Surgical management of prepubertal testicular tumors: A 30-year study in our institution.

OBJECTIVES: The 2021 European Association of Urology-European Society for Paediatric Urology guidelines on Pediatric Urology recommended testis-sparing surgery (TSS) as the primary approach to treat prepubertal testicular tumors exhibiting favorable preoperative ultrasound diagnoses. However, prepubertal testicular tumors are rare and clinical data regarding them is limited. Here, we analyzed the surgical management of prepubertal testicular tumors based on cases observed over approximately 30 years. METHODS: Data were retrospectively reviewed from medical records of consecutive patients aged <14 years with testicular tumors who received treatment at our institution between 1987 and 2020. We compared patients by their clinical characteristics, namely, those who underwent TSS versus radical orchiectomy (RO) and those who received surgery in 2005 onward versus prior to 2005. RESULTS: We identified 17 patients, with a median age at surgery of 3.2 years (range 0.6-14.0) and a median tumor size of 15 mm (range 6-67). The tumor size was significantly smaller in patients who underwent TSS than in those who underwent RO (p = 0.007). Patients treated in 2005 onward were more likely to undergo TSS than those treated prior to 2005 (71% vs. 10%, respectively), without significant differences in tumor size or the rate of preoperative ultrasound. No TSS cases required conversion to RO. CONCLUSIONS: Recent improvements in ultrasound imaging technology allow for more accurate clinical diagnosis. Therefore, the indications of TSS for prepubertal testicular tumors can be judged based not only on the tumor size but also on the diagnosis of benign tumors by preoperative ultrasound.

Low Serum Inhibin B/Follicle-Stimulating Hormones and Anti-Müllerian Hormone/Follicle-Stimulating Hormones Ratios as Markers of Decreased Germ Cells in Infants with Bilateral Cryptorchidism.

PURPOSE: In cryptorchidism, germ cell development failure presents from infancy and may be reflected by altered hormonal levels produced by Sertoli cells. Our object was to assess for associations between serum hormone levels and testicular histopathology in cryptorchidism with an infertility risk according to the pretreatment undescended testicular positions. MATERIALS AND METHODS: Prepubertal cryptorchid boys aged 7-91 (median 20) months who underwent orchidopexy between 2014 and 2019 were included (122 unilateral [median 19 months {range 7-91}], 23 bilateral [24 months {11-81}]). We evaluated the pretreatment testicular position and size; serum hormone levels; and the mean number of germ cells per tubule transverse section (G/T). We also performed a subgroup analysis of boys aged ≤24 months at orchidopexy. RESULTS: Serum inhibin B levels and G/T were significantly lower in bilateral than in unilateral cryptorchid boys (median 96 [range 46-197] pg/ml vs 125 [21-354] pg/ml, p=0.026; 0.20 [0-2.59] vs 0.65 [0-4.55], p <0.001, respectively). Inhibin B/follicle-stimulating hormones (FSH) and anti-Müllerian hormone (AMH)/FSH ratios were positively correlated with G/T in bilateral cryptorchid boys aged ≤24 months (12, p=0.008 and p=0.019, respectively). Low inhibin B/FSH and AMH/FSH ratios and high FSH were predictors of impaired G/T as per receiver operating characteristic curves (p=0.019, p=0.004 and p=0.004, respectively), whereas in unilateral cryptorchid boys aged ≤24 months, serum hormone levels and G/T did not differ with the pretreatment testicular positions. CONCLUSIONS: In bilateral cryptorchid boys aged ≤24 months at orchidopexy, low inhibin B/FSH and AMH/FSH ratios may reflect impaired G/T and future infertility risk.

Antireflux endoscopic injection therapy in post-pubertal patients via techniques adopted for the dilated ureteral orifice: a retrospective single-center study.

