Pathological analysis of spermatic dysfunction following testicular ischemia-reperfusion injury\n

　Introduction & Objectives: Torsion, which may result in testicular ischemia, requires emergency surgery to restore testicular blood flow. However, the risk of spermatic dysfunction remains even if surgery is performed. The pathology of spermatic dysfunction in testicular ischemia-reperfusion injury (TIRI) remains unclear. A previous study showed the relevance of inflammation and oxidative stress in the other organs of ischemia-reperfusion injury. We hypothesized that inflammation and oxidative stress play key roles in causing spermatic dysfunction following TIRI. We investigated the pathophysiology of spermatic dysfunction in TIRI focusing on inflammatory changes using TIRI model mice.　Materials and Methods: The study used C57BL/6J male mice aged 10 to 15 weeks. To create TIRI model mice, the unilateral (left side) testicular vessels were clamped using Dieffenbach clamps (Bulldog clamps) for 1 hour and de-clamped. The bilateral testes were removed at 0 (ischemic state), 1, 3, and 5 weeks after creating the TIRI model mice. Spermatic changes following TIRI were investigated by analyzing the histology of the testes and semen and assessing levels of inflammation and oxidative stress. Semen was collected from the bilateral cauda epididymites and investigated using the sperm motility analysis system (SMAS).　Results: Histological analysis after hematoxylin-eosin staining showed tissue thickening in interstitial tissues at week 1 and 3 on the left (affected) testis, and week 1, 3 and 5 on the right (unaffected) testis. The infiltration of lymphocytes-predominant inflammatory cells were observed at week 1 and week 3 on the left (affected) testis. The destruction of ductal structures and giant cells were observed at weeks 3 and 5 on the left (affected) testis and week 5 on the right (unaffected) testis. SMAS showed significantly decreased spermatic concentration and motility in both testes of TIRI model mice compared with those of sham-operated mice at weeks 1, 3 and 5. Inflammation analysis using an inflammation-related proteome assay showed significantly increased levels of cytokines (IL-2, IL-3, IL-17A, and IL-23) and chemokines (CCL2, CCL5, CXCL1, and CX3CL1) at weeks 1, 3, and 5 in both testes of TIRI model mice. For the assessment of oxidative stress, enzyme-linked immuno-sorbent assay (ELISA) for 8-hydroxy-2’-deoxyguanosine (8-OHdG) was performed, which showed that levels of 8-OHdG were significantly increased in the left (affected) testis of TIRI model mice compared with that of sham-operated mice at all observation periods. Meanwhile, ELISA showed that levels of 8-OHdG in the right (unaffected) testis were significantly increased in TIRI model mice at weeks 3 and 5 compared with that of sham-operated mice.　Conclusions: Spermatic dysfunction following TIRI is induced by inflammation and oxidative stress. Inflammation and oxidative stress may be novel regulatory factors to prevent spermatic dysfunction following TIRI

Preventive effect of indoleamine 2,3-dioxygenase 1 inhibition on lipopolysaccharide-induced prostatitis

　Introduction and Objectives: Bacterial infections are the main cause of acute prostatitis and are treated with appropriate antimicrobial therapy. However, approximately 5% of patients continue to have inflammatory symptoms even after receiving antibacterial therapy, leading to refractory conditions. Bacterial prostatitis requires additional therapy, focusing on inflammatory changes. Indoleamine 2,3-dioxygenase 1 (IDO1) catalysis is the first rate-limiting step of tryptophan metabolism. IDO1 is expressed in the prostate and plays a key role in the immune response. As the first step in investigating the relationship between acute prostatitis and IDO1, we investigated the preventive effect of IDO1 inhibition on lipopolysaccharide (LPS)- induced prostatitis using IDO knockout (Ido1 −/−) mice in this study.　Materials and Methods: The study used Ido1 −/− and wild-type (Ido1 +/+) C57BL/6J malemice aged 10–15 weeks. LPS Escherichia coli O26 (100μg/PBS, 100μL) was administered transurethrally into the lower urinary tract to create a mouse model of LPS-induced prostatitis. The prostates were removed 1, 3, 5, and 7 days after creating the model mice. Histological, immunohistochemical, and biochemical analyses were used to compare the preventive effect in Ido1 −/− mice compared with that in Ido1+/+ mice.　Results: HE staining showed suppression of ductal destruction following infiltration of inflammatory cells in Ido1 −/− mice compared with Ido1 +/+ mice. The enzyme-linked immunosorbent assay (ELISA) method was used for kynurenine pathway analysis, which showed significantly maintained tryptophan levels and decreased L-kynurenine levels in Ido1 −/− mice compared to Ido1 +/+ mice. The IDO1 assay in Ido1 +/+ mice showed significantly increased levels during all observation periods after creating the model compared with that under normal conditions. Immunofluorescent staining using five types of cytokines and chemokines (IL-2, IL-4, IL-17, CCL2, and CCL3) related to the pathophysiology of acute prostatitis showed decreased expression of these cytokines and chemokines in Ido1 -/- mice compared with Ido1 +/+ mice. Inflammation-related proteome assays showed decreased levels of IL-1β, IL-4, IL-5, IL-6, IL-17, CCL2, CCL3, CXCL1, CXCL11, and tissue inhibitor of matrix metalloproteinases (TIMP)-1 in Ido1 −/− mice compared with Ido1 −/− mice during all observation periods after model creation.　Conclusions: IDO1 is involved in LPS-induced prostatitis through cytokines and chemokines. IDO1 inhibition contributes to the prevention of LPS-induced prostatitis. IDO1 inhibition has the potential to serve as an additional therapy for acute prostatitis

