Inner retinal layer thinning in radiologically isolated syndrome predicts conversion to multiple sclerosis.

BACKGROUND AND PURPOSE: Individuals with radiologically isolated syndrome (RIS) are at increased risk of converting to multiple sclerosis (MS). Early identification of later converters is crucial for optimal treatment decisions. The purpose of this study was to assess the predictive potential of optical coherence tomography (OCT) measures in individuals with RIS regarding conversion to MS. METHODS: This prospective observational cohort study included 36 individuals with RIS and 36 healthy controls recruited from two German MS centers. All individuals received baseline OCT and clinical examination and were longitudinally followed over up to 6 years. The primary outcome measure was the conversion to MS. RESULTS: During clinical follow-up of 46 (26-58) months (median, 25%-75% interquartile range), eight individuals with RIS converted to MS. Individuals converting to MS showed a thinning of the peripapillary retinal nerve fiber layer (pRNFL) and the common ganglion cell and inner plexiform layer (GCIP) at baseline and during follow-up. Individuals with a pRNFL of 99 µm or lower or a GCIP of 1.99 mm3 or lower were at a 7.5- and 8.0-fold risk for MS conversion, respectively, compared to individuals with higher measures. After correction for other known risk factors, Cox proportional hazards regression revealed a hazard ratio of 1.08 for conversion to MS for each 1 µm decline in pRNFL. CONCLUSIONS: Reduction of the pRNFL might be a novel and independent risk factor for conversion to MS in individuals with RIS. OCT might be useful for risk stratification and therapeutic decision-making in individuals with RIS.

Evidence for a white matter lesion size threshold to support the diagnosis of relapsing remitting multiple sclerosis.

BACKGROUND: The number of white matter lesions (WML) in brain MRI is the most established paraclinical tool to support the diagnosis of multiple sclerosis (MS) and to monitor its course. Diagnostic criteria have stipulated a minimum detectable diameter of 3 mm per WML, although this threshold is not evidence-based. We aimed to provide a rationale for a WML size threshold for three-dimensional MRI sequences at 3 T by comparing patients with relapsing-remitting MS (RRMS) to control subjects (CS). METHODS: We analyzed MR images from two cohorts, obtained at scanners from two different vendors, each comprising patients with RRMS and CS. Both cohorts were examined with FLAIR and T1w sequences. In total, 232 patients with RRMS (Expanded Disability Status Scale: mean = 1.6 ± 1.2; age: mean = 36 ± 10) as well as 116 age- and sex-matched CS were studied. We calculated odds ratios across WML volumes. The WML size threshold, which discriminated best between patients and CS, was estimated with receiver operating characteristic curve analysis. RESULTS: In both cohorts, odds ratios increased continuously with increasing WML volumes, and discriminative power was highest at a WML size threshold corresponding to a diameter of about 3 mm. CONCLUSION: The stipulated WML size threshold of 3 mm in diameter for the diagnostic criteria of MS seems a reasonable choice for three-dimensional MRI sequences at 3 T.

The State Scientific Automated Medical Registry, Kazakhstan: an important resource for low-dose radiation health research.

Direct quantitative assessment of health risks following exposure to ionizing radiation is based on findings from epidemiological studies. Populations affected by nuclear bomb testing are among those that allow such assessment. The population living around the former Soviet Union's Semipalatinsk nuclear test site is one of the largest human cohorts exposed to radiation from nuclear weapons tests. Following research that started in the 1960s, a registry that contains information on more than 300,000 individuals residing in the areas neighboring to the test site was established. Four nuclear weapons tests, conducted from 1949 to 1956, resulted in non-negligible radiation exposures to the public, corresponding up to approximately 300 mGy external dose. The registry contains relevant information about those who lived at the time of the testing as well as about their offspring, including biological material. An international group of scientists worked together within the research project SEMI-NUC funded by the European Union, and concluded that the registry provides a novel, mostly unexplored, and valuable resource for the assessment of the population risks associated with environmental radiation exposure. Suggestions for future studies and pathways on how to use the best dose assessment strategies have also been described in the project. Moreover, the registry could be used for research on other relevant public health topics.

