bluuebunny/crossref_metadata_2025 huggingface dataset:
NRASQ61R Mutation-specific Immunohistochemistry is Highly Specific for Either NRAS Q61R or KRAS Q61R Mutation in Colorectal Carcinoma
Authors: Turchini John , Andrici Juliana , Sioson Loretta , Clarkson Adele , Watson Nicole , Toon Christopher W. , Shepherd Phillip , Ng Daniel , Dixon-McIver Amanda , Oei Paul , Gill Anthony J.
Published: February 2016

Anti–epidermal growth factor receptor–targeted therapy is only indicated in RAS wild-type colorectal carcinomas (CRCs). It is recommended that both NRAS and KRAS mutation testing to be performed before a CRC is considered RAS wild-type. Given that mutation-specific immunohistochemistry (IHC) has been shown to be sensitive and specific for the detection of NRAS

Q61R
mutations in melanoma, we assessed the specificity of NRASQ61R mutation-specific IHC in CRC. IHC was performed on tissue microarrays containing 2823 consecutive CRC undergoing surgery with curative intent using a novel mutation-specific antibody to the protein produced by the NRAS

Q61R
mutation (clone SP174). Tissue microarrays were assessed by 2 observers and all IHC-positive or equivocal cases were repeated on whole sections to confirm the result. Positive cases then underwent molecular testing by matrix-assisted laser desorption/ionization-time of flight polymerase chain reaction. In total, 22 of 2823 (0.8%) CRCs demonstrated confirmed positive staining with complete interobserver concordance. RAS mutations were confirmed in all IHC-positive CRCs. In total, 11 cases harbored the NRASQ61R mutation. Surprisingly, 11 cases demonstrated the KRASQ61R mutation. We conclude that mutation-specific IHC with this currently available NRASQ61R antibody is highly specific for the presence of either NRASQ61R or KRASQ61R mutations in CRC. We caution that we did not assess the sensitivity of IHC and that this antibody does not detect other RAS mutations. Therefore, negative staining does not exclude a clinically significant RAS mutation. However, positive staining confirms the presence of an NRASQ61R or KRASQ61R mutation without the need for further molecular testing.
Intratumoral FOXP3+ Regulatory T Cells in Diffuse Large B-Cell Lymphoma
Authors: Serag El-Dien Marwa M. , Abdou Asmaa G. , Asaad Nancy Y. , Abd El-Wahed Moshira M. , Kora Mona Abd El-Hamid M.
Published: February 2016

Diffuse large B-cell lymphoma (DLBCL) is the most common subtype of non-Hodgkin lymphoma in Egypt and worldwide. Gene expression profiling classifies DLBCL into: germinal center B cell-like (GCB) and non germinal center B cell-like (non-GCB) DLBCL. Hans’ algorithm has high concordance with gene expression profiling results. Regulatory T cells (Tregs) represent important modulators for the interaction between lymphoma cells and host microenvironment. FOXP3 is a popular single marker for Tregs. There is little information about the possible role of Tregs in high-grade lymphoma such as DLBCL. This study aims to assess the prognostic impact of FOXP3+ Tregs in DLBCL. The study was carried out on 70 archival cases (61 de novo DLBCL and 9 reactive follicular hyperplasia cases). DLBCL cases were classified into GCB and non-GCB groups using Hans’ algorithm. All studied cases are subjected to FOXP3 immunostaining. Density of FOXP3+ Tregs was higher in reactive cases compared with DLBCL (P=0.000). In DLBCL cases, FOXP3 expression was associated with free spleen (P=0.02), early stage (P=0.05), centroblastic variant (P=0.003), and absence of necrosis (P=0.05). In germinal cases, density of FOXP3 was significantly higher in cases with good PS (P=0.02), very good and good revised international prognostic index (P=0.002), and low-risk age-adjusted international prognostic index >60 (P=0.01). Non germinal DLBCL cases with negative FOXP3 were significantly associated with splenic involvement (P=0.005). DLBCL cases with high FOXP3 have longer survival (P=0.03). T cells in the background of DLBCL may play a role in modulation of tumor progression. Their presence is associated with favorable prognostic parameters in DLBCL.
IMP: a pipeline for reproducible integrated metagenomic and metatranscriptomic analyses
Authors: Narayanasamy Shaman , Jarosz Yohan , Muller Emilie E.L. , Laczny Cédric C. , Herold Malte , Kaysen Anne , Heintz-Buschart Anna , Pinel Nicolás , May Patrick , Wilmes Paul
Published: February 2016

We present IMP, an automated pipeline for reproducible integrated analyses of coupled metagenomic and metatranscriptomic data. IMP incorporates preprocessing, iterative co-assembly of metagenomic and metatranscriptomic data, analyses of microbial community structure and function as well as genomic signature-based visualizations. Complementary use of metagenomic and metatranscriptomic data improves assembly quality and enables the estimation of both population abundance and community activity while allowing the recovery and analysis of potentially important components, such as RNA viruses. IMP is containerized using Docker which ensures reproducibility. IMP is available athttp://r3lab.uni.lu/web/imp/.
Integrating regulatory information via combinatorial control of the transcription cycle
Authors: Scholes Clarissa , DePace Angela H. , Sánchez Álvaro
Published: February 2016

