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Humans, Infant, Infant, Newborn, Mitochondria metabolism, Mitochondrial Proteins genetics, Mutation, RNA, Transfer genetics, RNA, Transfer, Phe metabolism, Epilepsy pathology, Mitochondrial Diseases metabolism, Phenylalanine-tRNA Ligase genetics, and Phenylalanine-tRNA Ligase chemistry

FARS2 encodes the mitochondrial phenylalanyl-tRNA synthetase (mtPheRS), which is essential for charging mitochondrial (mt-) tRNA Phe with phenylalanine for use in intramitochondrial translation. Many biallelic, pathogenic FARS2 variants have been described previously, which are mostly associated with two distinct clinical phenotypes; an early onset epileptic mitochondrial encephalomyopathy or a later onset spastic paraplegia. In this study, we report on a patient who presented at 3 weeks of age with tachypnoea and poor feeding, which progressed to severe metabolic decompensation with lactic acidosis and seizure activity followed by death at 9 weeks of age. Rapid trio whole exome sequencing identified compound heterozygous FARS2 variants including a pathogenic exon 2 deletion on one allele and a rare missense variant (c.593G > T, p.(Arg198Leu)) on the other allele, necessitating further work to aid variant classification. Assessment of patient fibroblasts demonstrated severely decreased steady-state levels of mtPheRS, but no obvious defect in any components of the oxidative phosphorylation system. To investigate the potential pathogenicity of the missense variant, we determined its high-resolution crystal structure, demonstrating a local structural destabilization in the catalytic domain. Moreover, the R198L mutation reduced the thermal stability and impaired the enzymatic activity of mtPheRS due to a lower binding affinity for tRNA Phe and a slower turnover rate. Together these data confirm the pathogenicity of this FARS2 variant in causing early-onset mitochondrial epilepsy.
Competing Interests: Declaration of Competing Interest The authors have no conflicts of interest to disclose.
(Copyright © 2023 Elsevier Inc. All rights reserved.)

An adventive population of the exotic parasitoid wasp, Trissolcus japonicus (Ashmead) (Hymenoptera: Scelionidae), discovered in Michigan in 2018, is a promising biological control agent of the invasive Halyomorpha halys (Stål) (Hemiptera: Pentatomidae). Following its discovery, field releases of Tr. japonicus were conducted over 2 yr in southern Michigan, to test how release size or release frequency impacts establishment. Sentinel eggs of H. halys and of the native Podisus maculiventris (Say) (Hemiptera: Pentatomidae) were used alongside yellow sticky cards to monitor parasitoids. In 2019 and 2020, 7,200 Tr. japonicus were released at 16 sites. Monitoring between 2019 and 2021 yielded only 49 individuals. The captures suggest reproductive activity and overwintering success in the field but do not allow for evaluation of best release methods. Parasitism by native parasitoids was below 7%, which is similar to other states and unlikely to provide sufficient control of H. halys. The placement of sentinel eggs or sticky traps either in the lower or middle canopy of trees did not influence parasitoid capture rates. Frozen and fresh H. halys sentinel eggs were attacked at the same rate, but more native parasitoids emerged from frozen eggs. We did not find signs of nontarget effects on P. maculiventris thus parasitism rates overall were very low. These results could indicate dispersal of Tr. japonicus from the release sites or slow population growth. The latter may be due to the relatively low densities of H. halys in Michigan or may stem from the small founding size of our laboratory colony.
(© The Author(s) 2023. Published by Oxford University Press on behalf of Entomological Society of America.)

Animals, Humans, COUP Transcription Factor II genetics, Muscle Hypotonia, Syndrome, Abnormalities, Multiple genetics, Abnormalities, Multiple diagnosis, Heart Defects, Congenital genetics, Hernias, Diaphragmatic, Congenital genetics, and Intellectual Disability genetics

Nuclear receptor subfamily 2 group F member 2 (NR2F2 or COUP-TF2) encodes a transcription factor which is expressed at high levels during mammalian development. Rare heterozygous Mendelian variants in NR2F2 were initially identified in individuals with congenital heart disease (CHD), then subsequently in cohorts of congenital diaphragmatic hernia (CDH) and 46,XX ovotesticular disorders/differences of sexual development (DSD); however, the phenotypic spectrum associated with pathogenic variants in NR2F2 remains poorly characterized. Currently, less than 40 individuals with heterozygous pathogenic variants in NR2F2 have been reported. Here, we review the clinical and molecular details of 17 previously unreported individuals with rare heterozygous NR2F2 variants, the majority of which were de novo. Clinical features were variable, including intrauterine growth restriction (IUGR), CHD, CDH, genital anomalies, DSD, developmental delays, hypotonia, feeding difficulties, failure to thrive, congenital and acquired microcephaly, dysmorphic facial features, renal failure, hearing loss, strabismus, asplenia, and vascular malformations, thus expanding the phenotypic spectrum associated with NR2F2 variants. The variants seen were predicted loss of function, including a nonsense variant inherited from a mildly affected mosaic mother, missense and a large deletion including the NR2F2 gene. Our study presents evidence for rare, heterozygous NR2F2 variants causing a highly variable syndrome of congenital anomalies, commonly associated with heart defects, developmental delays/intellectual disability, dysmorphic features, feeding difficulties, hypotonia, and genital anomalies. Based on the new and previous cases, we provide clinical recommendations for evaluating individuals diagnosed with an NR2F2-associated disorder.
(© 2023. The Author(s), under exclusive licence to European Society of Human Genetics.)