BACKGROUND: To investigate the efficacy and safety of endoscopic injection therapy for vesicoureteral reflux in post-pubertal patients with dilated ureteral orifice via modified hydrodistension implantation techniques. METHODS: We retrospectively reviewed medical records including operational procedure and clinical course of all consecutive patients over 12 years old with a history of injection therapy. Endoscopic injection of dextranomer/hyaluronic acid copolymer was performed under hydrodistension implantation technique with some modifications in order to inject through dilated ureteral orifice align with the intramural ureter. Technical selections were done according to hydrodistension grade of the ureteral orifice. Voiding cystourethrography was evaluated at 3 months postoperatively. Hydronephrosis was evaluated using ultrasonography preoperatively until 6 months postoperatively. RESULTS: From 2016 to 2019, 12 patients (all female, 16 ureteral units; median age 32 [range 15-61] years) underwent endoscopic injection therapy at one of our institutions. We have identified grade II vesicoureteral reflux in 5 ureters, grade III in 8, and grade IV in 3 ureters. Grade 3 ureteral-orifice dilation were presented in 12 ureters (75%), grade 2 in 3 and grade 1 in 1 ureter in the present cases. Postoperatively, vesicoureteral reflux was diminished to grade 0 in 12 ureteral units (75%), decreased to grade I in 3 (9%), and remained grade III in 1 (6%). Three patients reported dull flank pain for several days postoperatively and there was 1 case of acute pyelonephritis. Temporary hydronephrosis was confirmed in 3 ureteral units (19%) at 1 month postoperatively. Median follow-up duration was 23 (range 13-63) months long. Although, 3 patients were experienced f-UTI 1-2 times, repeated VCUG showed no VUR recurrence. CONCLUSIONS: According to hydrodistension grade of the ureteral orifice, endoscopic injection therapy via modified hydrodistension implantation technique is an effective and safe treatment for vesicoureteral reflux in post-pubertal female patients with dilated ureteral orifice. While ureteral deformities or a history of anti-reflux surgery may increase the risks, these can be managed with appropriate methods that ensure sufficient mound appearance and height.

Appropriate timing of performing abdominal ultrasonography and termination of follow-up observation for antenatal grade 1 or 2 hydronephrosis.

BACKGROUND: Most cases of antenatal the Society of Fetal Urology (SFU) grade 1or 2 hydronephrosis (HN) improve or resolve spontaneously with conservative treatment. However, there is no consensus on the duration of follow-up for cases of grade 1or 2 HN. The aim of this study was to determine the need for continuous follow-up period and new management of children with antenatal grade 1or 2 HN. METHODS: Subjects underwent ultrasonographic assessment for HN according to the SFU classification. We retrospectively evaluated 112 patients with postnatal grade 1 HN and 69 with grade 2 HN using abdominal ultrasonography between January 2010 and December 2017. We examined the change in HN grade on repeat ultrasonography. Kaplan-Meier method was used to show the effect of HN grade on the rate of HN changes. RESULTS: The mean follow-up duration was 44.9 ± 36.4 months (range 12-274). Initial SFU grade 1 HN disappeared in 47.0% of cases at 12 months, 66.4% at 24 months and 73.2% at 48 months. Initial SFU grade 2 HN showed improvement in grade in 74.7% of cases at 12 months, 88.3% at 24 months and 89.5% at 48 months. However, 14.6% of SFU grade 1 and 2.8% of SFU grade 2 cases increased in grade and of the 17 cases, 16 cases worsened within the first 6 months. No cases with increased grade required pyeloplasty. Initial disappearance and later reappearance of HN occurred in 40.5% of SFU grade 1 and 2 cases. The mean duration of later reappearance of HN was 39.1 ± 36.2 months (range 12-137). No cases showed reappearance of HN after more than 1 year. CONCLUSIONS: Ultrasonography within the first 6 months was necessary for management of children with antenatal grade 1or 2 HN, because some patients showed worsening. After that, it is considered safe to spread the follow-up interval for stable cases. Most cases of grade 1or 2 HN resolved spontaneously, however a few cases reappeared within 1 year. Therefore, ultrasonography after 1 year was necessary in children with HN that spontaneously disappeared. The appropriate time to end the follow-up was considered to have been after 1 year or more has passed since the disappearance was confirmed.

Guidelines for the medical management of pediatric vesicoureteral reflux.

