Inferences to estimate consumer's diet using stable isotopes: Insights from a dynamic mixing model.

Stable isotope ratios are used to reconstruct animal diet in trophic ecology via mixing models. Several assumptions of stable isotope mixing models are critical, i.e., constant trophic discrimination factor and isotopic equilibrium between the consumer and its diet. The isotopic turnover rate (λ and its counterpart the half-life) affects the dynamics of isotopic incorporation for an organism and the isotopic equilibrium assumption: λ involves a time lag between the real assimilated diet and the diet estimated by mixing models at the individual scale. Current stable isotope mixing model studies consider neither this time lag nor even the dynamics of isotopic ratios in general. We developed a mechanistic framework using a dynamic mixing model (DMM) to assess the contribution of λ to the dynamics of isotopic incorporation and to estimate the bias induced by neglecting the time lag in diet reconstruction in conventional static mixing models (SMMs). The DMM includes isotope dynamics of sources (denoted δs), λ and frequency of diet-switch (ω). The results showed a significant bias generated by the SMM compared to the DMM (up to 50% of differences). This bias can be strongly reduced in SMMs by averaging the isotopic variations of the food sources over a time window equal to twice the isotopic half-life. However, the bias will persist (∼15%) for intermediate values of the ω/λ ratio. The inferences generated using a case study highlighted that DMM enhanced estimates of consumer's diet, and this could avoid misinterpretation in ecosystem functioning, food-web structure analysis and underlying biological processes.

Addressing the Biochemical Foundations of a Glucose-Based "Trojan Horse"-Strategy to Boron Neutron Capture Therapy: From Chemical Synthesis to In Vitro Assessment.

Boron neutron capture therapy (BNCT) for cancer is on the rise worldwide due to recent developments of in-hospital neutron accelerators which are expected to revolutionize patient treatments. There is an urgent need for improved boron delivery agents, and herein we have focused on studying the biochemical foundations upon which a successful GLUT1-targeting strategy to BNCT could be based. By combining synthesis and molecular modeling with affinity and cytotoxicity studies, we unravel the mechanisms behind the considerable potential of appropriately designed glucoconjugates as boron delivery agents for BNCT. In addition to addressing the biochemical premises of the approach in detail, we report on a hit glucoconjugate which displays good cytocompatibility, aqueous solubility, high transporter affinity, and, crucially, an exceptional boron delivery capacity in the in vitro assessment thereby pointing toward the significant potential embedded in this approach.

Pharmacokinetics of 10B-p-boronophenylalanine (BPA) in the blood and tumors in human patients: A critical review with special reference to tumor-to-blood (T/B) ratios using resected tumor samples.

We reviewed 10B concentration kinetics in the blood and tumors in human patients administered with BPA. The 10B concentration in the blood peaked at the end of intravenous infusion of BPA, followed by a biphasic-decreasing curve with half-lives for the first and second components of the curve being 0.7-3.7 and 7.2-12.0 h, respectively. The mean tumor-to-blood (T/B) ratio obtained from resected tumor samples was 3.40 ± 0.83 for melanoma and the ratio ranged from 1.4 to 4.7 for glioblastoma.

Methods for analyzing tellurium imaging mass cytometry data.

Imaging mass cytometry (IMC) is a technique allowing visualization and quantification of over 40 biological parameters in a single experiment with subcellular spatial resolution, however most IMC experiments are limited to endpoint analysis with antibodies and DNA stains. Small molecules containing tellurium are promising probes for IMC due to their cell permeability, synthetic versatility, and most importantly their application to sequential labelling with isotopologous probes (SLIP) experiments. SLIP experiments with tellurium-containing probes allow quantification of intracellular biology at multiple timepoints with IMC. Despite the promise of tellurium in IMC, there are unique challenges in image processing associated with tellurium IMC data. Here, we address some of these issues by demonstrating the removal of xenon background signal, combining channels to improve signal-to-noise ratio, and calculating isotope transmission efficiency biases. These developments add accuracy to the unique temporal resolution afforded by tellurium IMC probes.

BNCT induced immunomodulatory effects contribute to mammary tumor inhibition.

