Methods for cancer monitoring and early detection of the disease are of the utmost importance and represent one of the most active areas of current research. Cancer monitoring is crucial not only for early initial diagnosis of the disease, but also for followup of therapy outcome. Despite being well developed, most methods for cancer monitoring are unsuitable for clinical use because they either are insufficiently accurate, not sensitive enough, or require a lengthy complicated analysis. There is a great necessity for more effective cancer monitoring methods that can improve cancer management in routine clinical setting and increase treatment effectiveness. Advances in this field of research are based on a more detailed understanding of the fundamental biological mechanisms involved in the disease process, as well as on advances in genomic, transcriptomic, proteomic, and metabolomic research.This special issue encompasses articles on the state of the art, advantages and disadvantages, current limitations, and future perspectives of cancer monitoring methods. Dr. D. Musio with colleagues and Dr. B. Kasper with colleagues present advanced imaging methods in clinical followup of response to therapy. Dr. G. Bertino with colleagues, as well as Dr. P. Mirabelli and Dr. M. Incoronato, offer new insight into the use of some traditional cancer biomarkers in clinical and laboratory practice. The works of Dr. P. Sadlecki with colleagues, Dr. R. Zappacosta with colleagues, and Dr. S. Farivar with colleagues deal with the analysis of protein cancer biomarkers in different types of samples. Of special interest are the articles that report on development, implementation, and validation of novel techniques for cancer monitoring, by Dr. C.-F. Chen with colleagues and Dr. I. Macchia and colleagues.We would like to thank the authors for their excellent contributions to this special issue. We hope that this issue will be useful to the experts of all profiles dealing with cancer in both clinical and laboratory setting.Aleksandra NikolicOronza Antonietta BotrugnoJelena UrosevicNatasa Tosic


There was an error in the funding statement. The correct funding statement is: This work was supported in part by grants from National Institutes of Health, National Heart, Lung, and Blood Institute R01HL089599 to A.C., R01DK090053 to C.T., and R01CA127958 to A.G. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.


Dr. Eliana C. Martinez, M.D., Ph.D., from Department of Surgery, Yong Loo Lin School of Medicine, National University of Singapore, Singapore,” and the authors list should be read in the correct order as previously mentioned.This erratum corrects the listing of authors for the above paper published in this journal. The authors' list should also have included “


Dr. N. Kumar was born on 21/06/1952.He completed his MBBS in April 1976 and went on to do DMRD which he completed in April 1982 and then D. V. in October 1984. He also did his MD in Venereology in the year October 1987.He joined Tamilnadu Medical Service in 1984 and there he worked in various departments like Casualty, Forensic Medicine, Radiology and STD.He was the recipient of Ranganathan Gold medal in 1986. He worked as a Professor in STD Dept at Tirunelveli Medical College in 2005. He joined Institute of Venereology as an Additional Professor in 2007 and he served as Director (i/c), Institute of Venereology from 2009.He succumbed to his illness on 22/05/2010.We pray that his soul rest in peace.


This genus of nematodes was named after H.A. Baylis, a parasitologist at the British Museum of Natural History, London, who studied these organisms in the 1920s and 1930s. The most common cause of baylisascariasis in humans and animals is infection with the roundworm Baylisascaris procyonis, which takes its name from Procyon, a genus of raccoons. The species was first isolated from raccoons in the New York Zoological Park in 1931.From the Greek term for intestinal worms, Source: Gavin PJ, Kazacos KR, Shulman ST. Baylisascariasis. Clin Microbiol Rev. 2005;18:703–18.


Angiostrongylus cantonensis  is a parasite of murid rodents and causative agent of human neuro-angiostrongyliasis. In 2011, the Ogasawara Islands in the western North Pacific were assigned a World Natural Heritage site status. The occurrence of A. cantonensis is well documented in the Chichijima, Hahajima, and Anijima Islands. However, the occurrence of A. cantonensis in the other islands of the Ogasawara Islands has not been reported.Rattus norvegicus and 79 R. rattus were collected from 9 islands . Adult nematodes were found in the pulmonary artery of 46 R. norvegicus collected in the 5 islands of the Hahajima group . These nematodes were identified by molecular analysis as A. cantonensis. Comparison of the mitochondrial DNA sequences confirmed that all the samples from the Ogasawara Islands shared only a single lineage of A. cantonensis, which has been previously detected in the Okinawa, Hawaii, and Brazil.Between March 2010 and July 2011, 57 A. cantonensis are widely distributed in the Ogasawara Islands. Although human cases have not yet been reported in the Ogasawara Islands, the widespread detection of A. cantonensis could be of importance from the perspective of public health.We describe new endemic foci of rat angiostrongyliasis in the Hahajima group  of the Ogasawara Islands. These findings indicate that the endemic foci of  Angiostrongylus cantonensis  is an important public health concern in many countries A. cantonensis is widespread in the tropical and subtropical areas. It is reported mainly in Asia, the Pacific Islands, the Caribbean Islands, Australia, and the USA A. cantonensisNeuro-angiostrongyliasis due to infection with A. cantonensis. The occurrence of A. cantonensis is well documented in the Chichijima A. cantonensis in the other islands of the Ogasawara Islands has not been reported.The Ogasawara Islands is group of more than 30 small subtropical islands in the western North Pacific, located approximately 1,000 km south of mainland Japan. The Ogasawara Islands extend approximately 400 km from north to south and consist of the Ogasawara archipelago , the Iwojima groups, and isolated islands in the surrounding area. The Ogasawara Islands consists of only two of inhabited Islands of Chichijima (the biggest island in the Chichijima group) and Hahajima (the biggest island in the Hahajima group) Islands. In 2011, the Ogasawara Islands was assigned World Natural Heritage site status. It is an area known to be endemic for c oxidase subunit I (coxI) gene has proved to be a powerful marker in resolving phylogenetic relationships within closely related Angiostrongylus species A. cantonensis isolates A. cantonensis coxI gene in Asia A. cantonensis in these regions is likely a results of multiple introduction of infected hosts via human related transportation Nuclear small subunit (SSU) rRNA sequences generally show little variation within a nematode species, but substantial divergence among species, allowing for species differentiation A. cantonensis among invasive rats in the Ogasawara Islands. In addition, we have genotyped and investigated genetic differences among A. cantonensis on these islands by using SSU rRNA and coxI genes for monitoring the spread of A. cantonensis lineages.In the present study, we conducted extensive research on the presence of R. norvegicus, and 79 Black rats, R. rattus) were collected from 9 islands  in the Ogasawara Islands (2 and dissected in the field. Lung and heart samples were fixed with 70% ethanol. The Angiostrongylus worms in the plumonary arteries of these rats were collected by macroscopic inspection. A. cantonensis collected from Hawaii (Alicata strain) were kindly provided Drs. N. Nonaka and T. Irie . These worms were preserved at −30°C until DNA extraction. Detailed information about the host, prevalence, and sampling date is included in Between March 2010 and July 2011, a total number of 136 rats , in accordance with the Act on Welfare and Management of Animals of Japanese government.coxI gene was amplified and sequenced from 46 individuals of Ogasawara isolates and two Hawaiian isolates of A. cantonensis. Genomic DNA was extracted using sodium hydroxide (NaOH) direct lysis protocol coxI genes were amplified by PCR using SSU  cox1  primers Top DNA polymerase (0.5 U/µM) , and 1 µl of sample DNA. The PCR reactions were analyzed by electrophoresis on a 1.5% agarose gel and visualized by UV illumination by ethidium bromide staining. The PCR products were purified by Exosap-IT . Sequencing was performed using the BigDye Terminator version 3.1 Cycle Sequencing kit  according to the manufacturer’s instruction, and determined by ABI3100 automatic sequencer . All products were sequenced in both directions. Sequences were visualized by chromatograms, and then, manually corrected using Finch TV software .The SSU rRNA gene isolated from the worms collected from 5 islands in the Hahajima group was amplified and sequenced. The mitochondrial http://blast.ncbi.nlm.nih.gov/Blast.cgi) was carried out to elucidate any similarities between the obtained SSU rRNA and coxI sequences and the previously published sequences. Multiple sequence alignment was carried out using the online version of MAFFT ver 6.0 A BLAST search  were infected with Angiostrongylus worms. The overall prevalence was 33.8% (46/136), ranging from 0% to 100% at the individual collection sites. Detailed information on the location, host species, host number, and the infection rates are presented in After macroscopic inspection of the lung and heart tissues, we found that 46 A. cantonensis  were separately determined for each individual worm from the Anejima, Imoutojima, Meijima, Mukohjima, and Hirajima Islands. Sequence alignment showed no variation in these sequences. Upon querying the DDBJ/EMBL/GenBank database, we found no difference between the present sequences and coxI sequences of 46 A. cantonensis isolates from the Ogasawara archipelago and 2 isolates from Hawaii Islands were determined. The alignment of the coxI sequences of 48 isolates was 565 bp long, with no variable sites. A BLAST search against sequence databases revealed that the present sequence had 100% identity with the ac5 haplotype reported from Chichijima , and Brazil (GenBank accession nos. JX471060 and JX471063coxI sequences data reported are available in the DDBJ/EMBL/GenBank databases as follows: the Anejima (GenBank accession no. AB700676), Imoutojima (GenBank accession no. AB700677), Meijima (GenBank accession no. AB700678), Mukohjima (GenBank accession no. AB700679), Hirajima (GenBank accession no. AB700680), and Hawaii islands (Alicata strain) (GenBank accession no. AB700681).The partial A. cantonensis in rats in the endemic islands was high, ranging from 60% to 100%. This was similar to the other endemic regions such as Cuba (60%) A. cantonensis has already been established and is flourishing in the Hahajima group. In this study, the