We reviewed the literature regarding Japan's contribution to research in medicine in 1991-2000. Japan contributed 7.6% of all articles in English listed in the Medline database. The contribution ranged from 0.6 to 11.4% for various clinical science fields and 3.8 to 11.9% for basic science categories of reputable journals. The lowest contributions were in the categories “General and General Internal Medicine” and “Epidemiology”, where Japan contributed only 0.6% and 1.1% of the articles, respectively. The Japanese contribution to high quality clinical research (randomized controlled trials, case-control studies, cohort studies) was meager, while that to the basic sciences was more satisfactory than to the clinical science categories. Appropriate academic and social initiatives should be made to accelerate clinical research in Japan.

OBJECTIVE: To examine Japan's overall biomedical research productivity and its trend in the last decade.
METHODS: Articles published during 1991-2000 were accessed through Medline database. The number of articles having affiliation with a Japanese institution was elicited using standard search strategy.
RESULTS: In total 3.8 million articles were published during 1991-2000 while 330, 513 articles (8.7% of total) were originated from Japan. With language limited to English, there were 3.3 million articles in total and 252, 635 (7.6% of total) from Japan. Yearly numbers of articles significantly increased as a whole and also for Japan. The number of English-language articles from Japan increased by 63% during 2000 compared to 1991 while it was 34% on average for all other countries. On the other hand, the number of Japanese-language articles was 77, 878 with a 16.5% decrease in the same time.
CONCLUSION: The number of English-language articles originating from Japan has been increasing at a pace higher than that for all other countries together.

PURPOSE: Ticlopidine hydrochloride, an antiplatelet agent, is believed to have saved life years in many patients with ischemic cerebral vascular diseases in Japan. But severe adverse events have also been reported. The current investigation aimed to compare two hypothetical cohorts treated with and without ticlopidine in terms of risks and benefits of ticlopidine treatment using Markov model.
METHODS: We conducted Markov decision analysis to estimate the number of lives saved and the increase in quality-adjusted life years (QALYs) over the past 20 years by ticlopidine in Japan. Two cohorts of 60-year-old male patients with previous histories of cerebral infarction, one of which treated with ticlopidine and the other not treated with ticlopidine, were compared with respect to the number of deaths and quality of life (QOL) . Data incorporated were the probabilities of the recurrence of cerebral infarction and the associated mortality, adverse events of the drug, and the utility of health status treated with ticlopidine.
RESULTS: Approximately 1, 630, 000 patients were estimated to be on ticlopidine for variable periods of time during the past 20 years in Japan. With treatment, 17, 130 lives were saved, while 1, 338 patients died because of cerebral bleeding, agranulocytosis, severe hepatic dysfunction, or thrombotic thrombocytic purpura, resulting in a net benefit of 15, 792 lives saved by ticlopidine over the past 20 years. In terms of QOL, there was a total increase of 382, 191 QALYs. Sensitivity analyses showed that the older the patients when ticlopidine therapy was started, the smaller the benefits that were gained by treatment.
CONCLUSIONS: Ticlopidine is considered to have made a great contribution in savingmany lives and improving QALYs in the past 20 years in Japan. This kind of analysis based on Markov model can be employed to demonstrate effectiveness of drugs and medical technologies in terms of population health outcomes.