In the United States, breast cancer is one of the most common and the second leading cause of cancer-related death in women. Treatment modalities for mammary tumor are surgical removal of the tumor tissue followed by either chemotherapy or radiotherapy or both. Radiation therapy is a whole body irradiation regimen that suppresses the immune system leaving hosts susceptible to infection or secondary tumors. Boron neutron capture therapy (BNCT) in that regard is more selective, the cells that are mostly affected are those that are loaded with 109 or more 10B atoms. Previously, we have described that liposomal encapsulation of boron-rich compounds such as TAC and MAC deliver a high payload to the tumor tissue when injected intravenously. Here we report that liposome-mediated boron delivery to the tumor is inversely proportional to the size of the murine mammary (EMT-6) tumors. The plausible reason for the inverse ratio of boron and EMT-6 tumor size is the necrosis in these tumors, which is more prominent in the large tumors. The large tumors also have receding blood vessels contributing further to poor boron delivery to these tumors. We next report that the presence of boron in blood is essential for the effects of BNCT on EMT-6 tumor inhibition as direct injection of boron-rich liposomes did not provide any added advantage in inhibition of EMT-6 tumor in BALB/c mice following irradiation despite having a significantly higher amount of boron in the tumor tissue. BNCT reaction in PBMCs resulted in the modification of these cells to anti-tumor phenotype. In this study, we report the immunomodulatory effects of BNCT when boron-rich compounds are delivered systemically.

Use of Stable Isotopes to Evaluate Bioefficacy of Provitamin A Carotenoids, Vitamin A Status, and Bioavailability of Iron and Zinc.

The ability of nutrition scientists to measure the status, bioavailability, and bioefficacy of micronutrients is affected by lack of access to the parts of the body through which a nutrient may travel before appearing in accessible body compartments (typically blood or urine). Stable isotope-labeled tracers function as safe, nonradioactive tools to follow micronutrients in a quantitative manner because the absorption, distribution, metabolism, and excretion of the tracer are assumed to be similar to the unlabeled vitamin or mineral. The International Atomic Energy Agency (IAEA) supports research on the safe use of stable isotopes in global health and nutrition. This review focuses on IAEA's contributions to vitamin A, iron, and zinc research. These micronutrients are specifically targeted by the WHO because of their importance in health and worldwide prevalence of deficiency. These 3 micronutrients are included in food fortification and biofortification efforts in low- and middle-income regions of the world. Vitamin A isotopic techniques can be used to evaluate the efficacy and effectiveness of interventions. For example, total body retinol stores were estimated by using 13C2-retinol isotope dilution before and after feeding Zambian children maize biofortified with ß-carotene to determine if vitamin A reserves were improved by the intervention. Stable isotopes of iron and zinc have been used to determine mineral bioavailability. In Thailand, ferrous sulfate was better absorbed from fish sauce than was ferrous lactate or ferric ammonium citrate, determined with the use of different iron isotopes in each compound. Comparisons of one zinc isotope injected intravenously with another isotope taken orally from a micronutrient powder proved that the powder increased total absorbed zinc from a meal in Pakistani infants. Capacity building by the IAEA with appropriate collaborations in low- and middle-income countries to use stable isotopes has resulted in many advancements in human nutrition.

Radioiodinated Pentixather for SPECT Imaging of Expression of the Chemokine Receptor CXCR4 in Rat Myocardial-Infarction-Reperfusion Models.