Pre- and Postcontrast 3D Double Inversion Recovery Sequence in Multiple Sclerosis: A Simple and Effective MR Imaging Protocol.

BACKGROUND AND PURPOSE: The double inversion recovery sequence is known to be very sensitive and specific for MS-related lesions. Our aim was to compare the sensitivity of pre- and postcontrast images of 3D double inversion recovery and conventional 3D T1-weighted images for the detection of contrast-enhancing MS-related lesions in the brain to analyze whether double inversion recovery could be as effective as T1WI. MATERIALS AND METHODS: A postcontrast 3D double inversion recovery sequence was acquired in addition to the standard MR imaging protocol at 3T, including pre- and postcontrast 3D T1WI sequences as well as precontrast double inversion recovery of 45 consecutive patients with MS or clinically isolated syndrome between June and December 2013. Two neuroradiologists independently assessed precontrast, postcontrast, and subtraction images of double inversion recovery as well as T1WI to count the number of contrast-enhancing lesions. Afterward, a consensus reading was performed. Lin concordance was calculated between both radiologists, and differences in lesion detectability were assessed with the Student t test. Additionally, the contrast-to-noise ratio was calculated. RESULTS: Significantly more contrast-enhancing lesions could be detected with double inversion recovery compared with T1WI (16%, 214 versus 185, P = .007). The concordance between both radiologists was almost perfect (ρc = 0.94 for T1WI and ρc = 0.98 for double inversion recovery, respectively). The contrast-to-noise ratio was significantly higher in double inversion recovery subtraction images compared with T1-weighted subtraction images (double inversion recovery, 14.3 ± 5.5; T1WI, 6.3 ± 7.1; P < .001). CONCLUSIONS: Pre- and postcontrast double inversion recovery enables better detection of contrast-enhancing lesions in MS in the brain compared with T1WI and may be considered an alternative to the standard MR imaging protocol.

Deterministic effect of lens at leukergy of patients who received low doses of ionising radiation.

To explore the possibility to use the lens extract as an in vitro stimulator to conduct a test of stimulated leukergy in liquidators of the accident consequences (LAC) on Chernobyl Nuclear Power Plant (CNPP) with a cataract in the long-term period. The study sample included 72 men-LAC on CNPP, at the age from 42 to 65 y, who have a cataract. The comparison group consisted of 60 men, with a cataract, of the same age, and who were not exposed to radiation. The control group was composed of 60 men, at the age of 42-58 y without lens pathology. Phenomenon of the stimulated leukergy was revealed in persons who had been exposed to radiation in the dose of 18.2 ± 0.58 cGy and was observed in 5.7-8.05 % (P < 0.001), suggesting a continued high auto-aggression to the lens antigens, and the strength of cell-mediated immunity.

Immunohistochemical determination of the site of antidepressant-like effects of glucagon-like peptide-2 in ACTH-treated mice.

The intracerebroventicular administration (i.c.v.) of glucagon-like peptide-2 (GLP-2) had antidepressant-like effects on saline-treated mice in the forced-swim test. The GLP-2 treatment (3 µg, i.c.v.) for 6 days, but not that of imipramine had antidepressant-like effects on adrenocorticotropic hormone (ACTH)-treated mice. The immunohistochemical detection of the c-fos protein (Fos) revealed that the administration of GLP-2 induced Fos-immunoreactivity (Fos-IR) in the dorsomedial hypothalamic nucleus in saline-treated and ACTH-treated mice, and also in the hippocampal dentate gyrus in ACTH-treated mice, but not in saline-treated mice. In contrast, Fos-IR in the paraventricular nucleus of the hypothalamus decreased after the administration of GLP-2 to ACTH-treated mice. In ACTH-treated mice, the chronic administration of GLP-2 affected hippocampal neurogenesis, in addition to Fos-IR in hypothalamic GABAergic neurons and corticotrophin-releasing factor-containing neurons. These results suggest that GLP-2 acts on specific brain regions to regulate stress conditions, and induces antidepressant-like effects under imipramine-resistant conditions, which may be associated with the modulation of the hypothalamic-pituitary-adrenal-axis.

