NOX1/4 Inhibitor GKT-137831 Improves Erectile Function in Diabetic Rats by ROS Reduction and Endothelial Nitric Oxide Synthase Reconstitution.

BACKGROUND: Previous studies have shown that oxidative stress contributes to hyperglycemia-induced erectile dysfunction. A preferential direct inhibitor of NOX1 and NOX4, GKT-137831, exhibited a strong anti­oxidative role via blockade of reactive oxygen species (ROS) generation in endothelial cells, but whether GKT-137831 could improve erectile function was not clear. AIM: Our study was designed to investigate the effect of NOX1/4 inhibition on improving diabetic erectile dysfunction (ED) in rats. METHODS: We used streptozotocin to induce type 1 diabetes mellitus (DM) in 32 male Sprague Dawley (SD) rats (8 weeks old). Eight weeks later, type 1 diabetes mellitus-induced erectile dysfunction (DMED) in rats was confirmed using an apomorphine test. Our study consisted of 3 groups: (i) nondiabetic control group (n = 8), (ii) DMED + vehicle group (DMED group; n = 8), and (iii) DMED + GKT-137831 group (n = 9); GKT-137831 was given as a once-daily intraperitoneal injection for 4 weeks. Cavernous nerve electrostimulation was used to evaluate erectile function. Western blot, ELISA, immunohistochemistry, and immunofluorescence were used to measure expression of specific proteins, and DHE fluorescent probe was performed to detect ROS level. OUTCOMES: Intracavernous pressure (ICP), nitric oxide (NO)/cyclic guanosine monophosphate (cGMP) signaling pathway, oxidative stress level, inflammatory response, corporal autophagy, and apoptosis were measured. RESULTS: Erectile function in the DMED group was significantly impaired compared to the nondiabetic control group, whereas this impairment was improved with GKT-137831 treatment by 70%. Similarly, endothelial function and overactivated oxidative stress in the corpus cavernosum (CC) of the DMED + GKT-137831 group were improved. The DMED group showed serious inflammatory responses and excessive autophagy, which were inhibited by GKT-137831 treatment in the DMED + GKT-137831 group. CLINICAL TRANSLATION: Our study showed improvement in erectile function with GKT-137831 in a diabetic rat ED model. STRENGTH AND LIMITATIONS: This study suggested for the first time that GKT-137831, an NOX1/4 inhibitor undergoing clinical trials, is effective in improving erectile function in rats with type 1 DMED. However, we only investigated GKT-137831 treatment of streptozotocin-induced type 1 diabetic rats, and therapeutic evidence in other types of diabetes is lacking. CONCLUSION: GKT-137831 improves erectile function by 70% in type 1 DMED rats and constitutes a promising compound for the treatment of type 1 DMED, likely by inhibition of overactivated oxidative stress, down-regulation of proinflammatory factors, and amelioration of excessive autophagy and endothelial function. B Zhou, Y Chen, H Yuan, et al. NOX1/4 Inhibitor GKT-137831 Improves Erectile Function in Diabetic Rats by ROS Reduction and Endothelial Nitric Oxide Synthase Reconstitution. J Sex Med 2021;18:1970-1983.

Baicalein Alleviates Erectile Dysfunction Associated With Streptozotocin-Induced Type I Diabetes by Ameliorating Endothelial Nitric Oxide Synthase Dysfunction, Inhibiting Oxidative Stress and Fibrosis.

