Transposon-triggered innate immune response confers cancer resistance to the blind mole rat.

Blind mole rats (BMRs) are small rodents, characterized by an exceptionally long lifespan (>21 years) and resistance to both spontaneous and induced tumorigenesis. Here we report that cancer resistance in the BMR is mediated by retrotransposable elements (RTEs). Cells and tissues of BMRs express very low levels of DNA methyltransferase 1. Following cell hyperplasia, the BMR genome DNA loses methylation, resulting in the activation of RTEs. Upregulated RTEs form cytoplasmic RNA-DNA hybrids, which activate the cGAS-STING pathway to induce cell death. Although this mechanism is enhanced in the BMR, we show that it functions in mice and humans. We propose that RTEs were co-opted to serve as tumor suppressors that monitor cell proliferation and are activated in premalignant cells to trigger cell death via activation of the innate immune response. Activation of RTEs is a double-edged sword, serving as a tumor suppressor but contributing to aging in late life via the induction of sterile inflammation.

Shared genetic effect of kidney function on bipolar and major depressive disorders: a large-scale genome-wide cross-trait analysis.

BACKGROUND: Epidemiological studies have revealed a significant association between impaired kidney function and certain mental disorders, particularly bipolar disorder (BIP) and major depressive disorder (MDD). However, the evidence regarding shared genetics and causality is limited due to residual confounding and reverse causation. METHODS: In this study, we conducted a large-scale genome-wide cross-trait association study to investigate the genetic overlap between 5 kidney function biomarkers (eGFRcrea, eGFRcys, blood urea nitrogen (BUN), serum urate, and UACR) and 2 mental disorders (MDD, BIP). Summary-level data of European ancestry were extracted from UK Biobank, Chronic Kidney Disease Genetics Consortium, and Psychiatric Genomics Consortium. RESULTS: Using LD score regression, we found moderate but significant genetic correlations between kidney function biomarker traits on BIP and MDD. Cross-trait meta-analysis identified 1 to 19 independent significant loci that were found shared among 10 pairs of 5 kidney function biomarkers traits and 2 mental disorders. Among them, 3 novel genes: SUFU, IBSP, and PTPRJ, were also identified in transcriptome-wide association study analysis (TWAS), most of which were observed in the nervous and digestive systems (FDR < 0.05). Pathway analysis showed the immune system could play a role between kidney function biomarkers and mental disorders. Bidirectional mendelian randomization analysis suggested a potential causal relationship of kidney function biomarkers on BIP and MDD. CONCLUSIONS: In conclusion, the study demonstrated that both BIP and MDD shared genetic architecture with kidney function biomarkers, providing new insights into their genetic architectures and suggesting that larger GWASs are warranted.

Characterization and trajectories of hematological parameters prior to severe COVID-19 based on a large-scale prospective health checkup cohort in western China: a longitudinal study of 13-year follow-up.

