Is transvaginal mesh surgery with polytetrafluoroethylene mesh ORIHIME® feasible for anterior pelvic organ prolapse?-Randomized comparative study between ORIHIME® and Polyform™.

OBJECTIVE: Transvaginal mesh surgery for pelvic organ prolapse has been widely performed in Japan, but polypropylene mesh has not been used in Japan since the ban on TVM using polypropylene mesh in the United States. Currently, polytetrafluoroethylene mesh ORIHIME® is the only mesh available for TVM in Japan. Although polytetrafluoroethylene is a safe material, its low coefficient of friction and insufficient adhesion to the surrounding tissue make it difficult to maintain the mesh position when it is used in the transvaginal mesh surgery. The aim of this study was to evaluate the feasibility of TVM-A2 using ORIHIME®. METHODS: One hundred cases of TVM-A2 were included in the study. The patients were randomly assigned to two groups: the ORIHIME® group (Group O) and the PolyformTM group (Group P). With 50 patients in each group, the complications and recurrences up to the fourth year were compared. Surgeries were performed using the TVM-A2 method. Statistical analysis was performed using EZR. RESULTS: There were no significant differences in baseline parameters between the two groups. We observed no perioperative complications, and saw one case of postoperative abscess formation in Group O, which resolved successfully after incision and drainage. The 4-year recurrence rate was significantly higher in Group O. CONCLUSION: As the recurrence rate was significantly higher in Group O, we conclude that TVM-A2 using ORIHIME® which is the same procedure as TVM-A2 using polypropylene mesh is not feasible in repairing the pelvic organ prolapse.

Mitotic Spindle Positioning (MISP) Facilitates Colorectal Cancer Progression by Forming a Complex with Opa Interacting Protein 5 (OIP5) and Activating the JAK2-STAT3 Signaling Pathway.

Patients with inflammatory bowel disease (IBD) who experience long-term chronic inflammation of the colon are at an increased risk of developing colorectal cancer (CRC). Mitotic spindle positioning (MISP), an actin-binding protein, plays a role in mitosis and spindle positioning. MISP is found on the apical membrane of the intestinal mucosa and helps stabilize and elongate microvilli, offering protection against colitis. This study explored the role of MISP in colorectal tumorigenesis using a database, human CRC cells, and a mouse model for colitis-induced colorectal tumors triggered by azoxymethane (AOM)/dextran sodium sulfate (DSS) treatment. We found that MISP was highly expressed in colon cancer patient tissues and that reduced MISP expression inhibited cell proliferation. Notably, MISP-deficient mice showed reduced colon tumor formation in the AOM/DSS-induced colitis model. Furthermore, MISP was found to form a complex with Opa interacting protein 5 (OIP5) in the cytoplasm, influencing the expression of OIP5 in a unidirectional manner. We also observed that MISP increased the levels of phosphorylated STAT3 in the JAK2-STAT3 signaling pathway, which is linked to tumorigenesis. These findings indicate that MISP could be a risk factor for CRC, and targeting MISP might provide insights into the mechanisms of colitis-induced colorectal tumorigenesis.

Susceptibility to adriamycin-induced hepatotoxicity in mice depends on PRKDC polymorphism.

Adriamycin (ADR) is an effective chemotherapy drug for various cancers but has serious side effects. ADR-induced liver damage is a common problem during therapy, but the underlying mechanism remains to be fully understood. In contrast, ADR-induced glomerular damage is well studied in rodents, and sensitivity to ADR-induced nephropathy is because of the R2140C polymorphism of Prkdc gene. To investigate whether strain differences or sensitivity to ADR-induced liver damage are related to Prkdc polymorphism, this study compared the sensitivity to ADR-induced liver damage among C57BL/6J (B6J), B6-PrkdcR2140C, and BALB/c mice. Although B6J exhibits resistance to ADR-induced liver injury, BALB/c and B6-PrkdcR2140C are more susceptible to liver injury, which is exacerbated by the presence of R2140C mutation in PRKDC.

Molecular and Pathological Analyses of IARS1-Deficient Mice: An IARS Disorder Model.