BACKGROUND: Management of diabetes mellitus induced-erectile dysfunction (DMED) is challenging because of its poor responses to phosphodiesterase type 5 inhibitors. Increasingly important roles of 12-lipoxygenase (12-LOX) have been proven in diabetes mellitus. AIM: To investigate 12-LOX activity and therapeutic effect of its inhibitor, baicalein (BE), on DMED. METHODS: Intraperitoneal streptozotocin injection was used to induce type I DM, and an apomorphine test was used to evaluate erectile function. In experiment A, we assessed 12-LOX expression alteration in the corpus cavernosum (CC) of rats with DMED of different levels of severity. In experiment B, rats with DMED were intraperitoneally injected with BE for 4 weeks, and control rats were injected with vehicles. The erectile function was tested by cavernous nerve stimulation before penile tissue was harvested. We performed Western blot, immunohistochemistry, immunofluorescence, Masson trichrome staining, and enzyme-linked immunosorbent assays to measure related proteins in CC. MAIN OUTCOME MEASURE: The main outcome measures included rectile response, histologic examination, and expression alteration of related proteins. RESULTS: 12-LOX upregulation was associated with the progression of type I DMED. After 4 weeks treatment, compared with the DMED group, the DMED + BE group showed better erectile responses to cavernous nerve stimulation. In the DMED + BE group, significantly enhanced endothelial nitric oxide synthase/nitric oxide/cyclic guanosine monophosphate pathway, reduced 12-LOX expression, and inhibited p38 mitogen-activated protein kinase/arginase II/L-arginine pathway were showed in CC relative to the DMED group. In addition, overactivated oxidative stress and fibrosis in the DMED group were both partially ameliorated in the DMED + BE group. CLINICAL IMPLICATIONS: BE may be considered as an effective therapy for DMED, but needs to be verified in future human investigations. STRENGTHS & LIMITATIONS: The role of 12-LOX and its inhibitor, BE, is firstly demonstrated in rats with type I DMED. However, the experimental data are derived from animal models with without evidences from cellular-based experiments. CONCLUSION: 12-LOX might serve as an important factor in the pathogenesis of type I DMED. BE alleviated erectile dysfunction in rats with type I DMED probably by inhibiting 12-LOX expression, ameliorating endothelial nitric oxide synthase dysfunction, as well as suppressing oxidative stress and fibrosis. Chen Y, Zhou B, Yu Z, et al. Baicalein Alleviates Erectile Dysfunction Associated With Streptozotocin-Induced Type I Diabetes by Ameliorating Endothelial Nitric Oxide Synthase Dysfunction, Inhibiting Oxidative Stress and Fibrosis. J Sex Med 2020;17:1434-1447.

Symptomatic sinus tachycardia with perpetuating slow pathway: successful treatment with radiofrequency ablation.

We report a case of sinus tachycardia with perpetuating slow pathway (SP) conduction in a 42-year-old woman who developed severe symptoms as a result of atrioventricular (AV) desynchronization. The restoration of an AV synchrony, achieved with selective radiofrequency ablation of the SP, eliminated the symptomatic arrhythmia and may represent a reasonable therapeutic option despite the fact that the patient has no AV-node reentrant tachycardia. This case demonstrates the importance of AV timing.

A rare family outbreak of Mycobacterium abscessus infection in immunocompetent fraternal triplets.

Background: Mycobacterium abscessus (M. abscessus) infection is rare in children who were previously healthy, particularly in infants. We present the first report of a family outbreak of M. abscessus infection among immunocompetent infant triplets. Methods: We reviewed triplets' demographic data, laboratory tests and imaging examinations to describe their clinical features. We performed whole-exome sequencing to rule out primary immunodeficiency disorders. We used DNA sequencing for M. abscessus subspecies identification. Results: The fraternal triplets (triples A, B and C) presented with a 10-day history of cough. Triple A also experienced a brief episode of fever, and triple B had tachypnea. Chest CT scans showed pulmonary masses and nodules in triples A and C, and cavities in triple B. Cultures of sputum and bronchoalveolar lavage fluid from all triplets yielded M. abscessus. Further subspecies identification showed that isolates from triples A and C were M. abscessus subsp. massiliense, and isolates from triple B were M. abscessus subsp. abscessus (MAA). After eight months of combination therapy, the pulmonary lesions of the triplets improved significantly. Conclusion: Our study confirms that M. abscessus pulmonary disease can occur in immunocompetent infants. We hypothesize that the simultaneous infection of the triplets may be associated with their prematurity and extensive environmental exposure. This study highlights the importance to include M. abscessus infection in the differential diagnosis of pulmonary masses and/or cavities, regardless of the age of onset or the presence of underlying pathology or susceptible genes.

Alanine aminotransferase as a risk marker for new-onset metabolic dysfunction-associated fatty liver disease.

