bluuebunny/crossref_metadata_2025 huggingface dataset:
Population pharmacokinetic−pharmacodynamic modelling of mycophenolic acid in paediatric renal transplant recipients in the early post‐transplant period
Authors: Dong Min , Fukuda Tsuyoshi , Cox Shareen , de Vries Marij T. , Hooper David K. , Goebel Jens , Vinks Alexander A.
Published: May 2014

Aim

The purpose of this study was to develop a population pharmacokinetic and pharmacodynamic (PK−PD) model for mycophenolic acid (MPA) in paediatric renal transplant recipients in the early post‐transplant period.

Methods

A total of 214 MPA plasma concentrations−time data points from 24 patients were available for PK model development. In 17 out of a total of 24 patients, inosine monophosphate dehydrogenase (IMPDH) enzyme activity measurements (n = 97) in peripheral blood mononuclear cells were available for PK−PD modelling. The PK−PD model was developed using non‐linear mixed effects modelling sequentially by 1) developing a population PK model and 2) incorporating IMPDH activity into a PK−PD model using post hoc Bayesian PK parameter estimates. Covariate analysis included patient demographics, co‐medication and clinical laboratory data. Non‐parametric bootstrapping and prediction‐corrected visual predictive checks were performed to evaluate the final models.

Results

A two compartment model with a transit compartment absorption best described MPA PK. A non‐linear relationship between dose and MPA exposure was observed and was described by a power function in the model. The final population PK parameter estimates (and their 95% confidence intervals) were CL/F, 22 (14.8, 25.2) l h−1 70 kg−1; Vc/F, 45.4 (29.6, 55.6) l; Vp/F, 411 (152.6, 1472.6)l; Q/F, 22.4 (16.0, 32.5) l h−1; Ka, 2.5 (1.45, 4.93) h−1. Covariate analysis in the PK study identified body weight to be significantly correlated with CL/F. A simplified inhibitory Emax model adequately described the relationship between MPA concentration and IMPDH activity. The final population PK−PD parameter estimates (and their 95% confidence intervals) were: E0, 3.45 (2.61, 4.56) nmol h−1 mg−1 protein and EC50, 1.73 (1.16, 3.01) mg l−1. Emax was fixed to 0. There were two African‐American patients in our study cohorts and both had low IMPDH baseline activities (E0) compared with Caucasian patients (mean value 2.13 mg l−1 vs. 3.86 mg l−1).

Conclusion

An integrated population PK−PD model of MPA has been developed in paediatric renal transplant recipients. The current model provides information that will facilitate future studies and may be implemented in a Bayesian algorithm to allow a PK−PD guided therapeutic drug monitoring strategy.
Progress in central nervous system lymphomas
Authors: Wang Chia‐Ching , Carnevale Julia , Rubenstein James L.
Published: May 2014

Until recently, primary central nervous system lymphoma (PCNSL) was associated with a uniformly dismal prognosis. It is now reasonable to anticipate long‐term survival and possibly cure for a significant proportion of patients diagnosed with PCNSL. Accumulated data generated over the past 10 years has provided evidence that long‐term progression‐free survival (PFS) can reproducibly be attained in a significant fraction of PCNSL patients that receive dose‐intensive chemotherapy consolidation, without whole brain radiotherapy. One consolidative regimen that has reproducibly demonstrated promise is the combination of infusional etoposide plus high‐dose cytarabine (EA), administered in first complete remission after methotrexate, temozolomide and rituximab‐based induction. Given evolving principles of management and the mounting evidence for reproducible improvements in survival rates in prospective clinical series, our goal in this review is to highlight and update principles in diagnosis, staging and management as well as to review data regarding the pathogenesis of central nervous system lymphomas, information that is likely to constitute a basis for the implementation of novel therapies that are requisite for further progress in this unique phenotype of non‐Hodgkin lymphoma.
Phase II study of zoledronic acid combined with docetaxel for non‐small‐cell lung cancer: West Japan Oncology Group
Authors: Murakami Haruyasu , Yamanaka Takeharu , Seto Takashi , Sugio Kenji , Okamoto Isamu , Sawa Toshiyuki , Hirashima Tomonori , Takeda Koji , Atagi Shinji , Fukuoka Masahiro , Nakanishi Yoichi , Nakagawa Kazuhiko , Yamamoto Nobuyuki
Published: May 2014

The aim of this open‐label, multicenter, randomized phase II trial was to evaluate the efficacy and safety of zoledronic acid in combination with docetaxel in previously treated patients with non‐small‐cell lung cancer (NSCLC) and bone metastases. In this study, patients randomly received docetaxel (60 mg/m2) with (group DZ) or without (group D) zoledronic acid every 21 days. There were 50 patients in each group, and the primary endpoint was progression‐free survival. In an efficacy analysis of 94 patients (DZ, 48; D, 46), the median progression‐free survival was 2.7 months (95% confidence interval [CI], 1.5–3.5 months) for the DZ group and 2.6 months (95% CI, 1.5–3.4 months) for the D group (stratified log‐rank test, P = 0.89). The median overall survival was 10.4 months (95% CI, 7.0–15.8 months) for the DZ group and 9.7 months (95% CI, 6.1–12.5 months) for the D group (stratified log‐rank test, P = 0.62). There were no clinically relevant differences in the frequencies of grade 3 or 4 adverse events between the two groups. No treatment‐related deaths occurred in the DZ group. Zoledronic acid combined with docetaxel was well tolerated but did not meet the primary endpoint of demonstrating a longer progression‐free survival in advanced NSCLC patients with bone metastases compared with docetaxel alone. This trial was registered with the University Hospital Medical Information Network (UMIN000001098).
Procognitive Properties of Drugs with Single and Multitargeting H3 Receptor Antagonist Activities
Authors: Nikolic Katarina , Filipic Slavica , Agbaba Danica , Stark Holger
Published: May 2014

