Glutamyl-prolyl-tRNA synthetase (EPRS1) drives tubulointerstitial nephritis-induced fibrosis by enhancing T cell proliferation and activity.

Toxin- and drug-induced tubulointerstitial nephritis (TIN), characterized by interstitial infiltration of immune cells, frequently necessitates dialysis for patients due to irreversible fibrosis. However, agents modulating interstitial immune cells are lacking. Here, we addressed whether the housekeeping enzyme glutamyl-prolyl-transfer RNA synthetase 1 (EPRS1), responsible for attaching glutamic acid and proline to transfer RNA, modulates immune cell activity during TIN and whether its pharmacological inhibition abrogates fibrotic transformation. The immunological feature following TIN induction by means of an adenine-mixed diet was infiltration of EPRS1high T cells, particularly proliferating T and γδ T cells. The proliferation capacity of both CD4+ and CD8+ T cells, along with interleukin-17 production of γδ T cells, was higher in the kidneys of TIN-induced Eprs1+/+ mice than in the kidneys of TIN-induced Eprs1+/- mice. This discrepancy contributed to the fibrotic amelioration observed in kidneys of Eprs1+/- mice. TIN-induced fibrosis was also reduced in Rag1-/- mice adoptively transferred with Eprs1+/- T cells compared to the Rag1-/- mice transferred with Eprs1+/+ T cells. The use of an EPRS1-targeting small molecule inhibitor (bersiporocin) under clinical trials to evaluate its therapeutic potential against idiopathic pulmonary fibrosis alleviated immunofibrotic aggravation in TIN. EPRS1 expression was also observed in human kidney tissues and blood-derived T cells, and high expression was associated with worse patient outcomes. Thus, EPRS1 may emerge as a therapeutic target in toxin- and drug-induced TIN, modulating the proliferation and activity of infiltrated T cells.

IDO1 scavenges reactive oxygen species in myeloid-derived suppressor cells to prevent graft-versus-host disease.

Tryptophan-catabolizing enzyme indoleamine 2,3-dioxygenase 1 (IDO1) also has an immunological function to suppress T cell activation in inflammatory circumstances, including graft-versus-host disease (GVHD), a fatal complication after allogeneic bone marrow transplantation (allo-BMT). Although the mononuclear cell expression of IDO1 has been associated with improved outcomes in GVHD, the underlying mechanisms remain unclear. Herein, we used IDO-deficient (Ido1-/-) BMT to understand why myeloid IDO limits the severity of GVHD. Hosts with Ido1-/- BM exhibited increased lethality, with enhanced proinflammatory and reduced regulatory T cell responses compared with wild type (WT) allo-BMT controls. Despite the comparable expression of the myeloid-derived suppressor cell (MDSC) mediators, arginase-1, inducible nitric oxide synthase, and interleukin 10, Ido1-/- Gr-1+CD11b+ cells from allo-BMT or in vitro BM culture showed compromised immune-suppressive functions and were skewed toward the Ly6ClowLy6Ghi subset, compared with the WT counterparts. Importantly, Ido1-/-Gr-1+CD11b+ cells exhibited elevated levels of reactive oxygen species (ROS) and neutrophil numbers. These characteristics were rescued by human IDO1 with intact heme-binding and catalytic activities and were recapitulated by the treatment of WT cells with the IDO1 inhibitor L1-methyl tryptophan. ROS scavenging by N-acetylcysteine reverted the Ido1-/-Gr-1+CD11b+ composition and function to an MDSC state, as well as improved the survival of GVHD hosts with Ido1-/- BM. In summary, myeloid-derived IDO1 enhances GVHD survival by regulating ROS levels and limiting the ability of Gr-1+CD11b+ MDSCs to differentiate into proinflammatory neutrophils. Our findings provide a mechanistic insight into the immune-regulatory roles of the metabolic enzyme IDO1.

Efficacy of fosfomycin compared to second generation cephalosporin flumarin as antimicrobial prophylaxis for transrectal ultrasound-guided prostate biopsy: a single center retrospective study.