In this editorial, we comment on the article by Chen et al. Metabolic dysfunction-associated fatty liver disease (MAFLD) is a global public health burden whose incidence has risen concurrently with overweight and obesity. Given its detrimental health impact, early identification of at-risk individuals is crucial. MAFLD diagnosis is based on evidence of hepatic steatosis indicated by liver biopsy, imaging, or blood biomarkers, and one of the following conditions: Overweight/ obesity, type 2 diabetes mellitus, or metabolic dysregulation. However, in large-scale epidemiological studies, liver biopsies are not feasible. The application of techniques such as ultrasonography, computed tomography, magnetic resonance imaging, and magnetic resonance spectroscopy is restricted by their limited sensitivity, low effectiveness, high costs, and need for specialized software. Blood biomarkers offer several advantages, particularly in large-scale epidemiological studies or clinical scenarios where traditional imaging techniques are impractical. Analysis of cumulative effects of excess high-normal blood alanine aminotransferase (ALT) levels of blood ALT levels could facilitate identification of at-risk patients who might not be detected through conventional imaging methods. Accordingly, investigating the utility of blood biomarkers in MAFLD should enhance early detection and monitoring, enabling timely intervention and management and improving patient outcomes.

N6-methyladenosine dynamics in placental development and trophoblast functions, and its potential role in placental diseases.

N6-methyladenosine (m6A) is the most abundant modification controlling RNA metabolism and cellular functions, but its roles in placental development are still poorly understood. Here, we characterized the synchronization of m6A modifications and placental functions by mapping the m6A methylome in human placentas (n = 3, each trimester), revealing that the dynamic patterns of m6A were associated with gene expression homeostasis and different biological pathways in placental development. Then, we generated trophoblast-specific knockout mice of Wtap, a critical component of methyltransferase complex, and demonstrated that Wtap was essential for trophoblast proliferation, placentation and perinatal growth. Further in vitro experiments which includes cell viability assays and series molecular binding assays demonstrated that WTAP-m6A-IGF2BP3 axis regulated the RNA stability and translation of Anillin (ANLN) and VEGFA, promoting trophoblast proliferation and secretion. Dysregulation of this regulatory axis was observed in placentas from pregnancies with fetal growth restriction (FGR) or preeclampsia, revealing the pathogenic effects of imbalanced m6A modifications. Therefore, our findings provide novel insights into the functions and regulatory mechanisms of m6A modifications in placental development and placental-related gestational diseases.

Identification of signaling pathways that specify a subset of migrating enteric neural crest cells at the wavefront in mouse embryos.

During enteric nervous system (ENS) development, pioneering wavefront enteric neural crest cells (ENCCs) initiate gut colonization. However, the molecular mechanisms guiding their specification and niche interaction are not fully understood. We used single-cell RNA sequencing and spatial transcriptomics to map the spatiotemporal dynamics and molecular landscape of wavefront ENCCs in mouse embryos. Our analysis shows a progressive decline in wavefront ENCC potency during migration and identifies transcription factors governing their specification and differentiation. We further delineate key signaling pathways (ephrin-Eph, Wnt-Frizzled, and Sema3a-Nrp1) utilized by wavefront ENCCs to interact with their surrounding cells. Disruptions in these pathways are observed in human Hirschsprung's disease gut tissue, linking them to ENS malformations. Additionally, we observed region-specific and cell-type-specific transcriptional changes in surrounding gut tissues upon wavefront ENCC arrival, suggesting their role in shaping the gut microenvironment. This work offers a roadmap of ENS development, with implications for understanding ENS disorders.

N6-methyladenosine modifications in maternal-fetal crosstalk and gestational diseases.

As a medium among pregnant women, environment and fetus, placenta owns powerful and delicate epigenetic processes to regulate gene expression and maintain cellular homeostasis. N6-methyladenosine (m6A) is the most prevalent modification that determines the fate of RNA, and its dynamic reversibility indicates that m6A may serve as a sensitive responder to environmental stimuli. Emerging evidence suggests that m6A modifications play an essential role in placental development and maternal-fetal crosstalk, and are closely related to gestational diseases. Herein, we summarized the latest techniques for m6A sequencing and highlighted current advances of m6A modifications in maternal-fetal crosstalk and the underlying mechanisms in gestational diseases. Therefore, proper m6A modifications are important in placental development, but its disturbance mainly caused by various environmental factors can lead to abnormal placentation and function with possible consequences of gestational diseases, fetal growth and disease susceptibility in adulthood.