The histamine H3 receptor (H3R) is an important modulator of numerous central control mechanisms. Novel lead optimizations for H3R antagonists/inverse agonists involved studies of structure–activity relationships, cross‐affinities, and pharmacokinetic properties of promising ligands. Blockade of inhibitory histamine H3 autoreceptors reinforces histaminergic transmission, while antagonism of H3 heteroreceptors accelerates the corticolimbic liberation of acetylcholine, norepinephrine, glutamate, dopamine, serotonin and gamma‐aminobutyric acid (GABA). The H3R positioned at numerous neurotransmission crossroads indicates therapeutic applications of small‐molecule H3R modulators in a number of psychiatric and neurodegenerative diseases with various clinical candidates available. Dual target drugs displaying H3R antagonism/inverse agonism with inhibition of acetylcholine esterase (AChE), histamine N‐methyltransferase (HMT), or serotonin transporter (SERT) are novel class of procognitive agents. Main chemical diversities, pharmacophores, and pharmacological profiles of procognitive agents acting as H3R antagonists/inverse agonists and dual H3R antagonists/inverse agonists with inhibiting activity on AChE, HMT, or SERT are highlighted here.
Vagomimetic Effects of Fingolimod: Physiology and Clinical Implications
Authors: Vanoli Emilio , Pentimalli Francesco , Botto Gianluca
Published: May 2014

Fingolimod is a sphingosine 1‐phosphate (S1P) receptor modulator approved to treat relapsing‐remitting multiple sclerosis (MS). Initiation of treatment with fingolimod has been found to produce transient bradycardia and/or slowing of atrioventricular impulse conduction in a small proportion of patients. This effect is thought to be due to the interaction of fingolimod with S1P receptors on the surface membrane of atrial myocytes causing a vagomimetic effect, similar to the action of acetylcholine on muscarinic receptors. As a precaution, patients are under electrocardiogram (ECG) monitoring for 6 h after receiving their first dose. Fingolimod is contraindicated in patients with overt or concealed cardiac diseases. However, the Fingolimod Initiation and caRdiac Safety Trial (FIRST), which was designed specifically to investigate the cardiac profile of fingolimod, did not show an increased risk of clinically relevant cardiac events with fingolimod. This review examines the electrophysiology and pathophysiology of cardiac impulse formation in the context of fingolimod. It concludes that these vagomimetic effects should be considered benign and should not prevent the effective use of fingolimod in the treatment of patients withMS.
Modeling Mental Spatial Reasoning About Cardinal Directions
Authors: Schultheis Holger , Bertel Sven , Barkowsky Thomas
Published: May 2014

This article presents research into human mental spatial reasoning with orientation knowledge. In particular, we look at reasoning problems about cardinal directions that possess multiple valid solutions (i.e., are spatially underdetermined), at human preferences for some of these solutions, and at representational and procedural factors that lead to such preferences. The article presents, first, a discussion of existing, related conceptual and computational approaches; second, results of empirical research into the solution preferences that human reasoners actually have; and, third, a novel computational model that relies on a parsimonious and flexible spatio‐analogical knowledge representation structure to robustly reproduce the behavior observed with human reasoners.
Agents and Causes: Dispositional Intuitions As a Guide to Causal Structure
Authors: Mayrhofer Ralf , Waldmann Michael R.
Published: May 2014

Currently, two frameworks of causal reasoning compete: Whereas dependency theories focus on dependencies between causes and effects, dispositional theories model causation as an interaction between agents and patients endowed with intrinsic dispositions. One important finding providing a bridge between these two frameworks is that failures of causes to generate their effects tend to be differentially attributed to agents and patients regardless of their location on either the cause or the effect side. To model different types of error attribution, we augmented a causal Bayes net model with separate error sources for causes and effects. In several experiments, we tested this new model using the size of Markov violations as the empirical indicator of differential assumptions about the sources of error. As predicted by the model, the size of Markov violations was influenced by the location of the agents and was moderated by the causal structure and the type of causal variables.
Performance of EGFR mutant‐specific antibodies in different cytological preparations: a validation study
Authors: Bellevicine C. , Bianco A. , Malapelle U. , De Luca C. , Vigliar E. , Cacciola N. A. , Pallante P. , Troncone G.
Published: May 2014

Objectives

Molecular testing for epidermal growth factor receptor (EGFR) mutations is required to select the most appropriate treatment for advanced‐stage non‐small cell lung cancer (NSCLC). In routine practice, cytological samples are often the only specimens available for testing. When the number of neoplastic cells is large, DNA‐based assays are the gold standard. When cytological samples contain only a few neoplastic cells, immunocytochemistry (ICC) using anti‐EGFR mutant‐specific antibodies may be more effective. We aim to assess the specificity and sensitivity of IHC staining in cytological specimens using mutated cell lines subjected to different cytopreparations and staining methods.

Methods

HCC827 (exon 19 p.E746‐A750 del) and H3255 (exon 21 p.L858R) cell lines were subjected to different fixation (air dried, alcohol or CytoLyt®), staining (Diff‐Quik® or Papanicolaou) and preparation (smears or cell blocks) methods before ICC. In a second set of experiments, mutated cells were mixed with EGFR wild‐type cells to obtain low‐level (10%) mutated cytological samples. The intensity and percentage of cells stained were evaluated against validated molecular techniques. Moreover, the cell lines were subjected to poor growing conditions to simulate routine specimens that are less optimal than in vitro samples.

