cis- and trans-acting elements of the estrogen-regulated vitellogenin gene B1 of Xenopus laevis.

Vitellogenin genes are expressed under strict estrogen control in the liver of female oviparous vertebrates. Gene transfer experiments using estrogen-responsive cells have shown that the 13 bp perfect palindromic element GGTCACTGTGACC found upstream of the Xenopus laevis vitellogenin gene A2 promoter mediates hormonal stimulation and thus, was called the estrogen-responsive element (ERE). In the Xenopus vitellogenin genes B1 and B2 there are two closely adjacent EREs with one or more base substitutions when compared to the consensus ERE GGTCANNNTGACC. On their own, these degenerated elements have only a low or no regulatory capacity at all but act together synergistically to form an estrogen-responsive unit (ERU) with the same strength as the perfect palindromic 13 bp element. Analysis of estrogen receptor binding to the gene B1 ERU revealed a cooperative interaction of receptor dimers to the two adjacent imperfect EREs which most likely explains the synergistic stimulation observed in vivo. Furthermore, a promoter activator element located between positions --113 and --42 of the gene B1 and functional in the human MCF-7 and the Xenopus B3.2 cells has been identified and shown to be involved in the high level of induced transcription activity when the ERE is placed at a distance from the promoter. Finally, a hormone-controlled in vitro transcription system derived from Xenopus liver nuclear extracts was exploited to characterize two additional novel cis-acting elements within the vitellogenin gene B1 promoter. One of them, a negative regulatory element (NRE), is responsible for repression of promoter activity in the absence of hormone. The second is related to the NF-I binding site and is required, together with the ERE, to mediate hormonal induction. Moreover, we detected three trans-acting activities in Xenopus liver nuclear extracts that interact with these regions and demonstrated that they participate in the regulation of the expression of the vitellogenin promoter in vitro.

Official Positions for FRAX® Bone Mineral Density and FRAX® simplification from Joint Official Positions Development Conference of the International Society for Clinical Densitometry and International Osteoporosis Foundation on FRAX®.

Tools to predict fracture risk are useful for selecting patients for pharmacological therapy in order to reduce fracture risk and redirect limited healthcare resources to those who are most likely to benefit. FRAX® is a World Health Organization fracture risk assessment algorithm for estimating the 10-year probability of hip fracture and major osteoporotic fracture. Effective application of FRAX® in clinical practice requires a thorough understanding of its limitations as well as its utility. For some patients, FRAX® may underestimate or overestimate fracture risk. In order to address some of the common issues encountered with the use of FRAX® for individual patients, the International Society for Clinical Densitometry (ISCD) and International Osteoporosis Foundation (IOF) assigned task forces to review the medical evidence and make recommendations for optimal use of FRAX® in clinical practice. Among the issues addressed were the use of bone mineral density (BMD) measurements at skeletal sites other than the femoral neck, the use of technologies other than dual-energy X-ray absorptiometry, the use of FRAX® without BMD input, the use of FRAX® to monitor treatment, and the addition of the rate of bone loss as a clinical risk factor for FRAX®. The evidence and recommendations were presented to a panel of experts at the Joint ISCD-IOF FRAX® Position Development Conference, resulting in the development of Joint ISCD-IOF Official Positions addressing FRAX®-related issues.

Etude systématique, cladistique et biogéographique des Baetidae (Ephemeroptera) de Madagascar

