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This letter presents a simple technique that improves the symmetry of tapered fibers fabricated with a continuous-wave CO2 laser. The uniform heat distribution inside an optical fiber is achieved by using a nonscanning dual-spot laser beam which applies heat on two sides of the optical fiber simultaneously. In so doing, highly symmetric tapers are obtained with an ellipticity close to unity. These tapers can be used as low-loss and polarization-dependent loss optical fiber filters or other optical devices such as symmetric fibers lenses [ABSTRACT FROM PUBLISHER]

Introduction: Internal urethrotomy (IU) has been the most commonly used procedure for the treatment of urethral strictures (US) since it was described by Scahse in 1974. Although simple to perform and associated with a short recovery time, the main disadvantage is the high recurrence rate of stenosis. At present, there are no markers available for the prediction of recurrence after IU. The aim of this study was to evaluate the correlation between MHR and recurrence rates., Methods: The data of a total of 250 male patients who underwent IU for the first time for bulbar urethral stricture less than 2cm in our hospital between January 2011 and January 2019 were retrospectively analysed. The MHR was calculated as the ratio of monocytes to HDL-C., Results: In all, 78 patients experienced a recurrence while the remaining 177 did not. The stricture recurrence rate was recorded as 31.2% at the 3-year follow-up. There was a statistically significant difference in stricture length and MHR (P=0.015 and 0.001 respectively). MHR was high in the recurrent group. As a result of the Chi-square test, the positive predictive values (PPV) and negative predictive values (NPV) were 65.3% and 89.7%, respectively. ROC analysis was used to determine the optimal cut-off value. The cut-off value was found to be 1.72., Conclusion: In our opinion, a high MHR may indicate the presence of immune inflammation and it can be used as a prognostic factor for stricture recurrence after IU., (Copyright © 2024 Elsevier Masson SAS. All rights reserved.)

Backgrounds: In the renal intrarenal stone surgery (RIRS) procedure, ureteral access sheath (UAS) is still used in the majority of surgeries to both protect the flexible ureteroscope (FURS) and reduce intrarenal pressure. ClearPETRA is a new UAS that has an integrated aspiration port. We aimed to evaluate the clinical outcomes and effectiveness of Aspiration-Assisted UAS (ClearPETRA) in the RIRS procedure. Methods: One thousand six hundred twenty patients who underwent RIRS between January 2021 and January 2024 were evaluated retrospectively and 512 patients were included in the study. According to stone size, patients with stones less than 2 cm and those with stones between 2 and 3 cm were analyzed separately. Patient's demographic data, stone size, body mass index, Extracoporeal Shockwave Lithotripsy (ESWL) history, stone side, stone density (Hounsfield Unit), operation time, stone-free rate (SFR), and the number of patients with sepsis were recorded. SFR was evaluated with kidney urinary bladder 3 months after surgery for opaque calculi. Nonopaque calculi patients were evaluated with noncontrast computed tomography 3 months after surgery. In the postoperative evaluation, patients with stones less than 4 mm were evaluated as SFR. P value of <0.01 was considered statistically significant. Results: Patient's demographic data, stone characteristics, and history of ESWL were similar in the ClearPETRA and UAS groups ( P  > .05). A total of 328 patients who underwent RIRS for stones less than 2 cm were included (80 ClearPETRA, 248 UAS). Length of hospital stay, operation time, SFR, secondary intervention, or postoperative sepsis ( P  ≥ .01) were similar in both groups. The incidence of postoperative fever was statistically significantly lower in the ClearPETRA group ( P  = .006). A total of 184 patients who underwent RIRS for stones between 2 and 3 cm were included (42 ClearPETRA, 142 UAS). In the ClearPETRA group, operation time was statistically significantly shorter ( P  = .002), SFR was statistically significantly higher ( P  = .003), and the number of fever and sepsis were statistically significantly less ( P  = .003 and 0.002, respectively). Conclusion: We found that ClearPETRA reduces the likelihood of postoperative fever after RIRS surgeries. Moreover, we can say that the use of ClearPETRA in RIRS, especially for stones larger than 2 cm, reduces the operation time, increases the SFR, and also reduces sepsis rates.

