GNRI Sustainability during One Cycle of First-Line Chemotherapy as a Prognostic Indicator in Patients with Metastatic Urothelial Carcinoma.

INTRODUCTION: This study evaluated the prognostic value of a sustained high Geriatric Nutritional Risk Index (GNRI) during first-line chemotherapy for patients with metastatic urothelial carcinoma (mUC). METHODS: Between January 2018 and February 2022, 123 patients received platinum-based chemotherapy at Nagoya City University Hospital and affiliated institutions. Of these, 118 eligible patients who showed an Eastern Cooperative Oncology Group performance status (ECOG-PS) between 0 and 2 were retrospectively examined. Based on body mass index and serum albumin levels, GNRI was calculated immediately before and after the first primary chemotherapy cycle. Patients were divided into two groups based on GNRI: GNRI sustained ≥92 in sustainable (n = 63) and GNRI <92 in unsustainable (n = 55) groups, respectively. Clinical outcomes were compared. RESULTS: No significant differences were noted between the two groups for age, gender, cycle of first-line treatment, and type of series of sequential treatments after failure of first-line therapy. Median overall survival from the start of first-line chemotherapy was 30.2 months (95% confidence interval [CI]: 20.9-NA) for sustainable and 12.6 months (95% CI: 9.0-21.2) for unsustainable groups, respectively (p < 0.05). Multivariate analysis identified ECOG-PS:2 and fatigue, an adverse event, as independent predictors of unsustainable GNRI transition (95% CI: 1.29-90.6, odds ratio [OR]: 10.8; 95% CI: 1.06-26.9, OR: 5.34, respectively). CONCLUSION: Sustaining a high level of GNRI was an important prognostic indicator in patients with mUC receiving first-line chemotherapy. Appropriate intervention for controlling adverse events, including fatigue, may enhance physical strength during cancer treatment.

Development and Evaluation of a Novel Software Program, SAKURA-TDM, for Area Under the Concentration-Time Curve-Guided Vancomycin Dosing: A Short Communication.

BACKGROUND: The area under the concentration-time curve (AUC)-guided dosing of vancomycin has been introduced in Japan; however, the optimal dosing method remains controversial. Here, a novel software program was developed for AUC-guided vancomycin dosing and to estimate the theoretical threshold of the steady-state AUC 24 that could reduce the risk of renal injury. METHODS: A single-center, retrospective, observational study was conducted to develop a novel software program (SAKURA-TDM ver.1.0) for AUC-guided dosing. The estimation accuracy of pharmacokinetic parameters determined using SAKURA-TDM was compared with that of clinically available software programs and assessed with Bland-Altman analysis. In addition, theoretical cutoff points of the steady-state AUC 24 and the predicted trough values were estimated using Youden J statistic approach. RESULTS: The estimation accuracy of pharmacokinetic parameters and AUC determined using SAKURA-TDM was comparable to that of other TDM software programs. Of note, despite a good relationship between the predicted AUC 24 and trough values, the correlation between the predicted AUC 24 and measured trough values was not strong. The cutoff values of the steady-state AUC 24 and the predicted trough value for reducing the probability of a measured trough value of >20 mcg/mL were 513.1 mg·h/L and 15.6 mcg/mL, respectively. CONCLUSIONS: We demonstrated the equivalence of the estimated PK parameters between SAKURA-TDM and other TDM software programs available in Japan. Considering the threshold of both trough values and the steady-state AUC and monitoring of the AUC in a non-steady state, it would be possible to reduce the risk of vancomycin-associated renal injury.

High preoperative serum strontium levels increase the risk of acute kidney injury after cardiopulmonary bypass.