The purpose of this study is to develop a specific CXCR4-targeting radioiodinated agent (125I- or 131I-pentixather) for single-photon-emission-computed-tomography (SPECT) imaging of CXCR4 expression in myocardial-infarction-reperfusion (MI/R) rat models. After SPECT-CT imaging with 125I-pentixather at 4, 12, and 36 h and 3 and 7 days after MI/R, the models were validated by ex vivo autoradiography, TTC staining, and immunohistochemistry and in vivo echocardiography and classical 99mTc-MIBI perfusion imaging. The SPECT-CT images showed that the infarcted myocardium (IM) could be visualized with high quality as early as 4 h and reached the maximum at 3 days after MI/R and that CXCR4 upregulation was still visible at 7 days after MI/R. In the biodistribution study, high uptakes in the IM (0.99 ± 0.13, 1.52 ± 0.29, 1.75 ± 0.22, 1.94 ± 0.27, and 0.61 ± 0.14% ID/g at 4, 12, and 36 h and 3 and 7 days after MI/R, respectively) were observed that were much higher than that of normal myocardium. The highest uptake was reached at 3 days after MI/R, which agreed well with the SPECT results. In addition, the radioactivity uptakes of the IM in both the biodistribution and SPECT imaging could be blocked effectively by excess amounts of AMD3465, indicating the high specificity of radioiodinated pentixather to CXCR4. On the basis of its promising properties, 125I-pentixather may serve as a powerful CXCR4-expression diagnostic probe for evaluating lesions and monitoring therapy responses in patients with cardiovascular diseases.

Boron delivery agents for neutron capture therapy of cancer.

Boron neutron capture therapy (BNCT) is a binary radiotherapeutic modality based on the nuclear capture and fission reactions that occur when the stable isotope, boron-10, is irradiated with neutrons to produce high energy alpha particles. This review will focus on tumor-targeting boron delivery agents that are an essential component of this binary system. Two low molecular weight boron-containing drugs currently are being used clinically, boronophenylalanine (BPA) and sodium borocaptate (BSH). Although they are far from being ideal, their therapeutic efficacy has been demonstrated in patients with high grade gliomas, recurrent tumors of the head and neck region, and a much smaller number with cutaneous and extra-cutaneous melanomas. Because of their limitations, great effort has been expended over the past 40 years to develop new boron delivery agents that have more favorable biodistribution and uptake for clinical use. These include boron-containing porphyrins, amino acids, polyamines, nucleosides, peptides, monoclonal antibodies, liposomes, nanoparticles of various types, boron cluster compounds and co-polymers. Currently, however, none of these have reached the stage where there is enough convincing data to warrant clinical biodistribution studies. Therefore, at present the best way to further improve the clinical efficacy of BNCT would be to optimize the dosing paradigms and delivery of BPA and BSH, either alone or in combination, with the hope that future research will identify new and better boron delivery agents for clinical use.

An isotope dilution model for partitioning of phenylalanine and tyrosine uptake by the liver of lactating dairy cows.

An isotope dilution model to describe the partitioning of phenylalanine and tyrosine in the bovine liver was developed. The model comprises four intracellular and six extracellular pools and various flows connecting these pools and external blood. Conservation of mass principles were applied to generate the fundamental equations describing the behaviour of the system in the steady state. The model was applied to datasets from multi-catheterised dairy cattle during a constant infusion of [1-13C]phenylalanine and [2,3,5,6-2H]tyrosine tracers. Model solutions described the extraction of phenylalanine and tyrosine from the liver via the portal vein and hepatic artery. In addition, the exchange of free phenylalanine and tyrosine between extracellular and intracellular pools was explained and the hydroxylation of phenylalanine to tyrosine was estimated. The model was effective in providing information about the fates of phenylalanine and tyrosine in the liver and could be used as part of a more complex system describing amino acid metabolism in the whole animal.

Multiple breath washout of hyperpolarized 129 Xe and 3 He in human lungs with three-dimensional balanced steady-state free-precession imaging.

