Feasibility of metronomic chemotherapy with tegafur-uracil, cisplatin, and dexamethasone for docetaxel-refractory prostate cancer.

Objectives: To evaluate the efficacy of tegafur-uracil (UFT), a prodrug of 5-fluorouracil, plus cisplatin and dexamethasone in patients with docetaxel-refractory prostate cancers. Methods: Twenty-five patients with docetaxel-refractory prostate cancer were administered oral UFT plus intravenous cisplatin (UFT-P therapy) and dexamethasone. Treatment responses were assessed monthly via prostate-specific antigen (PSA) level measurements. Treatment-related adverse events and overall survival were also assessed. Results: UFT-P therapy resulted in decreased PSA levels in 14 (56%) patients and increased PSA levels in 11 (44%). In patients with increased PSA levels, 7 (64%) of the 11 patients displayed decreased PSA doubling times. The UFT-P therapy response rate was 84% (21/25 patients). Imaging studies revealed that tumor shrinkage during UFT-P therapy occurred in 1 patient in whom bilateral hydronephrosis caused by lymph node metastasis improved. The median survival time from docetaxel initiation was 36 months. In UFT-P-treated patients, the median PSA progression and overall survival times were 6 and 14 months, respectively. UFT-P treatment-related adverse events were mild diarrhea, general fatigue, and anorexia. Treatment was not discontinued for any of the patients. UFT-P therapy did not cause serious hepatic or renal dysfunction or pancytopenia. Conclusions: UFT-P therapy is a safe and effective treatment for patients with docetaxel-refractory prostate cancer, although large-scale, multicenter, prospective studies are needed to validate these findings.

Cyclooxygenase-2 protects germ cells against spermatogenesis disturbance in experimental cryptorchidism model mice.

The role of cyclooxygenases (COX) in the male reproductive organ remains unclear. However, there are some reports suggesting that COX-2 might have an effect on spermatogenesis or steroidogenesis. In this study, we examined whether COX-2 was induced in impaired testes, and we also investigated the possible role of COX in the testes using experimental cryptorchidism model mice. Five-week-old male mice underwent an operation to induce unilateral cryptorchidism via an abdominal incision and suturing of the left testes to the lateral abdominal wall, and they were then divided into 3 groups: 1) experimental cryptorchidism plus SC560 (selective COX-1 inhibitor) administration; 2) experimental cryptorchidism plus NS398 (selective COX-2 inhibitor) administration; 3) and experimental cryptorchidism alone. The expression levels of COX-1 and COX-2 were determined by immunohistologic staining and quantitative reverse transcription-polymerase chain reaction (RT-PCR). The influence of COX inhibitors on the testes was assessed by measuring the concentration of serum testosterone and evaluating the seminiferous tubules according to the Johnsen score. Terminal deoxynucleotidyl transferase-mediated dUTP-biotin nick-end labeling (TUNEL) staining was also performed to detect apoptosis in the testes. Immunohistologic staining and RT-PCR revealed that the expression of COX-2 was increased in the experimental cryptorchid testes (groups 1-3). The concentration of serum testosterone was significantly lower in group 2 at 5 weeks after surgery than in the other groups. The Johnsen score of the cryptorchid testes in group 2 was significantly lower than those in other groups at 5 weeks after surgery. TUNEL staining revealed that the number of apoptotic cells was significantly increased in group 2 compared with the other groups. However, the COX-1 inhibitor did not appear to affect spermatogenesis in the experimental cryptorchid testes. These results suggest that the COX-2 inhibitor provoked testicular damage in experimental cryptorchidism by inducing germ cell apoptosis. The expression of COX-2 might be induced to protect germ cells from heat stress caused by experimental cryptorchidism.

Loxoprofen sodium treatment for elderly men with refractory nocturia: effect on night-time urine production.

We evaluated the efficacy of loxoprofen sodium for refractory nocturia. Twelve men (mean age, 75.1 +/- 5.7) with nocturia were enrolled in this study. All patients received 60 mg loxoprofen sodium prior to sleeping at night for 14 days. Nine of 12 patients (75%) felt more satisfaction than previous treatments. Patients were grouped into a loxoprofen sodium-effective (n = 7) and ineffective groups (n = 5) based on the results of the frequency-volume chart. In the effective group, interestingly, night-time urine volume showed significant reduction (P < 0.05). On the other hand, the average single voided volume at night and 24-h urine volume showed no significant change. There was a statistically significant difference in the night-time urine volume after treatment between groups (P < 0.01). Loxoprofen sodium is an effective treatment for some patients with refractory nocturia. The main effect mechanism of loxoprofen sodium may involve the reduction of night-time urine production.

Azoospermia with Klippel-Feil anomaly.

