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Fatigue is one of the earliest nonspecific symptoms of radiation exposure in humans, but its etiology, mechanism, and dose dependency remain unexplained. Investigating initial behavioral changes caused by irradiation of animals might provide important information to aid understanding of early health effects of radiation exposure and clinical features of radiation injury. Although previous studies in rodents suggested that radiation exposure leads to reduced activity, detailed properties of the effects were unrevealed due to a lack of proper statistical analysis, which is needed to better elucidate details of changes in locomotor activity. Ten-week-old male Wistar rats were subjected to single point external whole-body irradiation with 60Co gamma rays at 0, 2.0, 3.5, and 5.0 Gy (4 rats per group). Infrared sensors were used to continuously record locomotor activity of each rat. Cumulative number of movements during the night was defined as “activity” for each day. A non-linear mixed effects model accounting for individual differences and daily fluctuation of activity was applied to analyze the rats’ longitudinal locomotor data. Despite a small number of animals per group, our statistical method successfully revealed characteristics of the changes in locomotor activity after radiation exposure, showing that 1) reduction in activity occurred immediately—and in a dose-dependent manner—after irradiation and 2) recovery to pre-irradiation levels required almost one week, with the same recovery rate in each dose group. In addition to improving our understanding of radiation effects on locomotor activity, this statistical framework should be useful to analyze other data with similar structure.

Groups of Japanese and American scientists, supported by international collaborators, have worked for many years to ensure the accuracy of the radiation dosimetry used in studies of health effects in the Japanese atomic bomb survivors. Reliable dosimetric models and systems are especially critical to epidemiologic studies of this population because of their importance in the development of worldwide radiation protection standards. While dosimetry systems, such as Dosimetry System 1986 (DS86) and Dosimetry System 2002 (DS02), have improved, the research groups that developed them were unable to propose or confirm an additional contribution by residual radiation to the survivor's total body dose. In recognition of the need for an up-to-date review of residual radiation exposures in Hiroshima and Nagasaki, a half-day technical session was held for reports on newer studies at the 59 th Annual HPS Meeting in 2014 in Baltimore, MD. A day-and-a-half workshop was also held to provide time for detailed discussion of the newer studies and to evaluate their potential use in clarifying the residual radiation exposure to atomic bomb survivors at Hiroshima and Nagasaki. The process also involved a re-examination of very early surveys of radioisotope emissions from ground surfaces at Hiroshima and Nagasaki and early reports of health effects. New insights were reported on the potential contribution to residual radiation from neutron-activated radionuclides in the airburst's dust stem and pedestal and in unlofted soil, as well as from fission products and weapon debris from the nuclear cloud. However, disparate views remain concerning the actual residual radiation doses received by the atomic bomb survivors at different distances from the hypocenter. The workshop discussion indicated that measurements made using thermal luminescence and optically stimulated luminescence, like earlier measurements, especially in very thin layers of the samples, could be expanded to detect possible radiation exposures to beta particles and to determine their significance plus the extent of the various residual radiation areas at Hiroshima and Nagasaki. Other suggestions for future residual radiation studies are included in this workshop report.

BACKGROUND AND PURPOSE: Volumetry may be useful for evaluating treatment response and prognosis of intraocular lesions. Phantom, volunteer, and patient studies were performed to determine whether ocular MR volumetry is reproducible. MATERIALS AND METHODS: Half-Fourier single-shot RARE and FSPGR sequences at 1.5T with a 76-mm-diameter surface coil were optimized to obtain still ocular images. Volumetry accuracies of each sequence were compared with simulated subretinal phantom volumes. Ocular volumetry was performed in 15 volunteers twice in 1 week by using contiguous axial images of the globes while the subjects stared at a target, and images were acquired in 2 seconds before the subjects were instructed to blink, with this process repeated as necessary. Imaging, intraobserver, and interobserver reproducibility for volumes of the whole eyeball and anterior chamber were assessed. Ocular volumetry was also performed in 6 patients with intraocular tumors before and after treatment. RESULTS: The phantom study demonstrated that measurement error rates with RARE were significantly lower than with FSPGR (P < .01). The volunteer study demonstrated excellent imaging and intraobserver reproducibility of RARE volumetry for whole eyeballs and anterior chambers (P < .01). Although no interobserver differences were observed in anterior chamber volume measurement (P = .33), there was a significant difference between the 2 observers in eyeball volume measurement (P < .01). Follow-up volumetric data were useful for treatment decisions in all patients. CONCLUSIONS: Ocular volumetry from contiguous ultrafast RARE images obtained during visual fixation is feasible in volunteer and patient studies and is superior to FSPGR images.