BACKGROUND: Acute kidney injury (AKI) is a common complication of cardiac surgeries. The incidence of AKI after cardiac surgeries using cardiopulmonary bypass (CPB-AKI) is high, emphasizing the need to determine strategies to prevent CPB-AKI. This study investigates the correlation between CPB-AKI and trace metal levels in clinical and animal studies. METHODS: Samples and clinical data were obtained from 74 patients from the Nagoya City University Hospital and Okazaki City Hospital. Blood samples were collected before, immediately after, and 2 h after CPB withdrawal. Trace metal levels were measured using inductively coupled plasma mass spectrometry. Sr or vehicle treatment was orally administered to the rats to determine if Sr was associated with CPB-AKI. After the treatment, ischemia-reperfusion (IR) injury was induced, and serum creatinine (SCr) and blood urea nitrogen (BUN) levels were measured. RESULTS: In this clinical study, the incidence of CPB-AKI was found to be 28% (21/74). The body mass index and estimated glomerular filtration rate were significantly different in patients with AKI. The intensive care unit and hospital stay were longer in AKI patients than in non-AKI patients. The Na, Fe, and Sr levels were significantly higher in AKI patients before CPB. Also, Fe and Sr were higher immediately after CPB withdrawal, and Sr was higher 2 h after CPB withdrawal in AKI patients. Animal studies showed that Sr-treated rats had significantly increased SCr and BUN levels than vehicle-treated rats at 24 h post-IR injury. CONCLUSIONS: High preoperative serum Sr levels may be associated with CPB-AKI.

Summary of the clinical practice manual for late-onset hypogonadism.

Testosterone plays an important role in maintaining both physical and mental function. Age-related testosterone depletion contributes to the development of angina, arteriosclerosis, obesity, metabolic syndrome, dementia, frailty, and a range of other conditions. A condition involving age-related testosterone depletion and the associated clinical symptoms is defined as late-onset hypogonadism (LOH). LOH is treated by testosterone replacement therapy. Indications for testosterone replacement therapy are determined by evaluating symptoms and signs.

A review of experimental techniques for erectile function researches and development of medical technology using animal erectile dysfunction models in sexual and reproductive medicine.

Background: Erectile dysfunction (ED) is one of the causes of male infertility and is a disease that requires treatment. The first-line drugs for ED are phosphodiesterase 5 (PDE-5) inhibitors, and further treatment options are currently limited. Medical technologies, such as genetic control and regenerative medicine, are developing rapidly. Research on erectile function is progressing rapidly, coupled with technological innovations in other areas. Methods: A PubMed search using the keywords "animal (rat, mouse, rabbit, dog, and monkey)" and "erectile" was conducted, and all relevant peer-reviewed English results were evaluated. Main findings: The methods for evaluating erectile function include intracavernous pressure (ICP) measurements, isometric tension studies, and dynamic infusion cavernosometry. Papers also reported various disease model animals for the study of diabetes mellitus, cavernous nerve injury, and drug-induced ED. Conclusion: Basic research on ED treatment has progressed rapidly over the past 20 years. In particular, research on the mechanism of ED has been accelerated by the publication of a study on the evaluation of erectile function using ICP measurements in rats. In addition, molecular biological experimental methods such as polymerase chain reaction (PCR) and western blotting have become relatively easy to perform due to technological progress, thus advancing research development.

Protective effects of tadalafil on damaged podocytes in an adriamycin-induced nephrotic syndrome model.

Podocyte injury is responsible for nephrotic syndrome. Previously, we found that tadalafil, a phosphodiesterase 5 inhibitor, might have protective effects on podocytes. Here, we investigated the effects of tadalafil in a nephrotic syndrome model and human podocyte cells. We divided adriamycin (ADR)-induced nephrotic syndrome model rats into the following groups: control + vehicle, control + tadalafil, ADR + vehicle, and ADR + tadalafil. The tadalafil-treated groups were orally administered 10 mg/kg tadalafil for 2 weeks. Renal parameters were measured. Immunohistology and immunofluorescence assays of glomerular injury were performed. Human primary podocytes were treated with or without tadalafil, and ADR. Cell viability and permeability assays were performed. ADR + vehicle exhibited severe proteinuria compared with control + vehicle and control + tadalafil. ADR + tadalafil attenuated proteinuria compared with ADR + vehicle. Wilms' tumor 1 (WT1) immunostaining revealed that the number of WT1-positive cells was decreased by ADR; however, this decrease was prevented by ADR + tadalafil. In human podocytes, tadalafil increased the viability of ADR-treated cells, which was abrogated by KT5823, a cGMP-dependent protein kinase (PKG) inhibitor. Moreover, tadalafil prevented albumin permeability in ADR-treated cells. ADR treatment alone increased the permeability of albumin compared with the control. Tadalafil might inhibit kidney injury progression by preventing damage to podocytes and dysfunction of the glomerular filtration barrier.

