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Computational genomics is now generating very large volumes of data that have the potential to be used to address important questions in both basic biology and biomedicine. Addressing these important biological questions becomes possible when mechanistic models rooted in biochemistry and evolutionary/population genetic processes are developed, instead of fitting data to off-the-shelf statistical distributions that do not enable mechanistic inference. Three examples are presented, the first involving ecological processes inferred from metagenomic data, the second involving mechanisms of gene regulation rooted in protein-DNA interactions with consideration of DNA structure, and the third involving existing models for the retention of duplicate genes that enables prediction of evolutionary mechanisms. This description of mechanistic models is generalized toward future developments in computational genomics and the need for biological mechanisms and processes in biological models.

Ranked gene trees, which consider both the gene tree topology and the sequence in which gene lineages separate, can potentially provide a new source of information for use in modeling genealogies and performing inference of species trees. Recently,we have calculated the probability distribution of ranked gene trees under the standard multispecies coalescent model for the evolution of gene lineages along the branches of a fixed species tree, demonstrating the existence of anomalous ranked gene trees (ARGTs), in which a ranked gene tree that does not match the ranked species tree can have greater probability under the model than the matching ranked gene tree. Here, we fully characterize the set of unranked species tree topologies that give rise to ARGTs, showing that this set contains all species tree topologies with five or more taxa, with the exceptions of caterpillars and pseudocaterpillars. The results have implications for the use of ranked gene trees in phylogenetic inference.

Chronograms from molecular dating are increasingly being used to infer rates of diversification and their change over time. A major limitation in such analyses is incomplete species sampling that moreover is usually nonrandom. While the widely used γ statistic with the Monte Carlo constant-rates test or the birth-death likelihood analysis with the δ AICrc test statistic are appropriate for comparing the fit of different diversification models in phylogenies with random species sampling, no objective automated method has been developed for fitting diversification models to nonrandomly sampled phylogenies. Here, we introduce a novel approach, CorSiM, which involves simulating missing splits under a constant rate birth-death model and allows the user to specify whether species sampling in the phylogeny being analyzed is random or nonrandom. The completed trees can be used in subsequent model-fitting analyses. This is fundamentally different from previous diversification rate estimation methods, which were based on null distributions derived from the incomplete trees. CorSiM is automated in an R package and can easily be applied to large data sets. We illustrate the approach in two Araceae clades, one with a random species sampling of 52% and one with a nonrandom sampling of 55%. In the latter clade, the CorSiM approach detects and quantifies an increase in diversification rate, whereas classic approaches prefer a constant rate model; in the former clade, results do not differ among methods (as indeed expected since the classic approaches are valid only for randomly sampled phylogenies). The CorSiM method greatly reduces the type I error in diversification analysis, but type II error remains a methodological problem.

Recent studies indicate that Neanderthal and Denisova hominins may have been separate species, while debate continues on the status of Homo floresiensis. The decade-long debate between "splitters," who recognize over 20 hominin species, and "lumpers," who maintain that all these fossils belong to just a few lineages, illustrates that we do not know how many extinct hominin species to expect. Here, we present probability distributions for the number of speciation events and the number of contemporary species along a branch of a phylogeny. With estimates of hominin speciation and extincton rates, we then show that the expected total number of extinct hominin species is 8, but may be as high as 27. We also show that it is highly unlikely that three very recent species disappeared due to natural, background extinction. This may indicate that human-like remains are too easily considered distinct species. Otherwise, the evidence suggesting that Neanderthal and the Denisova hominin represent distinct species implies a recent wave of extinctions, ostensibly driven by the only survivor, H. sapiens., (© 2012 The Author(s). Evolution© 2012 The Society for the Study of Evolution.)

Objectives: Radiotherapy (RT) is considered oncologically ineffective in metastatic renal cell cancer (mRCC). Inhibition of angiogenetic pathway may lead to radiosensitization in mRCC. The aim of this study was to evaluate the efficacy of the simultaneous combination of RT with systemic treatment of bulky (mRCC) using sunitinib., Methods and Materials: We included 22 patients with progressive mRCC between 04/2007 and 08/2008 at the University Hospital Munich Großhadern. All patients underwent high-dose hypofractionated RT while they were simultaneously treated systemically with sunitinib 50 mg., Results: Median age was 63.0 years (range 26.7-84.4). Median dose of radiation was 40 Gy (range 25-50) in a median of 8 fractions (range 5-30). Treatment sites were brain, retroperitoneal and mediastinal lymph nodes, spinal cord, bones, liver, and kidney. Median follow-up was 14.3 months. After 3 months, 2 patients had complete remission (CR), 9 patients showed partial remission (PR) as measured by response evaluation criteria in solid tumors (RECIST) criteria, 2 patients had minor response (MR), and 8 patients had stable disease (SD). Only 1 patient did not respond to therapy. Toxicity was very low with only 1 grade 4 hypertension. Skin toxicities were manageable with no grade 3 event during the combination period., Conclusions: The combination of RT with simultaneous systemic treatment using sunitinib is effective in patients with progressive mRCC. With high dose RT, complete response seems to be possible. Further evaluation should be based upon combination of RT with systemic therapy, rather than sequential RT regiments., (Copyright © 2012 Elsevier Inc. All rights reserved.)

Background: The ancestries of genes form gene trees which do not necessarily have the same topology as the species tree due to incomplete lineage sorting. Available algorithms determining the probability of a gene tree given a species tree require exponential computational runtime., Results: In this paper, we provide a polynomial time algorithm to calculate the probability of a ranked gene tree topology for a given species tree, where a ranked tree topology is a tree topology with the internal vertices being ordered. The probability of a gene tree topology can thus be calculated in polynomial time if the number of orderings of the internal vertices is a polynomial number. However, the complexity of calculating the probability of a gene tree topology with an exponential number of rankings for a given species tree remains unknown., Conclusions: Polynomial algorithms for calculating ranked gene tree probabilities may become useful in developing methodology to infer species trees based on a collection of gene trees, leading to a more accurate reconstruction of ancestral species relationships.