We present a case of azoospermia with Klippel-Feil anomaly. Klippel-Feil anomaly is characterized by the fusion of two or more cervical vertebrae and a short neck, limitation of head movement, and low posterior hairline. The association of this anomaly with MURCS (Müllerian-duct aplasia, renal agenesis, and cervical somite dysplasia) is traditionally regarded as being limited to females, but it has been hypothesized that men displaying the combination of azoospermia, segmentation abnormalities of the cervicothoracic spine, and renal anomalies have a male analog of MURCS. Here we describe the first case of MURCS in a male in whom testicular sperm extraction was carried out.

Role of nitric oxide/cyclic GMP pathway in regulating spontaneous excitations in detrusor smooth muscle of the guinea-pig bladder.

AIMS: The role of nitric oxide (NO)/cyclic GMP (cGMP) pathway in regulating detrusor smooth muscle (DSM) function is still to be elucidated. We have investigated the effects of NO donors and phosphodiesterase-5 (PDE5) inhibition on spontaneous excitations in DSM. METHODS: Multibundle DSM of the guinea-pig bladder generated spontaneous phasic contractions. The effects of sodium nitroprusside (SNP) and 3-morpholinosydnonimine (SIN-1), NO donors, 8-bromo-cyclicGMP (8-Br-cGMP), a cell-permeable cGMP analog and sildenafil, a PDE5 inhibitor on these contractions were examined. The effects of these agents on spontaneous action potentials were also studied using intracellular recording technique in single-bundle DSM. RESULTS: SNP and SIN-1 enhanced spontaneous contractions in multibundle DSM and increased the frequency of spontaneous action potentials in single-bundle DSM. These excitatory effects were not antagonized by 1H-[1,2,4]oxadiazolo[4,3-a]quinoxalin-1-one (ODQ), an inhibitor for guanylate cyclase, but were attenuated by cyclopiazonic acid (CPA), an inhibitor of sarco- and endoplasmic Ca ATPase (SERCA). 8-Br-cGMP invariably suppressed spontaneous contractility. Sildenafil inhibited spontaneous contractions in about 65% of multibundle DSM but had no effects on the remainder. In single-bundle DSM, sildenafil had no effect on spontaneous action potentials. CONCLUSIONS: These results suggested that NO caused an enhancement of spontaneous contractions in DSM by accelerating spontaneous action potentials through cGMP-independent mechanisms, which may involve the Ca release from intracellular stores, whilst cGMP itself has inhibitory effects on DSM contractility. Sildenafil may indirectly suppress DSM contractility by diminishing synchronicity between functional units of DSM bundles without inhibiting excitability of DSM themselves.

Effect of microsurgical repair of the varicocele on testicular function in adolescence and adulthood.

OBJECTIVE: Many reports on varicoceles suggest improved spermatic findings and increased pregnancy rates after correction of these lesions. Early repair during adolescence has been advocated, since clinically apparent varicoceles may affect testicular volume and sperm production in the future. We examined the efficacy of microsurgical varicocelectomy, and aimed to establish predictive parameters useful for ascertaining whether varicocele repair provides any benefits in adolescents and adults. METHODS: We carried out microsurgical varicocelectomy on nine boys and 19 men. In adolescents, catch-up growth of the testis, expressed by pre- and postoperative ratios of left and/or right testicular volume, grade and serum level of follicle-stimulating hormone (FSH) were evaluated. In adults, the ratio of sperm concentration improvement, grade, testicular volume, preoperative sperm concentration and serum FSH level were evaluated. All subjects were followed for 12 months. RESULTS: Catch-up growth was seen in 62.5% of boys. FSH level was significantly lower in boys with catch-up growth than in boys without catch-up growth. Improved sperm concentration was seen in 73.6% of adults. FSH level was significantly lower in adults with improved sperm concentration than in patients without improved sperm concentration. No correlations were seen between other parameters and catch-up growth in adolescents, or sperm concentration improvement in adults. CONCLUSIONS: Microsurgical varicocelectomy as a treatment for varicoceles with low FSH might be effective and the relevant predictive parameter for testicular development and function after surgery might be serum FSH level in both adults and adolescents.

Heterogeneous CPA sensitivity of spontaneous excitation in smooth muscle of the rabbit urethra.

