Association of TUSC1 and DPF3 gene polymorphisms with male infertility.

PURPOSE: Recently, genome-wide association studies of a Hutterite population in the USA revealed that five single nucleotide polymorphisms (SNPs) with a significant association with sperm quality and/or function in ethnically diverse men from Chicago were significantly correlated with family size. Of these, three SNPs (rs7867029, rs7174015, and rs12870438) were found to be significantly associated with the risk of azoospermia and/or oligozoospermia in a Japanese population. In this study, we investigated whether the rs10966811 (located in an intergenic region between the TUSC1 and IZUMO3 genes) and rs10129954 (located in the DPF3 gene) SNPs, previously related to family size, are associated with male infertility. In addition, we performed association analysis between rs12348 in TUSC1 and rs2772579 in IZUMO3 and male infertility. METHODS: We genotyped 145 patients with infertility (including 83 patients with azoospermia and 62 with oligozoospermia) and 713 fertile controls by PCR-RFLP technique for polymorphism. Because rs10966811 has no restriction sites, the SNP rs12376894 with strong linkage disequilibrium was selected as an alternative to rs10966811. RESULTS: There was a statistically significant association between rs12376894 proxy SNP of rs10966811 and oligozoospermia. Also, a statistically significant association between rs10129954 and azoospermia, and oligozoospermia was observed. When we assessed the relationship between rs12348 in TUSC1 and rs2772579 in IZUMO3 and male infertility traits, we found that rs12348 in TUSC1 was significantly associated with azoospermia and oligozoospermia, but rs2772579 in IZUMO3 was not associated with male infertility. CONCLUSION: We found that the polymorphisms in TUSC1 and DPF3 displayed strong associations with male infertility.

A replication study of a candidate locus for follicle-stimulating hormone levels and association analysis for semen quality traits in Japanese men.

In men, follicle-stimulating hormone (FSH) acts on the seminiferous tubules and enhances spermatogenesis. Recently, a candidate locus (rs2414095) for FSH levels was identified by a genome-wide association study (GWAS) in Chinese men. The rs2414095 single-nucleotide polymorphism (SNP) is found on the third intron of the cytochrome P450, family 19, subfamily A, peptide 1 (CYP19A1) gene encoding an aromatase. In the present study, we performed a replication study in 1687 Japanese men (901 from cohort 1 and 786 from cohort 2) to assess whether this SNP is associated with circulating FSH levels. Furthermore, we investigated whether the rs2414095 SNP is correlated with semen quality traits in 2015 Japanese men (1224 from cohort 1 and 791 from cohort 2). The rs2414095 SNP was significantly associated with circulating FSH levels (ßSTD=0.15, P=9.7 × 10-5), sperm concentration (ßSTD=0.073, P=0.032) and total sperm number (TSN) (ßSTD=0.074, P=0.027) in a combined analysis of the two Japanese male cohorts. We successfully replicated, in Japanese men, the results of the previous GWAS for the rs2414095 SNP in Chinese men, and found that the rs2414095 SNP was related with sperm production.

An association study of four candidate loci for human male fertility traits with male infertility.

