTX-R Na + channels., Conclusions: TTX-R I NaP apparently contributes to the differential properties of TTX-R Na + channels and neuronal excitability. Consequently, the selective modulation of TTX-R I NaP could be, at least in part, a new approach for the treatment of migraine headaches., (© 2022. The Author(s).)

The effects of transcription factors on the maintenance and differentiation of human-induced or embryonic pluripotent stem cells (iPSCs/ESCs) have been well studied. However, the importance of posttranscriptional regulatory mechanisms, which cause the quantitative dissociation of mRNA and protein expression, has not been explored in detail. Here, by combining transcriptome and proteome profiling, we identified 228 posttranscriptionally regulated genes with strict upregulation of the protein level in iPSCs/ESCs. Among them, we found 84 genes were vital for the survival of iPSCs and HDFs, including 20 genes that were specifically necessary for iPSC survival. These 20 proteins were upregulated only in iPSCs/ESCs and not in differentiated cells derived from the three germ layers. Although there are still unknown mechanisms that downregulate protein levels in HDFs, these results reveal that posttranscriptionally regulated genes have a crucial role in iPSC survival., Competing Interests: M.I. is a scientific adviser (without salary) of xFOREST Therapeutics. H.S. is an outside director of aceRNA Technologies, Co., Ltd. K.T. is on the scientific advisory board (without salary) of I Peace, Inc. S.Y. is a scientific advisor (without salary) of iPS Academia Japan. The authors declare no competing interests., (© 2022 The Authors.)

Background: To investigate the need for ureteral reimplantation for vesicoureteral reflux (VUR) during augmentation cystoplasty (AC) in the long term., Methods: A total of 19 patients with a median age at surgery of 14 years (3-38 years) who underwent AC for neurogenic bladder with VUR between 1983 and 2016 were included in this study. The changes in VUR grade and urodynamic findings were retrospectively evaluated. We evaluated the renal function by periodic inspection of serum creatinine level and estimated glomerular filtration rate; eGFR., Results: The median follow-up period from AC was 14.8 years (5.7-30 years). VUR was detected in 19 patients, involving 27 ureters. Reflux grade was V in 6, IV in 9, III in 5, II in 6, and I in 1. Ureteral reimplantation was not performed in 18 patients (26 ureters), whereas it was done for 1 patient (1 ureter) in the early era of our experience. Postoperative videourodynamics showed that the reflux was radiologically not verifiable in 23 ureters (85%), was downgraded in 3 ureters (11%), and was unchanged in 1 ureter (3%). There were no cases of deterioration of VUR., Conclusions: Ureteral reimplantation is not necessary for VUR during augmentation cystoplasty., (© 2022. The Author(s).)

Objective: Volatile anesthetics are widely used for general anesthesia during surgical operations. Voltage-gated Na+ channels expressed in central neurons are major targets for volatile anesthetics; but it is unclear whether these drugs modulate native tetrodotoxin-resistant (TTX-R) Na+ channels, which are involved in the development and maintenance of inflammatory pain., Methods: In this study, we examined the effects of sevoflurane on TTX-R Na+ currents (INa) in acutely isolated rat dorsal root ganglion neurons, using a whole-cell patch-clamp technique., Results: Sevoflurane slightly potentiated the peak amplitude of transient TTX-R INa but more potently inhibited slow voltage-ramp-induced persistent INa in a concentration-dependent manner. Sevoflurane (0.86 ± 0.02 mM) (1) slightly shifted the steady-state fast inactivation relationship to hyperpolarizing ranges without affecting the voltage-activation relationship, (2) reduced the extent of use-dependent inhibition of Na+ channels, (3) accelerated the onset of inactivation and (4) delayed the recovery from inactivation of TTX-R Na+ channels. Thus, sevoflurane has diverse effects on TTX-R Na+ channels expressed in nociceptive neurons., Conclusions: The present results suggest that the inhibition of persistent INa and the modulation of the voltage dependence and inactivation might be, at least in part, responsible for the analgesic effects elicited by sevoflurane., (Copyright © 2021 Wolters Kluwer Health, Inc. All rights reserved.)

Introduction: Recent guidelines do not recommend routine screening of vesicoureteral reflux after a first febrile urinary tract infection in children without abnormal findings on ultrasound or atypical/recurrent urinary tract infection. Currently, there are no clear ultrasonographic parameters for detecting abnormalities in renal size, especially in young children. The aim of the present study was to determine an optimal cutoff value for detecting small kidney in children without apparent congenital anomalies except vesicoureteral reflux by retrospective chart review., Patients and Methods: Children aged ≤3 years who had undergone nuclear renal scans and ultrasound were enrolled. Small kidney was defined as split renal function of <40%. Optimal cutoff values of various ultrasonographic parameters for detecting small kidney were calculated., Results: Of the 69 children included in the present study, small kidney was identified in 20. There was a significant difference in renal size between each kidney in patients with small kidney, whereas there was no significant difference in those without small kidney. With a ratio of estimated renal area of 74.26%, maximum area under the curve with the highest sensitivity, specificity, positive predictive value, negative predictive value, and accuracy rate were obtained. In addition, simple measurement of renal length with a cutoff of 4.97 cm showed high specificity comparable with estimated renal area., Conclusion: Small kidney may be screened by two-dimensional measurement on ultrasonographic examination, even in young children. With the cutoff described, risk stratification or an individualized approach may be possible., Competing Interests: The authors declare that they have no competing interests., (© 2021 Kon et al.)

