Thiopurines exert harmful effects on spermatogenesis in Nudt15R138C knock-in mice.

BACKGROUND: The association between thiopurine use and testicular reproductive functions remains unclear. In this study, we investigated whether thiopurines affect testicular functions based on the NUDT15 genotypes using Nudt15R138C knock-in mice. METHODS: The male Nudt15R138C knock-in mice (9-12 weeks) were treated with mercaptopurine (MP: 0.5 mg/kg/day) for 4 or 12 weeks. To examine reversibility, some mice were maintained for a further 12 weeks under MP-free condition. RESULTS: After MP treatment for 4 weeks, Nudt15R138C/R138C mice exhibited a significant reduction of testis weight compared to Nudt15+/+ mice and Nudt15+/R138C mice. The epithelial height and diameter of seminiferous tubules were significantly reduced in Nudt15R138C/R138C mice compared to Nudt15+/+ and Nudt15+/R138C mice. Apoptotic cells were significantly increased in Nudt15R138C/R138C mice, and most of apoptotic cells were spermatogonia. There were no significant changes in sperm counts and sperm morphology in MP-treated Nudt15R138C/R138C mice after 4-week MP treatment. On the other hand, after MP treatment for 12 weeks, the Nudt15+/R138C mice, but not Nudt15+/+ mice, exhibited a significant reduction in the testis weight and atrophic changes of seminiferous tubules, but these changes disappeared after 12-week rearing under MP-free condition. Despite a significant increase in abnormal sperm rate, there were no changes in the ability to conceive. No differences in serum levels of follicle-stimulating hormone or testosterone were observed between MP-treated Nudt15+/R138C and Nudt15+/+ mice after 12-week MP treatment. CONCLUSIONS: Thiopurines exert harmful effects on testicular reproductive function according to host NUDT15 genotypes.

Features of the gut prokaryotic virome of Japanese patients with Crohn's disease.

BACKGROUND/AIMS: The gut virome is mainly composed of bacteriophages and influences gut homeostasis and pathogenic conditions. In this study, we analyzed the gut prokaryotic virome in Japanese patients with Crohn's disease (CD). MATERIALS/METHODS: We collected 19 fecal samples from CD patients and 16 samples from healthy controls. The gut bacteriome was analyzed by 16S rRNA gene sequencing and the virome was profiled by shotgun metagenomic sequencing. RESULTS: Despite no differences in richness and evenness, there was a significant difference in the overall structure of the gut virome between CD patients and controls (P = 0.013). CrAssphage and Staphylococcus virus, belonging to the order Caudovirales, were dominant in the gut virome of controls and CD patients. The abundance of crAssphage was significantly greater in CD patients than controls (P = 0.021). Lactococcus, Enterococcus and Lactobacillus phages were present only in CD patients, while Xanthomonas and Escherichia phages were unique to the controls. In the gut bacteriome of CD patients, richness and evenness were significantly lower, and a significant difference in the overall structure was observed between groups (P = 0.014). The gut bacteriome of CD patients was characterized by a decrease of the genera Faecalibacterium, Roseburia, and Ruminococcus and an increase of the family Enterobacteriaceae. There were more significant correlations between viruses and bacteria in CD patients than controls. CONCLUSIONS: The gut virome of CD patients was distinct from that of healthy controls in a Japanese population. An altered gut virome may be one of the factors associated with the bacterial dysbiosis of CD.

Acquired Coagulation Factor V Inhibitor That Was Successfully Treated with Oral Corticosteroid Therapy.

Acquired coagulation factor V (FV) inhibitors are rare disorders in which antibodies against FV develop under various conditions. We herein report the case of a 71-year-old woman with FV inhibitor during radiochemotherapy for pancreatic cancer. Multiple purpuras suddenly appeared on her bilateral upper limbs with prolonged coagulation data (APTT 97.3 seconds). The FV activity was less than 3% and the FV inhibitor was positive (1.7 B.U./mL). Oral prednisolone induced a rapid normalization of the coagulation data and FV activity and a rapid disappearance of FV inhibitor within 7 days. Early diagnosis and treatment may therefore be important in cases of FV inhibitor.

Retrospective evaluation of secondary effects of hearing aids for tinnitus therapy in patients with hearing loss.

OBJECTIVE: Acoustic therapies including hearing aids and tinnitus control instruments are widely used in Japan but without high levels of evidence. The outpatient hearing aid clinic at our institution fits patients with hearing aids and instructs patients on how to use them to control tinnitus if present. In this study, we examined the effects of this approach on tinnitus. METHODS: One hundred and eleven of 138 patients who visited our hearing aid clinic from April 2016 to September 2018 purchased hearing aids after fitting. Sixty-six of these patients (31 men, 35 women; mean age 78.0 ± 8.0 years) had both hearing loss and tinnitus and were enrolled. The tinnitus was bilateral in 41 patients and unilateral in 25 (poor hearing ear, n = 16, good hearing ear, n = 9). Hearing aids were worn bilaterally by 23 patients and unilaterally by 43 (89 devices). Seventeen of the 23 patients wearing bilateral hearing aids had bilateral tinnitus and 6 had unilateral tinnitus, i.e., in 40 ears, the tinnitus side matched the hearing aid side (40 devices) and in 6 ears did not (6 devices). Twenty-four of 43 patients wearing unilateral hearing aids had bilateral tinnitus, meaning that in 24 ears the tinnitus side matched the hearing aid side (24 devices). In six of the remaining 19 cases with unilateral tinnitus, the hearing aid and tinnitus were on the same side (6 devices) and in 13 were on opposite sides (13 devices). Changes in the Tinnitus Handicap Inventory (THI), visual analog scale (VAS, for tinnitus discomfort, severity, and persistence), and Hospital Anxiety and Depression Scale scores were measured immediately before using a hearing aid and 12 months later. RESULTS: Significant effects of hearing aids on tinnitus were observed in all subjects (THI, p = 0.0000030), VAS (severity, p = 0.000000066; discomfort, p = 0.0000013). Significant effects were observed with bilateral hearing aids (THI, p = 0.0012; VAS for severity, p = 0.00069; VAS for discomfort, p = 0.00052) and with unilateral hearing aids (THI, p = 0.00055; VAS for severity, p = 0.000034; VAS for discomfort, p = 0.00007). Spearman's rank correlation coefficient showed a significant positive correlation between the THI and VAS scores (p = 0.0033). In cases of bilateral tinnitus, significant differences were observed with bilateral hearing aids (THI, p = 0.011; VAS for severity, p = 0.0019; VAS for discomfort; p = 0.020) and with unilateral hearing aids (THI, p = 0.00069; VAS for severity, p = 0.00071; VAS for discomfort, p = 0.000093). CONCLUSION: Acoustic therapy using hearing aids was effective for tinnitus. Even when bilateral, a unilateral hearing aid is able to improve tinnitus. When unilateral, the ipsilateral hearing aid is able to improve tinnitus.