LDL-C lowering is the main goal of atherosclerotic cardiovascular disease prevention, and proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibition is now a validated therapeutic strategy that lowers serum LDL-C and reduces coronary events. Ironically, the most widely used medicine to lower cholesterol, statins, has been shown to increase circulating PCSK9 levels, which limits their efficacy. Here, we show that geranylgeranyl isoprenoids and hepatic Rap1a regulate both basal and statin-induced expression of PCSK9 and contribute to LDL-C homeostasis. Rap1a prenylation and activity is inhibited upon statin treatment, and statin-mediated PCSK9 induction is dependent on geranylgeranyl synthesis and hepatic Rap1a. Accordingly, treatment of mice with a small-molecule activator of Rap1a lowered PCSK9 protein and plasma cholesterol and inhibited statin-mediated PCSK9 induction in hepatocytes. The mechanism involves inhibition of the downstream RhoA-ROCK pathway and regulation of PCSK9 at the post-transcriptional level. These data further identify Rap1a as a novel regulator of PCSK9 protein and show that blocking Rap1a prenylation through lowering geranylgeranyl levels contributes to statin-mediated induction of PCSK9., Competing Interests: Conflict of interest L. O. is an Editorial Board Member for Diabetes and was not involved in the editorial review or the decision to publish this article. All other authors declare that they have no conflicts of interest with the contents of this article., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Objective: The aim of the study is to investigate the validity and reliability of the "Telemedicine Awareness, Knowledge, Attitude, and Skills (AKAS) of Telemedicine" questionnaire and to convert the questionnaire to Turkish., Methods: The study is methodological research conducted among medical faculty students and medical residents. For the validity and reliability analysis of the "AKAS of Telemedicine" questionnaire, 425 medical faculty students and medical residents were included in the study, and the sample was 7-10 times the number of questionnaire items. Exploratory factor analysis was performed for construct validity. The test-retest method was engaged to assess reliability. Cronbach's alpha reliability coefficient and the item-total correlation coefficient were calculated for internal consistency. Descriptive statistics were given as mean, standard deviation, median, and first and third quartile values for numerical variables, and numbers and percentages for categorical variables. The Mann-Whitney U test, the Kruskal-Wallis test, and Spearman's correlation coefficient were conducted to evaluate the correlation between variables., Results: The Cronbach alpha reliability coefficient of the "AKAS of Telemedicine" questionnaire was found to be 0.950, 0.851, 0.970, and 0.952 in the sub-areas, respectively. When an item was removed, the Cronbach alpha reliability coefficient values ranged between 0.826 and 0.969, and no significant difference was detected. As a result of test-retest reliability analysis, a strong positive correlation was found between the total scores (awareness r=0.848, knowledge r=0.792, attitude r=0.787, and skill r=0.816; p<0.001 for each score)., Conclusion: The Turkish form of the "AKAS of Telemedicine" questionnaire is a valid and reliable measurement tool that can be used to evaluate the level of AKAS among physicians. It was concluded that research using the "AKAS of Telemedicine" questionnaire would be useful to determine the telemedicine AKAS levels among Turkiye, particularly in health sector workers., Competing Interests: No conflict of interest was declared by the authors., (© Copyright 2024 by Istanbul Provincial Directorate of Health.)

Introduction: The main challenge to the optimal use of neoadjuvant chemotherapy (NAC) is the difficulty in selecting patients who may or may not benefit from NAC. Our aim in this study was to investigate whether the Systemic Inflammatory Index (SII) predicts response to chemotherapy in patients who receive NAC prior to cystectomy., Methods: We retrospectively analysed the data of patients who underwent NAC followed by cystectomy at our institution between January 2010 and September 2015 and whose 5-year follow-up was completed. All patients who underwent diagnostic biopsy with complete transurethral resection of bladder tumour at our hospital and whose pathology result was muscle-invasive transitional cell carcinoma were included in the study. At least 3 courses of gemcitabine/cisplatin NAC were given to all patients. A pathological response was defined as a reduction in cystectomy to a lower pathological stage after NAC., Results: The SII was 320.8 ± 51 in the responders and 388.28 ± 50 in the non-responders. SII optimal cut-off of 350 was determined. The sensitivity and specificity of SII in predicting response were found to be 80% and 83%, respectively. Low SII (&lt;350) was found to be a significant predictor of response compared with the other factors on multivariate analysis. The mean overall survival time was 55.4 months in patients with a low SII value and 40.3 months in the high SII group., Conclusion: SII, together with known clinicopathological factors and newer genetic and molecular markers, can be used to select patients for NAC., (© 2024 S. Karger AG, Basel.)