BACKGROUND: Fluoroquinolone has been the historic choice of antimicrobial prophylaxis for transrectal ultrasound (TRUS) guided prostate biopsy. However, increased fluoroquinolone resistance and recent restrictions of its use for antimicrobial prophylaxis has led to the emergence of alternative agents for antimicrobial prophylaxis for TRUS guided prostate biopsy including fosfomycin and cephalosporins. This study aimed to compare the efficacy of fosfomycin and a second-generation cephalosporin flumarin as alternative antimicrobials for TRUS-guided prostate biopsy in terms of the incidence of infectious complications after TRUS-guided prostate biopsy. METHODS: A retrospective chart review of all patients who underwent TRUS-guided prostate biopsy between November 2009 to January 2023 was undertaken. Comparison of baseline characteristics and the incidence of infectious complications was done between those who received fosfomycin as antimicrobial prophylaxis for TRUS-guided prostate biopsy and those who received flumarin. Multivariate logistic regression analysis was conducted to identify risk factors for infectious complications after TRUS-guided prostate biopsy. RESULTS: Of 2,900 patients identified as eligible candidates for analysis, 333 (11.5%) received fosfomycin and 2,567 (88.5%) received flumarin. The overall rate of infectious complications was approximately 3% lower in patients who received fosfomycin, although such difference did not reach statistical significance (5.7% vs. 8.6%, p = 0.074). Multivariate logistic regression analysis showed that history of operation done under general anaesthesia within six months of the biopsy (odds ratio [OR]: 2.216; 95% confidence interval [CI]: 1.042-4.713; p = 0.039) and history of prior antimicrobial use within six months (OR: 1.457; 95% CI: 1.049-2.024; p = 0.025) were significant risk factors for infectious complications after TRUS-guided prostate biopsy. CONCLUSION: Fosfomycin was comparable to second-generation cephalosporin flumarin in preventing infectious complications after TRUS-guided prostate biopsy. Coupled with its properties such as ease of administration, low adverse effects, low resistance rate, and low collateral damage, fosfomycin might be an attractive alternative antimicrobial prophylaxis for TRUS-guided prostate biopsy.

The natural course of incidental ureteral polyp during ureteroscopic surgery: KSER research.

BACKGROUND: The natural course of polypoid lesions in the ureter during ureteroscopic stone surgery was not yet clarified. METHODS: Patient data were collected prospectively from six teaching hospitals between 2019 and 2021. Patients with polypoid lesions in the ureter distal to ureteral stones were included during ureteroscopy. Computed tomography was performed on all enrolled patients three months after the procedure. Follow-up ureteroscopy was performed only if the patient consented, due to the need for general anesthesia and ethical considerations. RESULTS: Among the 35 patients who were followed up, 14 had fibroepithelial polyps and 21 had inflammatory polyps. Twenty of the followed-up patients underwent ureteroscopy, and nine of them had fibroepithelial polyps. Although fibroepithelial polyps did not disappear in the follow-up ureteroscopy (p = 0.002), the rate of postoperative hydronephrosis was not higher in the fibroepithelial group than in the inflammatory group. Postoperative ureteral stricture and moderate-to-severe hydronephrosis were found to be closely related to the number of resected polyps, regardless of the type of polyp (p = 0.014 and 0.006, respectively). CONCLUSION: Fibroepithelial polyps in the ureter may persist after treatment of adjacent ureter stones. However, conservative management may be preferable to active removal of ureteral polyps because fibroepithelial polyps may not contribute to clinically significant hydronephrosis after surgery, and inflammatory polyps disappear spontaneously. Hasty resections of polyps may increase the risk of ureteral stricture.

Targeted Protein Upregulation of STING for Boosting the Efficacy of Immunotherapy.