Combinatorial regulation of gene expression by multiple transcription factors (TFs) enables cells to carry out sophisticated computations that are key to cellular decision-making. How is the information contained in multiple TF binding sites integrated to dictate the rate of transcription? The dominant model is that direct or indirect physical interactions between TFs enable them to combinatorially recruit each other and RNA polymerase to the promoter. Here we develop a quantitative framework to explore an alternative model, where combinatorial gene regulation can result from TFs working on different kinetic steps of the transcription cycle. Our results clarify the null hypotheses for independent action of TFs and show that combinatorial control of the transcription cycle can generate a wide range of analog and Boolean computations without requiring the input regulators to be simultaneously co-localized in the nucleus. This work emphasizes the importance of deciphering TF function beyond activation and repression, highlights the role of the basal promoter in processing regulatory information and suggests qualitative explanations for the flexibility of regulatory evolution.
Analysis of Two-State Folding Using Parabolic Approximation IV: Non-Arrhenius Kinetics of FBP28 WW Part-II
Authors: Sade Robert S.
Published: February 2016

A model which treats the denatured and the native conformers as being confined to harmonic Gibbs energy wells has been used to rationalize the physical basis for the non-Arrhenius behaviour of spontaneously-folding fixed two-state systems. It is shown that at constant pressure and solvent conditions: (i) the rate constant for folding will be a maximum when the heat released upon formation of net molecular interactions is exactly compensated by the heat absorbed to desolvate net polar and non-polar solvent accessible surface area (SASA), as the denatured conformers driven by thermal noise bury their SASA and diffuse on the Gibbs energy surface to reach the activated state; (ii) the rate constant for unfolding will be a minimum when the heat absorbed by the native conformers to break various net backbone and sidechain interactions is exactly compensated by the heat of hydration released due to the net increase in SASA, as the native conformers unravel to reach the activated state; (iii) the activation entropy for folding will be zero, and the Gibbs barrier to folding will be a minimum, when the decrease in the backbone and the sidechain mobility is exactly compensated by the increase in entropy due to solvent-release, as the denatured conformers bury their SASA to reach the activated state; (iv) the activation entropy for unfolding will be zero, and the Gibbs barrier to unfolding will be a maximum when the increase in the backbone and sidechain mobility is exactly compensated by the negentropy of solvent-capture on the protein surface, as the native conformers unravel to reach the activated state; (v) while cold denaturation is driven by solvent effects, heat denaturation is primarily due to chain effects; (vi) the speed-limit for the folding is ultimately due to conformational searching; and (vii) Levinthal’s paradox may have little basis if the entropy of solvent-release that accompanies protein folding is taken into consideration.
Detailed temporal structure of communication networks in groups of songbirds
Authors: Stowell Dan , Gill Lisa , Clayton David
Published: February 2016

Animals in groups often exchange calls, in patterns whose temporal structure may be influenced by contextual factors such as physical location and the social network structure of the group. We introduce a model-based analysis for temporal patterns of animal call timing, originally developed for networks of firing neurons. This has advantages over cross-correlation analysis in that it can correctly handle common-cause confounds and provides a generative model of call patterns with explicit parameters for the influences between individuals. It also has advantages over standard Markovian analysis in that it incorporates detailed temporal interactions which affect timing as well as sequencing of calls. Further, a fitted model can be used to generate novel synthetic call sequences. We apply the method to calls recorded from groups of domesticated zebra finch (Taenopyggia guttata) individuals. We find that the communication network in these groups has stable structure that persists from one day to the next, and that “kernels” reflecting the temporal range of influence have a characteristic structure for a calling individual’s effect on itself, its partner, and on others in the group. We further find characteristic patterns of influences by call type as well as by individual.
No evidence for the positive relationship between genetic correlations and heritabilities
Authors: Drobniak Szymon M. , Cichoń Mariusz
Published: February 2016

Quantitative genetics predicts, that traits subjected to strong selection should show low heritability and may yield biased estimates of genetic correlations (rg). Similar pattern may also appear if genetic sources of variation are confounded with non-genetic sources. Thus, a positive relationship between genetic correlations and heritabilities (h2) of underlying traits might be observed. Here we test this prediction using a large dataset of published estimates of genetic correlations and employing a powerful meta-analytical approach. We considered both between-traits and cross-sex genetic correlations. We failed to find support for the prediction about a positive rg– h2relationship: our analysis based on nearly 1000 published estimates of genetic parameters indicates that the predicted relationship is weak and statistically non-significant. Thus, low heritability does not preclude the possibility of detecting substantial genetic correlations. Our meta-analysis indicates that published estimates of genetic parameters coming from various experimental designs and obtained using different statistical techniques are not significantly biased in case of weakly-heritable traits.
Inferring the frequency spectrum of derived variants to quantify adaptive molecular evolution in protein-coding genes ofDrosophila melanogaster
Authors: Keightley Peter D. , Campos José L. , Booker Tom R. , Charlesworth Brian
Published: February 2016