Purpose of Review: The focus of this article is to highlight the importance of the small GTPase, Ras-associated protein 1 (Rap1), in proprotein convertase subtilisin/kexin type 9 (PCSK9) regulation and atherosclerosis and type 2 diabetes etiology and discuss the potential therapeutic implications of targeting Rap1 in these disease areas., Review Findings: Cardiometabolic disease characterized by obesity, glucose intolerance, dyslipidemia, and atherosclerotic cardiovascular disease remain an important cause of mortality. Evidence using mouse models of obesity and insulin resistance indicates that Rap1 deficiency increases proatherogenic PCSK9 and low-density lipoprotein cholesterol levels and predisposes these mice to develop obesity- and statin-induced hyperglycemia, which highlights Rap1's role in cardiometabolic dysfunction. Rap1 may also contribute to cardiovascular disease through its effects on vascular wall cells involved in the atherosclerosis progression. Rap1 activation, specifically in the liver, could be beneficial in the prevention of cardiometabolic perturbations, including type 2 diabetes, hypercholesterolemia, and atherosclerosis., (© 2023. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Aim: We aimed to determine the effectiveness of penis-root masturbation (PRM), a newly defined behavioral therapy (BT) technique, in patients with unsuccessful medical treatment due to premature ejaculation (PE)., Material and Methods: The study included 35 patients aged 25-43 years, who were diagnosed with lifelong PE. Patients and their partners were informed about the PRM technique and asked to practice PRM three times a week for three months, with or without sexual intercourse. The patients' Premature Ejaculation Diagnostic Tool (PEDT) scores and intravaginal ejaculatory latency time (IELT) were recorded and compared before PRM training (T0) and at the third (T3) month after the start of PRM training., Results: The mean±SD PEDT scores were 16.26±1.94 at T0, 10.63±1.14 at T3. When compared to T0, the PEDT values at T3 were significantly lower (P=0.021). In terms of IELT, the mean T3 values (192.43±56.71) were significantly longer (P=0.035) than at T0 (50.43±13.84seconds)., Conclusion: PRM BT shows promise for lifelong PE patients who do not benefit from or discontinue to pharmacotherapy. Larger prospective trials are required to confirm these findings., (Copyright © 2023 Elsevier Masson SAS. All rights reserved.)

Background: Although PCNL has been used for a long time to treat nephrolithiasis, there is still contradictory information concerning the use of the dilation method. In this study, we aimed to compare conventional sequential Amplatz dilatation (SAD) using ten dilators and a method using three dilators (12, 20, and 30 Fr), which we named "three-shot dilatation" (3SD), in terms of fluoroscopy time (FT), operation time, bleeding and stone-free rates., Methods: The study included patients who underwent PCNL with the SAD and 3SD methods. A different surgeon with extensive endourology experience applied each technique. One of the surgeons operated on the patients using the SAD method with ten dilators, and the other surgeon performed the operations using the 3SD method involving three Amplatz dilators (12, 20, and 30 Fr)., Results: A total of 283 patients, 138 in the 3SD group and 145 in the SAD group, were included in the study. The mean age of the patients was 47.32 ± 13.71 years. There was no statistically significant difference between the two groups regarding preoperative characteristics (p > 0.05). The FTs of access 2, total access, and total operation were significantly shorter in the 3SD group (p = 0.0001). The decrease in hemoglobin was statistically significant in the 3SD group compared to the SAD group (p = 0.022), while the blood transfusion requirements of the groups were similar (p = 0.176). There was no statistically significant difference between the two groups regarding stone-free rates (p = 0.973). In four patients in the SAD group, re-access was necessary due to the loss of passage due to the guide wire slipping out of its place., Conclusion: Intraoperative FT can be shortened using the described 3SD method without compromising surgical safety. However, this method can be used as an intermediate step in the transition to one-shot dilation by surgeons experienced in performing SAD., (© 2023. The Author(s).)

Objective: To investigate active surveillance (AS) for patients with prostate cancer to show the systemic inflammatory index (SII) progression and to evaluate whether SII will be an AS criterion in PCa patients., Study Design: Descriptive study. Place and Duration of the Study: Department of Urology, University of Health Sciences, Prof. Dr. Cemil Tascioglu City Hospital, from February 2015 to December 2021., Methodology: For active surveillance follow-up criteria, patients with prostate cancer who underwent AS with PSA <10 ng/ml, GS ≤6, clinical stage t1c-t2b, ≤2 core positive, and for each positive core had ≤50% tumour cells, were inducted and SII was determined., Results: As a result of the univariate analysis, high SII values, number of cores involved, and length of the tumour in one core significantly affected progression (in order of p = 0.009, B = 1.830, Exp(B) = 6.233, CI [1.58-24.497]; p = 0.018, B = 0.682, Exp(B) = 1.978, CI [1.123-3.482]; p=0.006, B = 1.835, Exp(B) = 6.263 CI [1.692-23.181]). High SII values (>443.42) had better explanations for progression than the number of core involvement but were similar to the length of the tumour in one core. As a result of the multivariate analysis, high SII values (>443.42) and the tumour 's length in one core had similar effects on progression (in order of p = 0.011, B = 1.978, Exp(B) = 7.227, CI [1.570-33.269]; p = 0.009, B = 1.958, Exp(B) = 7.084, CI [1.642-30.555])., Conclusion: Th use of SII early in the course of treatment can help to identify which prostate cancer patients can be selected for active treatment instead of active surveillance, and to assess the probability of progression., Key Words: Prostate cancer, Active surveillance, Systemic inflammatory index, Biomarker.