1. To investigate the role of intracellular Ca stores in generating spontaneous excitation of the urethra, the effects of cyclopiazonic acid (CPA) on spontaneous contractions, transient increases in intracellular calcium concentration ([Ca2+]i; Ca transients) and depolarizations were examined in smooth muscles of the rabbit urethra. 2. In about 90% of circular smooth muscle (CSM) preparations, CPA (10 microM) increased the amplitude of spontaneous contractions by about 180% and reduced their frequency to some 25% of control values (CPA-resistant), while it readily abolished the contractions in the remaining preparations. 3. In about 70% of CSM preparations, CPA prevented the generation of spontaneous depolarizations termed slow waves, but increased their amplitude and duration in the remainder. CPA also prevented the generation of spontaneous Ca transients in about 40% of CSM preparations, while increasing their amplitude and duration in the remaining preparations. In CPA-resistant preparations that had been exposed to nicardipine (1 microM), subsequent CPA invariably abolished residual spontaneous depolarizations or Ca transients. CPA abolished caffeine-induced Ca transients in Ca-free solutions, suggesting that it effectively depleted intracellular Ca stores. 4. Longitudinal smooth muscles generated spontaneous action potentials, which had a shape distinct from that of slow waves in CSM. Spontaneous action potentials were abolished by nicardipine but not CPA. 5. Transmural nerve stimulation increased the frequency of Ca transients to give a sustained rise in [Ca2+]i, but inhibited their generation after blocking alpha-adrenoceptors with phentolamine (1 microM). These nerve-evoked responses were preserved in preparations that had been exposed to CPA. Similarly, both in control and CPA-treated CSM preparations, spontaneous Ca transients were accelerated by noradrenaline (NAd, 1 microM) and were suppressed by 3-morpholino-sydnonimine (SIN-1, 10 microM), a nitric oxide (NO) donor. 6. In conclusion, CSM of the urethra generates spontaneous activity, which depends on Ca release from intracellular Ca stores. However, after blocking this primary pacemaking mechanism, L-type Ca channel-dependent action potentials may drive CSM. Irrespective of the origin of pacemaking, neurally-released NAd and NO are capable of modulating spontaneous excitation.

The role of Ni(2+)-sensitive T-type Ca(2+) channels in the regulation of spontaneous excitation in detrusor smooth muscles of the guinea-pig bladder.

OBJECTIVE: To explore the role of Ni(2+)-sensitive T-type Ca(2+) channels in the generation of spontaneous excitation of detrusor smooth muscles. MATERIALS AND METHODS: In isolated detrusor smooth muscle bundles of the guinea-pig bladder, changes in the membrane potential and muscle tension were measured using intracellular microelectrodes and isometric tension recording. Changes in the intracellular Ca(2+) concentration were recorded from bundles loaded with the fluorescent dye fura-PE3. RESULTS: Detrusor smooth muscles had two types of spontaneous electrical activity, i.e. individual and bursting action potentials. Ni(2+) (30 microM), a blocker for T-type Ca(2+) channels, reduced the frequency of individual action potentials without changing their amplitude. Higher concentrations of Ni(2+) (100-300 microM) converted individual action potentials into the bursts, as did apamin (0.1 microM), a blocker of small-conductance Ca(2+)-activated K(+) channels (SK). They also increased the amplitudes of spontaneous Ca(2+) transients and corresponding contractions whilst reducing their frequencies. In preparations which generated bursting action potentials, nifedipine (1 microm) converted action potentials into spontaneous transient depolarizations (STDs), and subsequent applications of Ni(2+) (100 microm) abolished STDs. Gadolinium (100 microM) and SKF96365 (10 microM), blockers for nonselective cation channels, and niflumic acid (100 microm), a blocker for Ca(2+)-activated Cl- channels, had no effect on either the amplitude or frequency of spontaneous action potentials. CONCLUSIONS: The T-type Ca(2+) channel may have dual roles in generating spontaneous excitation in detrusor smooth muscles. First, activity of these channels may account for the preceding depolarizations that lead to action potentials. Second, Ca(2+) influx through T-type Ca(2+) channels may couple functionally to SK channels, contributing to the stability of the resting membrane potential in detrusor smooth muscle. Thus, pharmacological manipulation of T-type Ca(2+) channels in detrusor smooth muscles could be of potential value for treating the overactive bladder.

Interaction between spontaneous and neurally mediated regulation of smooth muscle tone in the rabbit corpus cavernosum.