infection rate of R. norvegicus  was significantly higher than that of R. rattus , which is similar to the situations in Haiti A. cantonensis worms were not detected from the rats collected in the Nakoudojima, Yomejima, Minamijima, and Iwojima Islands. These results indicate that presently, there is limited or no colonization and establishment of A. cantonensis on these islands.In the present study, prevalence of et al. (1969) A. cantonensis larvae from Achatina fulica . Later surveys in the Chichijima Island confirmed widespread infections in A. fulica and R. rattusA. fulica, R. norvegicus, and R. rattus in Hahajima R. rattus in the Anijima Islands R. rattus among 62 sampled individuals A. cantonensis in R. norvegicus. This is the first report of the occurrence of A. cantonensis in the Anejima, Imoutojima, Meijima, Mukohjima, and Hirajima Islands–small satellite islands of the Hahajima group, located about 3.6–5.5 km away from the Hahajima Island. These newly detected foci could be of importance from a public health view. As far as we know, at least 67 parasitologically diagnosed human cases were reported in Japan at the end of 2007. These human cases were mostly from Okinawa Islands. Fortunately, no human cases have been reported so far in the Ogasawara Islands In 1968, Sasa A. cantonensis isolated from the Chichijima group (Chichijima Island) and the Hahajima group  in the Ogasawara archipelago share a single coxI sequence, named haplotype ac5. This could be considered the result of a single genomic origin followed by range expansion. Furthermore, our analyses demonstrated that this shared lineage is identical in not only the Ogasawara archipelago, but also the Okinawa Islands (Japan), Hawaii (USA), and Brazil. These findings indicate that a lineage-specific A. cantonensis has been spreading across the Pacific.In the present study, we have provided molecular evidence that R. rattus, R. norvegicus, and Mus musculus (house mouse) inhabit the Ogasawara Islands. Of these species, R. rattus and R. norvegicus are capable of transmitting A. cantonensis. The presence of R. rattus and R. norvegicus in the Chichijima Island has been recorded since the 1920s and 1862, respectively R. rattus in virtually all islands in the Ogasawara Islands R. norvegicus was found only in the Hahajima, Hirajima, Chichijima, and Iwojima Islands R. norvegicus in Anejima, Imoutojima, Meijima, and Mukohjima Islands. A. cantonensis population in the Ogasawara Islands originated from mainland Japan–we compared the lineages of A. cantonensis. Unfortunately, we could not find any shared lineages among the regions of interest and mainland Japan R. norvegicus are capable of swimming hundreds of meters across open water Previous studies have shown that the 3 species of invasive rodents, namely, A. fulica has been shown to be one of the most important intermediate hosts of A. cantonensisA. cantonensis in the Ogasawara Islands is responsible for the introduction of A. fulica. According to Mead (1961) A. fulica snails were introduced to the Chichijima Island from Taiwan via mainland Japan in 1935, as an item of primitive medicine. Subsequently, the giant snails were found one after another in the Hahajima, Anijima, and Higashijima Islands. In the present study, we discovered A. cantonensis worms in the Anejima, Imoutojima, Meijima, and Mukohjima Islands of the Hahajima group, where A. fulica snails had not been reported. Therefore, we suspected that organisms other than A. fulica snails might be involved in the lifecycle of A. cantonensis in these islands. The Ogasawara Islands is abundant with terrestrial gastropods. At least 97 snail species have been recorded, and over 90% of them are native to this Islands A. fulica snails, and these small snails play a more important role in the transmission of A. cantonensis. However, the susceptibility of native snails in the Ogasawara Islands to A. cantonensis and the epidemiology of A. cantonensis among these snails are uncertain.Virtually, all gastropods act as intermediate hosts, and are capable of transmitting this parasite. In the Ogasawara Islands, the giant African snail A. cantonensis in R. norvegicus from the Anejima, Imoutojima, Meijima, Mukohjima, and Hirajima Islands of the Ogasawara archipelago. We have also provided molecular evidence that a single shared lineage of A. cantonensis has been spreading in the Ogasawara archipelago. This lineage was found in the Okinawa, Hawaii, and Brazil. Future studied should focus on the transmission dynamics of this nematode parasite, and explore the potential role of the host in moving the parasite across a wide range of geographic regions.In conclusion, we demonstrated, for the first time, the occurrence of


General measures for diseases control and special control strategies are summarized.Water-related parasitic diseases are directly dependent on water bodies for their spread or as a habitat for indispensable intermediate or final hosts. Along with socioeconomic development and improvement of sanitation, overall prevalence is declining in the China. However, the heterogeneity in economic development and the inequity of access to public services result in considerable burden due to parasitic diseases in certain areas and populations across the country. In this review, we demonstrated three aspects of ten major water-related parasitic diseases,  Indeed, many infectious diseases are water-related, al hosts . Water-related parasites can be categorized into three groups according to their transmission route. The first group is associated with drinking water, which may be contaminated with cysts or oocysts, larvae, or eggs from various parasites. The second group is transmitted via penetration of the human skin during water contact. The parasites in this group may swim freely in water until they find a human host. The transmission of the third group of parasites depends on the consumption of uncooked freshwater products, e.g., plants, fish, snails or crustaceans. Obviously, the first two groups are closely related to water contact, while the key element of transmission of the third group is not water, but hosts and vectors living in the water.This review focuses on the most important members of water-related parasitic diseases in China. Since their prevalence is influenced by the provision of clean water and sanitation, they are a priority of many rural development programmes . We reviWe reviewed the scientific literature on water-related parasitic diseases: amoebiasis, giardiasis, cryptosporidiosis, cyclosporiasis, blastocystosis, schistosomiasis, fascioliasis, fasciolopsiasis, clonorchiasis, and paragonimiasis. Considered publications were published from 1 January 1990 to 31 December 2011. The English language literature was obtained from ScienceDirect Onsite, SpringerLink and PubMed, while the Chinese language literature was obtained through CNKI , Wanfang, and VIP.For each disease, we firstly reviewed its biology and pathogenicity of that disease. Then, its epidemiology in China, particularly the two nationwide community-based sampling surveys on major human parasitic diseases which had been carried out during 1988–1992  and 2001–2004  respectively ,4. ThirdEntamoeba histolytica . Excystation occurs in the ileum of the small intestine. Trophozoites multiply by binary fission in the large intestine. Most trophozoites remain in the lumen of the intestine. Cyst formation is triggered by dehydration of gut contents. Invasive forms of the disease lead to amoebic dysentery in which the trophozoites invade the intestinal wall, leading to the formation of amoebic ulcers. This results in severe diarrhea with blood and mucus in stools. If trophozoites penetrate the intestinal wall, serious health problems can occur, including liver abcesses (the most common manifestation), or spread to the lungs and brain, usually resulting in death, or other organs or tissues .E. histolytica is a major cause of dysentery. Four major intestinal syndromes include asymptomatic colonization, acute amoebic colitis, fulminant colitis and amoeboma [amoeboma   [Parasitic co-infections of HIV/AIDS patients are of particular concern . In a cos (3.1%) . E. histolytica had been initiated relatively early in China when compared to other intestinal protozoa. In addition to numerous clinical reports of intestinal amoebiasis, extra-intestinal abscesses due to ectopic location of E. histolytica and amoebiasis due to other species have been highlighted recently. The significance of E. histolytica for animal health is also drawing attention [E. histolytica with or without iodine staining routinely fails to differentiate E. histolytica from E. dispar, enzyme-linked immunosorbent assays (ELISA) for E. histolytica in stool samples have been developed and evaluated [Research pertaining to ttention ,19. Sincvaluated ,20,21. Pvaluated . Giardia intestinalis  and is one of the most common causes of parasitic diarrhea. Today, giardiasis, along with cryptosporidiosis, continues to represent the major parasite-related public health concern of water utilities in developed nations [G.intestinalis occurs worldwide and is a zoonotic parasite in certain areas while in others, the infection is believed to be limited to humans [G. intestinalis exists in two forms, namely a trophozoite (the active form) and a cyst (the inactive form)  .etc. in the centre. The motile trophozoite has two nuclei, four pairs of flagella, and one or two curved median bodies of unknown function. Reproduction is by binary fission; no sexual process is known. The infective stage is an oval cyst, which is excreted in the faeces and ingested with contaminated food or water. The cyst contains four small nuclei, grouped at one end, and a confused jumble of flagella, median bodies G. intestinalis infections, and the parasite has been isolated from ascites, pleural effusions and joint fluids [Diarrhea and associated symptoms may occur in various forms, depending on the stage of infection . Symptomt fluids ,31,32. Tt fluids .Giardiasis is the best-known intestinal protozoan infection in China where many field surveys have been conducted to reveal its epidemiology. Giardiasis occurs across the country and the overall prevalence has been estimated at 2.52% following the first national survey , translaG. intestinalis prevalence had decreased significantly, e.g., from 7.18% in Henan Province and 3.85% in Zhejiang Province to 2.55% and 1.00%, respectively [G. intestinalis does not always follow that of intestinal helminth infections, probably reflecting differences in the way of transmission with G. intestinalis more dependent on water and soil-transmitted helminths more dependent on faecal contamination of the solid environment. However, regional idiosyncrasies are also important. The prevalence of G. intestinalis was only 1.9% in a population in south Yunnan Province where the prevalence of each of the common soil-transmitted helminth species