Many approaches for inferring adaptive molecular evolution analyze the unfolded site frequency spectrum (SFS), a vector of counts of sites with different numbers of copies of derived alleles in a sample of alleles from a population. Accurate inference of the high copy number elements of the SFS is difficult, however, because of misassignment of alleles as derivedversusancestral. This is a known problem with parsimony using outgroup species. Here, we show that the problem is particularly serious if there is variation in the substitution rate among sites brought about by variation in selective constraint levels. We present a new method for inferring the SFS using one or two outgroups, which attempts to overcome the problem of misassignment. We show that two outgroups are required for accurate estimation of the SFS if there is substantial variation in selective constraints, which is expected to be the case for nonsynonymous sites of protein-coding genes. We apply the method to estimate unfolded SFSs for synonymous and nonsynonymous sites from Phase 2 of the Drosophila Population Genomics Project. We use the unfolded spectra to estimate the frequency and strength of advantageous and deleterious mutations, and estimate that ˜50% of amino acid substitutions are positively selected, but that less than 0.5% of new amino acid mutations are beneficial, with a scaled selection strength ofNes ≈12.
Inter- and intra-individual differences in fluid reasoning show distinct cortical responses
Authors: Kievit Rogier A. , Scholte H. Steven , Waldorp Lourens J. , Borsboom Denny
Published: February 2016

Fluid intelligence is a general cognitive ability associated with problem solving in the absence of task-specific knowledge. Neuroscientific studies of fluid intelligence have studied both fluid intelligence tasks of varying difficulty and individual differences in fluid intelligence ability, but have failed to appropriately distinguish the two dimensions. Here we use task-based fMRI (N=34) to show thatwithinandbetweensubject dimensions show both partial overlap and widespread differences. Individuals with higher ability showed widespread increased activity including bilateral frontoparietal systems, whereas more difficult items were associated with more focal activity increases in middle frontal gyri, frontal poles and superior frontal poles. Finally, we show that when difficulty is equated across individuals, those with higher ability tend to show more fronto-parietal activity, whereas low fluid intelligence individuals tend to show greater activity in higher visual areas. The fMRI and behavioural data for our paper are freely available in online repositories.
Legionella thermalis sp. nov., isolated from hot spring water in Tokyo, Japan
Authors: Ishizaki Naoto , Sogawa Kazuyuki , Inoue Hiroaki , Agata Kunio , Edagawa Akiko , Miyamoto Hiroshi , Fukuyama Masafumi , Furuhata Katsunori
Published: February 2016

Strain L‐47T of a novel bacterial species belonging to the genus Legionella was isolated from a sample of hot spring water from Tokyo, Japan. The 16S rRNA gene sequences (1477 bp) of this strain (accession number AB899895) had less than 95.0% identity with other Legionella species. The dominant fatty acids of strain L‐47T were a15:0 (29.6%) and the major ubiquinone was Q‐12 (71.1%). It had a guanine‐plus‐cytosine content of 41.5 mol%. The taxonomic description of Legionella thermalis sp. nov. is proposed to be type strain L‐47T (JCM 30970T = KCTC 42799T).
Phytochemical traits underlie genotypic variation in susceptibility of quaking aspen (Populus tremuloides) to browsing by a keystone forest ungulate
Authors: Holeski Liza M. , McKenzie Sean C. , Kruger Eric L. , Couture John J. , Rubert‐Nason Kennedy , Lindroth Richard L.
Published: February 2016

Overbrowsing by ungulates is a major cause of poor aspen stand regeneration across North America and Eurasia. In general, factors driving ungulate browser preferences include concentrations of plant secondary compounds and the nutritional composition (non‐structural carbohydrates, protein and minerals) of foliage. While each of these phytochemical factors has been shown to independently influence ungulate preference, the relative impact of each factor is unknown, as no study to date has examined them simultaneously.

Plant fitness depends not only on the capacity of plants to resist browsing, but also on their capacity to tolerate browsing once it has occurred. Little is known of aspen tolerance to browsing, which inflicts a different form of damage than insect herbivory.

We employed multiple aspen genotypes, replicate trees of which were subjected to different soil nutrient treatments, to investigate: (i) the effects of aspen genotype, nutrient treatment and genotype × nutrient interactions on susceptibility to browsing by white‐tailed deer, (ii) the phytochemical basis for the patterns observed in (i), and (iii) the effects of genotype, soil nutrients and their interaction on short‐term tolerance to deer browsing.

Aspen genotypes varied markedly in their vernal susceptibility to deer browsing. Genetic variation in early season levels of non‐structural carbohydrates (sugars), protein and multiple macro‐ and trace minerals had the strongest influence on tree susceptibility to browsing. In contrast, levels of phytochemical defences had minimal effects, although the range of levels expressed in this study was small. Soil nutrient availability did not significantly influence deer preference.

The extent of browsing affected post‐browse tolerance across genotypes. Soil nutrient treatment had little differential effect on tolerance, and, for the most part, genotypes did not display differential tolerance to browsing, regardless of which soil nutrient treatment they experienced.