BROWN marmorated stink bug, STINKBUGS, FIELD crops, PHEROMONE traps, CROPS, HEMIPTERA, and COTTON

Stink bugs (Hemiptera: Pentatomidae), including the exotic Halyomorpha halys (Stål), Nezara viridula (L.), and other indigenous species, are pests that damage a variety of agricultural crops. At a study site in the southeastern United States, we measured the density of stink bug species and patterns of parasitism and predation on corn, cotton, and soybean and host trees in an adjacent woodline. We assessed parasitism and predation of naturally laid egg masses in crops and sentinel egg masses in host trees and used pheromone-baited traps to determine H. halys seasonal development. Overall, H. halys and N. viridula were the dominant bugs observed. Adult H. halys were first detected each year on trees, followed by corn, and then cotton and soybean, suggesting that trees served as a source of H. halys dispersing into crops. For H. halys , more nymphs were captured in soybean than in corn or cotton. For N. viridula , more adults were captured in corn and cotton than in soybean, and more nymphs were captured in corn during 2019 and 2021 than in 2020. Percentage parasitism of N. viridula egg masses (74.2%) was higher than than that for H. halys egg masses (54.3%). Accordingly, conservation biological control has the potential to enhance parasitism of indigenous stink bugs and H. halys in field crop agroecosystems. [ABSTRACT FROM AUTHOR]

Adult, Humans, Prospective Studies, Cross-Sectional Studies, Models, Statistical, Prognosis, Fibrin Fibrinogen Degradation Products analysis, Venous Thromboembolism diagnosis, Venous Thromboembolism epidemiology, Pulmonary Embolism diagnosis, and Pulmonary Embolism epidemiology

Aims: Risk stratification is used for decisions regarding need for imaging in patients with clinically suspected acute pulmonary embolism (PE). The aim was to develop a clinical prediction model that provides an individualized, accurate probability estimate for the presence of acute PE in patients with suspected disease based on readily available clinical items and D-dimer concentrations.
Methods and Results: An individual patient data meta-analysis was performed based on sixteen cross-sectional or prospective studies with data from 28 305 adult patients with clinically suspected PE from various clinical settings, including primary care, emergency care, hospitalized and nursing home patients. A multilevel logistic regression model was built and validated including ten a priori defined objective candidate predictors to predict objectively confirmed PE at baseline or venous thromboembolism (VTE) during follow-up of 30 to 90 days. Multiple imputation was used for missing data. Backward elimination was performed with a P-value <0.10. Discrimination (c-statistic with 95% confidence intervals [CI] and prediction intervals [PI]) and calibration (outcome:expected [O:E] ratio and calibration plot) were evaluated based on internal-external cross-validation. The accuracy of the model was subsequently compared with algorithms based on the Wells score and D-dimer testing. The final model included age (in years), sex, previous VTE, recent surgery or immobilization, haemoptysis, cancer, clinical signs of deep vein thrombosis, inpatient status, D-dimer (in µg/L), and an interaction term between age and D-dimer. The pooled c-statistic was 0.87 (95% CI, 0.85-0.89; 95% PI, 0.77-0.93) and overall calibration was very good (pooled O:E ratio, 0.99; 95% CI, 0.87-1.14; 95% PI, 0.55-1.79). The model slightly overestimated VTE probability in the lower range of estimated probabilities. Discrimination of the current model in the validation data sets was better than that of the Wells score combined with a D-dimer threshold based on age (c-statistic 0.73; 95% CI, 0.70-0.75) or structured clinical pretest probability (c-statistic 0.79; 95% CI, 0.76-0.81).
Conclusion: The present model provides an absolute, individualized probability of PE presence in a broad population of patients with suspected PE, with very good discrimination and calibration. Its clinical utility needs to be evaluated in a prospective management or impact study.
Registration: PROSPERO ID 89366.
(© The Author(s) 2023. Published by Oxford University Press on behalf of the European Society of Cardiology. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

PULMONARY embolism, CLINICAL prediction rules, NURSING home patients, PREDICTION models, VENOUS thrombosis, THROMBOEMBOLISM, and SYMPTOMS

Aims Risk stratification is used for decisions regarding need for imaging in patients with clinically suspected acute pulmonary embolism (PE). The aim was to develop a clinical prediction model that provides an individualized, accurate probability estimate for the presence of acute PE in patients with suspected disease based on readily available clinical items and D-dimer concentrations. Methods and results An individual patient data meta-analysis was performed based on sixteen cross-sectional or prospective studies with data from 28 305 adult patients with clinically suspected PE from various clinical settings, including primary care, emergency care, hospitalized and nursing home patients. A multilevel logistic regression model was built and validated including ten a priori defined objective candidate predictors to predict objectively confirmed PE at baseline or venous thromboembolism (VTE) during follow-up of 30 to 90 days. Multiple imputation was used for missing data. Backward elimination was performed with a P -value <0.10. Discrimination (c-statistic with 95% confidence intervals [CI] and prediction intervals [PI]) and calibration (outcome:expected [O:E] ratio and calibration plot) were evaluated based on internal-external cross-validation. The accuracy of the model was subsequently compared with algorithms based on the Wells score and D-dimer testing. The final model included age (in years), sex, previous VTE, recent surgery or immobilization, haemoptysis, cancer, clinical signs of deep vein thrombosis, inpatient status, D-dimer (in µg/L), and an interaction term between age and D-dimer. The pooled c-statistic was 0.87 (95% CI, 0.85–0.89; 95% PI, 0.77–0.93) and overall calibration was very good (pooled O:E ratio, 0.99; 95% CI, 0.87–1.14; 95% PI, 0.55–1.79). The model slightly overestimated VTE probability in the lower range of estimated probabilities. Discrimination of the current model in the validation data sets was better than that of the Wells score combined with a D-dimer threshold based on age (c-statistic 0.73; 95% CI, 0.70–0.75) or structured clinical pretest probability (c-statistic 0.79; 95% CI, 0.76–0.81). Conclusion The present model provides an absolute, individualized probability of PE presence in a broad population of patients with suspected PE, with very good discrimination and calibration. Its clinical utility needs to be evaluated in a prospective management or impact study. Registration PROSPERO ID 89366. [ABSTRACT FROM AUTHOR]