The branching times of molecular phylogenies allow us to infer speciation and extinction dynamics even when fossils are absent. Troublingly, phylogenetic approaches usually return estimates of zero extinction, conflicting with fossil evidence. Phylogenies and fossils do agree, however, that there are often limits to diversity. Here, we present a general approach to evaluate the likelihood of a phylogeny under a model that accommodates diversity-dependence and extinction. We find, by likelihood maximization, that extinction is estimated most precisely if the rate of increase in the number of lineages in the phylogeny saturates towards the present or first decreases and then increases. We demonstrate the utility and limits of our approach by applying it to the phylogenies for two cases where a fossil record exists (Cetacea and Cenozoic macroperforate planktonic foraminifera) and to three radiations lacking fossil evidence (Dendroica, Plethodon and Heliconius). We propose that the diversity-dependence model with extinction be used as the standard model for macro-evolutionary dynamics because of its biological realism and flexibility.

The early functional response of a bacterial community from the sediments of a chronically oil-polluted retention basin located at the Etang de Berre (France) was investigated just after petroleum addition. After removing hydrocarbon compounds by natural abiotic and biotic processes, the sediments were maintained in microcosms and Vic Bilh petroleum was added. The diversity and the expression of genes encoding ring-hydroxylating dioxygenases (RHD) were examined just after the petroleum addition until 14 days focussing on the first hours following the contamination. RHD gene copy numbers and diversity were maintained throughout all the incubation period; however, transcripts were detected only during the first 2 days. One dominant RHD gene, immediately and specifically expressed in response to petroleum contamination, was related to RHD gene carried by a plasmid found in Pseudomonas spp. The expression of the RHD genes was correlated with high biodegradation levels observed for low molecular weight PAHs at 7 days of incubation. The study shows that the bacterial metabolism induced just after the oil input is a key stage that could determine the bacterial community structure changes. Monitoring the expression of RHD genes, key genes involved in hydrocarbon degradation, may provide useful information for managing bioremediation processes., (© 2011 Federation of European Microbiological Societies. Published by Blackwell Publishing Ltd. All rights reserved.)

The constant rate birth-death process is a popular null model for speciation and extinction. If one removes extinct and non-sampled lineages, this process induces 'reconstructed trees' which describe the relationship between extant lineages. We derive the probability density of the length of a randomly chosen pendant edge in a reconstructed tree. For the special case of a pure-birth process with complete sampling, we also provide the probability density of the length of an interior edge, of the length of an edge descending from the root, and of the diversity (which is the sum of all edge lengths). We show that the results depend on whether the reconstructed trees are conditioned on the number of leaves, the age, or both., (Copyright © 2011 Elsevier Ltd. All rights reserved.)

Diversification is nested, and early models suggested this could lead to a great deal of evolutionary redundancy in the Tree of Life. This result is based on a particular set of branch lengths produced by the common coalescent, where pendant branches leading to tips can be very short compared with branches deeper in the tree. Here, we analyze alternative and more realistic Yule and birth-death models. We show how censoring at the present both makes average branches one half what we might expect and makes pendant and interior branches roughly equal in length. Although dependent on whether we condition on the size of the tree, its age, or both, these results hold both for the Yule model and for birth-death models with moderate extinction. Importantly, the rough equivalency in interior and exterior branch lengths means that the loss of evolutionary history with loss of species can be roughly linear. Under these models, the Tree of Life may offer limited redundancy in the face of ongoing species loss.

In recent years, the release of information about the preventative and curative properties of garlic on different diseases and their benefits to human health has led to an increase in the consumption of garlic. To meet the requirements of international markets and reach competitiveness and profitability, farmers seek to extend the offer period of fresh garlic by increasing post-harvest life. As a result, the use of maleic hydrazide (1,2-dihydropyridazine-3,6-dione) [MH], a plant growth regulator, has been widespread in various garlic growing regions of the world. The present work was undertaken to develop and validate a new analytical procedure based on MH extraction from garlic previously frozen by liquid nitrogen and submitted to low temperature clean-up. The applicability of the method by analysis of garlic samples from a commercial plantation was also demonstrated. The influence of certain factors on the performance of the analytical methodology were studied and optimized. The approach is an efficient extraction, clean-up and determination alternative for MH residue-quantification due to its specificity and sensitivity. The use of liquid nitrogen during the sample preparation prevents the degradation of the analyte due to oxidation reactions, a major limiting factor. Moreover, the method provides good linearity (r(2): 0.999), good intermediate precision (coefficient of variation (CV): 8.39%), and extracts were not affected by the matrix effect. Under optimized conditions, the limit of detection (LOD) (0.33 mg kg(-1)) was well below the maximum residue level (MRL) set internationally for garlic (15 mg kg(-1)), with excellent rates of recovery (over 95%), good repeatability and acceptable accuracy (CV averaged 5.74%), since garlic is a complex matrix. The analytical performance of the methodology presented was compared with other techniques already reported, with highly satisfactory results, lower LOD and higher recoveries rates. In addition, the extraction process is simple, not expensive, easily executable and requires lower volumes of organic solvent. The proposed methodology removes the need of extensive typical laboratory extraction procedures, reducing the amount of time needed for pesticide analysis and increasing sample throughput. Adopting this method gives food safety laboratories the potential to increase cost savings by a suitable technique in routine testing to determine MH residues in garlic., (Copyright © 2011 Elsevier B.V. All rights reserved.)

Epidemiological processes leave a fingerprint in the pattern of genetic structure of virus populations. Here, we provide a new method to infer epidemiological parameters directly from viral sequence data. The method is based on phylogenetic analysis using a birth-death model (BDM) rather than the commonly used coalescent as the model for the epidemiological transmission of the pathogen. Using the BDM has the advantage that transmission and death rates are estimated independently and therefore enables for the first time the estimation of the basic reproductive number of the pathogen using only sequence data, without further assumptions like the average duration of infection. We apply the method to genetic data of the HIV-1 epidemic in Switzerland.