Estimation of the contribution of short-lived radioiodines to the thyroid dose for the public in case of inhalation intake following the Fukushima accident.

The purpose of this paper is to present (1) the method of assessing the contribution of short-lived radioiodines to the thyroid for members of the public in Fukushima and neighbouring prefectures based on available data and (2) the results of a realistic assessment of such a contribution. The estimates of that contribution for the inhalation intake that occurred on the day of the main fallout (15 March 2011) are within 15 % of the dose to the thyroid from (131)I. The contribution to the thyroid dose from intake of (132)Te is higher than that from the intake of (133)I by a factor of ∼3. The contribution of short-lived radioiodines to the thyroid dose for the public in the case of inhalation intake occurring as early as March 12 might be as great as 30-40 %.

Distribution of 60Co in steel samples from Hiroshima.

This paper describes ultra low-level gamma-ray spectrometry measurements of the (60)Co activity distribution inside one 52 mm and one 41 mm thick steel sample. The samples had been exposed to the Hiroshima atomic bomb and were from the Aioi bridge and the Yokogawa bridge. Both samples were measured in a recent study aiming to back up model calculation of Hiroshima dosimetry. The (60)Co activity distributions found in this study support the assumptions made in the previous study.

Lower plasma arginine in enteral tube-fed patients with pressure ulcer and improved pressure ulcer healing after arginine supplementation by Arginaid Water.

OBJECTIVES: To determine the presence or extent of arginine deficiency in pressure ulcer (PU) patients on percutaneous endoscopic gastrostomy (PEG) feeding and to examine the effects of arginine supplementation on PU healing. DESIGN: All eligible PEG patients, with and without PU, were cross-sectionally assessed for plasma arginine. Three-month supplementation with arginine-enriched water (Arginaid Water) was performed on a subset of patients with PU. This intervention study was a prospective, non-controlled trial with 5 PU patients. SETTING: Geriatric ward of a rural clinical hospital in Japan. PARTICIPANTS: Thirty-nine inpatients with PEG feeding were assessed for plasma arginine. Five of the 13 patients with PU and five of 26 patients without PU underwent amino acid profiling. INTERVENTION: Five of the patients with PU received Arginaid Water supplementation. MEASUREMENTS: Plasma amino acid measurements and biochemical analyses were performed. For those with PU on Arginaid Water supplementation, plasma arginine concentration and PU status were monitored every month. RESULTS: Patients with PU showed significantly lower plasma arginine concentration compared to those without PU (control vs. PU; 80.2±21.3 vs 62.8±14.7 nmol/ml, p<0.01). After the addition of Arginaid Water, plasma arginine concentration increased (before vs 3 months later; 57.9±1.8 vs 83.1±8.5, p<0.01), and PU area, perimeter, DESIGN-R and PUSH scores significantly improved. CONCLUSION: Plasma arginine was lower in PEG patients with PU. The healing rate of PU is improved with Arginaid Water supplementation. The findings from this study support the use of arginine supplementation in PEG patients with PU.

Feasibility of using 236U to reconstruct close-in fallout deposition from the Hiroshima atomic bomb.

