The Diagnostic Role of Neurophysiological Tests for Premature Ejaculation: A Prospective Multicenter Study.

PURPOSE: Premature ejaculation (PE) is one of the most common male sexual dysfunctions. Local anesthetics (LAs) and dapoxetine are frequently used to treat PE; however, previous studies show variable efficacy. This study aims to determine the efficacy of LAs and dapoxetine using a novel classification based on neurophysiological tests. MATERIALS AND METHODS: This multicenter cohort study enrolled adult men (568) with an intravaginal ejaculatory latency time (IELT) ≤2 minutes. Patients were divided into 4 groups according to the results of neurophysiological tests and assigned different treatments for 12 weeks: 1) penile sensory hyperexcitability type (Sens)-LAs; 2) penile sympathetic hyperexcitability type (Symp)-dapoxetine; 3) mixed type (Mixed)-both LAs and dapoxetine; 4) normal type (Norm)-both LAs and dapoxetine. Self-estimated IELT and patient-reported outcomes were recorded. RESULTS: The total percentage of men achieving IELT >2 minutes and ≥5 minutes after treatment were 82.7% and 76.7%, respectively. For men with abnormal results of neurophysiological tests, 401 (86.6%) had improved IELT >2 minutes after the 12-week treatment course, in which 375 (81.0%) achieved IELT ≥5 minutes. All patient-reported outcome measures improved in each group after 12 weeks of treatment, with greater improvements among those with abnormal neurophysiological tests. CONCLUSIONS: The efficacy of LAs and dapoxetine increased in PE patients with abnormal results of neurophysiological tests. This novel classification of PE using neurophysiological tests could help guide and improve efficacy of PE therapies.

Distinct Murine Pancreatic Transcriptomic Signatures during Chronic Pancreatitis Recovery.

We have previously demonstrated that the pancreas can recover from chronic pancreatitis (CP) lesions in the cerulein-induced mouse model. To explore how pancreatic recovery is achieved at the molecular level, we used RNA-sequencing (seq) and profiled transcriptomes during CP transition to recovery. CP was induced by intraperitoneally injecting cerulein in C57BL/6 mice. Time-matched controls (CON) were given normal saline. Pancreata were harvested from mice 4 days after the final injections (designated as CP and CON) or 4 weeks after the final injections (designated as CP recovery (CPR) and control recovery (CONR)). Pancreatic RNAs were extracted for RNA-seq and quantitative (q) PCR validation. Using RNA-seq, we identified a total of 3,600 differentially expressed genes (DEGs) in CP versus CON and 166 DEGs in CPR versus CONR. There are 132 DEGs overlapped between CP and CPR and 34 DEGs unique to CPR. A number of selected pancreatic fibrosis-relevant DEGs were validated by qPCR. The top 20 gene sets enriched from DEGs shared between CP and CPR are relevant to extracellular matrix and cancer biology, whereas the top 10 gene sets enriched from DEGs specific to CPR are pertinent to DNA methylation and specific signaling pathways. In conclusion, we identified a distinct set of DEGs in association with extracellular matrix and cancer cell activities to contrast CP and CPR. Once during ongoing CP recovery, DEGs relevant to DNA methylation and specific signaling pathways were induced to express. The DEGs shared between CP and CPR and the DEGs specific to CPR may serve as the unique transcriptomic signatures and biomarkers for determining CP recovery and monitoring potential therapeutic responses at the molecular level to reflect pancreatic histological resolution.

Inhibitory Role of Gamma-Aminobutyric Receptors in Paraventricular Nucleus on Ejaculatory Responses in Rats.

