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Familial cholesteryl ester transfer protein (CETP) deficiency is more common in some East Asian populations than elsewhere, suggesting the possibility of a selective advantage of this genetic defect against regional infectious diseases. Historically, infection with the Asian blood fluke Schistosoma japonicum has been endemic in these regions, including Japan. We previously reported that eggs of S. japonicum require cholesteryl ester uptake from normal high-density lipoprotein (HDL) but not from CETP-deficient HDL for their maturation to miracidia, a critical step of the hepatic pathogenesis of schistosomiasis. Herein we show that cholesteryl ester uptake is selective from HDL, and identified CD36-related protein (CD36RP) as a candidate to mediate the reaction. CD36RP was cloned from the adult and the egg developmental stages of S. japonicum, with 1880 bp encoding 506 amino acid residues exhibiting the CD36 domains and two transmembrane regions. Using antibodies against recombinant peptides representing the potential extracellular domains of CD36RP, Western blotting detected a protein with a molecular mass of 82 kDa in the particulate fraction of the adult parasite cells, which was reduced to 62 kDa after N-glycanase treatment. The extracellular domain peptide bound human HDL, as established by immunoblots following nondenaturing gel electrophoresis. Antibodies against the extracellular domain suppressed HDL cholesteryl ester uptake and maturation of the eggs in vitro. CD36RP is a candidate receptor on eggs of S. japonicum that facilitates uptake of HDL cholesteryl ester necessary for egg embryonation and maturation.

In order to develop an inexpensive, simple, and accurate method of monitoring for the reemergence of schistosomiasis japonica in Yamanashi Prefecture, Japan, the distribution and habitation density of the intermediate host, Oncomelania nosophora, were spatially analyzed using geographic information systems. The 1967-1968 density distribution maps prepared by Yamanashi Prefecture and Nihei were digitized and geocoded. The habitats and population density of O. nosophora were estimated by referring to the data compiled by the Yamanashi Association for Schistosomiasis Control (1977). These earlier findings were compared with average population densities between 1996 and 2000 previously recorded (Nihei, N., Kajihara, N., Kirinoki, M., et al., Parasitol. Int., 52, 395-401, 2003 and Nihei, N., Kajihara, N., Kirinoki, M., et al., Parasitol. Int., 53, 199-205, 2004). A variance map was created to compare the spatial distribution maps of population density from each of the two periods of interest. The changes in distribution were remarkable and the map was found to be effective for future control. The most appropriate monitoring sites were chosen on the basis of the spatial population density maps and the variance map. Moreover, the paddy fields at risk were extracted using the normalized difference vegetation index value based on Advanced Land Observation Satellite images. The combination of this method with the global positioning system provides an inexpensive means of monitoring modern schistosomiasis endemic areas in Japan and also in China, the Philippines, and other countries as well, where the intermediate snail grows in paddy fields and marshlands under consistently wet conditions.

A chronological research on the parasitic endemic disease, "Katayama Disease" in Hiroshima Prefecture was carried out. The present study was concerned mainly with the documents in the 20th century. It was confirmed that the development of excellent chemotherapeutic agents were not pivotal as a result. The eradication of the vector snails was clearly shown to be responsible for that of the infectious disease.

Although the incidence of human infection with Schistosoma japonicum in Japan fell to zero in 1977, the threat of the possible re-emergence of the disease caused by this trematode still exists. Surveillance of the parasite's intermediate host, Oncomelania nosophora, in Kofu basin therefore began in 1996. A simple, new method for monitoring O. nosophora in an at-risk area in Kofu, which is based on a geographical information system (GIS), was established. At each monitoring site (of which there were 120 from 1996 until 2000, and 60 from 2001 until 2003), the O. nosophora in two quadrats, each measuring 25 x 25 cm, were collected. During the study, the exact location of each site was determined using a hand-held global-positioning system (GPS). This allowed all the sites to be digitally mapped, so that anyone with a hand-held GPS could and can reach each site. The snail and location data were processed using commercial GPS/GIS software packages and used to create a risk map for schistosomiasis re-emergence. Although all snails collected between 1996 and 2003 were uninfected, the proportion of investigated sites in which O. nosophora was detected increased from 36.7% in 1996 to 56.7% in 2003. The mean number of O. nosophora collected per snail-positive site fluctuated widely, between 8.2 and 57.4, in each calendar year. Over the study period there appeared to be a shift southwards in the areas with high densities of O. nosophora. The present results indicate that it is possible to utilize a GIS-based method for the long-term monitoring of the possible re-emergence of schistosomiasis japonica in Japan.

Three hundred and forty-nine autopsy cases of schistosomiasis japonica were divided into two groups, based on the pathomorphology. Frequent regressive hepatic lesions such as active schistosomal lesion and destruction of limiting plates characterized the first group. The second group showed reparative hepatic lesions such as regeneration of the collapsed parenchyma, newly formed limiting plates and subsequent narrowing and disappearance of fibrous septa. Complications of liver cirrhosis and hepatocellular carcinoma related to viral hepatitis B and/or C also increased. Clonorchiasis was consistently found in both groups.