The first results on the feasibility of using (236)U to reconstruct the level and spatial distribution of close-in fallout deposition from the Hiroshima A-bomb are reported, coupled with the use of global fallout (137)Cs and (239+240)Pu. The results for global fallout (236)U in soil samples (0-30cm) from Ishikawa prefecture showed that the deposition density of (236)U from the global fallout can be accurately evaluated using AMS. All deposited (236)U, (137)Cs and (239+240)Pu appeared to have been recovered using 30-cm cores. It was also noted from the depth profiles for (236)U/(239+240)Pu and (236)U/(137)Cs ratios that the downward behavior of (236)U in the soil was apparently similar to that of (239+240)Pu, while the (137)Cs was liable to be retained in upper layers compared with (236)U and (239+240)Pu. The accumulated levels were 1.78×10(13)atomsm(-2) for (236)U, 4340Bqm(-2) for (137)Cs and 141Bqm(-2) for (239+240)Pu. The ratios of (236)U/(137)Cs and (236)U/(239+240)Pu were (4.10±0.12)×10(9) and (1.26±0.04)×10(11)atomsBq(-1), respectively. Results of (236)U, (137)Cs and (239+240)Pu measurements for the seven soil cores (0-30cm) from Hiroshima were discussed on the basis of ratios of (236)U/(137)Cs and (236)U/(239+240)Pu by comparing with those from the background area in Ishikawa, indicating that the global fallout dominates the current level of (236)U accumulation in soil in the Black-rain area around Hiroshima after the Hiroshima bomb, and the contribution of the close-in fallout (236)U produced by the Hiroshima A-bomb seems difficult to observe.

The consideration of biological effectiveness of low energy protons using biophysical modeling of the effects induced by exposure of V79 cells.

We have applied Monte Carlo track structure simulations to estimate relative biological effectiveness (RBE) of low-energy protons using biophysical modelling of radiation effects induced by exposure of V79 cells growing in mono-layer. The microscopic energy deposition in cell nucleus and sub-nucleus volumes was investigated in order to understand the reasons of enhanced biological effectiveness near Bragg peak. Theoretical estimations of RBE based on frequency/dose average lineal energy and calculated yields of initial DNA breaks were collated with experimental RBE(M) data. It was found: 1) dose average lineal energy for whole cell nucleus as a function of proton energy shows a distinct peak at 550 keV; 2) the peak values for sub-nucleus volumes are large compared with the whole cell nucleus; 3) the yield of complex DNA breaks correlates with experimental RBE(M) data.

Pharmacokinetics and disposition of CS-8958, a long-acting prodrug of the novel neuraminidase inhibitor laninamivir in rats.

CS-8958, a prodrug of laninamivir (R-125489), is currently under development as an inhaled anti-influenza drug. In this study, the pharmacokinetics and disposition of CS-8958 were characterized in rats. After intratracheal administration of 14C-CS-8958, radioactivity was retained over long periods in the target tissues (trachea and lung) as its active metabolite R-125489 - 19.12% of the dose was retained in the lung at 24 h. After intratracheal administration of CS-8958, plasma R-125489 concentration was slowly eliminated, and its half-life (14.1 h) was considerably longer than that after intravenous administration of R-125489. The radioactivity of intratracheally administered 14C-CS-8958 was mainly excreted into the urine (67.5% of dose), and this excretion lasted over long periods. R-125489 accounted for most of the urinary radioactivity recovered after 24 h. These results demonstrated that CS-8958 administered intratracheally to rats was converted/hydrolysed to R-125489 in the target tissues, and that the R-125489 was slowly excreted into the urine via an absorption rate-limiting process. Such distinctive pharmacokinetics attributed to the slow release of R-125489 suggests the potential for a long-acting anti-influenza drug.

Dental enamel EPR dosimetry: comparative testing of the spectra processing methods for determination of radiation-induced signal amplitude.