Most mitochondrial diseases are hereditary and highly heterogeneous. Cattle born with the V79L mutation in the isoleucyl-tRNA synthetase 1 (IARS1) protein exhibit weak calf syndrome. Recent human genomic studies about pediatric mitochondrial diseases also identified mutations in the IARS1 gene. Although severe prenatal-onset growth retardation and infantile hepatopathy have been reported in such patients, the relationship between IARS mutations and the symptoms is unknown. In this study, we generated hypomorphic IARS1V79L mutant mice to develop an animal model of IARS mutation-related disorders. We found that compared to wild-type mice, IARSV79L mutant mice showed a significant increase in hepatic triglyceride and serum ornithine carbamoyltransferase levels, indicating that IARS1V79L mice suffer from mitochondrial hepatopathy. In addition, siRNA knockdown of the IARS1 gene decreased mitochondrial membrane potential and increased reactive oxygen species in the hepatocarcinoma-derived cell line HepG2. Furthermore, proteomic analysis revealed decreased levels of the mitochondrial function-associated protein NME4 (mitochondrial nucleoside diphosphate kinase). Concisely, our mutant mice model can be used to study IARS mutation-related disorders.

Ligand Screening System for the RXRα Heterodimer Using the Fluorescence RXR Agonist CU-6PMN.

Retinoid X receptor (RXR), a nuclear receptor (NR) that regulates transcription of target genes in a ligand binding-dependent manner, is of interest as a drug target. RXR agonists have been developed as therapeutic agents for cutaneous invasive T-cell lymphoma (e.g., bexarotene (1)) and investigated as potential anti-inflammatory agents. Screening systems for the binding of RXR alone have been reported. However, although RXRs function as RXR heterodimers, information on systems to evaluate the differential binding of RXR agonists as RXR heterodimers has not been available until recently. Here we show that the fluorescent RXR agonist CU-6PMN (3), designed by our group, can be useful for assessing RXR binding to PPARγ/RXRα, and that the binding data differ from those of RXRα alone. This screening method opens a new avenue for binding assays for RXR heterodimers.

Investigation of predictive factors for the presence of voiding dysfunction after transvaginal mesh surgery-Can the flow curve shape on uroflowmetry be a predictor?

PURPOSE: This study established the prognostic significance of the uroflowmetry flow curve shape in the presence of voiding dysfunction following transvaginal mesh surgery. METHODS: This is a retrospective study of 439 symptomatic cystocele patients who underwent anterior wall repair with transvaginal mesh surgery. Uroflowmetry and postvoid residual were used to evaluate voiding function both preoperatively and 12 months postoperatively. The patients were divided into two groups: those with and without postoperative voiding dysfunction, and the predictors of postoperative voiding dysfunction were analyzed. The shape of the urine flow curve was analyzed for its influence on the presence of postoperative voiding dysfunction. RESULTS: Thirty-five participants were in the voiding dysfunction group, while 404 were in the nonvoiding dysfunction group. Multivariate analysis was conducted by adding an interrupted-shaped curve to age, Qmax, and postvoid residual, which showed significant differences in univariate analysis, found that age 68 years or older (odds ratio [OR]: 7.68, 95%CI 1.02-58, p = 0.048), postvoid residual ≥110 mL (OR: 2.8, 95%CI 1.25-6.29, p = 0.013) and interrupted-shaped curve (OR: 2.47, 95%CI 1.07-5.69, p = 0.034) were discovered to be independent risk factors for the presence of voiding dysfunction after transvaginal mesh surgery. CONCLUSIONS: Following transvaginal mesh surgery for cystocele, three variables were found to be predictive of voiding dysfunction: the old age, excessive postvoid residual, and an interrupted-shaped flow curve. The uroflowmetry flow curve shape has the potential to be a new predictor of postoperative voiding dysfunction.

Structural characterization of 1,3-bis-tert-butyl monocyclic benzene derivatives with agonistic activity towards retinoid X receptor alpha.

