Yasuhiro Kaiho

Impact of Nocturia on Bone Fracture and Mortality in Older Individuals: A Japanese Longitudinal Cohort Study

PURPOSE We evaluated the association of nocturia with fracture and death in a large, community based sample of Japanese individuals 70 years old or older. MATERIALS AND METHODS The baseline in this population based study was determined in 2003 by an extensive health interview with each participant. In this study we followed 784 individuals with a mean ± SD age of 76.0 ± 4.6 years (range 70 to 97). Information on mortality and fracture during the study period was provided by the National Health Insurance system and details on fractures were collected from medical records. We compared the risk of bone fracture and death with or without nocturia in a multivariate Cox proportional hazard model. RESULTS Nocturia (2 or greater voids per night) was present in 359 of the 784 participants (45.7%). Fracture was observed in 41 cases, including 32 fall related cases. For all fractures and fall related fractures with nocturia the HR was 2.01 (95% CI 1.04-3.87) and 2.20 (95% CI 1.04-4.68, each p = 0.04). Death occurred in 53 cases. The mortality rate in individuals with nocturia was significantly higher than in those without nocturia. For mortality in patients with nocturia the age-gender adjusted HR was 1.91 (95% CI 1.07-3.43, p = 0.03). Even when further adjusted for diabetes, smoking status, history of coronary disease, renal disease and stroke, tranquilizers, hypnotics and diuretics, the positive relationship was unchanged (HR 1.98, 95% CI 1.09-3.59, p = 0.03). CONCLUSIONS During a 5-year observation period elderly individuals with nocturia were at greater risk for fracture and death than those without nocturia.

Therapeutic receptor targets for lower urinary tract dysfunction

The functions of the lower urinary tract, to store and periodically release urine, are dependent on the activity of smooth and striated muscles in the bladder, urethra, and external urethral sphincter. During urine storage, the outlet is closed, and the bladder smooth muscle is quiescent. When bladder volume reaches the micturition threshold, activation of a micturition center in the dorsolateral pons (the pontine micturition center) induces a bladder contraction and a reciprocal relaxation of the urethra, leading to bladder emptying. During voiding, sacral parasympathetic (pelvic) nerves provide an excitatory input (cholinergic and purinergic) to the bladder and inhibitory input (nitrergic) to the urethra. These peripheral systems are integrated by excitatory and inhibitory regulation at the levels of the spinal cord and the brain. Injury or diseases of the nervous system, as well as drugs and disorders of the peripheral organs, can produce lower urinary tract dysfunction. In the overactive bladder (OAB) condition, therapeutic targets for facilitation of urine storage can be found at the levels of the urothelium, detrusor muscles, autonomic and afferent pathways, spinal cord, and brain. There is increasing evidence showing that the urothelium has specialized sensory and signaling properties including: (1) expression of nicotinic, muscarinic, tachykinin, adrenergic, bradykinin, and transient receptor potential (TRP) receptors, (2) close physical association with afferent nerves, and (3) ability to release chemical molecules such as adenosine triphosphate (ATP), acetylcholine, and nitric oxide. Increased expression and/or sensitivity of these urothelial-sensory molecules that lead to afferent sensitization have been documented as possible pathogenesis of OAB. Targeting afferent pathways and/or bladder smooth muscles by modulating activity of ligand receptors (e.g., neurokinin, ATP, or β3-adrenergic receptors) and ion channels (e.g., TRPV1 or K) could be effective to suppress OAB. In the stress urinary incontinence condition, pharmacotherapies targeting the neurally mediated urethral continence reflex during stress conditions such as sneezing or coughing could be effective for increasing the outlet resistance. Therapeutic targets include adrenergic and serotonergic receptors in the spinal cord as well as adrenergic receptors at the urethral sphincter, which can enhance urethral reflex activity during stress conditions and increase baseline urethral pressure, respectively.