The aim of this study was to compare the three-dimensional fat-suppressed balanced non-steady-state free precession (3D FS-nSSFP) sequence and the 3D T1-weighted spoiled gradient-recalled echo (3D T1-GRE) sequence for evaluating lumbar nerve root compression with continuous thin-slice coronal magnetic resonance (MR) images.The institutional review board approved this study, and written informed consent was obtained from all 35 patients. We optimized continuous 2.5-mm thick lumbar coronal images with 3D FS-nSSFP and 3D T1-GRE. We calculated the contrast-to-noise ratio (CNR) for nerve roots and other structures on images with the two sequences. With knowledge of the final diagnosis, we assessed the visibility of nerve root compression on these images.The CNR values of nerve roots were significantly higher on images with 3D FS-nSSFP than on those with 3D T1-GRE. These continuous thin-slice coronal images facilitated visualization of nerve root compression in91% of patients. There was no statistically significant difference between the two sequences in the detection of nerve root compression.Continuous thin-slice coronal MR images using 3D FS-nSSFP and 3D T1-GRE sequences are sufficient to evaluate lumbar nerve root compression, and 3D FS-nSSFP is superior to 3D T1-GRE for depiction of lumbar nerve roots.

Our previous report demonstrated a good correlation between high telomerase activity of cancer tissues and a poor prognosis of patients with colorectal cancers, except for several cases. To elucidate the additional factors that contribute to patient prognosis, the correlation among the expression levels of telomere binding proteins (TBP), the lengths of telomeres, the lengths of telomere 3'-overhang (3'-OH) and telomerase activity in 106 paired colorectal cancer and corresponding noncancerous mucosa (NCM) specimens were examined. The expression levels of eight TBP genes (TRF1, TRF2, TIN2, TANK1, TANK2, POT1, RAP1 and TPP1) were analyzed. Among the 106 cases, 35 cases had shortened telomeres (7 kb), 15 had shortened 3'-OH (3'-OH length ratio of cancer/NCM0.5) and 88 were classified as telomerase-activated cancers (activity ratio of cancer/NCM2). Comparison between NCM and cancer in each case showed that all TBP except for POT1 were downregulated in cancers. A survival analysis using a Cox proportional hazard model showed that the survival rate of the telomerase-activated cases with shortened 3'-OH and that of telomerase-inactivated cases were significantly better than that of telomerase-activated cases without 3'-OH shortening, that is, restored or maintained 3'-OH (P = 0.018). In the telomerase-activated cancers, the length of 3'-OH was significantly correlated with the expression levels of POT1. Elongation of telomeric overhang by telomerase, which might be regulated by POT1, may contribute to the increase of malignant potential in colorectal cancers.

Purpose: To compare a half-Fourier single-shot rapid acquisition with relaxation enhancement (RARE) sequence with a balanced steady-state free precession (b-SSFP) sequence in the evaluation of the eye using magnetic resonance (MR) microscopy imaging and to clarify the usefulness of RARE microscopy imaging in evaluating nonoperative glaucoma patients and patients who have undergone surgery for glaucoma or cataract. Materials and Methods: One-mm and 2-mm slice thickness images of RARE sequence and b-SSFP sequence using a 1.5 T MR unit and a 23-mm microscopy coil were obtained in eight healthy volunteers. The signal-to-noise (S/N) ratio of aqueous humor in the anterior chamber was measured quantitatively and visualization of the anterior chamber anatomy was assessed qualitatively. Furthermore, we evaluated 21 glaucoma patients (including six postoperative patients) and four patients after cataract surgery with 2-mm slice thickness RARE MRI. Results: The 2-mm slice thickness RARE imaging had a significantly greater S/N ratio than the 1-mm slice thickness RARE imaging (P < 0.05) and acquired the best image quality among the four types of images (P < 0.01). Additionally, 2-mm slice thickness RARE microscopy imaging could depict anterior chamber anatomy of glaucoma eyes and eyes after cataract surgery. Conclusion: We believe that optimal fast T2-weighted MR microimaging might become a useful ophthalmologic examination technique. J. Magn. Reson. Imaging 2010;31:1210–1214. ©2010 Wiley-Liss, Inc.

