Alpha emitter radium-223 and survival in metastatic prostate cancer

Radium-223 dichloride (radium-223), an alpha emitter, selectively targets bone metastases with alpha particles. We assessed the efficacy and safety of radium-223 as compared with placebo, in addition to the best standard of care, in men with castration-resistant prostate cancer and bone metastases.

A new radiocarbon chronology of Baumkirchen, stratotype for the onset of the Upper Wurmian in the Alps

ABSTRACT

The start of the Upper Wurmian in the Alps was marked by massive fluvioglacial aggradation prior to the arrival of the Central Alpine glaciers. In 1984, the Subcommission on European Quaternary Stratigraphy defined the clay pit of Baumkirchen (in the foreland of the Inn Valley, Austria) as the stratotype for the Middle to Upper Wurmian boundary in the Alps. Key for the selection of this site was its radiocarbon chronology, which still ranks among the most important datasets of this time interval in the Alps. In this study we re-sampled all available original plant specimens and established an accelerator mass spectrometry chronology which supersedes the published 40-year-old chronology. The new data show a much smaller scatter and yielded slightly older conventional radiocarbon dates clustering at ca. 31 C-14 ka BP. When calibrated using INTCAL13 the new data suggest that the sampled interval of 653-681 m in the clay pit was deposited 34-36 cal ka BP. Using two new radiocarbon dates of bone fragments found in the fluvioglacial gravel above the banded clays allows us to constrain the timing of the marked change from lacustrine to fluvioglacial sedimentation to ca. 32-33 cal ka BP, which suggests a possible link to the Heinrich 3 event in the North Atlantic. Copyright (c) 2013 John Wiley & Sons, Ltd.

Geochemical records of palaeoenvironmental controls on peat forming processes in the Mfabeni peatland, Kwazulu Natal, South Africa since the Late Pleistocene

The Mfabeni peatland is the only known sub-tropical coastal fen that transcends the Last Glacial Maximum (LGM). This ca. 10m thick peat sequence provides a continuous sedimentation record spanning from the late Pleistocene to present (basal age c. 47kcalyr BP). We investigated the paleaeoenvironmental controls on peat formation and organic matter source input at the Mfabeni fen by: 1) exploring geochemical records (mass accumulation rate, total organic carbon, carbon accumulation rate, δC, δN and C/N ratio) to delineate primary production, organic matter source input, preservation and diagenetic processes, and 2) employ these geochemical signatures to reconstruct the palaeoenvironmental conditions and prevailing climate that drove carbon accumulation in the peatland. We established that the Mfabeni peat sediments have undergone minimal diagenetic alteration. The peat sequence was divided into 5 linear sedimentation rate (LSR) stages indicating distinct changes in climate and hydrological conditions: LSR stage 1 (c. 47 to c. 32.2kcalyr BP): predominantly cool and wet climate with C4 plant assemblages, interrupted by two short warming events. LSR stage 2 (c. 32.2 to c. 27.6kcalyr BP): dry and windy climate followed by a brief warm and wet period with increased C4 sedge swamp vegetation. LSR stage 3 (c. 27.6 to c. 20.3kcalyr BP): initial cool and wet period with prevailing C4 sedge plant assemblage until c. 23kcalyr BP; then an abrupt change to dry and cool glacial conditions and steady increases in C3 grasses. LSR stage 4 (c. 20.3 to c. 10.4kcalyr BP): continuation of cool and dry conditions and strong C3 grassland signature until c. 15kcalyr BP, after which precipitation increases. LSR stage 5 (c. 10.4kcalyr BP to present): characterised by extreme fluctuations between pervasive wet and warm to cool interglacial conditions with intermittent abrupt millennial-scale cooling/drying events and oscillations between C3 and C4 plant assemblages. In this study we reconstructed a high-resolution record of local hydrology, bulk plant assemblage and inferred climate since the Late Pleistocene, which suggest an anti-phase link between Southern African and the Northern Hemisphere, most notably during Heinrich (5 to 2) and Younger Dryas events. © 2013 Elsevier B.V.