Modulating target proteins via the ubiquitin-proteasome system has recently expanded the scope of pharmacological inventions. Stimulator of interferon genes (STING) is an auspicious target for immunotherapy. Seminal studies envisioned the importance of STING as well as the utility of its agonists in immunotherapy outcomes. Herein, we suggest UPPRIS (upregulation of target proteins by protein-protein interaction strategy) to pharmacologically increase cellular STING levels for improved immunotherapy. We discovered the small molecule SB24011 that inhibits STING-TRIM29 E3 ligase interaction, thus blocking TRIM29-induced degradation of STING. SB24011 enhanced STING immunity by upregulating STING protein levels, which robustly potentiated the immunotherapy efficacy of STING agonist and anti-PD-1 antibody via systemic anticancer immunity. Overall, we demonstrated that targeted protein upregulation of STING can be a promising approach for immuno-oncology.

IL-7Rαlow CD8+ T Cells from Healthy Individuals Are Anergic with Defective Glycolysis.

Effector memory (EM) CD8+ T cells expressing lower levels of IL-7R α (IL-7Rαlow) from healthy individuals are partly compromised in vitro, but the identity of these cells has remained unclear. In this study, we demonstrate that human IL-7Rαlow EM CD8+ T cells are naturally occurring anergic cells in vivo and impaired in proliferation and IL-2 production but competent in IFN-γ and TNF-α production, a state that can be restored by IL-2 stimulation. IL-7Rαlow EM CD8+ T cells show decreased expression of GATA3 and c-MYC and are defective in metabolic reprogramming toward glycolysis, a process required for the proliferation of T cells. However, IL-7Rαlow EM CD8+ T cells can proliferate with TCR stimulation in the presence of IL-2 and IL-15, suggesting that these cells can be restored to normality or increased activity by inflammatory conditions and may serve as a reservoir for functional immunity.

Longitudinal Analysis of Human Memory T-Cell Response According to the Severity of Illness up to 8 Months After Severe Acute Respiratory Syndrome Coronavirus 2 Infection.

BACKGROUND: Understanding the memory T-cell response to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is crucial for assessing the longevity of protective immunity after SARS-CoV-2 infection or coronavirus disease 2019 (COVID-19) vaccination. However, the longitudinal memory T-cell response up to 8 months post-symptom onset (PSO) according to the severity of illness is unknown. METHODS: We analyzed peripheral blood mononuclear cells (PBMCs) from healthy volunteers or patients with COVID-19 who experienced asymptomatic, mild, or severe illness at 2, 5, and 8 months PSO. SARS-CoV-2 spike, nucleocapsid, and membrane protein-stimulated PBMCs were subjected to flow cytometry analysis. RESULTS: A total of 24 patients (7 asymptomatic, 9 with mild disease, and 8 with severe disease) and 6 healthy volunteers were analyzed. SARS-CoV-2-specific OX40+CD137+CD4+ T cells and CD69+CD137+CD8+ T cells persisted at 8 months PSO. Also, antigen-specific cytokine-producing or polyfunctional CD4+ T cells were maintained for up to 8 months PSO. Memory CD4+ T-cell responses tended to be greater in patients who had severe illness than in those with mild or asymptomatic disease. CONCLUSIONS: Memory response to SARS-CoV-2, based on the frequency and functionality, persists for 8 months PSO. Further investigations involving its longevity and protective effect from reinfection are warranted.

Effects of an alpha-1d adrenoreceptor antagonist (naftopidil) on bladder dysfunction after radiotherapy in female rats.