BACKGROUND: Although abnormal sympathetic nerve system (SNS) activity has been demonstrated in the pathogenesis of ejaculation disorders, few data are available on its underlying mechanism. AIM: To investigate whether differences in ejaculatory behavior of rats were associated with the state of SNS activity and gamma-aminobutyric (GABA) receptor expressions in the paraventricular nucleus (PVN) of the hypothalamus and the effects of GABA receptors in the PVN on ejaculatory behavior. METHODS: Based on ejaculatory performance, Sprague-Dawley rats were divided into "sluggish," "normal," and "rapid" ejaculators. PVN microinjection was performed to evaluate the role of GABA receptors on sexual behavior. OUTCOMES: The outcomes include differences in expression and distribution of GABA receptors and norepinephrine level among the 3 groups and changes in copulation behavior parameters after PVN microinjection. RESULTS: Compared with "normal" rats, the "rapid" group ejaculated more times with shorter latency (P < .001, P < .001) and had lower expression and distribution of both GABA-A and GABA-B receptors, while the opposed results appeared in the "sluggish" group. The norepinephrine level was successively increased among "sluggish," "normal," and "rapid" rats (P < .001) and correlated with ejaculation frequency (r = 0.896, P < .001) and ejaculation latency (r = -0.835, P < .001). In addition, bilateral microinjection of the GABA-A and GABA-B receptor agonist (isoguvacine and baclofen) into the PVN both significantly prolonged the intromission latency and inhibited ejaculation, which could be blocked by antagonist gabazine and CGP-35348, respectively. Vigabatrin, the GABA-transaminase inhibitor, caused a significantly reduced ejaculation frequency and extended ejaculation latency in rats, which could be offset by simultaneous injections of gabazine and CGP-35348. CLINICAL IMPLICATIONS: Our findings provide new understanding about GABA receptors in the PVN on sexual behavior and enhance the comprehension of neurobiological mechanisms involved in premature ejaculation. STRENGTHS & LIMITATIONS: Our results have indicated that GABA receptors in the PVN may inhibit ejaculation through restraining the activity of SNS. However, our study did not analyze the changes of GABA receptors in other brain areas, which needs further study. CONCLUSION: Ejaculation behaviors in male rats are associated with SNS activity and could be regulated by GABA receptors in the PVN, which may be of assistance in the treatment of ejaculation disorders in the future. Zhang QJ, Yang BB, Yang J, et al. Inhibitory Role of Gamma-Aminobutyric Receptors in Paraventricular Nucleus on Ejaculatory Responses in Rats. J Sex Med 2020;17:614-622.

Dopamine D2 receptors in the basolateral amygdala modulate erectile function in a rat model of nonorganic erectile dysfunction.

Nonorganic erectile dysfunction is a problem with unknown central mechanisms. Changes in brain activity in the amygdala have been observed in human patients. This study aimed to investigate the dopamine system in the basolateral amygdala of male rats with nonorganic erectile dysfunction. We applied chronic mild stress to induce nonorganic erectile dysfunction. After exposure to chronic mild stress, the sucrose consumption test, sexual behaviour test and apomorphine test were used to select depression-like rats with erectile dysfunction as nonorganic erectile dysfunction model rats. The sexual behaviour of these rats after central infusion of a dopamine D1/D2 receptor agonist/antagonist was observed. The expression levels of dopamine D1/D2 receptors and tyrosine hydroxylase in the basolateral amygdala were also measured. The result of the sucrose consumption test, sexual behaviour test and apomorphine test indicated a successful nonorganic erectile dysfunction model. Central infusion of a dopamine D2 receptor agonist increased intromission ratio in model rats. Lower expression levels of tyrosine hydroxylase and the dopamine D2 receptor in the basolateral amygdala were observed in rats with nonorganic erectile dysfunction. These results suggest that impairment of the dopamine D2 receptor pathway in the basolateral amygdala may contribute to the development of nonorganic erectile dysfunction.

Changes in Male Rat Sexual Behavior and Brain Activity Revealed by Functional Magnetic Resonance Imaging in Response to Chronic Mild Stress.