Wide QRS complex tachycardia with a mysterious mask-Tricuspid isthmus-dependent atrial flutter with preexcitation syndrome and dual atrioventricular nodal pathway conduction.

Key Clinical Message: Atrial flutter (AFL) and supraventricular tachycardia (SVT) are common arrhythmias in clinic. However, some AFL cases may present additional complexities, such as both accessory pathways (AP) and dual atrioventricular node pathways, putting on a mysterious mask and making it challenging to distinguish on electrocardiograms (ECGs). Abstract: A 60-year-old male patient had a sudden syncope, and an ECG showed wide QRS complex tachycardia. This diagnostic ambiguity is further compounded by the fact that SVT via AP conduction can exhibit wide QRS complex tachycardia characteristics resembling ventricular tachycardia (VT). Consequently, a definitive diagnosis through electrophysiological (EP) examination becomes imperative, as it dictates subsequent ablation strategies. In this article, we present a rare case involving three distinct arrhythmias including AFL, AP, and dual atrioventricular node pathways, and successfully treated through ablation.

Screening of undernutrition in children with Hirschsprung disease using preoperative anthropometric parameters: A multicenter cross-sectional study.

BACKGROUND: The prevalence of malnutrition is unknown in patients with Hirschsprung disease. Undernutrition is associated with poor clinical outcomes. This study aims to describe the nutrition status among patients with Hirschsprung disease at admission. METHODS: We retrospectively used data from children with Hirschsprung disease admitted to three pediatric surgery centers in China from January 2016 to December 2020. The weight-for-age z scores (WAZ), height-for-age z scores (HAZ), and body mass index-for-age z scores (BAZ) were calculated as the reference for nutrition risk according to the World Health Organization child growth standards. The nutrition status of enrolled children was described and nutrition risk in each clinical characteristic was compared. The association between nutrition status and clinical outcomes was analyzed using univariate and multivariate logistic regression. RESULTS: A total of 624 patients were included in this study. The mean WAZ, HAZ, and BAZ of all patients was -0.64 ± 1.40, -0.45 ± 1.78, and -0.43 ± 1.50, respectively. Moderate to severe overall undernutrition was 16.3% (102/624). We found that WAZ and BAZ were significantly reduced with the length of aganglionic segments (P = 0.001). Children who had a definitive surgery at 3 years of age or older had significantly lower HAZ (P = 0.001). A multivariate regression model assessing postoperative Hirschsprung-associated enterocolitis showed that the WAZ was one of the independent risk factors (P = 0.001). CONCLUSION: Undernutrition is prevalent among children with Hirschsprung disease. Nutrition assessment to identify individuals at risk of undernutrition for further intervention is necessary.

The utility of the 24-h delayed film of barium enema for detecting the dysganglionic bowel segment in Hirschsprung's disease.

Background: Preoperative evaluation of the dysganglionic bowel segment is critical for establishing the optimal resection strategy for Hirschsprung's disease (HSCR), which facilitates patient outcomes. Objective: We set out to determine the utility of the 24-h delayed film of barium retention in predicting the length of dysganglionic bowel segment in HSCR. Materials and methods: A retrospective study of patients with clinically suspicious HSCR who underwent a preoperative 24-h delayed film of barium enema and were surgically treated from January 2015 to December 2019 was conducted. Results: Two hundred and 58 patients were enrolled in this study. The sensitivity, specificity, positive and negative predictive values (NPVs) of the 24-h delayed film of barium enema to predict the neuropathological segment were 89.1, 91.5, 91.3, and 89.4%, respectively. The Youden index was 80.6%, with a kappa value of 0.806 (P < 0.001). The correlation rate between barium retention level and pathological results was 72.7% (16/22) when aganglionosis was restricted within the mid-distal rectum (short-segment type), increasing to 92.0% (46/50) and 93.5% (174/186) for patients that had aganglionosis extended beyond the mid-distal rectum (classical type) and sigmoid colon (long-segment type), respectively. Lastly, patients younger than 3 months showed a lower correlation rate (72.2%) compared to patients aged 3-12 months (91.0%) and > 12 months (92.6%). Conclusions: Our investigation of the 24-h delayed film of barium enema performed for patients suspected of having HSCR indicated that the barium retention level remains crucial in predicting dysganglionic bowel segment, which contributes to the decision-making for surgical physicians.

