Breast Cancer Index and prediction of benefit from extended endocrine therapy in breast cancer patients treated in the Adjuvant Tamoxifen-To Offer More? (aTTom) trial.

BACKGROUND: Extending the duration of adjuvant endocrine therapy reduces the risk of recurrence in a subset of women with early-stage hormone receptor-positive (HR+) breast cancer. Validated predictive biomarkers of endocrine response could significantly improve patient selection for extended therapy. Breast cancer index (BCI) [HOXB13/IL17BR ratio (H/I)] was evaluated for its ability to predict benefit from extended endocrine therapy in patients previously randomized in the Adjuvant Tamoxifen-To Offer More? (aTTom) trial. PATIENTS AND METHODS: Trans-aTTom is a multi-institutional, prospective-retrospective study in patients with available formalin-fixed paraffin-embedded primary tumor blocks. BCI testing and central determination of estrogen receptor (ER) and progesterone receptor (PR) status by immunohistochemistry were carried out blinded to clinical outcome. Survival endpoints were evaluated using Kaplan-Meier analysis and Cox regression with recurrence-free interval (RFI) as the primary endpoint. Interaction between extended endocrine therapy and BCI (H/I) was assessed using the likelihood ratio test. RESULTS: Of 583 HR+, N+ patients analyzed, 49% classified as BCI (H/I)-High derived a significant benefit from 10 versus 5 years of tamoxifen treatment [hazard ratio (HR): 0.35; 95% confidence interval (CI) 0.15-0.86; 10.2% absolute risk reduction based on RFI, P = 0.027]. BCI (H/I)-low patients showed no significant benefit from extended endocrine therapy (HR: 1.07; 95% CI 0.69-1.65; -0.2% absolute risk reduction; P = 0.768). Continuous BCI (H/I) levels predicted the magnitude of benefit from extended tamoxifen, whereas centralized ER and PR did not. Interaction between extended tamoxifen treatment and BCI (H/I) was statistically significant (P = 0.012), adjusting for clinicopathological factors. CONCLUSION: BCI by high H/I expression was predictive of endocrine response and identified a subset of HR+, N+ patients with significant benefit from 10 versus 5 years of tamoxifen therapy. These data provide further validation, consistent with previous MA.17 data, establishing level 1B evidence for BCI as a predictive biomarker of benefit from extended endocrine therapy. TRIAL REGISTRATION: ISRCTN17222211; NCT00003678.

Breast Cancer Index predicts pathological complete response and eligibility for breast conserving surgery in breast cancer patients treated with neoadjuvant chemotherapy.

BACKGROUND: The aim of neoadjuvant chemotherapy is to increase the likelihood of successful breast conservation surgery (BCS). Accurate identification of BCS candidates is a diagnostic challenge. Breast Cancer Index (BCI) predicts recurrence risk in estrogen receptor+lymph node-breast cancer. Performance of BCI to predict chemosensitivity based on pathological complete response (pCR) and BCS was assessed. METHODS: Real-time RT-PCR BCI assay was conducted using tumor samples from 150 breast cancer patients treated with neoadjuvant chemotherapy. Logistical regression and c-index were used to assess predictive strength and additive accuracy of BCI beyond clinicopathologic factors. RESULTS: BCI classified 42% of patients as low, 35% as intermediate and 23% as high risk. Low BCI risk group had 98.4% negative predictive value (NPV) for pCR and 86% NPV for BCS. High versus low BCI group had a 34 and 5.8 greater likelihood of achieving pCR and BCS, respectively (P=0.0055; P=0.0022). BCI increased c-index for pCR (0.875-0.924; P=0.017) and BCS prediction (0.788-0.843; P=0.027) beyond clinicopathologic factors. CONCLUSIONS: BCI significantly predicted pCR and BCS beyond clinicopathologic factors. High NPVs indicate that BCI could be a useful tool to identify breast cancer patients who are not eligible for neoadjuvant chemotherapy. These results suggest that BCI could be used to assess both chemosensitivity and eligibility for BCS.

High bone turnover and accumulation of osteoid in patients with neurofibromatosis 1.