BACKGROUND: Non-organic erectile dysfunction (noED) at functional imaging has been related to abnormal brain activity and requires animal models for further research on the associated molecular mechanisms. AIM: To develop a noED animal model based on chronic mild stress and investigate brain activity changes. METHODS: We used 6 weeks of chronic mild stress to induce depression. The sucrose consumption test was used to assess the hedonic state. The apomorphine test and sexual behavior test were used to select male rats with ED. Rats with depression and ED were considered to have noED. Blood oxygen level-dependent-based resting-state functional magnetic resonance imaging (fMRI) studies were conducted on these rats, and the amplitude of low-frequency fluctuations and functional connectivity were analyzed to determine brain activity changes. OUTCOMES: The sexual behavior test and resting-state fMRI were used for outcome measures. RESULTS: The induction of depression was confirmed by the sucrose consumption test. A low intromission ratio and increased mount and intromission latencies were observed in male rats with depression. No erection was observed in male rats with depression during the apomorphine test. Male rats with depression and ED were considered to have noED. The possible central pathologic mechanism shown by fMRI involved the amygdaloid body, dorsal thalamus, hypothalamus, caudate-putamen, cingulate gyrus, insular cortex, visual cortex, sensory cortex, motor cortex, and cerebellum. Similar findings have been found in humans. CLINICAL TRANSLATION: The present study provided a novel noED rat model for further research on the central mechanism of noED. STRENGTHS AND LIMITATIONS: The present study developed a novel noED rat model and analyzed brain activity changes based at fMRI. The observed brain activity alterations might not extend to humans. CONCLUSION: The present study developed a novel noED rat model with brain activity alterations related to sexual arousal and erection, which will be helpful for further research involving the central mechanism of noED. Chen G, Yang B, Chen J, et al. Changes in Male Rat Sexual Behavior and Brain Activity Revealed by Functional Magnetic Resonance Imaging in Response to Chronic Mild Stress. J Sex Med 2018;15:136-147.

[Establishment of an animal model of primary premature ejaculation].

OBJECTIVE: To investigate the feasibility and practicability of establishing an animal model of primary premature ejaculation using the ejaculation distribution theory. METHODS: We induced behavioral estrus in 32 ovariectomized female SD rats by subcutaneous injection of 20 µg estradiol benzoate at 48 hours and 500 µg progesterone at 4 hours before mating them with 49 male rats once a week for six times. During the last three opulations, we observed the male animals for mounting latency (ML), intromission latency (IL), ejaculation latency (EL), postejaculation interval (PEI), mounting frequency (MF), intromission frequency (IF), intromission rate (IR), and ejaculation frequency (EF). RESULTS: Finally, 22 of the male rats were included in this study. The mean EF>33 was deemed rapid ejaculation,EF<1 sluggish ejaculation, and EF 1.5－2.5 normal ejaculation. The EL was significantly shorter in the rapid ejaculation group than in the sluggish and normal ejaculation groups. The IF was the lowest in those with rapid ejaculation. No statistically significant differences were observed in the ML among the three groups of rats. CONCLUSIONS: Based on the mean ejaculation frequency, the male rats with rapid ejaculation were easily screened, and this animal model may play an important role in exploring the mechanisms of primary premature ejaculation.

Curcumin ameliorates pyroptosis in diabetic seminal vesicles by upregulating TRPV6.

BACKGROUND: Diabetes damages the seminal vesicle tissues leading to a decrease in seminal fluid secretion, so investigations are ongoing to identify specific therapeutic approaches to address diabetes-induced damage to seminal vesicles. OBJECTIVE: This study investigated the secretory dysfunction of seminal vesicles and how curcumin can ameliorate this dysfunction. MATERIALS AND METHODS: First, 40 diabetic males (DM group) and 40 nondiabetic males (control group) underwent seminal vesicle ultrasound evaluation and ejaculate volume measurements. Then, the effects of curcumin on seminal vesicle function were investigated in a diabetic rat model. Fifty 8-week-old SPF-grade SD rats were categorized into five groups: control, DM (diabetes mellitus), low-dose CUR (curcumin 50 mg/kg/d), medium-dose CUR (curcumin 100 mg/kg/d), and high-dose CUR (curcumin 150 mg/kg/d). After a month-long diet with varying curcumin doses, key parameters such as body weight, blood glucose levels, seminal vesicle volume, and seminal fluid secretion were measured. Transcriptome sequencing was performed to assess differences in gene expression and structural changes in rat seminal vesicle tissues were examined by HE staining. Finally, human seminal vesicle cell lines were cultured and divided into five groups (HG-CON, HG-CUR-5 µM, HG-CUR-10 µM, HG-CUR-20 µM, and HG-CUR-50 µM) to measure the fructose levels in the seminal vesicle cell culture fluids and evaluate the expression of CASP1, GSDMD, and TRPV6. Post TRPV6 interference, variations in the gene expression of CASP1, GSDMD, and TRPV6 were monitored. RESULTS: Diabetic patients exhibited a notable reduction in seminal vesicle volume and ejaculate volume compared with the control group, with a direct correlation between the decrease in ejaculate and seminal vesicle volume. Animal studies demonstrated that curcumin supplementation significantly augmented seminal vesicle volume in diabetic rats and notably improved their seminal vesicle secretory dysfunction, particularly in the high-dose curcumin group. Transcriptome sequencing and experimental verification pinpointed the differential expression of TPRV6 and pyroptosis-associated genes (CASP1, GSDMD), with reduced TRPV6 expression but increased markers of pyroptosis (CASP1 and GSDMD) in diabetic rats. Curcumin treatment reversed these effects with an increase in TRPV6 and a decrease in GSDMD and CASP1. Cell transfection experiments indicated that TRPV6 downregulation increased GSDMD and CASP1 gene expression. CONCLUSION: Curcumin effectively activates TRPV6, thereby diminishing pyroptosis in the seminal vesicle tissues of diabetic rats. This activation not only leads to an increase in the seminal vesicle volume but also significantly ameliorates the seminal vesicle secretory dysfunction in diabetic rats.