市区町村別死亡率データを使用した死亡危険度の地理分布を把握するための統計的方法について考察した．方法は，人口規模で規定される円状近傍を用いて空間平滑化された値を期待値とするポアソンモデルに基づくものである．さらに，その平滑値に対してガンマ揺らぎモデルに基づく経験ベイズ法および交叉型尤度による修正についても検討した．提案された方法により，相対死亡危険度に関する標準化死亡比（SMR）の縮小推定量が求められ，各市区町村別の粗SMRが局所的なその近傍平均値の方へ縮小される．我々は，本方法を1993年から2002年の期間における日本での部位別悪性新生物死亡率データへ適用し分析を試み，その性能を検証した．その結果，空間分布の概観を把握する上で，ガンマ揺らぎモデルによる調整が有効であることが分かったが，単純平滑化に較べて顕著な向上は観られなかった.

Two problems impede the study of age dependency of tooth loss rate using dental radiographs. One is that the exact time of tooth loss is often unknown. The other is that major causes of tooth loss are assumed to result from tooth extraction by dentists. Recently dentists have avoided performing tooth extraction as summarily as in years past due to developments in dental technique and increased concern on oral health. The effect of these changes in dental practice cannot be ignored on the estimation of tooth loss probability. We devised a modification of survival analysis taking into account these two problems by using data consisting of repeated observations for each individual. A flexible statistical model allowing for individual variation in tooth loss hazard was adopted. The proposed method was shown to be valid by a Monte Carlo simulation study in which the true parameters describing age-dependency of tooth loss probability were given. We illustrated our method by applying it to actual tooth loss data from 1,284 panoramic radiographs from 642 patients obtained in a daily clinical practice where each patient underwent panoramic examination at least twice. The age-dependency of tooth loss probability for all kinds of teeth were estimated. The smaller variance of tooth loss hazard between individuals is observed on the molars compared with those of other kinds of teeth.

The relationship between oral signs and osteoporosis was investigated to assess the possibility of using this as an indicator of postmenopausal osteoporosis. Sixty-four women between the ages of 50 and 70 years were evaluated. Osteoporotic signs consisted of thoracic spine fracture as demonstrated on lateral chest radiographs. Oral signs were the number of teeth present, mandibular cortical width, alveolar bone resorption, and the morphologic classification of the inferior cortex on panoramic radiographs. The number of teeth present (N) was highly related to the probability of thoracic spine fracture and was used to derive the probability equation for the presence of thoracic spine fracture: probability value = 1/(1 + e-z), Z = 18.68-0.29 age -0.27N. A probability value higher than 0.5 suggests the possibility of thoracic spine fracture. It was concluded that this equation could serve as a simple and useful tool for dentists to assess the possibility of latent osteoporosis.

We investigated the correlation between age and the fractional anisotropy (FA) values of peripheral nerves in healthy adults and compared the age-corrected FA values of peripheral nerves in healthy subjects and patients with polyneuropathy. The institutional review board approved this study and informed consent was obtained from all participants before entry into the study. We optimized diffusion tensor imaging using a 3-T magnetic resonance scanner and an extremity coil for scanning tibial nerves. The effect of age and sex on the FA values of tibial nerves in healthy volunteers was investigated and the age-corrected FA values of tibial nerves in healthy volunteers and patients with polyneuropathy were compared. The maximum FA values of the tibial nerves remained constant until age 45 (approximately 0.516); they subsequently decreased by 0.004/year in healthy volunteers. After removing the effect of age with an age-adjusted equation, the median maximum FA values in the volunteers and patients were 0.518 (range, 0.406–0.616) and 0.442 (range, 0.376–0.530), respectively. The age-corrected FA values were significantly lower in the patients than the healthy volunteers (p