UNLABELLED: Although it is known that neurofibromatosis 1 (NF1) patients suffer from vitamin D deficiency and display decreased bone mineral density (BMD), a systematic clinical and histomorphometrical analysis is absent. Our data demonstrate that NF1 patients display high bone turnover and accumulation of osteoid and that supplementation of vitamin D has a beneficial effect on their BMD. INTRODUCTION: Neurofibromatosis 1 results in a wide range of clinical manifestations, including decreased BMD. Although it has been reported that NF1 patients have decreased vitamin D serum levels, the manifestation of the disease at the bone tissue level has rarely been analyzed. METHODS: Thus, we performed a clinical evaluation of 14 NF1 patients in comparison to age- and sex-matched control individuals. The analysis included dual X-ray absorptiometry osteodensitometry, laboratory parameters, histomorphometric and quantitative backscattered electron imaging (qBEI) analyses of undecalcified bone biopsies. RESULTS: NF1 patients display significantly lower 25-(OH)-cholecalciferol serum levels and decreased BMD compared to control individuals. Histomorphometric analysis did not only reveal a reduced trabecular bone volume in biopsies from NF1 patients, but also a significantly increased osteoid volume and increased numbers of osteoblasts and osteoclasts. Moreover, qBEI analysis revealed a significant decrease of the calcium content in biopsies from NF1 patients. To address the question whether a normalization of calcium homeostasis improves BMD in NF1 patients, we treated four patients with cholecalciferol for 1 year, which resulted in a significant increase of BMD. CONCLUSION: Taken together, our data provide the first complete histomorphometric analysis from NF1 patients. Moreover, they suggest that low vitamin D levels significantly contribute to the skeletal defects associated with the disease.

Bone health and fracture rate in individuals with neurofibromatosis 1 (NF1).

BACKGROUND: Patients with neurofibromatosis 1 (NF1) are shorter than expected and often have low bone mineral density (BMD), but the pathogenesis of these bony problems is poorly understood. METHODS: We performed an exploratory study of BMD, 18 laboratory measures of bone metabolism, and fracture history in 72 adult NF1 patients. RESULTS: Eight of the 18 clinical biochemical measures of bone health had at least 10% of NF1 patients outside the standard reference range. Serum 25-hydroxy-vitamin D concentrations were low in 56% of the NF1 patients, serum parathyroid hormone (PTH) concentrations were high in 34%, and urine deoxypyridinoline cross-link concentrations were high in 50%. Mean serum 25-hydroxy-vitamin D concentrations were significantly lower in people with NF1 than in season matched controls in both summer (p = 0.008) and winter (p<0.001). 36 (50%) of the 72 people with NF1 studied had BMD consistent with osteopenia, and 14 (19%) had BMD consistent with osteoporosis. High serum PTH concentration, high serum bone tartrate resistant acid phosphatase concentration, and high serum calcium concentration were associated with lower BMD among the NF1 patients. Males were more likely than females to have low BMD. The reported frequency of fractures in individuals with NF1 was much higher than in their unaffected siblings and spouses (p<0.001), and pathological fractures were reported only in NF1 patients. CONCLUSION: People with NF1 often have a generalised abnormality of bone metabolism. Further studies are needed to determine the biochemical and molecular basis of this abnormality.

Scalable Production of Equine Platelet Lysate for Multipotent Mesenchymal Stromal Cell Culture.