Urinary tract infection is a bacterial infection that commonly occurs in children. Vesicoureteral reflux is a major underlying precursor condition of urinary tract infection, and an important disorder in the field of pediatric urology. Vesicoureteral reflux is sometimes diagnosed postnatally in infants with fetal hydronephrosis diagnosed antenatally. Opinions vary regarding the diagnosis and treatment of vesicoureteral reflux, and diagnostic procedures remain debatable. In terms of medical interventions, options include either follow-up observation in the hope of possible spontaneous resolution of vesicoureteral reflux with growth/development or provision of continuous antibiotic prophylaxis based on patient characteristics (age, presence/absence of febrile urinary tract infection, lower urinary tract dysfunction and constipation). Furthermore, there are various surgical procedures with different indications and rationales. These guidelines, formulated and issued by the Japanese Society of Pediatric Urology to assist medical management of pediatric vesicoureteral reflux, cover the following: epidemiology, clinical practice algorithm for vesicoureteral reflux, syndromes (dysuria with vesicoureteral reflux, and bladder and rectal dysfunction with vesicoureteral reflux), diagnosis, treatment (medical and surgical), secondary vesicoureteral reflux, long-term prognosis and reflux nephropathy. They also provide the definition of bladder and bowel dysfunction, previously unavailable despite their close association with vesicoureteral reflux, and show the usefulness of diagnostic tests, continuous antibiotic prophylaxis and surgical intervention using site markings.

Single Nucleotide Polymorphisms of HAAO and IRX6 Genes as Risk Factors for Hypospadias.

PURPOSE: We evaluated the association of hypospadias and 17 susceptibility loci previously identified by a European genome-wide association study in a cohort of Japanese patients. We also examined the expression of candidate genes in male mouse embryos to determine the possible underlying mechanisms of this disease. MATERIALS AND METHODS: We enrolled 169 Japanese patients (mean age at surgery 3.7 years) who underwent repair of hypospadias. Genotyping of 17 single nucleotide polymorphisms was performed using a multiplex polymerase chain reaction invader assay. We also performed in situ hybridization to determine whether candidate genes were expressed in the male genital tubercle during embryonic development of the external genitalia in mice. RESULTS: Single nucleotide polymorphism rs3816183 of HAAO was significantly associated with susceptibility to hypospadias in general (p = 0.0019) and to anterior/middle hypospadias (p = 0.0283) and posterior hypospadias (p = 0.0226), while single nucleotide polymorphism rs6499755 of IRX6 showed an association with susceptibility to anterior/middle hypospadias (p = 0.0472). In mouse embryos there was no significant upregulation of Haao expression in the developing male external genitalia. Irx3 and Irx5, which are linked to Irx6 within the IrxB cluster, were expressed in the mesenchyme remote from the urethral plate epithelium during the critical embryonic period for masculinization. Irx6 was expressed in the ectodermal epithelium, demonstrating prominent dorsal ectodermal expression without expression in the ventral ectoderm adjacent to the urethral plate during the same period. CONCLUSIONS: Genetic variations of HAAO and IRX6 influence susceptibility to hypospadias in the Japanese population. Further research is needed to clarify the mechanism by which variations in these genes contribute to the pathogenesis of hypospadias.

Active Phagocytosis and Diachronic Processing of Calcium Oxalate Monohydrate Crystals in an in vitro Macrophage Model.

BACKGROUND: We previously discovered that renal macrophages (Mφs) phagocytose renal calcium oxalate monohydrate (COM) crystals. This study investigated the processing of engulfed crystals using in vitro models. METHODS: J774.1 mouse Mφs were exposed to COM crystals and observed for 24 h using polarized light microscopy with/without cytochalasin B (CB), an inhibitor of phagocytosis, to confirm active crystal phagocytosis. LysoTracker and immunohistochemical staining using transmission electron microscopy for lysosomal-associated membrane protein 1 were used to confirm engulfed COM crystal uptake into lysosomes. Diachronic tracking of specific Mφs was performed to capture the entire course of engulfed COM crystal processing using polarized light microscopy. Follow-up studies of fluorescent COM (f-COM) crystals using imaging cytometry were performed in the presence and absence of nigericin to dissipate the pH gradient in acidic organelles. RESULTS: Phagocytosis rates increased with COM density and were significantly lower in cells treated with CB (p < 0.01). We observed that engulfed crystals colocalized within lysosomes of the Mφs; moreover, diachronic observation indicated that the engulfed COM crystals were subdivided during Mφ division and eliminated by the 7th day of culture. Additionally, imaging cytometry showed that the fluorescence level of f-COM crystals in the nigericin (-) group after 48 h was significantly lower than that in the nigericin (+) group. CONCLUSIONS: This study confirmed active phagocytosis and lysosomal processing of engulfed COM crystals by Mφs. This discovery is expected to contribute to the development of future drugs that enhance the COM crystal phagocytic ability of Mφs.

