High Rate of Awarding Compensation for Claims of Injuries Related to Clinical Trials by Pharmaceutical Companies in Japan: A Questionnaire Survey

Introduction

International norms and ethical standards have suggested that compensation for research-related injury should be provided to injured research volunteers. However, statistical data of incidence of compensation claims and the rate of awarding them have been rarely reported.

Method

Questionnaire surveys were sent to pharmaceutical companies and medical institutions, focusing on industry-initiated clinical trials aiming at new drug applications (NDAs) on patient volunteers in Japan.

Results

With the answers from pharmaceutical companies, the incidence of compensation was 0.8%, including 0.06% of monetary compensation. Of the cases of compensation claims, 99% were awarded. In turn, with the answers from medical institutions, the incidence of compensation was 0.6%, including 0.4% of serious but not death cases, and 0.04% of death cases. Furthermore, most claims for compensation were initiated by medical institutions, rather than by the patients. On the other hand, with the answers from clinical trial volunteers, 3% of respondents received compensations. These compensated cases were 25% of the injuries which cannot be ruled out from the scope of compensation.

Conclusion

Our study results demonstrated that Japanese pharmaceutical companies have provided a high rate of compensation for clinical trial-related injuries despite the possibility of overestimation. In the era of global clinical development, our study indicates the importance of further surveys to find each country''s compensation policy by determining how it is being implemented based on a survey of the actual status of compensation coming from statistical data.     

Growth and survival of peritrich ciliates in an urban stream

Summary A computerized system was devised to trace the attachment, growth and disappearance of peritrich ciliates in an urban river. By tracing the development of each Carchesium polypinum colony in the river, it was possible to estimate the actual growth rate of this species without considering the effect of immigration. The survival and colonization rates of the colonies and individuals of solitary species could also be estimated. C. polypinum showed high growth rates (r=1.370 day^-1, doubling time 12.14 h). The number of daily colonizers also increased at a high rate, and the combination of growth and colonization caused very high population increase rates at the area level. Because of its low survivorship, the rate of Vorticella microstoma increase was much lower than previously reported. The survival of solitary species and small colonies was lower than with large colonies, and fewer new colonizers survived with the development of the attached microbial community.     

Maximal Ca2+-activated force and myofilament Ca2+ sensitivity in intact mammalian hearts. Differential effects of inorganic phosphate and hydrogen ions

Myofilament Ca2+ sensitivity and maximal Ca2+-activated force are fundamental properties of the contractile proteins in the heart. Although these properties can be evaluated directly in skinned preparations, they have remained elusive in intact tissue. A novel approach is described that allows maximal Ca2+-activated force to be measured and myofilament Ca2+ sensitivity to be deduced from isovolumic pressure in intact perfused ferret hearts. Phosphorus nuclear magnetic resonance spectra are obtained sequentially to measure the intracellular inorganic phosphate (Pi) and hydrogen ion (H+) concentrations. After a period of perfusion with oxygenated, HEPES-buffered Tyrode solution, hypoxia is induced as a means of elevating [Pi]. The decline in twitch pressure can then be related to the measured increase in [Pi]. After recovery, hearts are perfused with ryanodine to enable tetanization and the measurement of maximal Ca2+-activated pressure. Hypoxia is induced once again, and maximal pressure is correlated with [Pi]. We then compare the relations between [Pi] and maximal pressure on the one hand, and [Pi] and twitch pressure on the other. If the two relations differ only by a constant scaling factor, then the decline in twitch pressure can be attributed solely to a decline in maximal pressure, with no change in myofilament sensitivity. We obtained such a result during hypoxia, which indicated that Pi accumulation decreases maximal force but does not change myofilament sensitivity. We compared these results with acidosis (induced by bubbling with 5% CO2). In contrast with Pi, the accumulation of H+ decreases twitch force primarily by shifting myofilament Ca2+ sensitivity. This approach in intact tissue has strengths and limitations complementary to those of skinned muscle experiments.     

Expression of inducible nitric oxide (NO) synthase but not prevention by its gene ablation of hepatocarcinogenesis with fibrosis caused by a choline-deficient, L-amino acid-defined diet in rats and mice.

Expression of inducible nitric oxide synthase (iNOS) and effects of iNOS gene ablation on the hepatocarcinogenesis associated with fibrosis caused by a choline-deficient, L-amino acid-defined (CDAA) diet, were examined in male F344 rats and C57BL/6J wild-type and iNOS-/- mice. Western blot, RT-PCR and immunohistochemical analyses revealed increased expression of iNOS protein and mRNA in the livers of rats and wild-type mice fed a CDAA diet for 12-80 weeks, associated with elevated serum NO(x) and liver nitrotyrosine levels. iNOS-/- mice demonstrated greater liver injury and fibrosis in the early stage than their wild-type counterparts, but this did not significantly affect the incidence and multiplicity of altered foci, adenomas and hepatocellular carcinomas in spite of immunohistochemical iNOS expression in these lesions. Results suggested no major determinant roles of the expressed iNOS in the development of liver tumors caused by the CDAA diet.     