Humans, Mice, Animals, Obesity metabolism, Myeloid Cells metabolism, Stress, Physiological, and Non-alcoholic Fatty Liver Disease metabolism

Although multiple populations of macrophages have been described in the human liver, their function and turnover in patients with obesity at high risk of developing non-alcoholic fatty liver disease (NAFLD) and cirrhosis are currently unknown. Herein, we identify a specific human population of resident liver myeloid cells that protects against the metabolic impairment associated with obesity. By studying the turnover of liver myeloid cells in individuals undergoing liver transplantation, we find that liver myeloid cell turnover differs between humans and mice. Using single-cell techniques and flow cytometry, we determine that the proportion of the protective resident liver myeloid cells, denoted liver myeloid cells 2 (LM2), decreases during obesity. Functional validation approaches using human 2D and 3D cultures reveal that the presence of LM2 ameliorates the oxidative stress associated with obese conditions. Our study indicates that resident myeloid cells could be a therapeutic target to decrease the oxidative stress associated with NAFLD.
(© 2023. The Author(s).)

Humans, Ferritins genetics, Ferritins metabolism, Iron metabolism, Iron Overload diagnosis, and Iron Overload genetics

Hyperferritinaemia is a common laboratory finding that is often associated with metabolic dysfunction and fatty liver. Metabolic hyperferritinaemia reflects alterations in iron metabolism that facilitate iron accumulation in the body and is associated with an increased risk of cardiometabolic and liver diseases. Genetic variants that modulate iron homeostasis and tissue levels of iron are the main determinants of serum levels of ferritin in individuals with metabolic dysfunction, raising the hypothesis that iron accumulation might be implicated in the pathogenesis of insulin resistance and the related organ damage. However, validated criteria for the non-invasive diagnosis of metabolic hyperferritinaemia and the staging of iron overload are still lacking, and there is no clear evidence of a benefit for iron depletion therapy. Here, we provide an overview of the literature on the relationship between hyperferritinaemia and iron accumulation in individuals with metabolic dysfunction, and on the associated clinical outcomes. We propose an updated definition and a provisional staging system for metabolic hyperferritinaemia, which has been agreed on by a multidisciplinary global panel of expert researchers. The goal is to foster studies into the epidemiology, genetics, pathophysiology, clinical relevance and treatment of metabolic hyperferritinaemia, for which we provide suggestions on the main unmet needs, optimal design and clinically relevant outcomes.
(© 2023. Springer Nature Limited.)

Animals, Insecta, Predatory Behavior, Larva, Nymph, Chenopodium quinoa, Heteroptera, and Aphids

In recent years, Liorhyssus hyalinus (Fabricius) (Hemiptera: Rhopalidae) and Nysius simulans Stål (Hemiptera: Lygaeidae) have emerged as important pests of quinoa in Peru, when the crop started to be cultivated at relatively low elevations. The potential of the native lacewing Chrysoperla externa (Hagen) (Neuroptera: Chrysopidae) was evaluated as a biological control agent of these two pest species. Prey consumption on all immature stages of L. hyalinus and N. simulans was assessed, as well as development on first instars of these heteropterans and eggs of Sitotroga cerealella (Olivier) (Lepidoptera: Pyralidae) as a factitious prey. In addition, prey preference was examined in the absence and presence of a preferred prey, Macrosiphum euphorbiae (Thomas) (Hemiptera: Aphididae). Larvae of the predator were not able to feed on L. hyalinus eggs, but they effectively did on N. simulans eggs as well as on all nymphal instars of both species. Nymphs of L. hyalinus were less suitable prey for larval development of C. externa than eggs of S. cerealella, whereas N. simulans was overall an unsuitable prey. There was a clear prey preference of C. externa for aphids over the two heteropteran species, as well as a preference for N. simulans over L. hyalinus. The predation rates in this study indicate the potential of C. externa as a predator of these heteropteran pests that can play a role in both conservation and augmentation biological control programs.
(© 2022. Sociedade Entomológica do Brasil.)

