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.

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.

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.

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.

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.

Regulatory mechanisms of the acrosome reaction revealed by multiview microscopy of single starfish sperm.

The acrosome reaction in many animals is a coupled reaction involving an exocytotic step and a dramatic change in cell shape. It has been proposed that these morphological changes are regulated by intracellular ions such as Ca2+ and H+. We report here simultaneous visualization, under a multiview microscope, of intracellular free Ca2+ concentration ([Ca2+]i), intracellular pH (pHi), and morphological changes in a single starfish sperm (Asterina pectinifera). [Ca2+]i and pHi were monitored with the fluorescent probes indo-1 and SNARF-1, respectively. The acrosome reaction was induced with ionomycin. After the introduction of ionomycin in the medium, [Ca2+]i increased gradually and reached a plateau in approximately 30 s. The fusion of the acrosomal vacuole took place abruptly before the plateau, during the rising phase. Although the speed of the [Ca2+]i increase varied among the many sperm tested, exocytosis in all cases occurred at the same [Ca2+]i of approximately 2 microM (estimated using the dissociation constant of indo-1 for Ca2+ of 1.1 microM). This result suggests that the exocytotic mechanism in starfish sperm responds to [Ca2+]i rapidly, with a reaction time of the order of one second or less. Unlike the change in [Ca2+]i, an abrupt increase in pHi was observed immediately after exocytosis, suggesting the presence of a proton mobilizing system that is triggered by exocytosis. The rapid increase in pHi coincided with the formation of the acrosomal rod and the beginning of vigorous movement of the flagellum, both of which have been proposed to be pHi dependent. The exocytotic event itself was visualized with the fluorescent membrane probe RH292. The membrane of the acrosomal vacuole, concealed from the external medium in an unreacted sperm, was seen to fuse with the plasma membrane.

Separation of the sperm agglutinin and the acrosome reaction-inducing substance in egg jelly of starfish.

The egg jelly of the starfish Asterias amurensis was separated into the fractions J1, J2, and J3 on a Sephadex G-100 column. The Jl fraction induced the acrosome reaction and J2 induced sperm agglutination. Chemical analysis and chromatography revealed that sperm agglutinin is similar to asterosaponin A.

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.

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.

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.

Spatial distribution of soil contamination by 137Cs and 239,240Pu in the village of Dolon near the Semipalatinsk nuclear test site: new information on traces of the radioactive plume from the 29 August 1949 nuclear test.

The village of Dolon located about 60 km northeast from the border of the Semipalatinsk Nuclear Test Site in Kazakhstan is one of the most affected inhabited settlements as a result of nuclear tests by the former USSR. Radioactive contamination in Dolon was mainly caused by the first USSR nuclear test on 29 August 1949. As part of the efforts to reconstruct the radiation dose in Dolon, Cs and Pu in soil samples collected from 26 locations in the vicinity of and within the village were measured to determine the width and position of the center-axis of the radioactive plume that passed over the village from the 29 August 1949 nuclear test. Measured soil inventories of Cs and Pu were plotted as a function of the distance from the supposed center-axis of the plume. A clear shape similar to a Gaussian function was observed in their spatial distributions with each maximum around a center-axis. It was suggested that the plume width that contaminated Dolon was at most 10 km and the real center-axis of the radioactive plume passed 0.7-0.9 km north of the supposed centerline. A peak-like shape with the maximum near the center-axis was also observed in the spatial distribution of the Pu/Cs activity ratio, which may reflect the fractionation effect between Pu and Cs during the deposition process. These results support the recently reported results. The data obtained here will provide useful information on the efforts to estimate radiation dose in Dolon as reliably as possible. Health Phys. 94(4):328-337; 2008.

A preliminary study on the use of (10)Be in forensic radioecology of nuclear explosion sites.

Cosmogenic (10)Be, known for use in dating studies, unexpectedly is also produced in nuclear explosions with an atom yield almost comparable to (e.g.) (137)Cs. There are major production routes via (13)C(n, alpha)(10)Be, from carbon dioxide in the air and the organic explosives, possibly from other bomb components and to a minor extent from the direct fission reaction. Although the detailed bomb components are speculative, carbon was certainly present in the explosives and an order of magnitude calculation is possible. The (n, alpha) cross-section was determined by irradiating graphite in a nuclear reactor, and the resulting (10)Be estimated by Accelerator Mass Spectrometry (AMS) giving a cross-section of 34.5+/-0.7mb (6-9.3MeV), within error of previous work. (10)Be should have applications in forensic radioecology. Historical environmental samples from Hiroshima, and Semipalatinsk (Kazakhstan) showed two to threefold (10)Be excesses compared with the background cosmogenic levels. A sample from Lake Chagan (a Soviet nuclear cratering experiment) contained more (10)Be than previously reported soils. (10)Be may be useful for measuring the fast neutron dose near the Hiroshima bomb hypocenter at neutron energies double those previously available.

Induction of starfish oocyte maturation by the beta gamma subunit of starfish G protein and possible existence of the subsequent effector in cytoplasm.

beta gamma subunits of G proteins were purified from starfish oocytes, and their role in the induction of oocyte maturation by 1-methyladenine was investigated. When injected into starfish oocytes, the purified beta gamma subunit of the starfish G protein induced germinal vesicle breakdown (GVBD) faster than that of bovine brain G protein. Injection of the starfish beta gamma into cytoplasm near the germinal vesicle (GV) induced GVBD earlier than when injected into the GV or the cytoplasm near the plasma membrane. Fluorescent-labeled beta gamma was retained in the injected area even after GVBD. Injected beta gamma also induced the formation of maturation-promoting factor as well as an increase of histone H1 kinase activity. These results suggest that beta gamma dissociates from alpha-subunit by the stimulation of 1-methyladenine and interacts with a cytoplasmic effector, which results in formation of active cdc2 kinase.