BACKGROUND: The relaxation of the "zero-COVID" policy on Dec. 7, 2022, in China posed a major public health threat recently. Complete blood count test was discovered to have complicated relationships with COVID-19 after the infection, while very few studies could track long-term monitoring of the health status and identify the characterization of hematological parameters prior to COVID-19. METHODS: Based on a 13-year longitudinal prospective health checkup cohort of ~ 480,000 participants in West China Hospital, the largest medical center in western China, we documented 998 participants with a laboratory-confirmed diagnosis of COVID-19 during the 1 month after the policy. We performed a time-to-event analysis to explore the associations of severe COVID-19 patients diagnosed, with 34 different hematological parameters at the baseline level prior to COVID-19, including the whole and the subtypes of white and red blood cells. RESULTS: A total of 998 participants with a positive SARS-CoV-2 test were documented in the cohort, 42 of which were severe cases. For white blood cell-related parameters, a higher level of basophil percentage (HR = 6.164, 95% CI = 2.066-18.393, P = 0.001) and monocyte percentage (HR = 1.283, 95% CI = 1.046-1.573, P = 0.017) were found associated with the severe COVID-19. For lymphocyte-related parameters, a lower level of lymphocyte count (HR = 0.571, 95% CI = 0.341-0.955, P = 0.033), and a higher CD4/CD8 ratio (HR = 2.473, 95% CI = 1.009-6.059, P = 0.048) were found related to the risk of severe COVID-19. We also observed that abnormality of red cell distribution width (RDW), mean corpuscular hemoglobin concentration (MCHC), and hemoglobin might also be involved in the development of severe COVID-19. The different trajectory patterns of RDW-SD and white blood cell count, including lymphocyte and neutrophil, prior to the infection were also discovered to have significant associations with the risk of severe COVID-19 (all P < 0.05). CONCLUSIONS: Our findings might help decision-makers and clinicians to classify different risk groups of population due to outbreaks including COVID-19. They could not only optimize the allocation of medical resources, but also help them be more proactive instead of reactive to long COVID-19 or even other outbreaks in the future.

Early-life tobacco smoke exposure and stroke risk: a prospective study of 341,783 and 352,737 UK Biobank participants.

INTRODUCTION: Stroke is a life-threatening condition that causes a major medical burden globally. The currently used methods for the prevention or prediction of stroke have certain limitations. Exposure to tobacco in early life, including smoking during adolescence and maternal smoking during pregnancy, can affect adolescent development and lead to several negative outcomes. However, the association between early-life tobacco exposure and stroke is not known. METHODS: In this prospective cohort study, for the analyses involving exposure to maternal smoking during pregnancy and age of smoking initiation, we included 304,984 and 342,893 participants, respectively., respectively from the UK Biobank. Cox proportional hazard regression model and subgroup analyses were performed to investigate the association between early-life tobacco exposure and stroke. Mediation analyses were performed to identify the mediating role of biological aging in the association between early tobacco exposure and stroke. RESULTS: Compared with participants whose mothers did not smoke during pregnancy, participants whose mothers smoked during pregnancy showed an 11% increased risk of stroke (HR: 1.11, 95% CI: 1.05-1.18, P < 0.001). Compared with participants who never smoked, participants who smoked during adulthood, adolescence and childhood showed a 22%, 24%, and 38% increased risk of stroke during their adulthood, respectively. Mediation analysis indicated that early-life tobacco exposure can cause stroke by increasing biological aging. CONCLUSION: This study reveals that exposure to tobacco during early life is associated with an increased risk of experiencing a stroke, and increased biological aging can be the underlying mechanism.

Causal network topology analysis: Characterizing causal context for risk management.

The ways that risk assessments are commonly performed in organizations have limitations that undermine their quality. They typically focus on individual risk events one at a time but are weak at integrating their relevant causal context, into decision-making processes. Network topology analysis has previously been applied to address this weakness through quantitatively characterizing the importance of the causal interactions of risk events. However, there remains a lack of both clarity and consistency in terminology, methods, and interpretation of the results of this approach. This paper presents and formalizes causal network topology analysis, a methodology that contributes to (1) characterizing the causal context of a risk event to inform its management, (2) articulating the ontological concepts underpinning a repeatable topology network analysis, and (3) justifying the selection and usage of network metrics for this purpose. The theory and methodology are discussed, and an exemplar application to a mining project feasibility study is presented.

The Underappreciated Placebo Effects and Responses in Randomized Controlled Trials on Neck Pain: A Systematic Review With Meta-analysis.