Synthesis. Genetic variation for susceptibility to browsing indicates that ungulate browsers have the potential to be agents of selection in aspen populations. In contrast with previous studies in aspen highlighting the importance of phytochemical defences in shaping preferences of browsing mammals, our results indicate that the nutritional composition of foliage (sugars, protein and mineral concentrations) can have sizable effects on preference. The observed lack of influence of soil nutrient availability on tree browsing tolerance contrasts with predictions of the limiting resource model, the prevailing model for plant tolerance.
Hope is a four‐letter word: riding the emotional rollercoaster of illness management
Authors: Nowakowski Alexandra C.H.
Published: February 2016

In this autoethnography, I explore the process and emotional experience of trying a new drug to improve my quality of life. In so doing, I synthesise personal history with extant research on chronic illness by analysing ways in which my experiences reflect and reject social norms. I also incorporate perspectives from research on aspirations and attainment, and the mental health consequences of cyclical disappointment. By weaving together lessons from each of these literatures, I articulate an integrative psychosocial understanding of the micro‐level processes and experiences involved in illness management as well as the ways that experiences of illness management may require integration of varied sociological insights concerning health. In closing, I draw out theoretical implications for understanding the integration and variation of insights from many areas of health research in the lived experiences of people with chronic conditions. A Virtual Abstract of this article can be seen at:
https://youtu.be/5aoaWGItDgM
Analogical Levelling and Optimisation: The Treatment of Pointless Lexical Allomorphy in Greek
Authors: Sims‐Williams Helen
Published: February 2016

Ancient Greek verbal morphology involved extensive allomorphy of lexical morphemes, most of which was phonologically and semantically arbitrary, lexically idiosyncratic, and functionally redundant. In the subsequent history of the language this allomorphy was reduced, partly through analogical levelling, where an allomorphic alternation is eliminated in favour of a single phonological expression of underlying meaning. This kind of reduction of arbitrary complexity is often observed in the development of morphological systems, which has inspired a common view of morphological change as being guided by universal preferences, which nudge morphological systems along paths which will lead them to a more optimal status. This paper uses some systematic empirical data from the history of Greek to put to the test two questions about analogical levelling and the role of ‘optimisation’. Firstly, is levelling motivated by a universal preference for a one‐to‐one alignment of meaning and form in language? Secondly, is the direction of levelling determined by universal preferences for particular ways of marking morphosyntactic distinctions? I will argue that the answer to both questions is no: the changes in the Greek data I have examined are remarkably well predicted by language‐specific, formal properties of paradigms, without the need to invoke universal preferences. These facts are best accommodated if speaker competence includes detailed probabilistic information about the predictive structure of paradigms, which has important implications for morphological theory, as well as historical linguistics.
‘Wrightsonian Incorporation’ and the Public Rhetoric of Mid‐Tudor England
Authors: Hoyle Richard
Published: February 2016

This article introduces the idea of ‘Wrightsonian incorporation’ in the later sixteenth century to a wider audience. A number of scholars have taken Wrightson's original idea, that village society split in the later sixteenth century as the ‘yeomen’ were incorporated into the state as officeholders, and elaborated upon it, particularly using it to explain why a late medieval tradition of rebellion should have ended in 1549. A number of reasons are offered as to why we should not readily accept the idea, but it is then shown how the public rhetoric of the period was deeply hostile to all forms of collective action, which it defined as rebellion. It is suggested that this context was as important as ‘incorporation’ in the sense that Wrightson and others have used it in changing the attitudes of the yeomen in the village by closing off options for political expression and activity.
The Fiscal Decentralisation and Economic Growth Nexus Revisited
Authors: Ligthart Jenny E. , van Oudheusden Peter
Published: February 2016

This paper addresses two challenges that the fiscal decentralisation and economic growth nexus faces – namely, endogeneity problems and inaccurate measurement of fiscal decentralisation. We introduce novel instrumental variables based on common legal system origin, common federal system, geographical position and relative country size. The positive relationship between fiscal decentralisation and economic growth that we find remains valid when using these instrumental variables. Using fiscal decentralisation measures that better reflect the autonomy of subnational governments changes this relationship. This finding, however, is the result of the accompanying changes in the sample rather than the use of these alternative measures themselves.
A randomized, 5‐arm dose finding study with a mite allergoid SCIT in allergic rhinoconjunctivitis patients
Authors: Pfaar O. , Nell M. J. , Boot J. D. , Versteeg S. A. , van Ree R. , Roger A. , Riechelmann H. , Sperl A. , Oude Elberink J. N. G. , Diamant Z. , Bachert C.
Published: February 2016

Background

The safety and tolerability of a mite allergoid subcutaneous allergen immunotherapy (SCIT) product was previously established. The aim of this study (EudraCT number: 2011–000393–61) was to find the optimally safe and effective allergoid dose by evaluating several dosages in patients with house dust mite (HDM)‐induced allergic rhinoconjunctivitis (ARC) using a titrated nasal provocation test (TNPT).