We previously demonstrated that hepatic activation of a small G protein of the Ras family, Rap1a, is suppressed in obesity, which results in increased hepatic glucose production and glucose intolerance in obese mice. Here, we show that Rap1a inhibition in obese mice liver also results in fatty liver formation, which is characteristic of the diabetic liver. Specifically, we report that Rap1a activity is decreased in the livers of patients with non-alcoholic steatohepatitis (NASH) and mouse models of non-alcoholic fatty liver disease (NAFLD) and NASH. Restoring hepatic Rap1a activity by overexpressing a constitutively active mutant form of Rap1a lowered the mature, processed form of lipogenic transcription factor, Srebp1, without an effect on the unprocessed Srebp1 and suppressed hepatic TG accumulation, whereas liver Rap1a deficiency increased Srebp1 processing and exacerbated steatosis. Mechanistically, we show that mTORC1, which promotes Srebp1 cleavage, is hyperactivated upon Rap1a deficiency despite disturbed insulin signaling. In proof-of-principle studies, we found that treatment of obese mice with a small molecule activator of Rap1a (8-pCPT) or inhibiting Rap1a's endogenous inhibitor, Rap1Gap, recapitulated our hepatic gain-of-function model and resulted in improved hepatic steatosis and lowered lipogenic genes. Thus, hepatic Rap1a serves as a signaling molecule that suppresses both hepatic gluconeogenesis and steatosis, and inhibition of its activity in the liver contributes to the pathogenesis of glucose intolerance and NAFLD/NASH development.

Low-density lipoprotein cholesterol (LDL-C) lowering is the main goal of atherosclerotic cardiovascular disease prevention, and proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibition is now a validated therapeutic strategy that lowers serum LDL-C and reduces coronary events. Ironically, the most widely used medicine to lower cholesterol, statins, has been shown to increase circulating PCSK9 levels, which limits their efficacy. Here, we show that geranylgeranyl isoprenoids and hepatic Rap1a regulate both basal and statin induced expression of PCSK9 and contribute to LDL-C homeostasis. Rap1a prenylation and activity is inhibited upon statin treatment, and statin mediated PCSK9 induction is dependent on geranylgeranyl synthesis and hepatic Rap1a. Accordingly, treatment of mice with a small molecule activator of Rap1a lowered PCSK9 protein and plasma cholesterol and inhibited statin mediated PCSK9 induction in hepatocytes. The mechanism involves inhibition of the downstream RhoA-ROCK pathway and regulation of PCSK9 at the post transcriptional level. These data further identify Rap1a as a novel regulator of PCSK9 protein and show that blocking Rap1a prenylation through lowering geranylgeranyl levels contributes to statin-mediated induction of PCSK9.

Background–: Type 2 diabetes is associated with an increased risk of atherosclerotic cardiovascular disease. It has been suggested that insulin resistance underlies this link, possibly by altering the functions of cells in the artery wall. We aimed to test whether improving systemic insulin sensitivity reduces atherosclerosis., Methods–: We used mice that are established to have improved systemic insulin sensitivity: those lacking FoxO transcription factors in hepatocytes. Three hepatic FoxO isoforms (FoxO1, FoxO3, and FoxO4) function together to promote hepatic glucose output, and ablating them lowers glucose production, lowers circulating glucose and insulin, and improves systemic insulin sensitivity. We made these mice susceptible to atherosclerosis in two different ways, by injecting them with gain-of-function AAV8.mPcsk9 D377Y and by crossing with Ldlr -/- mice., Results–: We verified that hepatic FoxO ablation improves systemic insulin sensitivity in these atherosclerotic settings. We observed that FoxO deficiency caused no reductions in atherosclerosis, and in some cases increased atherosclerosis. These phenotypes coincided with large increases in circulating triglycerides in FoxO-ablated mice., Conclusions–: These findings suggest that systemic insulin sensitization is insufficient to reduce atherosclerosis., Competing Interests: Conflict of interest statement. The authors have declared that no conflict of interest exists.