Phylogenetic relationships, divergence times, and patterns of biogeographic descent among primate species are both complex and contentious. Here, we generate a robust molecular phylogeny for 70 primate genera and 367 primate species based on a concatenation of 69 nuclear gene segments and ten mitochondrial gene sequences, most of which were extracted from GenBank. Relaxed clock analyses of divergence times with 14 fossil-calibrated nodes suggest that living Primates last shared a common ancestor 71-63 Ma, and that divergences within both Strepsirrhini and Haplorhini are entirely post-Cretaceous. These results are consistent with the hypothesis that the Cretaceous-Paleogene mass extinction of non-avian dinosaurs played an important role in the diversification of placental mammals. Previous queries into primate historical biogeography have suggested Africa, Asia, Europe, or North America as the ancestral area of crown primates, but were based on methods that were coopted from phylogeny reconstruction. By contrast, we analyzed our molecular phylogeny with two methods that were developed explicitly for ancestral area reconstruction, and find support for the hypothesis that the most recent common ancestor of living Primates resided in Asia. Analyses of primate macroevolutionary dynamics provide support for a diversification rate increase in the late Miocene, possibly in response to elevated global mean temperatures, and are consistent with the fossil record. By contrast, diversification analyses failed to detect evidence for rate-shift changes near the Eocene-Oligocene boundary even though the fossil record provides clear evidence for a major turnover event ("Grande Coupure") at this time. Our results highlight the power and limitations of inferring diversification dynamics from molecular phylogenies, as well as the sensitivity of diversification analyses to different species concepts.

The Bemisia tabaci Gennadius (Homoptera:Aleyrodidae) biotype complex is a key pest of several worldwide crops. The management and control of this pest has become difficult mainly due to its high reproductive rate and capacity to develop resistance to broad spectrum insecticides. In Argentina B. tabaci whitefly, causes economic losses in most areas of agricultural production. Eretmocerus mundus Mercet (Hymenoptera:Aphelinidae) is the most important parasitoid of B. tabaci and is commercialized as a biocontrol agent, mainly in Europe. Conservation of this biological control agent in Argentinean orchards requires the adoption of sustainable pest management practices due the negative impact of traditional pesticides on non-target organisms. Spirotetramat (Movento) belongs to a new class of pesticides that acts as a lipid biosynthesis inhibitor and claims to be selective towards natural enemies. The objectives of this work were 1) to evaluate the effectiveness of spirotetramat on eggs and nymphs of B. tabaci and 2) to determine the selectivity of spirotetramat towards E. mundus. Whitefly's eggs and nymphs (first nymphal settled instar) were exposed to the insecticide by foliar immersion whereas parasitoid adults (6 days old) were exposed to the insecticide by residual method for one hour, to simulate exposure of the parasitoid to the insecticide in the field. Lethal and sublethal effects of the insecticide were recorded daily. These preliminary studies have shown a high effectiveness of spirotetramat on the first nymphal instar of B. tabaci as well as a high selectivity for the pest in comparison to the parasitoid adults showing a low acute toxicity to them. These results suggest Movento could be included in Integrated Pest Management programs although more studies are required to complete its ecotoxicological profile.

Contact structure is believed to have a large impact on epidemic spreading and consequently using networks to model such contact structure continues to gain interest in epidemiology. However, detailed knowledge of the exact contact structure underlying real epidemics is limited. Here we address the question whether the structure of the contact network leaves a detectable genetic fingerprint in the pathogen population. To this end we compare phylogenies generated by disease outbreaks in simulated populations with different types of contact networks. We find that the shape of these phylogenies strongly depends on contact structure. In particular, measures of tree imbalance allow us to quantify to what extent the contact structure underlying an epidemic deviates from a null model contact network and illustrate this in the case of random mixing. Using a phylogeny from the Swiss HIV epidemic, we show that this epidemic has a significantly more unbalanced tree than would be expected from random mixing.

The properties of random gene tree topologies have recently been studied under a coalescent model that treats a species tree as a fixed parameter. Here we develop the analogous theory for random ranked gene tree topologies, in which both the topology and the sequence of coalescences for a random gene tree are considered. We derive the probability distribution of ranked gene tree topologies conditional on a fixed species tree. We then show that similar to the unranked case, ranked gene trees that do not match either the ranking or the topology of the species tree can have greater probability than the matching ranked gene tree., (Copyright © 2011 Elsevier Inc. All rights reserved.)

In this paper, I develop efficient tools to simulate trees with a fixed number of extant species. The tools are provided in my open source R-package TreeSim available on CRAN. The new model presented here is a constant rate birth-death process with mass extinction and/or rate shift events at arbitrarily fixed times 1) before the present or 2) after the origin. The simulation approach for case (2) can also be used to simulate under more general models with fixed events after the origin. I use the developed simulation tools for showing that a mass extinction event cannot be distinguished from a model with constant speciation and extinction rates interrupted by a phase of stasis based on trees consisting of only extant species. However, once we distinguish between mass extinction and period of stasis based on paleontological data, fast simulations of trees with a fixed number of species allow inference of speciation and extinction rates using approximate Bayesian computation and allow for robustness analysis once maximum likelihood parameter estimations are available.

In this article, I develop a methodology for inferring the transmission rate and reproductive value of an epidemic on the basis of genotype data from a sample of infected hosts. The epidemic is modeled by a birth-death process describing the transmission dynamics in combination with an infinite-allele model describing the evolution of alleles. I provide a recursive formulation for the probability of the allele frequencies in a sample of hosts and a Bayesian framework for estimating transmission rates and reproductive values on the basis of observed allele frequencies. Using the Bayesian method, I reanalyze tuberculosis data from the United States. I estimate a net transmission rate of 0.19/year [0.13, 0.24] and a reproductive value of 1.02 [1.01, 1.04]. I demonstrate that the allele frequency probability under the birth-death model does not follow the well-known Ewens' sampling formula that holds under Kingman's coalescent.