Effect of duloxetine, a norepinephrine and serotonin reuptake inhibitor, on sneeze-induced urethral continence reflex in rats

We investigated the effect of duloxetine, a norepinephrine (NE) and serotonin (5-HT) reuptake inhibitor, on the neurally evoked urethral continence reflex induced by sneezing in rats. To clarify the role of noradrenergic and serotonergic mechanisms in preventing stress urinary incontinence (SUI) during sneezing, we examined the effect of duloxetine followed by intrathecal (it) methiothepin maleate (5-HT receptor and alpha1-adrenoceptor antagonist) or terazosin or idazoxan (selective alpha1- and alpha2-adrenoceptor antagonists, respectively). Amplitude of urethral pressure responses during sneezing (A-URS), urethral baseline pressure (UBP) at the midurethra, and sneeze-induced leak point pressure (S-LPP) were measured in normal adult female rats and rats with SUI induced by vaginal distension (VD). In normal and VD rats, intravenous application of duloxetine (1 mg/kg) increased A-URS by 35% and 34% and UBP by 21% and 34%, respectively. Sneezing-induced fluid leakage from the urethral orifice was observed in VD rats but not in normal rats. S-LPP was increased from 39.1 to 92.2 cmH2O by intravenous duloxetine in incontinent VD rats. Duloxetine-mediated enhancement of A-URS was inhibited by terazosin but not methiothepin maleate (it). In addition, simultaneous intrathecal application of methiothepin and terazosin induced a reduction in A-URS during sneezing, which was not increased by intravenous duloxetine. However, the reduced A-URS after intrathecal application of methiothepin and terazosin returned to the control level when duloxetine (iv) was applied after intrathecal idazoxan administration. These results indicate that duloxetine can prevent SUI by facilitating noradrenergic and serotonergic systems in the spinal cord to enhance the sneeze-induced active urethral closure mechanism.

Suppression of detrusor overactivity in rats with bladder outlet obstruction by a type 4 phosphodiesterase inhibitor.

To investigate the effects of a selective type 4 cyclic nucleotide phosphodiesterase (PDE4) inhibitor, IC486051, on bladder activity in normal rats and those with and bladder outlet obstruction (BOO), as inhibition of PDE4 leads to elevation of intracellular cAMP levels and relaxation of smooth muscle.

The effects of a type 4 phosphodiesterase inhibitor and the muscarinic cholinergic antagonist tolterodine tartrate on detrusor overactivity in female rats with bladder outlet obstruction

To investigate the effects of the selective phosphodiesterase (PDE) type 4 inhibitor IC485 and the widely used antimuscarinic drug tolterodine tartrate on bladder activity in rats with bladder outlet obstruction (BOO), as inhibition of PDE4 leads to elevation of intracellular cAMP levels and relaxation of smooth muscle.

Pathological and biochemical outcomes after radical prostatectomy in men with low-risk prostate cancer meeting the Prostate Cancer International: Active Surveillance criteria.

Active surveillance has been widely accepted as a treatment tool for low‐risk prostate cancer, and use of the Prostate Cancer Research International: Active Surveillance (PRIAS) criteria can select smaller and less aggressive tumours in low‐risk disease. The study shows the pathological outcomes of radical prostatectomy for patients with low‐risk disease who met the PRIAS criteria. It found that ∼20% had unfavourable pathological features and only 30% satisfied insignificant cancer criteria with pT2 stage, a Gleason score ≤6 and tumour volume <2.5 mL. It concludes that close follow‐up including repeat biopsy or MRI is necessary to minimize unexpected progression of disease.

Single-center Outcome of Laparoscopic Unilateral Adrenalectomy for Patients With Primary Aldosteronism: Lateralizing Disease Using Results of Adrenal Venous Sampling

OBJECTIVES To assess the clinical effect of the universal use of adrenal venous sampling and to investigate the characteristics of patients with primary aldosteronism undergoing laparoscopic adrenalectomy at a single tertiary care center. METHODS After the screening examination, confirmatory test, and computed tomography (CT) scans were completed, all patients with biochemically diagnosed hyperaldosteronism underwent adrenal venous sampling to differentiate unilateral disease from bilateral idiopathic hyperaldosteronism. A total of 174 consecutive patients with unilateral aldosterone excess underwent unilateral laparoscopic adrenalectomy. RESULTS The surgically treated cohort was divided into 3 groups according to the CT findings. A total of 129 patients (74.1%) had findings associated with CT-positive macroadenoma (type 1A) and 42 (24.1%) with CT-negative microadenoma (type 2A). Only 3 patients (1.8%) had adrenocortical hyperplasia (type 3). The aldosterone level was normalized in all but 2 patients (98.9%), and the number of antihypertensive agents was significantly reduced within 1 month after adrenalectomy. Of the 174 patients, 155 (89.1%) showed resolution or improvement of hypertension. CONCLUSIONS The routine use of adrenal venous sampling could adequately detect lateralization in patients with unilateral aldosterone excess, which led to satisfactory short-term outcomes after surgery. The results of the present study showed that nearly one fourth of patients with the unilateral form had a CT-negative aldosterone-producing microadenoma.