Translation of multipotent mesenchymal stromal cell (MSC)-based therapies is advancing in human and veterinary medicine. One critical issue is the in vitro culture of MSC before clinical use. Using fetal bovine serum (FBS) as supplement to the basal medium is still the gold standard for cultivation of many cell types including equine MSC. Alternatives are being explored, with substantial success using platelet lysate-supplemented media for human MSC. However, progress lags behind in the veterinary field. The aim of this study was to establish a scalable protocol for equine platelet lysate (ePL) production and to test the ePL in equine MSC culture. Whole blood was harvested into blood collection bags from 20 healthy horses. After checking sample materials for pathogen contamination, samples from 19 animals were included. Platelet concentrates were prepared using a buffy coat method. Platelets, platelet-derived growth factor BB, and transforming growth factor ß1 concentrations were increased in the concentrates compared with whole blood or serum (p < 0.05), while white blood cells were reduced (p < 0.05). The concentrates were lysed using freeze/thaw cycles, which eliminated the cells while growth factor concentrations were maintained. Donor age negatively correlated with platelet and growth factor concentrations after processing (p < 0.05). Finally, all lysates were pooled and the ePL was evaluated as culture medium supplement in comparison with FBS, using adipose-derived MSC from four unrelated donor horses. MSC proliferated well in 10% FBS as well as in 10% ePL. However, using 5 or 2.5% ePL entailed highly inconsistent proliferation or loss of proliferation, with significant differences in generation times and confluencies (p < 0.05). MSC expressed the surface antigens CD90, CD44, and CD29, but CD73 and CD105 detection was low in all culture media. Adipogenic and osteogenic differentiation led to similar results in MSC from different culture media. The buffy coat method is useful to produce equine platelet concentrate with increased platelet and reduced white blood cell content in large scales. The ePL obtained supports MSC expansion similar as FBS when used at the same concentration (10%). Further investigations into equine MSC functionality in culture with ePL should follow.

Current approaches to avoid the culling of day-old male chicks in the layer industry, with special reference to spectroscopic methods.

The negative correlation between fattening and laying performance prevents breeding improvement in both laying performance and meat yield. Therefore, specialized chicken lines have been bred in order to achieve either an efficient production of high-quality eggs or high growth rates. As a result, day-old male chicks are culled in the layer hatchery, which poses animal welfare and ethical problems. Breeding companies, scientific groups, and hatcheries are attempting to resolve this issue, with a common aim to find feasible alternatives for the routine killing of male layer chicks. Some approaches aim to influence the sex ratio, while others target at the economically feasible use of the male layer offspring, such as the fattening of "laying hen brothers" or crossbreedings of layers and broilers to create "dual-purpose chickens." Another approach is the sex determination prior to hatch. One of the prerequisites of in ovo sex determination is a practicable method that can be used in industry. The analysis needs to be rapid, cost-efficient, and highly precise; in addition, negative impacts on hatching rate, animal health, and/or performance parameters should be limited. Furthermore, sex determination should be performed before the sensory nervous system's response of the chick embryo to certain or potentially harmful stimuli is developed, which according to current knowledge is before the d 7 of incubation.

Ectopic expression of S28A-mutated Histone H3 modulates longevity, stress resistance and cardiac function in Drosophila.

Histone H3 serine 28 (H3S28) phosphorylation and de-repression of polycomb repressive complex (PRC)-mediated gene regulation is linked to stress conditions in mitotic and post-mitotic cells. To better understand the role of H3S28 phosphorylation in vivo, we studied a Drosophila strain with ectopic expression of constitutively-activated H3S28A, which prevents PRC2 binding at H3S28, thus mimicking H3S28 phosphorylation. H3S28A mutants showed prolonged life span and improved resistance against starvation and paraquat-induced oxidative stress. Morphological and functional analysis of heart tubes revealed smaller luminal areas and thicker walls accompanied by moderately improved cardiac function after acute stress induction. Whole-exome deep gene-sequencing from isolated heart tubes revealed phenotype-corresponding changes in longevity-promoting and myotropic genes. We also found changes in genes controlling mitochondrial biogenesis and respiration. Analysis of mitochondrial respiration from whole flies revealed improved efficacy of ATP production with reduced electron transport-chain activity. Finally, we analyzed posttranslational modification of H3S28 in an experimental heart failure model and observed increased H3S28 phosphorylation levels in HF hearts. Our data establish a critical role of H3S28 phosphorylation in vivo for life span, stress resistance, cardiac and mitochondrial function in Drosophila. These findings may pave the way for H3S28 phosphorylation as a putative target to treat stress-related disorders such as heart failure.

Repression by HoxA7 is mediated by the homeodomain and the modulatory action of its N-terminal-arm residues.

