Mesenchymal stem cell (MSC) condensation contributes to membrane ossification by enhancing their osteodifferentiation. We investigated bone regeneration in rats using the human bone marrow-derived MSC-spheroids prepared by rotation culture, without synthetic or exogenous biomaterials. Bilateral calvarial defects (8 mm) were created in nude male rats; the left-sided defects were implanted with MSC-spheroids, β-tricalcium phosphate (β-TCP) granules, or β-TCP granules + MSC-spheroids, while the right-sided defects served as internal controls. Micro-computed tomography and immunohistochemical staining for osteocalcin/osteopontin indicated formation of new, full-thickness bones at the implantation sites, but not at the control sites in the MSC-spheroid group. Raman spectroscopy revealed similarity in the spectral properties of the repaired bone and native calvarial bone. Mechanical performance of the bones in the MSC-implanted group was good (50 and 60 % those of native bones, respectively). All tests showed poor bone regeneration in the β-TCP and β-TCP + MSC-spheroid groups. Thus, significant bone regeneration was achieved with MSC-spheroid implantation into bone defects, justifying further investigation.
Background: Cyanamide, an aversive drug widely used in Japan, develops ground‐glass inclusion bodies in the hepatocytes at high incidences, which may be associated with portal inflammation and fibrosis. When cyanamide‐treated alcoholics relapse drinking, the combined effect of cyanamide and alcohol produce more severe portal inflammation along with the emergence of ground‐glass inclusions. Disulfiram also causes hepatitis, but there have been no comparative studies of effects of cyanamide and disulfiram on liver function.Methods: We reviewed the laboratory data of 408 alcoholics admitted for a 3 month course of alcohol detoxification and rehabilitation. Patients tested negative for hepatitis virus markers and were diagnosed as not having cirrhosis. Among the subjects, 222 patients received cyanamide treatment (a daily dose of 70 mg) without a history of disulfiram treatment, and 186 received disulfiram (a daily dose of 200 mg) without a history of cyanamide treatment. Serum aspartate aminotransferase (AST) and alanine aminotransferase (ALT) levels obtained at 0, 4, 8, and 12 weeks of administration of each aversive drug were compared between the two alcoholic groups.Results: Elevation of serum transaminases (AST, > ALT) probably due to alcoholic liver disease quickly fell after abstinence. In patients who took cyanamide, the ALT levels were significantly higher at 4 and 12 weeks than in those who took disulfiram. Reelevations of ALT after alcohol detoxification were more frequently observed in those who took cyanamide than in those who took disulfiram (19.4% vs. 5.9%, p < 0.001). The reelevations of ALT were slight to moderate, being more than 3‐fold in three (1.4%) patients who took cyanamide and four (2.2%) who took disulfiram. The reelevations occurred more frequently in those with a history of cyanamide treatment before the present treatment than in those who took cyanamide for the first time (31.1% vs. 16.4%, p < 0.05).Conclusions: Cyanamide, compared with disulfiram, was more frequently associated with elevations of ALT that persisted after abstinence.
Background: Cyanamide, an aversive agent widely used in Japan, is known to induce various degrees of hepatic lesion with ground‐glass inclusion bodies. When cyanamide‐treated alcoholics relapse into drinking, more severe inflammation develops in the liver. However, it is controversial whether progressive hepatic lesions develop in complete abstainers as a result of long‐term cyanamide treatment.Case Reports: Case 1: A 53‐year‐old male alcoholic received cyanamide treatment for 4.5 months and completely abstained without cyanamide treatment for 6 years. A liver biopsy shortly after abstinence showed extensive pericellular fibrosis, but a biopsy after 6 years showed very mild fibrosis. Case 2: A 43‐year‐old male alcoholic remained completely abstinent with cyanamide treatment for 5 years and complained of general fatigue. His serum transaminases were slightly elevated and hepatic hyperechogenicity was observed on ultrasonography. Only mild pericellular fibrosis was present in the liver biopsy specimen obtained shortly after abstinence, but after 5 years the second liver biopsy showed that thin septum‐like fibrosis that formed portal‐to‐portal and portal‐to‐central linkage had developed and ground‐glass hepatocytes had emerged extensively. Case 3: A 29‐year‐old female alcoholic complained of general fatigue and a slight fever after 1.5 years of abstinence with cyanamide treatment. Slight elevation of serum transaminases and hepatic hyperechogenicity were observed. The liver biopsy showed extensive ground‐glass hepatocytes and thin septum‐like fibrosis that formed portal‐to‐portal linkage. Case 4: A 61‐year‐old male alcoholic who remained completely abstinent while taking cyanamide for 3 years showed slight elevation of serum transaminases. Liver biopsy showed extensive ground‐glass hepatocytes and extension of thin septum‐like fibers from portal tract to the lobule. Ultrasonography revealed hepatic hyperechogenicity.Conclusion: In some abstainers who take cyanamide for several years, thin septum‐like liver fibrosis progresses along with the emergence of ground‐glass hepatocytes. Hepatic hyperechogenicity on ultrasonography and slight elevation of serum transaminases might erroneously lead to a diagnosis of hepatic steatosis without liver histology.
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