The application of intraoperative neurophysiological monitoring in selective dorsal neurotomy for primary premature ejaculation: a prospective single-center study.

Selective dorsal neurotomy (SDN) is a surgical treatment for primary premature ejaculation (PE), but there is still no standard surgical procedure for selecting the branches of the dorsal penile nerves to be removed. We performed this study to explore the value of intraoperative neurophysiological monitoring (IONM) of the penile sensory-evoked potential (PSEP) for standard surgical procedures in SDN. One hundred and twenty primary PE patients undergoing SDN were selected as the PE group and 120 non-PE patients were selected as the normal group. The PSEP was monitored and compared between the two groups under both natural and general anesthesia (GA) states. In addition, patients in the PE group were randomly divided into the IONM group and the non-IONM group. During SDN surgery, PSEP parameters of the IONM group were recorded and analyzed. The differences in PE-related outcome measurements between the perioperative period and 3 months' postoperation were compared for the PE patients, and the differences in effectiveness and complications between the IONM group and the non-IONM group were compared. The results showed that the average latency of the PSEP in the PE group was shorter than that in the normal group under both natural and GA states (P < 0.001). Three months after surgery, the significant effective rates in the IONM and non-IONM groups were 63.6% and 34.0%, respectively (P < 0.01), and the difference in complications between the two groups was significant (P < 0.05). IONM might be useful in improving the short-term therapeutic effectiveness and reducing the complications of SDN.

Abnormal cortical surface-based spontaneous and functional connectivity in the whole brain in lifelong premature ejaculation patients.

Recent research has highlighted structural and functional abnormalities in the cerebral cortex of patients with premature ejaculation (PE). These anomalies could play a pivotal role in the physiological mechanisms underlying PE. This study leveraged functional magnetic resonance imaging (fMRI), a noninvasive technique, to explore these neural mechanisms. We conducted resting-state fMRI scans on 36 PE patients and 22 healthy controls (HC), and collected data on Premature Ejaculation Diagnostic Tool (PEDT) scores and intravaginal ejaculation latency time (IELT). Employing a surface-based regional homogeneity (ReHo) approach, we analyzed local neural synchronous spontaneous activity, diverging from previous studies that utilized a volume-based ReHo method. Areas with significant ReHo differences between PE and HC groups underwent surface-based functional connectivity (FC) analysis. Significant discrepancies in ReHo and FC across the cortical surface were observed in the PE cohort. Notably, PE patients exhibited decreased ReHo in the left triangular inferior frontal gyrus and enhanced ReHo in the right middle frontal gyrus. The latter showed heightened connectivity with the left lingual gyrus and the right orbital superior frontal gyrus. Furthermore, a correlation between ReHo and FC values with PEDT scores and IELT was found in the PE group. Our findings, derived from surface-based fMRI data, underscore specific brain regions linked to the neurobiological underpinnings of PE.

Pancreatic stromal Gremlin 1 expression during pancreatic tumorigenesis.