Identification of new urinary risk markers for urinary stones using a logistic model and multinomial logit model.

BACKGROUND: Risk assessment for urinary stones has been mainly based on urinary biochemistry. We attempted to identify the risk factors for urinary stones by statistically analyzing urinary biochemical and inflammation-related factors. METHODS: Male participants (age, 20-79 years) who visited Nagoya City University Hospital were divided into three groups: a control group (n = 48) with no history of stones and two stone groups with calcium oxalate stone experience (first-time group, n = 22; recurring group, n = 40). Using 25-µL spot urine samples, we determined the concentrations of 18 candidate urinary proteins, using multiplex analysis on a MagPix® system. RESULTS: In univariate logistic regression models classifying the control and first-time groups, interleukin (IL)-1a and IL-4 were independent factors, with significantly high areas under the receiver operating characteristic curve (1.00 and 0.87, respectively, P < 0.01 for both). The multivariate models with IL-4 and granulocyte-macrophage colony-stimulating factor (GM-CSF) showed higher areas under the receiver operating characteristic curve (0.93) compared to that for the univariate model with IL-4. In the classification of control, first-time, and recurrence groups, accuracy was the highest for the multinomial logit model with IL-4, GM-CSF, IL-1b, IL-10, and urinary magnesium (concordance rate 82.6%). CONCLUSIONS: IL-4, IL-1a, GM-CSF, IL-1b, and IL-10 were identified as urinary inflammation-related factors that could accurately distinguish control individuals from patients with urinary stones. Thus, the combined analysis of urinary biochemical data could provide an index that more clearly evaluates the risk of urinary stone formation.

Improvement in early urinary continence recovery after robotic-assisted radical prostatectomy based on postoperative pelvic anatomic features: a retrospective review.

BACKGROUND: We investigated the impact of postoperative membranous urethral length and other anatomic characteristics of the pelvic floor shape as measured by magnetic resonance imaging on the improvement in continence following robotic-assisted radical prostatectomy. METHODS: We retrospectively reviewed data from 73 patients who underwent postoperative prostate magnetic resonance imaging following robotic-assisted radical prostatectomy between 2013 and 2018. Patient demographics; pre-, peri-, and post-operative parameters; and pelvic anatomic features on magnetic resonance imaging were reviewed. Patients who used no urinary incontinence pads or pads for protection were considered to have achieved complete continence. RESULTS: Urinary continence was restored in 27.4, 53.4, 68.5, and 84.9% of patients at 1, 3, 6, and 12 months after robotic-assisted radical prostatectomy, respectively. When patients were divided into early and late continence groups based on urinary continence at 3 months after robotic-assisted radical prostatectomy, no significantly different clinical characteristics or surgical outcomes were found. However, the mean membranous urethral length (18.5 mm for the early continence group vs. 16.9 mm for the late continence group), levator muscle width (7.1 vs. 6.5 mm, respectively), and bladder neck width on the trigone side (7.2 mm vs. 5.4 mm, respectively) were significantly different between groups (all p < 0.05). Multivariate logistic regression analysis showed that membranous urethral length (odds ratio, 1.227; 95% confidence interval, 1.011-1.489; p = 0.038) and bladder neck width (odds ratio, 1.585; 95% confidence interval, 1.050-2.393; p = 0.028) were associated with the period of early urinary continence. CONCLUSIONS: Postoperative membranous urethral length and bladder neck width were significantly associated with early urinary continence recovery after robotic-assisted radical prostatectomy. It is highly recommended that surgeons focus on preserving the membranous urethral length and increasing the bladder neck width on the trigone side during surgery to achieve optimal continence outcomes after robotic-assisted radical prostatectomy.

Dihydrotestosterone induces minor transcriptional alterations in genital skin fibroblasts of children with and without androgen insensitivity.