Results

The cytological preparations showing the most intense staining were formalin‐fixed cell blocks and samples fixed with CytoLyt or alcohol, including Papanicolaou‐destained samples. Conversely, air‐dried slides showed the least intense staining. Mutant antibodies allowed the detection of mutated cells, even when representing only 10% of the total population. Although, in necrotic specimens, an aspecific background signal appeared, the viable cells still retained anti‐mutant EGFR positivity.

Conclusions

All cytological preparations are suitable for ICC using anti‐EGFR mutant‐specific antibodies, in particular formalin‐fixed cell blocks and alcohol‐ or CitoLyt‐fixed samples. the method is also validated to detect even a few mutant cells in less than optimal samples.
Mucosal healing of ileal lesions is associated with long‐term clinical remission after infliximab maintenance treatment in patients with Crohn's disease
Authors: Beppu Takahiro , Ono Yoichiro , Matsui Toshiyuki , Hirai Fumihito , Yano Yutaka , Takatsu Noritaka , Ninomiya Kazeo , Tsurumi Kozue , Sato Yuho , Takahashi Haruhiko , Ookado Yuuki , Koga Akihiro , Kinjo Ken , Nagahama Takashi , Hisabe Takashi , Takaki Yasuhiro , Yao Kenshi
Published: May 2014

Background and Aim

The aim of the present study was to endoscopically evaluate ileal mucosal healing during maintenance therapy with infliximab in order to investigate the clinical significance of endoscopic examination of ileal lesions in Crohn's disease patients.

Methods

This study retrospectively analyzed 54 patients who mainly had active ulcers of the ileum on endoscopy at baseline who were responsive to infliximab induction and who received infliximab maintenance therapy. Mucosal healing was defined as no ulcer or only ulcer scar. At the time of follow‐up endoscopy after starting infliximab, endoscopic score, mucosal healing, and clinical remission were evaluated. On long‐term follow up, correlations between mucosal healing and long‐term clinical remission, and between mucosal healing and the need for major abdominal surgery, were also evaluated.

Results

Ileal mucosal healing and complete mucosal healing were significantly correlated with clinical remission (P = 0.046, P = 0.0001, respectively). The rate of long‐term clinical remission was significantly higher in patients with complete mucosal healing (P = 0.025). The rate of major abdominal surgery for strictures was significantly lower in patients with complete mucosal healing (P = 0.044).

Conclusions

Complete mucosal healing after 1–2 years was a predictive factor for long‐term clinical remission up to 4 years after starting infliximab. A lack of complete mucosal healing was a predictive factor for major abdominal surgery for strictures. The present study suggests that endoscopic evaluation of ileal lesions is useful for long‐term prognosis of Crohn's disease patients.
Reducing an in‐group bias in preschool children: the impact of moral behavior
Authors: Hetherington Chelsea , Hendrickson Caroline , Koenig Melissa
Published: May 2014

How impressionable are in‐group biases in early childhood? Previous research shows that young children display robust preferences for members of their own social group, but also condemn those who harm others. The current study investigates children's evaluations of agents when their group membership and moral behavior conflict. After being assigned to a minimal group, 4‐ to 5‐year‐old children either saw their in‐group member behave antisocially, an out‐group member act prosocially, or control agents, for whom moral information was removed. Children's explicit preference for and willingness to share with their in‐group member was significantly attenuated in the presence of an antisocial in‐group member, but not a prosocial out‐group member. Interestingly, children's learning decisions were unmoved by a person's moral behavior, instead being consistently guided by group membership. This demonstrates that children's in‐group bias is remarkably flexible: while moral information curbs children's in‐group bias on social evaluations, social learning is still driven by group information.
Competitive release modifies the impacts of hydrologic alteration for a partially migratory stream predator
Authors: Hartson Richard B. , Kennedy Brian P.
Published: May 2014

Understanding ecological effects of altered stream flows is an essential objective. In a comparative field study of juvenile steelhead trout (Oncorhynchus mykiss) that compared natural‐ and reduced‐flow sites, we used mark–recapture modelling and information theory to quantify spatially and temporally explicit patterns of density, specific growth rate, survival and outmigration; and test predictions for biotic and abiotic drivers. Densities were lower in water withdrawal treatments, resulting in lower intraspecific competition and, higher specific growth rate and survival. We observed yearly differences in density and intraspecific competition, with a negative relationship between density and specific growth rate over a wide range of densities, but reductions in survival only at the highest densities. Moreover, individual variability within sites was important. At high density (sites and years), survival related negatively to body size. In contrast, when overall density was lower, specific growth rate was negatively related to body size. Lastly, individuals were more likely to outmigrate when they had larger body size, lower survival or reared in habitats with reduced flows, and these patterns appeared mediated by the intensity of intraspecific competition. Our results underscore the harsh bioenergetic conditions induced by higher temperatures and densities during summer baseflow (relative to other seasons), particularly for larger fish demanding more resources, and suggest a density‐dependent mechanism for why this period is important for regulating salmonid populations. We found that a complex combination of natural (e.g., density) and anthropogenic (e.g., withdrawal) factors affected juvenile salmon populations and life history expression in the face of altered flows.
An Ecological Approach to Experiential Learning in an Inner‐City Context
Authors: Garcia‐Reid Pauline , Reid Robert J. , Forenza Brad
Published: May 2014