Chronic pancreatitis (CP) is a major risk factor of pancreatic ductal adenocarcinoma (PDAC). How CP promotes pancreatic oncogenesis remains unclear. A characteristic feature of PDAC is its prominent desmoplasia in the tumor microenvironment, composed of activated fibroblasts and macrophages. Macrophages can be characterized as M1 or M2, with tumor-inhibiting or -promoting functions, respectively. We reported that Gremlin 1 (GREM1), a key pro-fibrogenic factor, is upregulated in the stroma of CP. The current study aimed to investigate the expression of GREM1 and correlation between GREM1 and macrophages within the pancreas during chronic inflammation and the development of PDAC. By mRNA in situ hybridization, we detected GREM1 mRNA expression within α-smooth muscle actin (SMA)-positive fibroblasts of the pancreatic stroma. These designated FibroblastsGrem1+ marginally increased from CP to pancreatic intraepithelial neoplasia (PanIN) and PDAC. Within PDAC, FibroblastsGrem1+ increased with higher pathological tumor stages and in a majority of PDAC subtypes screened. Additionally, FibroblastsGrem1+ positively correlated with total macrophages (MacCD68+) and M2 macrophages (M2CD163+) in PDAC. To begin exploring potential molecular links between FibroblastsGrem1+ and macrophages in PDAC, we examined the expression of macrophage migration inhibitory factor (MIF), an endogenous counteracting molecule of GREM1 and an M1 macrophage promoting factor. By IHC staining of MIF, we found MIF to be expressed by tumor cells, positively correlated with GREM1; by IHC co-staining, we found MIF to be negatively correlated with M2CD163+ expression. Our findings suggest that GREM1 expression by activated fibroblasts may promote PDAC development, and GREM1/MIF may play an important role in macrophage phenotype.

Does knowing pre-operative penile length influence patient satisfaction post penile prosthesis implantation?

Patients who undergo penile prosthesis implantation as treatment for erectile dysfunction commonly complain of penile shortening after implantation. We conducted a study to determine whether knowledge of pre-operative stretched penile length measurement influences patient satisfaction. This prospective study consisted of 149 patients undergoing inflatable penile prosthesis (IPP) implantation from August 2017 to December 2019. Study group participants underwent pre-operative stretched penile length measurement in clinic while the control group did not. Six months post-operatively, patients completed a modified 14-item Erectile Dysfunction Inventory of Treatment Satisfaction (EDITS) questionnaire to assess overall satisfaction and penile length satisfaction. A total of 102 patients were eligible for final analysis (49 in study group, 53 in control). Mean scores for overall treatment satisfaction were 3.57 and 3.53 (scale from 0 to 4) in the study versus control group, respectively (p = 0.483). Mean scores for satisfaction with penile length were 4.08 and 4.11 (scale from 1 to 5) in the study vs. control group (p = 0.645). The study suggests that knowledge of pre-operative stretched penile length does not influence post-operative satisfaction after penile prosthesis implantation. Therefore, performing pre-operative measurements in clinic solely for informing the patient may be unnecessary. Current interventions aimed at conserving penile length may be effective at maintaining satisfaction with penile length.Trial Registration- This trial is registered and approved by the IRB committee at our institution, ID: HSC-MS-19-0320.

The Role of Long Term Label-Retaining Cells in the Treatment of Erectile Dysfunction by Vacuum Erectile Device.

