The current state of family caregiver burden and support of toilet problems for elderly with mild cognitive impairment and Alzheimer's disease.

OBJECTIVE: To conduct an exploratory examination of caregiver burden involving toilet problems in patients with mild cognitive impairment (MCI) and Alzheimer's disease (AD) and related characteristics. METHODS: We included 50 outpatients with amnestic MCI and AD and their caregivers. Patients were subclassified into three groups: MCI, mild AD, and moderate/severe AD. We used the Japanese version of the Zarit Burden Interview (J-ZBI) to evaluate caregiver burden and conducted a questionnaire on the frequency of lower urinary tract symptoms and related caregiver burden. We compared the frequency of questionnaire items with the level of burden in each group and subsequently determined the J-ZBI correlation coefficient. RESULTS: Among the questionnaire items, the caregiver's burden of "increased daytime urinary frequency," "nocturia," "urinary incontinence," and "they cannot clean the toilet" statistically significantly correlated with J-ZBI scores (ρ = 0.52, 0.65, 0.79, and 0.83, respectively). Items including "they cannot clean the toilet," "the smell of excrement is bothersome," "assistance for transfer is necessary," "they soil the clothes and bed," and "they cannot clean the genital region" were significantly more common in the patient group with moderate/severe AD. CONCLUSIONS: Lower urinary tract symptoms and toilet problems were significantly correlated with caregiver burden. Toilet problems differ depending on the severity of dementia. Therefore, a support system based on dementia severity is required to address toilet problems.

A Review of Aging and the Lower Urinary Tract: The Future of Urology.

Lower urinary tract symptoms (LUTS) are common among elderly people, with significant effects on individuals, caregivers, and the wider health care system. As the elderly population with multiple comorbidities is increasing, the burden of LUTS will increase. This review describes the demographic trends in the aging society, changes in lower urinary tract function with aging, and deterioration of physical and cognitive function in aging, as well as what has been done regarding geriatric urology and what urologists should do to meet the health care needs of the aging population. Frailty and dementia are unmissable factors in the evaluation of elderly patients. Numerous reports have described associations between LUTS and frailty and between LUTS and dementia. Urologists must be aware of the multiplex physical, cognitive, and social characteristics of elderly people. Maintaining a geriatric viewpoint in the diagnosis, treatment, and management of elderly individuals with LUTS will fulfill the unmet needs of elderly people. It is also essential to discuss the treatment and management goals of LUTS with patients and caregivers. Active case identification, appropriate evaluations of LUTS and comorbidities, and a multidisciplinary approach with other health-care professionals are recommended for better treatment and management.

Prevalence of xerostomia with or without overactive bladder symptoms.

Overactive bladder (OAB) occurs idiopathic or secondary to a neurological cause. In addition, OAB may also occur due to xerostomia, because it causes excessive drinking of water. If xerostomia is one of the causes of OAB, treating xerostomia may be effective. This study aimed to investigate the prevalence of xerostomia with or without overactive bladder symptoms. A web-based questionnaire was administered to investigate the prevalence of xerostomia with or without overactive bladder symptoms. The survey included questions concerning age, gender, medical history, medications, OAB symptoms by the Overactive Bladder Symptom Score (OABSS), and xerostomia by the Dry Mouth Scale (DMS). From the analysis, a total of 21 (13.0%) participants were identified as having OAB. The prevalence of xerostomia was six (28.6%) in the OAB group and 14 (10.0%) in the non-OAB group. OABSS and DMS were significantly higher in the OAB group than in the non-OAB group. Urgency score and urgency incontinence score of OABSS were substantially higher in xerostomia participants than non-xerostomia participants. The adjusted odds ratio of OAB showed DMS total score, xerostomia symptoms, accompanying symptoms, and other symptoms that were all significantly associated with OAB. These results suggested that OAB subjects, even untreated subjects, had xerostomia. It may be beneficial for clinicians to perform dry mouth management in parallel with careful choice pharmacotherapy for the wellness of OAB patients.

Tadalafil Improves Nocturia and Nocturia-Related Quality of Life in Patients with Benign Prostatic Hyperplasia (KYU-PRO Study).