Introduction: Inadequate pain control frequently extends length of stay (LOS) and costs for patients undergoing mastectomy with implant-based reconstruction (IBR). We sought to examine the effects of Paravertebral blocks (PVB) and liposomal bupivacaine (LB) and compare LOS, pain scores and costs of hospitalization., Methods: Prospective database review of patients undergoing mastectomy with IBR was performed., Results: 541 patients were identified. 51/491 (9.4%) received PVB and 50 (9.2%) received LB. LOS in the PVB group was significantly less than that of the no block (NB) group (1 [1-2] days PVB vs 3 [2-4] days NB (p < 0.0001), but was not different from the LB group (1 [1-2] days LB, p = 0.23). PVB patients had lower PACU pain scores compared to NB patients (3.2 ± 2.9 PVB vs 5.7 ± 2.6 NB, p < 0.0001), but similar PACU pain scores to LB patients (4.1 ± 2.3). Patients who received PVB had higher total costs compared to NB patients ($27148±$7053 PVB vs $23113 ± 6860 NB, p = 0.003) but similar to LB patients ($26183 ± $3761)., Conclusion: PVB and LB are associated with shorter LOS and lower pain scores compared to NB., (Copyright © 2022. Published by Elsevier Inc.)

Excessive hepatic glucose production contributes to the development of hyperglycemia and is a key feature of type 2 diabetes. Here, we report that activation of hepatocyte Rap1a suppresses gluconeogenic gene expression and glucose production, whereas Rap1a silencing stimulates them. Rap1a activation is suppressed in obese mouse liver, and restoring its activity improves glucose intolerance. As Rap1a's membrane localization and activation depends on its geranylgeranylation, which is inhibited by statins, we show that statin-treated hepatocytes and the human liver have lower active-Rap1a levels. Similar to Rap1a inhibition, statins stimulate hepatic gluconeogenesis and increase fasting blood glucose in obese mice. Geranylgeraniol treatment, which acts as the precursor for geranylgeranyl isoprenoids, restores Rap1a activity and improves statin-mediated glucose intolerance. Mechanistically, Rap1a activation induces actin polymerization, which suppresses gluconeogenesis by Akt-mediated FoxO1 inhibition. Thus, Rap1a regulates hepatic glucose homeostasis, and blocking its activity, via lowering geranylgeranyl isoprenoids, contributes to statin-induced glucose intolerance., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2022 The Author(s). Published by Elsevier Inc. All rights reserved.)

Purpose: There is evidence that follicular phase progesterone rise [FPPR] adversely affects fresh in vitro fertilization [IVF] cycles. A single daily dose of cetrorelix has been used to prevent early luteinizing Hormone (LH) surge. We speculated that doubling the daily dose might have a positive effect in patients who have early LH surges despite receiving the single daily dose treatment. However, a double daily dose of cetrorelix seems to cause FPPR in poor ovarian response (POR) patients., Materials and Methods: On human chorionic gonadotropin [hCG] injection days, the progesterone levels of POR patients who received a single daily dose of cetrorelix (group 1, n = 59) were compared with progesterone levels of the patients who received a double daily dose of cetrorelix (group 2, n = 75). The two groups had statistically similar demographic data. The patients who had FPPR were detected, and a comparison of progesterone levels, using 0.8, 1.0, and 1.2 [ng/mL] of progesterone as cut-off levels, was made between patients of both groups., Results: FPPR patients in group 2 had significantly higher progesterone levels during hCG day, contrary to expectations. When progesterone cut-off levels of 0.8, 1.0, and 1.2 [ng/mL] were used for group 1 patients, 15.3%, 13.6%, and 6.8% of the patients developed FPPR, respectively When the progesterone cut-off levels of 0.8, 1.0, and 1.2 [ng/mL] were used for group 2, the results detected were 45.3%, 30.7%, and 21.3%, respectively. A significant statistical difference in progesterone levels was observed between the groups., Conclusion: While the double daily dose of cetrorelix was initially thought to more effectively suppress early LH rise by some authors, we have seen that it increases the FPPR more when compared to a single daily dose regime. We suggest using frozen cycles instead of fresh cycles in order to have better endometrial receptivity in patients who seem to benefit from higher daily doses of cetrorelix., (Copyright © 2021 Elsevier Masson SAS. All rights reserved.)

Objective: Obesity-related adipose tissue dysfunction has been linked to the development of insulin resistance, type 2 diabetes, and cardiovascular disease. Impaired calcium homeostasis is associated with altered adipose tissue metabolism; however, the molecular mechanisms that link disrupted calcium signaling to metabolic regulation are largely unknown. Here, we investigated the contribution of a calcium-sensing enzyme, calcium/calmodulin-dependent protein kinase II (CAMK2), to adipocyte function, obesity-associated insulin resistance, and glucose intolerance., Methods: To determine the impact of adipocyte CAMK2 deficiency on metabolic regulation, we generated a conditional knockout mouse model and acutely deleted CAMK2 in mature adipocytes. We further used in vitro differentiated adipocytes to dissect the mechanisms by which CAMK2 regulates adipocyte function., Results: CAMK2 activity was increased in obese adipose tissue, and depletion of adipocyte CAMK2 in adult mice improved glucose intolerance and insulin resistance without an effect on body weight. Mechanistically, we found that activation of CAMK2 disrupted adipocyte insulin signaling and lowered the amount of insulin receptor. Further, our results revealed that CAMK2 contributed to adipocyte lipolysis, tumor necrosis factor alpha (TNFα)-induced inflammation, and insulin resistance., Conclusions: These results identify a new link between adipocyte CAMK2 activity, metabolic regulation, and whole-body glucose homeostasis., (Copyright © 2021 The Author(s). Published by Elsevier GmbH.. All rights reserved.)