In‐depth, qualitative interviewing was employed to describe processes and competencies experienced by family science interns, who practiced in a high‐risk ecological context. Twenty interns from a 3‐year period were recruited. All had interned on the same federally funded, HIV/substance abuse prevention grant in the same focal city. Within this sample, it was determined that experiential learning—vis‐à‐vis the internship—facilitated both intrapersonal processes and ecological competencies for family science interns, who may otherwise have lacked this knowledge when assuming professional roles. Implications for policy and practice are discussed.
Pain, oedema and healing in venous ulcer patients treated with lymphotherapy
Authors: Azoubel Roberta , Torres Gilson de Vasconcelos , Salvetti Marina de Góes , Santos Washington da Silva , Xavier Thaiza Teixeira , Gomes Fabiano Veloso
Published: May 2014

Background

Pain and oedema are common symptoms in patients with venous ulcers.

Objectives

To evaluate the benefits of lymphotherapy as an additional intervention to compression therapy in venous ulcer treatment.

Methods

Quasi‐experimental study comparing lymphotherapy in combination with compression therapy (intervention) to dressings alone (control) for venous ulcer treatment. The outcomes of the study were pain, oedema and healing. The sample comprised of 67 venous ulcer patients in total, with 31 allocated to the intervention group and 36 to the control group. The instruments included a sociodemographic form, physiotherapy assessment, numerical pain rating scale, Godet test and a wound contraction measurement.

Results

The intervention group demonstrated a significant reduction in pain intensity (P>0.001), oedema (P>0.001) and ulcer area (P=0.004), and a significant increase in ulcer contraction (P>0.001) when compared with the control group at the end of 6 months.

Conclusions

The intervention group showed a significant reduction in pain and oedema, and a significant improvement in wound healing when compared to the control group from the third month of treatment, thus confirming the benefits of this therapy.
Ethnic or Political Fractionalisation? A District Level Analysis of the Provision of Public Goods in Sri Lanka
Authors: Cooray Arusha
Published: May 2014

This study investigates the influence of ethnic and political fractionalisation on the provision of public goods at a district level in Sri Lanka. Evidence shows that political fractionalisation has a greater negative impact on the provision of public goods compared with ethnic fractionalisation. Similarly, political polarisation has a greater negative effect on the provision of public goods compared with ethnic polarisation. The interaction between ethnic and political measures suggests that political fractionalisation (political polarisation) exacerbates the negative effects of ethnic fractionalisation (ethnic polarisation) on the provision of public goods. The ethnolinguistic fractionalisation (ELF) index assumes greater statistical significance under fixed effects estimation suggesting greater within district effects in the relationship between ELF and public good provision.
Field Observation of Diurnal Dissolved Oxygen Fluctuations in Shallow Groundwater
Authors: Schilling Keith E. , Jacobson Peter
Published: May 2014

Dissolved oxygen (DO) concentrations influence many biogeochemical processes in groundwater systems but studies of temporal variability in DO are lacking. In this study, we used an optical DO probe to measure rapid changes in concentration due to plant‐groundwater interaction at an alluvial aquifer field site in Iowa. Diurnal DO concentrations were observed during mid‐ to late‐summer when soil conditions were dry, fluctuating approximately 0.2 to 0.3 mg/L on a daily basis. DO fluctuations in groundwater were out‐of‐phase with diurnal water table fluctuations, increasing during the day and decreasing at night. DO consumption at night is likely due to increased soil autotrophic and heterotrophic respiration linked with patterns of carbon supply derived from daytime photosynthetic activity, and consistent with available literature on diurnal soil respiration patterns. Although more work is needed to quantify specific processes, our results indicate the potential usefulness of the new optical DO technology to reveal insights regarding many ecohydrological processes.
Increased cancer risk in patients with haemophilia A: a nationwide population‐based 14‐year study in Taiwan
Authors: Liu C.‐J. , Yu Y.‐B. , Teng C.‐J. , Hung Y.‐P. , Hu Y.‐W. , Hong Y.‐C. , Chen T.‐J. , Chiou T.‐J. , Tzeng C.‐H. , Hsu H.‐C. , Gau J.‐P.
Published: May 2014

Haemostasis is associated with the development and dissemination of cancer. Whether cancer incidence is increased in haemophiliacs remains uncertain; thus, we aimed to further examine this issue. By using data from the National Health Insurance Research Database in Taiwan, we obtained a cohort of 683 patients with haemophilia A, and compared the incidence rate ratio (IRR) of cancer in this cohort with an age‐ and sex‐matched control of 6830 patients. The log‐rank test was used to compare Kaplan–Meier curve of the cumulative cancer incidence between two cohorts. Cox regressions were used to identify independent risk factors of cancer in the study patients. The cancer incidence of patients with haemophilia A was significantly higher compared to the control group (IRR 1.95, 95% CI 1.18–3.09, P = 0.008) during the 14‐year follow‐up period. The non‐lymphoma and non‐liver cancer incidence in the haemophilia A cohort remained higher than that of the matched control (P = 0.050 by the log‐rank test). The multivariate Cox proportional hazards analysis indicated that age (per year, HR 1.09, 95% CI 1.06–1.12, P < 0.001) was the only significant risk factor for cancer development in haemophilia patients. Patients with haemophilia A had higher cancer incidence than the age‐ and sex‐matched patients, especially for the elderly. With increasing life expectancy for haemophiliacs, physicians should be aware of their cancer development.
Geology and age model of the Lower Pleistocene Nojima, Ofuna, and Koshiba Formations of the middle Kazusa Group, a forearc basin‐fill sequence on the Miura Peninsula, the Pacific side of central Japan
Authors: Nozaki Atsushi , Majima Ryuichi , Kameo Koji , Sakai Saburo , Kouda Atsuro , Kawagata Shungo , Wada Hideki , Kitazato Hiroshi
Published: May 2014

