FXR activation remodels hepatic and intestinal transcriptional landscapes in metabolic dysfunction-associated steatohepatitis.

The escalating obesity epidemic and aging population have propelled metabolic dysfunction-associated steatohepatitis (MASH) to the forefront of public health concerns. The activation of FXR shows promise to combat MASH and its detrimental consequences. However, the specific alterations within the MASH-related transcriptional network remain elusive, hindering the development of more precise and effective therapeutic strategies. Through a comprehensive analysis of liver RNA-seq data from human and mouse MASH samples, we identified central perturbations within the MASH-associated transcriptional network, including disrupted cellular metabolism and mitochondrial function, decreased tissue repair capability, and increased inflammation and fibrosis. By employing integrated transcriptome profiling of diverse FXR agonists-treated mice, FXR liver-specific knockout mice, and open-source human datasets, we determined that hepatic FXR activation effectively ameliorated MASH by reversing the dysregulated metabolic and inflammatory networks implicated in MASH pathogenesis. This mitigation encompassed resolving fibrosis and reducing immune infiltration. By understanding the core regulatory network of FXR, which is directly correlated with disease severity and treatment response, we identified approximately one-third of the patients who could potentially benefit from FXR agonist therapy. A similar analysis involving intestinal RNA-seq data from FXR agonists-treated mice and FXR intestine-specific knockout mice revealed that intestinal FXR activation attenuates intestinal inflammation, and has promise in attenuating hepatic inflammation and fibrosis. Collectively, our study uncovers the intricate pathophysiological features of MASH at a transcriptional level and highlights the complex interplay between FXR activation and both MASH progression and regression. These findings contribute to precise drug development, utilization, and efficacy evaluation, ultimately aiming to improve patient outcomes.

Obesity induced disruption on diurnal rhythm of insulin sensitivity via gut microbiome-bile acid metabolism.

The disruption of the diurnal rhythm has been recognized as a significant contributing factor to metabolic dysregulation. The important role of gut microbiota and bile acid metabolism has attracted extensive attention. However, the function of the gut microbiota-bile acid axis in regulating the diurnal rhythms of metabolic homeostasis remains largely unknown. Herein, we aimed to investigate the interplay between rhythmicity of host metabolism and gut microbiota-bile acid axis, as well as to assess the impact of obesity on them. We found that high fat diet feeding and Leptin gene deficiency (ob/ob) significantly disturbed the rhythmic patterns of insulin sensitivity and serum total cholesterol levels. The bile acid profiling unveiled a conspicuous diurnal rhythm oscillation of ursodeoxycholic acid (UDCA) in lean mice, concomitant with fluctuations in insulin sensitivity, whereas it was absent in obese mice. The aforementioned diurnal rhythm oscillations were largely desynchronized by gut microbiota depletion, suggesting the indispensable role of gut microbiota in diurnal regulation of insulin sensitivity and bile acid metabolism. Consistently, 16S rRNA sequencing revealed that UDCA-associated bacteria exhibited diurnal rhythm oscillations that paralleled the fluctuation in insulin sensitivity. Collectively, the current study provides compelling evidence regarding the association between diurnal rhythm of insulin sensitivity and gut microbiota-bile acid axis. Moreover, we have elucidated the deleterious effects of obesity on gut microbiome-bile acid metabolism in both the genetic obesity model and the diet-induced obesity model.

Comparison of laparoscopic excision versus open transvesical excision for symptomatic prostatic utricle in children.

PURPOSE: The aims of this study were to report our clinical experience with laparoscopic excision (LE) and to compare the outcomes of LE versus open transvesical excision (OTE) for the management of prostatic utricle (PU) in children. PATIENTS AND METHODS: This was a retrospective single-center study of 14 children who underwent OTE or LE for managing symptomatic PU between April 2003 and December 2014. Age, utricle size, operative time, estimated blood loss, duration of hospital stay, indwelling time of the urethral catheter, presence of residual postoperative utricular stump, and complications were compared between the two groups. RESULTS: There were no significant differences in age or utricle size between the two groups. Compared to the OTE group, the LE group experienced shorter operative times, lower estimated blood losses, and shorter hospital stays. Indwelling time of the urethral catheter was nearly 8days in the OTE group and 6days in the LE group. All patients had a follow-up visit between 6months and 2years after surgery. Two patients in the OTE group had transient UTI. Postoperative VCUG showed minimal residual utricular stump for 3 patients in the OTE group. However, no patient in either group required further operative therapy. CONCLUSIONS: LE is a safe and feasible procedure for symptomatic PU in children. Compared to OTE, LE can provide minimally invasive access for achieving good exposure with good short-term outcomes.

Comparison of tubularized incised plate urethroplasty combined with a meatus-based ventral dartos flap or dorsal dartos flap in hypospadias.