Cytological,genetic, and biochemical characteristics of an unusual non‐Chlorella photobiont of Stentor polymorphus collected from an artificial pond close to the shore of Lake Biwa,Japan

Stentor polymorphus (Müller) Ehrenberg (Heterotrichea, Ciliophora) is a trumpet‐form ciliate with endosymbiotic green algae (photobionts). Previous reports have indicated that this photobiont has a form typical of Chlorella Beijerinck (Trebouxiophyceae), with one chloroplast and a distinct pyrenoid. We collected S. polymorphus from an artificial pond on the shore of Lake Biwa in Japan. Microscopic examination demonstrated that there was no pyrenoid in the photobiont, and thus we analyzed the cytological, genetic, and biochemical characteristics of these algal cells. Cultured photobionts were smaller than those in hospite. Phylogenetic analyses placed the photobiont within the genus Mychonastes Simpson and Van Valkenburg, a chlorophycean alga occurring in fresh/brackish waters that lacks pyrenoids. Mychonastes provided little photosynthate to its host; the quantity of carbohydrate amounted to only 2% of that provided to Paramecium bursaria (Ehrenberg) Focker by its photobiont.     

Vorticella Linnaeus, 1767 (Ciliophora, Oligohymenophora, Peritrichia) is a grade not a clade: redefinition of Vorticella and the families Vorticellidae and Astylozoidae using molecular characters derived from the gene coding for small subunit ribosomal RNA

Recent phylogenetic analyses of the peritrich genus Vorticella have suggested that it might be paraphyletic, with one Vorticella species - Vorticella microstoma grouping with the swimming peritrichs Astylozoon and Opisthonecta in a distant clade. These results were based on very limited taxon sampling and thus could not be accepted as conclusive evidence for revising the generic classification. We tested paraphyly of the genus Vorticella by making a new analysis with a broad range of samples from three continents that yielded 52 new sequences of the gene coding for small subunit rRNA. Our results, together with the available sequences in Genbank, form a comprehensive set of data for the genus Vorticella. Analyses of these data showed that Vorticella microstoma morphotypes, Astylozoon, and Opisthonecta form a well-supported, monophyletic clade, that is distinct from and basal to the family Vorticellidae containing other species of Vorticella. Paraphyly of the genus Vorticella and family Vorticellidae was strongly confirmed by these results. Furthermore, the two clades of Vorticella identified by the SSU rRNA gene are so genetically diverse whereas the genetic distances within the one containing Vorticella microstoma morphotypes, Astylozoon, and Opisthonecta were so slight, which marked it as a separate family that must be defined by molecular characters in the absence of unifying morphological and morphogenetic characters. An emended characterization and status of the genus Vorticella, the families Vorticellidae and Astylozoidae are presented and discussed.     

Distributional survey of large branchiopods of rice paddies in Shiga Prefecture,Japan: a Lake Biwa Museum project based on lay amateur participation

A distributional survey of the large branchiopod crustaceans of the rice paddies of Shiga Prefecture, Japan, was conducted by the Lake Biwa Museum in May and June of 1999 and 2000. Collecting kits were issued to over 100 lay Field Reporters, who returned all samples, usually dried, to the museum for processing. Their 242 species-lots were augmented by 146 from Grygier, 46 from Ida, and 41 from other museum staff. Apart from this survey, 50 additional records in 1997–2000 were also taken into account. Seven species were recorded in the prefecture's southern half: Branchinella kugenumaensis (Ishikawa), Caenestheriella gifuensis (Ishikawa), and Lynceus biformis (Ishikawa) with wide distributions; Triops longicaudatus (LeConte) and Leptestheria kawachiensis Uéno limited to paddy areas around the south end of Lake Biwa; and Eulimnadia sp. mostly in remnant paddy areas threatened with urban development in Otsu city, with Triops granarius (Lucas) at a single such site in Otsu. In the prefecture's northern half, only B. kugenumaensis and C. gifuensis occurred to a limited degree. Possible reasons for these differences are discussed. Data pertaining to species co-occurrence and occurrence relative to the ongoing program of paddy field consolidation in the prefecture are presented and discussed. Success of the survey was due to the use of Field Reporters, who were able to provide a high degree of coverage of the study area, as well as the clearly defined habitat, the low number and easy recognizability of species, and the collection of voucher material from all sites. Conservation-related results included the listing of Eulimnadia sp. as a `rare' species by Shiga Prefecture.     

Morphology and gene sequence of Levicoleps biwae n. gen., n. sp. (Ciliophora, Prostomatida), a proposed endemic from the ancient Lake Biwa, Japan

Levicoleps biwae n. gen., n. sp. was discovered in organic mud on the shore of Lake Biwa, Japan. Its morphology and small subunit rRNA gene sequence were studied with standard methods. Further, we established a terminology for the colepid armour and selected four features for genus recognition: the number of armour tiers, the structure of the tier plates, the presence/absence of armour spines, and the number of adoral organelles (three or five). The Japanese colepid, a barrel-shaped ciliate with an average size of 75 x 45 microm, has six armour tiers and hirtus-type tier plates, but lacks armour spines, both in the environment and in laboratory culture. Thus, it is considered to represent a new genus. This rank is supported by the considerable genetic distance (7%) from the common Coleps hirtus. Although L. biwae looks quite similar to C. hirtus in vivo, it is very likely most closely related to Coleps amphacanthus, a species with conspicuous armour spines, as indicated by body size, the number of ciliary rows and, especially, the multiple caudal cilia. Lake Biwa is about four million years old and inhabited by many endemic organisms, ranging from algae to large fish. Thus, we suspect that L. biwae is restricted to Lake Biwa or, at least, to Asia. Based on literature data and the generic features established, we also propose the new genus Reticoleps for Coleps remanei Kahl, 1933, and resurrect the genus Pinacocoleps Diesing, 1865 to include Coleps incurvus Ehrenberg, 1833, Coleps pulcher Spiegel, 1926, Coleps tessalatus Kahl, 1930 and, probably, Baikalocoleps quadratus Obolkina, 1995a. Nine colepid genera are diagnosed and dichotomously keyed.