Les Ephéméroptères constituent un ordre très archaïque d?insectes ailés, comprenant un nombre réduit d?espèces (actuellement environ 2500 espèces). Les larves sont aquatiques; la durée de ce stade est en général d?une année. Le stade adulte est par contre extrêmement bref: de quelques heures à quelques jours. La fonction quasi unique de ce stade est la reproduction. Par sa superficie, Madagascar est la quatrième île du monde. Elle est située dans la partie occidentale de l?Océan Indien à plus de 300 km de la côte africaine. Madagascar faisait partie du super-continent Gondwana. Elle s?est séparée de l?Afrique (-165 M.a.), puis a migré vers le Sud (-125 M.a.) avant de se détacher du sous-continent indien (-65 M.a.). La connaissance des Ephéméroptères malgaches était, jusqu?à très récemment, extrêmement limitée. Grâce au programme Biodiversité et biotypologie des eaux continentales malgaches, lancé conjointement par l?ORSTOM (actuel IRD, France) et le CNRE (Madagascar), un inventaire à large échelle de la macrofaune benthique malgache a été entrepris. La systématique de plusieurs familles d?Ephéméroptères (Tricorythidae, Polymitarcyidae, Palingeniidae,?), ainsi que d?autres groupes d?invertébrés (Trichoptères, Simuliidae, macrocrustacés) a fait l?objet d?études approfondies. La présente étude consistue un des volets de ce programme. Jusqu?au milieu des années 1990, seules quatre espèces valides appartenant à trois genres différents étaient décrites de Madagascar. En 6 ans, ce ne sont pas moins de 25 articles qui sont consacrés à la systématique des Baetidae, permettant de décrire 50 espèces et 8 genres nouveaux. La faune malgache des Baetidae compte actuellement 22 genres et 54 espèces. Malgré sa taille, Madagascar possède une richesse, tant générique que spécifique équivalente à celle d?un continent. Notre connaissance des Baetidae est suffisamment avancée pour mener une étude cladistique et biogéographique. La reconstruction phylogénétique a permis de mettre en évidence cinq lignées principales à Madagascar et de préciser, pour chacune d?elles, les genres inclus et les caractères propres. La faune des Baetidae malgaches présente un taux d?endémicité très élevé: 53 des 54 espèces et un tiers des genres sont endémiques. Elle montre des affinités extrêmement fortes avec la faune africaine, puisque 90% des genres présents à Madagascar ou en Afrique ont une répartition strictement restreinte à cette région. Les autres composantes, notamment orientales et océaniennes, sont négligeables; ces régions n?ont en commun avec Madagascar qu?un nombre restreint de genres cosmopolites. Ces affinités sont en contradiction avec les données géologiques de la dislocation du Gondwana. Plusieurs explications peuvent être données pour résoudre cette contradiction. La plus vraisemblable est que le pouvoir de dispersion des Ephéméroptères, et des Baetidae en particulier, est nettement sous-estimé. L?étude des faunes des îles volcaniques récentes, telles que les Comores, démontre clairement que les Baetidae sont capables de dispersion sur une distance de plus de 300 km. Il est donc possible d?envisager une colonisation de Madagascar à partir de l?Afrique continentale postérieure à la séparation des deux plaques. Nous avons établi des scénarios retraçant l?histoire biogéographique de chacune des cinq lignées. Pour quatre d?entre elles, l?Afrique continentale est le centre d?origine. La cinquième lignée aurait une origine paléarctique; l?Afrique représenterait un centre secondaire de spéciation. Ces lignées auraient secondairement colonisé Madagascar à partir de l?Afrique continentale. Ce travail ouvre donc d?importantes perspectives. Il rend possible l?utilisation à un niveau générique, voire spécifique, des Baetidae pour des travaux de faunistique ou d?écologie, en particulier pour des études liées à la dégradation de la qualité de l?eau. Il devrait également pouvoir servir de base pour l?étude et la compréhension des phénomènes de dispersion et colonisation dans les îles et archipels de l?Ouest de l?Océan Indien.<br/><br/>Mayflies (Ephemeroptera) are among the oldest known flying insects and encompass a very small number of species (ca 2500 species). Larvae are strictly freshwater inhabitants; this stage lasts generally one year. The imaginal stage is extremely short, from few hours to few days, and is devoted almost entirely to reproduction. Madagascar is the fourth largest island in the world by area. It is situated in the western part of the Indian Ocean, at a distance of more than 300 km from the African coast. Madagascar belonged to Gondwana. It was first separated from the African plate (-165 M.y.), then moved to the South (-65 M.y.), before the break-off with the Indian plate (-65 M.y.). Knowledge of the Malagasy mayflies was until recently extremely poor. The program Biodiversity and Biotypology of Malagasy Freshwaters, jointly run by the French ORSTOM and the Malagasy CNRE, began a global survey of the freshwater macroinvertebrates. The systematics of several mayfly families (Tricorythidae, Polymitarcyidae, Palingeniidae,?), and other invertebrate groups (Caddisflies, Blackflies,?) was the subject of ground studies. Our present study is one part of this global program. Until the middle of the nineties, only four baetid species belonging to three different genera had been described from Madagascar. During the last six years, 25 papers were dedicated to the systematics of the Baetidae, allowing the description of 50 new species and 8 new genera. The Malagasy fauna encompasses now 22 genera and 54 species. Despite its size, Madagascar has the same diversity, at specific and generic level, as a continent. Our knowledge of the Baetidae is sufficient to perform a cladistic and biogeographical study. Our phylogenetic reconstruction allows us to propose five main lineages and to indicate, for each of them, the genera included and their features. The Malagasy fauna of Baetidae possesses a high level of endemicity: 53 of the 54 species and one third of the genera are endemic. It shows extremely strong affinities with the African fauna, as more than 90% of the genera present in Madagascar or in Africa have a distribution restricted to this area. Other components, especially Oriental and Oceanian, are negligible. These areas share with Madagascar only a few widespread genera. These African affinities are in contradiction with the geological events, especially the break-off history of Gondwana. Some explanations can be given to solve this contradiction. The most likely is that the dispersal power of the mayflies, especially of the Baetidae, is greatly underestimated. The study of recent volcanic islands, particularly of the Comoros, clearly demonstrates that the Baetidae are able to disperse over more than 300 km. Consequently, a colonisation by the Baetidae, of Madagascar from the continental Africa, after the break-off must be considered as possible. We have established scenarios explaining the biogeographical history of each of the five lineages. For four of them, Africa has to be regarded as the centre of origin. The fifth lineage probably has a Palearctic origin; Africa should be considered as a secondary centre of speciation. These lineages should have secondarily colonised Madagascar from continental Africa. This work opens up new perspectives. It allows the use of the Baetidae for faunistic and ecological studies, especially for problems related to water quality. It must be also considered as a first step for understanding the dispersion and colonisation of the islands of the western part of the Indian Ocean.