Objectives: The aim of this multisite quality improvement study was to evaluate patients' experiences with the patient-centered pathology (PCP) consultation program and to determine whether PCP enhanced their care experience., Methods: Patients were invited to attend PCP consultations to review their pathology report and slides and have their questions answered by the pathologist privately, with the option to attend the appointment with family members or friends for support. A patient experience questionnaire (PEQ) was administered to patients, who participated voluntarily in the PCP, and survey data were collected and stored in REDCap. Statistical analysis was performed using SAS 9.4 (SAS Institute)., Results: Sixty-seven patients (95.5% female) aged 18 to 84 years across 4 institutions completed the PEQ. Overall, 58% and 15.8% of patients had breast and brain tumors, respectively, and 59.7% of tumors were newly diagnosed. Most patients thought it was important for them to learn as much as they could about their health condition. However, the majority of patients reported some degree of difficulty learning about their health condition based on written information, despite 97% having completed high school and/or further education. The majority of patients rated their pathologist as "excellent" across communication metrics. Ultimately, 100% of respondents were satisfied, found their visits to be useful, and would recommend the PCP to other patients., Conclusions: Patients found that personalized clinical encounters with pathologists improved their understanding of their health condition and their satisfaction with their care experience. Patients thought pathologists communicated respectfully, effectively, and empathetically., (© American Society for Clinical Pathology, 2020. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Atherosclerotic vascular disease resulting from unstable plaques is the leading cause of morbidity and mortality in subjects with type 2 diabetes (T2D), and thus a major therapeutic goal is to discover T2D drugs that can also promote atherosclerotic plaque stability. Genetic or pharmacologic inhibition of mitogen-activated protein kinase-activated protein kinase-2 (MAPKAPK2 or MK2) in obese mice improves glucose homeostasis and enhances insulin sensitivity. We developed two novel orally active small-molecule inhibitors of MK2, TBX-1 and TBX-2, and tested their effects on metabolism and atherosclerosis in high-fat Western diet (WD)-fed Ldlr-/- mice. Ldlr-/- mice were first fed the WD to allow atherosclerotic lesions to become established, and the mice were then treated with TBX-1 or TBX-2. Both compounds improved glucose metabolism and lowered plasma cholesterol and triglyceride, without an effect on body weight. Most importantly, the compounds decreased lesion area, lessened plaque necrosis, and increased fibrous cap thickness in the aortic root lesions of the mice. Thus, in a preclinical model of high-fat feeding and established atherosclerosis, MK2 inhibitors improved metabolism and also enhanced atherosclerotic plaque stability, suggesting potential for further clinical development to address the epidemic of T2D associated with atherosclerotic vascular disease., Competing Interests: We have read the journal’s policy and the authors of this manuscript have the following competing interests: L.O., B.H., M.H.S.-W., and I.T. are members of Tabomedex Biosciences, Inc., which is developing allosteric MK2 inhibitors for the treatment of type 2 diabetes. All the authors confirm that this commercial affiliation does not alter our adherence to all PLOS ONE policies on sharing data and materials.

Objective: To compare the efficacy of statins and ɑ blockers drug therapies for benign prostatic hyperplasia (BPH) in patients with metabolic syndrome (MetS)., Materials and Method: A total of three hundred patients were randomly distributed into three groups of one hundred patients each. Group 1 received only ɑ-adrenoceptor antagonist (ɑ-blocker, AB) (Tamsulosin), group 2 received only statin (atorvastatin), and group 3 received AB plus statin (Tamsulosin + Atorvastatin). The efficacy measurement was assessed by analyzing the changes from baseline in the total International Prostate Symptom Score (IPSS), disease-specific QoL question score and maximum urinary flow rate at the end of 6 months in each group and between the three groups., Results: Pre-treatment and post-treatment value of triglycerides (TG), high-density lipoprotein (HDL), and prostate volüme (PV) were not significantly different in AB group, while TG and PV were significantly lower in patients taking statin and combined therapy. The significant decrease was demonstrated in maximum urinary flow rate ( Q max ) in three groups. However, the most significant decrease was observed in the combination therapy group. IPSS, postvoid residual urine volüme (PVR), and Quality of Life score (QoL) significantly changed in three groups., Conclusion: We recommend of the use of statins in those men with BPH accompanied by MetS in which AB is ineffective alone.