Purpose: To clarify the incidence of and risk factors for febrile urinary tract infection in children with persistent vesicoureteral reflux (VUR) after the discontinuation of continuous antibiotic prophylaxis (CAP), retrospective chart review was performed., Patients and Methods: Among children with primary VUR at 10 years of age or younger at presentation, those who had persistent VUR despite conservative management with CAP and who were subsequently followed after discontinuation of CAP were included. Kaplan-Meier curve and Cox's proportional hazard regression model were used for evaluation of the incidence of and risk factors for febrile urinary tract infection (fUTI) after stopping CAP., Results: Among 144 children (99 boys and 45 girls), fUTI developed in 34. The 5-year fUTI-free rate after discontinuation of CAP was 69.4%. On multivariate analyses, girls (p = 0.008) and abnormalities on nuclear renal scans (p = 0.0019), especially focal defect (p = 0.0471), were significant factors for fUTI. Although the fUTI-free rate was not different between children who had no or 1 risk factor, it was significantly lower in children with 2 risk factors than in those with no or 1 risk factor., Conclusions: The present study revealed that girls and abnormal renal scan, especially focal defect, are risk factors for fUTI. Active surveillance without CAP for persistent VUR seems to be a safe option for children with no or 1 risk factor. Prophylactic surgery or careful conservative follow-up may be an option for girls with abnormal renal scan results if VUR persists under CAP., (© 2021. Springer-Verlag GmbH Germany, part of Springer Nature.)

Human pluripotent stem cells (PSCs) express human endogenous retrovirus type-H (HERV-H), which exists as more than a thousand copies on the human genome and frequently produces chimeric transcripts as long-non-coding RNAs (lncRNAs) fused with downstream neighbor genes. Previous studies showed that HERV-H expression is required for the maintenance of PSC identity, and aberrant HERV-H expression attenuates neural differentiation potentials, however, little is known about the actual of function of HERV-H. In this study, we focused on ESRG, which is known as a PSC-related HERV-H-driven lncRNA. The global transcriptome data of various tissues and cell lines and quantitative expression analysis of PSCs showed that ESRG expression is much higher than other HERV-Hs and tightly silenced after differentiation. However, the loss of function by the complete excision of the entire ESRG gene body using a CRISPR/Cas9 platform revealed that ESRG is dispensable for the maintenance of the primed and naïve pluripotent states. The loss of ESRG hardly affected the global gene expression of PSCs or the differentiation potential toward trilineage. Differentiated cells derived from ESRG-deficient PSCs retained the potential to be reprogrammed into induced PSCs (iPSCs) by the forced expression of OCT3/4, SOX2, and KLF4. In conclusion, ESRG is dispensable for the maintenance and recapturing of human pluripotency., Competing Interests: I have read the journal’s policy and the authors of this manuscript have the following competing interests: K.T. is on the scientific advisory board of I Peace, Inc. without salary, S.Y. is a scientific advisor (without salary) of iPS Academia Japan, and other authors have declared that no competing interests exist.

Pluripotent stem cells are increasingly used to model different aspects of embryogenesis and organ formation 1 . Despite recent advances in in vitro induction of major mesodermal lineages and cell types 2,3 , experimental model systems that can recapitulate more complex features of human mesoderm development and patterning are largely missing. Here we used induced pluripotent stem cells for the stepwise in vitro induction of presomitic mesoderm and its derivatives to model distinct aspects of human somitogenesis. We focused initially on modelling the human segmentation clock, a major biological concept believed to underlie the rhythmic and controlled emergence of somites, which give rise to the segmental pattern of the vertebrate axial skeleton. We observed oscillatory expression of core segmentation clock genes, including HES7 and DKK1, determined the period of the human segmentation clock to be around five hours, and demonstrated the presence of dynamic travelling-wave-like gene expression in in vitro-induced human presomitic mesoderm. Furthermore, we identified and compared oscillatory genes in human and mouse presomitic mesoderm derived from pluripotent stem cells, which revealed species-specific and shared molecular components and pathways associated with the putative mouse and human segmentation clocks. Using CRISPR-Cas9-based genome editing technology, we then targeted genes for which mutations in patients with segmentation defects of the vertebrae, such as spondylocostal dysostosis, have been reported (HES7, LFNG, DLL3 and MESP2). Subsequent analysis of patient-like and patient-derived induced pluripotent stem cells revealed gene-specific alterations in oscillation, synchronization or differentiation properties. Our findings provide insights into the human segmentation clock as well as diseases associated with human axial skeletogenesis.