Objective: To investigate the comparative effects of Diospyros blancoi (Ebenaceae) leaves (DBL), root bark (DBRB) and stem bark (DBSB) on free radicals and cancer. Methods: The polyphenol contents, antioxidant and free radical scavenging properties were determined using standard spectrophotometric methods. Cytotoxicity and anticancer activ-ities were performed on brine shrimp nauplii and Ehrlich ascite carcinoma cells, respectively. Results: Among the extracts, DBSB showed the highest total antioxidant capacity and reducing capacity on ferrous ion. Based on 1,1-diphenyl-2-picrylhydrazyl and hydroxyl radical scavenging activities, DBSB showed (95.760 ± 0.343)%and (67.460 ± 2.641)%scavenging with IC50 of (3.10 ± 0.17) and (50.00 ± 3.11) mg/mL, respectively. The IC50 values of standard butylated hydroxytoluene and catechin (CA) for 1,1-diphenyl-2-picrylhydrazyl and hydroxyl radicals were (8.50 ± 0.25) and (75.00 ± 0.14) mg/mL, respectively suggesting that DBSB had a significant (P < 0.05) radical scavenging ac-tivity than standards. In lipid peroxidation inhibition assay, the inhibitory activity of the extracts and the standard was in the following order: DBSB > DBRB > CA > DBL. Also, the phenolic [(139.91 ± 3.924) mg gallic acid equivalent/g] and flavonoid contents [(412.00 ± 16.70) mg catechin equivalent/g)] of DBSB were higher than that of other extracts. In addition, the DBSB showed the moderate cytotoxic and anticancer properties. Conclusions: Our results indicate that Diospyros blancoi stem bark had the significant highest antioxidant and free radical scavenging properties as well as moderate anticancer activity. Hence, we assume that the anticancer activity of this plant can be, at least in part, attributed to its content in phenolic compounds as well as its significant free radical scavenging properties.

Background and Objectives: The therapeutic strategy for inflammation and degenerative calcification is of utmost importance for bioprosthetic heart valve (BHV) implanted patients.The purpose of this study was to compare the anti-inflammatory and anti-calcification effects of Entelon150® (grape seed extract), losartan, and rosuvastatin, in a rabbit model of intravascular BHV leaflet implantation in bovine pericardium. Methods: A total of 28 rabbits were implanted with BHV leaflet in the external jugular veins.The Entelon150® group was administered 7.7 mg/kg Entelon150® twice daily for 6 weeks after surgery. The losartan and rosuvastatin groups received 5.14 mg/kg and 1 mg/kg, respectively, once per day. The control group received 1 ml of saline once daily. And then, calcium concentration was measured in the implanted BHV, and histological and molecular analyses were performed on the surrounding tissues. Results: The calcium content of the implanted tissue in the Entelon150® group (0.013±0.004 mg/g) was lower than that in the control group (0.066±0.039 mg/g) (p=0.008). The losartan (0.024±0.016 mg/g, p=0.032) and rosuvastatin (0.022±0.011 mg/g, p=0.032) groups had lower calcium content than the control group, and higher tendency than the Entelon150® group. Immunohistochemistry revealed that the expressions of bone morphogenic protein 2 (BMP2), S-100, and angiotensin II type 1 receptor in the Entelon150® group showed lower tendency than those in the control group. The protein expression levels of BMP2 were reduced in the Entelon150® group compared with those in the control group. Conclusions Entelon150® exhibited a significant effect, similar to other drugs, in reducing calcification and inflammation in the intravascular bovine pericardium.

Background and Objectives: The therapeutic strategy for inflammation and degenerative calcification is of utmost importance for bioprosthetic heart valve (BHV) implanted patients.The purpose of this study was to compare the anti-inflammatory and anti-calcification effects of Entelon150® (grape seed extract), losartan, and rosuvastatin, in a rabbit model of intravascular BHV leaflet implantation in bovine pericardium. Methods: A total of 28 rabbits were implanted with BHV leaflet in the external jugular veins.The Entelon150® group was administered 7.7 mg/kg Entelon150® twice daily for 6 weeks after surgery. The losartan and rosuvastatin groups received 5.14 mg/kg and 1 mg/kg, respectively, once per day. The control group received 1 ml of saline once daily. And then, calcium concentration was measured in the implanted BHV, and histological and molecular analyses were performed on the surrounding tissues. Results: The calcium content of the implanted tissue in the Entelon150® group (0.013±0.004 mg/g) was lower than that in the control group (0.066±0.039 mg/g) (p=0.008). The losartan (0.024±0.016 mg/g, p=0.032) and rosuvastatin (0.022±0.011 mg/g, p=0.032) groups had lower calcium content than the control group, and higher tendency than the Entelon150® group. Immunohistochemistry revealed that the expressions of bone morphogenic protein 2 (BMP2), S-100, and angiotensin II type 1 receptor in the Entelon150® group showed lower tendency than those in the control group. The protein expression levels of BMP2 were reduced in the Entelon150® group compared with those in the control group. Conclusions Entelon150® exhibited a significant effect, similar to other drugs, in reducing calcification and inflammation in the intravascular bovine pericardium.