Fibrinolysis is initiated by tissue-type plasminogen activator (tPA) and inhibited by plasminogen activator inhibitor 1 (PAI-1). In obese humans, plasma PAI-1 and tPA proteins are increased, but PAI-1 dominates, leading to reduced fibrinolysis and thrombosis. To understand tPA-PAI-1 regulation in obesity, we focused on hepatocytes, a functionally important source of tPA and PAI-1 that sense obesity-induced metabolic stress. We showed that obese mice, like humans, had reduced fibrinolysis and increased plasma PAI-1 and tPA, due largely to their increased hepatocyte expression. A decrease in the PAI-1 (SERPINE1) gene corepressor Rev-Erbα increased PAI-1, which then increased the tPA gene PLAT via a PAI-1/LRP1/PKA/p-CREB1 pathway. This pathway was partially counterbalanced by increased DACH1, a PLAT-negative regulator. We focused on the PAI-1/PLAT pathway, which mitigates the reduction in fibrinolysis in obesity. Thus, silencing hepatocyte PAI-1, CREB1, or tPA in obese mice lowered plasma tPA and further impaired fibrinolysis. The PAI-1/PLAT pathway was present in primary human hepatocytes, and associations among PAI-1, tPA, and PLAT in livers from obese and lean humans were consistent with these findings. Knowledge of PAI-1 and tPA regulation in hepatocytes in obesity may suggest therapeutic strategies for improving fibrinolysis and lowering the risk of thrombosis in this setting.

Introduction: In this study we aimed to determine the effects of the 45 degrees sided prone position to the surgeon's comfort, operation time, fluoroscopy time and complications at the operation of percutaneous nephrolithotomy (PCNL) for the treatment of kidney stone of horseshoe kidney (HK) or rotation anomaly kidney., Material and Methods: Thirty eight patients (25 male, 13 female) with renal calculi and HK, underwent PCNL. After the amplatz sheath was inserted into the collecting system, the patients in group 1 (n:20) were taken to the 45 degrees side position to the side of the operation and patients in group 2 (n:18) were operated in classical prone position. Operative data of two groups were compared statistically., Results: Mean stone size of group 1 was 557.8 ±244.8 mm 3 (188-1175) and group 2 was 590.7 ±172.8 mm 3 (423-909) (p = 0.639). In group 1 mean operation time was 78.6 ±21.8 (45-120) minutes and in group 2 was 95.05 ±11.5 (69-120) minutes. The difference for operation time was statistically significant and shorter in the sided group (p = 0.02)., Conclusions: The working position of rigid nephroscope is 90 degrees to the body after the dorsomedial or dorsolateral access. In our study the position of patient is laterally sided 45 degree and the flexion on the surgeon's shoulder was minimised. This new position described for PCNL in HK allows comfortable working position for surgeon after upper pole posterior calyces access., Competing Interests: The authors declare no conflicts of interest., (Copyright by Polish Urological Association.)

Purpose of Review: The purpose of this review is to highlight the recent findings of one of the most promising therapeutic targets in LDL cholesterol (LDL-C) management, proprotein convertase subtilisin/kexin type 9 (PCSK9)., Recent Findings: Endoplasmic reticulum cargo receptor, surfeit locus protein 4 interacts with PCSK9 and regulates its exit from endoplasmic reticulum and its secretion. Once secreted, PCSK9 binds to heparin sulfate proteoglycans on the hepatocyte surface and this binding is required for PCSK9-LDL receptor (LDLR) complex formation and LDLR degradation. Posttranscriptionally, recent work has shown that PCSK9 gets degraded in lysosomes by activation of the glucagon receptor signaling, providing more data on the hormonal regulation of PCSK9. Finally, human studies with PCSK9 inhibitors offered more evidence on their benefits and safe use., Summary: Recent work on the regulation of PCSK9 has enhanced our understanding of its biology, which may provide important information for future PCSK9-based therapies.

Tissue-type plasminogen activator (tPA) is a major mediator of fibrinolysis and, thereby, prevents excessive coagulation without compromising hemostasis. Studies on tPA regulation have focused on its acute local release by vascular cells in response to injury or other stimuli. However, very little is known about sources, regulation, and fibrinolytic function of noninjury-induced systemic plasma tPA. We explore the role and regulation of hepatocyte-derived tPA as a source of basal plasma tPA activity and as a contributor to fibrinolysis after vascular injury. We show that hepatocyte tPA is downregulated by a pathway in which the corepressor DACH1 represses ATF6, which is an inducer of the tPA gene Plat Hepatocyte-DACH1-knockout mice show increases in liver Plat , circulating tPA, fibrinolytic activity, bleeding time, and time to thrombosis, which are reversed by silencing hepatocyte Plat Conversely, hepatocyte-ATF6-knockout mice show decreases in these parameters. The inverse correlation between DACH1 and ATF6 / PLAT is conserved in human liver. These findings reveal a regulated pathway in hepatocytes that contributes to basal circulating levels of tPA and to fibrinolysis after vascular injury., (© 2019 by The American Society of Hematology.)