Retinoid X receptor alpha (RXRα) plays pivotal roles in multiple biological processes, but limited information is available on the structural features of chemicals that show low affinity for RXRα, but nevertheless cause significant activation, though these may represent a human health hazard. We recently discovered that several industrial chemicals having 1,3-bis-tert-butylbenzene as a common chemical structure exhibit agonistic activity towards rat RXRα. In this study, we explored the structure-activity relationship of 1,3-bis-tert-butyl monocyclic benzene derivatives for RXRα activation by means of in vitro and in silico analyses. The results indicate that a bulky substituent at the 5-position is favorable for agonistic activity towards human RXRα. Since 1,3-bis-tert-butyl monocyclic benzene derivatives with bulky hydrophobic moieties differ structurally from known RXRα ligands such as 9-cis-retinoic acid and bexarotene, our findings may be helpful for the development of structural alerts in the safety evaluation of industrial chemicals for RXRα-based toxicity to living organisms.

Teratogenicity and Fetal-Transfer Assessment of the Retinoid X Receptor Agonist Bexarotene.

Bexarotene, a retinoid X receptor (RXR) agonist, is used to treat cutaneous T-cell lymphoma, and drug repositioning research has also been reported, despite warnings of teratogenicity. However, fetal transfer of bexarotene and its effect on rat fetal bone formation have not been examined. In this study, we conducted a detailed teratogenicity and fetal transferability assessment of bexarotene in rats. Repeated administration of bexarotene during pregnancy caused marked fetal atrophy and bone dysplasia. Although fetal transfer was not detectable by dynamic imaging of [11C]bexarotene by means of positron emission tomography, transfer to the fetus was confirmed by using a gamma counter. Similar levels were found in mother and fetus. In addition, we found that bexarotene was accumulated in the placenta. These findings will be useful for the toxicity assessment of bexarotene as well as for drug discovery research targeting RXR agonists, which are expected to have therapeutic effects in various diseases.

Transvaginal repair of enterocele following robot-assisted radical cystectomy using a mesh for abdominal wall hernia repair.

Introduction: This report aims to describe our experience in the pelvic floor reconstruction of anterior enterocele following radical cystectomy by transvaginal surgery using a mesh for abdominal wall hernia repair. Case presentation: An 84-years-old woman developed pelvic organ prolapse 4 months after undergoing robot-assisted radical cystectomy. After examination, she was diagnosed with a midline anterior enterocele. Considering the thinness of the vaginal wall and the large defect of the vaginal wall muscle layer, we performed transvaginal repair using a mesh for abdominal wall hernia repair designed to reduce the adhesion to the intestinal tract. Conclusion: At the 1-year follow-up, neither recurrence nor complications were observed. This showed that transvaginal mesh surgery for abdominal wall hernia repair could be a treatment option for pelvic organ prolapse with a vaginal wall muscle layer defect after radical cystectomy.

A mouse model of type B cystinuria due to spontaneous mutation in FVB/NJcl mice.

Cystinuria is an autosomal metabolic disorder caused by mutations in the SLC3A1 and SLC7A9 genes, encoding the amino acid transporter proteins rBAT and b0,+AT, respectively. Based on the causative gene, cystinuria is classified into 3 types: type A (SLC3A1), type B (SLC7A9), and type AB (SLC3A1 and SLC7A9). Patients with cystinuria exhibit hyperexcretion of cystine and dibasic amino acids in the urine and develop cystine crystals due to its low solubility in the urine, often resulting in calculus formation. In this study, we present an inbred strain FVB/NJcl mice affected with cystinuria. In the affected mouse kidney, Slc7a9 expression was completely abolished because of a large sequence deletion in the promoter region of the Slc7a9 mutant allele. Slc7a9-deficient mice with FVB/NJcl genetic background developed cystine calculi in the bladder with high penetrance, as compared to the previously reported mouse models of cystinuria. This model may be useful to understand the determinants of crystal aggregation, affecting calculus formation.

Are anterior mesh arms necessary in Japanese-style transvaginal mesh surgery for cystocele?