Background: The composition and bioactivity of essential oils from Tagetes terniflora Kunth, Cymbopogon citratus Stapf. and Elyonurus muticus (Spreng) Kuntz were evaluated against stored-grain pests., Results: Fumigant and contact toxicities were observed with T. terniflora on adults of both pests. In contact toxicity, this oil was less toxic to Tribolium castaneum (Herbst). Essential oils from C. citratus and E. muticus showed contact toxicity on S. oryzae. All essential oils produced: (a) repellency on larvae and adults of T. castaneum and adults of Sitophilus oryzae (L.); (b) post-ingestive toxicity on T. castaneum larvae and S. oryzae adults and alteration of nutritional index on T. castaneum and S. oryzae adults. Cymbopogon citratus reduced the relative growth rate and the efficiency of conversion of ingested food in T. castaneum larvae. Tagetes terniflora produced a feeding stimulant effect in T. castaneum adults. In addition, they had a feeding deterrent action against S. oryzae adults. The composition of essential oils from C. citratus and E. muticus varied only in one component., Conclusion: These results showed that the essential oils from T. terniflora, C. citratus and E. muticus should be studied further for their use in integrated pest management programmes for T. castaneum and S. oryzae control., (Copyright © 2011 Society of Chemical Industry.)

Phylogenetic trees of present-day species allow investigation of the rate of evolution that led to the present-day diversity. A recent analysis of the mammalian phylogeny challenged the view of explosive mammalian evolution after the Cretaceous-Tertiary (K/T) boundary (65 Mya). However, due to lack of appropriate methods, the diversification (speciation minus extinction) rates in the more recent past of mammalian evolution could not be determined. In this paper, I provide a method that reveals that the tempo of mammalian evolution did not change until ∼ 33 Mya. This constant period was followed by a peak of diversification rates between 33 and 30 Mya. Thereafter, diversification rates remained high and constant until 8.55 Mya. Diversification rates declined significantly at 8.55 and 3.35 Mya. Investigation of mammalian subgroups (marsupials, placentals, and the six largest placental subgroups) reveals that the diversification rate peak at 33-30 Mya is mainly driven by rodents, cetartiodactyla, and marsupials. The recent diversification rate decrease is significant for all analyzed subgroups but eulipotyphla, cetartiodactyla, and primates. My likelihood approach is not limited to mammalian evolution. It provides a robust framework to infer diversification rate changes and mass extinction events in phylogenies, reconstructed from, e.g., present-day species or virus data. In particular, the method is very robust toward noise and uncertainty in the phylogeny and can account for incomplete taxon sampling.

I consider the constant rate birth-death process with incomplete sampling. I calculate the density of a given tree with sampled extant and extinct individuals. This density is essential for analyzing datasets which are sampled through time. Such datasets are common in virus epidemiology as viruses in infected individuals are sampled through time. Further, such datasets appear in phylogenetics when extant and extinct species data is available. I show how the derived tree density can be used (i) as a tree prior in a Bayesian method to reconstruct the evolutionary past of the sequence data on a calender-timescale, (ii) to infer the birth- and death-rates for a reconstructed evolutionary tree, and (iii) for simulating trees with a given number of sampled extant and extinct individuals which is essential for testing evolutionary hypotheses for the considered datasets., (Copyright © 2010 Elsevier Ltd. All rights reserved.)

Changes in the methylation pattern in particular gene promoters as well as genetic sequence mutations play an important role in carcinogenesis. Molecular methods like pyrosequencing provide the specific analysis of these epigenetic and genetic modifications. In this review the relevance of these alterations for prostate cancer and the function of pyrosequencing will be described and explained on the basis of a search of the PubMed literature database. At present, in uro-oncology only a few studies outlining methylation in prostate cancer and pyrosequencing have been published. Nevertheless, it becomes evident that epigenetic mechanisms as well as specific gene sequence alterations have an impact on the carcinogenesis of prostate cancer and knowledge of these factors might open perspectives in diagnostic approaches of the future.

Reticulation networks are now frequently used to model the history of life for various groups of species whose evolutionary past is likely to include reticulation events such as horizontal gene transfer or hybridization. However, the reconstructed networks are rarely guaranteed to be temporal. If a reticulation network is temporal, then it satisfies the two biologically motivated timing constraints of instantaneously occurring reticulation events and successively occurring speciation events. On the other hand, if a reticulation network is not temporal, it is always possible to make it temporal by adding a number of additional unsampled or extinct taxa. In the first half of the paper, we show that deciding whether a given number of additional taxa is sufficient to transform a non-temporal reticulation network into a temporal one is an NP-complete problem. As one is often given a set of gene trees instead of a network in the context of hybridization, this motivates the second half of the paper which provides an algorithm, called TemporalHybrid, for reconstructing a temporal hybridization network that simultaneously explains the ancestral history of two trees or indicates that no such network exists. We further derive two methods to decide whether or not a temporal hybridization network exists for two given trees and illustrate one of the methods on a grass data set.

Introduction: Therapeutic strategies on treatment of T1G3 urothelial cancer of the urinary bladder are controversial. The objective of this study was to investigate the impact of photodynamic diagnosis (PDD) on the recurrence-free survival rate of patients with the initial diagnosis of T1G3 bladder cancer., Patients and Methods: Between 1995 and 2007, 153 patients were treated for T1G3 bladder cancer at our institution. In 77 patients, initial TUR-BT was performed under PDD condition at our hospital, and 76 patients underwent TUR-BT in a standard white light setting at other institutions. PDD was performed either using 5-aminolevulinate or hexaminolevulinate for induction of fluorescence. Average follow-up was 53.9 months. Fisher's exact test and Kaplan-Meier method were used to test data for significance., Results: Of the 77 patients who were treated using PDD at initial TUR-BT, recurrence was observed in 23 (29.9%) cases, whereas 43 of 76 (56.6%) patients treated without PDD showed recurrence (P < 0.001). The detection rate of additional carcinoma in situ was 35.4% in the PDD group versus 21.8% in the white light group (P = 0.077). A limitation of the present study is the retrospective, monocentre setting, which is more likely to be biased., Conclusion: PDD during initial TUR-BT in T1G3 bladder cancer seems to reduce significantly the rate of recurrence in our study population. Therefore, PDD seems to be associated with superior initial tumour control and more effective tumour treatment even in patients with highly aggressive tumours like T1G3 bladder cancer.