Except for imported cases, we have had no new Schistosoma japonicum infection in Japan since 1977. But there are still two habitats of the intermediate snail host: Oncomelania nosophora in the previous endemic areas of Kofu Basin and Obitsu. O. nosophora from Kofu Basin and Obitsu are susceptible to Chinese and Philippine strains of S. japonicum. The number of immigrants from current endemic areas in China or the Philippines is increasing. In order to prevent re-emerging of S. japonicum infections in Japan, we should continue monitoring on those existing snail hosts and investigate an adequate quarantine system. In Japan, elimination of schistosomiasis has been mainly accomplished by control of the snail host. As measures of snail control, cement-lining of ditches and chemical mollusciciding were most effective in Japan. But the cost of this joint program is too expensive compared with health budget in almost developing countries. In endemic areas of Japan, land reformation from paddy field to fruit farm was also effective. The intermediate snail host in the Philippines, Oncomelania quadrasi is much more aquatic than O. nosophora. For control of O. quadrasi, small drainage of the water and land reclamation from swampy field to rice-field were effective. Based on biological characteristics of Oncomelania spp., we can modify the past successful snail control program in Japan to be adapted ecologically and economically to each endemic area of developing countries.

There are still many Oncomelania snails that inhabit the Kofu Basin, Yamanashi Prefecture, Japan, which had been declared free of schistosomiasis japonica. Due to the need to monitor the situation, a fixed-point observation system using GIS from GPS is being examined. In addition, in broad present or former endemic areas, survey areas are being managed by remote sensing with satellite images or aerial photographs. A simple and effective monitoring method by mobile GIS using PDAs was developed, risk or hazard maps were prepared and a system that would enable a response in the event of reemergence is being examined.

In a preliminary study carried out in the study area we found that 19.1% (173/907) of patients with chronic liver disease and 51% (35/68) of hepatocellular carcinoma cases were infected with Japanese schistosomiasis. Analysis of data from 571 autopsies revealed a similarly high incidence of schistosomiasis among cases of hepatoma and other liver diseases. A prospective case-control study conducted over 10 years showed that hepatoma developed in 5.4% (26/484) of chronic schistosomiasis cases and in 7.5% (23/307) of patients with chronic liver disease (hepatitis, cirrhosis, etc). The difference was not statistically significant (P = 0.228). A high incidence of hepatitis C virus (HCV) antibody (HCVAb) was found in the schistosomiasis group (36.5%; 95% CI = 44.9-28.1%) and in the chronic liver disease group (56.0%), 39% of whom had chronic hepatitis (P = 0.028). Various factors that might have contributed to the development of hepatoma and schistosomiasis were investigated, but no evidence of a significant correlation between schistosomiasis and hepatoma was found. The high incidence of HCVAb was considered to have been responsible for the development of hepatocellular carcinoma in chronic schistosomiasis patients. The role of HBV infection in the development of hepatoma in schistosomiasis patients was not confirmed after an assay for HCVAb was included in the study.

Schistosomiasis japonica caused by Schistosoma japonicum, owes its name to the historical work of Japanese scientists during the period of 1904 to 1913. The disease is currently endemic in China and in the Philippines. It was highly endemic in three regions of Japan, but has been declared eradicated as of 1996. This paper presents epidemiologic data about when the disease was actively transmitted in Japan and how the disease was eradicated, and reviews evidence that fresh water even in the most heavily snail-infested areas is now safe from the disease. Information on epidemiology was obtained from Nation's Health published by the Japan Public Health Society. Similar information on numbers of fatal cases was obtained from the annual publication Morbidity and Mortality Record of the Ministry of Health of Japan.

Among the areas in Japan where schistosome infections have occurred for many years, three major areas were Katayama District, Kofu Basin and Chikugo River Basin and three minor areas were Numazu District, Tone River Basin and Obitsu River Bank. The presence of the disease had long been recognised in the Katayama Memoir written by Fujii (1847, in the Chinese Classics). The cause of this endemic disease had been studied by many researchers, and finally a new trematode, Schistosoma japonicum, was discovered by Katsurada in 1904 [Tokyo Iji Shinshi, Vol. 1371, pp. 13-32]. The route of percutaneous infection was proven by Fujinami & Nakamura (1909) [Kyoto Medical Journal, Vol. 6, pp. 224-252] using 17 calves. Miyairi & Suzuki (1913) [Tokyo Iji Shinshi, Vol. 1836, pp. 1961-1965] determined a small snail, Oncomelania nosophora, as being the intermediate host, and clarified the development of the schistosome in the snail. To kill schistosome eggs, human faecal matter ('night soil') was stored for 2 weeks or more before using as fertiliser. Control of the parasite used caustic lime and calcium cyanamide to kill eggs, cercariae and Oncomelania snails. Susceptible cows were replaced with horses, which were more resistant to infection as the animal of burden for agriculture. Ditches around the rice fields were cemented for destruction of snail habitats. For snail control, sodium pentachlorophenate (NaPCP) was sprayed extensively. Some wetlands were drained and reclaimed and in selected localities, the river bottom was dredged. Such projects were undertaken with government support and aided by community participation. Epidemiological surveys began in 1910, first at Kofu, and infected people were treated with sodium tartar emetic (Stibnal) after 1921. The total number of cases detected in Japan in 1920 was about 8000. This figure was reduced annually down to 438 by 1970. The last human case of new infection found in Japan was at Kofu in 1977. Although snails were eradicated in most areas by 1983, a limited number of uninfected snails remain at Kofu and Obitsu.