exceeded 85%. Earlier observations had already noted that the prevalences of pathogenic intestinal protozoa were generally low in southeast Asia [The prevalence of giardiasis in China is currently declining. According to the second national survey, the ectively ,11. Inteast Asia ,35.G. intestinalis infection is widespread in the general population, it is believed to be responsible for only a small fraction of all diarrhea cases. In a study conducted between 1996 and 2001, only 0.32% of 3,116 diarrheal patients were found to be infected with G.intestinalis while the combined prevalence of all intestinal prototoa was 21.7%. The majority of all intestinal protozoa were E. histolytica, infecting 17.65% of the samples [G.intestinalis in another study [Although  samples . Similarer study . G. intestinalis. Studies on viral infections of G.intestinalis will facilitate the study of mechanisms for invasion [Besides basic epidemiological surveys, ectopic and severe infections have recently received more attention. Infections in the joints , tonsil invasion ,41. G.intestinalis and Cryptosporidium spp. are the protozoan parasites most frequently found in water bodies [Cryptosporidium and Giardia in water by filtration/IMS/FA” initially published by the U.S. Environmental Protection Agency but certain procedures have been modified. r bodies ,43,44. WG.intestinalis has a zoonotic component and understanding its animal origins is crucial for the control of giardiasis. Based on electrophoretic evidence, there are at least seven valid assemblages (A–G) [G.intestinalis [es (A–G) , of whicstinalis ,47.Giardia lamblia virus (GLV) was first described as a specific double-stranded RNA virus in 1986 [G. canis was sequenced and found to be highly similar to GLV [G.intestinalis [Many protozoa have been found to be infected by a virus . The Gia in 1986 . GLV iso in 1986 . In anotr to GLV . Based ostinalis . Cryptosporidium species  of the screened AIDS patients were infected with C.parvum [Cryptosporidium infections. Two thirds of 108 patients with cancer were confirmed to be infected with Cryptosporidium in a recent study, and chemotherapy tended to be associated with higher prevalence than radiotherapy or combination therapy [The pathogenicity of .parvum , with a  therapy . Several therapy . In a si therapy . Of note therapy .Cryptosporidium in China is increasingly recognized. A high number of epidemiological investigations both in humans and animals have been conducted in the whole country, and prevalences in different population segments have been mapped. Co-infections of HIV and Cryptosporidium have attracted particular attention [Cryptosporidium has been isolated from a range of animals and the taxonomy is still debated. Consequently, more and more studies are looking for suitable biomarkers and identification techniques to differentiate isolates [Cryptosporidium [The importance of ttention ,94. Crypisolates . Geneticisolates . Isolatiporidium . Cyclospora cayetanensis and has been identified as an important cause of diarrhea worldwide. C. cayetanensis was classified into the subphylum Apicomplexa, family Eimeriidae in 1993 [C. cayetanensis is uncertain but of increasing concern.Human cyclosporiasis is caused by  in 1993  and receC. cayetanensis are often transient but chronic infections have also been described  and surrounding areas [Schistosomiasis japonica is one of the most important parasitic diseases in China and its epidemiology has been extensively studied and reviewed . When thng areas . Today, ng areas . Substanng areas ,128. A nng areas . In 2008ng areas .The schistosome-endemic areas of China have been stratified into three types, based on ecosystem characteristics, namely the plain and water-network region, marshland and lake region, and hilly and mountainous region. The parasite has been eliminated from the formerly most heavily endemic plain and water-network region and has largely been brought under control in the hilly and mountainous regions. However, control in the marshland and lake regions proved difficult and the disease remains prone to resurgence .The successes with schistosomiasis control in China have been attributed to strong government support and sustainable yet adaptable policies . Since tDisability adjusted life years (DALYs) have been widely used to measure disease burden and direct the allocation of health resources . HoweverS. japonicum is subject to environmental conditions and changes therein, including climate change [2 by 2050, accounting for 8.1% of the surface area of China [The transmission of e change ,138,139.of China . Based oof China . S. japonicum has been sequenced and published [O. hupensis has also been studied, and genetic markers have been used to analyze the spatial distribution of the snail in China [The genomes of ublished ,142. Traublished . Vaccineublished ,145,146.in China ,148.F. hepatica and F. gigantica. Both species are endemic in China. The life cycle of these two species are essentially similar [etc.). The eggs are released to the intestine and exit the host body with faeces. Hatched miracidia invade freshwater snail host and develop to cercaria. The latter emerge from snails and stick to aquatic plants and finally become metacercariae. Humans and mammals acquire infection by ingesting aquatic plants contaminated with metacercariae [Human fascioliasis is caused by  similar . They us similar . The aduercariae . Fasciola spp. worms in the bile ducts. Many cases of chronic fascioliasis are asymptomatic. Jaundice appears when biliary obstruction occurs. Ectopic parasitism in cutaneous tissue, lung and other organs has also been reported [Larval migration in the liver induces inflammation and hepatic dysfunction, which is the main base for acute symptoms . Intermireported ,156. Sevreported ,157.F. hepatica is considered the major cause of animal and human fascioliasis in China. Before 1990 a total of 45 human cases had been reported, including one case of fascioliasis gigantica [F. gigantica were localized in Hainan Island, the southernmost province of China. However, recent phylogenetic analysis of isolates from different areas in the country showed three distinct clades, i.e., F. hepatica, F. gigantica, and the “intermediate” type [F. gigantica is also distributed in southwest part of China, including Guangxi and Guizhou Provinces [F. gigantica probably occurred in southwest China. Fascioliasis is a common parasitic disease in domestic animals in China and hence causes huge economic losses. Human fascioliasis has rarely been reported in the past decades. igantica . The firte” type . F. gigarovinces ,160. TheAlthough the second national survey on major parasitic diseases did not include fascioliasis , sporadiFascioliasis is an important disease in livestock and hence veterinary studies are predominant in literature. In contrast, only few human case reports have been published in literature in recent years. Triclabendazole is the most efficacious drug for treating human fascioliasis. However, the drug is only registered in a few countries, and not in China . The majFasciola species was performed. Mitochondrial gene (cox1 and nad1) and internal transcribed spacers (ITS1 and ITS2) revealed F. hepatica, F. gigantica and the intermediate form coexist in China [Fasciola spp. due to small sample size. In the last ten years, molecular identification of in China ,162,163.Fasciolopsis buski, the largest intestinal fluke parasitizing humans . The cercariae are released from the snail and encyst as metacercariae on aquatic plants. The mammalian hosts become infected by ingesting metacercariae on the aquatic plants. After ingestion, the metacercariae excyst in the duodenum and attach to the intestinal wall. There they develop into adult flukes in approximately 3 months, attached to the intestinal wall of the mammalian hosts (humans and pigs). The adults have a life span of about one year.The symptoms of fasciolopsiasis manifest after an incubation period of 1–3 months and depend on several factors including the worm burden and physiologic state of the patient .F. buski [F. buski prevalence did not differ between sex, but were related to profession; farmers were at the highest risk of infection [F. buski had considerably lost prominence as a human parasite [Many reports indicate that fasciolopsiasis was heavily endemic in southern China in the 1970s and 1980s. For example, a survey performed in 8 villages in Putian County, Fujian Province, showed that 55.1% of 1,834 participants were infected with F. buski . In the F. buski . The firF. buski infections may be common in rural areas, few specific surveys have been conducted over the past decade. Only severe or ectopic infections, such as anemia and oedema, biliary fasciolopsiasis and intestinal obstruction, got attention from clinicians [F. buski to detect specific antibodies in human sera showed high sensitivity and specificity, and a low rate of cross reactions with schistosomes and Paragonimus spp. [F. buski infection by gastroscopy while their stool samples were egg-negative [Although human inicians ,168,169.mus spp. . Additionegative . Clonorchis sinensis. The parasite is transmitted between snail, fish and mammals. Like Fasciola spp. aforementioned, adult worms of C. sinensis parasitize the biliary system of definitive hosts . The eggs are released with faeces to environment. Freshwater snail ingests the eggs and a few weeks later larvae develop into cercariae in the liver and are released from the snail body. Swimming cercariae invade fish and become metacercariae. The latter are infective for humans, dogs and cats.Clonorchiasis is caused by a liver fluke, C. sinensis also is one of the parasites that are confirmed as a cause of cancer; cholangiocarcinoma is the most significant a malignant outcome [The early stage of infection is normally asymptomatic, particularly in light infection. However, some patients can have symptoms associated with the inflammation in the liver and biliary ducts . Chronic outcome ,173.C. sinensis, of which 84.3% are distributed in China [i.e., southern and northeast centers. The prevalence among males (2.94%) was significantly higher than that among females (1.84%), which correlated with the differences in eating habits [It is estimated that worldwide 15.3 million people were infected by in China . AccordiC. sinensis is the most common cause for surgery due to hepatobiliary and pancreatic diseases in endemic areas [C. sinensis infection. Nearly 1,000 cases due to C. sinensis infection are diagnosed annually in China, which may still an underestimate [Clonorchiais is an increasing public health concern in public health in China . Firstlyic areas . There mic areas . Third, estimate ,179.C. sinensis-related research in recent years. An expression library for each stage of C. sinensis was established. Based on the libraries, individual genes and proteins of important function have been studied for diagnosis