Unlabelled: The value of surgical resection of renal cell carcinoma (RCC) liver metastases still remains unclear., Objective: Of our study was to evaluate the efficacy of liver resection by comparing patients who could have undergone metastasectomy due to limited disease, but refused surgery., Materials and Methods: Eighty-eight patients were identified with liver metastases and indication of surgery between 1995 and 2006. In 68 patients, liver resection was performed, 20 patients denied surgery and served as comparison group. Patients were followed for survival., Results: Median age was 58. Median amount of liver metastases was 2 (range 1-30). Median follow-up was 26 months (range 1-187). In both groups, 79% received systemic therapy. The 5-year overall survival rate (OSR-5) after metastasectomy was 62.2% +/- 11.4% (SEM) with a median survival (MS) of 142 (95% confidence interval (CI) 115-169) months. OSR-5 in the control group was 29.3% +/- 22.0% (SEM) with a MS of 27 (95% CI 16-38) months (P = 0.003). MS was 155 (95% CI 133-175) months with metachronous metastases compared to 29 (95% CI 25-33) months in the comparison group (P = 0.001). Low-grade primary RCC had a MS of 155 (95% CI 123-187) months compared to 29 (95% CI 8-50) months without resection (P = 0.0036). High-grade RCC as well as patients with synchronous metastases did not benefit from surgery., Conclusions: Liver metastasectomy is an independent valuable tool in the treatment of metastatic RCC and significantly prolongs patient's survival, even if further systemic treatment is necessary. With the evidence given, patients may benefit from liver metastasis resection if technically feasible.

A wide range of evolutionary models for species-level (and higher) diversification have been developed. These models can be used to test evolutionary hypotheses and provide comparisons with phylogenetic trees constructed from real data. To carry out these tests and comparisons, it is often necessary to sample, or simulate, trees from the evolutionary models. Sampling trees from these models is more complicated than it may appear at first glance, necessitating careful consideration and mathematical rigor. Seemingly straightforward sampling methods may produce trees that have systematically biased shapes or branch lengths. This is particularly problematic as there is no simple method for determining whether the sampled trees are appropriate. In this paper, we show why a commonly used simple sampling approach (SSA)-simulating trees forward in time until n species are first reached-should only be applied to the simplest pure birth model, the Yule model. We provide an alternative general sampling approach (GSA) that can be applied to most other models. Furthermore, we introduce the constant-rate birth-death model sampling approach, which samples trees very efficiently from a widely used class of models. We explore the bias produced by SSA and identify situations in which this bias is particularly pronounced. We show that using SSA can lead to erroneous conclusions: When using the inappropriate SSA, the variance of a gradually evolving trait does not correlate with the age of the tree; when the correct GSA is used, the trait variance correlates with tree age. The algorithms presented here are available in the Perl Bio::Phylo package, as a stand-alone program TreeSample, and in the R TreeSim package.

Background: The worldwide need to produce an inexpensive and abundant food supply for a growing population is a great challenge that is further complicated by concerns about risks to environmental stability and human health triggered by the use of pesticides. The result is the ongoing development of alternative pest control strategies, and new, lower-risk insecticidal molecules. Among the recent technological advances in agricultural science, nanotechnology shows considerable promise, although its development for use in crop protection is in its initial stages., Results: This study reports for the first time the insecticidal effect of nanostructured alumina. Two species were used as model organisms, Sitophilus oryzae L. and Rhyzopertha dominica (F.), which are major insect pests in stored food supplies throughout the world. Both species experienced significant mortality after 3 days of continuous exposure to treated wheat. Nine days after treatment, the median lethal doses (LD(50)) observed ranged from 127 to 235 mg kg(-1)., Conclusion: Comparison of these results with recommended rates for commercial insecticidal dusts suggests that inorganic nanostructured alumina may provide a cheap and reliable alternative for control of insect pests. This study expands the frontiers for nanoparticle-based technologies in pest management. Further research is needed to identify its mode of action and its non-target toxicity, and to determine the potential of other nanostructured materials as pest control options for insects.

Chronic inflammation seems of importance in multiple types of cancer. Numerous reports have revealed a potential link between chronic prostatatic inflammation and prostate cancer. The aim of this paper is to review the epidemiological, moprphological, molecular and clinical aspects of prostattic inflammation and prostate cancer.

Objective: To retrospectively determine the growth rate of renal masses with a diameter of > or =4 cm at the time of surgery, as the average growth rate of untreated small (<4 cm) renal masses is assumed to be 0.1-0.7 cm/year, but little is known about the progression of large masses., Patients and Methods: Of 256 patients who had their renal tumour surgically removed between January and December 2008, we identified nine (five men and four women; median age 65.2 years, range 29.2-74.2) with solitary large renal masses (>4 cm) who had abdominal imaging with identification of renal masses >6 months before admission. In none of the patients had the initial imaging led to admission, either by accident or because the masses were overlooked. The tumour growth rate was calculated based on images taken > or =6 months before admission and actual imaging, as well as histological results., Results: All patients had surgical resection of their renal masses in 2008. The median (range) follow-up from initial diagnosis to surgery was 14.6 (6.5-58.4) months. The median observed tumour growth rate was 6.41 (2.47-8.66) cm/year. The histological diagnosis was clear cell renal cell carcinoma (RCC) in seven patients, papillary in one and clear cell RCC with portions of sarcomatoid de-differentiation in one; two patients had lymph node metastases and one had pulmonary metastases, and five had tumours of > or =T3., Conclusions: The growth rate of large tumours is much higher than of small renal masses and most patients present with advanced disease. Thus, tumours of > or =4 cm seem not to be candidates for active surveillance but require immediate therapy. Further studies are warranted to determine the clinical relevance of progressive tumour growth and the underlying mechanisms.