STUDY QUESTION: Are the four candidate loci (rs7867029, rs7174015, rs12870438 and rs724078) for human male fertility traits, identified in a genome-wide association study (GWAS) of a Hutterite population in the USA, associated with male infertility in a Japanese population? SUMMARY ANSWER: rs7867029, rs7174015 and rs12870438 are significantly associated with the risk of male infertility in a Japanese population. WHAT IS KNOWN ALREADY: Recently, a GWAS of a Hutterite population in the USA revealed that 41 single-nucleotide polymorphisms (SNPs) were significantly correlated with family size or birth rate. Of these, four SNPs (rs7867029, rs7174015, rs12870438 and rs724078) were found to be associated with semen parameters in ethnically diverse men from Chicago. STUDY DESIGN, SIZE, DURATION: This is a case-control association study in a total of 917 Japanese subjects, including 791 fertile men, 76 patients with azoospermia and 50 patients with oligozoospermia. PARTICIPANTS/MATERIALS, SETTING, METHODS: Azoospermia was diagnosed on the basis of semen analysis (the absence of sperm in ejaculate), serum hormone levels and physical examinations. Oligozoospermia was defined as a sperm concentration of <20 × 10(6)/ml. We excluded patients with any known cause of infertility (i.e. obstructive azoospermia, varicocele, cryptorchidism, hypogonadotropic hypogonadism, karyotype abnormalities or complete deletion of AZF a, b or c). The SNPs rs7867029, rs7174015, rs12870438 and rs724078 were genotyped using DNA from peripheral blood samples and either restriction fragment length polymorphism PCR or TaqMan probes. Genetic associations between the four SNPs and male infertility were assessed using a logistic regression analysis under three different comparative models (additive, recessive or dominant). MAIN RESULTS AND THE ROLE OF CHANCE: The genotypes of all four SNPs were in Hardy-Weinberg equilibrium in the fertile controls. The SNPs rs7867029 and rs7174015 are associated with oligozoospermia [rs7867029: odds ratio (OR) = 1.70, 95% confidence interval (CI) = 1.07-2.68, P = 0.024 (log-additive); rs7174015: OR = 6.52, 95% CI = 1.57-27.10, P = 0.0099 (dominant)] and rs12870438 is associated with azoospermia (OR = 10.90, 95% CI = 2.67-44.60, P = 0.00087 (recessive)] and oligozoospermia [OR = 8.54, 95% CI = 1.52-47.90, P = 0.015 (recessive)]. The association between rs7174015 and oligozoospermia under a dominant model and between rs12870438 and azoospermia under additive and recessive models remained after correction for multiple testing. There were no associations between rs724078 and azoospermia or oligozoospermia. LIMITATIONS, REASONS FOR CAUTION: Even though the sample size of case subjects was not very large, we found that three SNPs were associated with the risk of male infertility in a Japanese population. WIDER IMPLICATIONS OF THE FINDINGS: The three infertility-associated SNPs may be contributing to a quantitative reduction in spermatogenesis. STUDY FUNDING/COMPETING INTERESTS: This study was supported in part by the Ministry of Health and Welfare of Japan (1013201) (to T.I.), Grant-in-Aids for Scientific Research (C) (23510242) (to A.Ta.) from the Japan Society for the Promotion of Science, the European Union (BMH4-CT96-0314) (to T. I.) and the Takeda Science Foundation (to A.Ta.). None of the authors has any competing interests to declare.

Lack of replication of four candidate SNPs implicated in human male fertility traits: a large-scale population-based study.

STUDY QUESTION: Are the four candidate loci (rs7867029, rs12870438, rs7174015 and rs724078) for human male fertility traits, identified in a genome-wide association study (GWAS) of a Hutterite population in the USA, associated with semen quality traits in a Japanese population? SUMMARY ANSWER: The four single nucleotide polymorphisms (SNPs) rs7867029, rs12870438, rs7174015 and rs724078 have no association with semen parameters in a meta-analysis of two Japanese male cohorts. WHAT IS KNOWN ALREADY: Four (rs7867029, rs12870438, rs7174015 and rs724078) of the SNPs associated with family size or birth rate in the GWAS of a Hutterite population in the USA were associated with semen parameters in ethnically diverse men from Chicago, USA. STUDY DESIGN, SIZE, DURATION: This is a replication study in a total of 2015 Japanese subjects, including 791 fertile men and 1224 young men from the general population. PARTICIPANTS/MATERIALS, SETTING, METHODS: We performed a replication study in two cohorts to assess whether the SNPs rs7867029, rs12870438, rs7174015 and rs724078 are associated with sperm concentration, semen volume, total sperm numbers, total motile sperm numbers or sperm motility. The rs12870438 SNP was detected by restriction fragment length polymorphism PCR while rs7174015, rs724078 and rs7867029 SNPs were genotyped using TaqMan probes. MAIN RESULTS AND THE ROLE OF CHANCE: This study indicated that none of the four SNPs rs7867029, rs12870438, rs7174015 and rs724078 displayed a significant association with semen parameters in the meta-analysis of two Japanese male cohorts. LIMITATIONS, REASONS FOR CAUTION: Only four SNPs identified in the Hutterite GWAS were examined for associations with semen quality traits in a Japanese population. In addition, the linkage disequilibrium structures around the testing markers were different between ethnic groups. WIDER IMPLICATIONS OF THE FINDINGS: Locus mapping studies using a set of tagging SNPs across the loci will be necessary in populations with larger sample sizes in order to understand the contribution of specific genes to semen quality. STUDY FUNDING/COMPETING INTEREST S: This study was supported in part by the Ministry of Health and Welfare of Japan (1013201) (to T.I.), Grant-in-Aids for Scientific Research (C) (23510242) (to A.Ta.) from the Japan Society for the Promotion of Science, the European Union (BMH4-CT96-0314) (to T.I.), and the Takeda Science Foundation (to A.Ta.). None of the authors has any competing interests to declare.