Effect of Replicative Senescence on the Expression and Function of Transporters in Human Proximal Renal Tubular Epithelial Cells.

In the field of cosmetic research, there is a growing interest in alternatives to animal experiments, such as in vitro models using cultured cells. The trend is spreading to the field of food and drugs. Although various types of cells are used as in vitro models, the effect of cellular senescence on the expression and function of transporters in these models is unclear. In the present study, we examined the effect of replicative senescence (by passage culture) on the expression and function of transporters in renal proximal tubular epithelial cells (RPTECs). The increase in senescence-associated-ß-galactosidase (SA-ß-gal)-positive cells, cell cycle arrest markers, and senescence-associated secretory phenotype (SASP) markers was associated with an increase in passage numbers of RPTECs. Gene expression of various transporters in RPTEC was also altered. The mRNA level of organic cation transporter 2 decreased most rapidly with passage numbers among the transporters. The uptake of fluorescent cationic substrates in SA-ß-gal-positive RPTECs was less than that in SA-ß-gal-negative RPTECs. However, these changes in the expression of transporters seem to be significantly different from those observed in rodents and human kidneys in many aspects. As cellular senescence is observed in various situations, especially in RPTECs, it may be necessary to exclude it from toxicological and pharmacokinetic evaluations using in vitro models as much as possible. Additionally, when discussing cellular senescence, it is important to note the differences between aging in cells and aging and senescence in individuals.

Establishment of mouse line showing inducible priapism-like phenotypes.

Purpose: Penile research is expected to reveal new targets for treatment and prevention of the complex mechanisms of its disorder including erectile dysfunction (ED). Thus, analyses of the molecular processes of penile ED and continuous erection as priapism are essential issues of reproductive medicine. Methods: By performing mouse N-ethyl-N-nitrosourea mutagenesis and exome sequencing, we established a novel mouse line displaying protruded genitalia phenotype (PGP; priapism-like phenotype) and identified a novel Pitpna gene mutation for PGP. Extensive histological analyses on the Pitpna mutant and intracavernous pressure measurement (ICP) and liquid chromatography-electrospray ionization tandem mass spectrometry (LC-ESI/MS)/MS analyses were performed. Results: We evaluated the role of phospholipids during erection for the first time and showed the mutants of inducible phenotypes of priapism. Moreover, quantitative analysis using LC-ESI/MS/MS revealed that the level of phosphatidylinositol (PI) was significantly lower in the mutant penile samples. These results imply that PI may contribute to penile erection by PITPα. Conclusions: Our findings suggest that the current mutant is a mouse model for priapism and abnormalities in PI signaling pathways through PITPα may lead to priapism providing an attractive novel therapeutic target in its treatment.

Dynamic erectile responses of a novel penile organ model utilizing TPEM†.

Male penis is required to become erect during copulation. In the upper (dorsal) part of penis, the erectile tissue termed corpus cavernosum (CC) plays fundamental roles for erection by regulating the inner blood flow. When blood flows into the CC, the microvascular complex termed sinusoidal space is reported to expand during erection. A novel in vitro explant system to analyze the dynamic erectile responses during contraction/relaxation is established. The current data show regulatory contraction/relaxation processes induced by phenylephrine (PE) and nitric oxide (NO) donor mimicking dynamic erectile responses by in vitro CC explants. Two-photon excitation microscopy (TPEM) observation shows the synchronous movement of sinusoidal space and the entire CC. By taking advantages of the CC explant system, tadalafil (Cialis) was shown to increase sinusoidal relaxation. Histopathological changes have been generally reported associating with erection in several pathological conditions. Various stressed statuses have been suggested to occur in the erectile responses by previous studies. The current CC explant model enables to analyze such conditions through directly manipulating CC in the repeated contraction/relaxation processes. Expression of oxidative stress marker and contraction-related genes, Hypoxia-inducible factor 1-alpha (Hif1a), glutathione peroxidase 1 (Gpx1), Ras homolog family member A (RhoA), and Rho-associated protein kinase (Rock), was significantly increased in such repeated contraction/relaxation. Altogether, it is suggested that the system is valuable for analyzing structural changes and physiological responses to several regulators in the field of penile medicine.