We present field and core observations, nannofossil biostratigraphy, and stable oxygen isotope fluctuations in foraminiferal tests to describe the geology and to construct an age model of the Lower Pleistocene Nojima, Ofuna, and Koshiba Formations (in ascending order) of the middle Kazusa Group, a forearc basin‐fill succession, exposed on the northern Miura Peninsula on the Pacific side of central Japan. In the study area, the Nojima Formation is composed of sandy mudstone and alternating sandy mudstone and mudstone, the Ofuna Formation of massive mudstone, and the Koshiba Formation of sandy mudstone, muddy sandstone, and sandstone. The Kazusa Group contains many tuff beds that are characteristic of forearc deposits. Thirty‐six of those tuff beds have characteristic lithologies and stratigraphic positions that allow them to be traced over considerable distances. Examination of calcareous nannofossils revealed three nannofossil datum planes in the sequences: datum 10 (first appearance of large Gephyrocapsa), datum 11 (first appearance of Gephyrocapsa oceanica), and datum 12 (first appearance of Gephyrocapsa caribbeanica). Stable oxygen isotope data from the tests of the planktonic foraminifer Globorotalia inflata extracted from cores were measured to identify the stratigraphic fluctuations of oxygen isotope ratios that are controlled by glacial–interglacial cycles. The observed fluctuations were assigned to marine isotope stages (MISs) 49–61 on the basis of correlations of the fluctuations with nannofossil datum planes. Using the age model obtained, we estimated the ages of 24 tuff beds. Among these, the SKT‐11 and SKT‐12 tuff beds have been correlated with the Kd25 and Kd24 tuff beds, respectively, of the Kiwada Formation on the Boso Peninsula. The Kd25 and Kd24 tuff beds are widely recognized in Pleistocene strata in Japan. We used our age model to date SKT‐11 at 1573 ka and SKT‐12 at 1543 ka.
Does output predict unemployment? A look at Okun's law in Greece
Authors: KARFAKIS Costas , KATRAKILIDIS Constantinos , TSANANA Eftychia
Published: May 2014

Using a dynamic specification of Okun's law, the authors examine the relationship between unemployment and output in Greece over the period 2000–12. While Granger causality tests indicate that real output is important to understanding future movements in unemployment, Okun's ratio is found to be 3:1, implying that a 1 per cent increase in unemployment was associated with a 3 per cent decrease in real output during the 13‐year period under study. Also, asymmetric analysis shows that the response of unemployment to real output is stronger during contractions of real economic activity than in expansionary periods.
Prolonged isolation and persistence of a common endemic on granite outcrops in both mesic and semi‐arid environments in south‐western Australia
Authors: Tapper Sarah‐Louise , Byrne Margaret , Yates Colin J. , Keppel Gunnar , Hopper Stephen D. , Van Niel Kimberly , Schut Antonius G. T. , Mucina Laco , Wardell‐Johnson Grant W.
Published: May 2014

Aim

Granite outcrops may be able to act as refugia for species during adverse climate change, owing to their topographic complexity. We assessed this hypothesis by examining phylogeographical patterns in a common, geographically widespread granite endemic, Stypandra glauca (Hemerocallidaceae).

Location

Granite outcrops of the Southwest Australian Floristic Region, Western Australia.

Methods

Twenty‐four tetraploid individuals of the granite endemic Stypandra glauca were sampled from each of 12 granite outcrops: 7 from a mesic environment and 5 from the semi‐arid region. Phylogenetic reconstruction and divergence‐dating was achieved using Bayesian and parsimony analyses of chloroplast haplotypes from 90 individuals. Nuclear diversity and population differentiation were analysed across all individuals using 10 microsatellite loci.

Results

Stypandra glauca exhibited high (chloroplast) or moderate (nuclear) levels of divergence among, and low diversity within, outcrops. Haplotype diversity was high in both sampling regions, and each haplotype was unique to one outcrop. There was little correlation between geographical and genetic distance. Both nuclear and chloroplast diversity were higher in southern (mesic) outcrops than in northern (semi‐arid) outcrops, although the level of chloroplast divergence among outcrops was similar for both climatic regions.

Main conclusions

The levels of divergence and low diversity revealed in S. glauca support a scenario of prolonged isolation and persistence on granite outcrops in both mesic and semi‐arid climatic regions, with no evidence of contraction–expansion dynamics across the outcrop network. The higher levels of diversity in the southern populations may result from the maintenance of a larger effective population size in southern regions, which retained more mesic climates during drier glacial periods. Although the climatic conditions differ between outcrops in this study, our results indicate that outcrops in both regions have harboured S. glauca throughout climatic changes, accentuating the value of these habitats to biodiversity conservation under future changing climate.
Contact Electroanatomic Mapping Derived Voltage Criteria for Characterizing Left Atrial Scar in Patients Undergoing Ablation for Atrial Fibrillation
Authors: KAPA SURAJ , DESJARDINS BENOIT , CALLANS DAVID J. , MARCHLINSKI FRANCIS E. , DIXIT SANJAY
Published: May 2014

Voltage Criteria for Left Atrial Scar

Background

Criteria have not been established for identifying LA scar using electroanatomic mapping (EAM). It is also unclear if voltage criteria using EAM may assist in identifying areas of pulmonary vein (PV) reconnection in patients undergoing repeat AF ablation.