Detection of clusters using space-time scan statistics

This paper aims at detecting spatio-temporal clustering in fire sequences using space?time scan statistics, a powerful statistical framework for the analysis of point processes. The methodology is applied to active fire detection in the state of Florida (US) identified by MODIS (Moderate Resolution Imaging Spectroradiometer) during the period 2003?06. Results of the present study show that statistically significant clusters can be detected and localized in specific areas and periods of the year. Three out of the five most likely clusters detected for the entire frame period are localized in the north of the state, and they cover forest areas; the other two clusters cover a large zone in the south, corresponding to agricultural land and the prairies in the Everglades. In order to analyze if the wildfires recur each year during the same period, the analyses have been performed separately for the 4 years: it emerges that clusters of forest fires are more frequent in hot seasons (spring and summer), while in the southern areas, they are widely present during the whole year. The recognition of overdensities of events and the ability to locate them in space and in time can help in supporting fire management and focussing on prevention measures.

Justice and Court Administrations, Their Workings and Efficiency in Switzerland : Aspects of Sentencing And Its Outcome In Swiss Cantons

The comparison of the operations of the administration of justice among cantons shows on one side large differences in the three major types of sentencing, in the use of pre-trial detention and the unsuspended prison sanction. When combined, one finds however very weak relationships when considering absolute, percentage or weighted results. On the other side, the outcome of these different policies is much paradoxical as there are no differences when comparing recidivism rates among cantons, despite strong differences in the use of pre-trial detention and the sentencing with prison sanctions. The paradoxical outcome of crime policies in terms of recidivism - e.g. the absence of differences of the outcome based on sanctions in the domain of less severe delinquency - suggests the need for more empirically informed crime policies. The role of justice administrators could be to participate in the dissemination of those findings as well as the dissemination of best practices among cantons with regard to outcomes and the use of resources - especially with consideration to the use of the prison sanction as it is the most costly and the most inefficient of all sanctions. Furthermore, the observance of the principle of equality before the law would be most likely be promoted.

An outbreak of Arthroderma vanbreuseghemii dermatophytosis at a veterinary school associated with an infected horse.

We report a case of an outbreak of inflammatory dermatophytoses caused by Arthroderma vanbreuseghemii (formally Trichophyton mentagrophytes pro parte) that involved an infected horse, the owner and at least 20 students, staff and stablemen at a veterinary school in Bern (Switzerland) that presented highly inflammatory dermatitis of the body and the face. Transmission from human to human was also recorded as one patient was the partner of an infected person. Both the phenotypic characteristics and ITS sequence of the dermatophytes isolated from the horse and patients were identical, consistent with the conclusion that the fungus originated from the horse. Three infected persons had not been in direct contact with the horse. Although direct transmission from human to human cannot be ruled out, fomites were most likely the source of infection for these three patients. Inspection of the literature at the end of the nineteenth and beginning of the twentieth century revealed that this dermatophyte was frequently transmitted from horses to humans in contact with horses (stablemen, coachmen, carters and artillery soldiers). The rarity of the present case report at the present time is likely related to the transformation of civilisation from the nineteenth century to nowadays in Europe with the change of horse husbandry. In addition, the inadequate immune response of the horse and the high number of people in contact with it at the equine clinic may explain the exceptional aspect of this case report.