PURPOSE: To compare quantitative fractional ventilation measurements from multiple breath washout imaging (MBW-I) using hyperpolarized 3 He with both spoiled gradient echo (SPGR) and balanced steady-state free precession (bSSFP) three-dimensional (3D) pulse sequences and to evaluate the feasibility of MBW-I with hyperpolarized 129 Xe. METHODS: Seven healthy subjects were scanned using 3 He MBW-I with 3D SPGR and bSSFP sequences. Five also underwent MBW-I with 129 Xe. A dual-tuned coil was used to acquire MBW-I data from both nuclei in the same subject position, enabling direct comparison of regional information. RESULTS: High-quality MBW images were obtained with bSSFP sequences using a reduced dose (100 mL) of inhaled hyperpolarized 3 He. 3D MBW-I with 129 Xe was also successfully demonstrated with a bSSFP sequence. Regional quantitative ventilation measures derived from 3 He and 129 Xe MBW-I correlated well in all subjects (P < 0.001) with mean Pearson's correlation coefficients of r = 0.61 and r = 0.52 for 3 He SPGR-bSSFP and 129 Xe-3 He (bSSFP) comparisons. The average intersubject mean difference (and standard deviation) in fractional ventilation in SPGR-bSSFP and 129 Xe-3 He comparisons was 15% (28%) and 9% (38%), respectively. CONCLUSIONS: Improved sensitivity in MBW-I can be achieved with polarization-efficient bSSFP sequences. Same scan-session 3D MBW-I with 3 He and 129 Xe has been demonstrated using a dual-tuned coil. Magn Reson Med 77:2288-2295, 2017. © 2016 The Authors Magnetic Resonance in Medicine published by Wiley Periodicals, Inc. on behalf of International Society for Magnetic Resonance in Medicine. This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.

Selective Imaging of VEGFR-1 and VEGFR-2 Using 89Zr-Labeled Single-Chain VEGF Mutants.

Vascular endothelial growth factor-A (VEGF-A) acts via 2 vascular endothelial growth factor receptors, VEGFR-1 and VEGFR-2, that play important and distinct roles in tumor biology. We reasoned that selective imaging of these receptors could provide unique information for diagnostics and for monitoring and optimizing responses to anticancer therapy, including antiangiogenic therapy. Herein, we report the development of 2 first-in-class 89Zr-labeled PET tracers that enable the selective imaging of VEGFR-1 and VEGFR-2. METHODS: Functionally active mutants of scVEGF (an engineered single-chain version of pan-receptor VEGF-A with an N-terminal cysteine-containing tag for site-specific conjugation), named scVR1 and scVR2 with enhanced affinity to, respectively, VEGFR-1 and VEGFR-2, were constructed. Parental scVEGF and its receptor-specific mutants were site-specifically derivatized with the 89Zr chelator desferroxamine B via a 3.4-kDa PEG linker. 89Zr labeling of the desferroxamine B conjugates furnished scV/Zr, scVR1/Zr, and scVR2/Zr tracers with high radiochemical yield (>87%), high specific activity (≥9.8 MBq/nmol), and purity (>99%). Tracers were tested in an orthotopic breast cancer model using 4T1luc-bearing syngeneic BALB/c mice. For testing tracer specificity, tracers were coinjected with an excess of cold proteins of the same or opposite receptor specificity or pan-receptor scVEGF. PET imaging, biodistribution, and dosimetry studies in mice, as well as immunohistochemical analysis of harvested tumors, were performed. RESULTS: All tracers rapidly accumulated in orthotopic 4T1luc tumors, allowing for the successful PET imaging of the tumors as early as 2 h after injection. Blocking experiments with an excess of pan-receptor or receptor-specific cold proteins indicated that more than 80% of tracer tumor uptake is VEGFR-mediated, whereas uptake in all major organs is not affected by blocking within the margin of error. Critically, blocking experiments indicated that VEGFR-mediated tumor uptake of scVR1/Zr and scVR2/Zr was mediated exclusively by the corresponding receptor, VEGFR-1 or VEGFR-2, respectively. In contrast, uptake of pan-receptor scV/Zr was mediated by both VEGFR-1 and VEGFR-2 at an approximately 2:1 ratio. CONCLUSION: First-in-class selective PET tracers for imaging VEGFR-1 and VEGFR-2 were constructed and successfully validated in an orthotopic murine tumor model.

Neonatal Respiratory Diseases in the Newborn Infant: Novel Insights from Stable Isotope Tracer Studies.