INTRODUCTION: Tadalafil improves lower urinary tract symptoms (LUTS) including nocturia. However, the effect of tadalafil on the nocturia-related quality of life (QoL) is still unknown. OBJECTIVE: The effects of tadalafil on nocturia and nocturia-related QoL were evaluated prospectively in patients with benign prostatic hyperplasia (BPH) as a multicenter study. METHODS: Eligible men were ≥40 years with nocturia ≥2 and a prostate volume ≥20 mL. Patients were asked to complete a self-report questionnaire on the International Prostate Symptom Score (IPSS), the Nocturia Quality of Life questionnaire (N-QoL) and the International Index of Erectile Function 5 (IIEF5). Urinary frequency volume charts (FVCs) were also evaluated. These measures were evaluated at baseline, and after 4, 8, and 12 weeks of tadalafil administration (5 mg once daily). RESULTS: Thirty-one patients with a mean age of 74 years, a mean prostate volume of 31 mL, and a mean prostate-specific antigen level of 2.8 ng/mL were included. Treatment with tadalafil significantly improved their nocturia after 4 weeks, and these improvements were maintained for the 12-week treatment period. Total N-QoL score in new patients and several N-QoL items (inadequate sleep at night and overall bother) in all patients improved significantly after tadalafil treatment. FVCs revealed a significant improvement in the number of hours of undisturbed sleep (HUS) after treatment with tadalafil. No serious adverse events were observed. CONCLUSIONS: This study indicates that tadalafil 5 mg once daily improves nocturia, nocturia-related QoL, and HUS in BPH patients with nocturia. These results suggest that tadalafil can offer a clinically meaningful treatment option for BPH patients with nocturia.

Tadalafil Improves Symptoms, Erectile Function and Quality of Life in Patients with Lower Urinary Tract Symptoms Suggestive of Benign Prostatic Hyperplasia (KYU-PRO Study).

OBJECTIVES: Effect of tadalafil on lower urinary tract symptoms (LUTS), erectile function and quality of life (QoL) were prospectively evaluated in patients with benign prostatic hyperplasia (BPH) at multicenter. METHODS: Eligible men were ≥40 years who had no treatment with alpha-blocker for BPH, with total International Prostate Symptom Score (IPSS) ≥8, IPSS-QOL ≥2 and prostate volume ≥20 mL. Data were collected on age, body mass index (BMI), and prostate specific antigen (PSA). Patients were asked to complete a self-reported questionnaire regarding the IPSS, Overactive Bladder Symptom Score (OABSS), International Index of Erectile Function 5 (IIEF5), and Medical Outcome Study 8-Item Short-Form Health Survey (SF-8). These measures were assessed at baseline, 4-, 8-, 12-week of tadalafil treatment. In addition, uroflowmetry was also performed at baseline, and 12-week end point visit. RESULTS: Thirty five patients with mean age 67.3 years, mean BMI 23.6 kg/m2 , mean prostate volume 36 mL, and mean PSA 3.4 ng/mL were enrolled. Treatment with tadalafil significantly improved IPSS total score, IPSS voiding subscore, IPSS storage subscore, OABSS and IPSS-QoL score after 4 weeks and these improvements were maintained for 12-week treatment period. IIEF5 score and general health in SF-8 are significantly improved with the treatment of tadalafil. However, maximum flow rate and postvoiding residual volume were not significantly changed. There were not any serious adverse events. CONCLUSIONS: These results indicate that tadalafil 5 mg once daily would be effective and well tolerated treatment in Japanese men with BPH-LUTS.

Coincidence between malignant perivascular epithelioid cell tumor arising in the gastric serosa and lung adenocarcinoma.

A 4-mo history of both epigastralgia and back pain was presented in a 39-year-old male. Computed tomography showed right lung nodule and abdominal mass attached to the gastric wall, measuring approximately 30 mm and 70 mm in diameter. Since biopsy samples from the lung and abdomen revealed poorly differentiated adenocarcinoma and malignant tumor, clinicians first interpreted the abdominal mass as metastatic carcinoma, and a right lower lobectomy with following resection of the mass was performed. Gross examination of both lesions displayed gray-whitish to yellow-whitish cut surfaces with hemorrhagic and necrotic foci, and the mass attached to the serosa of the lesser curvature on the gastric body. On microscopic examination, the lung tumor was composed of a proliferation of highly atypical epithelial cells having abundant eosinophilic cytoplasm, predominantly arranged in an acinar or solid growth pattern with vessel permeation, while the abdominal tumor consisted of sheets or nests with markedly atypical epithelioid cells having pleomorphic nuclei and abundant eosinophilic to clear cytoplasm focally in a radial perivascular or infiltrative growth pattern. Immunohistochemically, the latter cells were positive for HMB45 or α-smooth muscle actin, but the former ones not. Therefore, we finally made a diagnosis of malignant perivascular epithelioid cell tumor (PEComa) arising in the gastric serosa, combined with primary lung adenocarcinoma. Furthermore, small papillary carcinoma of the thyroid gland was identified. The current case describes the coincidence of malignant PEComa with other carcinomas, posing a challenge in distinction from metastatic tumor disease.