BROWN marmorated stink bug, PREDATION, HEMIPTERA, STINKBUGS, PARASITISM, and LAURACEAE

The invasive brown marmorated stink bug, Halyomorpha halys (Stål) (Hemiptera: Pentatomidae), is a polyphagous pest that disperses from non-crop host plants into crops in search of food. Sassafras trees (Sassafras albidum (Nutt.) Nees; Lauraceae) are found commonly in woodland habitats in the southeastern US and may therefore be a potential host. The main objective of this 2-yr study was to determine if sassafras serves as a host plant for this pest in woodland habitats adjacent to crops in Prattville, Alabama, and Byron, Georgia, USA. Each yr pheromone-baited traps were deployed in the canopy of sassafras trees to capture H. halys. We also evaluated parasitism and predation of H. halys sentinel egg masses by native parasitoids and predators in sassafras. Halyomorpha halys adult males and females as well as second through fifth instars were captured in traps and observed in sassafras trees over the season at both locations each yr of the study. Trissolcus euschisti Ashmead (Hymenoptera: Scelionidae) (67.7%) and Anastatus reduvii (Howard) (Hymenoptera: Eupelmidae) (18.3%) were the primary parasitoid species that emerged from H. halys sentinel egg masses. Stylet sucking (62.3%) and chewing (32.0%) were the primary types of predation on H. halys eggs. We conclude that sassafras is a reproductive host plant for H. halys, and native natural enemies prey on and parasitize H. halys egg masses in this host plant. La chinche hedionda invasora marrón marmolada, Halyomorpha halys (Stål) (Hemiptera: Pentatomidae), es una plaga polífaga que se dispersa de plantas hospedantes no cultivadas a los cultivos en busca de alimento. Se les encuentran en los árboles de sasafrás (Sassafras albidum [Nutt.] Nees; Lauraceae) comúnmente en hábitats boscosos del sureste de los EE. UU. y por lo tanto este puede ser un hospedero potencial. El objetivo principal de este estudio de 2 años fue determinar si el sasafrás sirve como planta hospedera para esta plaga en hábitats boscosos adyacentes a cultivos en Prattville, Alabama, y Byron, Georgia, EE. UU. Cada año, se colocaron trampas cebadas con feromonas en el dosel de los árboles de sasafrás para capturar H. halys. También evaluamos el parasitismo y la depredación de masas de huevos centinela de H. halys por parasitoides nativos y depredadores en sasafrás. Se capturaron machos y hembras adultos así como ninfas del segundo al quinto estadio de Halyomorpha halys en las trampas, y se observaron en árboles de sasafrás durante la temporada en ambos lugares cada año del estudio. Trissolcus euschisti Ashmead (Hymenoptera: Scelionidae) (67,7%) y Anastatus reduvii (Howard) (Hymenoptera: Eupelmidae) (18,3%) fueron las principales especies de parasitoides que emergieron de las masas de huevos centinela de H. halys. La succión por los estiletes (62,3%) y la masticación (32,0%) fueron las principales clases de depredación sobre los huevos de H. halys. Concluimos que el sasafrás es una planta hospedera reproductiva para H. halys, y los enemigos naturales nativos se alimentan y parasitan las masas de huevos de H. halys en esta planta hospedera. [ABSTRACT FROM AUTHOR]

BROWN marmorated stink bug, STINKBUGS, PARASITISM, PREDATION, and HEMIPTERA

Stink bugs, including Halyomorpha halys (Stål) and Nezara viridula (L.), are agricultural pests that feed on fruit in a variety of crops. Monitoring predation and parasitism of stink bug egg masses furthers our understanding of potential biological control tactics. However, best practices for laboratory and field assessments of parasitism and predation of egg masses require further attention. We carried out a series of laboratory and field experiments to test whether parasitism and predation for three types of sentinel H. halys egg masses, fresh, frozen, and refrigerated, varied in agricultural commodities. In addition, we asked if predation and parasitism differed between sentinel and naturally occurring H. halys and N. viridula egg masses in soybean. In the laboratory, more H. halys eggs were parasitized by Trissolcus euschisti (Ashmead) (Hymenoptera: Scelionidae) if they were frozen or refrigerated compared to fresh eggs. Similarly, in the field, parasitism was higher for frozen egg masses than fresh. In 2018 and 2019, H. halys natural egg masses had higher parasitism and lower predation compared to sentinel egg masses in soybean. In a paired field test during 2020 and 2021, there was no difference in parasitism between H. halys natural and sentinel eggs, but much higher incidence of parasitism was detected in natural N. viridula egg masses than sentinel eggs. Collecting natural egg masses is the best methodology for field assessment of parasitism of stink bug egg masses; however, if natural egg masses are not easily available, deploying refrigerated sentinel egg masses is a good alternative. [ABSTRACT FROM AUTHOR]

Child, Humans, Fusidic Acid therapeutic use, Fusidic Acid pharmacology, Methicillin, Anti-Bacterial Agents pharmacology, Anti-Bacterial Agents therapeutic use, Netherlands epidemiology, Staphylococcus aureus, Disease Outbreaks, Microbial Sensitivity Tests, Methicillin-Resistant Staphylococcus aureus, Impetigo drug therapy, Impetigo epidemiology, Staphylococcal Infections drug therapy, and Staphylococcal Infections epidemiology

In this retrospective observational study, we analysed a community outbreak of impetigo with meticillin-resistant Staphylococcus aureus (MRSA), with additional resistance to fusidic acid (first-line treatment). The outbreak occurred between June 2018 and January 2020 in the eastern part of the Netherlands with an epidemiological link to three cases from the north-western part. Forty nine impetigo cases and eight carrier cases were identified, including 47 children. All but one impetigo case had community-onset of symptoms. Pharmacy prescription data for topical mupirocin and fusidic acid and GP questionnaires suggested an underestimated outbreak size. The 57 outbreak isolates were identified by the Dutch MRSA surveillance as MLVA-type MT4627 and sequence type 121, previously reported only once in 2014. Next-generation sequencing revealed they contained a fusidic acid resistance gene, exfoliative toxin genes and an epidermal cell differentiation inhibitor gene. Whole-genome multilocus sequence typing revealed genetic clustering of all 19 sequenced isolates from the outbreak region and isolates from the three north-western cases. The allelic distances between these Dutch isolates and international isolates were high. This outbreak shows the appearance of community-onset MRSA strains with additional drug resistance and virulence factors in a country with a low prevalence of antimicrobial resistance.