Rationale: Glucagon is a key hormone that regulates the adaptive metabolic responses to fasting. In addition to maintaining glucose homeostasis, glucagon participates in the regulation of cholesterol metabolism; however, the molecular pathways underlying this effect are incompletely understood., Objective: We sought to determine the role of hepatic Gcgr (glucagon receptor) signaling in plasma cholesterol regulation and identify its underlying molecular mechanisms., Methods and Results: We show that Gcgr signaling plays an essential role in LDL-C (low-density lipoprotein cholesterol) homeostasis through regulating the PCSK9 (proprotein convertase subtilisin/kexin type 9) levels. Silencing of hepatic Gcgr or inhibition of glucagon action increased hepatic and plasma PCSK9 and resulted in lower LDLR (LDL receptor) protein and increased plasma LDL-C. Conversely, treatment of wild-type (WT) mice with glucagon lowered LDL-C levels, whereas this response was abrogated in Pcsk9 -/- and Ldlr -/- mice. Our gain- and loss-of-function studies identified Epac2 (exchange protein activated by cAMP-2) and Rap1 (Ras-related protein-1) as the downstream mediators of glucagon's action on PCSK9 homeostasis. Moreover, mechanistic studies revealed that glucagon affected the half-life of PCSK9 protein without changing the level of its mRNA, indicating that Gcgr signaling regulates PCSK9 degradation., Conclusions: These findings provide novel insights into the molecular interplay between hepatic glucagon signaling and lipid metabolism and describe a new posttranscriptional mechanism of PCSK9 regulation.

Introduction: We investigated whether Oltipraz (OPZ) attenuated renal fibrosis in a unilateral ureteral obstruction (UUO) rat model., Materials and Methods: We randomly divided 32 rats into four groups, each consisting of eight animals as follows: Rats in group 1 underwent a sham operation and received no treatment. Rats in group 2 underwent a sham operation and received OPZ. Rats in group 3 underwent unilateral ureteral ligation and received no treatment. Group 4 rats were subjected to unilateral ureteral ligation plus OPZ administration. Transforming growth factor beta-1 (TGF-β1), E-cadherin, nitric oxide (NO) and hydroxyproline levels were measured. Histopathological and immunohistochemical examinations were carried out., Results: TGF-β1, NO and E-cadherin levels in the UUO group were significantly higher than the sham group and these values were significantly different in treated groups compared to the UUO group. In rats treated with UUO + OPZ, despite the presence of mild tubular degeneration and less severe tubular necrosis, glomeruli maintained a better morphology when compared to the UUO group. Expressions of α-SMA in immunohistochemistry showed that the staining positivity decreased in the tubules of the OPZ-treated group., Conclusions: While the precise mechanism of action remains unknown, our results demonstrated that OPZ exerted a protective role in the UUO-mediated renal fibrosis rat model highlighting a promising therapeutic potency of Nrf2-activators for alleviating the detrimental effects of unilateral obstruction in kidneys., Competing Interests: Conflict of interest: None declared., (Copyright® by the International Brazilian Journal of Urology.)

Purpose: Stress urinary incontinence (SUI) and pelvic organ prolapse (POP) are common medical problems, particularlyamong older women. In this study, we aim to explore the relationship between the neurotransmitter nNOS in the vaginal epithelium, and the occurrence of SUI and changes of nNOS levels according to menopausal status.Matherials and Methods: Fourty women were enrolled. The patients were divided into four groups according to menstruaiton status and SUI. The vagina specimens were taken during transobturator tape application. The specimens were examined pathologically in terms of n-NOS expression. nNOS expression was compared between SUI and control groups. The results were evaluated statistically., Result: Epithelial total nNOS score in group 1 and group 3 were 2.4 ± 0.5 and 1.4 ± 0.5 respectively (P = .003). Stromal total nNOS score was found 2.2 ± 0.4 in group 1 and 1.3 ± 0.5 in group 3 (P = .001). Epithelial total nNOS score in group 2 and group 4 were 4.4 ± 0.5 and 3.5 ± 0.5 respectively (P = .003). Stromal total nNOS score was found 4.4 ± 0.5 in group 2 and 3.6 ± 0.5 in group 4 ( P = .006)., Conclusion: Our results show that expression of nNOs in the anterior vaginal epithelium decreased significantly in the SUI group. Altough our findings indicate important results, well designed further studies are needed to comprehend the role of NOS pathways better in SUI pathophysiology.