Objectives

To characterize left atrial (LA) voltage in patients undergoing atrial fibrillation (AF) ablation.

Methods

An LA shell was created and bipolar voltage amplitude (in mV) at each point was measured. The shell was divided into 8 regions. Bipolar voltage values lower than the amplitude of 95% of sampled points was used as the upper cutoff value. Delayed enhancement (DE) cardiac magnetic resonance imaging (CMRI) sequences were performed to validate voltage cutoffs.

Results

Twenty patients participated. A mean of 141 ± 12 points constituted the LA map that was created during sinus rhythm (SR). In patients undergoing initial AF ablation, mean bipolar LA voltage was 1.44 ± 1.27 mV. In patients undergoing repeat AF ablation, scar along the posterior wall and LA–PV junction was identified using a voltage cutoff <0.2 mV, whereas a cutoff <0.45 mV best identified scar at other locations. This voltage range (0.2–0.45 mV) was useful to identify areas of reconnection around the PVs. On DE CMRI, a bipolar voltage cutoff of 0.27 mV performed best for delineating scar (sensitivity: 90%, specificity: 83%).

Conclusions

In patients undergoing AF ablation, EAM derived LA bipolar voltage shows regional variation. For maps acquired during SR, a voltage range of 0.2–0.45 mV can accurately demarcate LA scar distribution. This can be helpful in identifying PV reconnection in patients undergoing repeat AF ablation.
Infrequent Intraprocedural Premature Ventricular Complexes: Implications for Ablation Outcome
Authors: BASER KAZIM , BAS HATICE DUYGU , YOKOKAWA MIKI , LATCHAMSETTY RAKESH , MORADY FRED , BOGUN FRANK
Published: May 2014

Premature Ventricular Complexes

Background

Frequent premature ventricular complexes (PVCs) can be eliminated with an ablation procedure. Ablation success rates have been reported to be in the 80% range. Reasons for failure of ablation have not been described in detail. The purpose of this study was to determine whether the paucity of PVCs at the beginning of the ablation procedure affects the outcome.

Methods

Catheter ablation was attempted in a consecutive series of 194 patients (age: 50 ± 14 years, 91 male, ejection fraction: 56.4 ± 8.4%) with frequent idiopathic PVCs. Based on receiver operator characteristics (ROC) analysis, patients were divided into 2 groups: Patients with frequent PVCs (≥32 PVCs within the first 30 minutes of the procedure: n = 135 [70%]); and patients with infrequent PVCs (<32 PVCs within the first 30 minutes of the procedure: n = 59 [30%]). Procedural outcomes were compared at 3 months postablation. A successful ablation was defined as a ≥80% reduction in the PVC burden compared to baseline.

Results

A successful procedure was performed in 148 patients (76%) resulting in a decrease in the PVC burden from 19.1 ± 13.6% to 0.38 ± 0.98%(P < 0.0001). Patients with frequent intraprocedural PVCs had a higher success rate than patients with infrequent intraprocedural PVCs (85% vs. 56%, P = 0.0001). Administration of sedation was no different in the 2 groups. The paucity of PVCs was independent of the site of origin in predicting procedural failure (OR: 6.9, 95% CI: 3.0–16.2 P = 0.0001).

Conclusion

Paucity of PVCs at the beginning of an ablation procedure is associated with a lower ablation success rate independent of the site of origin.
Experimental evolution of external immune defences in the red flour beetle
Authors: Joop G. , Roth O. , Schmid‐Hempel P. , Kurtz J.
Published: May 2014

The red flour beetle, Tribolium castaneum, secretes quinones that control the microbial flora in the surrounding environment. These secretions act as an external immune defence that provides protection against pathogens. At high concentrations, however, these secretions are harmful to the host itself, and selection may thus have optimized the level of expression under natural conditions. Here, we show that the expression of external immunity responded to selection during experimental evolution within a few generations. At the same time, one component of internal immune defence (phenoloxidase activity) was compromised in beetles selected for either high or low external defences. Intriguingly, offspring protection against a natural pathogen was reduced in flour obtained from beetle lines selected for low amounts of secretions. Altogether, this suggests that external and internal immune defences work together efficiently under natural conditions, whereas every manipulation on the side of external immune defence comes with costs to the internal immune defence.
Estimating the surface area of nonconvex particles from central planar sections
Authors: THÓRISDÓTTIR Ó. , RAFATI A.H. , KIDERLEN M.
Published: May 2014

In this paper, we present a new surface area estimator in local stereology. This new estimator is called the ‘Morse‐type surface area estimator’ and is obtained using a two‐stage sampling procedure. First a plane section through a fixed reference point of a three‐dimensional structure is taken. In this section plane, a modification of the area tangent count method is used. The Morse‐type estimator generalizes Cruz‐Orive's pivotal estimator for convex objects to nonconvex objects. The advantages of the Morse‐type estimator over existing local surface area estimators are illustrated in a simulation study. The Morse‐type estimator is well suited for computer‐assisted confocal microscopy and we demonstrate its practicability in a biological application: the surface area estimation of the nuclei of giant‐cell glioblastoma from microscopy images. We also present an interactive software that allows the user to efficiently obtain the estimator.
Preclinical evaluation of the immunomodulatory lymphocyte trafficking drug FTY720 for HIV prevention in the female genital mucosa of macaques
Authors: Morris Monica , Aubert Rachael D. , Butler Katherine , Henning Tara , Mitchell James , Jenkins Leecresia , Garber David , McNicholl Janet , Kersh Ellen N.
Published: May 2014

