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The pharmacokinetics of vancomycin (VAN) was retrospectively examined based on trough concentrations at large scale to identify pharmacokinetic differences between Japanese hematologic malignancy and non-malignancy patients. Data from 261 hematologic malignancy patients and 261 non-malignancy patients, including the patient's background, VAN dose, and pharmacokinetics of VAN estimated by an empirical Bayesian method, were collected and analyzed. Our results showed significantly higher values for VAN clearance and shorter elimination half-lives in patients with hematologic malignancies than non-malignancy patients. In addition, multiple regression analysis under adjusting for confounding factors by propensity score, showed that VAN clearance significantly increased in relation to hematologic malignancies. In conclusion, since in hematologic cancer patients VAN clearance is increased, the blood concentration of VAN becomes lower than expected and this may contribute to the survival of resistant bacteria when VAN is administered at low doses. These results suggest that early monitoring of VAN levels in hematologic cancer patients might be recommended to maintain desired effects without side-effects.

Vancomycin (VAN) is an anti-microbial agent used to treat a number of bacterial infections, which has a high incidence of nephrotoxicity. We examined the pharmacokinetics of VAN retrospectively based on trough concentrations at large scale and identified pharmacokinetic differences between Japanese patients having solid malignancy and non-malignancy patients. Data were analyzed from 162 solid malignancy patients and 261 non-malignancy patients, including the patient's background, VAN dose, and pharmacokinetics of VAN. We failed to detect differences in values for VAN clearance or shorter elimination half-lives between these two groups. In contrast, multiple regression analysis under adjusting for confounding factors by propensity score, showed that VAN clearance significantly increased in relation to solid malignancies in each stage. We conclude that VAN clearance in solid malignancy patients is increased and that the blood concentration of VAN becomes lower than expected. These results suggest that early monitoring of VAN levels in solid malignancy patients might be essential for maintaining desired effects without side-effects.

Resembling lipstick,Lidocaine Stick (LS) is used for pinpoint anesthesia of the skin prior to invasive procedures in dermatology or plastic surgery treatments,and has been shown to produce a quick and sustained anesthetic effect.We designed a formula and preparation method for LS,and evaluated its anesthetic effect by conducting a prick test in volunteers and a clinical study in patients undergoing pimple excision.We were able to design a surfactant-containing oily formulation for LS and a preparation method for it.The results of the prick test indicated that the anesthetic effect of a 60% LS was comparable to that of a commercially available tape preparation containing the same volume of lidocaine.In the clinical study on patients undergoing pimple excision,the 60% LS produced an anesthesia rate of 65.5%.Furthermore in a questionnaire survey,both volunteers and patients responded favorably with regard to the smoothness and ease of use of the 60% LS.

Objective: To clinically evaluate the role of intravesical bacillus Calmette-Guerin (BCG) in the management of superficial bladder cancer, focusing on dose, age, high grade/stage, and pretreatment episodes with other therapies in long-term follow-up patients. Methods: A total of 213 patients with superficial (Ta-T1) transitional cell carcinoma of the bladder received 6–8 weekly instillations of 40, 60 or 80 mg of Tokyo strain BCG. Further 6–8 monthly applications were given in some cases. Results: Recurrence-free and progression-free survival rates were compared with reference to dose, age, previous treatment, grade, stage, and high risk categories. Overall recurrence-free rates for 3, 5, and 10 years were 70.8%, 67.1%, and 57.6%, with progression-free survival rates of 94.5%, 93.6%, 90.6%, respectively. In univariate analyses, younger cases demonstrated higher recurrence-free survival rates, but without statistical significance (P = 0.1229). Recurrence-free rates were significantly higher for cases without previous intravesical treatment (P = 0.0010). There was no significant BCG dose-dependence. High grade and high stage patients were confirmed as having higher recurrence and progression rates. Conclusions: Intravesical instillation of BCG is the most effective in the long term when chosen as the initial prophylactic therapy for the prevention of recurrence in superficial bladder cancer.

Background: The prospect of long-term residence in outer space is becoming a reality. Previously we found that testosterone secretion and spermatogenesis is reduced in model mice on which the shift of body fluids in space is simulated. The present study examines the effects of the microgravity (μG) environment on steroidogenesis of Leydig cells. Methods: I-10 cells were cultured for 24 h under a simulated μG environment. Progesterone production was evaluated as steroidogenesis. Western blots of the enzyme, 3βhydroxy dehydrogenase (HSD) as well as of the transcription factors, Ad4bp/SF-1 and DAX-1, the amount of adenosine3′,5′-cyclic monophosphate (cAMP) and cell morphology were investigated. The μG environment was simulated using clinostat rotation (CR). Rotational (Cont-1) and stationary (Cont-2) controls always received a regular gravity effect with and without rotatory motion, respectively. Results: Progesterone levels in cells under CR were significantly increased compared with those of both controls. Increased progesterone production was not related to the expression of either of the transcription factors or the enzyme. Although the cytoplasm expanded, the amount of cAMP produced under CR did not significantly differ from that produced under both control environments. Conclusions: Our findings showed that I-10 cells produced more progesterone under a μG, than under control environments. Since the amounts of 3βHSD, Ad4bp/SF-1, DAX-1 and cAMP were not altered, the increase in steroid production under CR might be due to the expansion of cytoplasm, where steroidogenesis occurs. Steroidogenesis should be investigated in more detail to predict the effects of outer space on humans.