INTRODUCTION: Vacuum erectile device (VED) therapy is commonly used for penile rehabilitation after radical prostatectomy, however, the underlying mechanism of this effect is not fully understood. AIM: To evaluate the presence of label-retaining cells (LRCs), cells with long-term retention of 5-ethynyl-2-deoxyuridine (EdU) labeling and recognized as adult stem cells or progenitor-like cells, in cavernous tissue after VED treatment using a BCNC rat model. METHODS: Postnatal pups (1 day old) of Sprague Dawley (SD) rats were intraperitoneally injected with EdU (50 ug/g, BID for 3 days) and BCNC surgery was conducted at 6 weeks old (designated as natal-labeled rats). Adult SD rats underwent BCNC surgery and EdU injection (50 ug/g, once) after surgery (designated as adult-labeled rats). One week after surgery, both natal- and adult-labeled rats received daily VED treatment for 4 weeks. Intracavernous pressure (ICP) and mean arterial pressure (MAP) were measured for all rats and then the penile tissue was harvested. The ratio of ICP/MAP was calculated to represent erectile function. Penile tissue was examined by immunofluorescence staining to detect EdU positive cells. MAIN OUTCOME MEASURES: The ratio of Intracavernous pressure (ICP) /MAP and the percentage of EdU positive cells were measured. RESULTS: The erectile function was impaired after BCNC and partially restored after VED treatment in both natal- and adult-labeled rats (P < .05). There was no difference in the percentage of EdU positive cells in natal-labeled rat cavernous tissue in BCNC group compared with VED group. Among the adult-labeled rats, the percentage of EdU positive cells increased in BCNC group (P < .05) but didn't change significantly after VED treatment (P = .35). CONCLUSION: LRCs may play a limited role in the restoration of erectile dysfunction through VED treatment after BCNC. Yang B, Luse D, Cao Y, et al. The Role of Long Term Label-Retaining Cells in the Treatment of Erectile Dysfunction by Vacuum Erectile Device. Sex Med 2021;9:100442.

Comparison of Satisfaction With Penile Prosthesis Implantation in Patients With Radical Prostatectomy or Radical Cystoprostatectomy to the General Population.

INTRODUCTION: Penile prosthesis implantation is a widely used treatment option for erectile dysfunction. Data is limited with regard to patient satisfaction with a penile prosthesis following radical prostatectomy/cystoprostatectomy vs patients with erectile dysfunction of other etiologies. AIM: To examine patient satisfaction with penile prosthesis implantation and determine if a difference in satisfaction exists in post-prostatectomy/cystoprostatectomy patients vs patients with erectile dysfunction of other etiologies. We hypothesize that etiology does not affect satisfaction. METHODS: A total of 164 patients underwent penile prosthesis implantation at our institution between August 2017 and December 2019, with 102 patients completing a validated 14 item questionnaire, Erectile Dysfunction Inventory of Treatment Satisfaction (EDITS), at 6 months postoperation. Demographics, surgical characteristics, and erectile dysfunction etiology were recorded. Patients were assigned to one of 2 groups: postprostatectomy/postcystoprostatectomy erectile dysfunction or other etiologies. The study group was further analyzed between radical prostatectomy or radical cystoprostatectomy. MAIN OUTCOME MEASURES: Satisfaction based on key EDITS questions with postradical prostatectomy/cystoprostatectomy vs patients with erectile dysfunction of other etiologies. RESULTS: Responses to 3 questions were analyzed: overall satisfaction, expectations met in the past 4 weeks, and confidence in the ability to participate in sexual activity. Chi-square analysis was performed to determine the difference in responses. No difference was seen in overall satisfaction (P = .96), expectations (P = .78), or confidence (P = .78) between groups. On subgroup analysis, there was no difference in reported overall satisfaction (P = .47) or confidence (P = .080) between postprostatectomy and postcystoprostatectomy patients. Postprostatectomy and postcystoprostatectomy patients differed in whether the penile prosthesis implantation met expectations (P = .033). Postprostatectomy patients reported a mean score of 3.5/4 compared to postcystoprostatectomy patients, who reported a mean of 3.0/4. CONCLUSIONS: Our analysis suggests that key erectile function scores are not significantly different between postprostatectomy/postcystoprostatectomy patients compared to other etiologies. The difference in measures between postprostatectomy and postcystoprostatectomy patients is not significant or of unclear significance. Registration # of clinical trial: HSC-MS-19-0320 Howell S, Palasi S, Green T, et al. Comparison of Satisfaction With Penile Prosthesis Implantation in Patients With Radical Prostatectomy or Radical Cystoprostatectomy to the General Population. Sex Med 2021;9:100300.

Characteristic pancreatic and splenic immune cell infiltration patterns in mouse acute pancreatitis.