Endogenous and exogenous androgens induce masculinization of external genitalia through binding to the androgen receptor (AR). The target genes of androgens in external genitalia remain to be determined, although previous studies have shown that the apolipoprotein D gene (APOD) was significantly upregulated by dihydrotestosterone (DHT), the most potent androgen in humans. In the present study, we performed microarray analysis for genital skin fibroblasts obtained from four boys with buried penis (the control individuals) and a patient with partial androgen insensitivity syndrome (PAIS) due to a hypomorphic mutation in AR (the PAIS patient). We identified 24 transcripts that were upregulated or downregulated by DHT in all samples of control individuals and, to a lesser extent, in the sample of the PAIS patient. Differences between DHT-treated and -untreated samples were small; the results of 24 transcripts did not reach statistical significance. The 24 transcripts included CYP1B1, a gene possibly involved in the development of genital tubercle in mice, and APOD, as well as several genes that have been reported as androgen targets in prostate or other tissues. The results of this study indicate that androgen-mediated masculinization of external genitalia is unlikely to depend on massive transcriptional changes in specific AR target genes. Rather, minor transcriptional changes of several genes, and/or a complex molecular network may play a major role in penile development. Importantly, our data suggest the possible involvement of CYP1B1 in human genital development and confirm the clinical importance of APOD as a biomarker for AR function.

Exploring disease-specific methylated CpGs in human male genital abnormalities by using methylated-site display-amplified fragment length polymorphism (MSD-AFLP).

The incidence of male reproductive system disorders, especially hypospadias, has been increasing in developed countries since the latter half of the 20th century. Endocrine-disrupting chemicals from the environment are considered to be involved in hypospadias onset through epigenetic alterations. This pilot study aimed to explore disease-specific methylated CpGs in human patient samples using the methylated-site display-amplified fragment length polymorphism (MSD-AFLP) technique developed by our research group [1]. We compared clinical samples from hypospadias and phimosis patients. Foreskin and blood samples were collected from one- to two-year-old patients with hypospadias (N = 3) and phimosis (N = 3) during surgical treatment. MSD-AFLP analysis showed significantly decreased CpG-methylation levels of genes such as MYH11 and increased CpG-methylation levels of genes such as PLA2G15 in hypospadias patients. Hierarchical clustering analysis showed that genes with significantly altered CpG levels were more markedly altered in DNA from blood than from foreskin. Because of the small number of samples, further investigation is necessary to elucidate the association between variations in CpG levels in foreskin and blood DNA and male genital abnormalities. However, our MSD-AFLP method appears to be a useful tool for exploring disease-specific methylated-CpGs in human epidemiological studies.

Improvement of psychiatrists' clinical knowledge of the treatment guidelines for schizophrenia and major depressive disorders using the 'Effectiveness of Guidelines for Dissemination and Education in Psychiatric Treatment (EGUIDE)' project: A nationwide dissemination, education, and evaluation study.

AIM: Although treatment guidelines for pharmacological therapy for schizophrenia and major depressive disorder have been issued by the Japanese Societies of Neuropsychopharmacology and Mood Disorders, these guidelines have not been well applied by psychiatrists throughout the nation. To address this issue, we developed the 'Effectiveness of Guidelines for Dissemination and Education in Psychiatric Treatment (EGUIDE)' integrated education programs for psychiatrists to disseminate the clinical guidelines. Additionally, we conducted a systematic efficacy evaluation of the programs. METHODS: Four hundred thirteen out of 461 psychiatrists attended two 1-day educational programs based on the treatment guidelines for schizophrenia and major depressive disorder from October 2016 to March 2018. We measured the participants' clinical knowledge of the treatment guidelines using self-completed questionnaires administered before and after the program to assess the effectiveness of the programs for improving knowledge. We also examined the relation between the participants' demographics and their clinical knowledge scores. RESULTS: The clinical knowledge scores for both guidelines were significantly improved after the program. There was no correlation between clinical knowledge and participant demographics for the program on schizophrenia; however, a weak positive correlation was found between clinical knowledge and the years of professional experience for the program on major depressive disorder. CONCLUSION: Our results provide evidence that educational programs on the clinical practices recommended in guidelines for schizophrenia and major depressive disorder might effectively improve participants' clinical knowledge of the guidelines. These data are encouraging to facilitate the standardization of clinical practices for psychiatric disorders.