Background: Former systemic therapy for metastatic renal cell cancer (mRCC) based on immunomodulation could achieve complete remissions (CR) in only some patients. Angiogenic therapy with sunitinib, sorafenib, and temsirolimus changed the paradigm of treating mRCC based on a doubled progression-free survival (PFS) and 10% to 30% of patients achieving partial remission (PR). Unfortunately, CR is rarely seen. Within our patients we could achieve some CR, which we are presenting in this study., Patients and Methods: We assessed 194 consecutive patients of an institutional database that were treated for mRCC with either sorafenib or sunitinib between 05/2006 and 12/2007. Restaging with repeated high-resolution computed tomography (CT) of thorax and abdomen was performed in an 8 to 10 weeks interval. Five patients who achieved CR in repeated CT under therapy are included in this analysis., Results: Of the patients in whom we achieved CR, two were female and three were male. Median age was 63.2 years (range 52-70). All patients had clear cell histology. In three of the five patients, CR was achieved by surgery after partial remission, and in two patients it was achieved by sole medical therapy. All patients remained in CR until now with a median duration of CR of 24 months (range 24-29 months). One patient still is on therapy, while four patients do not receive any systemic treatment., Conclusions: We proof long-term confirmed CR in mRCC achieved by anti-angiogenic therapy alone or in combination with surgery. Combining surgery and anti-angiogenic therapy based on sorafenib and sunitinib could render patients free of disease even after repeated cycles of systemic treatment., (Copyright 2010 Elsevier Inc. All rights reserved.)

A 74-year-old man with metastatic renal cell carcinoma and a history of cardiac failure was treated with sunitinib malate. MUGA echocardiography could not detect a relevant change in the ejection fraction although the clinical situation of the patient worsened dramatically. The only parameter to hint at the deteriorated cardiac function was plasma N-terminal pro-brain natriuretic peptide (BNP). Finally, the patient died after only one cycle of sunitinib treatment. We propose to prospectively include BNP for the early detection of cardiovascular decompensation in high-risk patients. Future studies concerning the relevance of BNP in drug-related cardiotoxicity are urgently needed., (Copyright 2010 S. Karger AG, Basel.)

The constant rate birth-death process is used as a stochastic model for many biological systems, for example phylogenies or disease transmission. As the biological data are usually not fully available, it is crucial to understand the effect of incomplete sampling. In this paper, we analyze the constant rate birth-death process with incomplete sampling. We derive the density of the bifurcation events for trees on n leaves which evolved under this birth-death-sampling process. This density is used for calculating prior distributions in Bayesian inference programs and for efficiently simulating trees. We show that the birth-death-sampling process can be interpreted as a birth-death process with reduced rates and complete sampling. This shows that joint inference of birth rate, death rate and sampling probability is not possible. The birth-death-sampling process is compared to the sampling-based population genetics model, the coalescent. It is shown that despite many similarities between these two models, the distribution of bifurcation times remains different even in the case of very large population sizes. We illustrate these findings on an Hepatitis C virus dataset from Egypt. We show that the transmission times estimates are significantly different-the widely used Gamma statistic even changes its sign from negative to positive when switching from the coalescent to the birth-death process.

In the age of nerve-sparing radical prostatectomy, rates of postoperative erectile dysfunction (ED) have significantly decreased. However, on comparing open retropubic, laparoscopic and robot-assisted procedures, none of these techniques seem to show specific advantages in this respect. PDE5 inhibitors are considered to be the gold standard in the first-line therapy of postoperative ED, as far as relevant contraindications can be excluded. Intraurethral and intracavernosal injections with prostaglandin E1 represent the second-line treatment. Implantation of penile prostheses still remains as the third-line and ultima ratio. Meanwhile, the administration of PDE5 inhibitors has been proven to be most effective. When applying this therapy regimen, these substances are highly useful when they are administered early after the intervention. After curative treatment of prostate cancer, testosterone substitution can be an efficient way to reduce hypo-gonadal symptoms in patients with manifest testosterone deficiency. It may even contribute to the improvement of post- interventional erectile disorders. According to the recent literature, testosterone substitution therapy is safe and does not show any additional risk of recurrence when there is a well considered indication and when patients are carefully selected., (Georg Thieme Verlag Stuttgart * New York.)

In this paper, we present a new way to describe the timing of branching events in phylogenetic trees. Our description is in terms of the relative timing of diversification events between sister clades; as such it is complementary to existing methods using lineages-through-time plots which consider diversification in aggregate. The method can be applied to look for evidence of diversification happening in lineage-specific "bursts", or the opposite, where diversification between 2 clades happens in an unusually regular fashion. In order to be able to distinguish interesting events from stochasticity, we discuss 2 classes of neutral models on trees with relative timing information and develop a statistical framework for testing these models. These model classes include both the coalescent with ancestral population size variation and global rate speciation-extinction models. We end the paper with 2 example applications: first, we show that the evolution of the hepatitis C virus deviates from the coalescent with arbitrary population size. Second, we analyze a large tree of ants, demonstrating that a period of elevated diversification rates does not appear to have occurred in a bursting manner.

Background: Carcinoma of the collecting ducts (CDC) of Bellini of the kidney is very rare but is among the most aggressive urologic entities., Patients and Methods: Radical nephrectomy revealed CDC in stage pT3a pN2 M0 G3 in 2 male patients. Four courses of adjuvant chemotherapy with cisplatin and gemcitabine were given., Results: Subsequent restaging revealed local recurrence and lymph node metastases. Both patients were operated on again, and metastatic CDC was found. Second-line therapy with sunitinib was administered. After 2 cycles, multiple liver, lung, and bone metastases and mediastinal lymphopathy occurred. Eight weeks later, the patients died, with a survival of 8 months from initial diagnosis., Conclusion: Nephrectomy, adjuvant gemcitabine/cisplatin, and sunitinib therapy did not alter the course of disease in these patients. Gross resection of disease was rapidly followed by local recurrence and, subsequently, widespread dissemination of disease. Clinical trial investigation is urgently needed because of the aggressive and refractory nature of CDC.