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.

We carried out clinostat and parabolic flight experiments to examine the effects of a microgravity (,uG) environment on human sperm motility. Semen samples were obtained manually from 18 healthy men (aged 27.4 ± 5.4 years) who had given their informed consent. In dinostat experiments, samples that were left stationary were used as a stationary control. Samples rotated vertically and horizontally were used as a rotation control and a dinostat rotation, respectively. In parabolic flight experiments using a jet plane, sperm motility was compared for each parameter at μG, 1G and 2G. The state of 1G during the flight was used as a control. Sperm motility was determined using an automatic motility analyzer HT-M2030 in a microgravity environment. All parameters of sperm motility tended to be lower in dinostat rotation compared with rotation control at both low-speed and high-speed, but the differences were not statistically significant. In parabolic flight, sperm motility and parameters of linear movement were decreased (P< 0.05). There was no significant difference between μG and 2G, but sperm motility was significantly decreased at μG than at 1G. Our findings suggest that sperm motility is reduced under μG.

We transferred the adventitious gene pCAGGS-lacZ to mouse testes with the use of a square-wave electroporator and investigated the efficiency of gene transfer (GT) and the influence of the procedure on testicular damage and spermatogenesis. Mice were divided into 5 groups: (1-2) injection of gene/phosphate-buffered saline (PBS) into the interstitial space followed by electroporation (EP), (3) EP alone, (4-5) injection of gene/PBS without EP. The presence of the lacZ gene was determined by X-gal (5-bromo-4-chloro-3-indolyl-beta-D-galactopyranoside) staining and the polymerase chain reaction (PCR). The influence of transfer on spermatogenesis was assessed by evaluating the seminiferous tubules according to the Johnsen score (JS). TdT-mediated dUTP-biotin nick end-labeling (TUNEL) staining was performed for the detection of apoptosis in the testes to evaluate the testicular damage caused by GT, and fertilization ability was assessed by mating male mice from each group with normal female mice at 1, 2, 4, 6, and 8 weeks after the procedure. LacZ expression was detected by X-gal staining and PCR for 4 weeks after GT in group 1. But in group 4, LacZ expression was not detected for all times. In groups 1 through 3, the JSs decreased gradually until 4 weeks and recovered at 6 and 8 weeks after GT. The JSs were significantly decreased at 4 weeks for groups 1 through 3 compared with groups 4 and 5. In groups 1 through 3, apoptotic cells were significantly more numerous at 1, 2, and 4 weeks after the procedure, and there were significant differences in their numbers between groups 1 through 3 and groups 4 and 5 until 4 weeks after the procedure. The number of offspring did not differ significantly between all groups. These results suggest that although spermatogenic damage caused by EP could present problems, GT by EP might be effective for transfecting germ cells or somatic cells and could be applicable for in vivo gene therapy for male infertility in the future.

Homocysteine plays a key role in several pathophysiological conditions. To assess the methionine-homocysteine kinetics by stable isotope methodology, we developed a simultaneous quantification method of [(2)H(7)]methionine, [(2)H(4)]methionine, methionine, [(2)H(4)]homocysteine and homocysteine in rat plasma by gas chromatography-mass spectrometry (GC-MS). [(13)C]Methionine and [(13)C]homocysteine were used as analytical internal standards to account for losses associated with the extraction, derivatization and chromatography. For labeled and non-labeled homocysteine measurements, disulfide bonds between homocysteine and other thiols or proteins were reduced by dithiothreitol. The reduced homocysteine and methionine species were purified by cation-exchange chromatography and derivatized with isobutyl chlorocarbonate in water-ethanol-pyridine. Quantification was carried out by selected ion monitoring of the molecular-related ions of N(O,S)-isobutyloxycarbonyl ethyl ester derivatives on the chemical ionization mode. The intra- and inter-day precision of the assay was less than 6% for all labeled and non-labeled methionine and homocysteine species. The method is sensitive enough to determine pharmacokinetics of labeled methionine and homocysteine.

To clinically evaluate the role of intravesical bacillus Calmette-Guérin (BCG) in the management of superficial bladder cancer, focusing on dose, age, high grade/stage, and pretreatment episodes with other therapies in long-term follow-up patients.A total of 213 patients with superficial (Ta-T1) transitional cell carcinoma of the bladder received 6-8 weekly instillations of 40, 60 or 80 mg of Tokyo strain BCG. Further 6-8 monthly applications were given in some cases.Recurrence-free and progression-free survival rates were compared with reference to dose, age, previous treatment, grade, stage, and high risk categories. Overall recurrence-free rates for 3, 5, and 10 years were 70.8%, 67.1%, and 57.6%, with progression-free survival rates of 94.5%, 93.6%, 90.6%, respectively. In univariate analyses, younger cases demonstrated higher recurrence-free survival rates, but without statistical significance (P = 0.1229). Recurrence-free rates were significantly higher for cases without previous intravesical treatment (P = 0.0010). There was no significant BCG dose-dependence. High grade and high stage patients were confirmed as having higher recurrence and progression rates.Intravesical instillation of BCG is the most effective in the long term when chosen as the initial prophylactic therapy for the prevention of recurrence in superficial bladder cancer.