Diploid males support a two-step mechanism of endosymbiont-induced thelytoky in a parasitoid wasp.

BACKGROUND: Haplodiploidy, where females develop from diploid, fertilized eggs and males from haploid, unfertilized eggs, is abundant in some insect lineages. Some species in these lineages reproduce by thelytoky that is caused by infection with endosymbionts: infected females lay haploid eggs that undergo diploidization and develop into females, while males are very rare or absent. It is generally assumed that in thelytokous wasps, endosymbionts merely diploidize the unfertilized eggs, which would then trigger female development. RESULTS: We found that females in the parasitoid wasp Asobara japonica infected with thelytoky-inducing Wolbachia produce 0.7-1.2 % male offspring. Seven to 39 % of these males are diploid, indicating that diploidization and female development can be uncoupled in A. japonica. Wolbachia titer in adults was correlated with their ploidy and sex: diploids carried much higher Wolbachia titers than haploids, and diploid females carried more Wolbachia than diploid males. Data from introgression lines indicated that the development of diploid individuals into males instead of females is not caused by malfunction-mutations in the host genome but that diploid males are most likely produced when the endosymbiont fails to activate the female sex determination pathway. Our data therefore support a two-step mechanism by which endosymbionts induce thelytoky in A. japonica: diploidization of the unfertilized egg is followed by feminization, whereby each step correlates with a threshold of endosymbiont titer during wasp development. CONCLUSIONS: Our new model of endosymbiont-induced thelytoky overthrows the view that certain sex determination mechanisms constrain the evolution of endosymbiont-induced thelytoky in hymenopteran insects. Endosymbionts can cause parthenogenesis through feminization, even in groups in which endosymbiont-diploidized eggs would develop into males following the hosts' sex determination mechanism. In addition, our model broadens our understanding of the mechanisms by which endosymbionts induce thelytoky to enhance their transmission to the next generation. Importantly, it also provides a novel window to study the yet-poorly known haplodiploid sex determination mechanisms in haplodiploid insects.

Localization and expression of EDS5H a homologue of the SA transporter EDS5.

BACKGROUND: An important signal transduction pathway in plant defence depends on the accumulation of salicylic acid (SA). SA is produced in chloroplasts and the multidrug and toxin extrusion transporter ENHANCED DISEASE SUSCEPTIBILITY5 (EDS5; At4g39030) is necessary for the accumulation of SA after pathogen and abiotic stress. EDS5 is localized at the chloroplast and functions in transporting SA from the chloroplast to the cytoplasm. EDS5 has a homologue called EDS5H (EDS5 HOMOLOGUE; At2g21340) but its relationship to EDS5 has not been described and its function is not known. RESULTS: EDS5H exhibits about 72% similarity and 59% identity to EDS5. In contrast to EDS5 that is induced after pathogen inoculation, EDS5H was constitutively expressed in all green tissues, independently of pathogen infection. Both transporters are located at the envelope of the chloroplast, the compartment of SA biosynthesis. EDS5H is not involved with the accumulation of SA after inoculation with a pathogen or exposure to UV stress. A phylogenetic analysis supports the hypothesis that EDS5H may be an H(+)/organic acid antiporter like EDS5. CONCLUSIONS: The data based on genetic and molecular studies indicate that EDS5H despite its homology to EDS5 does not contribute to pathogen-induced SA accumulation like EDS5. EDS5H most likely transports related substances such as for example phenolic acids, but unlikely SA.

Genetic consequences of population expansions and contractions in the common hippopotamus (Hippopotamus amphibius) since the Late Pleistocene.

Over the past two decades, an increasing amount of phylogeographic work has substantially improved our understanding of African biogeography, in particular the role played by Pleistocene pluvial-drought cycles on terrestrial vertebrates. However, still little is known on the evolutionary history of semi-aquatic animals, which faced tremendous challenges imposed by unpredictable availability of water resources. In this study, we investigate the Late Pleistocene history of the common hippopotamus (Hippopotamus amphibius), using mitochondrial and nuclear DNA sequence variation and range-wide sampling. We documented a global demographic and spatial expansion approximately 0.1-0.3 Myr ago, most likely associated with an episode of massive drainage overflow. These events presumably enabled a historical continent-wide gene flow among hippopotamus populations, and hence, no clear continental-scale genetic structuring remains. Nevertheless, present-day hippopotamus populations are genetically disconnected, probably as a result of the mid-Holocene aridification and contemporary anthropogenic pressures. This unique pattern contrasts with the biogeographic paradigms established for savannah-adapted ungulate mammals and should be further investigated in other water-associated taxa. Our study has important consequences for the conservation of the hippo, an emblematic but threatened species that requires specific protection to curtail its long-term decline.

