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Kōbe-shi, Japan

Kamakura T.,Kyoto University | Makiyama T.,Kyoto University | Sasaki K.,Kyoto University | Yoshida Y.,Kyoto University | And 8 more authors.
Circulation Journal | Year: 2013

Background: In the short- to mid-term, cardiomyocytes generated from human-induced pluripotent stem cells (hiPSC-CMs) have been reported to be less mature than those of adult hearts. However, the maturation process in a long-term culture remains unknown. Methods and Results: A hiPSC clone generated from a healthy control was differentiated into CMs through embryoid body (EB) formation. The ultrastructural characteristics and gene expressions of spontaneously contracting EBs were analyzed through 1-year of culture after cardiac differentiation was initiated. The 14-day-old EBs contained a low number of myofibrils, which lacked alignment, and immature high-density Z-bands lacking A-, H-, I-, and Mbands. Through the long-term culture up to 180 days, the myofibrils became more tightly packed and formed parallel arrays accompanied by the appearance of mature Z-, A-, H-, and I-bands, but not M-bands. Notably, M-bands were finally detected in 360-day-old EBs. The expression levels of the M-band-specific genes in hiPSC-CMs remained lower in comparison with those in the adult heart. Immunocytochemistry indicated increasing number of MLC2v-positive/MLC2a-negative cells with decreasing number of MLC2v/MLC2a double-positive cells, indicating maturing of ventricular-type CMs. Conclusions: The structural maturation process of hiPSC-CMs through 1-year of culture revealed ultrastructural sarcomeric changes accompanied by delayed formation of M-bands. Our study provides new insight into the maturation process of hiPSC-CMs.


Ishii H.,Kyorin University | Seymour J.F.,Peter MacCallum Cancer Center | Tazawa R.,Niigata University | Inoue Y.,Clinical Research Center | And 11 more authors.
BMC Pulmonary Medicine | Year: 2014

Background: Secondary pulmonary alveolar proteinosis (sPAP) is a very rare lung disorder comprising approximately 10% of cases of acquired PAP. Hematological disorders are the most common underlying conditions of sPAP, of which 74% of cases demonstrate myelodysplastic syndrome (MDS). However, the impact of sPAP on the prognosis of underlying MDS remains unknown. The purpose of this study was to evaluate whether development of sPAP worsens the prognosis of MDS.Methods: Thirty-one cases of sPAP and underlying MDS were retrospectively classified into mild and severe cases consisting of very low-/low-risk groups and intermediate-/high-/very high-risk groups at the time of diagnosis of MDS, according to the prognostic scoring system based on the World Health Organization classification. Next, we compared the characteristics, disease duration, cumulative survival, and prognostic factors of the groups.Results: In contrast to previous reports on the prognosis of MDS, we found that the cumulative survival probability for mild MDS patients was similar to that in severe MDS patients. This is likely due to the poor prognosis of patients with mild MDS, whose 2-year survival rate was 46.2%. Notably, 75% and 62.5% of patients who died developed fatal infectious diseases and exacerbation of PAP, respectively, suggesting that the progression of PAP per se and/or PAP-associated infection contributed to poor prognosis. The use of corticosteroid therapy and a diffusing capacity of the lung for carbon monoxide of less than 44% were predictive of poor prognosis.Conclusion: Development of sPAP during the course of MDS may be an important adverse risk factor in prognosis of patients with mild MDS. © 2014 Ishii et al.; licensee BioMed Central Ltd.


Hattori N.,Ritsumeikan University | Ishihara T.,Kobe City General Hospital | Shimatsu A.,Clinical Research Institute
European Journal of Endocrinology | Year: 2016