OBJECTIVE: To quantify placebo effects and responses in randomized controlled trials (RCTs) on neck pain and explore how they would influence the treatment of neck pain. DATA SOURCES: We searched MEDLINE (PubMed), EMBASE (Ovid), CINAHL (EBSCO), Physiotherapy Evidence Database (PEDro), and World Health Organization International Clinical Trials Registry Platform from the inception of August 15, 2021, to identify relevant RCTs. STUDY SELECTION AND DATA EXTRACTION: The abstracts and full texts of potential studies were independently screened, and data extraction was also independently performed by 2 researchers. Scales of the score measuring neck pain and the scores both at baseline and the endpoint were extracted. DATA SYNTHESIS: A total of 60 RCTs were included. The mean improvement in the pain score after placebo treatment was 15.65 (mean difference [MD]=-15.65, 95% confidence interval; CI [-19.19, -12.12]; P<.05), which we defined as the placebo response. In the active groups, it was 25.91 (MD=-25.91, 95% CI [-29.15, -22.68]; P<.05), and in the no-treatment groups, it was 5.80 (MD=-5.80, 95% CI [13.28, 1.69]; P=.13). Using the 3 MDs from the 3 groups, the placebo effect was calculated to account for 38.0% of the pain score improvement in the active group. CONCLUSIONS: The pain scores of patients with neck pain were reduced after treatment with placebos, but the magnitude of pain score reduction was not clinically significant enough. The 38.0% amount of pain score reduction in patients treated with active interventions was caused by placebo. Interventions with considerable clinically significance for neck pain were still required.

Identification of upper GI diseases during screening gastroscopy using a deep convolutional neural network algorithm.

BACKGROUND AND AIMS: The clinical application of GI endoscopy for the diagnosis of multiple diseases using artificial intelligence (AI) has been limited by its high false-positive rates. There is an unmet need to develop a GI endoscopy AI-assisted diagnosis system (GEADS) to improve diagnostic accuracy and clinical utility. METHODS: In this retrospective, multicenter study, a convolutional neural network was trained to assess upper GI diseases based on 26,228 endoscopic images from Dazhou Central Hospital that were randomly assigned (3:1:1) to a training dataset, validation dataset, and test dataset, respectively. To validate the model, 6 external independent datasets comprising 51,372 images of upper GI diseases were collected. In addition, 1 prospective dataset comprising 27,975 images was collected. The performance of GEADS was compared with endoscopists with 2 professional degrees of expertise: expert and novice. Eight endoscopists were in the expert group with >5 years of experience, whereas 3 endoscopists were in the novice group with 1 to 5 years of experience. RESULTS: The GEADS model achieved an accuracy of .918 (95% confidence interval [CI], .914-.922), with an F1 score of .884 (95% CI, .879-.889), recall of .873 (95% CI, .868-.878), and precision of .890 (95% CI, .885-.895) in the internal validation dataset. In the external validation datasets and 1 prospective validation dataset, the diagnostic accuracy of the GEADS ranged from .841 (95% CI, .834-.848) to .949 (95% CI, .935-.963). With the help of the GEADS, the diagnosing accuracies of novice and expert endoscopists were significantly improved (P < .001). CONCLUSIONS: The AI system can assist endoscopists in improving the accuracy of diagnosing upper GI diseases.

Is the CyberKnife© radiosurgery system effective and safe for patients? An umbrella review of the evidence.

Background: The CyberKnife© system combines real-time image guidance and a dynamic tracking system to implement frameless radiotherapy. This umbrella review is aimed to evaluate the effectiveness and safety of CyberKnife. Methods: A comprehensive search of health technology assessments and systematic reviews was performed among the Embase, PubMed and other grey databases until July 2020. Treatment outcomes were extracted, and the quality of included studies were assessed using AMSTAR-2. Results: Nineteen studies were eligible. CyberKnife not only had a wide range of applications, long overall survival and great local control, but also had a limited toxicity and good cost-effectiveness compared with other radiotherapy equipment. Conclusion: Despite the relatively low quality of the evidence, our findings can still provide a decision reference for policymakers.