BRAF/MEK inhibitor-associated nephrotoxicity in a real-world setting and human kidney cells.

Acute kidney injury (AKI) associated with cancer chemotherapy can be life-threatening. Inhibitors of rapidly accelerated fibrosarcoma kinase B (BRAF)-mutants and mitogen-activated extracellular signal-regulated kinase (MEK) administered as combination therapy are effective against BRAF-mutant melanoma, but drug-associated AKI events were reported after marketing. Here, we examined the nephrotoxicity of two BRAF inhibitors, vemurafenib and dabrafenib, and two MEK inhibitors, cobimetinib and trametinib, in a real-world setting and human kidney cells. Target drug-associated AKI signals were detected by reporting odds ratio (ROR) derived from report data in the Food and Drug Administration Adverse Events Reporting System database. In-vitro cytotoxicity was evaluated in proximal renal tubular epithelial cells (RPTEC), glomerular endothelial cells (GEnC), and glomerular epithelial cells (GEpC). AKI RORs associated with vemurafenib [ROR, 3.28; confidence interval (CI), 2.91-3.69] and cobimetinib (ROR, 4.40; CI, 3.55-5.45) were higher than those associated with dabrafenib (ROR, 1.35; CI, 1.15-1.60) and trametinib (ROR, 1.32; CI, 1.11-1.56). Vemurafenib reduced cell viability and increased cell death in RPTEC and GEpC at 10 µM, which was below the mean maximum concentration in blood under steady-state condition [115.7 µM (56.7 µg/mL)]. No vemurafenib-associated cytotoxicity was detected in GEnC. Mean maximum concentrations of cobimetinib, dabrafenib and trametinib did not induce cell death. This work revealed that vemurafenib had stronger cytotoxic effects on tubular and glomerular epithelial cells than the other BRAF and MEK inhibitors. Hence, we recommend careful monitoring for clinical signs of kidney injury in patients treated with vemurafenib.

Oxaliplatin, an Anticancer Agent, Causes Erectile Dysfunction in Rats due to Endothelial Dysfunction.

BACKGROUND: Chemotherapeutics, one of the standard treatment options for cancer worldwide, have various adverse effects, including erectile dysfunction (ED). AIM: To investigate erectile function in an animal model after administration of the anticancer agent oxaliplatin (L-OHP). METHODS: Male Wistar/ST rats were divided into 2 groups: L-OHP rats (n = 21), which were intravenously administered L-OHP (4 mg/kg; twice a week for 4 weeks), and Control rats (n = 21), which were injected with the same volume of 5% glucose solution, using the same dosing schedule. At the end of the study period, erectile function was evaluated by measuring intracavernous pressure (ICP) and mean arterial pressure (MAP) after cavernous nerve stimulation (n = 9-10). Endothelial function was evaluated with an isometric tension study using corpus cavernosum strips (n = 11). Western blot analysis was used to assess neuronal nitric oxide (nNOS) and endothelial NO synthase (eNOS) protein levels (n = 7). Real-time quantitative polymerase chain reaction (qRT-PCR) was used to assess the expression of inflammation- and oxidative stress-related markers (nicotinamide adenine dinucleotide phosphate oxidase-1, p22phox, interleukin [IL]-6, and nuclear factor-kappa B) (n = 6). Statistical significance was determined using the Student's t-test. OUTCOMES: The L-OHP group had a significantly lower ICP:MAP ratio than the control group (P < .05). Compared to the Control group, the L-OHP group exhibited significantly lower responses to ACh and eNOS protein levels and significantly higher inflammatory biomarker levels. CLINICAL TRANSLATION: The results based on this animal model indicate that use of the anticancer agent L-OHP should be considered as a risk factor for ED occurring via reduction of NO bioavailability in humans; our results provide possible treatment strategies for maintaining the erectile function of cancer survivors. STRENGTHS AND LIMITATIONS: Our study showed that the anticancer agent L-OHP has the propensity to cause ED in rats. A major limitation of this study is the lack of an established cure for ED associated with L-OHP and the lack of clinical evidence. CONCLUSIONS: L-OHP causes ED in rats via reduction of NO bioavailability caused by endothelial dysfunction. Kataoka T, Mori T, Suzuki J, et al. Oxaliplatin, an Anticancer Agent, Causes Erectile Dysfunction in Rats due to Endothelial Dysfunction. J Sex Med 2021;18:1337-1345.