BACKGROUND: A systemic evaluation of immune cell infiltration patterns in experimental acute pancreatitis (AP) is lacking. Using multi-dimensional flow cytometry, this study profiled infiltrating immune cell types in multiple AP mouse models. METHODS: Three AP models were generated in C57BL/6 mice via cerulein (CAE) injection, alcohol and palmitoleic acid (EtOH + POA) injection, and alcohol diet feeding and cerulein (EtOH + CAE) injection. Primary pancreatic cells and splenocytes were prepared, and multi-dimensional flow cytometry was performed and analyzed by manual gating and computerized PhenoGraph, followed by visualization with t-distributed stochastic neighbor embedding (t-SNE). RESULTS: CAE treatment induced a time-dependent increase of major innate immune cells and a decrease of follicular B cells, and TCD4+ cells and the subtypes in the pancreas, whereas elicited a reversed pattern in the spleen. EtOH + POA treatment resulted in weaker effects than CAE treatment. EtOH feeding enhanced CAE-induced amylase secretion, but unexpectedly attenuated CAE-induced immune cell regulation. In comparison with manual gating analysis, computerized analysis demonstrated a remarkable time efficiency and reproducibility on the innate immune cells and B cells. CONCLUSIONS: The reverse pattern of increased innate and decreased adaptive immune cells was consistent in the pancreas in CAE and EtOH + POA treatments. Alcohol feeding opposed the CAE effect on immune cell regulation. Together, the immune profiling approach utilized in this study provides a better understanding of overall immune responses in AP, which may facilitate the identification of intervention windows and new therapeutic strategies. Computerized analysis is superior to manual gating by dramatically reducing analysis time.

Identification of Fibrinogen as a Key Anti-Apoptotic Factor in Human Fresh Frozen Plasma for Protecting Endothelial Cells In Vitro.

Resuscitation with human fresh frozen plasma (FFP) in hemorrhagic shock (HS) patients is associated with improved clinical outcomes. Our group has demonstrated that the beneficial effect of FFP is due to its blockade on endothelial hyperpermeability, thereby improving vascular barrier function. The current study aimed to investigate HS-induced endothelial cell apoptosis, a potential major contributor to the endothelial hyperpermeability, and to determine the effect and the key components/factors of FFP on protecting endothelial cells from apoptosis. We first measured and demonstrated an increase in apoptotic endothelial microparticles (CD146AnnexinV) in patients in shock compared to normal subjects, indicating the induction of endothelial cell activation and apoptosis in shock patients. We then transfused HS rats with FFP and showed that FFP blocked HS-induced endothelial cell apoptosis in gut tissue. To identify the anti-apoptotic factors in FFP, we utilized high-performance liquid chromatography, fractionated FFP, and screened the fractions in vitro for the anti-apoptotic effects. We selected the most effective fractions, performed mass spectrometry, and identified fibrinogen as a potent anti-apoptotic factor. Taken together, our findings suggest that HS-induced endothelial apoptosis may constitute a major mechanism underlying the vascular hyperpermeability. Furthermore, the identified anti-apoptotic factor fibrinogen may contribute to the beneficial effects of FFP resuscitation, and therefore, may have therapeutic potential for HS.

Opposing Roles of BMP and TGF-ß Signaling Pathways in Pancreatitis: Mechanisms and Therapeutic Implication.

Bone morphogenetic proteins (BMPs) comprise a major subgroup of the transforming growth factor (TGF)-ß superfamily. They play pivotal roles in embryonic development and tissue homeostasis in adults. Deregulation of BMP and TGF-ß signaling contributes to developmental anomalies and multiple diseases. In this mini-review, we focus on BMP signaling in inflammatory disorders of the pancreas, acute and chronic pancreatitis, in contrast to TGF-ß signaling. We then discuss molecular mechanisms that interact with and connect between the BMP and TGF-ß signaling pathways. Lastly, we review potential implications of these molecular mechanisms for therapeutic development. In summary, BMP signaling pathway plays different roles during pancreatitis disease development, and the antagonism between BMP and TGF-ß signaling can be manipulated for therapeutic development against pancreatitis.

Epalrestat, an Aldose Reductase Inhibitor, Restores Erectile Function in Streptozocin-induced Diabetic Rats.