Methods

In total, 290 adult ARC patients (148 females; 142 males) with established HDM allergy and with a positive TNPT were randomized to receive placebo or mite allergoid SCIT 6667, 20 000, 50 000 or 100 000 AUeq/ml for 12 months. Patients were updosed weekly, followed by monthly maintenance dosing. The primary study endpoint comprised the clinical response to TNPT after 12 months of treatment. Secondary endpoints included response to TNPT after 6 months, PNIF measurements, symptom and medication scores during the last 8 weeks of treatment, serum immunoglobulins and safety assessments.

Results

After 12 months, a dose–response was observed showing statistically significant improvements in the TNPT with SCIT concentrations of ≥20 000 AUeq/ml, while no significantly different outcomes were reached after 6 months. Specific serum IgG and IgG4 levels were dose dependently increased. In the highest dose group, more treatment‐emergent adverse events were observed compared with the lower dose groups.

Conclusion

In this mite allergoid SCIT dose finding study in HDM‐induced ARC, concentrations of ≥20 000 AUeq/ml showed both immunological effects and clinical efficacy in the TNPT compared with placebo. The risk–benefit ratio favours 20 000 AUeq/ml and 50 000 AUeq/ml strengths for further clinical development.
Validity of a selection of pregnancy complications in the Medical Birth Registry of Norway
Authors: Moth Fredrikke N. , Sebastian Tharani R. , Horn Julie , Rich‐Edwards Janet , Romundstad Pål R. , Åsvold Bjørn O.
Published: February 2016

Introduction

The validity of information on pregnancy complications in the Medical Birth Registry of Norway (MBRN) is insufficiently studied. The objective was to examine the validity of information on gestational age, birthweight, medically initiated delivery, and gestational hypertension in the MBRN.

Material and methods

We randomly sampled MBRN records among women who participated in the population‐based HUNT Study in Nord‐Trøndelag county and who gave birth during 1967–2012. We estimated the sensitivity, specificity, positive predictive value (PPV) and negative predictive value of information in the MBRN, using hospital records as the reference standard.

Results

Hospital records were available for 786 out of 797 sampled MBRN records. The PPVs of preterm (<37 weeks of gestation) and early preterm birth (<34 weeks of gestation) were approximately 90%, and the PPVs of low (<2500 g) and high (>4500 g) birthweight were 100%. For medically initiated delivery, the PPV was 28% during 1967–85, but 80% during 1986–2012 and higher among preterm (76%) than among term (51%) births. For gestational hypertension, the PPV was 68%, but 88% of women labeled with gestational hypertension in the MBRN had evidence of gestational hypertension or preeclampsia in hospital records.

Conclusions

The validity of information on gestational age and birthweight in the MBRN was very good. For medically initiated delivery, the validity was poor before 1985 and satisfactory thereafter. For gestational hypertension, lack of information in hospital records made the evaluation difficult, but our results suggest that most women labeled with gestational hypertension in the MBRN did have a hypertensive disorder of pregnancy.
Cumulative drought and land‐use impacts on perennial vegetation across a North American dryland region
Authors: Munson Seth M. , Long A. Lexine , Wallace Cynthia S.A. , Webb Robert H.
Published: February 2016

Question

The decline and loss of perennial vegetation in dryland ecosystems due to global change pressures can alter ecosystem properties and initiate land degradation processes. We tracked changes of perennial vegetation using remote sensing to address the question of how prolonged drought and land‐use intensification have affected perennial vegetation cover across a desert region in the early 21st century?

Location

Mojave Desert, southeastern California, southern Nevada, southwestern Utah and northwestern Arizona, USA.

Methods

We coupled the Moderate‐Resolution Imaging Spectroradiometer Enhanced Vegetation Index (MODIS‐EVI) with ground‐based measurements of perennial vegetation cover taken in about 2000 and about 2010. Using the difference between these years, we determined perennial vegetation changes in the early 21st century and related these shifts to climate, soil and landscape properties, and patterns of land use.

Results

We found a good fit between MODIS‐EVI and perennial vegetation cover (2000: R2 = 0.83 and 2010: R2 = 0.74). The southwestern, far southeastern and central Mojave Desert had large declines in perennial vegetation cover in the early 21st century, while the northeastern and southeastern portions of the desert had increases. These changes were explained by 10‐yr precipitation anomalies, particularly in the cool season and during extreme dry or wet years. Areas heavily impacted by visitor use or wildfire lost perennial vegetation cover, and vegetation in protected areas increased to a greater degree than in unprotected areas.

Conclusions

We find that we can extrapolate previously documented declines of perennial plant cover to an entire desert, and demonstrate that prolonged water shortages coupled with land‐use intensification create identifiable patterns of vegetation change in dryland regions.
The Role of Nitric Oxide and Hydrogen Sulfide in Urinary Tract Function
Authors: Fernandes Vítor S. , Hernández Medardo
Published: February 2016