Complete disruption of all nitric oxide synthase genes causes markedly accelerated renal lesion formation following unilateral ureteral obstruction in mice in vivo.

The role of nitric oxide (NO) derived from all three NO synthases (NOSs) in renal lesion formation remains to be fully elucidated. We addressed this point in mice lacking all NOSs. Renal injury was induced by unilateral ureteral obstruction (UUO). UUO caused significant renal lesion formation (tubular apoptosis, interstitial fibrosis, and glomerulosclerosis) in wild-type, singly, and triply NOS(-/-) mice. However, the extents of renal lesion formation were markedly and most accelerated in the triply NOS(-/-) genotype. UUO also elicited the infiltration of inflammatory macrophages, up-regulation of transforming growth factor (TGF)-ß1, and induction of epithelial mesenchymal transition (EMT) in all of the genotypes; however, the extents were again largest by far in the triply NOS(-/-) genotype. Importantly, long-term treatment with the angiotensin II type 1 (AT(1))-receptor blocker olmesartan significantly prevented the exacerbation of those renal structural changes after UUO in the triply NOS(-/-) genotype, along with amelioration of the macrophage infiltration, TGF-ß1 levels, and EMT. These results provide the first evidence that the complete disruption of all NOS genes results in markedly accelerated renal lesion formation in response to UUO in mice in vivo through the AT(1)-receptor pathway, demonstrating the critical renoprotective role of all NOSs-derived NO against pathological renal remodeling.

Involvement of orexin-A on micturition reflex in normal and cyclophosphamide-induced cystitis bladder in rat.

The purpose of the present study was to investigate the effect of orexin-A in the spinal cord on bladder function in normal rats and cyclophosphamide (CYP)-induced cystitis rat models. The effects of intrathecal (i.t.) injection of orexin-A (0.01, 0.1 and 1.0 nmol) on bladder function were examined during continuous infusion cystometrogram (CMG) in urethane anesthetized normal and CYP-induced cystitis rats. The effects of i.t. injection of selective orexin-1 receptor (OXR1) antagonist SB334867 (10 nmol) on orexin-A-induced bladder overactivity in normal rats and SB334867 (10 and 30 nmol) on changes in bladder function in normal and CYP-induced cystitis rats were investigated. The effects of intravenous (i.v.) injection of orexin-A (0.3 and 1.0 nmol) on micturition reflex were also investigated in normal rats. I.t. injection of orexin-A (0.1 and 1.0 nmol) significantly decreased the intercontraction intervals (ICI) in normal and CYP-induced cystitis rats. I.t. injection of SB334867 (10 nmol) significantly increased the ICI of orexin-A induced overactive bladder in normal rats and i.t. injection of SB334867 (30 nmol) also increased the ICI in normal rat bladder. However, in CYP-injected cystitis rat models, i.t. injection of SB334867 did not change the bladder function. I.v. injection of orexin-A failed to affect the bladder function in normal rats. Orexin mRNA levels in the lateral hypothalamus were significantly decreased in CYP-induced cystitis rats. These results indicate that orexin-A in the spinal cord activates micturition reflex via OXR1 in normal rats. In addition, OXR1 antagonist did not have any effect on micturition reflex in CYP-induced cystitis rats.

Effect of eviprostat on bladder overactivity in an experimental cystitis rat model.

OBJECTIVE: The purpose of this study was to investigate the effects of eviprostat, a phytotherapeutic drug, on bladder overactivity and inflammation in a cyclophosphamide (CYP)-induced cystitis rat model. METHODS: Female Sprague-Dawley rats received a single intraperitoneal injection of CYP (200 mg/kg) or saline. After the CYP injection, eviprostat (9, 18 or 54 mg/kg per day) or a vehicle was orally given twice each day. Four days after the CYP injection, bladder function was evaluated by cystometrograms under urethane anesthesia. In a separate group, bladder inflammation was compared between the eviprostat- or vehicle-treated animals. Furthermore, the effects of eviprostat on carbachol-induced muscle contraction were evaluated by an in vitro experiment. RESULTS: The intercontraction interval (ICI) significantly decreased in the CYP-injected rats in comparison to the saline-injected rats. In the CYP-injected group, 18 and 54 mg/kg per day of eviprostat treatment significantly increased the ICI, but did not change the maximum voiding pressure in comparison to the vehicle treatment. In the saline-injected group, no significant changes of any parameters in the cystometrograms were observed between the eviprostat- and vehicle-treated groups. CYP-induced bladder inflammation tended to be lower in the eviprostat-treated group in comparison to the vehicle-treated group. An in vitro experiment revealed that eviprostat failed to inhibit carbachol-induced muscle contraction. CONCLUSION: The oral administration of eviprostat suppressed CYP-induced bladder overactivity. The effects of eviprostat on the micturition reflex may be irrespective of antimuscarinic action. The present findings raise the possibility that eviprostat could be an effective treatment for bladder overactivity associated with inflammation.