Left polyorchidism was found in a 2-month-old boy with a left scrotal mass. As he was asymptomatic and all testes were in the scrotum, he was conservatively followed up. At 17 years of age, he presented with left acute scrotum due to testicular torsion of the left supernumerary testis. Counterclockwise 720-degree rotation of the left supernumerary testis was noted during emergency surgery, and orchidopexy of the 3 testes (2 left testes and 1 right testis) was performed. Biopsy of the left supernumerary testis demonstrated spermatogenesis and no malignancy. One and a half years after surgery, all testes were viable without atrophy.Polyorchidism is a rare condition and there is no consensus on the management of asymptomatic cases detected early in life. The position of the supernumerary testis (intrascrotal or extrascrotal) is important when deciding the management strategy because of the risk of malignancy. If conservative management is selected initially, elective surgery, such as prophylactic orchiectomy or orchidopexy, may be needed because of the risk of malignancy and torsion.

Purpose: The factors affecting spermatogenesis in adulthood in patients with hypospadias (HS) are not clearly understood. In the present study, risk factors affecting post-pubertal high serum follicle-stimulating hormone (FSH) were evaluated in patients with HS., Materials and Methods: Among those with a history of HS surgery, patients in whom endocrinological evaluation regarding pituitary-gonadal axis was performed at 15 years of age or older between March 2004 and April 2018 were enrolled in the present study. High serum FSH was defined as greater than 10 mIU/ml. The severity of HS was divided into mild and severe. Factors affecting the post-pubertal high serum FSH were estimated., Results: Seventy-nine patients were included in the present study. The severity of HS was mild in 35 and severe in 44. History of undescended testis (UDT) was confirmed in 12. High serum FSH was detected in nine. On logistic regression model analysis, a history of UDT was the only significant factor for high serum FSH. The incidence of high serum FSH in patients with UDT was significantly higher than that in those without UDT (58.3% vs 7.5%, p < 0.01). When stratified by severity of HS and the presence of UDT, high serum FSH was detected in 70% in patients with severe HS and UDT, whereas less than 10% in other groups., Conclusions: A history of UDT was a significant factor for post-pubertal high serum FSH in patients with HS. Accordingly, the presence of UDT may be a marker for impaired spermatogenesis in patients with HS, especially in severe cases.

The functional effect of a gene edit by designer nucleases depends on the DNA repair outcome at the targeted locus. While non-homologous end joining (NHEJ) repair results in various mutations, microhomology-mediated end joining (MMEJ) creates precise deletions based on the alignment of flanking microhomologies (µHs). Recently, the sequence context surrounding nuclease-induced double strand breaks (DSBs) has been shown to predict repair outcomes, for which µH plays an important role. Here, we survey naturally occurring human deletion variants and identify that 11 million or 57% are flanked by µHs, covering 88% of protein-coding genes. These biologically relevant mutations are candidates for precise creation in a template-free manner by MMEJ repair. Using CRISPR-Cas9 in human induced pluripotent stem cells (hiPSCs), we efficiently create pathogenic deletion mutations for demonstrable disease models with both gain- and loss-of-function phenotypes. We anticipate this dataset and gene editing strategy to enable functional genetic studies and drug screening.

New, more effective pharmacologic treatments for epilepsy are needed, as a substantial portion of patients (>30%) are refractory to currently available anti-epileptic drugs. Cenobamate (YKP3089) is an investigational anti-epileptic drug in clinical development. Two completed adequate and well-controlled studies demonstrated a significant reduction in focal seizures with cenobamate in patients with epilepsy. In this study, we characterized the effects of cenobamate on voltage-gated Na + channels in acutely isolated rat hippocampal CA3 neurons using a whole-cell patch-clamp technique. While cenobamate had little effect on the peak component of transient Na + current (I NaT ) induced by brief depolarizing step pulses, it potently inhibited the non-inactivating persistent component of I Na (I NaP ). In addition, cenobamate potently inhibited the current by slow voltage-ramp stimuli. Cenobamate significantly shifted the steady-state fast inactivation relationship toward a hyperpolarizing range, indicating that cenobamate binds to voltage-gated Na + channels at the inactivated state with a higher affinity. Cenobamate also accelerated the development of inactivation and retarded recovery from inactivation of voltage-gated Na + channels. In current clamp experiments, cenobamate hyperpolarized membrane potentials in a concentration-dependent manner, and these effects were mediated by inhibiting the I NaP . Cenobamate also increased the threshold for generation of action potentials, and decreased the number of action potentials elicited by depolarizing current injection. Given that the I NaP plays a pivotal role in the repetitive and/or burst generation of action potentials, the cenobamate-mediated preferential blockade of I NaP might contribute to anti-epileptic activity., (Copyright © 2019 The Authors. Published by Elsevier B.V. All rights reserved.)

"Comfort set for palliative care"is narrowly defined as a set of drugs used to alleviate symptoms at the terminal stage. However, we think that the followingis important(1)The practice of advance care planning(ACP)is indispensable and it is done accordingto the situation after the start of the visit, but our clinic emphasizes careful consultation before the start as a means of team formation with the patient's family and the doctor.(2)Introduction of visitingmedicine management by pharmacist of dispensingpharmacy is preferable for the method of supply/inventory of drugs. 98% of cancer patients in our clinic use it. In addition, we have injection drugs, devices and emergency drugs in the clinic so that we can respond quickly.(3) Seamless collaboration with visitingnursingis necessary for understandingand implementingthe situation that medicines should be used. All cancer patients in our clinic are receivingvisitingnursingby in-clinic nurses. We mentioned the point that seems to be important points in past practice for "comfort of patient, family member and medical staff" in home palliative care.