Preoperative risk stratification for cancer-specific survival of patients with upper urinary tract urothelial carcinoma treated by nephroureterectomy.

BACKGROUND: This study aimed to identify preoperative parameters for predicting cancer-specific survival (CSS) in patients with upper urinary tract urothelial carcinoma (UTUC) who have undergone radical nephroureterectomy (RNU). METHODS: The preoperative clinical and laboratory records of 357 UTUC patients who underwent RNU at three different institutions were retrospectively reviewed (256, training set; 101, test set). Univariate and multivariate analyses were performed on the training set data to identify preoperative prognostic factors, using which a risk stratification model was developed. The model was validated using test set data. RESULTS: In univariate analysis, clinical T stage classification and preoperative concentrations of hemoglobin, C-reactive protein, sodium, and albumin showed significant association with CSS. Multivariate analysis showed that low preoperative sodium and hemoglobin concentrations were significantly associated with a poor prognosis. A risk stratification model was developed using the preoperative sodium (<141 mEq/L) and hemoglobin concentrations (below normal). Three subgroups were formed depending on the presence of no (favorable group), one (intermediate), or two (poor) prognostic factors, and the 5-year CSS estimates were found to be 96.5, 75.5, and 47.0 %, respectively (P < 0.01). The risk model was significantly associated with the adverse pathological findings of stage pT3 or more and lymphovascular invasion (P = 0.005). CONCLUSION: We identified low preoperative sodium and hemoglobin concentrations as prognostic factors for patients with UTUC treated with RNU. Our risk stratification model may help physicians design a therapeutic strategy.

Y chromosome gr/gr subdeletion is associated with lower semen quality in young men from the general Japanese population but not in fertile Japanese Men.

Several case-control studies have investigated whether Y chromosome haplogroups or deletions are associated with spermatogenic failure. However, the relationships between Y chromosome haplogroups or deletions and semen quality in general population have not been elucidated. In this study, we assessed relationships between Y chromosome haplogroups or deletions and semen parameters in 791 fertile Japanese men and 1221 young men from the general Japanese population. We found that the haplogroup D2 (M55 lineage) was significantly associated with lower semen parameters, especially total motile sperm count (P = 0.00051, beta = -0.097), in men from the general population but not in fertile men. In addition, we found that the gr/gr subdeletion was associated with semen quality and in particular, strongly associated with decreased sperm motility (P = 0.00041, beta = -3.14) and total motile sperm count (P = 0.00031, beta = -0.099) in men from the general population but not in fertile men. The combined analysis of fertile Japanese men and men from the general Japanese population showed that the haplogroup D2 (M55 lineage) and the gr/gr subdeletion were strongly associated with reduced sperm motility (P = 0.00056, beta = -2.71, and P = 7.7 × 10(-5), beta = -3.05, respectively) and that haplogroup O2b1 was strongly associated with elevated sperm motility (P = 0.00089, beta = 2.94). These observations add further support for the view that the gr/gr subdeletion diminishes sperm motility that consequently may result in male infertility.

[A case of giant testicular tumor in a schizophrenic patient].

A 55-year-old man with schizophrenia presented with right scrotal enlargement. Clinical examination revealed a right adult -head-sized testicular tumor, multiple lymph node metastasis with marked elevation of serum lactic dehydrogenase (LDH) and ß -human chorionic gonadotropin (ß -HCG). Right high orchiectomy followed by chemotherapy with bleomysin, etoposide and cisplatin (BEP) for 4 cycles was performed. The tumor weighed 5,270 g, and was pathologically diagnosed as seminoma. After the treatment, the tumor markers were normalized, but he refused to undergo retroperitoneal lymph node dissection.

[Case of Behcet's disease diagnosed by bilateral epididymitis].

A 24-year-old man visited our emergency room with testicular pain and left shoulder pain, and was admitted to our hospital for diagnosis of bilateral epididymitis. Antibiotics and anti-inflammatory medication were started, but the symptoms did not improve. During hospitalization, ulcerous lesions, erythema nodosum, folliculitis-like exanthema and multiple oral aphtha appeared. Then, we consulted the department of dermatology. As he had a combination of arthritis and epididymitis, he was diagnosed with the abortive form of Behcet's disease. After diagnosis, we began administering colchicine. Then, all symptoms improved in a few days, and he has remained free of the disease after the discontinuation of colchicine.

[Castleman's disease of the kidney: a case report].