Background: Thrombosis is a frequent and severe complication in patients with coronavirus disease 2019 (COVID-19) admitted to the intensive care unit (ICU). Lupus anticoagulant (LA) is a strong acquired risk factor for thrombosis in various diseases and is frequently observed in patients with COVID-19. Whether LA is associated with thrombosis in patients with severe COVID-19 is currently unclear.
Objective: To investigate if LA is associated with thrombosis in critically ill patients with COVID-19.
Patients/methods: The presence of LA and other antiphospholipid antibodies was assessed in patients with COVID-19 admitted to the ICU. LA was determined with dilute Russell's viper venom time (dRVVT) and LA-sensitive activated partial thromboplastin time (aPTT) reagents.
Results: Of 169 patients with COVID-19, 116 (69%) tested positive for at least one antiphospholipid antibody upon admission to the ICU. Forty (24%) patients tested positive for LA; of whom 29 (17%) tested positive with a dRVVT, 19 (11%) tested positive with an LA-sensitive aPTT, and 8 (5%) tested positive on both tests. Fifty-eight (34%) patients developed thrombosis after ICU admission. The odds ratio (OR) for thrombosis in patients with LA based on a dRVVT was 2.5 (95% confidence interval [CI], 1.1-5.7), which increased to 4.5 (95% CI, 1.4-14.3) in patients at or below the median age in this study (64 years). LA positivity based on a dRVVT or LA-sensitive aPTT was only associated with thrombosis in patients aged less than 65 years (OR, 3.8; 95% CI, 1.3-11.4) and disappeared after adjustment for C-reactive protein.
Conclusion: Lupus anticoagulant on admission is strongly associated with thrombosis in critically ill patients with COVID-19, especially in patients aged less than 65 years.
(© 2022 The Authors. Research and Practice in Thrombosis and Haemostasis published by Wiley Periodicals LLC on behalf of International Society on Thrombosis and Haemostasis (ISTH).)

Animals, Biology, Diet, Female, Nymph growth development, Ovum, Heteroptera growth development, Temperature, and Zea mays

When quinoa, Chenopodium quinoa Willd., is cultivated in South America outside of its Andean origin, the heteropterans Liorhyssus hyalinus (Fabricius) and Nysius simulans Stål may emerge as important pests. Here we studied the development and reproduction of both species at different constant temperatures in the laboratory. Egg and nymphal development were investigated at 18, 22, 26, 30, 34, and 36°C. For both species, egg incubation time significantly decreased as the temperature increased. Nymphs did not successfully develop at 18°C and the total nymphal time significantly decreased as the temperature increased from 22 to 36°C. Based on a linear day-degree (DD) model, the lower developmental threshold (LDT) temperatures for eggs and nymphs were estimated to be 16.0 and 17.9°C for L. hyalinus, and 16.1 and 19.7°C for N. simulans, respectively. Thermal requirements for egg and nymphal development were 68.6 and 114.8 DD for L. hyalinus, and 77.7 and 190.3 DD for N. simulans, respectively. Reproduction and adult longevity were studied at 22, 26, 30, and 34°C. For both species preoviposition time decreased as temperature increased, and the oviposition period was longest at 26°C. The highest fecundity and egg viability were observed at 30°C, whereas longevities were higher at 22-26°C than at 30-34°C. As the lowest tested temperatures were not suitable to both heteropterans and 30°C was found to be the optimal temperature for development and reproduction, peak densities are expected in warm areas and seasons.
(© The Author(s) 2022. Published by Oxford University Press on behalf of Entomological Society of America.)

STINKBUGS, BROWN marmorated stink bug, CARBON dioxide, FUMIGATION, ATMOSPHERIC carbon dioxide, HEMIPTERA, and DILUTION

BACKGROUND: The brown marmorated stink bug (BMSB), Halyomorpha halys, has caused significant agricultural damage to numerous hosts, so agricultural producers seek to limit its spread. Where established, BMSB can also cause substantial urban and commercial disturbance, as overwintering adults may seek refuge inside dwellings, covered spaces, vehicles, and consignments. Phytosanitary authorities are most concerned with the importation of 'hitchhiking' adults in this refugia, with certain countries requiring a quarantine treatment to mitigate risk. This study explores fumigation with ethyl formate, applied as 16.7% by mass dilution in carbon dioxide, for control of adult BMSB. RESULTS: The induction of diapause, to simulate overwintering physiology, resulted in 2‐ and 3‐fold increases in the tolerance of adults toward this ethyl formate fumigation at 10 ± 0.5 °C (x¯±2s) lasting for 8 and 12 h, respectively. However, a decreased tolerance (0.7‐fold) of diapausing specimens was observed for a 4‐h duration. Diapausing and nondiapausing adult BMSB can be controlled at the probit 9 level if the headspace concentration of ethyl formate, [EF], in the carbon dioxide mixture is maintained ≥7.68 mg L−1 for 12 h at 10 ± 0.5 °C (x¯±2s). If the duration is shortened to 4 h, [EF] must be maintained ≥14.73 mg L−1 over the course of fumigation. CONCLUSION: The toxicity of ethyl formate in this mixture can be distinct for different physiological states of the same life stage, as evidenced by a ca. 3‐fold increase in the Haber's z parameter for adult BMSB when in diapause. Respective to the physiological state of adults, this study identifies how the applied dose and/or treatment duration can be modulated (i.e. tuned) to ensure adequate toxicological efficacy toward BMSB infesting hosts or refuge at temperatures ca. >10 °C. Published 2022. This article is a U.S. Government work and is in the public domain in the USA. [ABSTRACT FROM AUTHOR]