Thalamic neural activation in the cyclophosphamide-induced visceral pain model in mice.

The afferent nociceptive information from the lower urinary tract terminates in the dorsal horn of the spinal cord, and then projects to the thalamus. In the present study, we examined the effects of visceral nociception from the lower urinary tract on the neural activity of thalamic neurons using cyclophosphamide (CP)-induced cystitis, a model of visceral nociception. The levels of c-fos mRNA as well as protein, a marker of neural activation, were investigated in the thalamus using in situ hybridization histochemistry and immunohistochemistry. The effects of pretreatment with capsaicin were also examined. In the CP-treated group, the c-fos mRNA as well as protein was significantly induced predominantly in the paraventricular area of the thalamus. The induction of c-fos mRNA exhibited a dose-dependency. The induction of c-fos mRNA of CP-treated mice was significantly inhibited by capsaicin pretreatment to deplete C-fibers. Our results indicate that visceral nociception from the lower urinary tract activates thalamic neurons and this activation is mediated in part through the activation of the capsaicin-sensitive C-fiber afferents. The present findings suggest that the levels of c-fos in the paraventricular area of the thalamus may be a useful marker for evaluating the afferent nerve activity from the lower urinary tract.

An angiotensin II receptor blocker increases sexual behavior in type 2 diabetic mice.

The present study was conducted to examine the effects of olmersartan, angiotensin (ANG) II type 1 (AT(1)) receptor antagonist, on the sexual function in type 2 diabetes model mice. Twenty-week-old KK/Ta mice were used as a model of type 2 diabetes. Age-matched ICR and BALB/C mice were used as non-diabetic controls. The animals were fed powder chow either with or without olmesartan (7.5 microg/g in chow) for 4 weeks. The levels of sexual behavior, activity, and anxiety were then examined between the groups treated with and without olmesartan. The KK/Ta mice treated with olmesartan exhibited a significant increase in the number of mounts and intromission and a decrease in the latency to the first mount in comparison to the KK/Ta mice treated without olmesartan. These effects of olmesartan were not observed in the non-diabetic BALB/C and ICR mice. In addition, the olmesartan treatment did not affect the activity and anxiety regardless of the mouse strain. These findings suggest that the interaction between ANG II and AT(1) receptor may be involved in the pathogenesis of the sexual dysfunction associated with type 2 diabetes and a blockade of ANG II may therefore be a potentially useful treatment for male sexual dysfunction in type 2 diabetes.

Up-regulation of galanin and corticotropin-releasing hormone mRNAs in the key hypothalamic and amygdaloid nuclei in a mouse model of visceral pain.

Cyclophosphamide (CP)-induced cystitis is often used as an animal model of visceral pain. Various neuropeptides in the hypothalamic and amygdaloid nuclei are implicated in pain-induced responses. However, little information is available regarding the regulation of the neuropeptides in response to visceral pain. In the present study, we examined the effects of CP-induced cystitis on the levels of mRNAs encoding galanin, corticotropin-releasing hormone (CRH), substance P, and enkephalins in the hypothalamic and limbic nuclei using in situ hybridization histochemistry in mouse. Galanin mRNA levels in CP-treated group increased significantly in the arcuate nucleus and the paraventricular nucleus (PVN) but not in the medial preoptic area after the intraperitoneal administration of CP (200 mg/kg body weight) in comparison to those in saline-treated group. CRH mRNA levels in CP-treated group also increased significantly in the central amygdala as well as the PVN after the CP administration. In contrast, CP-induced cystitis failed to upregulate the preprotachykinin-A and preproenkephalin genes which encode substance P and enkephalins, respectively in the hypothalamic and limbic nuclei at any of the time points examined. These results suggest that visceral nociception may upregulate both galanin and CRH gene expression in the hypothalamic and limbic nuclei.