The prospect of long-term residence in outer space is becoming a reality. Previously we found that testosterone secretion and spermatogenesis is reduced in model mice on which the shift of body fluids in space is simulated. The present study examines the effects of the microgravity (muG) environment on steroidogenesis of Leydig cells.I-10 cells were cultured for 24 h under a simulated muG environment. Progesterone production was evaluated as steroidogenesis. Western blots of the enzyme, 3betahydroxy dehydrogenase (HSD) as well as of the transcription factors, Ad4bp/SF-1 and DAX-1, the amount of adenosine3',5'-cyclic monophosphate (cAMP) and cell morphology were investigated. The muG environment was simulated using clinostat rotation (CR). Rotational (Cont-1) and stationary (Cont-2) controls always received a regular gravity effect with and without rotatory motion, respectively.Progesterone levels in cells under CR were significantly increased compared with those of both controls. Increased progesterone production was not related to the expression of either of the transcription factors or the enzyme. Although the cytoplasm expanded, the amount of cAMP produced under CR did not significantly differ from that produced under both control environments.Our findings showed that I-10 cells produced more progesterone under a muG, than under control environments. Since the amounts of 3betaHSD, Ad4bp/SF-1, DAX-1 and cAMP were not altered, the increase in steroid production under CR might be due to the expansion of cytoplasm, where steroidogenesis occurs. Steroidogenesis should be investigated in more detail to predict the effects of outer space on humans.

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.

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.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.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.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.

Background: We examined the expressions of Ad4BP/SF-1 and DAX-1 in primary and metastatic lesions of advanced adrenocortical carcinoma with normal hormonal findings by immunohistochemistry and discussed their usefulness as immunohistochemical markers for diagnosis. Patients and Methods: Four patients (average age 54.3 ± 3.9) with retroperitoneal and metastatic tumors were enrolled in this study. All patients had normal hormonal findings. Ad4BP/SF-1 and DAX-1 underwent immunohistochemical study using needle biopsy specimens from the retroperitoneal tumor or metastatic tumor of these patients to diagnose primary adrenocortical carcinoma. Results: Immunoreactivity for Ad4BP/SF-1 and DAX-1 indicated that it was localized exclusively in the nuclei. Ad4BP/SF-1 immunoreactivity was observed in the carcinoma cells of 2 patients, but not in the others, whereas DAX-1 immunoreactivity was observed in the carcinoma cells of all 4 patients. Conclusion: The expressions of Ad4BP/SF-1 and DAX-1 are considered essential to maintain the biological characteristics of adrenocortical cells even without abnormal hormonal findings or even after malignant transformation and metastasis. These markers are useful to distinguish other retroperitoneal tumors, especially in patients with bulky tumors, and to diagnose the metastatic site of origin as adrenocortical carcinoma in patients clinically presenting with widespread metastasis.

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 (Mullerian-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.

INTRODUCTION AND OBJECTIVES: The roles of Cyclooxygenases (COXs) in the male reproductive tract remain unclear. However, there are some reports that suggest the COX-2 might have effect on spermatogenesis or steroidogenesis. In this study, we examined whether COX-2 is induced in impaired testes and also investigated the possible role of COXs in the testes using experimental cryptorchidism model mice. METHODS: Five-week-old male mice underwent an operation to induce unilateral cryptorchidism by an abdominal incision and suturing of the left testes to the lateral abdominal wall, and were then divided into three groups: (1) experimental cryptorchidism plus SC560 (selective COX-1 inhibitor) administration; (2) experimental cryptorchidism plus NS398 (selective COX-2 inhibitor) administration; (3) experimental cryptorchidism alone. The expressions of COX-1 and COX-2 were determined by immunohistological staining and quantitative reverse transcriptional polymerase chain reaction (RT-PCR). The influence of COX inhibitors on the testis was assessed by measuring the concentration of serum testosterone and evaluating the seminiferous tubules according to the Johnsen score (JS). TdT-mediated dUTP-biotin nick end-labeling (TUNEL) staining was also performed to detect apoptosis in the testes. RESULTS: Immunohistological staining and RT-PCR revealed that the expression of COX-2 was increased in the experimental cryptorchidism testes (group 1-3). The concentration of serum testosterone was significantly lower in group 2 at 5 weeks after surgery than that in other groups; however, not in the level of castration. The Johnsen score of cryptorchidism testes in group 2 was significantly lower than that in other groups at 5 weeks after surgery. TUNEL staining revealed that the apoptotic cells were significantly increased in group 2 compared with that in other groups. Meanwhile, COX-1 inhibitor did not appear to affect spermatogenesis in the experimental cryptorchid testes. CONCLUSIONS: These results suggest that COX-2 inhibitor could reinforce testicular damage in the 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.