Clinical Practice Changes After Post-Market Safety Reports on Desmopressin Orally Disintegrating Tablet in Japan: A Single-Center Retrospective Study

Background: Desmopressin orally disintegrating tablet (ODT) was approved in March 2012 in Japan; the post-market safety reports, which warned about adequate initial dose of desmopressin ODT, were published in 2014. However, it is unclear how the warning affected physician and patient behavior. Methods: We performed a retrospective single-center study to compare the clinical situation of Japanese central diabetes insipidus patients before and after the report. Results: Thirty-four patients before October 2014 and 16 patients after November 2014 switched from intranasal desmopressin to desmopressin ODT. The mean follow-up period after the switch to desmopressin ODT was 38 ± 3 months. Patients switching after November 2014 tended to have lower ratios of oral to nasal desmopressin dose at switching and 3 months after the switch (at switching; P = 0.20, 3 months; P = 0.42, respectively), and higher ratios from 6 to 12 months than before October 2014 (6 months; P = 0.93, 9 months; P = 0.52, 12 months; P = 0.80, respectively). Relative doses per initial desmopressin ODT at 9 and 12 months were significantly higher in patients switching after November 2014 than in patients switching before October 2014 (9 months; P = 0.02, 12 months; P = 0.04, respectively). Moreover, logistic regression analysis revealed that the incidence of hyponatremia was dependent on the ratio of nasal to oral desmopressin dose (P = 0.02). In addition, in four out of six patients who had serum sodium level reduced below 130 mEq/L, hyponatremia occurred within 1 month after the switch. Conclusions: A more gradual dose titration after the safety reports was performed, which involved the long-term safety of desmopressin ODT use. Vigilance of hyponatremia in early phase of desmopressin ODT use should be noted

Differentiation of human embryonic stem cells and human induced pluripotent stem cells into steroid-producing cells.

Although there have been reports of the differentiation of mesenchymal stem cells and mouse embryonic stem (ES) cells into steroid-producing cells, the differentiation of human ES/induced pluripotent stem (iPS) cells into steroid-producing cells has not been reported. The purpose of our present study was to establish a method for inducing differentiation of human ES/iPS cells into steroid-producing cells. The first approach we tried was embryoid body formation and further culture on adherent plates. The resultant differentiated cells expressed mRNA encoding the steroidogenic enzymes steroidogenic acute regulatory protein, 3β-hydroxysteroid dehydrogenase, cytochrome P450-containing enzyme (CYP)-11A1, CYP17A1, and CYP19, and secreted progesterone was detected in the cell medium. However, expression of human chorionic gonadotropin was also detected, suggesting the differentiated cells were trophoblast like. We next tried a multistep approach. As a first step, human ES/iPS cells were induced to differentiate into the mesodermal lineage. After 7 d of differentiation induced by 6-bromoindirubin-3'-oxime (a glycogen synthase kinase-3β inhibitor), the human ES/iPS cells had differentiated into fetal liver kinase-1- and platelet derived growth factor receptor-α-expressing mesodermal lineage cells. As a second step, plasmid DNA encoding steroidogenic factor-1, a master regulator of steroidogenesis, was introduced into these mesodermal cells. The forced expression of steroidogenic factor-1 and subsequent addition of 8-bromoadenosine 3',5'-cyclic monophosphate induced the mesodermal cells to differentiate into the steroidogenic cell lineage, and expression of CYP21A2 and CYP11B1, in addition to steroidogenic acute regulatory protein, 3β-hydroxysteroid dehydrogenase, CYP11A1, and CYP17A1, was detected. Moreover, secreted cortisol was detected in the medium, but human chorionic gonadotropin was not. These findings indicate that the steroid-producing cells obtained through the described multistep method are not trophoblast like; instead, they exhibit characteristics of adrenal cortical cells

Transplantation of vascular cells derived from human embryonic stem cells contributes to vascular regeneration after stroke in mice