Design: Macro TSH is a large molecular-sized TSH that is mostly a complex of TSH and IgG. Patients with macro TSH have elevated serum TSH and normal free thyroxine levels, mimicking subclinical hypothyroidism. The aim of this study was to clarify the degree of cross-reactivity of macro TSH to different commercial immunoassay systems. Methods: Screening for macro TSH was done using a polyethylene glycol (PEG) method and confirmed with gel filtration chromatography in serum samples from 1901 patients with subclinical hypothyroidism. Interference due to human anti-mouse antibodies (HAMA) was examined using HAMA blockers. TSH was measured with an enzyme immunoassay for the analysis of macro TSH. Serum TSH values in patients with macro TSH were also determined with the widely used commercial immunoassay platforms Elecsys, Centaur and Architect, and the detectability of macro TSH was compared among them. Results: Gel filtration chromatography was performed with 174 serum samples with PEG-precipitable TSH ratios >75%. Twenty serum samples were found to contain large molecular-sized TSH, five of which were due to interference by HAMA. The prevalence of macro TSH was eventually 0.79% (15/1901). Commercial immunoassay systems variably recognized macro TSH. The Architect TSH immunoassay platform was the least reactive to macro TSH, but still recognized it in 60% of macro TSH-containing serum samples. Conclusions: There were no commercial TSH immunoassay platforms that did not cross-react with macro TSH. Screening for macro TSH should be performed before hormone replacement therapy is initiated for subclinical hypothyroidism. © 2016 European Society of Endocrinology.


Hattori N.,Ritsumeikan University | Adachi T.,Kansai Medical University | Ishihara T.,Kobe City General Hospital | Shimatsu A.,Clinical Research Institute
European Journal of Endocrinology | Year: 2012

Objective: Macroprolactinaemia is a condition in which serum prolactin (PRL) consists mainly of large molecular weight PRL (macroPRL). The aim of this study was to examine the natural history of macroprolactinaemia. Design and participants: Six hundred and fifty-four hospital workers participated in this study, including 27 subjects with macroprolactinaemia and 627 controls. MacroPRL and serum PRL concentrations were evaluated over a 4-year period. The ratio of macroPRL was examined by the polyethylene glycol (PEG) method and gel filtration chromatography. IgG-bound PRL and anti-PRL autoantibodies were examined by protein G and 125I-PRL binding studies respectively. Results: Over the 4 years of the study, all 27 macroprolactinaemic subjects had persistent macroprolactinaemia without the development of raised free PRL, while none of the 627 controls developed macroprolactinaemia. The ratios of PEG-precipitable PRL and IgG-bound PRL did not significantly change, but 125I-PRL binding ratios significantly increased. As a whole, total and free serum PRL concentrations did not significantly change in subjects with macroprolactinaemia over the 4-year period. However, hyperprolactinaemia developed in five of the 18 macroprolactinaemic subjects who were initially normoprolactinaemic along with an increase in anti-PRL autoantibody titres. One of the remaining nine macroprolactinaemic subjects who were initially hyperprolactinaemic showed a decrease in serum PRL concentrations, which occurred concomitantly with a decrease in the anti-PRL autoantibody titre. Conclusions: Macroprolactinaemia may develop before middle age and is likely a chronic condition leading to hyperprolactinaemia. © 2012 European Society of Endocrinology.


Horie T.,Kyoto University | Ono K.,Kyoto University | Horiguchi M.,Kyoto University | Nishi H.,Kyoto University | And 10 more authors.
Proceedings of the National Academy of Sciences of the United States of America | Year: 2010

Sterol regulatory element-binding protein 2 (SREBP-2) transcription factor has been identified as a key protein in cholesterol metabolism through the transactivation of the LDL receptor and cholesterol biosynthesis genes. Here, we generated mice lacking microRNA (miR)-33, encoded by an intron of the Srebp2, and showed that miR-33 repressed the expression of ATP-binding cassette transporter A1 (ABCA1) protein, a key regulator of HDL synthesis by mediating cholesterol efflux from cells to apolipoprotein A (apoA)-I. In fact, peritoneal macrophages derived from miR-33-deficient mice showed a marked increase in ABCA1 levels and higher apoA-I-dependent cholesterol efflux than those from WT mice. ABCA1 protein levels in liver were also higher in miR-33-deficient mice than in WT mice. Moreover, miR-33-deficient mice had significantly higher serum HDL cholesterol levels than WT mice. These data establish a critical role for miR-33 in the regulation of ABCA1 expression and HDL biogenesis in vivo.

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