An umbrella review on the effectiveness and safety of the CyberKnife^© system was performed by comprehensively searching for all related publications. The CyberKnife system had excellent effect on treatment of cancer and some noncancer diseases, with limited toxicity. Additionally, it was a cost-effective treatment compared with other types of radiotherapy. Despite the relatively low quality of the included evidence, our findings can still provide a comprehensive decision reference for policymakers of patients, government and hospitals.

Hemostatic Agent May Improve Perioperative Outcomes in Partial Nephrectomy: A Systematic Review and Meta-Analysis.

BACKGROUND: Hemostatic agents (HAs) are used to achieve hemostasis and prevent postoperative complications in multiple surgeries, but the role of HAs is ambiguous during partial nephrectomy (PN), so this study aimed to assess the role of HAs in PN. METHODS: PubMed, Embase, CENTRAL and ClinicalTrials.gov were searched for randomized controlled trials and cohort studies regarding the comparison of HA use alone and standard suturing during PN on January 17, 2020. RevMan 5.3 was used to conduct meta-analysis. Sensitivity analyses and subgroup analyses were performed based on surgical procedures and HA types. RESULTS: Six studies involving 1,066 patients were included. The quality of studies was moderate to high. There were significant reductions in warm ischemia time (mean difference [MD] = -6.30 min, 95% confidence interval [CI] -7.70 to -4.90, p < 0.00001), operative time (MD = -19.81 min, 95% CI -27.54 to -12.08, p < 0.00001), and estimated blood loss (MD = -108.62 mL, 95% CI -177.27 to -39.9, p = 0.002) in the HA group, and HA use alone did not increase postoperative complications. The results were similar in the subgroup analyses and sensitivity analyses. CONCLUSION: HA may be an effective and safe surgical material in PN, which can improve postoperative outcomes. High-quality and randomly designed studies are needed to validate the applicability.

Using an optimized generative model to infer the progression of complications in type 2 diabetes patients.

BACKGROUND: People live a long time in pre-diabetes/early diabetes without a formal diagnosis or management. Heterogeneity of progression coupled with deficiencies in electronic health records related to incomplete data, discrete events, and irregular event intervals make identification of pre-diabetes and critical points of diabetes progression challenging. METHODS: We utilized longitudinal electronic health records of 9298 patients with type 2 diabetes or prediabetes from 2005 to 2016 from a large regional healthcare delivery network in China. We optimized a generative Markov-Bayesian-based model to generate 5000 synthetic illness trajectories. The synthetic data were manually reviewed by endocrinologists. RESULTS: We build an optimized generative progression model for type 2 diabetes using anchor information to reduce the number of parameters learning in the third layer of the model from [Formula: see text] to [Formula: see text], where [Formula: see text] is the number of clinical findings, [Formula: see text] is the number of complications, [Formula: see text] is the number of anchors. Based on this model, we infer the relationships between progression stages, the onset of complication categories, and the associated diagnoses during the whole progression of type 2 diabetes using electronic health records. DISCUSSION: Our findings indicate that 55.3% of single complications and 31.8% of complication patterns could be predicted early and managed appropriately to potentially delay (as it is a progressive disease) or prevented (by lifestyle modifications that keep patient from developing/triggering diabetes in the first place). CONCLUSIONS: The full type 2 diabetes patient trajectories generated by the chronic disease progression model can counter a lack of real-world evidence of desired longitudinal timeframe while facilitating population health management.

The role of interleukin-6/interleukin-6 receptor signaling in the mechanical stress-induced extracellular matrix remodeling of bladder smooth muscle.