Respiratory distress syndrome is a common problem in preterm infants and the etiology is multifactorial. Lung underdevelopment, lung hypoplasia, abnormal lung water metabolism, inflammation, and pulmonary surfactant deficiency or disfunction play a variable role in the pathogenesis of respiratory distress syndrome. High-quality exogenous surfactant replacement studies and studies on surfactant metabolism are available; however, the contribution of surfactant deficiency, alteration or dysfunction in selected neonatal lung conditions is not fully understood. In this article, we describe a series of studies made by applying stable isotope tracers to the study of surfactant metabolism and lung water. In a first set of studies, which we call 'endogenous studies', using stable isotope-labelled intravenous surfactant precursors, we showed the feasibility of measuring surfactant synthesis and kinetics in infants using several metabolic precursors including plasma glucose, plasma fatty acids and body water. In a second set of studies, named 'exogenous studies', using stable isotope-labelled phosphatidylcholine tracer given endotracheally, we could estimate surfactant disaturated phosphatidylcholine pool size and half-life. Very recent studies are focusing on lung water and on the endogenous biosynthesis of the surfactant-specific proteins. Information obtained from these studies in infants will help to better tailor exogenous surfactant treatment in neonatal lung diseases.

Effect of oxygen pressure during incubation with a (10)B-carrier on (10)B uptake capacity of cultured p53 wild-type and mutated tumor cells: dependency on p53 status of tumor cells and types of (10)B-carriers.

Purpose To evaluate the effect of oxygen pressure during incubation with a (10)B-carrier on (10)B uptake capacity of cultured p53 wild-type and mutated tumor cells. Materials and methods Cultured human head and neck squamous cell carcinoma cell line transfected with mutant TP53 (SAS/mp53), or with a neo vector as a control (SAS/neo) was incubated with L-para-boronophenylalanine-(10)B (BPA) or sodium mercaptoundecahydrododecaborate-(10)B (BSH) as a (10)B-carrier at the (10)B concentration of 60 ppm for 24 h under aerobic (20.7% of oxygen) or hypoxic (0.28% of oxygen) conditions. Immediately after incubation, cultured tumor cells received reactor thermal neutron beams, and a cell survival assay was performed. (10)B concentration of cultured SAS/neo or SAS/mp53 cells incubated under aerobic or hypoxic conditions was determined with a thermal neutron guide tube. Results Hypoxic incubation significantly decreased (10)B concentration of cultured cells with a clearer tendency observed following BPA than BSH treatment in both SAS/neo and SAS/mp53 cells. Following neutron beam irradiation, SAS/mp53 cells showed significantly higher relative biological effectiveness values than SAS/neo cells because of the significantly lower radiosensitivity of SAS/mp53 to γ-rays than SAS/neo cells. Conclusion Oxygen pressure during incubation with a (10)B-carrier had a critical impact on (10)B uptake of cultured tumor cells.

Distribution of toxic elements and transfer from the environment to humans traced by using lead isotopes. A case of study in the Sarno River basin, south Italy.

The results of a large geochemical study on various environmental media (soil, stream sediment, groundwater, surface water, lettuce and human hair) of the Sarno River basin, which is one of the most polluted areas in Italy, are presented. Further, it aims to deepen our understanding of the distribution of Pb and its isotope composition for the differentiation between natural and anthropogenic metal sources. Our results show the environmental media to be significantly enriched in Cr, Cu, Pb, Hg, Zn, and to a lesser extent in Sb, Cd and Ni compared to the natural local background variation. The numerous industrial activities (mainly tanneries) have caused environmental pollution especially Cr and Hg in soils and sediment samples. Such contamination is also evident in lettuce and in the hair of the resident population, which shows particularly high values for both Cr and Hg. The unusually high As, Be and Sn concentrations arise mostly from natural sources due to the volcanic nature of the investigated area. Lead isotope measurements indicate a trend suggesting mixing between two end-members, one of clear natural origin (geogenic) and another related to human activities (anthropogenic). Lead isotope results demonstrate that Pb in hair of inhabitants is similar to those in the local topsoil and that gasoline is one of the main, but not the only source of metal pollution. The most important exposure risks within the study area are associated with toxic elements levels in topsoil and stream sediment, and the ingestion of locally grown lettuce. The high concentrations of these elements in hair are a further confirmation of this exposure pathway.

Multibreath alveolar oxygen tension imaging.