Hox genes encode homeodomain-containing proteins that are presumed to control spatial patterning during murine embryogenesis through their actions as transcriptional regulatory proteins. In this study, we have investigated the transcriptional function of a prototypic member of this family, HoxA7. We demonstrate that HoxA7 function as a potent transcriptional repressor and that its action as such requires several domains, including both activator and repressor regions. The repressor regions are contained within the homeodomain and a C-terminal acidic region, both of which are well conserved among members of the Hox family. Accordingly, we show that two other members of this family also function as repressors, although they vary in their relative repressor potency. Finally, we explore the novel observation that the homeodomain of HoxA7 functions as a transcriptional repressor domain. We show that the homeodomain compared with two other DNA-binding domains, is unique in its ability to function as a repressor domain and that repression requires conserved residues, in helix III. We further show that residues in the N-terminal arm of the homeodomain contribute to the differential repressor actions of various Hox proteins. These findings demonstrate that the transcriptional function of HoxA7 and possibility of Hox proteins in general is determined by their unique combination of conserved and nonconserved regions as well as through the complex actions of their homeodomains.

Hox proteins have different affinities for a consensus DNA site that correlate with the positions of their genes on the hox cluster.

The hox genes, members of a family of essential developmental regulators, have the intriguing property that their expression in the developing murine embryo is colinear with their chromosomal organization. Members of the hox gene family share a conserved DNA binding domain, termed the homeodomain, which mediates interactions of Hox proteins with DNA regulatory elements in the transcriptional control regions of target genes. In this study, we characterized the DNA binding properties of five representative members of the Hox family: HoxA5, HoxB4, HoxA7, HoxC8, and HoxB1. To facilitate a comparative analysis of their DNA binding properties, we produced the homeodomain regions of these Hox proteins in Escherichia coli and obtained highly purified polypeptides. We showed that these Hox proteins interact in vitro with a common consensus DNA site that contains the motif (C/G)TAATTG. We further showed that the Hox proteins recognize the consensus DNA site in vivo, as determined by their ability to activate transcription through this site in transient transfection assays. Although they interact optimally with the consensus DNA site, the Hox proteins exhibit subtle, but distinct, preferences for DNA sites that contain variations of the nucleotides within the consensus motif. In addition to their modest differences in DNA binding specificities, the Hox proteins also vary in their relative affinities for DNA. Intriguingly, their relative affinities correlate with the positions of their respective genes on the hox cluster. These findings suggest that subtle differences in DNA binding specificity combined with differences in DNA binding affinity constitute features of the "Hox code" that contribute to the selective functions of Hox proteins during murine embryogenesis.

Trimeric association of Hox and TALE homeodomain proteins mediates Hoxb2 hindbrain enhancer activity.

Pbx/exd proteins modulate the DNA binding affinities and specificities of Hox proteins and contribute to the execution of Hox-dependent developmental programs in arthropods and vertebrates. Pbx proteins also stably heterodimerize and bind DNA with Meis and Pknox1-Prep1, additional members of the TALE (three-amino-acid loop extension) superclass of homeodomain proteins that function on common genetic pathways with a subset of Hox proteins. In this study, we demonstrated that Pbx and Meis bind DNA as heterotrimeric complexes with Hoxb1 on a genetically defined Hoxb2 enhancer, r4, that mediates the cross-regulatory transcriptional effects of Hoxb1 in vivo. The DNA binding specificity of the heterotrimeric complex for r4 is mediated by a Pbx-Hox site in conjunction with a distal Meis site, which we showed to be required for ternary complex formation and Meis-enhanced transcription. Formation of heterotrimeric complexes in which all three homeodomains bind their cognate DNA sites is topologically facilitated by the ability of Pbx and Meis to interact through their amino termini and bind DNA without stringent half-site orientation and spacing requirements. Furthermore, Meis site mutation in the Hoxb2 enhancer phenocopies Pbx-Hox site mutation to abrogate enhancer-directed expression of a reporter transgene in the murine embryonic hindbrain, demonstrating that DNA binding by all three proteins is required for trimer function in vivo. Our data provide in vitro and in vivo evidence for the combinatorial regulation of Hox and TALE protein functions that are mediated, in part, by their interdependent DNA binding activities as ternary complexes. As a consequence, Hoxb1 employs Pbx and Meis-related proteins, as a pair of essential cofactors in a higher-order molecular complex, to mediate its transcriptional effects on an endogenous Hox response element.