Extracellular matrix (ECM) remodeling is strongly associated with pathological changes induced by bladder outlet obstruction (BOO). In this study, we investigated the role of interleukin-6 (IL-6) in mechanical stretch-induced ECM remodeling of bladder smooth muscle. To construct a BOO animal model, the urethras of female Sprague-Dawley rats were partially ligated. In addition, increased hydrostatic pressure and mechanical stretching were applied to human bladder smooth muscle cells (HBSMCs) as an in vitro model. The expression of rat inflammatory genes was analyzed using DNA microarrays. We used quantitative RT-PCR (qRT-PCR) and immunohistochemical staining to detect IL-6 in the bladder smooth muscle of rats. To determine the specificity of IL-6, small interfering ribonucleic acid (siRNA) transfection and IL-6 receptor inhibitor (SC144) were applied to HBSMCs. qRT-PCR with siRNA transfection was also used to determine the specificity of downstream signaling. Moreover, western blotting was conducted to verify the expression results. In the animal model, the expression of ECM components and inflammatory genes was significantly upregulated. The expression of IL-6 was increased at both the mRNA level and the protein level in BOO rats. In vitro, hydrostatic pressure, and mechanical stretching both promoted MMP7 and MMP11 expression. Additionally, downregulation of collagen III occurred in both the hydrostatic pressure group and the mechanical stretch group. However, the expression of fibronectin exhibited opposing patterns between the hydrostatic pressure and mechanical stretch groups. The application of targeted siRNA transfection and an inhibitor (SC144) that targeted IL-6 significantly reversed the changes in MMP7 and MMP11 under mechanical stress and partially increased the expression of collagen III and fibronectin. In summary, IL-6 participated in the ECM remodeling of HBSMCs under mechanical stress, indicating that IL-6 may play an essential role in BOO..

M3 receptor modulates extracellular matrix synthesis via ERK1/2 signaling pathway in human bladder smooth muscle cells.

Extracellular matrix (ECM) accumulation plays a key role in the progression of bladder outlet obstruction (BOO). Muscarinic receptors have been widely reported to serve as pivotal regulators in lung tissue remodeling. However, the influence of them on human bladder smooth muscle cells (HBSMCs) and the underlying molecular mechanisms have not yet been evaluated. The purposes of the present study are to investigate the effect of muscarinic receptors on the synthesis of ECM in HBSMCs and the involvement of intracellular signal transducers. The results indicated that M1 -M5 muscarinic receptors were all encoded in HBSMCs. The expression rank order was M2 > M1 > M5 > M3 > M4 . The gene and protein expression of collagen I (COL1), TIMP-1, and TIMP-2 was carbachol (CCH) concentration-dependently enhanced. The synthesis of COL1 in the supernatant of cell culture medium was significantly elevated by exposure to CCH. The CCH-induced protein expression of COL1, TIMP-1, and TIMP-2, however, was obviously reduced by the pretreatment of muscarinic receptor antagonists, atropine, and M3 -preferring antagonist (1,1-dimethyl-4-diphenyl-acetoxypiperidinium iodide [4-DAMP]). Furthermore, ERK1/2 was activated by 100 µM CCH when compared with the control group and the pretreatment of ERK1/2 inhibitor significantly suppressed the synthesis of COL1 induced by 100 µM CCH. Besides, CCH-induced phosphorylation of ERK1/2 was remarkably restrained by the pretreatment of 4-DAMP. All in all, these findings demonstrated that M3 receptor can modulate extracellular matrix synthesis via the ERK1/2 signaling pathway, which may provide potential novel therapeutic targets for BOO.

Shared genetic architecture between metabolic traits and Alzheimer's disease: a large-scale genome-wide cross-trait analysis.