The aim of this investigation is to find out the optimal algorithm for mathematical processing of the EPR spectra of irradiated tooth enamel for estimating the amplitude of the radiation-induced signal, which is used for determination of the absorbed dose in enamel for retrospective individual dosimetry. A recently developed analytical model, which takes into account the line shape variation of the enamel EPR spectral components registered at different microwave power, was applied to spectra processing in various operation modes to simulate spectra processing techniques differing by the number of fitted parameters. The precision of dose determination at spectra processing was assessed by the root mean square deviation between experimental and nominal doses for sets of spectra of enamel samples irradiated in different doses and measured at different microwave power. It is shown that in the case of pooled enamel samples prepared as a mixture from different teeth, the higher precision of spectra processing is obtained using a model with fixed native background signal line shape (characterized by width and asymmetry parameters). In case of individual samples prepared each from a different tooth, better results are obtained using a model with variable background signal line shape.

The neutron dose conversion coefficients calculation in human tooth enamel in an anthropomorphic phantom.

In the present study, MCNP4B simulation code is used to simulate neutron and photon transport. It gives the conversion coefficients that relate neutron fluence to the dose in tooth enamel (molars and pre-molars only) for 20 energy groups of monoenergetic neutrons with energies from 10-9 to 20 MeV for five different irradiation geometries. The data presented are intended to provide the basis for connection between EPR dose values and standard protection quantities defined in ICRP Publication 74. The results of the calculations for critical organs were found to be consistent with ICRP data, with discrepancies generally less than 10% for the fast neutrons. The absorbed dose in enamel was found to depend strongly on the incident neutron energy for neutrons over 10 keV. The dependence of the data on the irradiation geometry is also shown. Lower bound estimates of enamel radiation sensitivity to neutrons were made using obtained coefficients for the secondary photons. Depending on neutron energy, tooth enamel was shown to register 10-120% of the total neutron dose in the human body in the case of pure neutron exposure and AP irradiation geometry.

First results on 236U levels in global fallout.

The global fallout (236)U level in soil was deduced from measurements of (236)U, (239+240)Pu and (137)Cs in surface soils which are solely influenced by global fallout. A total of 12 soil cores from the depths of 0-10, 0-20 and 0-30 cm were collected at a flat forest area in Japan. Concentrations of (239+240)Pu and (238)U were determined by alpha-particle spectrometry, while the (236)U/(238)U ratio was measured with accelerator mass spectrometry (AMS). Consistent (236)U/(239)Pu ratios between 0.212 and 0.253 were found. Using this ratio, the total global fallout of (236)U on the earth is estimated to be as much as ca. 900 kg. This knowledge will contribute to the promotion of research on U isotopes, including (236)U, for the fields of geo-resources, waste management and geochemistry.

Fast neutrons measured in copper from the Hiroshima atomic bomb dome.

The first measurements of (63)Ni produced by A-bomb fast neutrons (above approximately 1 MeV) in copper samples from Hiroshima encompassed distances from approximately 380 to 5062 m from the hypocenter (the point on the ground directly under the bomb). They included the region of interest to survivor studies (approximately 900 to 1500 m) and provided the first direct validation of fast neutrons in that range. However, a significant measurement gap remained between the hypocenter and 380 m. Measurements close to the hypocenter are important as a high-value anchor for the slope of the curve for neutron activation as a function of distance. Here we report measurements of (63)Ni in copper samples from the historic Hiroshima Atomic Bomb Dome, which is located approximately 150 m from the hypocenter. These measurements extend the range of our previously published data for (63)Ni providing a more comprehensive and consistent A-bomb activation curve. The results are also in good agreement with calculations based on the current dosimetry system (DS02) and give further experimental support to the accuracy of this system that forms the basis for radiation risk estimates worldwide.

Estrogen receptor gene polymorphisms in Japanese patients with systemic sclerosis.