Interaction between spontaneous and neurally mediated regulation of tone in the corpus cavernosum smooth muscle (CCSM) of the rabbit was investigated. Changes in isometric muscle tension, intracellular Ca2+ concentration ([Ca2+]i) and membrane potential were recorded. CCSM developed spontaneous contractions, transient increases in [Ca2+]i (Ca2+ transients) and depolarizations. This spontaneous activity was abolished by blocking L-type Ca2+ channels (nicardipine, 1 mum), sarcoplasmic reticulum Ca2+ pump activity (cyclopiazonic acid, 10 microm), Ca2(+)-activated Cl- channels (niflumic acid, 10 mum) or cyclooxygenase-2 (COX-2; NS-398, 1 microm). Transmural nerve stimulation initiated either alpha-adrenergic contractions or nitrergic relaxations of CCSM depending on the level of muscle tone. NS-398 suppressed nerve-evoked contractions by about 70% but caused only a 40% reduction in the corresponding Ca2+ transient. Blocking nitric oxide synthase with N(omega)-nitro-l-arginine (LNA, 100 microm) reinforced nerve-evoked Ca2+ transients by about 150%, whilst increasing the corresponding Ca2+ transients by only 20%. In CCSM preparations that had been pre-contracted with either noradrenaline (0.3 microm) or prostaglandin F(2alpha) (0.1 microm), nerve stimulation inhibited about 70% of the contraction and caused only a 20% decrease in [Ca2+]i. Fluorescent immunohistochemistry with COX-2 antibodies and the reverse transcriptase-polymerase chain reaction (RT-PCR) method showed that the enzyme and its mRNA were highly expressed in the CCSM. These results suggest that spontaneously produced prostaglandins (PGs) not only contribute to the generation of spontaneous contractions but also facilitate nerve-evoked contractions. Conversely, spontaneously released nitric oxide (NO) suppresses excitation. Thus, interaction between spontaneous and neurally mediated regulation of CCSM tone may be fundamental to maintaining the muscle contractility. In addition, both PGs and NO appear to alter CCSM tone with only small changes in [Ca2+]i.

Role of interstitial cells and gap junctions in the transmission of spontaneous Ca2+ signals in detrusor smooth muscles of the guinea-pig urinary bladder.

To investigate mechanisms underlying the transmission of spontaneous Ca2+ signals in the bladder, changes in intracellular concentrations of Ca2+ ([Ca2+]i) were visualized in isolated detrusor smooth muscle bundles of the guinea-pig urinary bladder loaded with a fluorescent Ca2+ indicator, fura-PE3 or fluo-4. Spontaneous increases in [Ca2+]i (Ca2+ transients) preferentially originated along the boundary of muscle bundles and then spread to the other boundary (Ca2+ waves). The synchronicity of Ca2+ waves across the bundles was disrupted by 18beta-glycyrrhetinic acid (18beta-GA, 40 microm), carbenoxolone (30 microm) or 2-aminoethoxydiphenylborate (2-APB, 50-100 microm), while CPA (10 microm), ryanodine (100 microm), xestospongin C (3 microm) and U-73122 (10 microm) had no effect. Intracellular recordings using two independent microelectrodes demonstrated that 2-APB (100 microm) blocked electrical coupling between detrusor smooth muscle cells. Nifedipine (10 microm) but not nominal Ca2+-free solution diminished the synchronicity of Ca2+ waves before preventing their generation. Staining for c-kit identified interstitial cells (IC) located along both boundaries of muscle bundles. IC were also scattered amongst smooth muscle cells and were more dominantly distributed in connective tissue between muscle bundles. IC generated nifedipine-resistant spontaneous Ca2+ transients, which occurred independently of those of smooth muscles. In conclusion, the propagation of Ca2+ transients in the bladder appears to be exclusively mediated by the spread of action potentials through gap junctions being facilitated by the regenerative nature of L-type Ca2+ channels, without significant contribution of intracellular Ca2+ stores. IC in the bladder may modulate the transmission of Ca2+ transients originating from smooth muscle cells rather than being the pacemaker of spontaneous activity.

[Cellular mechanism of the generation of spontaneous activity in gastric muscle].

In gastric smooth muscles, interstitial cells of Cajal (ICC) might be the pacemaker cells of spontaneous activities since ICC are rich in mitochondria and are connected with smooth muscle cells via gap junctions. Several types of ICC are distributed widely in the stomach wall. A group of ICC distributed in the myenteric layer (ICC-MY) were the pacemaker cells of gastrointestinal smooth muscles. Pacemaker potentials were generated in ICC-MY, and the potentials were conducted to circular smooth muscles to trigger slow waves and also conducted to longitudinal muscles to form follower potentials. In circular muscle preparations, interstitial cells distributed within muscle bundles (ICC-IM) produced unitary potentials, which were conducted to circular muscles to form slow potentials by summation. In mutant mice lacking inositol trisphosphate (IP(3)) receptor, slow waves were absent in gastric smooth muscles. The generation of spontaneous activity was impaired by the inhibition of Ca(2+)-release from internal stores through IP(3) receptors, inhibition of mitochondrial Ca(2+)-handling with proton pump inhibitors, and inhibition of ATP-sensitive K(+)-channels at the mitochondrial inner membrane. These results suggested that mitochondrial Ca(2+)-handling causes the generation of spontaneous activity in pacemaker cells. Possible involvement of protein kinase C (PKC) in the Ca(2+) signaling system was also suggested.