Inflammatory bowel disease is associated with worse sexual function: a systematic review and meta-analysis.

Background: Several studies report that sexuality is often affected by inflammatory bowel diseases (IBD). The aim of this meta-analysis was to investigate the association between IBD and sexual function. Methods: A literature search was conducted in PubMed, Web of Science, and EMBASE databases (up to September 1, 2020). Scores of sexual functions with a standard deviation and odds ratio (OR) or relative risk (RR) with a 95% CI were used to analysis the association between IBD and sexual function. Results: Eleven studies with 7,018 male IBD cases and 1,803 female IBD cases were included in the meta-analysis. In male individuals, the pooled results revealed that IBD was significantly associated with impaired erectile function and poor sexual satisfaction (RR for erectile function =1.50, 95% CI: 1.22 to 1.84, P<0.0001; standard mean difference for sexual satisfaction =-0.24, 95% CI: -0.33 to -0.15, P<0.0001). And among female individuals, IBD had impact on most sub-domains of sexual function, except pains. Conclusions: IBD is associated with worse sexual function. It has significant impact on erectile function and satisfaction for male individuals and has impact on most sub-domains of sexual function for female individuals.

Early diagnosis and rescue pericardiocentesis for acute cardiac tamponade during radiofrequency ablation for arrhythmias. Is fluoroscopy enough?

BACKGROUND: With the number of complex catheter ablation procedures increasing, procedure-related acute cardiac tamponade is encountered more frequently in the cardiac catheterization laboratory. Survival depends on prompt recognition and rescue pericardiocentesis. OBJECTIVE: The aim of this report was to validate fluoroscopic heart silhouette characteristics associated with cardiac tamponade as a diagnostic method, and evaluate the safety and effectiveness of fluoroscopy-guided pericardiocentesis during catheter ablation. METHODS: All cases of acute cardiac tamponade that occurred in the cardiac catheterization laboratory during radiofrequency catheter ablation from March 2004 to November 2009 were reviewed retrospectively. RESULTS: Of 1,832 catheter ablation procedures performed during a 5-year period, 10 (0.55%) were complicated by cardiac tamponade. Fluoroscopic examination confirmed the diagnosis in all 10 patients and demonstrated effusions before hypotension in four patients. All patients were stabilized by fluoroscopy-guided pericardiocentesis with placement of an indwelling catheter and autologous transfusion. The time interval between recognition of cardiac tamponade and completion of pericardiocentesis was 6.0 ± 1.8 minutes (range 3-9 minutes). The mean aspirated blood volume was 437 mL (range 110-1,400 mL), and the mean autotransfused blood volume was 425 mL (range 100-1,384 mL). Surgical repair of the cardiac perforation was needed in one patient. No procedure-related death occurred. CONCLUSION: A reduction in the excursion of cardiac silhouette on fluoroscopy is an early diagnostic sign of cardiac tamponade during radiofrequency ablation. Fluoroscopy-guided pericardiocentesis is a safe and effective management strategy for cardiac tamponade developed in the cardiac catheterization laboratory.

Challenges Facing Percutaneous Ablation in the Treatment of Hepatocellular Carcinoma: Extension of Ablation Criteria.