Migraine is a neurological disorder characterized by recurrent and disabling severe headaches. Although several anticonvulsant drugs that block voltage-dependent Na + channels are widely used for migraine, far less is known about the therapeutic actions of carbamazepine on migraine. In the present study, therefore, we characterized the effects of carbamazepine on tetrodotoxin-resistant (TTX-R) Na + channels in acutely isolated rat dural afferent neurons, which were identified by the fluorescent dye DiI. The TTX-R Na + currents were measured in medium-sized DiIpositive neurons using the whole-cell patch clamp technique in the voltage-clamp mode. While carbamazepine had little effect on the peak amplitude of transient Na + currents, it strongly inhibited steady-state currents of transient as well as persistent Na + currents in a concentration-dependent manner. Carbamazepine had only minor effects on the voltage-activation relationship, the voltage-inactivation relationship, and the use-dependent inhibition of TTX-R Na + channels. However, carbamazepine changed the inactivation kinetics of TTX-R Na + channels, significantly accelerating the development of inactivation and delaying the recovery from inactivation. In the current-clamp mode, carbamazepine decreased the number of action potentials without changing the action potential threshold. Given that the sensitization of dural afferent neurons by inflammatory mediators triggers acute migraine headaches and that inflammatory mediators potentiate TTX-R Na + currents, the present results suggest that carbamazepine may be useful for the treatment of migraine headaches., Competing Interests: CONFLICTS OF INTEREST: The authors declare no conflicts of interest.

Dural afferent neurons are implicated in primary headaches including migraine. Although a significant portion of primary afferent neurons innervating the dura are myelinated A-type neurons, previous electrophysiological studies have primarily characterized the functional properties of small-sized C-type sensory neurons. Here we show the functional characterization of dural afferent neurons identified with the fluorescent dye DiI. DiI-positive neurons were divided into three types: small-, medium-, and large-sized neurons, based on their diameter, area, and membrane capacitance. The immunoreactivity of NF200, a marker of A-type myelinated neurons, was detected in most large-sized, but it was also present in a limited number of small- and medium-sized DiI-positive neurons. Capsaicin, a transient receptor potential vanilloid 1 agonist, induced the membrane currents in most small- and medium-sized neurons, but not in large-sized DiI-positive neurons. Tetrodotoxin-resistant Na + channels were expressed in almost all types of DiI-positive neurons. Mechanosensitive currents were detected from a majority of large-sized, and to a lesser extent, small- and medium-sized DiI-positive neurons. The results suggest that most dural afferent neurons are nociceptive, e.g., polymodal C-type for small- and medium-sized neurons, and high-threshold nociceptive A-type mechanoreceptors for large-sized neurons. We also found that DiI-positive neurons differed with respect to passive and active membrane properties, and that sumatriptan, a representative drug used for the acute treatment of migraine attack, inhibited voltage-gated Ca 2+ currents in all types of DiI-positive neurons. The present results showing the nociceptive properties of dural afferent neurons would contribute to understand the pathophysiology of primary headaches., (Copyright © 2018 Elsevier B.V. All rights reserved.)

Here, we report that MYC rescues early human cells undergoing reprogramming from a proliferation pause induced by OCT3/4, SOX2, and KLF4 (OSK). We identified ESRG as a marker of early reprogramming cells that is expressed as early as day 3 after OSK induction. On day 4, ESRG positive (+) cells converted to a TRA-1-60 (+) intermediate state. These early ESRG (+) or TRA-1-60 (+) cells showed a proliferation pause due to increased p16INK4A and p21 and decreased endogenous MYC caused by OSK. Exogenous MYC did not enhance the appearance of initial reprogramming cells but instead reactivated their proliferation and improved reprogramming efficiency. MYC increased expression of LIN41, which potently suppressed p21 post-transcriptionally. MYC suppressed p16 INK4A. These changes inactivated retinoblastoma protein (RB) and reactivated proliferation. The RB-regulated proliferation pause does not occur in immortalized fibroblasts, leading to high reprogramming efficiency even without exogenous MYC., (Copyright © 2018 The Authors. Published by Elsevier Inc. All rights reserved.)

Objective: To clarify the impact of endoscopic incision (EI) for ureterocele as an initial procedure, by performing a retrospective chart review, focusing on the prevalence of and risk factors for symptomatic urinary tract infection (UTI) after EI., Materials and Methods: In the present study we included children with ureterocele, managed between September 1994 and April 2016, who were observed conservatively without additional surgical management after EI. Ureterocele was categorized as intravesical or ectopic. Symptomatic UTI was defined as either recurrent non-febrile or febrile UTI. The prevalence of and risk factors for symptomatic UTI were analysed using Cox proportional hazard models or Kaplan-Meier curves, and the log-rank test., Results: A total of 36 children met the inclusion criteria. The median age of the participants at EI was 8.9 months. Eleven children had symptomatic UTIs (febrile, n = 9; recurrent non-febrile, n = 2) during the median follow-up of 75.5 months. Initial symptomatic UTI in each child occurred <25 months after EI. The symptomatic UTI-free rate after EI was 65.6%. The risk factors for symptomatic UTI were female gender, duplex system, ectopic ureterocele, and unchanged hydronephrosis after EI., Conclusions: The present study determined the critical period and risk factors for symptomatic UTI after EI for the treatment of ureterocele. The results suggest that when conservative management is indicated after EI, patients, especially those with risk factors, should be followed carefully at least for 25 months after EI for symptomatic UTI., (© 2017 The Authors BJU International © 2017 BJU International Published by John Wiley & Sons Ltd.)