Castleman's disease is a rare disorder characterized by benign proliferation of lymphoid tissue. A 61-year-old man was referred to our department for a renal mass incidentally detected by magnetic resonance imaging. Computed tomography showed a 18 × 20 × 14 mm mass in the upper pole of the right kidney, which enhanced at the early phase and washed out at the late phase. On the diagnosis of renal cell carcinoma, laparoscopic partial nephrectomy was performed. Pathological examinations revealed a hyaline-vascular type of Castleman's disease confined to the kidney.

[Successful treatment of spontaneous rupture of pheochromocytoma with laparoscopic adrenalectomy: a case report].

A 46-year-old man had sudden onset of severe left hypochondrial pain and went into shock following hospitalization. Computed tomography, echocardiography, and endocrinological tests revealed spontaneous rupture of a pheochromocytoma associated with catecholamine cardiomyopathy. After he underwent conservative management with fluid replacement, his blood pressure stabilized and cardiac function improved. Twenty-two days later, he was referred to our hospital. After admission, as his circulatory dynamics was stable, we performed elective laparoscopic left adrenalectomy. He was discharged on the tenth postoperative day. Spontaneous rupture of a pheochromocytoma is very rare : laparoscopic surgery for this condition has been reported only on 2 previous occasions worldwide.

[Poor outcome due to spontaneous rupture of renal cell carcinoma : a case report].

A 54-year-old man experienced sudden onset of severe pain in his left lower back. Because the pain persisted for two days, he visited our hospital. Abdominal computed tomography revealed a hematoma around his left kidney, which was diagnosed as spontaneous rupture of a renal tumor. He was immediately admitted and was scheduled to undergo elective surgery. However, because his hemoglobin level decreased suddenly on Day 9 and rebleeding from the renal tumor was suspected, we chose to perform left radical nephrectomy following emergency transcatheter arterial embolization of his left renal artery. The resected specimen was a solid brownish-red mass surrounded by hematoma, and the histopathological findings revealed that it was a renal clear cell carcinoma (G3＞G2, INFα, pT1b, and pV0). On Day 51, he was found to have a local recurrence of carcinoma, and died five months after surgery. Spontaneous rupture of renal cell carcinoma is relatively rare : this is the 104th report on surgery for this carcinoma in Japan.

[A case of bladder cancer with metastasis to the bone of the hand].

Metastasis to the bone of the hand is rare. In addition, metastasis to the bone of the hand from bladder cancer is extremely rare. We herein report a case of distal phalanx metastasis from bladder cancer. A 64- year-old man who was diagnosed with bladder cancer (cT2bN0M0) received total cystectomy (pT3bN2). Two months after the surgery, a roentgenogram revealed lung metastasis. Then we administered 2 cycles of chemotherapy using gemcitabine and cisplatin. Computed tomography revealed a partial response. However, several months after chemotherapy, we noted that his left ring finger was swollen and showed erythema. We made a diagnosis of metastasis to the distal phalanx of the left ring finger and amputated the finger. Pathological findings showed no conflict with metastasis from bladder cancer. Postoperative course was good, but he died about three months after the diagnosis of metastasis.

[Primary adenocarcinoma of the seminal vesicle difficult to differentiate from rectal carcinoma : a case report].

A 78-year-old man with urinary retention visited our hospital in June 2011. He presented with intestinal bleeding one month later and was admitted immediately. Contrast enhancement computed tomography revealed a lobulated intrapelvic tumor and liver metastasis. The prostate specific antigen level was normal, but his carcinoembryonic antigen level was elevated. Based on these results, his tumor was diagnosed as rectal carcinoma. On day 26, total pelvic exenteration and pelvic lymph node dissection to arrest bleeding were performed. We created an ileal conduit for urinary diversion and performed a sigmoid colostomy. The final histopathological assessment confirmed that he had primary adenocarcinoma of the seminal vesicle. The patient received the best supportive care because he rejected postoperative adjuvant chemotherapy and hormonal therapy. He died three months postoperatively. Primary adenocarcinoma of the seminal vesicle is very rare. The prognosis for this carcinoma is poor.

[IgG4-related idiopathic segmental ureteritis which was difficult to distinguish from ureteral cancer: a case report].

A 79-year-old woman was admitted with a chief complaint of gross hematuria, pollakisuria, lower abdominal pain. Urine cytology, intravenous pyelography, and cystoscopy were performed but showed no abnormal findings. About 6 months later, abdominal computed tomography (CT) revealed a 5cm long segment of ureteral narrowing with wall thickening, hydronephrosis, para-aortic lymph node swelling. Retrogradepyelography (RP) was done. Pelvic urine cytology was class IV. Under the clinical diagnosis of ureteral carcinoma and lymph node metastasis, a left nephroureterectomy with lymph node dissection was performed. The pathological diagnosis was IgG4-related idiopathic segmental ureteritis.