and drug targets. However, the conclusive findings have not been achieved. In 2011, the genome of C. sinensis has been published [Bioinformatics is a hotspot in the field of ublished . In-deptAlthough most of infections may be asymptomatic, some can cause severe outcomes . The larC. sinensis-infected rats and in vitro and hence might be potential new drug candidates for treating infections [Praziquantel is confirmed to be efficacious against clonorchiasis . Howeverfections . Recentlfections .Paragonimus have been described in China, among which 10 species are able to infect humans [P. westermani and P. skrjabini (Pagumogonimus skrjabini) are the most common cause of human paragonimiasis. The life cycle of Paragonimus spp. involves three kinds of host. In mammalian definitive host, paired adult worms live in lung capsules. The eggs are released with sputum or swallowed and excreted in faeces. Hatched miracidiae penetrates the first intermediate host snail (Melania spp.), and ultimately develop into cercaria. Crustaceans  serve as second intermediate hosts, which are infected via direct penetration of cercariae or ingestion of infected mollusks. Cercariae encyst and develop into metacercariae. Mammals acquire an infection by consuming raw or undercooked infected crustaceans. Metacercariae excyst in the small intestine and migrate through the intestinal wall to reach the abdominal cavity, enter the abdominal wall, and migrate to the pleural cavity.At least 29 species of t humans . P. westParagonimus spp. and worms migrate along a mostly defined route to their final destination, the lung [etc. ” were published in 2006 and list rges Dam ,202,203.Sanitation and the proper management of wastewater are important elements for ensuring the supply of clean drinking water. Improving sanitation includes the construction of latrines or water-flush toilets and sewers, the collection of wastewater of domestic and industrial origin and its separation from environmental water bodies, and waste water treatment. Almost all studies on the effect of latrine construction and usage demonstrate their effectiveness in reducing the prevalence of different water-based and -related infectious diseases ,205. HowDiseases occur in a complex socio-ecological context characterized by feedback loops across space and time, self-organization, holarchies, and sudden changes in organization when thresholds are reached . TherefoWater-related parasitic diseases have generally declined in China. This has often been attributed to socioeconomic development, which has improved living conditions and alleviated the financial burden due to parasitic diseases in many areas. However, some parasitic diseases still occur at considerable prevalence in certain areas and populations, owing to the heterogeneity in natural conditions and economic development and the inequity of access to public services including preventive and curative health care. Emerging and re-emerging pathogens and risk factors are also challenging the achievements made with regard to the control of parasitic diseases . The groThe majority of all parasitic infections are diseases of poverty . However


To the Editor: Coccidian protozoans that belong to the genus Cryptosporidium frequently cause gastrointestinal infection in humans and animals and are distributed worldwide. Cryptosporidium hominis and the cattle genotype of C. parvum are responsible for most human infections. However, other species and genotypes of Cryptosporidium, such as C. felis, C. muris, C. meleagridis, C. canis, C. parvum pig genotype, and C. parvum cervine genotype, have also been detected in stool samples of immunosuppressed and immunocompetent patients  .A pediatrician requested a parasitologic study for an immunocompetent, 4-year-old boy with diarrhea. The child came from an orphanage in Calcutta, India; he had arrived in Spain 10 days earlier after having been adopted by a Spanish family. Stool specimens were tested for a wide panel of enteric pathogens, including bacteria, viruses, and parasites. SspI for species diagnosis or VspI for C. parvum genotype identification. For DNA sequencing, PCR products of the 18S rRNA gene fragments were purified and used for direct sequencing in an ABI377 automated sequencer .DNA was extracted as described elsewhere .RFLP analysis showed a profile distinct from those of C. felis have been reported in the literature. Only 3 of them have occurred in immunocompetent patients: 2 in the United Kingdom (C. felis infection diagnosed in Spain. The child had been in Spain for only 10 days, no pet animals lived in his new home, and he had not gone to kindergarten. Consequently, the infection was likely acquired in India.To date, >30 cases of human infection by Cryptosporidium species is unclear. In the study by Matos et al., only 1 of 4 immunocompromised patients with C. felis had been in close contact with cats at home (C. hominis and C. parvum that infect humans, and the transmission routes of such agents, has relevance for better understanding of the epidemiologic features of cryptosporidiosis.The transmission route for the unusual


There was information omitted from the Funding statement.The correct Funding statement should read: This work was supported by the Netherlands Organization for Scientific Research (NWO-ALW 834.11.002 and 036.002.598). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.


To the Editor: Fleas (order Siphonaptera) are obligate hematophagous insects. They are laterally flattened, holometabolous, and wingless ectoparasites. More than 2,500 species of flea, belonging to 16 families and 238 genera, have been described. A minority of these genera live in close association with humans (synanthropic), including fleas of these species: Pulex irritans, Ctenocephalides felis, Ctenocephalides canis, Xenopsylla cheopis, Nosopsyllus fasciatus, Echidnophaga gallinacea, and Tunga penetrans ; viruses ; protozoa ; or helminths  , and 30 fleas were collected from Mizan Teferi . The specimens were collected by using a plate filled with soapy water with a candle in the middle of the plate. Because fleas are thermotropic, they jumped toward the candle and fell onto the plate, where they rapidly drowned in the soapy water. The fleas were identified by morphologic features and stored in 90% ethanol until DNA extraction.P. irritans and C. felis) based on the sequences of mitochondrial cytochrome oxidase gene published in GenBank  that were specific for 2 species of flea  of 53 P. irritans specimens also contained DNA of R. felis. We amplified and sequenced nearly the entire rickettsial gltA gene from 3 C. felis and 10 P. irritans specimens and found that the sequence was identical to that of R. felis (GenBank accession no. NC_007111).We screened rickettsial DNA by using qPCR with a P. irritans and C. felis fleas facilitated the identification of damaged samples and also precluded the laborious and time-consuming procedure of identification by morphologic features.During the field collection of the fleas, the conservation of specimens may be difficult. Degradation of specimens may pose a problem for the ensuing morphologic identification. For fleas, a specific preparation is required that destroys internal organs and produces a chitin complex of the insect. This type of preparation makes it difficult, and sometimes impossible, to use the insect later for molecular studies. The development of qPCR specific for R. felis in Ethiopia include both C. felis and P. irritans fleas. In Ethiopia, P. irritans fleas have been reported to be prevalent (P. irritans fleas have been shown to be infected by R. felis in several locations, notably in the Democratic Republic of the Congo and in the United States, and another rickettsia phylogenetically similar to R. felis has been detected in P. irritans fleas in Hungary (R. felis in Senegal and Kenya (,R. felis in Ethiopia reveals the epidemiologic background for the fleaborne spotted fever in this region. We speculate that the elucidation of the full range of possible vectors of R. felis may facilitate the development of prevention measures that will help control this disease.We conclude that the reservoirs of


Nonylphenol (NP) is an ultimate degradation product of nonylphenol polyethoxylates (NPE) that is primarily used in cleaning and industrial processes. Its widespread use has led to the wide existence of NP in various environmental matrices, such as water, sediment, air and soil. NP can be decreased by biodegradation through the action of microorganisms under aerobic or anaerobic conditions. Half-lives of biodegradation ranged from a few days to almost one hundred days. The degradation rate for NP was influenced by temperature, pH and additions of yeast extracts, surfactants, aluminum sulfate, acetate, pyruvate, lactate, manganese dioxide, ferric chloride, sodium chloride, hydrogen peroxide, heavy metals, and phthalic acid esters. Although NP is present at low concentrations in the environment, as an endocrine disruptor the risks of long-term exposure to low concentrations remain largely unknown. This paper reviews the occurrence of NP in the environment and its aerobic and anaerobic biodegradation in natural environments and sewage treatment plants, which is essential for assessing the potential risk associated with low level exposure to NP and other endocrine disruptors. Since the early 1990s, a lot of research has been performed concerning the endocrine disruptors which are widespread in the environment. Previous studies have demonstrated that nonylphenol (NP) is one of the endocrine disruptors, and many studies have shown that NP can exert adverse effects to an ecosystem.etc., have drastically limited the use of NPEs. Switzerland has completely banned the use of these substances [NP is usually reacted to produce nonylphenol polyethoxylates (NPEs). NPEs are mainly used in a number of industrial processes and products, including cleaners, detergents and plastics. Annual world production of NPEs was about 520,000 tons in 1995, and the demand is increasing annually. In China, the production of NPEs is about 50,000 tons per year, and most enters into the aquatic environment . Due to bstances . In 2006NP is a compound which has numerous isomers. The side chain has nine carbons and can be attached to phenol at different points on the ring, thus producing different isomers. 