PURPOSE: Storage-phase bladder dysfunction can develop after pelvic radiotherapy. As the alpha-1d adrenoreceptor (a1d-AR) is dominant in the human detrusor, we aimed to investigate the effect of an a1d-AR antagonist on bladder dysfunction after pelvic radiotherapy in a rat model. MATERIALS AND METHODS: Twenty-four female Wistar rats were used. Eight rats (14-15 weeks, 250-300 g) were randomized to three groups (normal reference group, radiation alone group and radiation plus naftopidil group). An 18-Gy dose of radiotherapy was applied to the radiation alone and radiation plus naftopidil groups. Naftopidil (20 mg/kg) was administered daily to the radiation plus naftopidil group. Four weeks after radiation, all rats underwent cystometry and were killed for reverse transcription polymerase chain reaction to detect mRNAs [a1d-AR, brain-derived neurotrophic factor (BDNF) and vascular endothelial growth factor (VEGF)], Western blot to detect proteins (a1d-AR, extracellular-signal-regulated kinase, BDNF and VEGF) and immunohistochemistry. RESULTS: Compared to the radiation alone group, (1) the decrease in the mRNA and protein expression of a1d-AR and VEGF was ameliorated, (2) the increase in the expression of BDNF mRNA and proteins such as extracellular-signal-regulated kinase and BDNF was suppressed, (3) submucosal thickness and vascularity on immunohistochemistry were improved, and (4) the baseline intravesical pressure and intercontraction interval in cystometry were ameliorated in the radiation plus naftopidil group. CONCLUSION: Administration of an a1d-AR antagonist could improve storage-phase bladder dysfunction after radiotherapy not only by upregulating a1d-AR, which might decrease bladder compliance, but also by enhancing vascularity, which might protect the urinary bladder from chronic ischemic inflammation.

Cancer Stem Cells in the Immune Microenvironment.

Cancer stem cells are a subpopulation of cancer cells responsible for the most demanding and aggressive cancer cell phenotypes: therapy resistance, a self-protective feature of stem cells; distant metastasis, requiring anchorage independence for survival in the circulation; and recurrence, which is related to the dormant-active cycling of stem cells. Normal tissues are composed of parenchymal cells, supportive connective components, and cellular disposal systems for removing the products of physiological wear and tear. Cancer stem cells develop from normal counterparts and progressively interact with their microenvironments, modifying and conditioning the cancer microenvironment. Cancer-associated myeloid cells constitute a major element of the cancer microenvironment. During the process of carcinogenesis, cancer stem cells and their intimately associated myeloid cells mutually interact and evolve, such that the cancer cells potentiate the activity of the myeloid cells and, in return, the myeloid cells increase cancer stem cell characteristics. Normal myeloid cells function as key accessory cells to maintain homeostasis in normal tissues and organs; in cancers, these cells co-evolve with the malignant parenchymal cells and are involved in every aspect of cancer cell biology, including proliferation, invasion, distant metastasis, and the development of resistance to therapy. In this way, cancer-associated myeloid cells provide two of the key hallmarks of cancer: evasion of immune destruction and cancer-promoting inflammation.

Wireless, intraoral hybrid electronics for real-time quantification of sodium intake toward hypertension management.

Recent wearable devices offer portable monitoring of biopotentials, heart rate, or physical activity, allowing for active management of human health and wellness. Such systems can be inserted in the oral cavity for measuring food intake in regard to controlling eating behavior, directly related to diseases such as hypertension, diabetes, and obesity. However, existing devices using plastic circuit boards and rigid sensors are not ideal for oral insertion. A user-comfortable system for the oral cavity requires an ultrathin, low-profile, and soft electronic platform along with miniaturized sensors. Here, we introduce a stretchable hybrid electronic system that has an exceptionally small form factor, enabling a long-range wireless monitoring of sodium intake. Computational study of flexible mechanics and soft materials provides fundamental aspects of key design factors for a tissue-friendly configuration, incorporating a stretchable circuit and sensor. Analytical calculation and experimental study enables reliable wireless circuitry that accommodates dynamic mechanical stress. Systematic in vitro modeling characterizes the functionality of a sodium sensor in the electronics. In vivo demonstration with human subjects captures the device feasibility for real-time quantification of sodium intake, which can be used to manage hypertension.

Transfer of a healthy microbiota reduces amyloid and tau pathology in an Alzheimer's disease animal model.