AIM: In this study, we retrospectively analyzed the medium-term efficacy and safety of surgery with transobturator two-arm transvaginal mesh for cystocele and to verify whether the anterior arms are necessary for Japanese-style transvaginal mesh surgery. METHODS: The study included 203 patients with cystocele who underwent transobturator two-arm transvaginal mesh at our hospital between August 2015 and June 2017 and received appropriate follow-up care for at least 48 months after surgery. RESULTS: The Pelvic Organ Prolapse Quantification stage was III in all the patients. Intraoperative complications included two cases of bladder injury and one case of more than 200 mL of blood loss. The mean observation period was 51.9 months, and prolapse recurred in the operated compartment in nine patients (4.4%). No cases of mesh exposure were observed. In comparing the preoperative characteristics of the 9 patients with prolapse recurrence at the surgical site with those of the other 194 patients, we found that the recurrence rate was significantly higher among patients in whom point Ba being 3.5 cm or more and among patients younger than 66 years. CONCLUSIONS: Transobturator two-arm transvaginal mesh for cystocele was as good and safe as the procedure previously reported with four-arm mesh; thus, it was possible to omit the anterior mesh arms in Japanese-style transvaginal mesh surgery. Patients should be informed preoperatively that prolapse recurs at a significantly higher rate among younger patients and in those whose point Ba being 3.5 cm or more.

Differential volume reductions in the subcortical, limbic, and brainstem structures associated with behavior in Prader-Willi syndrome.

Individuals with Prader-Willi syndrome (PWS) exhibit complex behavioral characteristics, including hyperphagia, autistic features, and subsequent age-related maladaptive behaviors. While this suggests functional involvements of subcortical, limbic, and brainstem areas, developmental abnormalities in such structures remain to be investigated systematically. Twenty-one Japanese individuals with PWS and 32 healthy controls with typical development were included. T1-weighted three-dimensional structural magnetic resonance images were analyzed for subcortical, limbic, and brainstem structural volumes, with age as a covariate, using a model-based automatic segmentation tool. Correlations were determined between each volume measurement and behavioral characteristics as indexed by questionnaires and block test scores for hyperphagia (HQ), autistic and obsessional traits, non-verbal intelligence (IQ), and maladaptive behavior (VABS_mal). Compared with the control group, the PWS group showed significantly reduced relative volume ratios per total intracranial volume (TIV) in thalamus, amygdala, and brainstem structures, along with TIV and native volumes in all substructures. While the brainstem volume ratio was significantly lower in all age ranges, amygdala volume ratios were significantly lower during early adulthood and negatively correlated to HQ and VABS_mal but positively correlated to Kohs IQ. Thus, limbic and brainstem volume alterations and differential volume trajectories may contribute to the developmental and behavioral pathophysiology of PWS.

Is transvaginal mesh procedure a potential measure for pelvic organ prolapse repair when performed by expert surgeons?

OBJECTIVES: The aim of this study was to verify the safety and efficacy of transvaginal mesh by analyzing the 2-year follow-up data of patients performed by a surgeon with a high volume of procedures. METHODS: A total of 617 patients with pelvic organ prolapse underwent transvaginal mesh by a single surgeon. Complications and anatomical status of each patient were examined up to 24 months after surgery. Risk factors for the recurrence were also analyzed. RESULTS: Regarding complications, we experienced 10 patients (3.8%) of bladder injuries in anterior transvaginal mesh and eight (3.4%) in anterior and posterior transvaginal mesh. Massive blood loss was observed in four patients, but there was no case of blood transfusion. Mesh exposures were seen in seven patients (1.2%). A total of 100 patients (16.2%) had prolapse recurrence, defined as the Pelvic Organ Prolapse Quantification System stage ≥II. As to recurrences on the operated compartments, we observed five patients (2.0%) for anterior transvaginal mesh, three (6.5%) for posterior transvaginal mesh, five (7.4%) for combined transvaginal mesh, and 31 (14.2%) in anterior and posterior transvaginal mesh. Regarding Point C before operation in the anterior and posterior transvaginal mesh, the recurrence rates were more than 23% in patients with a Point C of 4 or more. Binominal regression analyses showed that higher body mass index, younger age, and higher stage of uterine prolapse were significant risk factors. CONCLUSIONS: The transvaginal mesh surgery is safe when conducted by experts. However, the recurrence rate may exceed 20% for high-stage uterine prolapse even when conducted by experts.

Genetic determinants of risk in autoimmune pulmonary alveolar proteinosis.