Pathophysiological analysis of detrusor overactivity following partial bladder outlet obstruction

　Introduction: Detrusor overactivity (DO) following partial bladder outlet obstruction (PBOO) is a common urological condition in humans, with 50-70% patients with PBOO complicated with DO. The pathological mechanisms of DO following PBOO are largely unknown, but inflammatory changes may play a key role. We hypothesized that inflammation is important in the earlier pathophysiological phase before overproduction of oxidative stress in DO following PBOO. Therefore, we investigated the relationships among bladder function, ischemia, oxidative stress and inflammation in DO following PBOO in PBOO model mice.　Materials and Methods: C57BL/6J male mice aged 10 to 15 weeks were used in the study. PBOO model mice were created surgically by ligation of the proximal urethra with 5-0 nylon suture under inhalation anesthesia. Sham-operated mice were used as controls. Pathophysiological changes in the bladder at 1, 3 and 5 weeks after creation of the PBOO model mice were compared with those in sham-operated mice using functional, histological, biochemical and immunohistochemical analyses.　Results: Functional analysis using a pressure flow study showed increased maximum detrusor pressure at 1 week and DO from 3 to 5 weeks after creation of the PBOO model. Histological analysis using hematoxylin-eosin and Masson-Trichrome staining showed greater invasion of inflammatory cells and fibrosis in PBOO model mice compared with sham-operated mice at 3 and 5 weeks. Inflammatory cells were mainly present in interstitial tissue, and fibrosis gradually infiltrated from interstitial tissue to the muscular layer. Ischemia analysis showed significantlyincreased HIF-1α in PBOO model mice at all time points. Oxidative stress analysis indicated significantly increased levels of ROS from 1 week and 8-OHdG from 3weeks in PBOO model mice. An inflammation-related proteome assay showed high levels of colony stimulating factor (CSF) family proteins at 1 week and IL-2, IL-3, IL-17A, IL-23, MMP-3, MMP-9 and periostin from 3 to 5 weeks in PBOO model mice.　Conclusions: Oxidative stress and inflammatory changes showed contemporaneous increase in pathophysiology of detrusor overactivity following partial bladder outlet obstruction. Especially, CSF family and ROS changes are showed in the early stage, and might be a predict marker in the pathophysiology of DO following PBOO at the early stage

当院の女性過活動膀胱患者における抗コリン薬とβ3アドレナリン受容体作動薬の内服継続率に関する検討

　過活動膀胱（overactive bladder：以下OAB）は，尿意切迫感や頻尿などの下部尿路症状を有し，加齢とともに増加する傾向がある．OAB 患者の治療薬として，本邦では抗コリン薬とβ3アドレナリン受容体作動薬が推奨，使用されている．今回，女性OAB 患者に対する，抗コリン薬とβ3アドレナリン受容体作動薬の内服継続率，副作用，内服中止理由に関してretrospective に検討した．対象は，2013年１月から12月の１年間に当院泌尿器科を受診した初診の女性OAB 患者，87名とした．β3アドレナリン受容体作動薬投与群と抗コリン薬投与群の内服継続率は，β3アドレナリン受容体作動薬投与群は，12か月で38.8％，60か月で18.1％，抗コリン薬投与群は，12か月18.4%，60か月で7.9％であり，β3アドレナリン受容体作動薬投与群の方が若干継続率は良いものの，両群間に差は認めなかった．副作用に関しては，抗コリン薬投与群の方が多く，口喝が17例（44.7%），便秘が15例（39.5%）であった．薬剤中止の理由は両群とも自然寛解によるものが多かった．　Overactive bladder (OAB) involves lower urinary tract symptoms such as urinary urgency and polyuria, and tends to increase with age. In Japan, the drugs recommended and used for treatment of OAB patients are anticholinergic agents and β3 adrenalin receptor agonists. The present study was a retrospective investigation of the rates of long-term administration of anticholinergic agents and β3 adrenalin receptor agonists, adverse effects with these drugs, and reasons for discontinuation of administration, with female OAB patients. The subjects were 87 female patients who were examined at this hospital\u27s Urology Dept. over 1 year between January and December 2013, and diagnosed as having OAB for the first time. With respect to the rates of long-term administration, in the β3 adrenalin receptor agonist group the rates of administration for 12 and 60 months, respectively, were 38.8% and 18.1%, and these rates in the anticholinergic agent group were 18.4% and 7.9%, so the long-term administration rates were somewhat higher in the β3 adrenalin receptor agonist group, but no difference between the groups was found. Adverse effects were more frequent in the anticholinergic agent group, with 17 subjects in that group (44.7%) developing buccal dryness, and 15 (39.5%) developing constipation. In both groups, the most frequent reason for discontinuation of administration was spontaneous remission

Preventive effect of indoleamine 2,3-dioxygenase 1 inhibition on lipopolysaccharide-induced prostatitis

Regular Articlejournal articl

Pathological analysis of spermatic dysfunction following testicular ischemia-reperfusion injury\n

Regular Articlejournal articl

Pathophysiological analysis of detrusor overactivity following partial bladder outlet obstruction

Regular Articlejournal articl