Detrusor underactivity causes neurogenic voiding dysfunction in a rat bilateral accessory nerve-injury model.

We aimed to investigate detrusor function in a previously developed rat neurogenic voiding dysfunction model that we have developed previously. We performed sham or bilateral accessory nerve injury (BACNI) surgeries on ten-week-old male Wistar/ST rats. One week after surgery, we evaluated detrusor contractility in the bladder using isometric tension and mRNA expression assays. Cholinergic contraction was attenuated in the injury model, whereas carbachol-evoked contraction was enhanced, and mRNA expression of the cholinergic receptor increased. These findings suggest that there was a reduction in neurotransmitter release causing detrusor underactivity.

Control of rat bladder neck relaxation with NORD-1, a red light-reactive nitric oxide releaser: In vitro study.

We aimed to control the relaxation of rat bladder neck specimens by using NORD-1, a red light-reactive nitric oxide (NO) releaser. Female and male 10-11-week-old Wistar/ST rats were divided into three groups: NORD-1, vehicle, and NORD-1+[1,2,4]oxadiazolo[4,3-a]quinoxalin-1-one (ODQ; a soluble guanylyl cyclase inhibitor). We infused 10-4 M NORD-1 into the bladders of NORD-1 and NORD-1+ODQ group rats and the vehicle into those of vehicle group rats. Isometric tension was analyzed using circular bladder neck specimens with 10-5 M NG-nitro-l-arginine methyl ester, an NO synthase inhibitor. Moreover, 10-5 M ODQ was added into the NORD-1+ODQ group bath. After precontraction with 10-5 M carbachol, the specimens were irradiated with red light and their relaxation responses were measured. We evaluated NORD-1 tissue permeability by observing the sliced bladder neck specimens. The NORD-1 group specimens relaxed during red light irradiation; the relaxation response increased with the increase in light intensity. The vehicle and NORD-1+ODQ group specimens did not respond to irradiation. Sex-related differences in responsiveness were not noted. NORD-1 permeated into the urothelium of NORD-1 group specimens. Rat bladder neck relaxation was controlled by NORD-1 and light irradiation in vitro. NORD-1 might be a novel therapeutic agent for voiding dysfunction.

Impairment of accessory nerves around major pelvic ganglion leading to overflow urinary incontinence in rats.