Epalrestat, an aldose reductase inhibitor (ARI), was adopted to improve the function of peripheral nerves in diabetic patients. The aim of this study was to investigate whether epalrestat could restore the erectile function of diabetic erectile dysfunction using a rat model. From June 2016, 24 rats were given streptozocin (STZ) to induce the diabetic rat model, and epalrestat was administered to ten diabetic erectile dysfunction (DED) rats. Intracavernous pressure (ICP) and mean systemic arterial pressure (MAP), levels of aldose reductase (AR), nerve growth factor (NGF), neuronal nitric oxide synthase (nNOS), α-smooth muscle antigen (α-SMA), and von Willebrand factor (vWF) in the corpus cavernosum were analyzed. We discovered that epalrestat acted on cavernous tissue and partly restored erectile function. NGF and nNOS levels in the corpora were increased after treatment with epalrestat. We also found that the content of α-SMA-positive smooth muscle cells and vWF-positive endothelial cells in the corpora cavernosum were declined. Accordingly, epalrestat might improve erectile function by increasing the upregulation of NGF and nNOS to restore the function of the dorsal nerve of the penis.

Correction: Epalrestat, an Aldose Reductase Inhibitor, Restores Erectile Function in Streptozocin-induced Diabetic Rats.

This Article was originally published under Nature Research's License to Publish, but has now been made available under a CC BY 4.0 license. The PDF and HTML versions of the Article have been modified accordingly.

Lack of association between aryl hydrocarbon receptor gene Arg554Lys polymorphism and male infertility risk: A systematic review and meta-analysis.

OBJECTIVES: The association between aryl hydrocarbon receptor gene (AhR) polymorphism and male infertility risk remains conflicting. We conducted a meta-analysis to examine the AhR Arg554Lys polymorphism in relation to the susceptibility to male infertility. STUDY DESIGN: Studies concerning the association between AHR polymorphism and male infertility were searched and related information were extracted from the included studies. The STATA 12.0 software was used to perform a meta-analysis. Pooled odd ratios (ORs) and corresponding 95% confidence intervals (CIs) were calculated to estimate the association. RESULTS: Six case-control studies with 1234 cases and 1755 controls were included after literature research and data collection. Overall, the results indicated there was no association between the AhR Arg554Lys polymorphism and male infertility risk (G versus A, OR (95%CI) = 0.958 (0.710-1.291); GG vs AA, OR (95%CI) = 0.874 (0.702-1.088); GA versus AA, OR (95%CI) = 0.911(0.477-1.740); GG + GA vs AA, OR (95%CI) = 0.891 (0.468-1.696); GG versus GA + AA, OR (95%CI) = 1.049(0.896-1.229)). Subgroup analysis by study population revealed there was no association between AhR Arg554Lys polymorphism and susceptibility to male infertility in Asian population (G versus A, OR (95%CI) = 1.099 (0.940-1.286); GG vs AA, OR (95%CI) = 0.982 (0.781-1.235); GA versus AA, OR (95%CI) = 1.220 (0.726-2.052); GG + GA vs AA, OR (95%CI) = 1.221 (0.740-1.982); GG versus GA + AA, OR (95%CI) = 1.087 (0.919-1.286)). CONCLUSIONS: The association between AHR Arg55Lys polymorphism and male infertility risk was not confirmed in our meta-analysis. However, the results should be interpreted with caution and further studies are required.

No effect of abstinence time on nerve electrophysiological test in premature ejaculation patients.

The nerve electrophysiological tests may differentiate the treatment of primary premature ejaculation (PPE) in our previous studies. However, no study verifies if the results will be affected by abstinence time. From January to December in 2016, fifty PPE patients ejaculated within 2 min and 28 control subjects were enrolled. The nerve electrophysiological tests, including dorsal nerve somatosensory evoked potential (DNSEP), glans penis somatosensory evoked potential (GPSEP), and penile sympathetic skin response (PSSR), were recorded before and immediately after ejaculation. The abstinence day was not correlated with the latencies of SEPs or PSSR neither in PE group (P = 0.170, 0.064, and 0.122, respectively) nor in control group (P = 0.996, 0.475, and 0.904, respectively). No statistically differences were found in the latencies of SEPs and PSSR before and after ejaculation in PE patients (P = 0.439, 0.537, and 0.576, respectively) or control subjects (P = 0.102, 0.198, and 0.363, respectively). Thus, abstinence time does not interfere with the nerve electrophysiological test, which is stable in determining the nerve function of PPE patients.