Voltage-gated Na + channels in primary afferent neurons can be divided into tetrodotoxin-sensitive (TTX-S) and tetrodotoxin-resistant (TTX-R) Na + channels. Although previous studies have shown the acid modulation of TTX-R Na + channels, the effect of acidic pH on tetrodotoxin-sensitive (TTX-S) Na + channels is still unknown. Here we report the effect of acidic pH on TTX-S Na + channels expressed in large-sized trigeminal ganglion (TG) neurons using a whole-cell patch clamp technique. The application of acidic extracellular solution decreased the peak amplitude of TTX-S currents (I Na ) in a pH-dependent manner, but weak acid (≥pH 6.0) had no inhibitory effect on TTX-S I Na . Acidic pH (pH 6.0) shifted both the activation and steady-state fast inactivation relationships of TTX-S Na + channels toward depolarized potentials. However, acidic pH (pH 6.0) had no effect on use-dependent inhibition in response to high-frequency stimuli, development of inactivation, and accelerated the recovery from inactivation of TTX-S Na + channels, suggesting that TTX-S Na + channels in large-sized TG neurons are less sensitive to acidic pH. Given that voltage-gated Na + channels play a pivotal role in the generation and conduction of action potentials in neural tissues, the insensitivity of TTX-S Na + channels expressed in large-sized TG neurons to acidic pH would ensure transmission of innocuous tactile sensation from orofacial regions at acidic pH conditions., (Copyright © 2016. Published by Elsevier B.V.)

Objectives: To evaluate actual post-pubertal penile size and factors affecting it in hypospadias patients, we retrospectively reviewed medical charts., Patients and Methods: Hypospadias patients whose external genitalia were categorized into Tanner stage 5, and whose stretched penile length was evaluated at 15 years old or older from April 2008 to April 2015, were enrolled in the present study. Stretched penile length was measured by a single examiner. Actual post-pubertal stretched penile length and factors affecting the post-pubertal stretched penile length were estimated. Statistical analysis was performed using Mann-Whitney U test and univariate and multivariate linear regression models for the determination of independent factors., Results: Thirty patients met the inclusion criteria. Median age at evaluation was 17.2 years. Thirteen and 17 had mild and severe hypospadias, respectively. Endocrinological abnormality was identified in 5. Multivariate analysis showed that the severity of hypospadias and endocrinological abnormality were significant factors affecting stretched penile length. Stretched penile length in 25 patients without endocrinological abnormality was significantly longer than that in those with endocrinological abnormality (p = 0.036). Among patients without endocrinological abnormality, stretched penile length in 13 with severe hypospadias was significantly shorter than that in 12 with mild hypospadias (p = 0.004)., Conclusions: While the severity of hypospadias and endocrinological abnormality at post-pubertal evaluation were factors affecting post-pubertal penile size, stretched penile length in patients with severe hypospadias was shorter even in cases without endocrinological abnormality. These results suggest that severe hypospadias is not only a disorder of urethral development, but also a disorder of penile development.

Non-steroidal anti-inflammatory drugs (NSAIDs) are well-known inhibitors of cyclooxygenases (COXs) and are widely used for the treatment of inflammatory pain; however several NSAIDs display COX-independent analgesic action including the inhibition of voltage-gated Na(+) channels expressed in primary afferent neurons. In the present study, we examined whether NSAIDs modulate tetrodotoxin-resistant (TTX-R) Na(+) channels and if this modulation depends on the extracellular pH. The TTX-R Na(+) currents were recorded from small-sized trigeminal ganglion neurons by using a whole-cell patch clamp technique. Among eight NSAIDs tested in this study, several drugs, including aspirin and ibuprofen, did not affect TTX-R Na(+) channels either at pH 7.4 or at pH 6.0. However, we found that indomethacin, and, to a lesser extent, ibuprofen and naproxen potently inhibited the peak amplitude of TTX-R Na(+) currents at pH 6.0. The indomethacin-induced inhibition of TTX-R Na(+) channels was more potent at depolarized membrane potentials. Indomethacin significantly shifted both the voltage-activation and voltage-inactivation relationships to depolarizing potentials at pH 6.0. Indomethacin accelerated the development of inactivation and retarded the recovery from inactivation of TTX-R Na(+) channels at pH 6.0. Given that indomethacin and several other NSAIDs could further suppress local nociceptive signals by inhibiting TTX-R Na(+) channels at an acidic pH in addition to the classical COX inhibition, these drugs could be particularly useful for the treatment of inflammatory pain., (Copyright © 2016 Elsevier Ltd. All rights reserved.)