OBJECTIVE: To investigate whether single-nucleotide polymorphisms (SNPs) within the estrogen receptor (ER) alpha and Beta genes are associated with disease susceptibility and clinical presentation in Japanese patients with systemic sclerosis (SSc). METHODS: Three SNPs, ERalpha PvuII T/C, ERalpha XbaI A/G, and ERBeta RsaI G/A, were genotyped using polymerase-chain reaction combined with restriction fragment length polymorphisms in 103 patients with SSc and 56 race-matched healthy controls. The distribution of the individual ER SNPs in SSc patients with or without SSc-related organ involvement and serum antinuclear antibodies was determined. RESULTS: The frequency of the ERalpha XbaI GG phenotype was significantly lower in SSc patients than in healthy controls (2% vs. 13%, p=0.005, odds ratio=0.14, 95%CI 0.03-0.69), and no significant association was detected for the other SNPs. Except in the case of heart involvement accompanying SSc, there was no significant association of the ER SNPs with SSc-related individual organ involvement or with antinuclear antibody profiles. Specifically, the ERalpha PvuII CC phenotype was significantly more frequent among patients with heart involvement compared with those without it (75% vs. 14%, p=0.0001, odds ratio=17.4, 95%CI 3.2-94.8). CONCLUSION: SNPs located within the ERalpha gene may contribute to disease susceptibility and to certain clinical manifestations of SSc patients.

Determination of 240Pu/239Pu isotopic ratios in human tissues collected from areas around the Semipalatinsk Nuclear Test Site by sector-field high resolution ICP-MS.

Information on the 240Pu/239Pu isotope ratios in human tissues for people living around the Semipalatinsk Nuclear Test Site (SNTS) was deduced from 9 sets of soft tissues and bones, and 23 other bone samples obtained by autopsy. Plutonium was radiochemically separated and purified, and plutonium isotopes (239Pu and 240Pu) were determined by sector-field high resolution inductively coupled plasma-mass spectrometry. For most of the tissue samples from the former nine subjects, low 240Pu/239Pu isotope ratios were determined: bone, 0.125 +/- 0.018 (0.113-0.145, n = 4); lungs, 0.063 +/- 0.010 (0.051-0.078, n = 5); and liver, 0.148 +/- 0.026 (0.104-0.189, n = 9). Only 239Pu was detected in the kidney samples; the amount of 240Pu was too small to be measured, probably due to the small size of samples analyzed. The mean 240Pu/239Pu isotope ratio for bone samples from the latter 23 subjects was 0.152 +/- 0.034, ranging from 0.088 to 0.207. A significant difference (a two-tailed Student's t test; 95% significant level, alpha = 0.05) between mean 240Pu/239Pu isotope ratios for the tissue samples and for the global fallout value (0.178 +/- 0.014) indicated that weapons-grade plutonium from the atomic bombs has been incorporated into the human tissues, especially lungs, in the residents living around the SNTS. The present 239,240Pu concentrations in bone, lung, and liver samples were, however, not much different from ranges found for human tissues from other countries that were due solely to global fallout during the 1970's-1980's.

Experimental derivation of relative biological effectiveness of A-bomb neutrons in Hiroshima and Nagasaki and implications for risk assessment.

Epidemiological data on the health effects of A-bomb radiation in Hiroshima and Nagasaki provide the framework for setting limits for radiation risk and radiological protection. However, uncertainty remains in the equivalent dose, because it is generally believed that direct derivation of the relative biological effectiveness (RBE) of neutrons from the epidemiological data on the survivors is difficult. To solve this problem, an alternative approach has been taken. The RBE of polyenergetic neutrons was determined for chromosome aberration formation in human lymphocytes irradiated in vitro, compared with published data for tumor induction in experimental animals, and validated using epidemiological data from A-bomb survivors. The RBE of fission neutrons was dependent on dose but was independent of the energy spectrum. The same RBE regimen was observed for lymphocyte chromosome aberrations and tumors in mice and rats. Used as a weighting factor for A-bomb survivors, this RBE system was superior in eliminating the city difference in chromosome aberration frequencies and cancer mortality. The revision of the equivalent dose of A-bomb radiation using DS02 weighted by this RBE system reduces the cancer risk by a factor of 0.7 compared with the current estimates using DS86, with neutrons weighted by a constant RBE of 10.