This MiniReview focuses on the role played by nitric oxide (NO) and hydrogen sulfide (H2S) in physiology of the upper and lower urinary tract. NO and H2S, together with carbon monoxide, belong to the group of gaseous autocrine/paracrine messengers or gasotransmitters, which are employed for intra‐ and intercellular communication in almost all organ systems. Because they are lipid‐soluble gases, gaseous transmitters are not constrained by cellular membranes, so that their storage in vesicles for later release is not possible. Gasotransmitter signals are terminated by falling concentrations upon reduction in production that are caused by reacting with cellular components (essentially reactive oxygen species and NO), binding to cellular components or diffusing away. NO and, more recently, H2S have been identified as key mediators in neurotransmission of the urinary tract, involved in the regulation of ureteral smooth muscle activity and urinary flow ureteral resistance, as well as by playing a crucial role in the smooth muscle relaxation of bladder outlet region. Urinary bladder function is also dependent on integration of inhibitory mediators, such as NO, released from the urothelium. In the bladder base and distal ureter, the co‐localization of neuronal NO synthase with substance P and calcitonin gene‐related peptide in sensory nerves as well as the existence of a high nicotinamide adenine dinucleotide phosphate‐diaphorase activity in dorsal root ganglion neurons also suggests the involvement of NO as a sensory neurotransmitter.
Oncological and functional outcomes 1 year after radical prostatectomy for very‐low‐risk prostate cancer: results from the prospective LAPPRO trial
Authors: Carlsson Stefan , Jäderling Fredrik , Wallerstedt Anna , Nyberg Tommy , Stranne Johan , Thorsteinsdottir Thordis , Carlsson Sigrid V. , Bjartell Anders , Hugosson Jonas , Haglind Eva , Steineck Gunnar
Published: February 2016

Objectives

To analyse oncological and functional outcomes 12 months after treatment of very‐low‐risk prostate cancer with radical prostatectomy in men who could have been candidates for active surveillance.

Patients and Methods

We conducted a prospective study of all men with very‐low‐risk prostate cancer who underwent radical prostatectomy at one of 14 participating centres. Validated patient questionnaires were collected at baseline and after 12 months by independent healthcare researchers. Biochemical recurrence (BCR) was defined as prostate‐specific antigen (PSA) ≥0.25 ng/mL or treatment with salvage radiotherapy or with hormones. Urinary continence was defined as <1 pad changed per 24 h. Erectile function was defined as ability to achieve erection hard enough for penetration more than half of the time after sexual stimulation. Changes in tumour grade and stage were obtained from pathology reports. We report descriptive frequencies and proportions of men who had each outcome in various subgroups. Fisher's exact test was used to assess differences between the age groups.

Results

Of the 4003 men in the LAPPRO cohort, 338 men fulfilled the preoperative national criteria for very‐low‐risk prostate cancer. Adverse pathology outcomes included upgrading, defined as pT3 or postoperative Gleason sum ≥7, which was present in 35% of the men (115/333) and positive surgical margins, which were present in 16% of the men (54/329). Only 2.1% of the men (7/329) had a PSA concentration >0.1 ng/mL 6–12 weeks postoperatively. Erectile function and urinary continence were observed in 44% (98/222) and 84% of the men (264/315), respectively, 12 months postoperatively. The proportion of men achieving the trifecta, defined as preoperative potent and continent men who remained potent and continent with no BCR, was 38% (84/221 men) at 12 months.

Conclusions

Our prospective study of men with very‐low‐risk prostate cancer undergoing open or robot‐assisted radical prostatectomy showed that there were favourable oncological outcomes in approximately two‐thirds. Approximately 40% did not have surgically induced urinary incontinence or erectile dysfunction 12 months postoperatively. These results provide additional support for the use of active surveillance in men with very‐low‐risk prostate cancer; however, the number of men with risk of upgrading and upstaging is not negligible. Improved stratification is still urgently needed.
Multikinase inhibitor regorafenib inhibits the growth and metastasis of colon cancer with abundant stroma
Authors: Takigawa Hidehiko , Kitadai Yasuhiko , Shinagawa Kei , Yuge Ryo , Higashi Yukihito , Tanaka Shinji , Yasui Wataru , Chayama Kazuaki
Published: February 2016

Interaction between tumor cells and stromal cells plays an important role in the growth and metastasis of colon cancer. We previously found that carcinoma‐associated fibroblasts (CAFs) expressed platelet‐derived growth factor receptor‐β (PDGFR‐β) and that PDGFR targeted therapy using imatinib or nilotinib inhibited stromal reaction. Bone marrow‐derived mesenchymal stem cells (MSCs) migrate to tumor stroma and differentiate into CAFs. A novel oral multikinase inhibitor regorafenib inhibits receptor tyrosine kinases expressed on stromal cells (vascular endothelial growth factor receptor 1–3, TIE2, PDGFR‐β, and fibroblast growth factors) and tumor cells (c‐KIT, RET, and BRAF). These molecules are involved in tumor growth, angiogenesis, lymphangiogenesis, and stromal activation. Therefore, we examined whether regorafenib impaired the tumor‐promoting effect of CAFs/MSCs. KM12SM human colon cancer cells alone or KM12SM cells with MSCs were transplanted into the cecal wall of nude mice. Co‐implantation of KM12SM cells with MSCs into the cecal wall of nude mice produced tumors with abundant stromal component and promoted tumor growth and lymph node metastasis. Single treatment with regorafenib inhibited tumor growth and metastasis by inhibiting both tumor cells and stromal reaction. This tumor‐inhibitory effect of regorafenib was more obvious in tumors developed by co‐implanting KM12SM cells with MSCs. Our data suggested that targeting of the tumor microenvironment with regorafenib affected tumor cell–MSC interaction, which in turn inhibited the growth and metastasis of colon cancer.
Integrated care for Down syndrome
Authors: Lee Ni‐Chung , Chien Yin‐Hsiu , Hwu Wuh‐Liang
Published: February 2016