AIMS: To investigate the relationship between lower urinary tract function and the accessory nerve (ACN) arising from the major pelvic ganglion (MPG). METHODS: Ten-week-old male Wistar/ST rats were randomly divided into eight groups according to the type of treatment (sham or bilateral accessory nerve injury [BACNI]) and the duration of observation (3 days, 1 week, 2 weeks, or 4 weeks: Sham-3d, Sham-1w, Sham-2w, Sham-4w, BACNI-3d, BACNI-1w, BACNI-2ws, and BACNI-4w. BACNI was induced in the following manner: the ACN was crushed for 1 min (2 mm away from the MPG) using reverse-action tweezers. The same procedure was performed on both sides. On the last day of each observation period, the bladder function was measured by awake cystometry, and histological evaluation was performed. RESULTS: All rats in the Sham groups micturated normally. In the BACNI-3d and BACNI-1w groups, all rats showed symptoms of overflow urinary incontinence (OUI). This OUI improved gradually over time. The bladder's size in the BACNI group was significantly larger than that in the Sham group (p < .01). In addition, fibrosis was observed in the subserosa of the bladder of rats in BACNI groups. CONCLUSION: The BACNI model rats exhibited OUI, suggesting that ACN is involved in the lower urinary tract function. It might be possible that ACN controls the function of either the bladder, the urethra, or both.

3D reconstruction and histopathological analyses on murine corporal body.

PURPOSE: Erectile dysfunction (ED) is one of the increasing diseases with aging society. The basis of ED derived from local penile abnormality is poorly understood because of the complex three-dimensional (3D) distribution of sinusoids in corpus cavernosum (CC). Understanding the 3D histological structure of penis is thus necessary. Analyses on the status of regulatory signals for such abnormality are also performed. METHODS: To analyze the 3D structure of sinusoid, 3D reconstruction from serial sections of murine CC were performed. Histological analyses between young (2 months old) and aged (14 months old) CC were performed. As for chondrogenic signaling status of aged CC, SOX9 and RBPJK staining was examined. RESULTS: Sinusoids prominently developed in the outer regions of CC adjacent to tunica albuginea. Aged CC samples contained ectopic chondrocytes in such regions. Associating with the appearance of chondrocytes, the expression of SOX9, chondrogenic regulator, was upregulated. The expression of RBPJK, one of the Notch signal regulators, was downregulated in the aged CC. CONCLUSIONS: Prominent sinusoids distribute in the outer region of CC which may possess important roles for erection. A possibility of ectopic chondrogenesis induced by alteration of SOX9/Notch signaling with aging is indicated.

High Salt Intake Impairs Erectile Function in Salt-Sensitive Rats Through Mineralocorticoid Receptor Pathway Beyond Its Effect on Blood Pressure.

BACKGROUND: High salt intake is a risk factor for hypertension, which can potentially lead to erectile dysfunction (ED); however, the underlying pathological mechanisms remain unclear. AIM: To investigate whether erectile function is directly impaired by high salt intake and whether selective inhibition of mineralocorticoid receptor (MR) could provide protection from ED. METHODS: 6-week-old male Dahl salt-sensitive rats were randomly divided into 3 groups: normal diet (0.3% NaCl; control, n = 8), high-salt diet (8% NaCl; HS, n = 8), and high-salt diet plus eplerenone (HS + EPL, n = 11). HS + EPL rats were orally administered daily doses of EPL (75 mg/kg) for 6 weeks; control and HS rats received purified water on the same schedule. OUTCOMES: At the end of the study period, erectile function was evaluated by measuring intracavernosal pressure and mean arterial pressure after cavernous nerve stimulation. Serum levels of asymmetric dimethylarginine and L-arginine were determined using ultraperformance liquid chromatography-tandem mass spectrometry. Quantitative PCR was used to assess the expression of MR, inflammation, and oxidative stress markers (nicotinamide adenine dinucleotide phosphate oxidase-1/4, p22phox, interleukin-6, and superoxide dismutase-1), and protein arginine N-methyltransferase-1. RESULTS: The intracavernosal pressure/mean arterial pressure ratio was significantly lower, whereas systolic blood pressure, MR expression, serum asymmetric dimethylarginine levels, oxidative stress, and levels of inflammatory biomarkers were significantly higher in HS rats than in control rats (P < .05). EPL administration significantly improved each of these parameters except systolic blood pressure and MR expression. No significant intergroup differences were observed for L-arginine and superoxide dismutase-1 levels. CLINICAL TRANSLATION: Our results provide a rationale for the need of salt restriction and the use of selective MR inhibitors in prophylaxis or treatment of ED in men consuming a high-salt diet. STRENGTHS & LIMITATIONS: We are the first to report that the adverse impact of high salt intake on erectile function is mediated via MR activation, independent of its effect on blood pressure. A major limitation of this study is that responses of salt-resistant rats were not studied. CONCLUSIONS: High salt intake directly impaired erectile function in Dahl salt-sensitive rats, whereas selective MR inhibition ameliorated this effect. Kishimoto T, Kataoka T, Yamamoto Y, et al. High Salt Intake Impairs Erectile Function in Salt-Sensitive Rats Through Mineralocorticoid Receptor Pathway Beyond Its Effect on Blood Pressure. J Sex Med 2020;17:1280-1287.