A growing number of studies clearly demonstrate a substantial link between metabolic dysfunction and the risk of Alzheimer's disease (AD), especially glucose-related dysfunction; one hypothesis for this comorbidity is the presence of a common genetic etiology. We conducted a large-scale cross-trait GWAS to investigate the genetic overlap between AD and ten metabolic traits. Among all the metabolic traits, fasting glucose, fasting insulin and HDL were found to be genetically associated with AD. Local genetic covariance analysis found that 19q13 region had strong local genetic correlation between AD and T2D (P = 6.78 × 10- 22), LDL (P = 1.74 × 10- 253) and HDL (P = 7.94 × 10- 18). Cross-trait meta-analysis identified 4 loci that were associated with AD and fasting glucose, 3 loci that were associated with AD and fasting insulin, and 20 loci that were associated with AD and HDL (Pmeta < 1.6 × 10- 8, single trait P < 0.05). Functional analysis revealed that the shared genes are enriched in amyloid metabolic process, lipoprotein remodeling and other related biological pathways; also in pancreas, liver, blood and other tissues. Our work identifies common genetic architectures shared between AD and fasting glucose, fasting insulin and HDL, and sheds light on molecular mechanisms underlying the association between metabolic dysregulation and AD.

Genetic overlap of chronic obstructive pulmonary disease and cardiovascular disease-related traits: a large-scale genome-wide cross-trait analysis.

BACKGROUND: A growing number of studies clearly demonstrate a substantial association between chronic obstructive pulmonary disease (COPD) and cardiovascular diseases (CVD), although little is known about the shared genetics that contribute to this association. METHODS: We conducted a large-scale cross-trait genome-wide association study to investigate genetic overlap between COPD (Ncase = 12,550, Ncontrol = 46,368) from the International COPD Genetics Consortium and four primary cardiac traits: resting heart rate (RHR) (N = 458,969), high blood pressure (HBP) (Ncase = 144,793, Ncontrol = 313,761), coronary artery disease (CAD)(Ncase = 60,801, Ncontrol = 123,504), and stroke (Ncase = 40,585, Ncontrol = 406,111) from UK Biobank, CARDIoGRAMplusC4D Consortium, and International Stroke Genetics Consortium data. RESULTS: RHR and HBP had modest genetic correlation, and CAD had borderline evidence with COPD at a genome-wide level. We found evidence of local genetic correlation with particular regions of the genome. Cross-trait meta-analysis of COPD identified 21 loci jointly associated with RHR, 22 loci with HBP, and 3 loci with CAD. Functional analysis revealed that shared genes were enriched in smoking-related pathways and in cardiovascular, nervous, and immune system tissues. An examination of smoking-related genetic variants identified SNPs located in 15q25.1 region associated with cigarettes per day, with effects on RHR and CAD. A Mendelian randomization analysis showed a significant positive causal effect of COPD on RHR (causal estimate = 0.1374, P = 0.008). CONCLUSION: In a set of large-scale GWAS, we identify evidence of shared genetics between COPD and cardiac traits.

Slow Dynamics in a Quasi-Two-Dimensional Binary Complex Plasma.

Slow dynamics in an amorphous quasi-two-dimensional complex plasma, comprised of microparticles of two different sizes, was studied experimentally. The motion of individual particles was observed using video microscopy, and the self-part of the intermediate scattering function as well as the mean-squared particle displacement was calculated. The long-time structural relaxation reveals the characteristic behavior near the glass transition. Our results suggest that binary complex plasmas can be an excellent model system to study slow dynamics in classical supercooled fluids.

The application of barbed suture during the partial nephrectomy may modify perioperative results: a systematic review and meta-analysis.

BACKGROUND: Barbed sutures can avoid knot tying and speed the suture placement in the PN(partial nephrectomy). On account of the impact on clinical outcomes are ambiguous, this study is determined to identify the application of barbed suture during PN. METHODS: ClinicalTrials.gov, Cochrane Register of Clinical Studies, PubMed and EMBASE were searched for RCTs(randomized controlled trials) and cohort studies focusing on the comparison of barbed and traditional sutures in PN(last updated on Feb in 2015). According to Cochrane Library's suggestion, quality assessment was performed. Review Manager was applied to analyze all the data and sensitivity analyses were performed through omitting each study sequentially. RESULTS: Eight cohort studies and none of RCTs proved eligible (risk of bias: moderate to low,431 patients). Warm ischemia time(MD = - 6.55,95% CI -8.86 to - 4.24, P < 0.05) decreased statistically in the barbed suture group, as well as operative time(MD = - 11.29,95% CI -17.87 to-4.71, P < 0.05). Postoperative complications also reduced significantly(OR = 0.44, 95% CI 0.24 to0.80, P < 0.05). Unidirectional barbed suture resulted in fewer postoperative complications based on the subgroup analysis(OR = 0.48,95% CI 0.24 to 0.94, P < 0.05). CONCLUSIONS: The barbed suture may be a useful surgical innovation which can modify perioperative results for surgeons and patients. Randomly-designed studies with longer follow up and larger sample sizes are in the need of to explore the applicability.