4-NP is the most common commercial forms of NP, which is often used in experimentation and the analysis ,6. At roNP is the biological breakdown products of widely used nonionic surfactant, NPEs, which is directly discharged into the environment. NP has been widely found in the environment: in water, sediment, air, soil, aquatic organisms and even human food.Generally, NP occurs in the aquatic environment with concentrations varying widely in surface water from tens of ng/L ,9 to dozet al. [Duong C.N. et al.  estimateetc. Temperature was the key factor affecting the seasonal variation of NP in water and suspended particles. In Seine River Estuary, NP maximum levels in the dissolved phase and in the suspended particulate matter were observed during winter periods while significant decreases were observed during spring and autumn periods [The domestic and industrial wastewater produced, as well as surface runoff, could possibly be sources of NP in the aquatic environment. The distribution and characteristics of pollution sources along the river affected the spatial variation of NP . There w periods . These d periods . The hig periods . As to t periods ,16.Due to its hydrophobic properties, NP in surface water tends to be absorbed by sediment particles, which caused a preferential accumulation in sediments . The repet al. [High NP accumulation made the sediments a long-term pollutant sink and reservoir. The adsorbed compounds can be released into the water phase and become source of contaminants when hydraulic regimes of rivers change. However, De Weert et al.  thought Groundwater is of special interest because it makes up about twenty percent of the world’s fresh water supply and it is extraordinarily vulnerable to contamination by a variety of contaminants due to urban activities . Micropoet al. [Generally speaking, concentrations of NP in the groundwater were very low. In some area NP was not detected . When NPet al.  collecteet al. . The NP et al. [Recently, drinking water safety has received significant attention. Contaminants, such as NP, in drinking water might pose health risks to some residents. NP were detected in bottled water with the concentration of about 7.9 ng/L . Li X. eet al.  investiget al. . Althouget al. , more atNP are the most abundant compounds in raw wastewater as well as in effluents from all the treatment stages of sewage treatment plants. In influent wastewater, concentrations of NP ranging from 0.08 to 96.4 μg/L –49 have et al. thought that warm temperature and a high MLSS concentration would benefit the removal of NP from wastewater in the Anaerobic/Anoxic/Oxic (A/A/O) bioreactor [In a wastewater treatment plant many factors can influence the removal of NP, such as influent load, water quality of influents, plant configurations, hydraulic residence time (HRT), sludge retention time (SRT), biomass characteristics and the environmental conditions ,53,55,56oreactor .During wastewater treatment, NP accumulated in sewage sludge at a concentration of several hundred mg/kg ,60,61. BThe occurrence of NP in the air was ubiquitous in urban, remote, industrialized, coastal regions, and even in the central part of the North Sea . NP is nThe atmospheric concentration of NP showed declining trends from land to the open sea, suggesting that the atmosphere is a significant pathway for the transport of alkylphenols in the environment . Sea couNP can be introduced into soils in various ways, for example from atmospheric deposition, from soil amendment with sewage sludge, and from wastewater for irrigation of agricultural land . During Although NP is capable of being leached from soil, its short half-life means that its passage from soil to freshwater will be low . PreviouC. vulgaris [NP can be decreased by biodegradation in the water, sediment and soils through the action of microorganisms. In the Jialu River, about 23.7% of total decrease in NP concentration was caused by biodegradation . As thervulgaris .NP degradation under anaerobic conditions has only recently been demonstrated. Half-lives of anaerobic degradation ranged from 23.9 to 69.3 days ,83. Anaeet al. showed that NP degraded rapidly during incubation at low concentrations, but was more persistent at higher concentrations [Upon entering soil, NP can undergo a number of reactions  that ultimately control its fate and potential environmental hazard . The contrations . Approprtrations . Some trtrations .et al. [et al. [During recent years, a lot of research has been performed concerning the molecular mechanism for degradation of nonylphenol by a number of different strains. Understanding in more detail the molecular events in degradation of nonylphenol were illuminated from two different pathways. The ring cleavage pathway was elucidated through gene cloning and biochemical studies ,89, whicet al.  investig [et al. –96, in w [et al. ,97.NP is a virtually ubiquitous contaminant in the environment. The occurrence of NP has been reported around the world in waters, sediment, airs and soils. It can be decreased by biodegradation in natural environments and sewage treatment plants through the action of microorganisms under aerobic or anaerobic conditions. Although NP is present at low concentrations, the risks of long-term exposure to low concentrations remain largely unknown. More research needs to be done to determine the potential human and environmental health risks posed by exposure to NP in the environment.


Multiple sclerosis (MS) is a chronic inflammatory demyelinating disease of the central nervous system, for which no definitive treatment is available. Most patients start with a relapsing-remitting course (RRMS). Disease-modifying drugs (DMDs) reduce relapses and disability progression. First line DMDs include glatiramer acetate (GA), interferon-beta (INFb)-1a and INFb-1b, which are all administered via injections. Effectiveness of DMD treatment depends on adequate adherence, meaning year-long continuation of injections with a minimum of missed doses. In real-life practice DMD-treated patients miss 30% of doses. The 6-month discontinuation rate is up to 27% and most patients who discontinue do so in the first 12 months.Treatment adherence is influenced by the socio-economic situation, health care and caregivers, disease, treatment and patient characteristics. Only a few studies have dealt with adherence-related factors in DMD-treated patients. Self-efficacy expectations were found to be related to GA adherence. Patient education and optimal support improve adherence in general. Knowledge of the aspects of care that significantly relate to adherence could lead to adherence-improving measures. Moreover, identification of patients at risk of inadequate adherence could lead to more efficient care.In the near future new drugs will become available for RRMS. Detailed knowledge on factors prognostic of adherence and on care aspects that are associated with adequate adherence will improve the chances of these drugs becoming effective treatments. We investigate in RRMS patients the relationship between drug adherence and multidisciplinary care, as well as factors associated with adherence. Given the differences in the frequency of administration and in the side effects between the DMDs we decided to study patients treated with the same DMD, GA.The Correlative analyses of Adherence In Relapsing remitting MS (CAIR) study is an investigator-initiated, prospective, web-based, patient-centred, nation-wide cohort study in the Netherlands.The primary objective is to investigate whether GA adherence is associated with specific disciplines of care or quantities of specific care. The secondary objective is to investigate whether GA adherence is associated with specific aspects of the socio-economic situation, health care and caregivers, disease, treatment or patient characteristics.All data are acquired on-line via a study website. All RRMS patients in the Netherlands starting GA treatment are eligible. Patients are informed by neurologists, nurses, and websites from national MS patient organisations. All data, except on disability, are obtained by patient self-reports on pre-defined and random time points. The number of missed doses and the number of patients having discontinued GA treatment at 6 and 12 months are measures of adherence. Per care discipline the number of sessions and the total duration of care are measures of received care. The full spectrum of non-experimental care that is available in the Netherlands is assessed. Care includes 'physical' contacts, contacts by telephone or internet, health-promoting activities and community care activities. Care received over the preceding 14 days is assessed by patients at baseline and every other week thereafter up to month 12. Every 3 months neurologists and nurses record care disciplines to which patients have been referred.The Dutch Adherence Questionnaire-90 (DAQ-90) is a 90-item questionnaire based on the World Health Organisation (WHO) 2003 report on adherence and comprehensively assesses five domains of evidence-based determinants of adherence: socio-economic, health care and caregivers, disease, treatment, and patient-related factors. In addition, self-efficacy is assessed by the MS Self-Efficacy Scale (MSSES), and mood and health-related quality of life (HRQoL) by the Multiple Sclerosis Quality of Life-54 questionnaire (MSQoL-54). Relapses and adverse events probably or definitively related to GA are also reported.In this study data is mainly acquired by patients' self-reporting via the internet. On-line data acquisition by patients does not require study visits to the hospital and can easily be integrated into daily life. The web-based nature of the study is believed to prevent missing data and study drop-outs. Moreover, the automated process of filling in questionnaires ensures completeness and consistency, thus improving data quality. The combination of patient-reported outcomes, fully web-based data capture and nation-wide information to all eligible patients are distinguishing features of the study and contribute to its scientific potential.NTR2432Netherlands Trial Register (NTR):  Multiple sclerosis (MS) is a chronic inflammatory demyelinating disease of the central nervous system, for which no definite cure is available. Most patients start with a relapsing-remitting (RR) phase during which incomplete remissions often cause an increase in disability. Glatiramer acetate (GA), interferon-beta (INFb)-1a and INFb-1b are first-line disease-modifying drugs (DMDs) for RRMS treatment  and GA tAdherence to pharmacotherapy is inadequate in 30% to 50% of patients, irrespective of disease, prognosis or treatment settings . MedicatThere are two levels of inadequate adherence: a) missing doses and b) discontinuation for other reasons than severe or persistent side effects or insufficient clinical benefit . Data onAfter 4 months up to 11% of DMD-treated RRMS patients have discontinued treatment , and aftStudies agree that early DMD discontinuation mostly occurs in the first 12 months -11. RetrFactors relating to the missing of doses may be different from those relating to discontinuation . The WHOA pilot study in the Netherlands assessed 16 patient-related items that might affect GA adherence: the attitude towards self-injecting, previous immunomodulation, the reason for switching, concurrent chronic disease, disability, cognition, disease duration, type of skin, bodily constitution, working in the open, acceptance of disease, family support, social activities, personality, motivation