OBJECTIVE: Cerebral amyloidosis and severe tauopathy in the brain are key pathological features of Alzheimer's disease (AD). Despite a strong influence of the intestinal microbiota on AD, the causal relationship between the gut microbiota and AD pathophysiology is still elusive. DESIGN: Using a recently developed AD-like pathology with amyloid and neurofibrillary tangles (ADLPAPT) transgenic mouse model of AD, which shows amyloid plaques, neurofibrillary tangles and reactive gliosis in their brains along with memory deficits, we examined the impact of the gut microbiota on AD pathogenesis. RESULTS: Composition of the gut microbiota in ADLPAPT mice differed from that of healthy wild-type (WT) mice. Besides, ADLPAPT mice showed a loss of epithelial barrier integrity and chronic intestinal and systemic inflammation. Both frequent transfer and transplantation of the faecal microbiota from WT mice into ADLPAPT mice ameliorated the formation of amyloid ß plaques and neurofibrillary tangles, glial reactivity and cognitive impairment. Additionally, the faecal microbiota transfer reversed abnormalities in the colonic expression of genes related to intestinal macrophage activity and the circulating blood inflammatory monocytes in the ADLPAPT recipient mice. CONCLUSION: These results indicate that microbiota-mediated intestinal and systemic immune aberrations contribute to the pathogenesis of AD in ADLPAPT mice, providing new insights into the relationship between the gut (colonic gene expression, gut permeability), blood (blood immune cell population) and brain (pathology) axis and AD (memory deficits). Thus, restoring gut microbial homeostasis may have beneficial effects on AD treatment.

Kidney residency of VISTA-positive macrophages accelerates repair from ischemic injury.

Tissue-resident macrophages have unique tissue-specific functions in maintaining homeostasis and resolving inflammation. However, the repair role and relevant molecules of kidney-resident macrophages after ischemic injury remain unresolved. To this end, mice without kidney-resident R1 macrophages but containing infiltrating monocyte-derived R2 macrophages were generated using differential cellular kinetics following clodronate liposome treatment. When ischemia-reperfusion injury was induced in these mice, late phase repair was reduced. Transcriptomic and flow cytometric analyses identified that V-domain Ig suppressor of T cell activation (VISTA), an inhibitory immune checkpoint molecule, was constitutively expressed in kidney-resident R1 macrophages, but not in other tissue-resident macrophages. Here, VISTA functioned as a scavenger of apoptotic cells and served as a checkpoint to control kidney-infiltrating T cells upon T cell receptor-mediated stimulation. Together these functions improved the repair process after ischemia-reperfusion injury. CD14+ CD33+ mononuclear phagocytes of human kidney also expressed VISTA, which has similar functions to the mouse counterpart. Thus, VISTA is upregulated in kidney macrophages in a tissue-dependent manner and plays a repair role during ischemic injury.

The Role of Testosterone in Amplifying the Effect of a Phosphodiesterase Type 5 Inhibitor After Pelvic Irradiation.