CREB binding protein interacts with nucleoporin-specific FG repeats that activate transcription and mediate NUP98-HOXA9 oncogenicity.

Genes encoding the Phe-Gly (FG) repeat-containing nucleoporins NUP98 and CAN/NUP214 are at the breakpoints of several chromosomal translocations associated with human acute myeloid leukemia (AML), but their role in oncogenesis is unclear. Here we demonstrate that the NUP98-HOXA9 fusion gene encodes two nuclear oncoproteins with either 19 or 37 NUP98 FG repeats fused to the DNA binding and PBX heterodimerization domains of the transcription factor HOXA9. Both NUP98-HOXA9 chimeras transformed NIH 3T3 fibroblasts, and this transformation required the HOXA9 domains for DNA binding and PBX interaction. Surprisingly, the FG repeats acted as very potent transactivators of gene transcription. This NUP98-derived activity is essential for transformation and can be replaced by the bona fide transactivation domain of VP16. Interestingly, FG repeat-containing segments derived from the nucleoporins NUP153 and CAN/NUP214 functioned similarly to those from NUP98. We further demonstrate that transactivation by FG repeat-rich segments of NUP98 correlates with their ability to interact functionally and physically with the transcriptional coactivators CREB binding protein (CBP) and p300. This finding shows, for the first time, that a translocation-generated fusion protein appears to recruit CBP/p300 as an important step of its oncogenic mechanism. Together, our results suggest that NUP98-HOXA9 chimeras are aberrant transcription factors that deregulate HOX-responsive genes through the transcriptional activation properties of nucleoporin-specific FG repeats that recruit CBP/p300. Indeed, FG repeat-mediated transactivation may be a shared pathogenic function of nucleoporins implicated human AML.

HoxA9-mediated immortalization of myeloid progenitors requires functional interactions with TALE cofactors Pbx and Meis.

Specific Hox genes are implicated in leukemic transformation, and their selective genetic collaboration with TALE homeobox genes, Pbx and Meis, accentuates their oncogenic potential. The molecular mechanisms underlying these coordinate functions, however, have not been characterized. In this study, we demonstrate that HoxA9 requires its Pbx interaction motif as well as its amino terminus to enhance the clonogenic potential of myeloid progenitors in vitro. We further show that HoxA9 forms functional trimeric DNA binding complexes with Pbx and Meis-like proteins on a modified enhancer. DNA binding complexes containing HoxA9 and TALE homeoproteins display cooperative transcriptional activity and are present in leukemic cells. Trimeric complex formation on its own, however, is not sufficient for HoxA9-mediated immortalization. Rather, structure-function analyses demonstrate that domains of HoxA9 which are necessary for cellular transformation are coincident with those required for trimer-mediated transcriptional activation. Furthermore, the amino terminus of HoxA9 provides essential transcriptional effector properties and its requirement for myeloid transformation can be functionally replaced by the VP16 activation domain. These data suggest that biochemical interactions between HoxA9 and TALE homeoproteins mediate cellular transformation in hematopoietic cells, and that their transcriptional activity in higher order DNA binding complexes provides a molecular basis for their collaborative roles in leukemogenesis.

Expression of Pbx1b during mammalian organogenesis.

Mammalian Pbx genes (Pbx1-3) encode a family of TALE homeodomain proteins that function as transcriptional regulators in numerous cell types (Curr. Opin. Genet. Dev. 8 (1998) 423). The present study highlights distinctive features of Pbx1b expression during mouse embryonic development as a framework to understand its biological functions. Immunohistochemical analyses demonstrate extensive expression of Pbx1b throughout post-implantation development, with highest levels observed during early to mid-gestation. Its initial distribution is predominantly associated with condensing mesoderm, however, Pbx1b displays dynamic expression patterns in derivatives of all principal germ layers. In particular, Pbx1b localizes to sites of mesenchymal-epithelial interactions during periods of active morphogenesis in tissues such as the lung, kidney, tooth buds and vibrissae follicles. Furthermore, BrdU labeling studies reveal that Pbx1b expression domains partially overlap with regions of cellular proliferation. Taken together, these data suggest that Pbx1b contributes to multiple cellular processes during embryogenesis, which may include roles in cell-autonomous regulation as well as in the mediation of tissue interactions.