As an emerging minimally invasive treatment method, percutaneous ablation is more and more widely used in the treatment of liver tumors. It has been recommended by guidelines for diagnosis and treatment of hepatocellular carcinoma (HCC) as a curative treatment alongside surgical resection and liver transplantation. In recent years, with the continuous advancement and innovation of percutaneous ablation technologies, their clinical efficacy and safety have been significantly improved, which has led to the expanded application of percutaneous ablation in the treatment of HCC-more and more patients who were previously considered unsuitable for ablation therapies are now being treated with percutaneous ablation. Obviously, percutaneous ablation can reduce the risk of treatment changes from curative strategies to palliative strategies. Based on clinical practice experience, this review enumerates the advantages and disadvantages of different ablative modalities and summarizes the existing combinations of ablation techniques, thus will help clinicians choose the most appropriate ablative modality for each patient and will provide scientific guidance for improving prognosis and making evidence-based treatment decisions. In addition, we point out the challenges and future prospects of the ablation therapies, thereby providing direction for future research.

Flexible Cyclosiloxane-Linked Fluorescent Porous Polymers for Multifunctional Chemical Sensors.

The construction of porous polymers linked by flexible building units has been considered a great challenge. Here, we address this challenge by using flexible 2,4,6,8-tetramethyl-2,4,6,8-tetravinylcyclotetrasiloxanes to react with brominated pyrene, tetraphenylethene, and spirobifluorene via the Heck reaction, resulting in three cyclosiloxane-linked fluorescent porous polymers. The materials exhibit high porosity, strong fluorescence, and tunable emission colors. Such properties impart the promise of these polymers as candidates for multifunctional chemical sensors to identify latent fingerprints with a strong anti-interference ability under actual conditions (e.g., rainy environment) and to detect nitroaromatic explosives and metal ions, especially 2,4,6-trinitrotoluene or picric acid, and the Fe3+ ion, with low limits of detection and a high selectivity. Moreover, a paper sensor was further developed and is found to be sensitive to the solution, solid, and vapor phases of explosives and the Fe3+ ion, complete with a rapid response time and visual detection. These results may open up new horizons for exploring porous polymers, particularly those with a strong fluorescence, based on flexible linkers.

Advances of Naturally Derived and Synthetic Hydrogels for Intervertebral Disk Regeneration.

Intervertebral disk (IVD) degeneration is associated with most cases of cervical and lumbar spine pathologies, amongst which chronic low back pain has become the primary cause for loss of quality-adjusted life years. Biomaterials science and tissue engineering have made significant progress in the replacement, repair and regeneration of IVD tissue, wherein hydrogel has been recognized as an ideal biomaterial to promote IVD regeneration in recent years. Aspects such as ease of use, mechanical properties, regenerative capacity, and their applicability as carriers for regenerative and anti-degenerative factors determine their suitability for IVD regeneration. This current review provides an overview of naturally derived and synthetic hydrogels that are related to their clinical applications for IVD regeneration. Although each type has its own unique advantages, it rarely becomes a standard product in truly clinical practice, and a more rational design is proposed for future use of biomaterials for IVD regeneration. This review aims to provide a starting point and inspiration for future research work on development of novel biomaterials and biotechnology.

Hazardous waste generation and management in China: a review.

Associated with the rapid economic growth and tremendous industrial prosperity, continues to be the accelerated increase of hazardous waste generation in China. The reported generation of industrial hazardous waste (IHW) was 11.62 million tons in 2005, which accounted for 1.1% of industrial solid waste (ISW) volume. An average of 43.4% of IHW was recycled, 33.0% was stored, 23.0% was securely disposed, and 0.6% was discharged without pollution controlling. By the end of 2004, there were 177 formal treatment and disposal centers for IHW management. The reported quantity of IHW disposed in these centers was only 416,000 tons, 65% of which was landfilled, 35% was incinerated. The quantity of waste alkali and acid ranked the first among IHW categories, which accounted for 30.9%. And 39.0% of IHW was generated from the raw chemical materials and chemical products industry sectors. South west China had the maximum generation of IHW, accounted for 40.0%. In addition, it was extrapolated that 740,000 tons of medical wastes were generated per year, of which only 10% was soundly managed. The generation of discarded household hazardous waste (HHW) is another important source of hazardous waste. A great proportion of HHW was managed as municipal solid waste (MSW). Hazardous waste pollution controlling has come into being a huge challenge faced to Chinese environmental management.