Down syndrome (DS), caused by an extra copy of chromosome 21 (trisomy 21), is the most intensively studied human aneuploidy condition. It is the leading cause of intellectual disability and birth defects. Although most prenatally diagnosed DS fetuses are aborted in Taiwan, there are still some infants with DS who are diagnosed after birth. In addition to intellectual disability, people with DS face systemic problems that include short stature, dysmorphism, congenital heart disease, congenital anomalies of gastrointestinal and genitourinary tracts, abnormal endocrine function, leukemia and leukemoid reactions. To provide better care for people with DS in Taiwan, we began the DS multi‐disciplinary clinic that has opened once per month since November 2013. The multi‐disciplinary clinic consists of several subspecialists who provide care for DS people. To date, approximately 200 patients have used the clinic. The average number of patients who use the clinic per month is 27±6 with a mean patient age of 16±12 years old (range 0.3–53 years). The average number of patients per specialist on each clinic day is 5.2±4.9 (range 0.5–20.9 patients). We focus on early detection and prevention of medical and developmental issues associated with DS. This coordinated approach allows DS patients and family to have more comprehensive care.
Horizontal mucosal thickness at implant sites as it correlates with the integrity and thickness of the buccal bone plate
Authors: Schwarz Frank , Sager Martin , Golubovic Vladimir , Iglhaut Gerhard , Becker Kathrin
Published: February 2016

Objectives

To histologically assess the association between the horizontal mucosal thickness (MT) at implant sites with the integrity and thickness of the buccal bone plate in a canine model.

Materials and methods

Two‐piece titanium implants were placed at chronic‐type lateral ridge defects. The resulting vestibular dehiscence‐type defects (vertical dimensions of 2–8 mm) were left untreated. After a submerged healing period of 2 and 8 weeks (n = 6 fox hounds each), dissected blocks were processed for histomorphometrical analyses [e.g.MT, bone thickness (BT) and residual defect length].

Results

Linear regression revealed significant associations between vestibularMTandBTvalues after 2 (R2 = 0.22,B = −0.37,P < 0.0001) and 8 weeks (R2 = 0.37,B = −0.45,P < 0.001) of healing.

Conclusion

The present analysis has pointed to an inverse relationship between horizontalMTandBTvalues at the vestibular aspect of submerged titanium implants.MTwas most pronounced in the absence of a buccal bone plate.
Peri‐implant bone adaptations to overloading in rat tibiae: experimental investigations and numerical predictions
Authors: Piccinini Marco , Cugnoni Joel , Botsis John , Ammann Patrick , Wiskott Anselm
Published: February 2016

Objectives

(i) To assess the effects of mechanical overloading on implant integration in rat tibiae, and (ii) to numerically predict peri‐implant bone adaptation.

Materials and methods

Transcutaneous titanium implants were simultaneously placed into both tibiae of rats (n = 40). After 2 weeks of integration, the implants of the right tibiae were stimulated daily for 4 weeks with loads up to 5N (corresponding to peak equivalent strains of 3300 ± 500 με). The effects of stimulation were assessed by ex vivo mechanical tests and quantification of bone mineral density (BMD) in selected regions of interests (ROIs). Specimen‐specific finite element models were generated and processed through an iterative algorithm to mimic bone adaptation.

Results

Bilateral implantation provoked an unstable integration that worsened when mild (2–4N) external loads were applied. In contrast, a stimulation at 5N tended to “counterbalance” the harmful effects of daily activity and, if applied to well‐integrated specimens, significantly augmented the implants' resistance to failure (force: +73% P < 0.01, displacement: +50% P < 0.01 and energy: +153% P < 0.01). Specimen‐specific numerical predictions were in close agreement with the experimental findings. Both local and overall BMD variations, as well as the implants' lateral stability, were predicted with small errors (0.14 gHA/cm3 and 0.64%, respectively).

Conclusions

The rats' daily activity detrimentally affects implant integration. Conversely, external stimulations of large magnitudes counterbalance this effect and definitively improve integration. These changes can be predicted using the proposed numerical approach.
Multimethod, multistate Bayesian hierarchical modeling approach for use in regional monitoring of wolves
Authors: Jiménez José , García Emilio J. , Llaneza Luis , Palacios Vicente , González Luis Mariano , García‐Domínguez Francisco , Múñoz‐Igualada Jaime , López‐Bao José Vicente
Published: February 2016