Iodine-129 in soils from Northern Ukraine and the retrospective dosimetry of the iodine-131 exposure after the Chernobyl accident.

Forty-eight soil profiles down to a depth of 40 cm were taken in Russia and Ukraine in 1995 and 1997, respectively, in order to investigate the feasibility of retrospective dosimetry of the 131I exposure after the Chernobyl accident via the long-lived 129I. The sampling sites covered areas almost not affected by fallout from the Chernobyl accident such as Moscow/Russia and the Zhitomir district in Ukraine as well as the highly contaminated Korosten and Narodici districts in Ukraine. 129I was analyzed by radiochemical neutron activation analysis (RNAA) and accelerator mass spectrometry (AMS). 127I was measured for some profiles by RNAA or ion chromatography (IC). The results for 127I demonstrated large differences in the capabilities of the soils to store iodine over long time spans. The depth profiles of 129I and of 137Cs showed large differences in the migration behavior between the two nuclides but also for each nuclide among the different sampling sites. Though it cannot be quantified how much 129I and 137Cs was lost out of the soil columns into deeper depths, the inventories in the columns were taken as proxies for the total inventories. For 129I, these inventories were at least three orders of magnitude higher than a pre-nuclear value of 0.084+/-0.017 mBq m(-2) derived from a soil profile taken in 1939 in Lutovinovo/Russia. From the samples from Moscow and Zhitomir, a pre-Chernobyl 129I inventory of (44+/-24) mBq m(-2) was determined, limiting the feasibility of 129I retrospective dosimetry to areas where the 129I inventories exceed 100 mBq m(-2). Higher average 129I inventories in the Korosten and Narodici districts of 130 and 848 mBq m(-2), respectively, allowed determination of the 129I fallout due to the Chernobyl accident. Based on the total 129I inventories and on literature data for the atomic ratio of 129I/131I=13.6+/-2.8 for the Chernobyl emissions and on aggregated dose coefficients for 131I, the thyroid exposure due to 131I after the Chernobyl accident was estimated for the inhabitants of four villages in the Korosten and of three villages in the Narodici districts. The limitations and uncertainties of the 129I retrospective dosimetry are discussed.

Influences of age and sex on leukocytes of healthy horses and their ex vivo cytokine release.

Leukocytes and their functional capacities are used extensively as biomarkers in immunological research. Commonly employed indicators concerning leukocytes are as follows: number, composition in blood, response to discrete stimuli, cytokine release, and morphometric characteristics. In order to employ leukocytes as biomarkers for disease and therapeutic monitoring, physiological variations and influencing factors on the parameters measured have to be considered. The aim of this report was to describe the ranges of selected leukocyte parameters in a sample of healthy horses and to analyse whether age, sex, breed, and sampling time point (time of day) influence peripheral blood leukocyte composition, cell morphology and release of cytokines ex vivo. Flow cytometric comparative characterisation of cell size and complexity in 24 healthy horses revealed significant variance. Similarly, basal release of selected cytokines by blood mononuclear cells also showed high variability [TNFα (65-16,624pg/ml), IFNγ (4-80U/ml), IL-4 (0-5069pg/ml), IL-10 (49-1862pg/ml), and IL-17 (4-1244U/ml)]. Each animal's age influenced leukocyte composition, cell morphology and cytokine release (TNFα, IL-4, IL-10) ex vivo. Geldings showed smaller monocytes and higher spontaneous production of IL-10 when compared to the mares included. The stimulation to spontaneous release ratios of TNFα, IL-4 and IL-17 differed in Warmblood and Thoroughbred types. Sampling time influenced leukocyte composition and cell morphology. In summary, many animal factors - age being the dominant one - should be considered for studies involving the analysis of equine leukocytes. In addition, high inter-individual variances argue for individual baseline measurements.

On the analysis of iodine-129 and iodine-127 in environmental materials by accelerator mass spectrometry and ion chromatography.