Drawing inferences about macroevolutionary processes from phylogenetic trees is a fundamental challenge in evolutionary biology. Understanding stochastic models for speciation is an essential step in solving this challenge. We consider a neutral class of stochastic models for speciation, the constant rate birth-death process. For trees with n extant species - which might be derived from bigger trees via random taxon sampling - we calculate the expected time of the kth speciation event (k=1,...,n-1). Further, for a tree with n extant species, we calculate the density and expectation for the number of lineages at any time between the origin of the process and the present. With the developed methods, expected lineages-through-time (LTT) plots can be drawn analytically. The effect of random taxon sampling on LTT plots is discussed.

Introduction: Carcinoma of the collecting ducts of Bellini of the kidney (CDC) is very rare but among the most aggressive urological entities. Standard therapy is not well defined with questionable efficacy., Methods: We present two cases of male patients (49 and 66 years old) with pT3a pN2 CDC treated with a combination of cisplatin plus gemcitabine in an adjuvant setting. Following recurrence the multi-kinase inhibitor sunitinib was administered., Results: Radical nephrectomy with lymphadenectomy revealed CDC in stage pT3a pN2 M0 G3 R0 in both patients. 4 courses of adjuvant chemotherapy with cisplatin 70 mg/m superset2 and gemcitabine 1,500 mg/m superset2 were given. Side effects according to the NCI 3.0 common toxicity criteria were limited to grade 2 asthenia and grade 2 thrombozytopenia/leucopenia. Restaging revealed local recurrence and lymph node metastases. Both patients were re-operated and metastatic CDC was found. Second line therapy with sunitinb malatat (Sutent superset, Pfizer Inc. U.S.) at 50mg p.o. was given. Grade 3 leucopenia and thrombocytopenia and grade 2 asthenia and mucositis were not dose-limiting. After two cycles multiple liver, lung and bone metastases and mediastinal lymphopathy occured. 8 weeks later the patients died with a survival of 8 months from initial diagnosis., Conclusions: Adjuvant gemcitabine plus cisplatin did not delay recurrence of CDC after surgery. Metastasectomy either had no influence on the course of disease. Anti-angiogenetic therapy with sunitinib treatment was not effective, possibly related to a low vascular density (CD31 expression) in CDC.

Objectives: To evaluate the surgical complications in a contemporary group of elderly patients with renal masses, as almost a quarter of patients with newly diagnosed renal mass are aged >74 years, with the potential for significant comorbidity., Patients and Methods: From April 2004 to June 2007, of 379 surgical resections of renal tumours, we assessed 117 consecutive patients aged >or=75 years, who had either radical nephrectomy (RN) or partial nephrectomy (PN) for assumed renal cell carcinoma. Also elderly patients who had nephroureterectomy (NU) for upper urothelial cancer were followed., Results: Fifty patients had RN, 57 PN and 10 had NU; the median (range) age of all patients was 78.1 (72.7-92.5) years and was similar in all groups. No patient died during surgery and only one died within 90 days. The complication rates during and after surgery RN, PN and NU were 12%, 15% and 20%, respectively; the major complications within 30 days were 4%, 7% and 10%; major complications included bleeding during surgery and one acute bleeding event after surgery in the PN group., Conclusions: Open renal surgery in elderly patients can be done safely; there was no difference in morbidity among RN, PN and NU. Renal surgery in the elderly patient is safe if done at a specialized centre. Mortality and morbidity can be very low, rendering this a feasible approach in the treatment of renal masses even if the prognosis is not determined by the oncological situation but by comorbidity.

Objective: To review the literature and answer questions about semen quality in young cancer patients before and after therapy and the importance of sperm cryopreservation., Methods: All aspects of sperm cryopreservation and effects of therapies on semen quality were examined on the basis of MedLine database searches., Results: Chemotherapy, radiation, or their combination results in a significant reduction of sperm quality and as a consequence an indefinite time of infertility follows. The type of cancer and the pretreatment sperm concentrations were the most significant factors governing posttreatment semen quality and recovery of spermatogenesis. Due to their age, fertility and sexual functioning are key issues for these patients. Yet there is no medical protection of the germinal epithelium available. Male germ cell transplantation is in its infancy and still there are no therapeutical options to improve spermatogenesis after damage has occurred. Consequently, cryopreservation represents the only preemptive measure for conserving fertility., Conclusion: This manuscript updates the current knowledge of diverse chemotherapeutic treatment regimens and their gonadotoxic effects as well as the development of posttreatment fertility in cancer patients. The importance and rationale of sperm cryopreservation are discussed and possible future options are highlighted.

Sexual dysfunctions (SD) are adverse effects of common drug therapies that have rarely been considered in investigations so far. Possibly it is barely known that many widespread and frequently prescribed medications and drug therapies can have significant impact on vascular and nerval processes as well as on endocrinologic and psychoneuroendocrinologic systems and therefore can influence sexual functions. Impotence and disorders of the erectile function can mainly be caused by antidopaminergic mechanisms, whereas ejaculatory disorders and anorgasmia often can be explained by antiserotoninergic effects. Anticholinergic and adrenoloytic agents can also cause a particular impairment of erectile functions. The following considerations will show that the detection and treatment of SD (also in women!) should be given much more attention since drug-induced SDs occur predominantly in indications where a SD itself can be a symptom of the disease.

Sunitinib and Sorafenib are both effective angiogenetic inhibitors for the treatment of renal cell carcinoma. With these drugs of a new class of chronic therapy is performed. During chronic treatment, the inherent side effects may necessitate stopping the application of these drugs thus preventing the required effective therapy. Most of the effects can be avoided or attenuated by prophylaxis. In this paper the published data are reviewed and added with our experience in 138 patients over up to two and a half years.