Pulmonary alveolar proteinosis (PAP) is a devastating lung disease caused by abnormal surfactant homeostasis, with a prevalence of 6-7 cases per million population worldwide. While mutations causing hereditary PAP have been reported, the genetic basis contributing to autoimmune PAP (aPAP) has not been thoroughly investigated. Here, we conducted a genome-wide association study of aPAP in 198 patients and 395 control participants of Japanese ancestry. The common genetic variant, rs138024423 at 6p21, in the major-histocompatibility-complex (MHC) region was significantly associated with disease risk (Odds ratio [OR] = 5.2; P = 2.4 × 10-12). HLA fine-mapping revealed that the common HLA class II allele, HLA-DRB1*08:03, strongly drove this signal (OR = 4.8; P = 4.8 × 10-12), followed by an additional independent risk allele at HLA-DPß1 amino acid position 8 (OR = 0.28; P = 3.4 × 10-7). HLA-DRB1*08:03 was also associated with an increased level of anti-GM-CSF antibody, a key driver of the disease (ß = 0.32; P = 0.035). Our study demonstrated a heritable component of aPAP, suggesting an underlying genetic predisposition toward an abnormal antibody production.

Cancer Awareness and Understanding of Students in Japan: What Do Students Having Close Relatives with Cancer Think About the Disease?

Students have become more familiar with cancer because of media, such as television or the Internet, reporting on celebrity cancer cases. Moreover, with Japan's increasing age and cancer rates, the number of students whose parents/relatives develop cancer is likely to increase. This study examined cancer awareness and understanding among students aged 10 to 16 or more. A cross-sectional nationwide survey was conducted using a self-administered questionnaire. Cancer awareness and cancer understanding were assessed using a self-administered questionnaire. We collected a total of 9139 questionnaires and excluded those with missing data. Thus, we analyzed the responses of 8701 students: 2135, 2902, and 3664 from elementary, junior, and high school, respectively. Data were analyzed using a multivariable model adjusted for gender and grade. Approximately 30% of respondents had parents/relatives with cancer. In addition, there was a significant association between having parents/relatives with cancer and cancer awareness; however, students having parents/relatives with cancer had more negative awareness (i.e., "I think cancer is scary," "I think I will get cancer in the future," and "I think cancer is preventable"). Furthermore, there was a significant association between cancer understanding and awareness. These findings suggest that cancer education could have a desirable effect on students whose parents/relatives have cancer. Further, cancer education offers benefits to students who are naive about cancer and ill prepared to cope when a family member discloses a cancer diagnosis.

Application of 7 tesla magnetic resonance imaging for pediatric neurological disorders: Early clinical experience.

Ultra-high field magnetic resonance imaging (MRI) has been introduced for use in pediatric developmental neurology. While higher magnetic fields have certain advantages, optimized techniques with specific considerations are required to ensure rational and safe use in children and those with pediatric neurological disorders (PNDs). Here, we summarize our initial experience with clinical translational studies that utilized 7 tesla (T)-MRI in the fields of developmental neurology. T2-reversed images and three-dimensional anisotropy contrast imaging enabled the depiction of targeted pathological brain structures with better spatial resolution. Diffusion imaging and susceptibility-weighted imaging enabled visualization of intracortical, subcortical, and intratumoral microstructures in vivo within highly limited scan times appropriate for patients with PNDs. 7T-MRI appears to have significant potential to enhance the depiction of the structural and functional properties of the brain, particularly those associated with atypical brain development.

[The Clinical Course of α1 Blocker Discontinuation in Patients with LUTS/BPH Receiving Combination Therapy of Dutasteride and α1 Blocker].