<p>Abstract</p> <p>Background</p> <p>We previously demonstrated that vascular endothelial growth factor receptor type 2 (VEGF-R2)-positive cells induced from mouse embryonic stem (ES) cells can differentiate into both endothelial cells (ECs) and mural cells (MCs) and these vascular cells construct blood vessel structures in vitro. Recently, we have also established a method for the large-scale expansion of ECs and MCs derived from human ES cells. We examined the potential of vascular cells derived from human ES cells to contribute to vascular regeneration and to provide therapeutic benefit for the ischemic brain.</p> <p>Methods</p> <p>Phosphate buffered saline, human peripheral blood mononuclear cells (hMNCs), ECs-, MCs-, or the mixture of ECs and MCs derived from human ES cells were intra-arterially transplanted into mice after transient middle cerebral artery occlusion (MCAo).</p> <p>Results</p> <p>Transplanted ECs were successfully incorporated into host capillaries and MCs were distributed in the areas surrounding endothelial tubes. The cerebral blood flow and the vascular density in the ischemic striatum on day 28 after MCAo had significantly improved in ECs-, MCs- and ECs+MCs-transplanted mice compared to that of mice injected with saline or transplanted with hMNCs. Moreover, compared to saline-injected or hMNC-transplanted mice, significant reduction of the infarct volume and of apoptosis as well as acceleration of neurological recovery were observed on day 28 after MCAo in the cell mixture-transplanted mice.</p> <p>Conclusion</p> <p>Transplantation of ECs and MCs derived from undifferentiated human ES cells have a potential to contribute to therapeutic vascular regeneration and consequently reduction of infarct area after stroke.</p

Augmentation of Neovascularizaiton in Hindlimb Ischemia by Combined Transplantation of Human Embryonic Stem Cells-Derived Endothelial and Mural Cells

BACKGROUND: We demonstrated that mouse embryonic stem (ES) cells-derived vascular endothelial growth factor receptor-2 (VEGF-R2) positive cells could differentiate into both endothelial cells (EC) and mural cells (MC), and termed them as vascular progenitor cells (VPC). Recently, we have established a method to expand monkey and human ES cells-derived VPC with the proper differentiation stage in a large quantity. Here we investigated the therapeutic potential of human VPC-derived EC and MC for vascular regeneration. METHODS AND RESULTS: After the expansion of human VPC-derived vascular cells, we transplanted these cells to nude mice with hindlimb ischemia. The blood flow recovery and capillary density in ischemic hindlimbs were significantly improved in human VPC-derived EC-transplanted mice, compared to human peripheral and umbilical cord blood-derived endothelial progenitor cells (pEPC and uEPC) transplanted mice. The combined transplantation of human VPC-derived EC and MC synergistically improved blood flow of ischemic hindlimbs remarkably, compared to the single cell transplantations. Transplanted VPC-derived vascular cells were effectively incorporated into host circulating vessels as EC and MC to maintain long-term vascular integrity. CONCLUSIONS: Our findings suggest that the combined transplantation of human ES cells-derived EC and MC can be used as a new promising strategy for therapeutic vascular regeneration in patients with tissue ischemia

Diabetes mellitus itself increases cardio- cerebrovascular risk and renal complications in primary aldosteronism

This is a pre-copyedited, author-produced version of an article accepted for publication in The Journal of Clinical Endocrinology & Metabolism following peer review. The version of record Aya Saiki, Michio Otsuki, Daisuke Tamada, Tetsuhiro Kitamura, Iichiro Shimomura, Isao Kurihara, Takamasa Ichijo, Yoshiyu Takeda, Takuyuki Katabami, Mika Tsuiki, Norio Wada, Toshihiko Yanase, Yoshihiro Ogawa, Junji Kawashima, Masakatsu Sone, Nobuya Inagaki, Takanobu Yoshimoto, Ryuji Okamoto, Katsutoshi Takahashi, Hiroki Kobayashi, Kouichi Tamura, Kohei Kamemura, Koichi Yamamoto, Shoichiro Izawa, Miki Kakutani, Masanobu Yamada, Akiyo Tanabe, Mitsuhide Naruse, Diabetes Mellitus Itself Increases Cardio-Cerebrovascular Risk and Renal Complications in Primary Aldosteronism, The Journal of Clinical Endocrinology & Metabolism, Volume 105, Issue 7, July 2020, Pages e2531–e2537 is available online at: https://doi.org/10.1210/clinem/dgaa177