Somatosensory evoked magnetic fields elicited by dorsal penile, posterior tibial and median nerve stimulation

The aim of this study is to localize the primary sensory cortex of urogenital organs in the human brain. Using a newly developed MRI-linked magnetoencephalography system, we measured somatosensory evoked magnetic fields (SEFs) for unilateral stimuli on the dorsal penile nerve (DPN), posterior tibial nerve (PTN) and median nerve (MN). In five healthy male subjects, SEFs were clearly observed. Peak latency of the first cortical components were 63.8 +/- 9.2 ms for DPN, 39.8 +/- 3.0 ms for PTN and 20.7 +/- 0.7 ms for MN stimuli. Peak amplitude of the first cortical components were 63.1 +/- 10.8 fT for DPN, 160.2 +/- 50.1 fT for PTN and 335.2 +/- 70.3 fT for MN stimuli. Isofield map for the peak latencies indicated a single dipolar pattern for DPN as well as for PTN and MN stimuli. Using a single current dipole model, all SEF sources were localized on the contralateral central sulcus to the stimuli, indicating the primary sensory cortex. The DPN sources were localized on the interhemispheric surfaces, corresponding to previous speculations by direct cerebral stimulation. This non-invasive SEF technique promises further brain functional mapping for the urogenital organs.

Laparoscopic simultaneous bilateral adrenalectomy: assessment of feasibility and potential indications.

Objective:  To report a single‐center experience with laparoscopic simultaneous bilateral adrenalectomy (LSBA) and to evaluate its safety, surgical outcomes, and potential indications of the procedure.

Role of spinal serotonergic pathways in sneeze-induced urethral continence reflex in rats

To clarify the role of spinal serotonergic mechanisms in preventing stress urinary incontinence (SUI) during sneezing, we investigated the effect of intrathecal (it) application of 8-OH-DPAT (a 5-HT(1A) agonist), mCPP (a 5-HT(2B/2C) agonist), and fluoxetine (a serotonin reuptake inhibitor) using a rat model that can examine the neurally evoked continence reflex during sneezing. Amplitudes of urethral pressure responses during sneezing (A-URS), urethral baseline pressure (UBP) at the midurethra, and sneeze-induced leak point pressure (S-LPP) were measured in normal female adult rats and rats with SUI induced by vaginal distention (VD). In normal rats, 8-OH-DPAT decreased A-URS by 48.9%, whereas mCPP increased A-URS by 33.6%. However, A-URS was not changed after fluoxetine. 8-OH-DPAT, mCPP, or fluoxetine did not alter UBP. The effect of 8-OH-DPAT and mCPP was antagonized by WAY-100635 (it), a selective 5-HT(1A) antagonist, and RS-102221 (it), a selective 5-HT(2C) antagonist, respectively. Fluoxetine in the presence of WAY-100635 did not change either A-URS or UBP, but fluoxetine in the presence of RS-102221 decreased A-URS. In VD rats, S-LPP was decreased by 14.6 cmH2O after 8-OH-DPAT, whereas it was increased by 12.8 cmH2O after mCPP. However, S-LPP was not changed after fluoxetine. These results indicate that activation of 5-HT(2C) receptors enhances the active urethral closure reflex during sneezing at the spinal level, whereas 5-HT(1A) inhibits it and that no apparent changes in the sneeze-induced continence reflex after fluoxetine treatment are due to coactivation of excitatory 5-HT(2C) receptors and inhibitory 5-HT receptors other than the 5-HT(1A) subtype. Thus, activation of excitatory 5-HT receptor subtypes such as 5-HT(2C) could be effective for the treatment of SUI.