Kidney stone formers have more renal parenchymal crystals than non-stone formers, particularly in the papilla region.

BACKGROUND: We investigated the renoprotective ability of healthy people against kidney stone formation. To clarify intratubular crystal kinetics and processing in human kidneys, we performed a quantitative and morphological observation of nephrectomized renal parenchyma tissues. METHODS: Clinical data and pathological samples from 60 patients who underwent radical nephrectomy for renal cancer were collected from June 2004 to June 2010. The patients were retrospectively classified as stone formers (SFs; n = 30, kidney stones detected by preoperative computed tomography) and non-stone formers (NSFs; n = 30, no kidney stone history). The morphology of parenchymal intratubular crystals and kidney stone-related gene and protein expression levels were examined in noncancerous renal sections from both groups. RESULTS: SFs had a higher smoking rate (P = 0.0097); lower red blood cell, hemoglobin, and hematocrit values; and higher urinary red blood cell, white blood cell, and bacterial counts than NSFs. Scanning electron microscopy revealed calcium-containing crystal deposits and crystal attachment to the renal tubular lumen in both groups. Both groups demonstrated crystal transmigration from the tubular lumen to the interstitium. The crystal diffusion analysis indicated a significantly higher crystal existing ratio in the medulla and papilla of SFs and a significantly higher number of papillary crystal deposits in SFs than NSFs. The expression analysis indicated relatively high osteopontin and CD68, low superoxide dismutase, and significantly lower Tamm-Horsfall protein expression levels in SFs. Multivariate logistic regression analysis involving the above factors found the presence of renal papillary crystals as a significant independent factor related to SFs (odds ratio 5.55, 95% confidence interval 1.08-37.18, P = 0.0395). CONCLUSIONS: Regardless of stone formation, intratubular crystals in the renal parenchyma seem to transmigrate to the interstitium. SFs may have reduced ability to eliminate renal parenchymal crystals, particularly those in the papilla region, than NSFs with associated gene expression profiles.

Genome-Wide Gene Expression Profiling of Randall's Plaques in Calcium Oxalate Stone Formers.

Randall plaques (RPs) can contribute to the formation of idiopathic calcium oxalate (CaOx) kidney stones; however, genes related to RP formation have not been identified. We previously reported the potential therapeutic role of osteopontin (OPN) and macrophages in CaOx kidney stone formation, discovered using genome-recombined mice and genome-wide analyses. Here, to characterize the genetic pathogenesis of RPs, we used microarrays and immunohistology to compare gene expression among renal papillary RP and non-RP tissues of 23 CaOx stone formers (SFs) (age- and sex-matched) and normal papillary tissue of seven controls. Transmission electron microscopy showed OPN and collagen expression inside and around RPs, respectively. Cluster analysis revealed that the papillary gene expression of CaOx SFs differed significantly from that of controls. Disease and function analysis of gene expression revealed activation of cellular hyperpolarization, reproductive development, and molecular transport in papillary tissue from RPs and non-RP regions of CaOx SFs. Compared with non-RP tissue, RP tissue showed upregulation (˃2-fold) of LCN2, IL11, PTGS1, GPX3, and MMD and downregulation (0.5-fold) of SLC12A1 and NALCN (P<0.01). In network and toxicity analyses, these genes associated with activated mitogen-activated protein kinase, the Akt/phosphatidylinositol 3-kinase pathway, and proinflammatory cytokines that cause renal injury and oxidative stress. Additionally, expression of proinflammatory cytokines, numbers of immune cells, and cellular apoptosis increased in RP tissue. This study establishes an association between genes related to renal dysfunction, proinflammation, oxidative stress, and ion transport and RP development in CaOx SFs.

Expression of Xenobiotic Biomarkers CYP1 Family in Preputial Tissue of Patients with Hypospadias and Phimosis and Its Association with DNA Methylation Level of SRD5A2 Minimal Promoter.