and linguistic barrier [unpublished data]. Scoring each item for presence (1) or absence (0) the adding up of the scores yields the Discontinuation Risk Score (DRS), ranging from 0 to 16. Preliminary data suggest that patients with a DRS > 7 have an increased risk of GA discontinuation.According to the WHO 2003 report  and a reAt present new DMDs for RRMS are becoming available. More knowledge on which aspects of multidisciplinary care are related to adherence, and the factors prognostic of inadequate adherence could increase the chances that the new efficacious drugs become effective treatments.We conceived the idea to investigate adherence and multidisciplinary care in RRMS patients starting DMD treatment. The INFbs and GA have clearly different side effect profiles and injection frequencies. As both these aspects of treatment are likely to influence adherence we choose to study patients treated with one type of DMD, thus guaranteeing a homogenous study population. Because pilot data on discontinuation and risk factors were available for GA-treated patients in the Netherlands, it was decided to study patients starting GA treatment.Appendix A lists the questions of the study.Primary objective is to investigate whether GA adherence is associated with specific disciplines of care or quantities of specific care.Secondary objective is to investigate whether GA adherence is associated with specific characteristics of socio-economic situation, health care or caregivers, disease, treatment, or the patient.Tertiary objective is to assess the predictive value of the DRS with respect to GA adherence.An investigator-initiated, prospective, web-based, patient-centred, nation-wide, observational cohort study in the Netherlands. The study's name is an acronym from the principal analytical method, main theme and study population: Correlative analysis of Adherence In Relapsing remitting MS: CAIR. The study duration is 12 months. Nederlands Trial Register (NTR) code: TC2432.®). GA is administered by the patient according to the instructions in the package leaflet.GA is prescribed by neurologists as per regular care and dispensed as a commercial drug by general pharmacies (CopaxonePrimary outcomes:a) relations between numbers of missed doses and numbers of care sessions per discipline s. quantity of care per discipline,b) relations between number of patients who discontinued treatment and numbers of care sessions per discipline s. quantity of care per discipline.Secondary outcomes:a) relations between numbers of missed doses and presence s. degree of specific characteristics of the patient, socio-economic situation, health care, caregivers, disease, or treatment,b) relations between number of patients who discontinued treatment, and presence s. degree of specific characteristics of the patient, socio-economic situation, health care, caregivers, disease, or treatment.Tertiary outcomes:a) predictive value of DRS with respect to missed doses,a) predictive value of DRS with respect to number of patients who discontinued treatment.http://www.cairstudie.nl). For further information they may contact the study helpdesk by telephone or e-mail, or the coordinating investigator (PJJ) by e-mail.Patients are informed by neurologists, MS-nurses, or specialised nurses who teach patients to self-inject, and the websites of patient organisations. Patients are also advised to visit the study website  indication for GA treatment, 2) being relapse free and having stable symptoms for at least 30 days, 3) willing and able to comply with the protocol for the duration of the study, 4) having given written informed consent.Exclusion criteria: 1) contra-indication to GA as defined in the Summary of Product Characteristics text, 2) hypersensitivity to GA or mannitol, 3) worsening of symptoms suggestive of relapse, 4) pregnancy or lactation, 5) the time interval between the first GA injection and baseline assessment is more than 4 weeks.The protocol has been submitted to the Independent Review Board (IRB), an approved ethical committee residing in Amsterdam, the Netherlands. The IRB concluded that, because of the observational design of the study, a review by an ethical committee was not required, as the study did not qualify for being tested according to the Dutch Medical Research Involving Human Subjects Act of 1999 [Data is acquired via the study website. Patients log in with a code provided by the help desk and choose a username and password. On-line they go through various web pages containing the case record forms (CRFs) with questions and questionnaires. These electronic CRFs (eCRFs) are similar to paper questionnaires and data sheets. Questions relate to missing doses, GA discontinuation, adverse events, medication and relapses. Questionnaires pertain to self-efficacy, mood, other adherence-related factors and HR-QoL.Patients, neurologists and MS-nurses are informed by e-mail that an assessment is due and that the corresponding eCRFs have been made available for completion. eCRFs are to be completed within one week. Within this time frame eCRFs may be filled in at moments that are suitable to the participant. Completion may take as many sessions as needed, as answers are saved automatically. After confirmation by the participant the eCRF is automatically sent to the study centre. Incomplete eCRFs are returned. In case an eCRF has not been completed within one week the help desk reminds the participant by telephone. Patients who do not have a personal computer (PC) at their disposal or who are not capable of using a PC are sent a paper-and-pencil version of the questionnaires, whereas short eCRFs are completed by telephone.The number of missed doses in the preceding 14 days, and discontinuation of GA, the date of discontinuation and the date of restart, which ever is applicable, are recorded by patients at 3, 6, 9 and 12 months. In addition, the number of missed doses are documented at 6 random time points unknown to patients, neurologists and MS-nurses. Neurologist or MS-nurse also record the date of discontinuation or the date of restart.Care given by the following disciplines is assessed 1) neurologist, 2) MS-nurse, 3) general practitioner 4) home care 5) psychologist, 6) occupational therapy, 7) physiotherapy, 8) social worker, 9) dietician, 10) pharmacist, 11) rehabilitation doctor, 12) other medical specialists, 13) community care, 14) others. Care includes 'physical' contacts, contacts by telephone, internet, health-promoting activities that are coached or counselled by caregivers , or any community care activities.Care received in the preceding 14 days is assessed by patients at baseline and bi-weekly (once every 2 weeks) thereafter up to week 52. For every discipline in which care is received, the number of care sessions and time per care session  are recorded. Moreover, every 3 months neurologists and nurses record the care disciplines to which they have referred the patient.Self-efficacy is the subjective belief that one can overcome challenges that one is faced with, and has been found to be a determinant of GA adherence in patients with RRMS . Self-efMood is assessed by the questions 25 and 28 from the Multiple Sclerosis Quality of Life-54 questionnaire (MSQoL-54) . Health-The Dutch Adherence Questionnaire-90 (DAQ-90) is a 90-item questionnaire designed to assess all factors identified by the WHO 2003 report  as evideAt baseline the 16 items of the DRS are scored for absence (0) or presence (1) by the nurses who teach patients to self-administer. The adding up of item scores yields the DRS.Adverse events considered by patients, neurologists or nurses as probably or definitely related to GA treatment are reported on-line at 3, 6, 9 and 12 months. As the study is observational and does not interfere with care, patients always report adverse events to their neurologist or MS-nurse. Serious adverse events are recorded by neurologists or MS-nurses and reported to the coordinating investigator within 48 hours.At baseline neurologists or MS-nurses provide the following data: disease course, disease duration, medication, previous immunomodulation, the number of relapses in the last 12 and 24 months, the number of steroid-treated relapses in the last 12 and 24 months. Assessment of disability  at baseline and 12 months is optional. Relapses occurring during the study and eventual steroid treatment are reported by patients and neurologists or MS-nurses at months 3, 6, 9 and 12.The schedule of assessments is presented in Table In order to determine the size of the study, we first assumed that the analysis would be based on a t-test: For each factor we form three tertiles: patients with low, intermediate and high scores. When a t-test is carried out to compare a parameter between the lowest and highest tertile, 65 patients per tertile are required in order to detect a difference of 0.5 standard deviations with 80% power . As we will use linear regression instead of a t-test, the power of the regression analysis may even be higher, but will be at least comparable. In a previous on-line study in GA-treated patients compliance was very high, both with respect to missing data and drop outs . TherefoIn phase II of the recruitment all Dutch patients who start GA treatment are informed of the study. Based on data from a previous study we hypothesize that 50% of patients are willing to participate . Based oPer discipline the relations between missed doses and the number of care sessions s. care duration will be evaluated using linear regression; and the relations between discontinuation and the number of care sessions s. care duration will be evaluated in a similar way, but by a proportional hazard analysis, with stepwise selection. In addition, univariable analyses will be carried out. Two-sided 95% confidence intervals will be calculated.A manuscript, based on the study report, will be submitted to a peer-reviewed international scientific journal for publication. Oral or poster communications will be given on international and national symposia. Participating patients will receive a summary of the study report , written in a wording that is understandable to lay persons, as soon as the report has been finalized.The CAIR study investigates relations between adherence to GA treatment and disciplines or quantity of care, based on data on missing doses, discontinuation and received care as reported by patients. Neurologists or MS-nurses may refer patients to caregivers or give advice on health promoting activities. However, as adherence is often sub-optimal in patients with chronic disease, self-reporting by patients on the care they actually did receive is likely to better reflect reality .The patient-centred character of the study is realized by the web-based approach. Data is obtained by the patient's on-line self-reporting. Thus, data acquisition does not require study visits to the hospital and can be integrated into daily life. This