[Endocervicosis/endosalpingiosis of the bladder: a case report].

Endocervicosis/ endosalpingiosis of the bladder is a very rare benign condition, with a total of 34 documented cases found in the literature. Herein, we report a 35-year-old woman with suspected bladder cancer following a cystoscopic examination, which revealed a mass on the right posterior bladder wall. Transurethral resection of the lesion was performed, and both pathological and immunohistochemical findings confirmed a diagnosis of endocervicosis/ endosalpingiosis. Recurrence was seen 6 months later in a follow-up cystoscopic examination and a partial cystectomy was performed. Since endocervicosis/ endosalpingiosis tends to recur, a partial cystectomy is the best therapeutic option for patients with persistent symptoms or recurrence.

[A case of metabolic acidosis and tetany after ileal neobladder replacement].

A 64-year-old man visited our hospital with the complaint of macrohematuria and bilateral hydronephrosis. He had undergone total cystectomy and ileal neobladder replacement under the diagnosis of muscle invasive bladder cancer (cT2bN0M0). Tetany due to hyperventilation syndrome appeared on postoperative day 42. Blood gas analysis showed metabolic acidosis (pH 7.260, pO2 148.1 mmHg, pCO2 20.7 mmHg, HCO3 9.1 mmHg, BE -16.0 mmol/l). His condition was immediately improved after a urethral catheter was placed and sodium bicarbonate was administered. After re-removal of the urethral catheter, however, hyperventilation syndrome recurred. He was discharged from the hospital with the urethral catheter placed.

[Panhypopituitarism caused by an intrasellar cystic mass in late-onset hypogonadism clinic].

A 74-year-old man who was referred to our late onset hypogonadism clinic presented with sweating and loss of appetite. His aging males' symptoms (AMS) and international index of erectile function (IIEF-5) scores were 59 and 2, respectively. His hormonal examination revealed extremely low free testosterone values. The patient was started on androgen replacement therapy, but his symptoms did not improve. Additional hormonal examinations revealed low values for other anterior pituitary hormones. Magnetic resonance imaging revealed an intrasellar cystic mass with suprasellar extension. We considered this mass caused hypothalamic hypopituitarism. A load test for anterior pituitary hormones revealed panhypogonadism. His symptoms improved after administration of adrenal and thyroid hormones and androgen. Five months after start of drug administration, his AMS score improved to 29, but IIEF-5 score showed little change. As a matter of course, not only androgen but all pituitary-related hormones are needed for hypopituitarism patients.

Climatic influence on the reproductive characteristics of Japanese males.

We previously performed a survey of the sperm characteristics of the partners of pregnant women in four cities in Japan. In the present study, we analyzed the sperm characteristics of these subjects and the correlations between these sperm characteristics and climatic changes or Y chromosome haplogroups. Our results showed that more haplogroup D2a1 males than O2b1 males were born in the first half of the year (January to June), whereas more O2b1 males were born in the last half of the year (July to December) (P<0.05). This was agreed and correlated with the seasonal variations in their mean sperm concentrations. The haplogroup C, D* and D2a1 males displayed lower sperm concentrations from March to May, followed by an increase in their sperm concentrations starting in June or July, while the O2b1 males displayed higher sperm concentrations in the first half of the year followed by a sudden decrease from July to August (P<0.05). We hypothesize that the Japanese climate has different effects on the sperm characteristics and reproductive seasonality of males from different lineages; and therefore, has influenced the modern population of Japan.

[Three cases of penile self-mutilation].

Penile self-mutilation is rare. We report our experience with 3 cases of penile self-amputation. One case was in a 48-year-old man who had no background history of mental disorders. He amputated his penis using a utility knife. He was referred to our hospital and underwent suture of the wound, but he took his own life one week after the surgery. Another case was in a 42-year-old man who had intelligence impairment. He amputated his penis using a kitchen knife. The other case was in a 41-year-old man who had schizophrenia. He amputated his penis using a piece of broken glass.

[A case of solitary epididymis rupture after blunt scrotal trauma].

Blunt trauma of the scrotum is sometimes associated with severe injuries such as testis rupture. However, there are few reports of traumatic rupture of the epididymis with blunt scrotal trauma. In addition, severe epididymis injuries after scrotal trauma are always associated with severe testis trauma. We experienced a case of solitary rupture of the left epididymis that occurred in a traffic accident. We report herein such a case and review the literature. To our knowledge, this case is the 4th case of solitary epididymis rupture by blunt scrotal trauma.