Dexmedetomidine is safe and reduces the additional dose of midazolam for sedation during endoscopic retrograde cholangiopancreatography in very elderly patients.

BACKGROUND: Endoscopic retrograde cholangiopancreatography (ERCP) often requires deep sedation. Dexmedetomidine, a highly selective α2-adrenoceptor agonist with sedative activity and minimal effects on respiration, has recently been widely used among patients in the intensive care unit. However, its use in endoscopic procedures in very elderly patients is unclear. In this study, we retrospectively investigated the safety and efficacy of dexmedetomidine sedation during ERCP. METHODS: The study included 62 very elderly patients (aged over 80 years) who underwent ERCP from January 2014, with sedation involving dexmedetomidine (i.v. infusion at 3.0 µg/kg/h over 10 min followed by continuous infusion at 0.4 µg/kg/h) along with midazolam. For comparison, the study included 78 patients who underwent ERCP before January 2014, with midazolam alone. We considered additional administration of midazolam as needed to maintain a sedation level of 3-4, according to the Ramsay sedation scale. The outcome measures were amount of midazolam, adverse events associated with sedation, and hemodynamics. RESULTS: The incidence of decreased SpO2 and median dose of additional midazolam were significantly lower in the dexmedetomidine group than in the conventional group. The minimum systolic blood pressure and minimum heart rate during and after examination was significantly lower in the dexmedetomidine group than in the conventional group. However, serious acute heart failure or arrhythmia was not noted. CONCLUSIONS: Dexmedetomidine can decrease the incidence of respiratory complications and the total dose of other sedative agents. It can be used as an alternative to conventional methods with midazolam for adequate sedation during ERCP in very elderly patients.

Surgical results and psychological status in patients with intractable Ménière's disease.

OBJECTIVES: Mental disorder is often one of the causes to make treatments for Ménière's disease more difficult. The aim in the present study is to examine ratios of the neurosis and depression in patients with intractable Ménière's disease and also relationships between the ratios and surgical results after endolymphatic sac drainage with large doses of steroids. METHODS: Between 1998 and 2009, we enrolled 263 intractable Ménière's patients and divided into two groups, 207 in surgical group and 56 in non-surgical group. We used the Cornell Medical Index (CMI) and the Self-rating Depression Scale (SDS) at the diagnosis in our hospital to evaluate their psychological condition before treatments. CMI domains III and IV were defined as neurosis and SDS scores more than 40 as depression as a matter of convenience. Two years as well as seven years after surgery, patients with vertigo zero/month and hearing change>-10dB were evaluated in success group and the others in non-success group. RESULTS: Neurosis and depression were diagnosed in approximately 40% and 60%, respectively, of intractable Ménière's disease. Our results showed that surgical treatment significantly improved vertigo suppression and hearing gain in patients with no psychological symptoms compared with those exhibiting psychological symptoms both in surgical and non-surgical groups. Furthermore, surgical results in cases with mental disorder were superior to non-surgical results in cases without mental distress. CONCLUSIONS: All taken together, psychological supports could be necessary for improving results both in the surgical and non-surgical treatments for patients with intractable Ménière's disease. Some cases with intractable Ménière's disease should really require additional surgical treatments even after psychological therapies.

Efficacy of additional treatment with azathioprine in a patient with prednisolone-dependent gastric sarcoidosis.

Gastric sarcoidosis with noncaseating granuloma is rare. Although corticosteroid produces a dramatic clinical response, it is unknown whether azathioprine show efficacy in prednisolone-dependent cases. Here, we report a case of gastric sarcoidosis in a 25-year-old man with severe epigastlargia. Gastroendoscopy revealed multiple map-like ulcerations. Histological examination showed multiple noncaseating granulomatous lesions in gastric mucosa, which were incompatible with diagnoses of Crohn's disease or tuberculosis. He was started on prednisolone at 30 mg/d, and his symptoms improved within 7-d. The prednisolone was gradually tapered by 5 mg every 2-wk, but oral azathioprine at 50 mg was added after symptoms recurred at tapered dose of 10 mg. Endoscopy 4-wk later showed healing ulcers, and, lymphocytic infiltration was absent. The efficacy of additional azathioprine in gastric sarcoidosis is not well defined. Here, we report a case of prednisolone-dependent gastric sarcoidosis that improved after additional azathioprine, and also review the literature concerning the treatment, especially for prednisolone-dependent cases.