Non-steroidal anti-inflammatory drugs (NSAIDs) are widely used for the treatment of inflammatory pain. It is well established that NSAIDs exert their analgesic effects by inhibiting cyclooxygenase to prevent the production of prostaglandins; however, several NSAIDs including diclofenac also modulate other ion channels expressed in nociceptive neurons. In this study, we investigated the pH-dependent effects of diclofenac on tetrodotoxin-resistant (TTX-R) Na(+) channels in rat trigeminal sensory neurons by using the whole-cell patch clamp technique. Diclofenac decreased the peak amplitude of TTX-R Na(+) currents (INa) in a concentration dependent manner. While diclofenac had little effect on the voltage-activation relationship, it significantly shifted the steady-state fast inactivation relationship toward hyperpolarized potentials. Diclofenac increased the extent of use-dependent inhibition of TTX-R Na(+) currents. Diclofenac also significantly accelerated the development of inactivation and retarded the recovery from inactivation of TTX-R Na(+) channels. The effects of diclofenac on TTX-R Na(+) channels were stronger at pH 6.0 than at pH7.4 for most of the parameters tested. Considering that the extracellular pH falls in inflamed tissues, and that TTX-R Na(+) channels expressed on nociceptive neurons are implicated in the prostaglandin-mediated development and maintenance of inflammatory hyperalgesia, our findings could provide an additional analgesic effect of diclofenac under acidic pH conditions., (Copyright © 2015 Elsevier Inc. All rights reserved.)

Under pathological conditions including inflammation, ischemia and incision, extracellular pH falls down as low as 5.4. Although some mediators play pivotal roles in the development and maintenance of inflammatory hyperalgesia by affecting the functional properties of tetrodotoxin-resistant (TTX-R) Na(+) channels, the roles of tissue acidosis in nociceptive transmission mediated by TTX-R Na(+) channels are largely unknown. In the present study, we have investigated the effect of acidic pH on TTX-R Na(+) currents (I(Na)) in small-sized sensory neurons isolated from rat trigeminal ganglia using a whole-cell patch clamp technique. Acidic pH decreased the peak amplitude of TTX-R I(Na) in a pH-dependent manner, but weak acid (≥pH 6.0) had a minor inhibitory effect on the TTX-R I(Na). Acidic pH also significantly shifted both the activation and steady-state fast inactivation relationships toward depolarized potentials. In addition, acidic pH had little effect on the use-dependent inhibition, and significantly retarded the development of inactivation and accelerated the recovery from inactivation of TTX-R Na(+) channels. The results suggest that weak acid (≥pH 6.0) makes TTX-R Na(+) channels to be suitable for the repetitive activation at depolarized membrane potentials. Given that both tissue acidosis and inflammatory mediators in inflamed or injured tissues act synergistically to promote nociceptive transmission by affecting the functional properties of TTX-R Na(+) channels, these channels would be, at least in part, a good target to treat inflammatory pain., (Copyright © 2014 Elsevier Ltd. All rights reserved.)

Purpose: We retrospectively assessed the incidence of and risk factors for febrile urinary tract infection in children during active surveillance after early discontinuation of antibiotic prophylaxis., Materials and Methods: We retrospectively evaluated 9 females and 61 uncircumcised males diagnosed with primary vesicoureteral reflux before age 1 year who had persistent reflux on followup voiding cystourethrogram and were subsequently followed under active surveillance without continuous antibiotic prophylaxis. Patients with secondary vesicoureteral reflux or associated urological abnormality were excluded. Clinical outcomes, including incidence of febrile urinary tract infection and new scar formation, were evaluated. Risk factors for febrile urinary tract infection were also analyzed., Results: Mean age at stopping continuous antibiotic prophylaxis was 21 months, and mean followup was 61 months. During active surveillance 21 patients had febrile urinary tract infection, and the 5-year infection-free rate under active surveillance was 67.5%. One or 2 foci of minimal new scarring developed in 4 of 16 patients who underwent followup dimercapto-succinic acid scan after febrile urinary tract infection. On multivariate analysis dilated vesicoureteral reflux on followup voiding cystourethrogram was the only significant risk factor for febrile urinary tract infection., Conclusions: This study revealed that about two-thirds of patients with persistent vesicoureteral reflux were free of febrile urinary tract infection during 5 years of active surveillance. Those with dilated vesicoureteral reflux on followup voiding cystourethrogram are at significantly greater risk for febrile urinary tract infection. Accordingly active surveillance, especially in patients with nondilated vesicoureteral reflux on followup voiding cystourethrogram, seems to be a safe option even in children who have not yet been toilet trained., (Copyright © 2015 American Urological Association Education and Research, Inc. Published by Elsevier Inc. All rights reserved.)

