The Tokyo Oldest Old Survey on Total Health (TOOTH): A longitudinal cohort study of multidimensional components of health and well-being

<p>Abstract</p> <p>Background</p> <p>With the rapid worldwide increase in the oldest old population, considerable concern has arisen about the social and economic burden of diseases and disability in this age group. Understanding of multidimensional structure of health and its life-course trajectory is an essential prerequisite for effective health care delivery. Therefore, we organized an interdisciplinary research team consisting of geriatricians, dentists, psychologists, sociologists, and epidemiologists to conduct a longitudinal observational study.</p> <p>Methods/Design</p> <p>For the Tokyo Oldest Old Survey on Total Health (TOOTH) study, a random sample of inhabitants of the city of Tokyo, aged 85 years or older, was drawn from the basic city registry. The baseline comprehensive assessment consists of an in-home interview, a self-administered questionnaire, and a medical/dental examination. To perform a wide variety of biomedical measurements, including carotid ultrasonography and a detailed dental examination, participants were invited to our study center at Keio University Hospital. For those who were not able to visit the study center, we provided the option of a home-based examination, in which participants were simultaneously visited by a geriatrician and a dentist. Of 2875 eligible individuals, a total of 1152 people were recruited, of which 542 completed both the in-home interview and the medical/dental examination, with 442 completed the in-home interview only, and another 168 completed self or proxy-administered data collection only. Carotid ultrasonography was completed in 458 subjects, which was 99.6% of the clinic visitors (n = 460). Masticatory assessment using a colour-changeable chewing gum was completed in 421 subjects, a 91.5% of the clinic visitors.</p> <p>Discussion</p> <p>Our results demonstrated the feasibility of a new comprehensive study that incorporated non-invasive measurements of subclinical diseases and a detailed dental examination aiming at community-dwelling individuals aged 85 years or older. The bimodal recruitment strategy is critically important to capture a broad range of health profiles among the oldest old. Results form the TOOTH study will help develop new models of health promotion, which are expected to contribute to an improvement in lifelong health and well-being.</p> <p>Trial Registration</p> <p>This study has been registered in the UMIN-Clinical Trial Registry (CTR), ID: UMIN000001842.</p

A cell-based high-throughput screening method to directly examine transthyretin amyloid fibril formation at neutral pH

Transthyretin (TTR) is a major amyloidogenic protein associated with hereditary (ATTRm) and nonhereditary (ATTRwt) intractable systemic transthyretin amyloidosis. The pathological mechanisms of ATTR-associated amyloid fibril formation are incompletely understood, and there is a need for identifying compounds that target ATTR. C-terminal TTR fragments are often present in amyloid-laden tissues of most patients with ATTR amyloidosis, and on the basis of in vitro studies, these fragments have been proposed to play important roles in amyloid formation. Here, we found that experimentally-formed aggregates of full-length TTR are cleaved into C-terminal fragments, which were also identified in patients' amyloid-laden tissues and in SH-SY5Y neuronal and U87MG glial cells. We observed that a 5-kDa C-terminal fragment of TTR, TTR81–127, is highly amyloidogenic in vitro, even at neutral pH. This fragment formed amyloid deposits and induced apoptosis and inflammatory gene expression also in cultured cells. Using the highly amyloidogenic TTR81–127 fragment, we developed a cell-based high-throughput screening method to discover compounds that disrupt TTR amyloid fibrils. Screening a library of 1280 off-patent drugs, we identified two candidate repositioning drugs, pyrvinium pamoate and apomorphine hydrochloride. Both drugs disrupted patient-derived TTR amyloid fibrils ex vivo, and pyrvinium pamoate also stabilized the tetrameric structure of TTR ex vivo in patient plasma. We conclude that our TTR81–127–based screening method is very useful for discovering therapeutic drugs that directly disrupt amyloid fibrils. We propose that repositioning pyrvinium pamoate and apomorphine hydrochloride as TTR amyloid-disrupting agents may enable evaluation of their clinical utility for managing ATTR amyloidosis

Two coral fluorescent proteins of distinct colors for sharp visualization of cell-cycle progression