Anagliptin, a dipeptidyl peptidase-4 inhibitor, improved bladder function and hemodynamics in rats with bilateral internal iliac artery ligation.

AIMS: To investigate the effect of anagliptin (Ana), a dipeptidyl peptidase-4 (DPP-4) inhibitor, on acute ischemia-induced bladder dysfunction in rats. METHODS: Eight-week-old female Wistar-ST rats were randomly assigned into four groups: (a) sham; (b) ligation (Lig); (c) Lig + Ana; and (d) Lig + Liraglutide (a glucagon-like peptide-1 [GLP-1] receptor agonist; Lira). Rats in the Lig, Lig + Ana, and Lig + Lira groups underwent ligature of the bilateral internal iliac arteries. Ana was orally administered mixed with the CE-2 diet. Lira was subcutaneously administered once a day. Blood glucose levels, plasma dipeptidyl peptidase 4 (DPP-4) activity, GLP-1 levels, and bladder function were measured in all groups. Bladder blood flow was measured in the sham, Lig, and Lig + Ana groups, 4 weeks postsurgery. RESULTS: No differences in blood glucose levels among the groups were observed. DPP-4 activity decreased in the Lig + Ana group (P < .01). GLP-1 levels in the Lig + Ana and Lig + Lira groups were higher than those in the sham and Lig groups (P < .01). Intercontraction intervals (ICIs) were longer in the Lig and Lig + Lira groups than in the sham group (P < .05), but similar to those observed in the Lig + Ana and sham groups. The Lig group exhibited reduced bladder blood flow relative to the sham group (P < .01); however, this measure improved in the Lig + Ana group (P < .01). CONCLUSIONS: Ana administration improved ICIs and bladder blood flow after acute bladder ischemia through a GLP-1 receptor-independent signaling pathway, without altering the blood glucose levels. Therefore, Ana dosing might be useful to prevent ischemia-induced bladder dysfunctions.

Prognostic significance of hyponatremia induced by systemic chemotherapy in a hospital-based propensity score-matched analysis.

BACKGROUND: During chemotherapy, hyponatremia is one of the most frequently encountered adverse effects. This study aimed to investigate the prognostic impact of hyponatremia induced by systemic chemotherapy (HIC) using a propensity matching method in cumulative pooled data. METHODS: Between January 2011 and July 2017, 2129 patients were administered systemic chemotherapy for malignancy in various organs at Nagoya City University Hospital. Patients were divided into two groups: a grade 0-1 group (control group) and a grade 3-4 group (severe group) according to the severity of HIC appearing within 30 days after starting treatment. Kaplan-Meier curves were used for survival and recurrence analyses using a propensity case-matched analysis. RESULT: The number of severe HIC patients was 93 (4.4%). In platinum-containing regimens, HIC appeared at higher frequencies. In the 21.2 months median follow-up period, the median OS (mOS) in the severe group was 49.1 months, which was significantly worse than the mOS in the control group; the OS in the control group did not reach the median. Univariate and multivariate analyses of associated factors in patients with grade 3-4 HIC revealed that renal dysfunction, cisplatin-containing regimen, and infusion of more than 5000 mL fluid was associated with HIC. CONCLUSION: This study suggests that severe HIC in the first treatment cycle affects survival time. Chemotherapy patients receiving extensive hydration should be required to undergo frequent monitoring of serum sodium levels, especially patients receiving platinum-containing regimens.