Based on a review of literature about the abundances of 129I (T1/2 = 15.7 Ma) in the environment we show that there is a severe lack of knowledge, in particular about natural, pre-nuclear levels. Among the two analytical techniques which are sensitive enough to investigate 129I in environmental materials, namely radiochemical neutron activation analysis (RNAA) and accelerator mass spectrometry (AMS), only AMS is capable of covering the natural, pre-nuclear levels. Since such AMS measurements require chemical separation of iodine from the matrix, a wide variety of separation schemes are necessary for environmental analyses. We report here on such schemes for the analysis of soils, plants and soft tissue. They are applied exemplarily to analyses of soils from the vicinity of Chernobyl. For chemical separations prior to analysis, contamination control and blank analyses are essential. Here, we discuss quality control procedures in detail, both for RNAA and AMS. In the case of AMS we use ion-chromatography (IC) for the determination of stable iodine. The IC analysis is included in the separation schemes for environmental materials. First AMS-analyses of terrestrial biospheric materials demonstrate that natural environmental levels of 129I are lower than previously deduced from investigations using RNAA, but higher than expected from model calculations. AMS is capable of providing the missing knowledge about the radioecology of 129I.

Changes of concentrations of the elements Co, Cr, Sb, and Sc in tissues of persons with joint implants.

Elevated levels of Co and Cr were found in several organs of decreased implant bearers (CoCr-alloy/polyethylene joint prostheses) by means of instrumental and radiochemical neutron activation analysis as compared to normal persons. For comparative purposes, concentrations of the elements Co, Cr, Sb, and Sc were measured in heart, kidney, liver, and spleen of the patients and normal persons. For Cr determination, a new radiochemical separation technique with sufficiently low determination limit was employed. The importance of such investigations for studying possible carcinogenic effects of corrosion products and wear particles of metallic prostheses is mentioned.

Wet and dry deposition of 129I in Seville (Spain) measured by accelerator mass spectrometry.

Iodine-129 (T1/2 = 1.57 x 10(7) yr) concentrations have been determined by accelerator mass spectrometry in rainwater samples taken at Seville (southwestern Spain) in 1996 and 1997. This technique allows a reduction in the detection limits for this radionuclide in comparison to radiometric counting and other mass spectrometric methods such as ICP-MS. Typical 129I concentrations range from 4.7 x 10(7) 129I atoms/l (19.2%) to 4.97 x 10(9) 129I atoms/l (5.9%), while 129I depositions are normally in the order of 10(8)-10(10) atoms/m2d. These values agree well with other results obtained for recent rainwater samples collected in Europe. Apart from these, the relationship between 129I deposition and some atmospheric factors has been analyzed, showing the importance of the precipitation rate and the concentration of suspended matter in it.

Determination of 129I in atmospheric samples by accelerator mass spectrometry.

A method for the radiochemical extraction of 129I from atmospheric charcoal filters and its measurement by accelerator mass spectrometry is presented. Either the 129I concentration or the 129I/127I atom ratio can be determined in the sample. With this method, air filters from Seville, in the Southwest of Spain (37.4 degrees N, 6 degrees W) have been analyzed. Sensitivities in the order of 10(4) atoms/m3 for 129I concentrations and 10(-10) for 129I/127I atom ratios are obtained. AMS measurements are performed with the 6 MV tandem accelerator at the ETH-Hönggerberg in Zurich.

Rapid thinning of the Late Pleistocene Patagonian Ice Sheet followed migration of the Southern Westerlies.

Here we present the first reconstruction of vertical ice-sheet profile changes from any of the Southern Hemisphere's mid-latitude Pleistocene ice sheets. We use cosmogenic radio-nuclide (CRN) exposure analysis to record the decay of the former Patagonian Ice Sheet (PIS) from the Last Glacial Maximum (LGM) and into the late glacial. Our samples, from mountains along an east-west transect to the east of the present North Patagonian Icefield (NPI), serve as 'dipsticks' that allow us to reconstruct past changes in ice-sheet thickness, and demonstrates that the former PIS remained extensive and close to its LGM extent in this region until ~19.0 ka. After this time rapid ice-sheet thinning, initiated at ~18.1 ka, saw ice at or near its present dimension by 15.5 ka. We argue this rapid thinning was triggered by a combination of the rapid southward migration of the precipitation bearing Southern Hemisphere (SH) westerlies and regional warming.