Objective: Chronic hepatic schistosomiasis japonica is a disorder characterized by broad fibrous septa in the liver. The ability to recognize these septa on MR images might enable distinction of this lesion from other cirrhotic disorders. The purpose of this study was to analyze the MR appearance of these septa., Materials and Methods: MR images of 18 patients who had typical calcifications of hepatic septa on CT scans were reviewed. The diagnosis was proved by biopsy in six patients. In the remaining 12, stool examinations were positive for schistosomiasis. T1-weighted MR images and T2-weighted and intermediate (long repetition time and short echo time) MR images acquired with the use of gradient-moment nulling were obtained in all 18 patients. In eight of 18 patients, additional T2-weighted and intermediate images were obtained without gradient-moment nulling. Fifteen patients had contrast-enhanced T1-weighted images. The presence of abnormal MR signal and its intensity at sites corresponding to the septa seen on CT scans were studied., Results: MR images showed the septa as linear abnormalities frequently seen in the subdiaphragmatic portion of the right lobe of the liver. On T1-weighted images, septa had low signal intensity and were identified in nine of 18 patients. On T2-weighted images obtained with gradient-moment nulling, septa had high signal intensity and were seen in 13 of 18 patients. On T2-weighted images obtained without gradient-moment nulling, the septa had primarily low signal intensity and were seen in five of eight patients. On intermediate MR images obtained with gradient-moment nulling, the septa had primarily high signal intensity and were seen in nine of 18 patients. On intermediate images obtained without gradient-moment nulling, the septa had primarily low signal intensity and were seen in four of eight patients. In nine of 15 patients, septa were visualized as high-signal-intensity lesions on contrast-enhanced T1-weighted images. In 14 of 18 patients, the septa were detected in one or more sequences., Conclusion: Our experience suggests that MR imaging in patients with chronic schistosomiasis of the liver depicts the morphologic features of hepatic septa. MR signal characteristics of septa are not unique, but use of gradient-moment nulling alters the signal intensity of septa, similar to that of blood vessels, on intermediate and T2-weighted images.

In Yamanashi Prefecture, schistosomiasis japonica has been endemic since the 16th century. Control of the disease has been very successful and no new case has been reported since 1977. Research has been conducted on the relationship between schistosomiasis and liver cancer, but no definite conclusion has been reached. We carried out several studies on this subject from the viewpoint of epidemiology. A descriptive study showed a higher mortality rate for liver cancer in the endemic area of schistosomiasis than in the country as a whole, but not much difference from the mortality rate in the non-endemic area. A case-control study showed a high odds-ratio for cases with a history of schistosomiasis; however, the value is almost the same as for cases which had hepatitis B (HB) antigen. This study suggested a multiplicative effect of HB antigen, history of schistosomiasis and history of alcohol intake. A retrospective cohort study showed a significantly high mortality rate for liver cancer in male inhabitants of the endemic area. These results confirm that schistosomiasis was closely related to liver cancer. However, the follow-up study of liver cirrhosis showed no difference in the survival curve and death rate from liver cancer between schistosoma positive cases and negative cases. A cross-sectional study of the prevalence of HB virus showed a higher rate in inhabitants with a history of schistosomiasis than those without such a history. Although the above two studies were carried out in small samples, it is considered now that schistosomiasis is one of the co-factors of liver cancer and indirectly associated with it.

Epidemiologic studies' on schistosomiasis japonica were carried out in the Obitsu River basin of central Boso Peninsula, a newly found habitat of Oncomelania snails in Japan. Forty-five (4.1%) of 1,102 schoolchildren and 64 (10.4%) of 618 junior high school students were positive for the skin test with veronal buffered saline-extracted Schistosoma japonicum antigen. None was positive by the enzyme-linked immunosorbent assay, complement fixation test, double diffusion test in agar, and circumoval precipitin test. About one fifth of 356 adult inhabitants showed positive reactions in the enzyme-linked immunosorbent assay and complement fixation test as well as in the skin test, although only 25 individuals (7%) were positive for the circumoval precipitin test. All of 70 individuals who had shown positive reactions in at least two of the immunological tests were negative for a series of 5 stool examinations with the AMS III method. Release of S.japonicum cercariae was not observed in 15,000 O. hupensis nosophora collected in this area. Repeated examinations by dipping mice into irrigation ditches were negative. These observations, with the fact that all of 15 patients reported from nearby hospitals to have schistosome eggs in their tissues were over 45 years old, suggest that schistosomiasis has become a disease of the past in this area.