COMPASS identifies T-cell subsets correlated with clinical outcomes.

Advances in flow cytometry and other single-cell technologies have enabled high-dimensional, high-throughput measurements of individual cells as well as the interrogation of cell population heterogeneity. However, in many instances, computational tools to analyze the wealth of data generated by these technologies are lacking. Here, we present a computational framework for unbiased combinatorial polyfunctionality analysis of antigen-specific T-cell subsets (COMPASS). COMPASS uses a Bayesian hierarchical framework to model all observed cell subsets and select those most likely to have antigen-specific responses. Cell-subset responses are quantified by posterior probabilities, and human subject-level responses are quantified by two summary statistics that describe the quality of an individual's polyfunctional response and can be correlated directly with clinical outcome. Using three clinical data sets of cytokine production, we demonstrate how COMPASS improves characterization of antigen-specific T cells and reveals cellular 'correlates of protection/immunity' in the RV144 HIV vaccine efficacy trial that are missed by other methods. COMPASS is available as open-source software.

In vivo electrochemical corrosion study of a CoCrMo biomedical alloy in human synovial fluids.

The present study was initiated with the aim to assess the in vivo electrochemical corrosion behaviour of CoCrMo biomedical alloys in human synovial fluids in an attempt to identify possible patient or pathology specific effects. For this, electrochemical measurements (open circuit potential OCP, polarization resistance Rp, potentiodynamic polarization curves, electrochemical impedance spectroscopy EIS) were carried out on fluids extracted from patients with different articular pathologies and prosthesis revisions. Those electrochemical measurements could be carried out with outstanding precision and signal stability. The results show that the corrosion behaviour of CoCrMo alloy in synovial fluids not only depends on material reactivity but also on the specific reactions of synovial fluid components, most likely involving reactive oxygen species. In some patients the latter were found to determine the whole cathodic and anodic electrochemical response. Depending on patients, corrosion rates varied significantly between 50 and 750mgdm(-2)year(-1).

Phylogeny and biogeography of Primula sect. Armerina: implications for plant evolution under climate change and the uplift of the Qinghai-Tibet Plateau.

BACKGROUND: The historical orogenesis and associated climatic changes of mountain areas have been suggested to partly account for the occurrence of high levels of biodiversity and endemism. However, their effects on dispersal, differentiation and evolution of many groups of plants are still unknown. In this study, we examined the detailed diversification history of Primula sect. Armerina, and used biogeographic analysis and macro-evolutionary modeling to investigate a series of different questions concerning the evolution of the geographical and ecological distribution of the species in this section. RESULTS: We sequenced five chloroplast and one nuclear genes for species of Primula sect. Armerina. Neither chloroplast nor nuclear trees support the monophyly of the section. The major incongruences between the two trees occur among closely related species and may be explained by hybridization. Our dating analyses based on the chloroplast dataset suggest that this section began to diverge from its relatives around 3.55 million years ago, largely coinciding with the last major uplift of the Qinghai-Tibet Plateau (QTP). Biogeographic analysis supports the origin of the section in the Himalayan Mountains and dispersal from the Himalayas to Northeastern QTP, Western QTP and Hengduan Mountains. Furthermore, evolutionary models of ecological niches show that the two P. fasciculata clades have significantly different climatic niche optima and rates of niche evolution, indicating niche evolution under climatic changes and further providing evidence for explaining their biogeographic patterns. CONCLUSION: Our results support the hypothesis that geologic and climatic events play important roles in driving biological diversification of organisms in the QTP area. The Pliocene uplift of the QTP and following climatic changes most likely promoted both the inter- and intraspecific divergence of Primula sect. Armerina. This study also illustrates how niche evolution under climatic changes influences biogeographic patterns.

A probable dual mode of action for both L- and D-lactate neuroprotection in cerebral ischemia.