PURPOSE: Tubularized incised plate urethroplasty (TIPU) is the preferred surgical option for distal and mid-shaft hypospadias repair. Neourethra dartos flap coverage is routinely used as a protective layer with good results. We modified meatus-based ventral dartos flap (MBVDF) to TIPU by dissecting the proximal mid-ventral dartos attached urethra and leaving the subcutaneous fascia connecting the meatus, and retrospectively compared the outcomes of using MBVDF with single dorsal dartos flap (DDF) on the complication rates of TIPU. METHODS: We present 2 surgeons' experiences with 356 patients with distal and mid-shaft hypospadias between January 2010 and December 2014. Patients were divided into two groups. Group DDF included 185 patients (mean age 29 months) underwent TIPU with DDF rotated laterally covering the suture lines of the neourethra. Group MBVDF included 171 patients (mean age 26 months) underwent TIPU with MBVDF covering the suture lines of the neourethra. Statistical analysis of patient basic information and complications was performed by two independent sample t test and Chi square test or Fisher's exact test. RESULTS: There were no statistical differences in age, type of hypospadias, and follow-up time between the two groups. The mean operative time in the group MBVDF (68.93 ± 8.32 min) was significantly shorter than in the group DDF (73.60 ± 9.06 min). Ventral skin necrosis (2.7%) and penile rotation (3.8%) in group DDF was significantly higher than group MBVDF which did not occur. The differences in other complication rates including fistula rate (2.7 vs 2.9%) between the groups were not statistically significant. CONCLUSION: DDF and MBVDF with TIPU are similarly effective methods for decreasing fistula in hypospadias repair. MBVDF with TIPU may be an easier method and can avoid ventral skin necrosis and penile rotation.

Modified penoplasty for concealed penis in children.

OBJECTIVE: To report a modified penoplasty technique for concealed penis in children. METHODS: Between January 2006 and June 2012, 201 cases of concealed penis were surgically repaired with modified penoplasty. The modified penoplasty technique consisted of 3 major steps: (1) degloved the penile skin and excised the inner prepuce, (2) advanced penoscrotal skin to cover penile shaft, and (3) fixed the penis base and reconstructed the penoscrotal angle. RESULTS: Two hundred one cases of concealed penis were enrolled in this study over a period of 6 years. Mean age at the time of surgery was 5.3 years (range 1-13 years) and mean operative time was 40 minutes (range 30-65minutes). All patients were routinely followed up at 1, 3, and 6 months after surgery. Most patients developed postoperative edema and were resolved within 1 month, whereas 20 cases developed prolonged postoperative edema, especially at the site of frenulum, which took 3 months to be resolved. Ten cases had retraction after surgery. No erection difficulties were recorded. Patients/parents reported better hygiene and improved visualization and accessibility of penis after surgery and were satisfied with the cosmetic outcome. CONCLUSION: The result of this study shows that the modified penoplasty technique is a simple, safe, and effective procedure for concealed penis with satisfied cosmetic outcome.

Considerations before repair of acquired rectourethral and urethrovaginal fistulas in children.

BACKGROUND: Acquired rectourethral or urethrovaginal fistula between the rectum or vaginal and lower urinary tract is an uncommon entity, which occurs as a consequence of pelvic disorder, including trauma, iatrogenic injury, inflammatory bowel disease, pelvic neoplasm or infection. But when is it appropriate to repair the fistula and what methods to be chosen? There has been no consensus on them. This study was undertaken to determine the timing of the procedure and the repair of rectourethral and urethrovaginal fistula. METHODS: From 1998 to 2006, we treated 19 children with rectourethral or urethrovaginal fistula, including rectourethral fistula in 15 boys and urethrovaginal fistula in 4 girls. The mean age of the patients was 6.2 years (range, 8 months to 11.5 years). The fistula occurred after pelvic fracture in 10 patients, and after iatrogenic injury in 9 including 4 after radical operation for Hirschsprung's disease and 5 due to anorectal malformation. Preoperatively, the general and local infections were controlled thoroughly, and complications such as urethral stricture and secondary megacolon were treated at first. At least 6 months after the last procedure, all patients underwent the 1-stage York-Mason procedure (via parasacrococcygeal incision) without colostomy and suprapubic cystostomy. Intraoperatively, the entire fistulous tract was excised completely. RESULTS: Infection and partial dehiscence of the wound occurred in 2 patients respectively. All fistulae were closed successfully without fecal incontinence or postoperative anal stricture. No patient suffered from urinary incontinence after fistula repair. The scars around the fistula were removed because they would shrink and lead to subsequent urethral occlusion or stricture. CONCLUSIONS: The timing of operation for acquired rectourethral or urethrovaginal fistula is appropriate at least 6 months after the last procedure. The 1-stage York-Mason procedure for the repair of the fistula is feasible and effective.