feature of the study is believed to promote compliance and prevent study drop-outs. Moreover, the use of the internet contributes to data quality assurance, as the automated process of data capture ensures completeness and consistency.According to the cohort-based, nation-wide design we aim to inform every RRMS patient in the Netherlands who starts GA treatment. Neurologists and MS-nurses in 15 MS-dedicated hospitals, evenly distributed over the country, actively recruit patients. In addition, the nurses, who teach patients to self-inject, inform patients of the possibility of participating. Patients' awareness of the study is promoted by information on websites from national MS patients organisations. Recruitment is on schedule, with 119 patients being enrolled as per October 2010.In all, the combination of patient-reported outcomes, fully on-line data capture, and nation-wide information of all eligible patients are distinguishing features of the CAIR study. The nation-wide cohort design makes sure that results will be applicable to Dutch RRMS patients. Implementation of the study's conclusions might well improve the effectiveness of present and future DMD treatments, and increase the efficiency of MS care.Dr. Jongen has received honoraria from Merck-Serono, Novartis, Bayer-Schering, Biogen-Idec, Sanofi-Aventis, Teva, and Allergan for activities as speaker or advisory committee member, research support, or travel grants for conferences.PJJ initiated the study, contributed to the conception and design of the study, coordinates the study, and drafted the manuscript. GH contributed to the conception and design of the study. RH, HS, JG, JHV, EH, MvH, EvM, JS, EdS, TS, MT, EZ, JtH and RvdK all contributed to the acquisition of data. GB contributed to the conception and design of the study and co-drafted the manuscript. All authors read and approved the final version of the manuscript.Peter Joseph Jongen is a neurologist and the founding director of the MS4 Research Institute, Nijmegen, the Netherlands. He has been involved in MS clinical research and patient care for more than 15 years. He is a member of the International Medical and Scientific Board of the Multiple Sclerosis International Federation (MSIF), a former director of the MS Centre Nijmegen, a former council member of the European Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS), and author of over 90 peer-reviewed scientific articles. The MS4 Research Institute is an independent non-profit organisation, that conceives, performs, and coordinates scientific research on the therapeutic value of treatments in MS.List of Questions of the StudyI. What are the relations between GA adherence and multidisciplinary care?neurologist  related to GA adherence ?1. Is the quantity of care given by the MS-nurse  related to GA adherence ?2. Is (the quantity of) care given by the general practitioner  related to GA adherence ?3. Is (the quantity of care) given by the home care  related to GA adherence ?4. Is (the quantity of) psychologist  related to GA adherence ?5. Is (the quantity of) care given by a occupational care  related to GA adherence ?6. Is (the quantity of) physiotherapy  related to GA adherence ?7. Is (the quantity of) social worker  related to GA adherence ?8. Is (the quantity of) care given by a dietician  related to GA adherence ?9. Is (the quantity of) care given by a pharmacist  related to GA adherence ?10. Is (the quantity of) care given by the rehabilitation doctor  related to GA adherence ?11. Is (the quantity of) care given by a community care  related to GA adherence ?12. Is (the quantity of) What characteristics of the patient, the socio-economic situation, health care or caregivers, disease, or treatment are related to GA adherence?II. 1. Is self-efficacy related to GA adherence?2. Is mood related to GA adherence?3. What other characteristics of the patient are related to GA adherence?4. What characteristics of the socio-economic situation, health care or caregivers, disease, or treatment are related to GA adherence?III. What is the predictive value of the DRS with respect to GA adherence?1. What is the predictive value of the DRS with respect to GA discontinuation?2. What is the predictive value of the DRS with respect to missed GA doses?Dutch Adherence Questionnaire-90 (DAQ-90) Table Based on WHO report 2003© P.J. Jongen, MS4 Research Institute, Nijmegen, the Netherlands 2009Version for Glatiramer AcetatePatient ID: ........................................................................Date: ..............................................................................Study site: ........................................................................© P.J. Jongen, MS4 Research Institute, Nijmegen, the Netherlands 2009The pre-publication history for this paper can be accessed here:http://www.biomedcentral.com/1471-2377/11/40/prepub


A vital function of the mammalian cortex is the processing of dynamical stimuli. These stimuli are encoded in cortical neurons as modifications of the input current, which can be brief, prolonged or periodic, all depending on the type of the sensory stimulus, e.g. ,2. While


Apis mellifera encompasses Europe, Africa, and the Middle East, whereas the nine other species of Apis are found exclusively in Asia. It is therefore commonly assumed that A. mellifera arose in Asia and expanded into Europe and Africa. However, other hypotheses for the origin of A. mellifera have also been proposed based on phylogenetic trees constructed from genetic markers. In particular, an analysis based on >1000 single-nucleotide polymorphism markers placed the root of the tree of A. mellifera subspecies among samples from Africa, suggestive of an out-of-Africa expansion. Here, we re-evaluate the evidence for this and other hypotheses by testing the robustness of the tree topology to different tree-building methods and by removing specimens with a potentially hybrid background. These analyses do not unequivocally place the root of the tree of A. mellifera subspecies within Africa, and are potentially consistent with a variety of hypotheses for honeybee evolution, including an expansion out of Asia. Our analyses also support high divergence between western and eastern European populations of A. mellifera, suggesting they are likely derived from two distinct colonization routes, although the sources of these expansions are still unclear.The native range of the honeybee  Apis mellifera, is a species of crucial economic, agricultural, and environmental importance. Due to the activities of beekeepers it is now spread across the entire world, but its native range is large and diverse, spanning Europe, Africa, and the Middle East. Including A. mellifera, 10 species of honeybee belonging to the genus Apis are generally recognized , giant bees , and dwarf bees   and their colonization of their present ranges (beginning around 1 million years ago). However, genetic and morphological relationships between extant subspecies can be used to infer the timing and location of their common origin.The A. mellifera, summarized in A. mellifera has its historic center in the Middle East or northeast Africa from where it colonized Europe through two routes: a direct eastern route and a western route via north Africa and the Iberian peninsula  is typed in 341 individuals from 14 geographical subspecies of A. mellifera and three outgroups  argued in favor of this hypothesis  from the other members of the A group. The tree therefore splits into two main clades, one grouping the M lineage (A. m. mellifera and A. m. iberiensis) together with A. m. intermissa and the other containing all other subspecies of the A, C, and O lineages. Based on the position of the root within the A lineage, it was suggested that modern populations of A. mellifera can trace their origin to Africa via two distinct migrations – a western expansion of the M lineage into Europe and one or more eastern expansions of the O and C lineages into Europe and Asia (The hypothesis of an African origin was espoused by E. O. Wilson (quoting C. D. Michener) based on an assumption that the ability of domestic s Wilson . It was and Asia B, iii.A. mellifera is important for tracing the evolution of novel and local adaptations in a species increasingly threatened by disease, climate change, habitat loss, and introgression , 31 from West Europe , 42 from Asia , and 67 from Africa . Samples from three related Apis species were also included .Detailed information about samples, locations, and SNPs identification are described in Whitfield et al. . The datθ , including the three outgroup species using a custom perl script  but not present in other subspecies, and no examples of SNPs that are fixed in a group but absent in other groups. That the majority of genetic variation is shared indicates that A. mellifera subspecies have not experienced long periods of isolation and makes interpretation of bifurcating trees problematic.In total, 1029 SNPs from Whitfield et al.  exhibit bspecies A. The maFST distances among the 14 A. mellifera subspecies and three outgroup species  and A. m. lamarckii (A group) appear closer to the C group. This could potentially indicate recent hybridization due to beekeeping with a popular race such as A. m. carnica (C group). In addition, samples of A. m. intermissa appear intermediate to the A and M groups, as previously observed. It is clear from these analyses that samples cluster tightly into the four lineage groups, but that within each group, subspecies are less easily distinguishable from each other by genetic differences.When bspecies B. Howevebspecies C. Insteased tree A. Hence,features A. First,vidually . In thisA. m. intermissa and A. m. iberiensis removed, as these subspecies occur close to the boundary between Western Europe and North Africa  an ancient split with other cavity-nesting honeybee species followed by (2) dispersal and differentiation of subspecies across their native ranges of Europe, Africa, and the Middle East, and finally (3) further dispersal and admixture of subspecies via the activities of humans. The oldest evidence for an association between humans and honeybees is a cave painting in Spain depicting honey hunting, dated at around 7000 years ago  a Middle-Eastern origin, including colonization of Europe via a western route  subspecies is well supported by genetic and morphological evidence. However, studies have come to conflicting results about how these clusters are related. One point of contention is whether there is evidence for a close relationship between the A and M lineages, which could support a western route of colonization of Europe. Such a link is indicated from the morphological evidence (Ruttner et al. The presence of at least four distinct lineage groups of A. mellifera originated. One question is whether the source population of expansions of A. mellifera was adapted to temperate climates. One theory maintains that development