ND3, ND1 and 39 kDa subunits are more exposed in the de-active form of bovine mitochondrial complex I

An intriguing feature of mitochondrial complex I from several species is the so-called A/D transition, whereby the idle enzyme spontaneously converts from the active (A) form to the de-active (D) form. The A/D transition plays an important role in tissue response to the lack of oxygen and hypoxic deactivation of the enzyme is one of the key regulatory events that occur in mitochondria during ischaemia. We demonstrate for the first time that the A/D conformational change of complex I does not affect the macromolecular organisation of supercomplexes in vitro as revealed by two types of native electrophoresis. Cysteine 39 of the mitochondrially-encoded ND3 subunit is known to become exposed upon de-activation. Here we show that even if complex I is a constituent of the I + III + IV (S) supercomplex, cysteine 39 is accessible for chemical modification in only the D-form. Using lysine-specific fluorescent labelling and a DIGE-like approach we further identified two new subunits involved in structural rearrangements during the A/D transition: ND1 (MT-ND1) and 39 kDa (NDUFA9). These results clearly show that structural rearrangements during de-activation of complex I include several subunits located at the junction between hydrophilic and hydrophobic domains, in the region of the quinone binding site. De-activation of mitochondrial complex I results in concerted structural rearrangement of membrane subunits which leads to the disruption of the sealed quinone chamber required for catalytic turnover.

Integrated care pathways for airway diseases (AIRWAYS-ICPs)

The objective of Integrated Care Pathways for Airway Diseases (AIRWAYS-ICPs) is to launch a collaboration to develop multi-sectoral care pathways for chronic respiratory diseases in European countries and regions. AIRWAYS-ICPs has strategic relevance to the European Union Health Strategy and will add value to existing public health knowledge by: 1) proposing a common framework of care pathways for chronic respiratory diseases, which will facilitate comparability and trans-national initiatives; 2) informing cost-effective policy development, strengthening in particular those on smoking and environmental exposure; 3) aiding risk stratification in chronic disease patients, using a common strategy; 4) having a significant impact on the health of citizens in the short term (reduction of morbidity, improvement of education in children and of work in adults) and in the long-term (healthy ageing); 5) proposing a common simulation tool to assist physicians; and 6) ultimately reducing the healthcare burden (emergency visits, avoidable hospitalisations, disability and costs) while improving quality of life. In the longer term, the incidence of disease may be reduced by innovative prevention strategies. AIRWAYSICPs was initiated by Area 5 of the Action Plan B3 of the European Innovation Partnership on Active and Healthy Ageing. All stakeholders are involved (health and social care, patients, and policy makers).

The latest LGM culmination of the Garda Glacier (Italian Alps) and the onset of glacial termination. Age of glacial collapse and vegetation chronosequence

In the deglacial sequence of the largest end moraine system of the Italian Alps, we focused on the latest culmination of the Last Glacial Maximum, before a sudden downwasting of the piedmontane lobe occupying the modern lake basin. We obtained a robust chronology for this culmination and for the subsequent deglacial history by cross-radiocarbon dating of a proximal fluvioglacial plain and of a deglacial continuous lake sedimentation. We used reworked dinocysts to locate sources of glacial abrasion and to mark the input of glacial meltwater until depletion. The palynological record from postglacial lake sediments provided the first vegetation chronosequence directly reacting to the early Lateglacial withdrawal so far documented in the Alps.

Glacier collapse occurred soon after 17.46 +/- 0.2 ka cal BP, which is, the Manerba advance culmination. Basin deglaciation of several overdeepened foreland piedmont lakes on southern and northern sides of the Alps appears to be synchronous at millennial scale and near-synchronous with large-scale glacial retreat at global scale. The pioneering succession shows a first afforestation step at a median modeled age of 64 years after deglaciation, while rapid tree growth lagged 7 centuries. Between 16.4 +/- 0.16 and 15.5 +/- 0.16 ka cal BP, a regressive phase interrupted forest growth marking a Lateglacial phase of continental-dry climate predating GI-1. This event, spanning the most advanced phases of North-Atlantic H1, is consistently radiocarbon-framed at three deglacial lake records so far investigated on the Italian side of the Alps. Relationships with the Gschnitz stadial from the Alpine record of Lateglacial advances are discussed