Acid-sensing ion channels (ASICs) are widely expressed in central as well as peripheral neurons. Here we have characterized the proton-induced currents in acutely isolated rat trigeminal mesencephalic nucleus (Vmes) neurons using a whole cell patch-clamp technique. In a voltage-clamp condition, the application of acid extracellular solution (≤ pH 6.5) induced the inward currents in a pH-dependent manner. The proton-induced currents disappeared in the Na(+)-free external solution, and were concentration-dependently blocked by amiloride, a general ASIC blocker. The reversal potential of proton-induced currents was similar to the theoretical Na(+) equilibrium potential, suggesting that the proton-induced currents are mainly mediated by the activation of ASICs, which are highly selective to Na(+). The modulation of proton-induced currents by divalent cations and the expression patterns of ASIC transcripts using by the multi-cell RT-PCR assay suggest that Vmes neurons express functional ASIC2a and ASIC1b subunits. In a current-clamp condition, acidic pH directly depolarized the membrane potential and generated a burst of action potentials at Vmes neurons, which innervate the masseter muscle spindles. Considering that cell bodies of Vmes neurons are located within the central nervous system, ASICs expressed on Vmes neurons, by sensing peripheral and/or central acidosis, might play pivotal roles in the transduction of proprioceptive information from the masseter muscles and periodontal ligaments., (Copyright © 2014 Elsevier B.V. All rights reserved.)

Pluripotency can be induced in somatic cells by overexpressing transcription factors, including POU class 5 homeobox 1 (OCT3/4), sex determining region Y-box 2 (SOX2), Krüppel-like factor 4 (KLF4), and myelocytomatosis oncogene (c-MYC). However, some induced pluripotent stem cells (iPSCs) exhibit defective differentiation and inappropriate maintenance of pluripotency features. Here we show that dynamic regulation of human endogenous retroviruses (HERVs) is important in the reprogramming process toward iPSCs, and in re-establishment of differentiation potential. During reprogramming, OCT3/4, SOX2, and KLF4 transiently hyperactivated LTR7s--the long-terminal repeats of HERV type-H (HERV-H)--to levels much higher than in embryonic stem cells by direct occupation of LTR7 sites genome-wide. Knocking down LTR7s or long intergenic non-protein coding RNA, regulator of reprogramming (lincRNA-RoR), a HERV-H-driven long noncoding RNA, early in reprogramming markedly reduced the efficiency of iPSC generation. KLF4 and LTR7 expression decreased to levels comparable with embryonic stem cells once reprogramming was complete, but failure to resuppress KLF4 and LTR7s resulted in defective differentiation. We also observed defective differentiation and LTR7 activation when iPSCs had forced expression of KLF4. However, when aberrantly expressed KLF4 or LTR7s were suppressed in defective iPSCs, normal differentiation was restored. Thus, a major mechanism by which OCT3/4, SOX2, and KLF4 promote human iPSC generation and reestablish potential for differentiation is by dynamically regulating HERV-H LTR7s.

Pluripotency can be induced in somatic cells by forced expression of POU domain, class 5, transcription factor 1 (OCT3/4), sex determining region Y-box 2 (SOX2), Kruppel-like factor 4 (KLF4), myelocytomatosis oncogene (c-MYC) (OSKM). However, factor-mediated direct reprogramming is generally regarded as an inefficient and stochastic event. Contrary to this notion, we herein demonstrate that most human adult dermal fibroblasts initiated the reprogramming process on receiving the OSKM transgenes. Within 7 d, ~20% of these transduced cells became positive for the TRA-1-60 antigen, one of the most specific markers of human pluripotent stem cells. However, only a small portion (~1%) of these nascent reprogrammed cells resulted in colonies of induced pluripotent stem cells after replating. We found that many of the TRA-1-60-positive cells turned back to be negative again during the subsequent culture. Among the factors that have previously been reported to enhance direct reprogramming, LIN28, but not Nanog homeobox (NANOG), Cyclin D1, or p53 shRNA, significantly inhibited the reversion of reprogramming. These data demonstrate that maturation, and not initiation, is the limiting step during the direct reprogramming of human fibroblasts toward pluripotency and that each proreprogramming factor has a different mode of action.

Histaminergic neurons within the tuberomammillary nucleus (TMN) play an important role in sleep-wakefulness regulation. Here, we report the muscarinic modulation of GABAergic spontaneous miniature inhibitory postsynaptic currents (mIPSCs) in mechanically dissociated rat histaminergic neurons using a conventional whole-cell patch clamp technique. Muscarine, a nonselective muscarinic acetylcholine (mACh) receptor agonist, reversibly decreased mIPSC frequency without affecting the current amplitude, indicating that muscarine acts presynaptically to decrease the probability of spontaneous GABA release. The muscarine action on GABAergic mIPSC frequency was completely blocked by atropine, a nonselective mACh receptor antagonist, and tropicamide, an M(4) receptor antagonist. The muscarine-induced decrease in mIPSC frequency was completely occluded in the presence of Cd(2+), a general voltage-dependent Ca(2+) channel blocker, or in a Ca(2+)-free external solution. However, pharmacological agents affecting adenylyl cyclase or G-protein coupled inwardly rectifying K(+) channel activity did not prevent the inhibitory action of muscarine on GABAergic mIPSCs. These results suggest that muscarine acts on M(4) receptors on GABAergic nerve terminals projecting to histaminergic neurons to inhibit spontaneous GABA release via the inhibition of Ca(2+) influx from the extracellular space. Muscarine also inhibited action potential-dependent GABA release by activating presynaptic M(4) receptors in more physiological conditions. The M(4) receptor-mediated modulation of GABAergic transmission onto TMN neurons may contribute to the regulation of sleep-wakefulness., (Copyright © 2012 Elsevier Ltd. All rights reserved.)