In many cases, the first step in large‐carnivore management is to obtain objective, reliable, and cost‐effective estimates of population parameters through procedures that are reproducible over time. However, monitoring predators over large areas is difficult, and the data have a high level of uncertainty. We devised a practical multimethod and multistate modeling approach based on Bayesian hierarchical‐site‐occupancy models that combined multiple survey methods to estimate different population states for use in monitoring large predators at a regional scale. We used wolves (Canis lupus) as our model species and generated reliable estimates of the number of sites with wolf reproduction (presence of pups). We used 2 wolf data sets from Spain (Western Galicia in 2013 and Asturias in 2004) to test the approach. Based on howling surveys, the naïve estimation (i.e., estimate based only on observations) of the number of sites with reproduction was 9 and 25 sites in Western Galicia and Asturias, respectively. Our model showed 33.4 (SD 9.6) and 34.4 (3.9) sites with wolf reproduction, respectively. The number of occupied sites with wolf reproduction was 0.67 (SD 0.19) and 0.76 (0.11), respectively. This approach can be used to design more cost‐effective monitoring programs (i.e., to define the sampling effort needed per site). Our approach should inspire well‐coordinated surveys across multiple administrative borders and populations and lead to improved decision making for management of large carnivores on a landscape level. The use of this Bayesian framework provides a simple way to visualize the degree of uncertainty around population‐parameter estimates and thus provides managers and stakeholders an intuitive approach to interpreting monitoring results. Our approach can be widely applied to large spatial scales in wildlife monitoring where detection probabilities differ between population states and where several methods are being used to estimate different population parameters.
Using citizen science data to identify the sensitivity of species to human land use
Authors: Todd Brian D. , Rose Jonathan P. , Price Steven J. , Dorcas Michael E.
Published: February 2016

Conservation practitioners must contend with an increasing array of threats that affect biodiversity. Citizen scientists can provide timely and expansive information for addressing these threats across large scales, but their data may contain sampling biases. We used randomization procedures to account for possible sampling biases in opportunistically reported citizen science data to identify species’ sensitivities to human land use. We analyzed 21,044 records of 143 native reptile and amphibian species reported to the Carolina Herp Atlas from North Carolina and South Carolina between 1 January 1990 and 12 July 2014. Sensitive species significantly associated with natural landscapes were 3.4 times more likely to be legally protected or treated as of conservation concern by state resource agencies than less sensitive species significantly associated with human‐dominated landscapes. Many of the species significantly associated with natural landscapes occurred primarily in habitats that had been nearly eradicated or otherwise altered in the Carolinas, including isolated wetlands, longleaf pine savannas, and Appalachian forests. Rare species with few reports were more likely to be associated with natural landscapes and 3.2 times more likely to be legally protected or treated as of conservation concern than species with at least 20 reported occurrences. Our results suggest that opportunistically reported citizen science data can be used to identify sensitive species and that species currently restricted primarily to natural landscapes are likely at greatest risk of decline from future losses of natural habitat. Our approach demonstrates the usefulness of citizen science data in prioritizing conservation and in helping practitioners address species declines and extinctions at large extents.
Effects of Manipulation on Attributions of Causation, Free Will, and Moral Responsibility
Authors: Murray Dylan , Lombrozo Tania
Published: February 2016

If someone brings about an outcome without intending to, is she causally and morally responsible for it? What if she acts intentionally, but as the result of manipulation by another agent? Previous research has shown that an agent's mental states can affect attributions of causal and moral responsibility to that agent, but little is known about what effect one agent's mental states can have on attributions to another agent. In Experiment 1, we replicate findings that manipulation lowers attributions of responsibility to manipulated agents. Experiments 2–7 isolate which features of manipulation drive this effect, a crucial issue for both philosophical debates about free will and attributions of responsibility in situations involving social influence more generally. Our results suggest that “bypassing” a manipulated agent's mental states generates the greatest reduction in responsibility, and we explain our results in terms of the effects that one agent's mental states can have on the counterfactual relations between another agent and an outcome.
Spirometric reference equations for Swedish adults
Authors: Brisman Jonas , Kim Jeong‐Lim , Olin Anna‐Carin , Torén Kjell , Bake Björn
Published: February 2016

New spirometric reference equations for Swedish adults are required. Three different older sets of reference equations clinically used in Sweden have various drawbacks and the recently published ‘The Global Lung Function 2012 (GLI) equations’ have been shown not to be adequate for Swedish normal, healthy non‐smokers. We have recently concluded that a piecewise linear model presented by Lubinski and Gólczewski accurately describes the distribution of spirometric variables in a large Swedish random population sample. This piecewise linear model also offers the important advantage of implementing easily physiologically interpretable coefficients. The present study aimed at presenting piecewise linear reference equations for Swedish adults based on a random population sample of 6685 individuals aged 25–75 years. Predicted normal values by the piecewise linear reference equations and lower limit normal (LLN) were compared with the three reference equations frequently used clinically in Sweden and the GLI equations. We found predicted normal values according to the present piecewise linear reference equations close to 100% predicted normal as expected, whereas the other equations either overestimated or underestimated normal subjects. Concerning LLN, the present equations, i.e. 1·645 × RSD, showed the least deviation from the expected 5% and, e.g., the GLI equations systematically identified too few subjects below LLN. We conclude that the present piecewise linear reference equations, based on a relatively large general population sample, ought to be considered for clinical use in Sweden. Application of 1·645 × RSD below predicted value gave an acceptably accurate LLN.