Up-regulation of interleukin-6 gene expression in cyclophosphamide-induced cystitis in mice: An in situ hybridization histochemical study.

AIM: To determine the time course and the cellular sources of interleukin (IL)-6 in the bladder during experimental cystitis, the expression of the IL-6 gene and IL-6 protein was examined in the bladder during cyclophosphamide (CP)-induced cystitis. METHODS: Mice were killed at 0, 1, 2, 6, 12 and 48 h after the intraperitoneal administration of 0.9% saline containing either CP (200 mg/kg) or saline. The expression of IL-6 gene and IL-6 protein were detected using in situ hybridization histochemistry and immunocytochemistry, respectively. RESULTS: In situ hybridization histochemistry showed that IL-6 gene expression was significantly up-regulated in the bladder at 1 h in comparison to that at 0 h after CP administration. The levels of IL-6 gene expression peaked at 6 h after CP administration and then declined thereafter. In contrast, only a few IL-6 transcripts were expressed in the bladder but they remained unchanged following the administration of saline at all time points examined. The IL-6 transcripts were predominantly distributed in the perivascular area of the submucosal layers during CP-induced cystitis. Immunocytochemistry demonstrated IL-6 immunoreactivity in the spindle-shaped cells located in the vicinity of the dilated vessels of the submucosal layers during CP-induced cystitis. CONCLUSION: IL-6 gene expression was up-regulated in the submucosal layer of the bladder and peaked at 6 h after CP administration, suggesting that the primary source of IL-6 may be fibroblasts in the bladder during CP-induced cystitis.

The hypothalamo-pituitary axis responses to lipopolysaccharide-induced endotoxemia in mice lacking inducible nitric oxide synthase.

Nitric oxide (NO) generated by inducible NO synthase (iNOS) may be implicated in the biological responses of the central nervous system to immune stimuli. To elucidate the role of iNOS in the hypothalamo-pituitary axis in responses to endotoxemia, using iNOS knockout (KO) mice, we examined the levels of c-fos, a neural activational marker, and corticotropin-releasing hormone (CRH) gene transcription in the paraventricular nucleus (PVN) and central amygdala (CeAMY) during lipopolysaccharide (LPS)-induced endotoxemia. In addition, the serum adrenocorticotropic hormone (ACTH) levels were also examined during endotoxemia. Following the intraperitoneal administration of LPS (1 mg/kg), the levels of the c-fos gene expression significantly increased in the PVN and the CeAMY regardless of the genotype. However, the disruption of the iNOS gene resulted in a significant decrease in the c-fos gene induction in the PVN in comparison to that observed in control mice. LPS administration caused a significant increase in CRH mRNA levels in the PVN and CeAMY regardless of genotype. However, the LPS-induced upregulation of CRH mRNA was significantly attenuated in the PVN of iNOS KO mice in comparison to that in the control mice. In contrast, no such genotype differences in the neural activity or CRH gene transcription were observed in the CeAMY. The serum ACTH responses to LPS were also significantly blunted in the iNOS KO mice in comparison to the control mice. These results suggest that iNOS-derived NO may therefore play a stimulatory role in the activity of the hypothalamo-pituitary axis during endotoxemia.

Involvement of estrogen in the pathogenesis of cyclophosphamide-induced cystitis in rats.

We examined the effects of ovariectomy and castration on the histology of cyclophosphamide (CP)-induced cystitis in rats. The animals were injected with CP (100 mg/kg) or saline intraperitoneally twice with an intervening 4 d and were euthanized at 1 or 2 wk after the initial CP administration. Saline treatment did not cause an apparent histological change in the bladder regardless of surgery, i.e., ovariectomy, castration, and sham-operation. CP treatment resulted in submucosal edema, urothelial damage, hemorrhage, and leukocyte infiltration in the bladder at 1 wk after the initial CP administration regardless of surgery. However, these histological changes were more severe in ovariectomized rats than in the sham-operated rats. In contrast, there were no significant differences in CP-induced histological changes in the bladder between castrated and sham-operated groups. We further examined the role of estrogen and progesterone on the CP-induced histology in the bladder by the replacement with estrogen only or estrogen plus progesterone for 2 wk in overiectomized rats. Estrogen treatment ameliorated CP-induced histological changes compared to oil treatment, whereas estrogen plus progesterone treatment did not produce any differences in the histology of the bladder compared to estrogen treatment. These results suggest that estrogen may play a role in the pathogenesis of bladder inflammation.