Several epidemiological studies have suggested that the incidence of male reproductive organ malformations, including hypospadias or cryptorchidism, has increased due to fetal-stage exposure to environmental pollutants. However, the association of chemical exposure with the expression of target regulatory genes in the tissues of patients has not yet been reported. Because experimental approaches or clinical trials in human studies are limited, especially those using fetal and/or infants, it is difficult to obtain clear physiological evidence of mechanisms underlying male reproductive malformations. Thus, the lack of physiological evidence makes this issue controversial. We analyzed preputial tissues from patients with hypospadias (n = 23) and phimosis (n = 16). The atypical CYP1 family genes, CYP1A1 and CYP1B1, are potential biomarkers of environmental chemical exposure. We then compared the expression levels of CYP1A1 and CYP1B1 between hypospadias and phimosis samples by quantitative RT-PCR analysis. The mRNA expression levels of SRD5A2 and AR also were measured, because the androgen-related genes involved in the onset of disorders of male reproductive system. A significantly higher CYP1B1 expression level and a lower AR expression level were observed in the hypospadias groups than in the phimosis group. Positive correlations (P < 0.001) between the mRNA expression levels of the CYP1 family and SRD5A2 were found in patients with hypospadias but not in those with phimosis. Moreover, the methylation levels of the four genes were determined by bisulfite genomic sequencing. Although the SRD5A2 promoter region showed moderate methylation, no methylation was detected in CYP1A1, CYP1B1, or AR. There was no significant difference in SRD5A2 promoter methylation level between hypospadias and phimosis patients. Negative correlations were found between the methylation level of SRD5A2, especially at the - 221 Sp1 site, and the CYP1 family mRNA expression levels (CYP1A1, p = 0.002; CYP1B1, p = 0.007) in hypospadias patients, but not in phimosis patients. The significant positive association of mRNA expression level and the negative association of methylation level of the SRD5A2 gene with the mRNA expression levels of CYP1 family genes in the preputial tissue seem to indicate the chemical exposure of patients with hypospadias.

New steps of robot-assisted radical prostatectomy using the extraperitoneal approach: a propensity-score matched comparison between extraperitoneal and transperitoneal approach in Japanese patients.

BACKGROUND: Robot-assisted radical prostatectomy (RARP) is commonly performed using the transperitoneal (TP) approach with six trocars over an 8-cm distance in the steep Trendelenburg position. In this study, we investigated the feasibility and the benefit of using the extraperitoneal (EP) approach with six trocars over a 4-cm distance in a flat or 5° Trendelenburg position. We also introduced four new steps to the surgical procedure and compared the surgical results and complications between the EP and TP approach using propensity score matching. METHODS: Between August 2012 and August 2016, 200 consecutive patients without any physical restrictions underwent RARP with the EP approach in a less than 5° Trendelenburg position, and 428 consecutive patients underwent RARP with the TP approach in a steep Trendelenburg position. Four new steps to RARP using the EP approach were developed: 1) arranging six trocars; 2) creating the EP space using laparoscopic forceps; 3) holding the separated prostate in the EP space outside the robotic view; and 4) preventing a postoperative inguinal hernia. Clinicopathological results and complications were compared between the EP and TP approaches using propensity score matching. Propensity scores were calculated for each patient using multivariate logistic regression based on the preoperative covariates. RESULTS: All 200 patients safely underwent RARP using the EP approach. The mean volume of estimated blood loss and duration of indwelling urethral catheter use were significantly lower with the EP approach than the TP approach (139.9 vs 184.9 mL, p = 0.03 and 5.6 vs 7.7 days, p < 0.01, respectively). No significant differences in the positive surgical margin were observed. None of the patients developed an inguinal hernia postoperatively after we introduced this technique. CONCLUSIONS: The EP approach to RARP was safely performed regardless of patient physique or contraindications to a steep Trendelenburg position. Our method, which involved using the EP approach to perform RARP, can decrease the amount of perioperative blood loss, the duration of indwelling urethral catheter use, and the incidence of postoperative inguinal hernia development.

Involvement of the bone morphogenic protein/SMAD signaling pathway in the etiology of congenital anomalies of the kidney and urinary tract accompanied by cryptorchidism.