FTY720 has been shown to reduce inflammatory cytokines and immune cells in the genital mucosa of macaques. This pilot study examined the ability of FTY720 to inhibit HIV acquisition. Systemic treatment with FTY720 failed to prevent or delay vaginal SHIV transmission.
Repeated cocaine enhances ventral hippocampal‐stimulated dopamine efflux in the nucleus accumbens and alters ventral hippocampal NMDA receptor subunit expression
Authors: Barr Jeffrey L. , Forster Gina L. , Unterwald Ellen M.
Published: May 2014

Dopaminergic neurotransmission in the nucleus accumbens is important for various reward‐related cognitive processes including reinforcement learning. Repeated cocaine enhances hippocampal synaptic plasticity, and phasic elevations of accumbal dopamine evoked by unconditioned stimuli are dependent on impulse flow from the ventral hippocampus. Therefore, sensitized hippocampal activity may be one mechanism by which drugs of abuse enhance limbic dopaminergic activity. In this study, in vivo microdialysis in freely moving adult male Sprague–Dawley rats was used to investigate the effect of repeated cocaine on ventral hippocampus‐mediated dopaminergic transmission within the medial shell of the nucleus accumbens. Following seven daily injections of saline or cocaine (20 mg/kg, ip), unilateral infusion of N‐methyl‐d‐aspartate (NMDA, 0.5 μg) into the ventral hippocampus transiently increased both motoric activity and ipsilateral dopamine efflux in the medial shell of the nucleus accumbens, and this effect was greater in rats that received repeated cocaine compared to controls that received repeated saline. In addition, repeated cocaine altered NMDA receptor subunit expression in the ventral hippocampus, reducing the NR2A : NR2B subunit ratio. Together, these results suggest that repeated exposure to cocaine produces maladaptive ventral hippocampal‐nucleus accumbens communication, in part through changes in glutamate receptor composition.

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A behaviorally sensitizing regimen of cocaine (20 mg/kg, ip 7 days) also sensitized ventral hippocampus (hipp)‐mediated dopaminergic transmission within the nucleus accumbens (Nac) to NMDA stimulation (bolts). This was associated with reduced ventral hippocampal NR2A:NR2B subunit ratio, suggesting that repeated exposure to cocaine produces changes in hippocampal NMDA receptor composition that lead to enhanced ventral hippocampus–nucleus accumbens communication.
Tempest in the Andes? Part 2: Peasant Organization and Development Agencies in Cotopaxi (Ecuador)
Authors: Bretón Solo De Zaldívar Víctor
Published: May 2014

This paper, published in two parts, is an analysis of the links between the ‘agrarian question’ in the Ecuadorian Andes and the creation of a network of indigenous‐peasant organizations that became the backbone of the national indigenous movement. I explore the relations between agrarian change and social change, drawing on a monographic study carried out in Cotopaxi Province, in the central sierra of Ecuador, from the 1960s to the beginning of the twenty‐first century. In the first part, I emphasized how the transformations unleashed by the crisis of the hacienda regime marked a rupture that consolidated the dense organizational scaffolding in the rural milieu. In this second part, I examine how development agencies, especially non‐governmental organizations (NGOs), played a fundamental role in strengthening those structures (1980s and 1990s). The history of the Union of Peasant Organizations of Northern Cotopaxi (UNOCANC) is one such example: born from the struggle for haciendas, inputs from the development apparatus enabled the rise of local elites who turned the organization into one of the most militant in the country. In this paper, I draw attention to aspects seldom mentioned in the specialized bibliography, namely a detailed study of how peasant differentiation, the origins of which lay in hacienda hierarchies, and which was upheld in turn by the agrarian distribution, was accelerated by the actions of NGOs, which continued to favour those indigenous peasants with more power and economic resources. Thus, divergences were consolidated and internal fissures opened up in organizations that are at the root of the crisis of representation experienced by ethnic platforms in the Ecuadorian Andes today.
Characterization and Sensitivity to Fungicides of Rhizoctonia spp. Recovered from Potato Plants in Bolu, Turkey
Authors: Özer Göksel , Bayraktar Harun
Published: May 2014

Isolates of Rhizoctonia spp. associated with stem canker and black scurf disease of potato were examined for their anastomosis group, sequence variations in the ITS‐5.8S rDNA region, pathogenicity and sensitivity to fungicides. A total of 92 isolates were obtained from diseased tuber, stolon and sprouts of the potato plants, collected from five districts of Bolu province, Turkey. Based on the anastomosis group and the similarity of the nucleotide sequence of the ITS‐5.8S rDNA, most of the isolates (81.5%) were identified as AG 3 PT. Other isolates belonged to AG 2‐1 (1.08%), AG 2‐2 IV (1.08%), AG 4 HG II (8.07%), AG 5 (2.17%), binucleate Rhizoctonia AG A (1.08%) and AG K (4.35%). Pathogenicity tests showed that isolates of AG 3 PT, AG 4 HG II and AG 5 caused similar degrees of disease severity on 45‐day‐old potato seedlings, whereas AG 2‐1 was moderately virulent. AG 2‐2 IV and binucleate Rhizoctonia spp. were weakly pathogenic or non‐pathogenic on potato seedlings. In this study, anastomosis groups of Rhizoctonia spp. isolates associated with potato in Turkey were characterized for the first time using molecular techniques and classified at the level of subgroups. Furthermore, the effect of selected fungicides was evaluated on disease development caused by soil‐borne inoculums of different anastomosis groups (AGs). Flutolanil and Bacillus subtilis QST 713 were found to be most effective against the Rhizoctonia isolates tested. These results revealed significant differences among the fungicides on disease development resulted from the different AGs.
The Role of Regulatory Proteins and S-nitrosylation of Endothelial Nitric Oxide Synthase in the Human Clitoris: Implications for Female Sexual Function
Authors: Oliver Janine L. , Kavoussi Parviz K. , Smith Ryan P. , Woodson Robin I. , Corbett Sean T. , Costabile Raymond A. , Palmer Lisa A. , Lysiak Jeffrey J.
Published: May 2014