North Atlantic surface ocean 14C variability between 30 – 40 kyr. BP

The Faroe-Shetland channel is situated in the main path of the inflow of warm North Atlantic surface water to the Nordic seas and further provides an escape route for the cold Norwegian Sea Deep Water. AMS 14C dates of planktonic foraminifera covering Marine Isotope Stage 3 from two cores in the Faroe-Shetland channel will be used to trace past variability of the Atlantic Meridional Overturning Circulation (AMOC). The reservoir age R shows considerable variability ranging between 50 to 2750 14C years. In particular high R values are observed during Heinrich event 4 (H4) with values around 1550 14C years and during the Laschamp magnetic excursion with R values as high as 2700 14C years. The period between Greenland interstadial 8 (GI8) and GI5 show highly variable R values with interstadial R values around 500 – 650 14C years, i.e. slightly higher than ‘normal’, whereas stadials show either significantly higher or lower R values. From GI5 towards the Last Glacial Maximum R values are generally around 1000 14C years or higher. Using magnetic susceptibility, IRD and δ13C and δ18O values measured on the planktic foraminifera species Neogloboquadrina pachyderma, we compare the observed R variability with reconstructed changes in the Atlantic Meridional Overturning Circulation (AMOC). Furthermore a climate model of intermediate complexity (GENIE) including 14C is used as conceptual tool for identifying oceanographic configuration explaining the observed R variability.

Late-Glacial and early Holocene marine 14C reservoir ages off North Iceland (16-9 cal kyr BP)

Tephrochronological age models and 48 14C age determinations on molluscs and foraminifera (planktonic and benthic) are applied for the calculation of marine 14C reservoir age variability during a time period covering the Heinrich event H1 to early Holocene (16–9 cal kyr BP). Our data source consists of four high-resolution marine sediment cores (HM107-04, HM107-05, MD99-2271, MD99-2275) from the North Icelandic shelf. The marine reservoir age (ΔR) is found to be extremely variable, ranging from 385 to 1065 14C years. Extreme ΔR values occur at the end of H1, with values around 1000 14C years (~15 cal kyr BP), probably due to reduced northward flow of well-ventilated subtropical surface waters and a southward expansion of polar waters, as well as an expansion of sea ice limiting air-sea gas exchange. With the onset of the Bølling-Allerød interstadial, the ΔR values decrease towards 0 14C years suggesting a more vigorous North Atlantic Current and an active meridional overturning circulation system. During the Younger Dryas stadial, ΔR values are consistently around 700 14C years suggesting e renewed expansion of polar waters and a weakened meridional overtuning circulation. Interestingly, ΔR values remain high (~200 14C years) at the onset of the Holocene suggesting continued high influence of polar waters. Subsequently, ΔR values rapidly decrease to ~¬ 250 14C years around 11 cal kyr BP, indicating increased air-sea CO2 exchange with the coeval atmosphere. The ΔR values average around 0 14C years from around 10.5 to 9.0 cal kyr BP.

Effect of radium-223 dichloride on symptomatic skeletal events in patients with castration-resistant prostate cancer and bone metastases: results from a phase 3, double-blind, randomised trial

BACKGROUND: Bone metastases frequently cause skeletal events in patients with metastatic castration-resistant prostate cancer. Radium-223 dichloride (radium-223) selectively targets bone metastases with high-energy, short-range α-particles. We assessed the effect of radium-223 compared with placebo in patients with castration-resistant prostate cancer and bone metastases.

METHODS: In this phase 3, double-blind, randomised ALSYMPCA trial, we enrolled patients who had symptomatic castration-resistant prostate cancer with two or more bone metastases and no known visceral metastases, who were receiving best standard of care, and had previously either received or were unsuitable for docetaxel. Patients were stratified by previous docetaxel use, baseline total alkaline phosphatase level, and current bisphosphonate use, then randomly assigned (2:1) to receive either six intravenous injections of radium-223 (50 kBq/kg) or matching placebo; one injection was given every 4 weeks. Randomisation was done with an interactive voice response system, taking into account trial stratification factors. Participants and investigators were masked to treatment assignment. The primary endpoint was overall survival, which has been reported previously. Here we report on time to first symptomatic skeletal event, defined as the use of external beam radiation to relieve bone pain, or occurrence of a new symptomatic pathological fracture (vertebral or non-verterbal), or occurence of spinal cord compression, or tumour-related orthopeadic surgical intervention. All events were required to be clinically apparent and were not assessed by periodic radiological review. Statistical analyses of symptomatic skeletal events were based on the intention-to-treat population. The study has been completed and is registered with ClinicalTrials.gov, number NCT00699751.