PURPOSE: This study tested the ability of a multibreath hyperpolarized HP (3) He MRI protocol to increase the accuracy of regional alveolar oxygen tension (PA O2 ) measurements by lessening the influence of gas-flow artifacts. Conventional single-breath PA O2 measurement has been susceptible to error induced by intervoxel gas flow, particularly when used to study subjects with moderate-to-severe chronic obstructive pulmonary disease (COPD). METHODS: Both single-breath and multibreath PA O2 imaging schemes were implemented in seven human subjects (one healthy, three asymptomatic smokers, and three COPD). The number and location of voxels with nonphysiologic PA O2 values generated by intervoxel gas flow were compared between the two protocols. RESULTS: The multibreath scheme resulted in a significantly lower total percentage of nonphysiologic PA O2 values (6.0%) than the single-breath scheme (13.7%) (P = 0.006). PA O2 maps showed several patterns of gas-flow artifacts that were present in the single-breath protocol but mitigated by the multibreath approach. Multibreath imaging also allowed for the analysis of slow-filling areas that presented no signal after a single breath. CONCLUSION: A multibreath approach enhances the accuracy and completeness of noninvasive PA O2 measurement by significantly lessening the proportion of nonphysiologic values generated by intervoxel gas flow. Magn Reson Med 76:1092-1101, 2016. © 2015 Wiley Periodicals, Inc.

Exogenous arachidonic acid mediates permeability of human brain microvessel endothelial cells through prostaglandin E2 activation of EP3 and EP4 receptors.

The blood-brain barrier, formed by microvessel endothelial cells, is the restrictive barrier between the brain parenchyma and the circulating blood. Arachidonic acid (ARA; 5,8,11,14-cis-eicosatetraenoic acid) is a conditionally essential polyunsaturated fatty acid [20:4(n-6)] and is a major constituent of brain lipids. The current study examined the transport processes for ARA in confluent monolayers of human brain microvascular endothelial cells (HBMEC). Addition of radioactive ARA to the apical compartment of HBMEC cultured on Transwell(®) inserts resulted in rapid incorporation of radioactivity into the basolateral medium. Knock down of fatty acid transport proteins did not alter ARA passage into the basolateral medium as a result of the rapid generation of prostaglandin E2 (PGE2 ), an eicosanoid known to facilitate opening of the blood-brain barrier. Permeability following ARA or PGE2 exposure was confirmed by an increased movement of fluorescein-labeled dextran from apical to basolateral medium. ARA-mediated permeability was attenuated by specific cyclooxygenase-2 inhibitors. EP3 and EP4 receptor antagonists attenuated the ARA-mediated permeability of HBMEC. The results indicate that ARA increases permeability of HBMEC monolayers likely via increased production of PGE2 which acts upon EP3 and EP4 receptors to mediate permeability. These observations may explain the rapid influx of ARA into the brain previously observed upon plasma infusion with ARA. The blood-brain barrier, formed by microvessel endothelial cells, is a restrictive barrier between the brain parenchyma and the circulating blood. Radiolabeled arachidonic acid (ARA) movement across, and monolayer permeability in the presence of ARA, was examined in confluent monolayers of primary human brain microvessel endothelial cells (HBMECs) cultured on Transwell(®) plates. Incubation of HBMECs with ARA resulted in a rapid increase in HBMEC monolayer permeability. The mechanism was mediated, in part, through increased prostaglandin E2 production from ARA which acted upon EP3 and EP4 receptors to increase HBMEC monolayer permeability.

Longitudinal assessment of infarct progression, brain metabolism and behavior following anterior cerebral artery occlusion in rats.