Prior laboratory prediction of individual drug response is of key importance in esophageal squamous cell carcinoma (ESCC), because of the extremely narrow therapeutic index of chemotherapy. However, very few critical markers have been validated to date for ESCC. We previously demonstrated that simultaneous performance of two different types of comprehensive gene expression analysis might provide a way to identify potent marker genes for drug sensitivity from the expression-sensitivity correlation analysis alone, but the screening method appeared not to be always effective. Therefore, we attempted to identify novel potent marker genes using a new statistical analysis of oligonucleotide microarray expression data, based on a two-dimensional mixed normal model, and selected 3 and 7 novel candidates for 5-fluorouracil (5-FU) and cis-platinum (CDDP), respectively. Interferon induced transmembrane protein 1 (IFITM1) gene alone, being suggested as a key gene of Wnt pathway, was commonly selected in both screening methods. The transfection analyses and siRNA-mediated knock-down experiments revealed that expression of IFITM1 closely related to cellular sensitivity to CDDP. Considering the fact that drug sensitivity is determined by multiple genes, we established the best linear model using quantified expression data of a set of all the selected marker genes including IFITM1, which converted the quantified expression data of ESCC cell lines into an IC50 value of each drug. In the same way, using the representative genes selected in vitro, we developed highly predictive formulae for disease-free survival (DFS) of the CDDP/5-FU combination after curative operation in esophageal cancer patients (R=0.917). A two-dimensional mixed normal model can be a powerful tool to identify novel drug-response determinants, and the IFITM1 gene selected by the statistical method a novel critical biomarker of CDDP response in ESCC.

Esophageal cancer is a highly lethal disease and the optimal therapy remains unclear. Since adjuvant chemotherapy gives a better chance of survival, we attempted to develop a chemosensitivity prediction model to improve individual responses to therapy. Comprehensive gene expression analyses (cDNA and oligonucleotide microarrays) and MTT assay of 8 drugs in 20 KYSE squamous cell carcinoma cell lines were performed to distinguish candidate marker genes whose expression levels reproducibly correlated with cellular drug sensitivities. After confirmation with real-time RT-PCR, we performed multiple regression analyses to develop drug-sensitivity prediction formulae using the quantified expression data of selected marker genes. Using the same sets of genes, we also constructed prediction models for individual clinical responses to 5-FU-based chemotherapy using 18 cases. We selected 5 better marker genes, known as drug sensitivity determinants, identified 9 novel predictive genes for 4 of 8 anticancer drugs [5-FU, CDDP, DOX, and CPT-11 (SN-38)], and developed highly predictive formulae of in vitro sensitivities to the 4 drugs and clinical responses to 5-FU-based adjuvant chemotherapies in terms of overall and disease-free survivals. Our selected genes are likely to be effective drug-sensitivity markers and formulae using the 9 novel genes would provide advantages in prediction.

We developed concise, accurate prediction models of the in vitro activity for 8 anticancer drugs (5-FU, CDDP, MMC, DOX, CPT-11, SN-38, TXL and TXT), along with individual clinical responses to 5-FU using expression data of 12 genes. We first performed cDNA microarray analysis and MTT assay of 19 human cancer cell lines to sort out genes which were correlative in expression levels with cytotoxicities of the 8 drugs; we selected 13 genes with proven functional significance to drug sensitivity from a huge number of potent prediction marker genes. The correlation significance of each was confirmed using expression data quantified by real-time RT-PCR, and finally 12 genes (ABCB1, ABCG2, CYP2C8, CYP3A4, DPYD, GSTP1, MGMT, NQO1, POR, TOP2A, TUBB and TYMS) were selected as more reliable predictors of drug response. Using multiple regression analysis, we fixed 8 prediction formulae which embraced the variable expressions of the 12 genes and arranged them in order, to predict the efficacy of the drugs by referring to the value of Akaike's information criterion for each sample. These formulae appeared to accurately predict the in vitro efficacy of the drugs. For the first clinical application model, we fixed prediction formulae for individual clinical response to 5-FU in the same way using 41 clinical samples obtained from 30 gastric cancer patients and found to be of predictive value in terms of survival, time to treatment failure and tumor growth. None of the 12 selected genes alone could predict such clinical responses.

While there is a considerable number of studies on the relationship between the risk of disease or death and direct exposure from the atomic bomb in Hiroshima, the risk for indirect exposure caused by residual radioactivity has not yet been fully evaluated. One of the reasons is that risk assessments have utilized estimated radiation doses, but that it is difficult to estimate indirect exposure. To evaluate risks for other causes, including indirect radiation exposure, as well as direct exposure, a statistical method is described here that evaluates risk with respect to individual location at the time of atomic bomb exposure instead of radiation dose. In addition, it is also considered to split the risks into separate risks due to direct exposure and other causes using radiation dose. The proposed method is applied to a cohort study of Hiroshima atomic bomb survivors. The resultant contour map suggests that the region west to the hypocenter has a higher risk compared to other areas. This in turn suggests that there exists an impact on risk that cannot be explained by direct exposure.