Sialylated glycans play a prominent role in the Drosophila nervous system where they are involved in the regulation of neural transmission. However, the functional pathway of sialylation in invertebrates, including Drosophila, remains largely unknown. Here we used a combination of genetic and behavioral approaches to shed light on the Drosophila sialylation pathway. We examined genetic interactions between Drosophila sialyltransferase (DSiaT) and β1,4-N-acetylgalactosaminyltransferase (β4GalNAcT) genes. Our results indicated that β4GalNAcTA and DSiaT cooperate within the same functional pathway that regulates neural transmission. We found that β4GalNAcTA is epistatic to DSiaT. Our data suggest an intriguing possibility that β4GalNAcTA may participate in the biosynthesis of sialylated glycans.

Accelerated repopulation is a reason for loco-regional failure after radiotherapy for head and neck carcinoma. Accelerated fractionation(AF) is a radiotherapy regimen reducing the total treatment time, with the aim of counteracting tumor cell repopulation. AF administers the same or a similar total dose as conventional treatment in a reduced overall time by giving conventionally-sized or smaller fractions more than once daily. Several different clinical trials on AF have proved to be of benefit in loco-regional control, although no benefit in survival was generally detected. The metaanalysis of altered fractionated radiotherapy in head and neck cancer has showed a benefit with AF with conventional fractionation(CF). However, the magnitude of the survival benefit is lower with AF than with hyperfractionation (HF). In particular, AF using reduced total doses or a split course does not improve treatment benefits. AF that employs continuous RT schedules, without compromising the total dose, improves local control. More data on this AF regimen are needed. Acute morbidity is significantly more frequent with AF. Whether late toxicity is also worse with AF is unclear. Some trials suggest no increase in late toxicity, while others suggest the opposite. The effect of AF seems to be greater for the primary tumor than for the metastatic lymph-nodes. Also, the reduction of the treatment time is more beneficial in well- to moderately-differentiated tumors.

Conduct disorder (CD) is a serious psychiatric disorder of children and adolescents. A common association is the presence of attention-deficit hyperactivity disorder. The present paper reviews empirical findings on CD. The correlative factors were analyzed according to their bio-psycho-social aspects. To be effective, early detection and intervention on CD must be multimodal. We should address treatments on multiple foci, and continue them over an extensive period of time.

A 73-year-old man presented with gross hematuria. Ultrasonography and computerized tomography showed small bladder tumors and a left renal mass protruding to renal pelvis. Transurethral resection of bladder tumor and ureteroscopic tumor biopsy were performed, and pathological examinations revealed transitional cell carcinoma in the bladder and renal cell carcinoma in the kidney. He underwent left radical nephrectomy. A 4-month postoperative cystoscopy revealed a solitaly non-papillary tumor in the bladder. Transurethral resection was performed and pathological diagnosis was metastasis from renal cell carcinoma. At that time, multiple metastases to ureteral stump and lung were found. He had undergone palliative treatment because of his poor general condition until he died 26 months postoperatively. Care should be taken for management of ureteral stump when diagnostic ureteroscopy was done for renal cell carcinoma invading the renal pelvis.

GABAergic afferent inputs are thought to play an important role in the control of the firing pattern of substantia nigra pars compacta (SNc) dopaminergic neurons. We report here the actions of presynaptic kainite (KA) receptors in GABAergic transmission of rat SNc dopaminergic neurons. In mechanically dissociated rat SNc dopaminergic neurons attached with native presynaptic nerve terminals, GABAergic miniature inhibitory postsynaptic currents (mIPSCs) were recorded by use of conventional whole cell patch recording mode. In the voltage-clamp condition, KA (3 microM) significantly increased GABAergic mIPSC frequency without affecting the current amplitude. This facilitatory effect of KA was not affected in the presence of 20 microM GYKI52466, a selective AMPA receptor antagonist, but was completely inhibited in the presence of 20 microM CNQX, an AMPA/KA receptor antagonist. Presynaptic KA receptors on GABAergic terminals were mainly permeable to Na+ but impermeable to Ca2+ because KA-induced facilitation of mIPSC frequency was completely suppressed in either Na+-free or Ca2+-free external solutions, and in the presence of 200 microM Cd2+, a general voltage-dependent Ca2+ channel blocker. In the slice preparation, KA increased GABAergic spontaneous mIPSC frequency, but significantly suppressed evoked IPSC (eIPSC) amplitude. However, this inhibitory action on eIPSCs was reversed by 10 microM CGP55845, a selective GABAB receptor antagonist, implicating the possible involvement of GABAB autoreceptors in KA-induced modulation of GABAergic transmission. Thus presynaptic KA receptors on GABAergic nerve terminals synapsing onto SNc neurons may play functional roles contributing the fine control of neuronal excitability and firing pattern of SNc.