Lactate has been shown to offer neuroprotection in several pathologic conditions. This beneficial effect has been attributed to its use as an alternative energy substrate. However, recent description of the expression of the HCA1 receptor for lactate in the central nervous system calls for reassessment of the mechanism by which lactate exerts its neuroprotective effects. Here, we show that HCA1 receptor expression is enhanced 24 hours after reperfusion in an middle cerebral artery occlusion stroke model, in the ischemic cortex. Interestingly, intravenous injection of L-lactate at reperfusion led to further enhancement of HCA1 receptor expression in the cortex and striatum. Using an in vitro oxygen-glucose deprivation model, we show that the HCA1 receptor agonist 3,5-dihydroxybenzoic acid reduces cell death. We also observed that D-lactate, a reputedly non-metabolizable substrate but partial HCA1 receptor agonist, also provided neuroprotection in both in vitro and in vivo ischemia models. Quite unexpectedly, we show D-lactate to be partly extracted and oxidized by the rodent brain. Finally, pyruvate offered neuroprotection in vitro whereas acetate was ineffective. Our data suggest that L- and D-lactate offer neuroprotection in ischemia most likely by acting as both an HCA1 receptor agonist for non-astrocytic (most likely neuronal) cells as well as an energy substrate.

A spatial modelling framework for assessing climate change impacts on freshwater ecosystems: Response of brown trout (Salmo trutta L.) biomass to warming water temperature

Mountain regions worldwide are particularly sensitive to on-going climate change. Specifically in the Alps in Switzerland, the temperature has increased twice as fast than in the rest of the Northern hemisphere. Water temperature closely follows the annual air temperature cycle, severely impacting streams and freshwater ecosystems. In the last 20 years, brown trout (Salmo trutta L) catch has declined by approximately 40-50% in many rivers in Switzerland. Increasing water temperature has been suggested as one of the most likely cause of this decline. Temperature has a direct effect on trout population dynamics through developmental and disease control but can also indirectly impact dynamics via food-web interactions such as resource availability. We developed a spatially explicit modelling framework that allows spatial and temporal projections of trout biomass using the Aare river catchment as a model system, in order to assess the spatial and seasonal patterns of trout biomass variation. Given that biomass has a seasonal variation depending on trout life history stage, we developed seasonal biomass variation models for three periods of the year (Autumn-Winter, Spring and Summer). Because stream water temperature is a critical parameter for brown trout development, we first calibrated a model to predict water temperature as a function of air temperature to be able to further apply climate change scenarios. We then built a model of trout biomass variation by linking water temperature to trout biomass measurements collected by electro-fishing in 21 stations from 2009 to 2011. The different modelling components of our framework had overall a good predictive ability and we could show a seasonal effect of water temperature affecting trout biomass variation. Our statistical framework uses a minimum set of input variables that make it easily transferable to other study areas or fish species but could be improved by including effects of the biotic environment and the evolution of demographical parameters over time. However, our framework still remains informative to spatially highlight where potential changes of water temperature could affect trout biomass. (C) 2015 Elsevier B.V. All rights reserved.-

The role of adjuvant chemotherapy for lymph node-positive upper tract urothelial carcinoma following radical nephroureterectomy: a retrospective study.

OBJECTIVE: To evaluate the effect of adjuvant chemotherapy (AC) on mortality after radical nephroureterectomy (RNU) for upper tract urothelial carcinoma (UTUC) with positive lymph nodes (LNs) and to identify patient subgroups that are most likely to benefit from AC. PATIENTS AND METHODS: We retrospectively analysed data of 263 patients with LN-positive UTUC, who underwent full surgical resection. In all, 107 patients (41%) received three to six cycles of AC, while 156 (59.3%) were treated with RNU alone. UTUC-related mortality was evaluated using competing-risks regression models. RESULTS: In all patients (Tall N+), administration of AC had no significant impact on UTUC-related mortality on univariable (P = 0.49) and multivariable (P = 0.11) analysis. Further stratified analyses showed that only N+ patients with pT3-4 disease benefited from AC. In this subgroup, AC reduced UTUC-related mortality by 34% (P = 0.019). The absolute difference in mortality was 10% after the first year and increased to 23% after 5 years. On multivariable analysis, administration of AC was associated with significantly reduced UTUC-related mortality (subhazard ratio 0.67, P = 0.022). Limitations of this study are the retrospective non-randomised design, selection bias, absence of a central pathological review and different AC protocols. CONCLUSIONS: AC seems to reduce mortality in patients with pT3-4 LN-positive UTUC after RNU. This subgroup of LN-positive patients could serve as target population for an AC prospective randomised trial.