MEDICAL personnel, BLOOD testing, COVID-19 testing, SICK leave, and HOSPITALS

Background: COVID-19 is an ongoing pandemic leading to exhaustion of the hospital care system. Our health care system has to deal with a high level of sick leave of health care workers (HCWs) with COVID-19 related complaints, in whom an infection with SARS-CoV-2 has to be ruled out before they can return back to work. The aim of the present study is to investigate if the recently described CoLab-algorithm can be used to exclude COVID-19 in a screening setting of HCWs. Methods: In the period from January 2021 till March 2021, HCWs with COVID-19-related complaints were prospectively collected and included in this study. Next to the routinely performed SARS-CoV-2 RT-PCR, using a set of naso- and oropharyngeal swab samples, two blood tubes (one EDTA- and one heparin-tube) were drawn for analysing the 10 laboratory parameters required for running the CoLab-algorithm. Results: In total, 726 HCWs with a complete CoLab-laboratory panel were included in this study. In this group, 684 HCWs were tested SARS-CoV-2 RT-PCR negative and 42 cases RT-PCR positive. ROC curve analysis showed an area under the curve (AUC) of 0.853 (95% CI: 0.801–0.904). At a safe cut-off value for excluding COVID-19 of -6.525, the sensitivity was 100% with a specificity of 34% (95% CI: 21 to 49%). No SARS-CoV-2 RT-PCR cases were missed with this cut-off and COVID-19 could be safely ruled out in more than one third of HCWs. Conclusion: The CoLab-score is an easy and reliable algorithm that can be used for screening HCWs with COVID-19 related complaints. A major advantage of this approach is that the results of the score are available within 1 hour after collecting the samples. This results in a faster return to labour process of a large part of the COVID-19 negative HCWs (34%), next to a reduction in RT-PCR tests (reagents and labour costs) that can be saved. [ABSTRACT FROM AUTHOR]

Cross-Sectional Studies, Disease Progression, Humans, Phenotype, Leukoencephalopathies diagnostic imaging, and Leukoencephalopathies genetics

Purpose: Recent reports of individuals with cytoplasmic transfer RNA (tRNA) synthetase-related disorders have identified cases with phenotypic variability from the index presentations. We sought to assess phenotypic variability in individuals with AARS1-related disease.
Methods: A cross-sectional survey was performed on individuals with biallelic variants in AARS1. Clinical data, neuroimaging, and genetic testing results were reviewed. Alanyl tRNA synthetase (AlaRS) activity was measured in available fibroblasts.
Results: We identified 11 affected individuals. Two phenotypic presentations emerged, one with early infantile-onset disease resembling the index cases of AARS1-related epileptic encephalopathy with deficient myelination (n = 7). The second (n = 4) was a later-onset disorder, where disease onset occurred after the first year of life and was characterized on neuroimaging by a progressive posterior predominant leukoencephalopathy evolving to include the frontal white matter. AlaRS activity was significantly reduced in five affected individuals with both early infantile-onset and late-onset phenotypes.
Conclusion: We suggest that variants in AARS1 result in a broader clinical spectrum than previously appreciated. The predominant form results in early infantile-onset disease with epileptic encephalopathy and deficient myelination. However, a subgroup of affected individuals manifests with late-onset disease and similarly rapid progressive clinical decline. Longitudinal imaging and clinical follow-up will be valuable in understanding factors affecting disease progression and outcome.
(© 2021. The Author(s), under exclusive licence to the American College of Medical Genetics and Genomics.)

Anti-Bacterial Agents pharmacology, Geography, Medical, History, 21st Century, Humans, Microbial Sensitivity Tests, Multilocus Sequence Typing, Netherlands epidemiology, Phylogeny, Pilot Projects, Pseudomonas Infections history, Pseudomonas aeruginosa classification, Pseudomonas aeruginosa drug effects, Pseudomonas aeruginosa isolation purification, Public Health Surveillance, beta-Lactam Resistance, beta-Lactamases biosynthesis, Disease Outbreaks, Pseudomonas Infections epidemiology, Pseudomonas Infections microbiology, Pseudomonas aeruginosa genetics, and beta-Lactamases genetics