レイチョウルイ ト マウス ユライ ハイセイ カンサイボウ ニ オケル ケッカン ゼンク サイボウ ノ ブンカ ドウタイ ノ ソウイ ニ カンスル ケンキュウ

京都大学0048新制・課程博士博士(医学)甲第10730号医博第2714号新制||医||859(附属図書館)UT51-2004-G577京都大学大学院医学研究科内科系専攻(主査)教授 北 徹, 教授 中辻 憲夫, 教授 中尾 一和学位規則第4条第1項該当Doctor of Medical ScienceKyoto UniversityDA

Forkhead box A1 (FOXA1) and A2 (FOXA2) oppositely regulate human type 1 iodothyronine deiodinase gene in liver.

Type 1 iodothyronine deiodinase (D1), a selenoenzyme that catalyzes the bioactivation of thyroid hormone, is expressed mainly in the liver. Its expression and activity are modulated by several factors, but the precise mechanism of its transcriptional regulation remains unclear. In the present study, we have analyzed the promoter of human D1 gene (hDIO1) to identify factors that prevalently increase D1 activity in the human liver. Deletion and mutation analyses demonstrated that a forkhead box (FOX)A binding site and an E-box site within the region between nucleotides -187 and -132 are important for hDIO1 promoter activity in the liver. EMSA demonstrated that FOXA1 and FOXA2 specifically bind to the FOXA binding site and that upstream stimulatory factor (USF) specifically binds to the E-box element. Overexpression of FOXA2 decreased hDIO1 promoter activity, and short interfering RNA-mediated knockdown of FOXA2 increased the expression of hDIO1 mRNA. In contrast, overexpression of USF1/2 increased hDIO1 promoter activity. Short interfering RNA-mediated knockdown of FOXA1 decreased the expression of hDIO1 mRNA, but knockdown of both FOXA1 and FOXA2 restored it. The response of the hDIO1 promoter to USF was greatly attenuated in the absence of FOXA1. Taken together, these results indicate that a balance of FOXA1 and FOXA2 expression modulates hDIO1 expression in the liver

C-type natriuretic peptide (CNP)/guanylate cyclase B (GC-B) system and endothelin-1(ET-1)/ET receptor A and B system in human vasculature

To assess the physiological and clinical implications of the C-type natriuretic peptide (CNP)/guanylyl cyclase B (GC-B) system in the human vasculature, we have examined gene expressions of CNP and its receptor, GC-B, in human vascular endothelial cells (ECs) and smooth muscle cells (SMCs) and have also compared the endothelin-1(ET-1)/endothelin receptor-A (ETR-A) and endothelin receptor-B (ETR-B) system in human aortic ECs (HAECs) and vascular SMCs (HSMCs) in vitro. We also examined these gene expressions in human embryonic stem (ES)/induced pluripotent stem cell (iPS)-derived ECs and mural cells (MCs). A little but significant amount of mRNA encoding CNP was detected in both human ES-derived ECs and HAECs. A substantial amount of GC-B was expressed in both ECs (iPS-derived ECs and HAECs) and SMCs (iPS-derived MCs and HSMCs). ET-1 was expressed solely in ECs. ETR-A was expressed in SMCs, while ETR-B was expressed in ECs. These results indicate the existence of a vascular CNP/GC-B system in the human vascular wall, indicating the evidence for clinical implication of the CNP/GC-B system in concert with the ET-1/ETR-A and ETR-B system in the human vasculature.The accepted manuscript in pdf format is listed with the files at the bottom of this page. The presentation of the authors' names and (or) special characters in the title of the manuscript may differ slightly between what is listed on this page and what is listed in the pdf file of the accepted manuscript; that in the pdf file of the accepted manuscript is what was submitted by the author