The Antimuscarinic Agent Tolterodine Regulates Bladder Extracellular Matrix in Partial Bladder Outlet Obstruction in Rats.

BACKGROUND/AIMS: Antimuscarinic agents can delay the progression of bladder dysfunction caused by bladder outlet obstruction (BOO). To date, the relationship between muscarinic receptor activity and the bladder extracellular matrix (ECM) remains unclear. Thus, an animal model of partial BOO (PBOO) in female rats was established to explore the variation in bladder wall ECM proteins under PBOO conditions with antimuscarinic agent administration. METHODS: Rats were randomly divided into three groups: sham, PBOO, and PBOO plus tolterodine. Picrosirius red staining was used to examine the smooth muscle and collagen content of bladder samples. Gene microarray and RT-PCR were performed to survey the expression of ECM proteins, receptors, and metabolism regulators in the rat bladder. Positive results were further evaluated by immunohistochemistry. RESULTS: Picrosirius red staining showed that smooth muscle volume significantly increased in the PBOO and PBOO plus tolterodine groups (p < 0.05), while collagen significantly increased in the PBOO group (p < 0.05) but not in the PBOO plus tolterodine group. Gene microarray and RT-PCR revealed that none of the collagen subtypes exhibited significant changes after PBOO establishment and tolterodine administration. However, matrix metalloproteinases (MMPs) increased significantly in the PBOO plus tolterodine group (p < 0.05). Additionally, PBOO inhibited the expression of non-collagen ECM proteins in the rat bladder wall, while tolterodine induced the expression of non-collagen ECM proteins and ECM receptors. CONCLUSIONS: Tolterodine decreased the volume of collagen in PBOO rat bladder wall, possibly via MMPs, and regulated the expression of ECM proteins and receptors.

Perineal midline vertical incision verses inverted-U incision in the urethroplasty: which is better?

OBJECTIVE: To compare postoperative outcomes between the perineal inverted-U and the vertical midline incision approaches of the urethroplasty and clarify them via gross anatomy. PATIENTS AND METHODS: A total of 461 male patients, from Jan. 2006 to Jun. 2014, who underwent the urethroplasty via perineal midline vertical or inverted-U incision approach were recruited retrospectively. By match pairing for etiology and stricture length, 410 patients from two groups (205 for each group) were selected. Anatomy experiments were also performed. Outcome measurements and statistical analysis: the Chi-square, Student's t and binary logistic regression analyses were performed to compare the operative and postoperative data on the two groups. RESULTS: With regard to patients with bulbar urethral stricture, the rate of surgical site infection (SSI) in perineal inverted-U group was 18.6% while 1.9% in the midline vertical group (p < 0.001). As for patients with posterior urethral stricture, the rate of SSI in the perineal inverted-U group was 16.4% while 3.1% in the midline vertical group (p = 0.001). Mean hospital stay between both groups were 15.8 ± 9.0 vs. 12.7 ± 3.8 days (p < 0.001). Anatomy experiments showed the number of damaged vessels and nerves involved in the inverted-U incision were approximately 1.6 to 2.0 folds more than the vertical midline, but the visual operation fields are similar between two approaches. CONCLUSIONS: The perineal midline vertical incision is a safer approach with fewer SSI and shorter hospital stay than the perineal inverted-U incision for bulbar and posterior urethroplasty.