FINDINGS: Between June 12, 2008, and Feb 1, 2011, 921 patients were enrolled, of whom 614 (67%) were randomly assigned to receive radium-223 and 307 (33%) placebo. Symptomatic skeletal events occurred in 202 (33%) of 614 patients in the radium-223 group and 116 (38%) of 307 patients in the placebo group. Time to first symptomatic skeletal event was longer with radium-223 than with placebo (median 15·6 months [95% CI 13·5-18·0] vs 9·8 months [7·3-23·7]; hazard ratio [HR]=0·66, 95% CI 0·52-0·83; p=0·00037). The risks of external beam radiation therapy for bone pain (HR 0·67, 95% CI 0·53-0·85) and spinal cord compression (HR=0·52, 95% CI 0·29-0·93) were reduced with radium-233 compared with placebo. Radium-223 treatment did not seem to significantly reduce the risk of symptomatic pathological bone fracture (HR 0·62, 95% CI 0·35-1·09), or the need for tumour-related orthopaedic surgical intervention (HR 0·72, 95% CI 0·28-1·82).

INTERPRETATION: Radium-223 should be considered as a treatment option for patients with castration-resistant prostate cancer and symptomatic bone metastases.

FUNDING: Algeta and Bayer HealthCare Pharmaceuticals.

Progress towards improving chronologies for marine sediment records.

The North Atlantic has played a key role in abrupt climate changes due to the sensitivity of the Atlantic Meridional Overturning Circulation (AMOC) to the location and strength of deep water formation. It is crucial for modelling future climate change to understand the role of the AMOC in the rapid warming and gradual cooling cycles known as Dansgaard-Oescher (DO) events which are recorded in the Greenland ice cores. However, palaeoceanographic research into DO events has been hampered by the uncertainty in timing due largely to the lack of a precise chronological time frame for marine records. While tephrochronology provides links to the Greenland ice core records at a few points, radiocarbon remains the primary dating method for most marine cores. Due to variations in the atmospheric and oceanic 14C concentration, radiocarbon ages must be calibrated to provide calendric ages. The IntCal Working Group provides a global estimate of ocean 14C ages for calibration of marine radiocarbon dates, but the variability of the surface marine reservoir age in the North Atlantic particularly during Heinrich or DO events, makes calibration uncertain. In addition, the current Marine09 radiocarbon calibration beyond around 15 ka BP is largely based on 'tuning' to the Hulu Cave isotope record, so that the timing of events may not be entirely synchronous with the Greenland ice cores. The use of event-stratigraphy and independent chronological markers such as tephra provide the scope to improve marine radiocarbon reservoir age estimates particularly in the North Atlantic where a number of tephra horizons have been identified in both marine sediments and the Greenland ice cores. Quantification of timescale uncertainties is critical but statistical techniques which can take into account the differential dating between events can improve the precision. Such techniques should make it possible to develop specific marine calibration curves for selected regions.

Evangélicos en América Latina

Considerada tradicionalmente "el continente católico" por excelencia, Latinoamérica siempre ha contado con una presencia minoritaria protestante, y en los últimos treinta años, a pesar de llegar a concentrar en su territorio a la mitad de los católicos del mundo, ha visto una acelerada diversificación del universo religioso, con una proliferación impresionante de denominaciones y grupos, cuya mayorÍa se declara "evangélica". Este proceso, con frecuencia descrito con expresión simplista "invasión de las sectas", se muestra complejo en sus características y articulado en su composición. Frente a tal crecimiento numérico, que en el año 2000 deberÍa involucrar al 20% de la población del continente, la Iglesia Católica parece oscilar entre la crÍtica al papel "alienante" de estos movimientos y la adopción de sus formas culturales celebrativas y espiritualizantes. Además, desde la mitad de los años 80, luego -y acaso como consecuencia- de tal expansión, los evangélicos empezaron a afirmar una inédita presencia polÍtica, culminada en l991 con la obtención en Guatemala del máximo cargo del Estado por parte de Jorge Serrano, primer presidente evangélico elegido en Latinoamérica. Contando con un sólido arraigo popular, los partidos y políticos evangélicos ya están difundidos en todos los paÍses, con un papel que alterna el conservadorismo milenarista, el corporativismo confesional y la concientización liberadora. Con este número especial, SIAL pretende principalmente ofrecer algunos materiales para un mejor conocimiento de este dinámico y complejo fenómeno religioso y social.

Organização e variabilidade das indústrias líticas durante o Gravetense no Sudoeste Peninsular

Tese de doutoramento, Arqueologia, Faculdade de Ciências Humanas e Sociais, Universidade do Algarve, 2013

Personalisiertes Lernen in der Bibliothek: das Düsseldorfer Online-Tutorial (DOT) Informationskompetenz

Die Autoren beschreiben das von ihnen entwickelte Lerninformationssystem zur Informationskompetenz. Der Artikel behandelt den Aufbau und die Perspektiven des Systems.