Aims To compare the occurrence of cerebral, cardiovascular, and renal events in patients with hyperuricaemia treated with febuxostat and those treated with conventional therapy with lifestyle modification. Methods and results This multicentre, prospective, randomized open-label, blinded endpoint study was done in 141 hospitals in Japan. A total of 1070 patients were included in the intention-to-treat population. Elderly patients with hyperuricaemia (serum uric acid >7.0 to ≤9.0 mg/dL) at risk for cerebral, cardiovascular, or renal disease, defined by the presence of hypertension, Type 2 diabetes, renal disease, or history of cerebral or cardiovascular disease, were randomized to febuxostat and non-febuxostat groups and were observed for 36 months. Cerebral, cardiovascular, and renal events and all deaths were defined as the primary composite event. The serum uric acid level at endpoint (withdrawal or completion of the study) in the febuxostat ( n = 537) and non-febuxostat groups ( n = 533) was 4.50 ± 1.52 and 6.76 ± 1.45 mg/dL, respectively ( P < 0.001). The primary composite event rate was significantly lower in the febuxostat group than in non-febuxostat treatment [hazard ratio (HR) 0.750, 95% confidence interval (CI) 0.592–0.950; P = 0.017] and the most frequent event was renal impairment (febuxostat group: 16.2%, non-febuxostat group: 20.5%; HR 0.745, 95% CI 0.562–0.987; P = 0.041). Conclusion Febuxostat lowers uric acid and delays the progression of renal dysfunction. Registration ClinicalTrials.gov (NCT01984749).

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This study describes the testicular levels of inhibin/activin subunits by Northern analysis and in situ hybridization and serum and testicular levels of inhibins A and B and activin A by enzyme linked immunosorbent assays (ELISA) during postnatal development in the rat. We show that serum inhibin A levels are less than 4 pg/ml throughout postnatal life. Serum inhibin B levels peak at 572 +/- 119 pg/ml (mean +/- se) at d 40 post partum (pp) before falling to 182 +/- 35 pg/ml in mature males. Serum activin A decreases from 294 +/- 29 pg/ml at d 6 to 132 +/- 27 pg/ml at maturity. Within the testis, inhibin A levels fall from 0.330 +/- 0.108 ng/g at d 15 to less than 0.004 ng/g at maturity. Inhibin B levels peak at 43.9 +/- 4.2 ng/g at d 6 before falling to 1.6 +/- 0.13 ng/g at maturity. Testicular activin A levels fall from 18.6 +/- 2.2 ng/g at d 6 to 0.094 +/- 0.013 ng/g at maturity. Northern profiles of testicular inhibin/activin subunits correlate with immunoreactive levels demonstrated by ELISA. In situ hybridization suggests that beta(A) and beta(B) subunit expression is largely restricted to the seminiferous tubule, particularly Sertoli cells, spermatogonia, and primary spermatocytes. These data support the view that inhibin B is the major inhibin in the male rat and that levels relate to Sertoli cell number and activity. Furthermore, the demonstration of high local concentrations of activin A during the period of Sertoli cell proliferation and the onset of spermatogenesis support its proposed role because a modulator of testicular development and function.

It has already been demonstrated that the Notch signaling system is essential for gametogenesis in the adult germ line of Caenorhabditis elegans. However, the role of the Notch signaling system in mammalian spermatogenesis has not been well investigated. Recently, it has been revealed that this signaling system is expressed in the mammalian testis by showing coexpression of Jagged 2 and its receptor, Notch 1, is consistent with Notch 1 being a cognate receptor for Jagged 2 in the mammalian testis. Therefore, we investigated expressions of messenger RNAs of Notch 1 and Jagged 2 in the testicular tissues of developing Sprague-Dawley rats by reverse transcription-polymerase chain reaction and Northern blot analysis, expressions of their proteins in the testicular tissues of developing rats, fertile human controls and infertile human patients with maturation arrest by immunohistochemistry, and effects of antibodies to this system by culturing rat testicular tissues with these antibodies. Transcripts of Notch 1 and Jagged 2 in the rat testis were positive throughout the examined period; these intensities became higher at day 13 after birth, coincidence with the formation of spermatocytes, and peaked at day 19 after birth. Expressions of Notch 1 and Jagged 2 were recognized at first in the perinuclear regions of spermatocytes in the rat testis as a round structure at day 19 after birth and thereafter in further differentiated germ cells as meiosis proceeded. In the adult rat testis, positive staining was present as a round structure in spermatocytes, as a typical horseshoe-shaped structure in round spermatids, and as a covering structure spreading around the nucleus of elongated spermatids, but not in spermatozoa. Notch 1 was recognized in the vacuole of the Golgi complex of primary spermatocytes and the acrosome of elongated spermatids with electron microscopy. When rat testicular tissues were cultured with anti-Notch 1 or anti-Jagged 2 antibody, round and elongated spermatids decreased after 5 and 7 days of culture, respectively, and disappeared at around 9 and 12 days of culture, respectively, with shrinkage of the diameter of seminiferous tubules. Spermatocytes, however, increased after 11 days of culture. Expressions of both proteins have been detected in the testicular tissues of human fertile controls as in the rat testicular tissues. However, Notch 1 expression has not been detected in testicular tissues of 11 patients with maturation arrest, whereas Jagged 2 expression has been recognized in all of them. In conclusion, the results presented in this study offer the possibility that Notch 1/Jagged 2 signaling system plays an important role for male germ cells to differentiate or at least to survive in the rat testis and fails to express in the testis of spermatogenic maturation arrest patients.

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