Simulated physiological stretch increases expression of extracellular matrix proteins in human bladder smooth muscle cells via integrin α4/αv-FAK-ERK1/2 signaling pathway.

OBJECTIVES: To investigate the effect of simulated physiological stretch on the expression of extracellular matrix (ECM) proteins and the role of integrin α4/αv, focal adhesion kinase (FAK), extracellular regulated protein kinases 1/2 (ERK1/2) in the stretch-induced ECM protein expression of human bladder smooth muscle cells (HBSMCs). METHODS: HBSMCs were seeded onto silicone membrane and subjected to simulated physiological stretch at the range of 5, 10, and 15% elongation. Expression of primary ECM proteins in HBSMCs was analyzed by real-time polymerase chain reaction and Western blot. Specificity of the FAK and ERK1/2 was determined by Western blot with FAK inhibitor and ERK1/2 inhibitor (PD98059). Specificity of integrin α4 and integrin αv was determined with small interfering ribonucleic acid (siRNA) transfection. RESULTS: The expression of collagen I (Col1), collagen III (Col3), and fibronectin (Fn) was increased significantly under the simulated physiological stretch of 10 and 15%. Integrin α4 and αv, FAK, ERK1/2 were activated by 10% simulated physiological stretch compared with the static condition. Pretreatment of ERK1/2 inhibitor, FAK inhibitor, integrin α4 siRNA, or integrin αv siRNA reduced the stretch-induced expression of ECM proteins. And FAK inhibitor decreased the stretch-induced ERK1/2 activity and ECM protein expression. Integrin α4 siRNA or integrin αv siRNA inhibited the stretch-induced activity of FAK. CONCLUSION: Simulated physiological stretch increases the expression of ECM proteins in HBSMCs, and integrin α4/αv-FAK-ERK1/2 signaling pathway partly modulates the mechano-transducing process.

Risk factors for recurrence in female urethral diverticulectomy: a retrospective study of 66 patients.

PURPOSE: We aimed to report surgical outcomes in female urethral diverticula and to investigate the risk factors for diverticula recurrence. METHODS: A total of 66 patients underwent urethral diverticulectomies from January 2009 to October 2015 at out institution. Patient and diverticula characteristics were collected. Mean follow-up was 28.8 months (range 4-85 months). Recurrence was defined as requiring a repeat diverticulectomy. RESULTS: Mean age was 44.9 years. Mean duration of symptoms was 28.1 months. Seven cases had previous urethral surgeries. Mean diverticula size was 2.8 cm. Main clinical symptoms included dribbling (n = 41), vaginal mass (n = 41), dysuria (n = 33), frequency/urgency (n = 29), infection (n = 24), stress urinary incontinence (SUI) (n = 20) and dyspareunia (n = 8). 10 cases had proximal diverticula, 10 cases had multiple diverticula, and 35 cases had horseshoe/circumferential diverticula. Postoperatively, the recurrence rate was 19.7 %. Preoperative SUI disappeared in 14 cases, and de novo SUI was developed in six cases. One case developed urethral stricture, and no cases reported urinary fistula. Among 60 cases with pathological results, neoplastic change was seen in one case (1.7 %). Besides, atypical hyperplasia (n = 2) and metaplasia (n = 3) were observed. Univariate analysis suggested that age, duration, follow-up, diverticula size and diverticula shape were not associated with surgical outcomes. Patients with multiple diverticula (p = 0.032), proximal diverticula (p = 0.042) and those with previous urethral procedures (p = 0.004) were at risk of recurrent diverticula confirmed by multivariate logistic regression analysis. CONCLUSIONS: The surgical outcomes of urethral diverticulectomies were acceptable. Multiple diverticula, proximal diverticula and previous urethral surgery were three independent risk factors for recurrent diverticula.