We retrospectively investigated the clinical course of α1 blocker discontinuation in patients who had lower urinary tract symptoms with benign prostate hypertrophy (LUTS/BPH) and received combination therapy ofdutasteride and α1 blocker. Among the patients with LUTS/BPH who had been receiving combination therapy, those who wished to reduce the number ofprescribed drugs and discontinue the use of α1 blocker because ofsymptom improvement were recruited in this study. Symptom scores including International Prostate Symptom Score (IPSS) and overactive bladder symptom score (OABSS), parameters ofuroflowmetry and prostate volume (PV) were evaluated at the time of α 1 blocker discontinuation. Twenty-two patients discontinued the use of α 1 blocker. The mean PV at the time of α 1 blocker discontinuation was 43.2 ml, and the mean duration ofcombination therapy was 39.4 months. In 11 (50%) patients, dutasteride monotherapy without α1 blocker was maintained for a mean follow-up of 10.5 months (9-12 months) after α1 blocker discontinuation (Non-resumption group). In the other 11 patients (50%), α1 blocker was resumed because ofthe patient's request to resume the use of α1 blocker (Resumption group). The mean length ofdutasteride monotherapy was 4. 5 months (1-8 months) in the resumption group. Compared with the non-resumption group, IPSS total score and storage sub-score ofIPSS at the time of α1 blocker discontinuation were significantly higher in the resumption group. Based on the ROC curve, IPSS total score <16, IPSS voiding/storage symptom score <7, OABSS <7 and PV 54 ml or more at the time of α1 blocker discontinuation were predictors ofnon-resumption of α1 blocker. These results suggest that if LUTS is controlled by a long-term combination therapy ofdutasteride and α1 blocker and still PV is large enough, α1 blocker can be discontinued.

[Initial Experiences of Dynamic Sentinel Lymph Node Biopsy (DSNB) in Patients with Penile Cancer].

We present 2 cases of penile cancer in which the inguinal lymph node was not palpable and inguinal lymph node dissection (ILND) could be safely avoided by conducting dynamic sentinel lymph node biopsy (DSNB). The first case was in a 54-year-old man complaining of penile tumor for at least 3 months. We performed partial penectomy and DSNB. The pathological diagnosis was squamous cell carcinoma (SCC), pT2-3. There was no cancer metastasis in sentinel nodes (0/2). There has been no recurrence for 6 years after operation. The second case was 65-year-old man suffering from penile tumor for at least 6 months. We performed partial penectomy and DSNB. The pathological diagnosis was SCC,pT2. There was no cancer metastasis in sentinel nodes (0/3). There has been no recurrence for 1 year after operation. ILND has been recommended for intermediate and high-risk penile cancer even in patients with non-palpable inguinal lymph nodes. However,the complication of ILND is very high. DSNB has the potential to avoid ILND if there is no cancer metastasis in sentinel nodes.

[Relationship between Early Complications after Radical Cystectomy and Psoas Muscle Mass].

Psoas muscle mass index (PMI) is related to sarcopenia. We examined whether PMI is associated with early complications after radical cystectomy. Seventy one male and 29 female patients who were 65 years old or older and who had undergone radical cystectomy at our hospital from April 2005 to March 2018 were retrospectively analyzed. Psoas muscle section area was measured manually on preoperative computed tomography (CT) scan and normalized by patient's height. Early postoperative complications of grade 3 or more occurred in 12 male (16.9%) and 5 female (17.2%) patients. PMI was lower in male patients who had early postoperative complications of grade 3 or more than in those without complications (5.61 vs 6.54 cm2 /m2, p=0. 08), although the difference was not statistically significant. There was suggested to be a relationship between early postoperative complications after radical cystectomy and preoperative PMI in elderly male patients.

Fluorine-18 (18F)-labeled retinoid x receptor (RXR) partial agonist whose tissue transferability is affected by other RXR ligands.

Bexarotene (1), a retinoid X receptor (RXR) agonist approved for the treatment of cutaneous T cell lymphoma (CTCL), was reported to migrate into baboon brain based on findings obtained by positron emission tomography (PET) with a 11C-labeled tracer. However, co-administration of non-radioactive 1 had no effect on the distribution of [11C]1, probably due to non-specific binding of 1 as a result of its high lipophilicity. Here, we report a fluorine-18 (18F)-labeled PET tracer [18F]6 derived from RXR partial agonist CBt-PMN (2), which has lower lipophilicity and weaker RXR-binding ability than [11C]1. The concomitant administration of 1 or 2 with [18F]6 with resulted in decreased accumulation of [18F]6 in liver, together with increased brain uptake and increased accumulation in kidney and muscle, as visualized by PET. A plausible explanation of these findings is the inhibition of [18F]6 uptake into the liver by concomitantly administered 1 or 2, leading to an increase in blood concentration of [18F]6 followed by increased accumulation in other tissues.