Introduction

During female sexual arousal, clitoral blood flow is controlled by endothelial nitric oxide synthase (eNOS) and its product, nitric oxide (NO). The mechanisms regulating eNOS activity and NO bioavailability in the clitoris are largely unknown.

Aim

To identify proteins involved in regulation of eNOS activity within the clitoris and to evaluate the effects of S-nitrosoglutathione reductase (GSNO-R) and eNOS nitrosylation/denitrosylation on clitoral blood flow.

Methods

Immunohistochemistry for eNOS, caveolin-1 (Cav1), heat shock protein-90 (Hsp90), phosphodiesterase type 5 (PDE5), GSNO-R, and soluble guanylate cyclase (sGC) was performed on human and murine clitoral tissue. Western blot analysis was performed for eNOS, phosphorylated eNOS (phospho-eNOS, Ser1177), Cav1, Hsp90, sGC, PDE5, phosphoinositide 3-kinase (PI3K), Akt (protein kinase B), and GSNO-R on protein from human clitoral tissue. A biotin switch assay was used to analyze the S-nitrosylation of eNOS, nNOS, and GSNO-R. Clitoral blood flow was measured in wild-type and GSNO-R-/- mice at baseline and during cavernous nerve electrical stimulation (CNES).

Main Outcome Measures

Localization of eNOS regulatory proteins and clitoral blood flow.

Results

eNOS and GSNO-R co-localized to the vascular endothelium and sinusoids of human clitoral tissue. Immunohistochemistry also localized Cav1 and Hsp90 to the endothelium and PDE5 and sGC to the trabecular smooth muscle. Expression of S-nitrosylated (SNO)-eNOS and SNO-GSNO-R was detected by biotin switch assays. Wild-type control mice exhibited increased clitoral blood flow with CNES whereas GSNO-R-/- animals failed to show an increase in blood flow.

Conclusions

Several key eNOS regulatory proteins are present in the clitoral tissue in a cellular specific pattern. S-nitrosylation of eNOS may also represent a key regulatory mechanism governing eNOS activation/deactivation since mice deficient in GSNO-R failed to increase clitoral blood flow. Additional studies are necessary to define the role of S-nitrosylation in the genital vascular response and its subsequent impact on female sexual function.
Insulin Resistance Is an Independent Predictor of Severe Lower Urinary Tract Symptoms and of Erectile Dysfunction: Results from a Cross-Sectional Study
Authors: Russo Giorgio Ivan , Cimino Sebastiano , Fragalà Eugenia , Privitera Salvatore , La Vignera Sandro , Condorelli Rosita , Calogero Aldo E. , Castelli Tommaso , Favilla Vincenzo , Morgia Giuseppe
Published: May 2014

Introduction

Several studies have linked the association between lower urinary tract symptoms (LUTS), erectile dysfunction (ED), and the presence of insulin resistance (IR) due to an underlined metabolic syndrome (MetS).

Aim

This study aims to determine the relationship between IR, sexual function, and LUTS and to demonstrate the ability of IR in predicting ED and severe LUTS.

Methods

Between January 2008 to January 2013, 544 consecutive patients with benign prostatic hyperplasia-related LUTS were enrolled. LUTS and sexual function of the patients were evaluated by the International Index of Erectile Function (IIEF) and the International Prostate Symptom Score (IPSS). MetS was defined by the International Diabetes Federation. IR was defined as a homeostasis model assessment (HOMA) index of 3 or greater.

Main Outcome Measures

Uni- and multivariate logistic regression analysis was performed to assess significant predictors of severe LUTS (IPSS ≥20) and ED (IIEF-Erectile Function [IIEF-EF] <26), including MetS component, prostate volume, prostate-specific antigen, total testosterone, and HOMA index.

Results

IR patients resulted in higher values of IPSS (19.0 vs. 15.0; P < 0.01), IPSS-storage (6.0 vs. 5.0; P < 0.01), IPSS-voiding (12.0 vs. 9.0; P < 0.01), total prostate volume (54.8 vs. 36.5; P < 0.01), and lower values of IIEF-EF (17.0 vs. 20.0; P < 0.01), IIEF-Intercourse Satisfaction (3.0 vs. 10.0; P < 0.01), IIEF-Orgasmic Function (8.0 vs. 9.0; P < 0.01), IIEF-Overall Satisfaction (6.0 vs. 8.0; P < 0.01), and total testosterone (3.83 vs. 4.44; P < 0.01). IR was demonstrated to be a strong predictor of ED (IIEF-EF <26) (odds ratio [OR] = 6.20, P < 0.01) after adjusting for confounding factors. Finally, IR was also an independent predictor of severe LUTS (IPSS ≥20) (OR = 2.0, P < 0.01) after adjusting for confounding factors.

Conclusions

IR patients are at high risk of having severe LUTS and contemporary sexual dysfunctions. We strongly suggest to prevent LUTS and ED by reducing insulin resistance.