It had been found earlier that the chloronicotinyl insecticide thiacloprid (as the 480 g litre(-1) SC Calypso) poses a favourably low toxicity hazard to the honeybee, Apis mellifera L. As with pyrethroids, the metabolization of chloronicotinyl compounds involves monooxygenases, which are known to be inhibited by some ergosterol biosynthesis inhibitor (EBI) fungicides potentially co-applied with these insecticides. The potential synergistic enhancement of the toxicity of thiacloprid to honeybees when co-applied with such fungicides was therefore studied under laboratory and semi-field conditions. Fungicides of other chemical classes were also examined for synergistic potential to reveal other metabolic interactions. In the laboratory, only a slight synergistic effect was observed with the anilinopyrimidine fungicide examined, while a significant enhancement of thiacloprid toxicity to honeybees was found with EBI fungicides. In three tunnel tests conducted under different environmental conditions to simulate field exposure, no increased mortality was observed when honeybees were directly sprayed with thiacloprid (Calypso) alone or in combination with the EBI fungicide tebuconazole (250 g litre(-1) EW, Folicur). There was also no synergized reduction in the foraging intensity on the treated crop. In general, the foraging intensity decreased after thiacloprid treatment but was restored within 24-48 h. The hive vitality was not affected by either thiacloprid or its tank mix with tebuconazole. Our results suggest that, at the recommended use rates, thiacloprid poses a negligible lethal risk to honeybees when applied either alone or in tank mixes with fungicides of various chemical classes.

In a post-marketing-surveillance study the use of a sustained-release tramadol preparation (Tramal long 100, 150, 200 mg) was investigated in 3153 patients. The intention was to comply with the legal obligation to carry out product surveillance and to collect data on prescribing behaviour. We focused our attention on drug safety and efficacy. Tramal long was used mainly for severe and very severe pain. The most frequently reported causes of pain were diseases of the locomotor system (49.9%), tumours (24.3%), traumas and fractures (10.1%), and neurogenic (9.3%). The mean daily dose was 235.7 mg, usually divided into two doses. The analgesic effect was described as very good or good by 82.5% of the patients. Adverse events occurred in 6.5% of the patients, mostly in the form of typical opioid side-effects such as nausea (3.4%), dizziness (1.5%) and vomiting (1.1%). Severe or unknown side-effects were not reported.

Osteoclast differentiation is a complex process requiring multiple factors and sequential regulation. We have determined that CD44, a cell surface glycoprotein that is known to function as an adhesion receptor, is involved in this process. By immunocytochemistry, we show that CD44 is expressed in mouse osteoclasts that develop in primary cultures of bone marrow cells treated with 1 alpha, 25-dihydroxyvitamin D3. Monoclonal antibodies to CD44 inhibit osteoclast formation in bone marrow cultures in a dose- and time-dependent manner. In contrast, CD44 Fab monomer antibodies have no effect on osteoclast development, suggesting that the inhibition of differentiation by the whole antibodies is facilitated by cross-linking of CD44 molecules. Cocultures of spleen cells and ST2 bone marrow stromal cells indicate that hematopoietic cells mediate the CD44 antibody inhibitory effect. CD44 antibodies do not inhibit osteoclast resorption of calcified matrix, indicating that CD44 is not absolutely required for resorption activity. These observations demonstrate that CD44 may play a role in osteoclast formation and suggest mechanisms by which CD44 antibody effects are mediated.

To date, no universally applicable recommendations are available for the treatment of patients with postherpetic neuralgia. A mixture of clinical anecdotes, experimental findings and observations from clinical trials form the basis of the medical arsenal for this condition. Tricyclic antidepressants are commonly used, and clinical experience and several investigations have documented their effectiveness. Today, single entity antidepressants, which can be combined with neuroleptics to increase analgesia, are generally recommended for the treatment of postherpetic neuralgia. Some authors also recommend the additional administration of an opioid if analgesia is inadequate. Just over a decade ago, opioids were considered ineffective for the treatment of neuropathic pain; however, more recent investigations relating to the use of opioids, primarily in the treatment of nontumour-related chronic pain, have led to a revision of their use in neuropathic pain. Nevertheless, the use of opioid therapy for neurogenic pain remains controversial. Tramadol is a synthetic, centrally acting analgesic with both opioid and nonopioid analgesic activity. The nonopioid component is related to the inhibition of noradrenaline (norepinephrine) reuptake and stimulation of serotonin (5-hydroxytryptamine; 5-HT) release at the spinal level. In this regard, there are parallels with antidepressants, which are believed to potentiate the effect of biogenic amines in endogenous pain-relieving systems. There is evidence that, in tramadol, both mechanisms act synergistically with respect to analgesia. The aim of this pilot study was to investigate, for the first time, the analgesic efficacy and tolerability of tramadol, compared with the antidepressant clomipramine, in the treatment of postherpetic neuralgia. If necessary, clomipramine was used in combination with the neuroleptic levomepromazine. The study allowed individualised dosages at predetermined intervals up to a maximum daily dose of tramadol 600mg and clomipramine 100mg, or clomipramine 100mg with or without levomepromazine 100mg. 21 (60%) of 35 randomised patients (> or = 65 years) received the study medication over the 6-week period [tramadol n = 10; clomipramine with or without levomepromazine) n = 11]. After 3 weeks' treatment the dosage in both groups remained almost constant for the rest of the 6-week treatment phase (mean daily dose: tramadol 250 to 290mg; clomipramine 59.1 to 63.6mg). Only 3 patients required the combination of clomipramine and levomepromazine. At the outset, both groups recorded an average pain level of 'moderate' to 'very severe'. In correlation with increasing the study medication, this had decreased to 'slight' by the end of the treatment, when 9 of 10 patients in the tramadol group and of 6 of 11 patients in the clomipramine group retrospectively rated their analgesia as excellent, good or satisfactory. The psychological/physical condition of the patients did not change significantly during tramadol treatment. Sensitivity and depression parameters decreased in the clomipramine group. The incidence of adverse events for all patients was similar in both groups (tramadol 76.5%; clomipramine with or without levomepromazine 83.3%). In conclusion, tramadol would appear to be an interesting therapeutic alternative for pain relief in postherpetic neuralgia, particularly in patients who are not depressed. In clinical practice, tramadol and clomipramine can best be used differentially. For example, tramadol could be the drug of first choice in patients with obvious cardiovascular disease (not an uncommon problem in the > or = 65 year age group) in whom antidepressants are contraindicated, and similarly in patients in whom an antidepressant effect is not required. (ABSTRACT TRUNCATED)