BACKGROUND: After radiotherapy, the risk of hypogonadism increases, and the incidence of erectile dysfunction increases with time. AIM: We investigated the effect of testosterone and a phosphodiesterase type 5 inhibitor (PDE5I) on erectile tissue after radiotherapy. METHODS: 12 male Wistar rats were assigned to each of 5 groups (group C: control; group R: radiation; group RPT: radiation, testosterone, and a PDE5I; group RP: radiation and a PDE5I; and group RT: radiation and testosterone). A 12.5 Gy/fraction dose was administered to the rectum in groups R, RPT, RP, and RT. Udenafil (20 mg/kg) was administered daily via nasogastric tubes in group RPT and group RP for 4 weeks starting 1 day after radiotherapy. Testosterone enanthate (25 mg/kg, IM) was administered immediately after radiotherapy in group RT and group RPT. 6 rats from each group were used to evaluate endothelial nitric oxide synthase (eNOS), neuronal nitric oxide synthase (nNOS), and NOX2, and cavernosal pressure was evaluated in the other 6 rats in each group. OUTCOME: Testosterone enhanced the effect of PDE5I on penile tissue after radiotherapy by amplifying the nitric oxide synthase activity. RESULTS: eNOS mRNA expression increased in response to either testosterone replacement or PDE5I administration after radiotherapy. nNOS mRNA expression did not significantly increase in response to testosterone replacement, but testosterone significantly enhanced the effect of PDE5I on nNOS mRNA expression. Testosterone significantly amplified the effect of PDE5I on both eNOS and nNOS protein expression. Both testosterone and PDE5I reduced NOX2 protein expression. The intracavernosal pressure during electrical stimulation showed that testosterone alone did not significantly enhance erectile function. CLINICAL TRANSLATION: Clinicians should consider both hypoxic tissue damage and hypogonadism during and after radiation, and the combination of testosterone and PDE5I could be more beneficial for preserving erectile tissue than either individual treatment. STRENGTHS & LIMITATIONS: This study describes the role of testosterone in amplifying the effect of a PDE5I on pelvic radiotherapy-induced hypogonadism. However, we did not show the time-dependent effects of testosterone and PDE5I. CONCLUSIONS: Despite the fact that the intracavernosal pressure during electrical stimulation did not significantly increase with testosterone replacement after radiotherapy, important changes in nitric oxide synthase activity and superoxide regulation might have amplifying effects on erectile tissue. Therefore, we recommend that physicians monitor testosterone levels and should not hesitate to combine testosterone and PDE5I in cases of radiation-induced hypogonadism if testosterone replacement is not contraindicated. Lee DS, Sohn DW. The Role of Testosterone in Amplifying the Effect of a Phosphodiesterase Type 5 Inhibitor After Pelvic Irradiation. J Sex Med 2020;17:1268-1279.

Transurethral prostate surgery as a preventive method against progression of chronic kidney disease in patients with urodynamically proven bladder outlet obstruction.

OBJECTIVE: The present study was aimed to investigate (1) whether urodynamic factors are responsible for kidney damage in patients with bladder outlet obstruction (BOO) and (2) whether transurethral prostate surgery for BOO can alleviate the damage to the kidneys. METHODS: This prospective observational study involved men aged 50-80 years. Prostate size and urodynamic test were performed during screening period. Laboratory tests to measure the glomerular filtration rate, the urinary protein to creatinine ratio and dipstick urinalysis were performed before and 6 months after the transurethral prostate surgery. RESULTS: Sixty-seven patients completed the laboratory study among a hundred enrolled patients with urodynamically proven BOO. Among the urodynamic parameters, only low bladder compliance (lower than 60 mL/cmH2O) was associated with clinically significant proteinuria (p < 0.001). Transurethral prostate surgery significantly improved proteinuria (p = 0.007), especially in patients with low bladder compliance (p = 0.004), and subsequently decreased the risk grade of CKD progression (p < 0.001). CONCLUSIONS: Low bladder compliance in patients with BOO may be a risk factor for kidney damage. Transurethral prostate surgery to relieve BOO could be a preventive method against CKD progression in patients with low bladder compliance.

Critical causes in severe bleeding requiring angioembolization after percutaneous nephrolithotomy.

BACKGROUND: To identify the risk factors for severe bleeding requiring angioembolization among patients who received transfusions after PCNL, particularly those who underwent anatomically incorrect renal puncture. METHODS: A total of 53 patients, who received transfusions after PCNL and simultaneously had a postoperative CT scan performed between November 2009 and May 2019 at two teaching hospitals, were retrospectively reviewed. The patients were divided into two groups: those who underwent angioembolization and those who did not. Patient, stone and procedural factors were compared between the two groups. Puncture correctness was evaluated using postoperative CT scans. Puncture was defined as being a correct puncture if the fornix or papilla of the posterior calyx was punctured and the trajectory of the tract was within 20 degrees posterior to the frontal plane of the kidney (i.e., within Brödel's line). RESULTS: 21 patients underwent angioembolization after PCNL. Incorrect puncture was seen in 14/21 (66.7%) patients who underwent angioembolization after PCNL, whereas it was seen in 11/32 (34.4%) patients who did not undergo angioembolization (p = 0.021). On multivariable regression analysis, puncture correctness was found to be the only significant factor, with an OR of 3.818, 95% CI of 1.192-12.231 and p value of 0.024. CONCLUSIONS: Incorrect renal puncture was related to severe bleeding requiring angioembolization after PCNL. Our results emphasize the importance of the basic principle of renal puncture for PCNL.