of these adaptations allowed expansion into Europe from Africa, where the only native tropical populations of A. mellifera are found today (Wilson A. cerana inhabit temperate climates within Asia (Corlett A. mellifera in Africa are numerous, whereas in Europe honeybees are mainly restricted to managed colonies at a much lower density (Moritz et al. The other point of discussion is where modern subspecies of y Wilson . However Corlett , so cold Corlett . Higher A. mellifera can also be gained from locating the position of the root of the tree of subspecies. This is problematic because of the large amount of shared variation and inconsistencies in internal branches. The root appears close to the node joining A and M branches but different analyses place it either within A lineages, or ancestral to both lineage groups. The SNP data therefore does not provide an unequivocal answer to the root of the tree. Here, we have shown that the shape of the SNP tree of A. mellifera subspecies is sensitive to inclusion of A. m. intermissa, which does not appear genetically distinct. The A. m. intermissa samples included in this data set could have been affected by gene flow from the M lineage group, or alternatively the results could indicate a hybrid origin of A. m. intermissa. It is likely that unbiased sampling of SNPs will provide a more comprehensive answer. In summary, while it is not possible to conclusively rule out any of the major hypotheses for the origin of A. mellifera, the hypothesis first proposed by Ruttner (Insight into the origin of  Ruttner  (Fig. 1BA. mellifera is important for several reasons. During colonization of current ranges they experienced strong selection for adaptation (Zayed and Whitfield A. mellifera colonized new environments is crucial for understanding how and when these adaptations arose. Furthermore, subspecies differ in their susceptibility to major diseases and African subspecies in particular appear to have greater tolerance to Varroa destructor mites (Dietemann et al. A full understanding of origin of


Embedded systems are playing an increasingly important role in control engineering. Despite their popularity, embedded systems are generally subject to resource constraints and it is therefore difficult to build complex control systems on embedded platforms. Traditionally, the design and implementation of control systems are often separated, which causes the development of embedded control systems to be highly time-consuming and costly. To address these problems, this paper presents a low-cost, reusable, reconfigurable platform that enables integrated design and implementation of embedded control systems. To minimize the cost, free and open source software packages such as Linux and Scilab are used. Scilab is ported to the embedded ARM-Linux system. The drivers for interfacing Scilab with several communication protocols including serial, Ethernet, and Modbus are developed. Experiments are conducted to test the developed embedded platform. The use of Scilab enables implementation of complex control algorithms on embedded platforms. With the developed platform, it is possible to perform all phases of the development cycle of embedded control systems in a unified environment, thus facilitating the reduction of development time and cost. The evidence includes the fact that of the 9 billion processors manufactured in 2005, less than 2% were used in PCs, Macs, and Unix workstations, while the remainder went into embedded systems . An embeThe majority of embedded control systems in use today are implemented on microcontrollers or programmable logic controllers (PLC). Although microcontrollers and programmable logic controllers provide most of the essential features to implement basic control systems, the programming languages for embedded control software have not evolved as in other software technologies ,5. A larhttp://www.artist-embedded.org). Another example is the CEmACS project (http://www.hamilton.ie/cemacs/) that aims to devise a systematic, modular, model-based approach for designing complex automotive control systems. From a technical point of view, a classical solution for developing complex embedded control software is to use the Matlab/Simulink platform that has been commercially available for many years. For instance, Bucher and Balemi [There are quite a lot of efforts in both industry and academia to address the above-mentioned problem. One example is the ARTIST2 network of excellence on embedded systems design  development board running a Linux operating system. Since Scilab was originally designed for general-purpose computers such as PCs, we port Scilab to the embedded ARM-Linux platform. To enable data acquisition from sensors and control of physical processes, the drivers for interfacing Scilab with several communication protocols including serial, Ethernet, and Modbus are implemented, respectively. The developed platform has the following main features:et al. [et al. [et al. [et al. [While Scilab has attracted significant attention around the world, limited work has been conducted in applying it to the development/implementation of practically applicable control applications. Bucher et al.  presente [et al.  develope [et al.  proposed [et al.  presenteThe rest of this paper is organized as follows. In the next Section, we introduce the primary software tool used, i.e., Scilab. Section 3 discusses the software design lifecycle in embedded control systems and presents the design methodology adopted in this paper. In Section 4, the implementation of the platform is described. Details of three major components, i.e., hardware, software, and interfaces, are given. The developed system is tested in Section 5 using an illustrative example. Experimental results are presented. We conclude the paper in Section 6.2.http://www.scilab.org) [Scilab (lab.org) , 13 is aScilab provides hundreds of built-in powerful primitives in the form of mathematical functions. It supports all basic operations on matrices such as addition, multiplication, concatenation, extraction, and transpose, etc. It has an open programming environment in which the user can define new data types and operations on these data types. In particular, it supports a character string type that allows the online creation of functions. It is easy to interface Scilab with Fortran, C, C++, Java, Tck/Tk, LabView, and Maple, for example, to add interactively Fortran or C programs. Scilab has sophisticated and transparent data structures including matrices, lists, polynomials, rational functions, linear systems, among others. It includes a high-level programming language, an interpreter, and a number of toolboxes for linear algebra, signal processing, classic and robust control, optimization, graphs and networks, etc. In addition, a large (and increasing) number of contributions can be downloaded from the Scilab website. The latest stable release of Scilab (version 4.1.2) can work on GNU/Linux, Windows 2000/XP/VISTA, HP-UX, and Mac OS.http://www.scicos.org), which corresponds to Simulink in Matlab. Scicos is particularly useful in signal processing, systems control, and study of queuing, physical, and biological systems. It enables the user to model and simulate the dynamics of hybrid dynamical systems through creating block diagrams using a GUI-based editor and to compile models into executable codes. There are a large number of standard blocks available in the palettes. It is possible for the user to program new blocks in C, Fortran, or Scilab Language and construct a library of reusable blocks that can be used in different systems. Scicos allows running simulations in real time and generating C code from Scicos model using a code generator. Scilab/Scicos is the open source alternative to commercial software packages for system modeling and simulation such as Matlab/Simulink. Scilab includes a graphical system modeler and simulator toolbox called Scicos , a three-port USB 2.0 host, running at 12 Mbps, three UARTs, and external interfaces to SPI, AC97, IIS audio, PCMCIA, Raster/LCD, IDE storage peripherals, keypad and touchscreen, etc. In addition, a LG-Philips LB064V02-TD01 LCD is used to achieve user-friendly display.4.2.The key software packages used include Linux, TinyX, JWM, and Scilab/Scicos. All these tools can be freely downloaded from the Internet, see TinyX is a family of X servers designed to be particularly small, which is well suited for embedded systems. TinyX tends to avoid large memory allocations at runtime, and tries to perform operations on-the-fly whenever possible. Unlike the usual XFree86 server, TinyX does not require any configuration files, and will function even if no on-disk fonts are available. With TinyX, the users can easily build their own GUI applications. JWM is a window manager for the X11 window system. It is written in C and uses only Xlib at a minimum.4.2.1.Scilab/Scicos was originally designed for PC-based systems but not embedded ARM-Linux systems. Therefore, it is necessary to port Scilab/Scicos onto the embedded platform. Since the majority of core codes of Scilab are written in Fortran, we first build a cross-compiler for g77 in order to support cross-compilation of GUI, for example. The GUI system of Scilab/Scicos is based on X11, and therefore the X11 server TinyX is included. To reduce runtime overheads, we optimize/modify some programs in Scilab/Scicos.Port Linux to the ARM platform;Port TinyX to ARM-Linux;Port JWM to ARM-Linux;Port Scilab/Scicos to ARM-Linux;Configure and optimize the embedded Scilab/Scicos.We have successfully ported Scilab/Scicos to the ARM-Linux system see . To achiFor the first three tasks, technical instructions are available in the literature  ; exit 1; } ;{  is given for different sampling periods, i.e., h = 0.1s and 0.5s, respectively. It is seen that the control system delivers quite good performance, especially when the sampling period is 0.1s. In both cases, the water level successfully reaches the desired value (i.e. 10 in the experiment) and remains steady after a transient process.The control performance of the system is shown in 6.In this paper we have developed an embedded platform that can be used to design and implement embedded control systems in a rapid and cost-efficient fashion. This platform is built on free and open source software such as Scilab and Linux. Therefore, the system development cost can be minimized. Since the platform provides a unified environment in which the users are able to perform all phases of the development cycle of control systems, the development time can be reduced while the resulting performance may potentially be improved. In addition to industrial control, the platform can also be applied to many other areas such as optimization, image processing, instrument, and education. Our future work includes test and application of the developed platform in real-world systems where real sensors and actuators are deployed.