Efficacy of tapentadol for first-line opioid-resistant neuropathic pain in Japan.

BACKGROUND: Cancer-related neuropathic pain is sometimes unresponsive to multidrug treatment. Novel drugs are required to treat such severe pain without necessitating the use of adjuvant analgesics. Tapentadol is a new drug that has a dual mechanism as both an opioid agonist and noradrenalin reuptake inhibitor. The study objective was to investigate the effectiveness of oral tapentadol for relieving cancer-related neuropathic pain. METHODS: A retrospective, single-center, open, non-randomized study was conducted at the Nagoya City University Hospital. The study included 38 Japanese patients with advanced cancer who received opioids, such as tramadol, oral oxycodone and transdermal fentanyl, with or without adjuvant analgesics. Eastern Cooperative Oncology Group performance status, Numerical Rating Scale, primary tumor type, primary opioid and tapentadol doses, adjuvant analgesic prescriptions, outcomes and adverse events of opioid switching were assessed for 7 days. RESULTS: Eighteen (47.3%) out of 38 patients were enrolled in this study. The average performance status was 2.13 ± 0.94 (mean ± standard deviation). After switching to oral tapentadol, the pain score decreased from 3.78 to 2.78. The patients who had clinically improved effective pain scores had a higher percentage of prior opioid use for more than 2 months. After switching to tapentadol, adverse events were usually mild, with a grade of 1-2 by the Common Terminology Criteria for Adverse Events v4.03. CONCLUSIONS: Tapentadol appears to have an acceptable safety margin and promising efficacy to relieve cancer-related neuropathic pain that is refractory to first-line opioid treatment.

Testosterone Deficiency Causes Endothelial Dysfunction via Elevation of Asymmetric Dimethylarginine and Oxidative Stress in Castrated Rats.

BACKGROUND: Testosterone is believed to mediate the penile erectile response by producing adequate nitric oxide; therefore, testosterone deficiency results in erectile dysfunction through decreased nitric oxide bioavailability. However, the mechanisms underlying endothelial dysfunction in testosterone deficiency remain unclear. AIM: To investigate the mechanism of endothelial dysfunction in a rat model of testosterone deficiency. METHODS: Rats were distributed into 3 groups: castrated (Cast), castrated and supplemented with testosterone (Cast + T), and sham (Sham). In the Cast + T group, castrated rats were treated daily with subcutaneous testosterone (3 mg/kg daily) for 4 weeks; Sham and Cast rats received only the vehicle. OUTCOMES: Erectile function using intracavernosal pressure and mean arterial pressure measurements after electrical stimulation of the cavernous nerve, endothelial function using isometric tension, asymmetric dimethylarginine (ADMA) levels using ultra-performance liquid chromatography and tandem mass spectrometry, and inflammatory biomarker expression were performed 4 weeks after the operation. RESULTS: In the Cast group, the ratio of intracavernosal pressure to mean arterial pressure significantly decreased, acetylcholine-induced relaxation was lower, and serum ADMA, oxidative stress, and inflammation biomarker levels were significantly increased (P < .01). Testosterone injection significantly improved each of these parameters (P < .01). CLINICAL TRANSLATION: The present results provide scientific evidence of the effect of testosterone deficiency on erectile function and the effect of testosterone replacement therapy. STRENGTHS AND LIMITATIONS: This study provides evidence of the influence of testosterone deficiency on endothelial function by investigating ADMA and oxidative stress. A major limitation of this study is the lack of a direct link of increased ADMA by oxidative stress to inflammation. CONCLUSION: Testosterone deficiency increased not only ADMA levels but also oxidative stress and inflammation in castrated rats, which can cause damage to the corpus cavernosum, resulting in erectile dysfunction. Kataoka T, Hotta Y, Maeda Y, Kimura K. Testosterone Deficiency Causes Endothelial Dysfunction via Elevation of Asymmetric Dimethylarginine and Oxidative Stress in Castrated Rats. J Sex Med 2017;14:1540-1548.