Does deep sedation with analgesia have positive effects on anxiety, pain and compliance in patients before and after prostate biopsy?

AIMS: To investigate whether deep sedation for transrectal prostate biopsy could reduce anxiety and pain and enhance rebiopsy compliance. METHODS: A two-centre prospective observation study was conducted under two different anaesthetic conditions: deep sedation with analgesia and local anaesthesia with lidocaine. A 12-core prostate biopsy was taken in all patients. Scores on a 0-10 visual analogue scale, the State-Trait Anxiety Inventory-X-1, the Beck Anxiety Inventory and a five-level Likert satisfaction scale were evaluated. Finally, all patients were asked about their willingness to undergo the same procedure again if necessary and whether they wanted to change the anaesthetic method (deep sedation to local anaesthesia or local to sedation) if a repeat procedure was required. RESULTS: A total of 135 patients were included in this study, including 69 patients in the sedation group and 66 patients in the local group. Lower pain scores (P < .001) and higher satisfaction scores (P = .019) were observed in the sedation group than in the local group after the procedure. Anxiety scores in the sedation group were significantly decreased after the procedure, whereas those were not changed in the local group. The question regarding rebiopsy compliance tended to be more positive in the sedation than in the local group (73.9% vs 62.1%, respectively, P = .099). The proportion of patients who wanted to change their anaesthetic method was much higher in the local than in the sedation group (68.2% vs 11.6%, respectively, P < .001). CONCLUSION: Deep sedation with analgesia during transrectal prostate biopsy could reduce pain and postprocedural anxiety and enhance rebiopsy compliance. Considering the psychological and oncological benefits, we strongly recommend inducing deep sedation during transrectal prostate biopsy.

Impact of Sleep Deprivation on the Hypothalamic-Pituitary-Gonadal Axis and Erectile Tissue.

INTRODUCTION: It is unclear how sleep deprivation (SD) exerts a negative effect on men's health in terms of hypogonadism. AIM: To evaluate the hypothalamic-pituitary-gonadal (HPG) axis in subjects with SD and ultimately to evaluate the erectile tissue in response to the hormonal changes. METHODS: 56 male Wistar rats were used. First, 16 rats (16 weeks old) were subjected to 72 hours of SD, and the following were compared with 16 control rats: (i) levels of gonadotropin-releasing hormone (GnRH), luteinizing hormone (LH), follicle-stimulating hormone (FSH), testosterone (T), and cortisol; (ii) the expression of the kisspeptin mRNA in the brain; and (iii) assessment of immunohistochemistry (IHC) of brain and testis. To further investigate whether testosterone reduction due to SD could affect erectile tissue, an additional 24 rats were divided into 3 groups (control, SD, and SD with T supplementation [SDT]) and compared: (i) T and cortisol levels were quantified, and (ii) endothelial nitric oxide synthase (eNOS)/ neuronal nitric oxide synthase (nNOS)/NOX-2 expression in cavernosal tissue was assessed by measuring mRNA levels and performing Western blotting and IHC. MAIN OUTCOME MEASURE: Compared with the levels in the control group, the LH level was markedly decreased, and T levels were subsequently decreased in the SD group, whereas the level of the kisspeptin mRNA and IHC for kisspeptin, GnRH, and FSH were not different. RESULTS: In cavernosal tissues, levels of the eNOS/nNOS mRNAs and proteins tended to be lower, and NOX-2 levels (mRNA and protein) tended to be higher in the SD group than those in the control group and SDT group. IHC for eNOS/nNOS revealed lower-intensity staining in the SD group than in the control and SDT groups, whereas the NOX-2 intensity was higher in the SD group than in the other groups. A lower cortisol level was observed in the control group than in the SD and SDT groups, whereas the level was similar between the SD and SDT groups. The intracavernosal pressure/mean arterial blood pressure (%) values were also decreased in the SD group but not on testosterone injection. CLINICAL IMPLICATIONS: Even short-term SD can produce secondary hypogonadism, which impairs men's health. STRENGTH & LIMITATIONS: To the best of our knowledge, this study is the first to show the effects of SD on the whole HPG axis. The weakness is that this study only investigated acute SD. CONCLUSION: Based on the findings from this study, acute SD causes pituitary hypogonadism, and reduced T levels decrease erectile function by inducing superoxide accumulation in the cavernosal tissue and inhibiting nitric oxide synthase activity. Lee DS, Choi JB, Sohn DW. Impact of Sleep Deprivation on the Hypothalamic-Pituitary-Gonadal Axis and Erectile Tissue. J Sex Med 2019;16:5-16.