BACKGROUND: Congenital anomalies of the kidney and urinary tract (CAKUT), such as renal dysplasia, hydronephrosis, or vesicoureteral reflux, are the most common causes of end-stage renal disease. However, the genetic etiology of CAKUT remains unclear. In this study, we performed whole exome sequencing (WES) to elucidate the genetic etiology of symptomatic CAKUT and CAKUT accompanied by cryptorchidism. METHODS: Three patients with unilateral renal dysplasia accompanied by ipsilateral cryptorchidism were included in this analysis. Genomic DNA was extracted from peripheral blood, and WES was performed. Disease-specific single nucleotide polymorphisms (SNPs) were determined by comparison with the human genome reference sequence (hg19). Additionally, we searched for SNPs that were common to all three patients, with a particular focus on the coding regions of the target genes. RESULTS: In total, 8710 SNPs were detected. Of the genes harboring these SNPs, 32 associated with renal or testicular development were selected for further analyses. Of these, eight genes (i.e., SMAD4, ITGA8, GRIP1, FREM1, FREM2, TNXB, BMP8B, and SALL1) carried a single amino acid substitution that was common to all three patients. In particular, SNPs in SMAD4 (His290Pro and His291Pro) have not been reported previously in patients with symptomatic CAKUT. Of the candidate genes, four genes (i.e., ITGA8, GRIP1, FREM1, and FREM2) were Fraser syndrome-related genes, encoding proteins that functionally converged on the glial cell-derived neurotrophic factor/RET/bone morphogenic protein (BMP) signaling pathways. As another candidate gene, the protein encoded by BMP8B activates the nuclear translocation of SMAD4, which regulates the expression of genes associated with the differentiation of primordial germ cells or testicular development. Additionally, BMP4, a member of the BMP family, regulates the interaction between metanephric mesenchyme and ureteric buds by suppressing GDNF. CONCLUSIONS: Taken together, our findings suggested that the development of the kidney and urinary tract is intimately linked with that of male reproductive organs via BMP/SMAD signaling pathways.

Hemiscrotal agenesis: Pathogenesis and management strategies.

Hemiscrotal agenesis is among the rarest anomalies in scrotal development disorders. As it has only been reported in three cases, the clinical manifestations remain unclear. We report a case of hemiscrotal agenesis with ipsilateral cryptorchidism. Based on the thermal assessment of the scrotum, concurrent scrotoplasty and orchiopexy were carried out, and the scrotoplasty improved the thermal environment of the fixed left testis. Furthermore, the low expression of androgen receptor and steroid-5-alpha-reductase, alpha polypeptide 2 in the affected side of the scrotum likely resulted in the characteristics of absent scrotal rugae, and pigmentation on histological and biological analyses. For future fertility, we believe that scrotoplasty should be considered as a management option for hemiscrotal agenesis.

Proinflammatory and Metabolic Changes Facilitate Renal Crystal Deposition in an Obese Mouse Model of Metabolic Syndrome.

PURPOSE: To clarify metabolic syndrome induced stone formation mechanisms we investigated the metabolic and immunohistochemical characteristics associated with renal crystal deposition using a model of mice with metabolic syndrome administered a high fat diet and ethylene glycol. MATERIALS AND METHODS: Ob/Ob mice with Leptin gene deficiencies and metabolic syndrome related characteristics were compared with wild heterozygous lean mice. Four study groups were fed standard food and water (control group), a high fat diet and normal water (high fat diet group), 1% ethylene glycol and standard food (ethylene glycol group) or a high fat diet and 1% ethylene glycol (high fat diet plus ethylene glycol group). Blood, urine and kidney samples were taken after 14 days. RESULTS: Ob/Ob mice in the high fat diet plus ethylene glycol group showed diffuse renal crystal depositions. Lean and Ob/Ob mice in the high fat diet plus ethylene glycol group showed significant excretion of urinary calcium oxalate crystals. Ob/Ob mice had significant hypercalciuria, hyperphosphaturia and hyperlipidemia, massive lipid fragments in tubular lumina and fat droplets in renal tubular cells. Ob/Ob mice in the high fat diet plus ethylene glycol group had markedly increased expression of osteopontin, monocyte chemoattractant protein-1, interleukin-6 and tumor necrosis factor-α. In Ob/Ob mice the number of proinflammatory macrophages was considerably elevated. CONCLUSIONS: We induced renal crystal deposition in mice with metabolic syndrome using a high fat diet and ethylene glycol. Increases in luminal mineral and lipid density, and proinflammatory adipocytokines and macrophages facilitated renal crystal formation in mice with metabolic syndrome.