Background and Objectives: The therapeutic strategy for inflammation and degenerative calcification is of utmost importance for bioprosthetic heart valve (BHV) implanted patients.The purpose of this study was to compare the anti-inflammatory and anti-calcification effects of Entelon150® (grape seed extract), losartan, and rosuvastatin, in a rabbit model of intravascular BHV leaflet implantation in bovine pericardium. Methods: A total of 28 rabbits were implanted with BHV leaflet in the external jugular veins.The Entelon150® group was administered 7.7 mg/kg Entelon150® twice daily for 6 weeks after surgery. The losartan and rosuvastatin groups received 5.14 mg/kg and 1 mg/kg, respectively, once per day. The control group received 1 ml of saline once daily. And then, calcium concentration was measured in the implanted BHV, and histological and molecular analyses were performed on the surrounding tissues. Results: The calcium content of the implanted tissue in the Entelon150® group (0.013±0.004 mg/g) was lower than that in the control group (0.066±0.039 mg/g) (p=0.008). The losartan (0.024±0.016 mg/g, p=0.032) and rosuvastatin (0.022±0.011 mg/g, p=0.032) groups had lower calcium content than the control group, and higher tendency than the Entelon150® group. Immunohistochemistry revealed that the expressions of bone morphogenic protein 2 (BMP2), S-100, and angiotensin II type 1 receptor in the Entelon150® group showed lower tendency than those in the control group. The protein expression levels of BMP2 were reduced in the Entelon150® group compared with those in the control group. Conclusions Entelon150® exhibited a significant effect, similar to other drugs, in reducing calcification and inflammation in the intravascular bovine pericardium.

Objective: To investigate the comparative effects of Diospyros blancoi (Ebenaceae) leaves (DBL), root bark (DBRB) and stem bark (DBSB) on free radicals and cancer. Methods: The polyphenol contents, antioxidant and free radical scavenging properties were determined using standard spectrophotometric methods. Cytotoxicity and anticancer activities were performed on brine shrimp nauplii and Ehrlich ascite carcinoma cells, respectively. Results: Among the extracts, DBSB showed the highest total antioxidant capacity and reducing capacity on ferrous ion. Based on 1,1-diphenyl-2-picrylhydrazyl and hydroxyl radical scavenging activities, DBSB showed (95.760 ± 0.343)% and (67.460 ± 2.641)% scavenging with IC

Objective: To investigate the protective effects of Nigella sativa seed extract (NSSE) against acetaminophen (APAP)-induced hepatotoxicity in TIB-73 cells and rats. Methods: Toxicity in TIB-73 cells was induced with 10 μmol/L APAP and the protective effects of NSSE were evaluated at 25, 50, 75, 100 μg/mL. For in vivo examination, a total of 30 rats were equally divided into five experimental groups; normal control (vehicle), APAP (800 mg/kg body weight single IP injection) as a hepatotoxic control, and three APAP and NS pretreated (2 weeks) groups (APAP + NSSE 100 mg; APAP + NSSE 300 mg and APAP + NSSE 900 mg/kg). Results: TIB-73 cell viability was drastically decreased by (49.0 ± 1.9)% after the 10 μmol/LAPAP treatment, which also increased reactive oxygen species production. Co-treatment with NSSE at 25, 50, 75, and 100 μg/mL significantly improved cell viability and suppressed reactive oxygen species generation. In vivo, the APAP induced alterations in blood lactate levels, pH, anionic gap, and ion levels (HCO