Effect of steroids and relevant cytokine analysis in acute tubulointerstitial nephritis.

BACKGROUND: Acute tubulointerstitial nephritis (ATIN) is an important cause of acute kidney injury and often a potentially reversible disease. However, the role of steroids in ATIN remains controversial and the underlying mechanisms remain unresolved. METHODS: A total of 113 adult patients with biopsy-proven ATIN were recruited from three tertiary referral centers. Of 102 patients with idiopathic or drug-induced ATIN, outcomes such as renal recovery, end-stage renal disease, and all-cause mortality were compared between the steroid-treated and non-treated groups. Plasma and urine inflammatory cytokine levels at the time of biopsy were analyzed in patients (n = 33) using a bead-based multiplex assay and compared with those of healthy individuals (n = 40). RESULTS: Steroids were used in 92 (81.4%) of the total patients and in 82 (80.3%) patients with idiopathic or drug-induced ATIN. The rate of renal recovery and the risks of end-stage renal disease and mortality were not different between the steroid-treated and non-treated groups. Despite using a propensity score matching method (n = 20 in each group), none of the outcomes were different between the two groups. Several cytokines, such as monocyte chemotactic protein-1, interferon-α, and interleukin-6 and interleukin-8 levels, were markedly elevated in plasma and urine of patients compared with those in healthy individuals. However, cytokines related to Th2 response, such as IL-10, IL-33, were not different between the two groups. CONCLUSIONS: Steroid use does not affect the overall outcome of ATIN. Based on the fact that targeting therapy should be investigated to improve outcomes, the present cytokine results will be helpful for developing a novel therapy for ATIN.

Anterograde irrigation - assisted ureteroscopic lithotripsy in patients with percutaneous nephrostomy.

In complicated urinary tract infection with ureteral calculi, urinary diversion is inevitable. So, stenting or percutaneous drainage can be an option. In hemodynamically unstable patients, percutaneous drainage is superior to ureteral stenting (1). Once acute infection is controlled, definite treatment of the stone is necessary. According to a guideline, semirigid ureteroscopy is recommended for lower and mid - ureter stone and flexible ureteroscopy for upper ureter stone (2). Semi - rigid ureteroscopy can migrate stone to kidney, especially in upper ureter stone, lowering stone free rate (3). Not only flexible ureteroscopy creates additional costs but also is barely available in developing countries (4, 5). So, the authors would like to introduce anterograde irrigation - assisted ureteroscopic lithotripsy in patients with percutaneous nephrostomy. Retrograde irrigation was connected and flowed minimally enough to secure visual field. Once stone is noted, another saline irrigation, which is placed above 40 cm over the patient is connected to nephrostomy. Retrograde irrigation is disconnected from ureteroscope and the previous connected channel on ureteroscope is opened. Actual pressure detected by barometer from the opened channel of ureteroscope is usually about 30 cmH2O while anterograde irrigation is administered in maximal flow, which means fully opened anterograde irrigation is not hazardous to kidney. There was no complication in 17 patients submitted to this method. Video shows advantages of our practice: clear visual field; reduced risk of stone migration into kidney; induced spontaneous passage of fragments without using instrumentation; and decreased operation time. In short, most of surgeons, even unexperienced, can perform an excellent procedure with less time consuming using our method.