Verona Integron-encoded Metallo-beta-lactamase (VIM) is the most frequently-encountered carbapenemase in the healthcare-related pathogen Pseudomonas aeruginosa. In the Netherlands, a low-endemic country for antibiotic-resistant bacteria, no national surveillance data on the prevalence of carbapenemase-producing P. aeruginosa (CPPA) was available. Therefore, in 2016, a national surveillance pilot study was initiated to investigate the occurrence, molecular epidemiology, genetic characterization, and resistomes of CPPA among P. aeruginosa isolates submitted by medical microbiology laboratories (MMLs) throughout the country. From 1221 isolates included in the study, 124 (10%) produced carbapenemase (CIM-positive); of these, the majority (95, 77%) were positive for the bla VIM gene using PCR. Sequencing was performed on 112 CIM-positive and 56 CIM-negative isolates (n = 168), and genetic clustering revealed that 75/168 (45%) isolates were highly similar. This genetic cluster, designated Group 1, comprised isolates that belonged to high-risk sequence type ST111/serotype O12, had similar resistomes, and all but two carried the bla VIM-2 allele on an identical class 1 integron. Additionally, Group 1 isolates originated from around the country (i.e. seven provinces) and from multiple MMLs. In conclusion, the Netherlands had experienced a nationwide, inter-institutional, clonal outbreak of VIM-2-producing P. aeruginosa for at least three years, which this pilot study was crucial in identifying. A structured, national surveillance program is strongly advised to monitor the spread of Group 1 CPPA, to identify emerging clones/carbapenemase genes, and to detect transmission in and especially between hospitals in order to control current and future outbreaks.
(© 2021. The Author(s).)

STINKBUGS, BROWN marmorated stink bug, CYTOCHROME oxidase, GENETIC variation, and HEMIPTERA

The arrival, establishment and pest status of Halyomorpha halys in Europe and non-native countries in Asia have been well-documented, with thorough characterisation of the genetic diversity and occurrence of cytochrome oxidase I (COI) haplotypes in Switzerland, France, Hungary, Italy and Greece. However, a number of gaps exist in terms of the characterisation of the haplotype diversity and occurrence of H. halys along the invasion front that covers eastern Europe, western and central Asia. To contribute towards filling this gap, the COI haplotype diversity and distribution were investigated for H. halys collected in Serbia, Ukraine, Russia, Georgia and Kazakhstan. A total of 646 specimens were analysed and five haplotypes were found (H1, H3, H8, H33 and H80). Haplotype H1 was present in all five countries investigated and was the only haplotype detected amongst > 500 specimens collected from Ukraine, Russia and Georgia. H1 (82%) was the dominant haplotype found in Kazakhstan, alongside H3 (18%). In contrast to the low or no diversity observed in these four countries, Serbia had higher haplotype diversity and was represented by five haplotypes. Although H3 was dominant (47%) in Serbia, H1 was also prevalent (40%); the remaining haplotypes (H8, H33 and H80) were minor contributors (1-11%) to the haplotype composition. The results are discussed in context with other known populations in neighbouring countries and patterns of haplotype diversity indicate the movement of successful invasive populations in Europe to generate secondary invasions along the eastern front of the invasion in Eurasia. Possible scenarios regarding the spread of particular haplotypes in these regions are discussed, along with suggestions for future research to fill existing gaps. [ABSTRACT FROM AUTHOR]

We report the first detection of Trissolcus mitsukurii in France. More than 1860 sentinel egg masses of Halyomorpha halys (BMSB) were exposed in the field during the 2018-2020 period, and 12 specimens of T. mitsukurii emerged from one egg mass. Their taxonomic identification was confirmed both by morphological and molecular analysis. Trissolcus mitsukurii , similar to T. japonicus , is an egg parasitoid of BMSB in its area of origin in Asia, and both species are considered to be candidates for a classical biological control strategy against BMSB. Trissolcus mitsukurii was previously recorded in Italy where it is well established and widespread, and this may be the source of the French population. Possible permanent establishment and dispersion of T. mitsukurii in France should be monitored with emphasis on its potential effect on BMSB populations.

STINKBUGS, BROWN marmorated stink bug, PREDATION, HEMIPTERA, SPECIES, and LANDSCAPES

This study evaluated parasitism and predation on sentinel egg masses of three stink bug species, the spined soldier bug, Podisus maculiventris (Say), the brown stink bug, Euschistus servus (Say), and the invasive brown marmorated stink bug (BMSB), Halyomorpha halys (Stål), in ornamental landscapes composed of either native or exotic plants. This study also compared the species composition of parasitoids attacking two native stink bug species (P. maculiventris and E. servus) with those attacking the invasive BMSB on the same tree species in the same habitat. Overall, egg parasitism and predation were much higher on the two native stink bug species compared with BMSB, with an average parasitism rate of 20.6% for E. servus , 12.7% for P. maculiventris , and only 4.2% for H. halys and an average predation rate of 8.2% for E. servus, 17.7% for P. maculiventris, and 2.3% for H. halys. Egg predation was also significantly higher on P. maculiventris than on E. servus eggs. Eight parasitoid species attacked sentinel stink bug eggs in the ornamental landscaped plots. Trissolcus euschisti (Ashmead) (Hymenoptera: Scelionidae) was the predominant parasitoid for all three stink bug species. There were no significant differences in parasitism and predation rates on any of the stink bug species between native and exotic plots. Therefore, there is no evidence that ornamental landscapes composed of native plants increased parasitism or predation rates of sentinel egg masses of two native stink bug species or the invasive BMSB, compared with those composed entirely of exotic plants. [ABSTRACT FROM AUTHOR]

Adolescent, Adult, Aged, Amylases blood, Biopsy, Diabetes Mellitus, Type 2 complications, Diabetes Mellitus, Type 2 drug therapy, Dose-Response Relationship, Drug, Double-Blind Method, Female, Glucagon-Like Peptides adverse effects, Humans, Injections, Subcutaneous, Lipase blood, Liver pathology, Liver Cirrhosis drug therapy, Liver Cirrhosis etiology, Liver Cirrhosis pathology, Male, Middle Aged, Non-alcoholic Fatty Liver Disease blood, Non-alcoholic Fatty Liver Disease complications, Non-alcoholic Fatty Liver Disease pathology, Young Adult, Glucagon-Like Peptides administration dosage, and Non-alcoholic Fatty Liver Disease drug therapy