Radioactivity in atomic-bomb samples from exposure to environmental neutrons.

For about one decade, activation measurements performed on environmental samples from a distance larger than 1 km from the hypocenter of the atomic-bomb explosion over Hiroshima suggested much higher thermal neutron fluences to the survivors than predicted. This caused concern among the radiation protection community and prompted a complete re-evaluation of all aspects of survivor dosimetry. While it was shown recently that secondary neutrons from cosmic radiation and other sources have probably been the reason for the high measured concentrations of the long-lived radioisotope 36Cl in these samples, the source for high measured concentrations of the short-lived radionuclides 152Eu and 60Co has not yet been investigated in detail. In order to quantify the production of 152Eu and 60Co in environmental samples by secondary neutrons from cosmic radiation, thermal neutron fluxes were measured by means of a He gas proportional counter in various buildings where these samples had been and still are being stored. Because a 252Cf neutron source has been operated occasionally close to one of the sample storage rooms, additional neutron flux measurements were carried out when the neutron source was in operation. The thermal neutron fluxes measured ranged from 0.00017 to 0.00093 n cm(-2) s(-1) and depended on the floor number of the investigated building. Based on the measured neutron fluxes, the specific activities from the reactions 151Eu(n,gamma)152Eu and 59Co(n,gamma)60Co in the atomic-bomb samples were estimated to be 7.9 mBq g(-1) Eu and 0.27 mBq g(-1) Co, respectively, in saturation. These activities are much lower than those recently measured in samples that had been exposed to atomic-bomb neutrons. It is therefore concluded that environmental and moderated 252Cf neutrons are not the source for the high activities that had been measured in these samples.

Atomic bomb induced 152Eu: reconciliation of discrepancy between measurements and calculation.

In order to resolve the discrepancy between the measured and calculated 152Eu activity induced by the atomic bomb at Hiroshima, extremely low background gamma-ray spectrometry was performed for 17 granite samples collected from 134 m to more than 3 km from the hypocenter. Measurements agreed well with theoretical calculations based on DS02 up to 1.4 km from hypocenter.

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.

The Third International Intercomparison on EPR Tooth Dosimetry: part 2, final analysis.

The objective of the Third International Intercomparison on EPR Tooth Dosimetry was to evaluate laboratories performing tooth enamel dosimetry <300 mGy. Final analysis of results included a correlation analysis between features of laboratory dose reconstruction protocols and dosimetry performance. Applicability of electron paramagnetic resonance (EPR) tooth dosimetry at low dose was shown at two applied dose levels of 79 and 176 mGy. Most (9 of 12) laboratories reported the dose to be within 50 mGy of the delivered dose of 79 mGy, and 10 of 12 laboratories reported the dose to be within 100 mGy of the delivered dose of 176 mGy. At the high-dose tested (704 mGy) agreement within 25% of the delivered dose was found in 10 laboratories. Features of EPR dose reconstruction protocols that affect dosimetry performance were found to be magnetic field modulation amplitude in EPR spectrum recording, EPR signal model in spectrum deconvolution and duration of latency period for tooth enamel samples after preparation.

Sialosphingolipids of sea urchin eggs and spermatozoa showing a characteristic composition for species and gamete.

1. Sialosphingolipids of four species of the Japanese sea urchin were compared. The composition of sialosphingolipids was characteristic for species and gamete. 2. It is suggested that sialosphingolipids may have a common carbohydrate backbone composed solely of hexoses and sialic acids.

Novel sialosphingolipids from spermatozoa of the sea urchin Anthocidaris crassispina.

Sialosphingolipids obtained from spermatozoa of the sea urchin, Anthocidaris crassispina gave nine spots by thin-layer chromatography. Two of them were isolated by silicic acid column chromatography. The predominant one was proposed to be N-acetylneuraminyl (2 yields 8) N-acetylneuraminyl (2 yields 6) glucopyranosyl ceramide, and the second to be N-acetylneuraminyl (2 yields 6) glucopyranosyl ceramide.

Identification and synthetic pathway of sialyl-Lewis(x)-containing neolacto-series gangliosides in lens tissues. 2. Enzymatic synthesis of sialyl-Lewis(x) gangliosides in monkey and rat lenses.

In Japanese monkey lenses, 3H-labeled fucose and N-acetylneuraminic acid were enzymatically transferred to neolactotetraosylceramide (nLc4) and III 3 FucnLc4, respectively, suggesting the presence of a synthetic pathway of IV3 NeuAcIII3 FucnLc4 via III3 FucnLc4 in monkey lenses. Six rat strains, Wistar, Sprague-Dawley and pigmented strains, contained sialyl-Lewis(x) gangliosides in non-cataractous lenses in a strain-specific manner. Glycosyltransferase assay revealed that the transfer of 3H-labeled fucose to nLc4 occurred in all the strains, but that the transfer of 3H-labeled N-acetylneuraminic acid to III3 FucnLc4 was strain-specific. These results suggested that sialyl-Lewis(x) gangliosides were generally synthesized from neolactotetraosylceramide via Lewis(x) glycolipid (III3 FucnLc4) in lens tissues, differing from other tissues. Combining our results, we propose two synthetic pathways of sialyl-Le(x)- containing neolacto-series gangliosides and A-pathway ganglio-series gangliosides in human senile cataractous lens: one to sialyl-Lewis(x) gangliosides from nLc4 via Lewis(x) glycolipid, and the other to GD1a from GM3, via GM2 and GM1.