BACKGROUND: Stroke patients suffering from occlusion of the anterior cerebral artery (ACAo) develop cognitive and executive deficits. Experimental models to investigate such functional impairments and recovery are rare and not satisfyingly validated. NEW METHOD: We stereotactically injected the vasoconstrictor endothelin-1 (ET-1) close to the ACA of rats and assessed magnitude and course of CBF reduction using [(14)C]iodoantipyrine autoradiography and [(15)O]H2O-PET. [(18)F]FDG-PET and T2-weighted MRI determined regional metabolic and structural alterations. To test cognitive and executive functions, we analyzed decision-making in a food-carrying task, spatial working memory in a spontaneous alternation task and anxiety in an elevated plus maze test before and 1 month after ACAo. RESULTS: CBF decreased immediately after ET-1 injection, started to recover 1-2h and returned to control 4h thereafter. Metabolic and structural lesions developed permanently in the ACA territory. Hypometabolism occurring bilaterally in the piriform region may reflect diaschisis. Behavioral testing after ACAo revealed context-dependent changes in decision making, exploratory activity and walking speed, as well as decreased anxiety and spatial working memory. COMPARISON WITH EXISTING METHOD(S): Aside from modeling a known entity of stroke patients, ACAo in rats allows to longitudinally study deterioration of cognitive and executive function without major interference by disturbed primary motor function. It complements therefore stroke research since common models using middle cerebral artery occlusion (MCAo) all affect motor function severely. CONCLUSION: The established ACAo model in rats effectively reflects deficits characteristic for ACA stroke in humans. It is furthermore highly suitable for longitudinal assessment of cognitive and executive functions.

Nickel and zinc isotope fractionation in hyperaccumulating and nonaccumulating plants.

Until now, there has been little data on the isotope fractionation of nickel (Ni) in higher plants and how this can be affected by plant Ni and zinc (Zn) homeostasis. A hydroponic cultivation was conducted to investigate the isotope fractionation of Ni and Zn during plant uptake and translocation processes. The nonaccumulator Thlaspi arvense, the Ni hyperaccumulator Alyssum murale and the Ni and Zn hyperaccumulator Noccaea caerulescens were grown in low (2 µM) and high (50 µM) Ni and Zn solutions. Results showed that plants were inclined to absorb light Ni isotopes, presumably due to the functioning of low-affinity transport systems across root cell membrane. The Ni isotope fractionation between plant and solution was greater in the hyperaccumulators grown in low Zn treatments (Δ(60)Ni(plant-solution) = -0.90 to -0.63‰) than that in the nonaccumulator T. arvense (Δ(60)Ni(plant-solution) = -0.21‰), thus indicating a greater permeability of the low-affinity transport system in hyperaccumulators. Light isotope enrichment of Zn was observed in most of the plants (Δ(66)Zn(plant-solution) = -0.23 to -0.10‰), but to a lesser extent than for Ni. The rapid uptake of Zn on the root surfaces caused concentration gradients, which induced ion diffusion in the rhizosphere and could result in light Zn isotope enrichment in the hyperaccumulator N. caerulescens. In high Zn treatment, Zn could compete with Ni during the uptake process, which reduced Ni concentration in plants and decreased the extent of Ni isotope fractionation (Δ(60)Ni(plant-solution) = -0.11 to -0.07‰), indicating that plants might take up Ni through a low-affinity transport system of Zn. We propose that isotope composition analysis for transition elements could become an empirical tool to study plant physiological processes.

Type-1 cannabinoid receptor activity during Alzheimer's disease progression.

The activity of CB1 cannabinoid receptors was studied in postmortem brain samples of Alzheimer's disease (AD) patients during clinical deterioration. CB1 activity was higher at earlier AD stages in limited hippocampal areas and internal layers of frontal cortex, but a decrease was observed at the advanced stages. The pattern of modification appears to indicate initial hyperactivity of the endocannabinoid system in brain areas that lack classical histopathological markers at earlier stages of AD, indicating an attempt to compensate for the initial synaptic impairment, which is then surpassed by disease progression. These results suggest that initial CB1 stimulation might have therapeutic relevance.

Dose estimation for internal organs during boron neutron capture therapy for body-trunk tumors.

Radiation doses during boron neutron capture therapy for body-trunk tumors were estimated for various internal organs, using data from patients treated at Kyoto University Research Reactor Institute. Dose-volume histograms were constructed for tissues of the lung, liver, kidney, pancreas, and bowel. For pleural mesothelioma, the target total dose to the normal lung tissues on the diseased side is 5Gy-Eq in average for the whole lung. It was confirmed that the dose to the liver should be carefully considered in cases of right lung disease.