We cloned and characterized two new coral fluorescent proteins: h2-3 and 1-41. h2-3 formed an obligate dimeric complex and exhibited bright green fluorescence. On the other hand, 1-41 formed a highly multimeric complex and exhibited dim red fluorescence. We engineered 1-41 into AzaleaB5, a practically useful red-emitting fluorescent protein for cellular labeling applications. We fused h2-3 and AzaleaB5 to the ubiquitination domains of human Geminin and Cdt1, respectively, to generate a new color variant of Fucci (Fluorescent Ubiquitination-based Cell-Cycle Indicator): Fucci5. We found Fucci5 provided more reliable nuclear labeling for monitoring cell-cycle progression than the 1st and 2nd generations that used mAG/mKO2 and mVenus/mCherry, respectively. Key words: fluorescent protein, cell cycle, time-lapse imaging, flow cytometr

Moments reconstruction and local dynamic range compression of high order superresolution optical fluctuation imaging.

Super-resolution optical fluctuation imaging (SOFI) offers a simple and affordable alternative to other super-resolution (SR) imaging techniques. The theoretical resolution enhancement of SOFI scales linearly with the order of cumulants, while the imaging conditions exhibit less photo-toxicity to the living samples as compared to other SR methods. High order SOFI could, therefore, be a method of choice for dynamic live cell imaging. However, due to the cusp-artifacts and dynamic range expansion of pixel intensities, this promise has not been materialized as of yet. Here we investigated and compared high order moments vs. high order cumulant SOFI reconstructions. We demonstrate that even-order moments reconstructions are intrinsically free of cusp artifacts, allowing for a subsequent deconvolution operation to be performed, hence enhancing the resolution even further. High order moments reconstruction performance was examined for various (simulated) conditions and applied to (experimental) imaging of QD labeled microtubules in fixed cells, and actin stress fiber dynamics in live cells

The Identification, Diagnosis, Prospective, and Action (IDPA) Method for Facilitating Dialogue between Stakeholders: Application to the Radiological Protection Domain

This article reviews the experience of applying the Identification, Diagnosis, Prospective, and Action (IDPA) facilitating method as a means of promoting practices of dialogue between stake-holders in the radiological protection field. After presenting the characteristics of the IDPA method and its ability to promote active listening, participation, and dialogue among stake-holders facing complex situations, as well as the procedural aspects associated with its practical implementation, the article describes three examples of the application of the method in the field of radiological protection. The first one presents how the IDPA method supported a debate among decision-akers, authorities, experts, professionals, and representatives of non-gov-ernmental organizations about how to engage stakeholders in radiological protection. The sec-ond example presents how the IDPA method was used in a series of dialogue meetings to ex-plore the challenges of the post-nuclear accident situation resulting from the Fukushima Daiichi Nuclear Power Plant accident. The third one presents the application of the method in the con-text of a training course organized by Nagasaki University in the affected area close to the dam-aged plant. Experience has shown that the IDPA method makes it possible to develop responses to problems posed in very different contexts and, in many cases, to find compromises regarding their solutions. The IDPA method has the merit of allowing each of the participants to better understand the situation they are faced with, even if such a positive result is not always achieved.Journal of Radiation Protection and Research, 48(3), pp.107-116; 202

Development and application of traffic accident density estimation models using kernel density estimation

Traffic accident frequency has been decreasing in Japan in recent years. Nevertheless, many accidents still occur on residential roads. Area-wide traffic calming measures including Zone 30, which discourages traffic by setting a speed limit of 30 km/h in residential areas, have been implemented. However, no objective implementation method has been established. Development of a model for traffic accident density estimation explained by GIS data can enable the determination of dangerous areas objectively and easily, indicating where area-wide traffic calming can be implemented preferentially. This study examined the relations between traffic accidents and city characteristics, such as population, road factors, and spatial factors. A model was developed to estimate traffic accident density. Kernel density estimation (KDE) techniques were used to assess the relations efficiently. Besides, 16 models were developed by combining accident locations, accident types, and data types. By using them, the applicability of traffic accident density estimation models was examined. Results obtained using Spearman rank correlation show high coefficients between the predicted number and the actual number. The model can indicate the relative accident risk in cities. Results of this study can be used for objective determination of areas where area-wide traffic calming can be implemented preferentially, even if sufficient traffic accident data are not available