Background: Nonalcoholic steatohepatitis (NASH) is a common disease that is associated with increased morbidity and mortality, but treatment options are limited. The efficacy and safety of the glucagon-like peptide-1 receptor agonist semaglutide in patients with NASH is not known.
Methods: We conducted a 72-week, double-blind phase 2 trial involving patients with biopsy-confirmed NASH and liver fibrosis of stage F1, F2, or F3. Patients were randomly assigned, in a 3:3:3:1:1:1 ratio, to receive once-daily subcutaneous semaglutide at a dose of 0.1, 0.2, or 0.4 mg or corresponding placebo. The primary end point was resolution of NASH with no worsening of fibrosis. The confirmatory secondary end point was an improvement of at least one fibrosis stage with no worsening of NASH. The analyses of these end points were performed only in patients with stage F2 or F3 fibrosis; other analyses were performed in all the patients.
Results: In total, 320 patients (of whom 230 had stage F2 or F3 fibrosis) were randomly assigned to receive semaglutide at a dose of 0.1 mg (80 patients), 0.2 mg (78 patients), or 0.4 mg (82 patients) or to receive placebo (80 patients). The percentage of patients in whom NASH resolution was achieved with no worsening of fibrosis was 40% in the 0.1-mg group, 36% in the 0.2-mg group, 59% in the 0.4-mg group, and 17% in the placebo group (P<0.001 for semaglutide 0.4 mg vs. placebo). An improvement in fibrosis stage occurred in 43% of the patients in the 0.4-mg group and in 33% of the patients in the placebo group (P = 0.48). The mean percent weight loss was 13% in the 0.4-mg group and 1% in the placebo group. The incidence of nausea, constipation, and vomiting was higher in the 0.4-mg group than in the placebo group (nausea, 42% vs. 11%; constipation, 22% vs. 12%; and vomiting, 15% vs. 2%). Malignant neoplasms were reported in 3 patients who received semaglutide (1%) and in no patients who received placebo. Overall, neoplasms (benign, malignant, or unspecified) were reported in 15% of the patients in the semaglutide groups and in 8% in the placebo group; no pattern of occurrence in specific organs was observed.
Conclusions: This phase 2 trial involving patients with NASH showed that treatment with semaglutide resulted in a significantly higher percentage of patients with NASH resolution than placebo. However, the trial did not show a significant between-group difference in the percentage of patients with an improvement in fibrosis stage. (Funded by Novo Nordisk; ClinicalTrials.gov number, NCT02970942.).
(Copyright © 2020 Massachusetts Medical Society.)

Adolescent, Autism Spectrum Disorder genetics, Autism Spectrum Disorder pathology, Child, Child, Preschool, Chromosome Deletion, Chromosome Disorders physiopathology, DNA Methylation genetics, Epigenesis, Genetic genetics, Female, Haploinsufficiency genetics, Humans, Intellectual Disability genetics, Intellectual Disability physiopathology, Male, Neurodevelopmental Disorders genetics, Neurodevelopmental Disorders physiopathology, Phenotype, Young Adult, Chromosome Disorders genetics, Chromosomes, Human, Pair 1 genetics, Chromosomes, Human, X genetics, DNA-Binding Proteins genetics, and RNA-Binding Proteins genetics

Deletion 1p36 (del1p36) syndrome is the most common human disorder resulting from a terminal autosomal deletion. This condition is molecularly and clinically heterogeneous. Deletions involving two non-overlapping regions, known as the distal (telomeric) and proximal (centromeric) critical regions, are sufficient to cause the majority of the recurrent clinical features, although with different facial features and dysmorphisms. SPEN encodes a transcriptional repressor commonly deleted in proximal del1p36 syndrome and is located centromeric to the proximal 1p36 critical region. Here, we used clinical data from 34 individuals with truncating variants in SPEN to define a neurodevelopmental disorder presenting with features that overlap considerably with those of proximal del1p36 syndrome. The clinical profile of this disease includes developmental delay/intellectual disability, autism spectrum disorder, anxiety, aggressive behavior, attention deficit disorder, hypotonia, brain and spine anomalies, congenital heart defects, high/narrow palate, facial dysmorphisms, and obesity/increased BMI, especially in females. SPEN also emerges as a relevant gene for del1p36 syndrome by co-expression analyses. Finally, we show that haploinsufficiency of SPEN is associated with a distinctive DNA methylation episignature of the X chromosome in affected females, providing further evidence of a specific contribution of the protein to the epigenetic control of this chromosome, and a paradigm of an X chromosome-specific episignature that classifies syndromic traits. We conclude that SPEN is required for multiple developmental processes and SPEN haploinsufficiency is a major contributor to a disorder associated with deletions centromeric to the previously established 1p36 critical regions.
(Copyright © 2021 American Society of Human Genetics. Published by Elsevier Inc. All rights reserved.)

Adult, Antineoplastic Agents, Hormonal therapeutic use, Biomarkers, Tumor metabolism, Breast Neoplasms drug therapy, Female, Humans, Lymphatic Metastasis, Middle Aged, Neoplastic Stem Cells pathology, Prognosis, Randomized Controlled Trials as Topic, Retrospective Studies, Survival Rate, Adaptor Proteins, Vesicular Transport metabolism, Breast Neoplasms metabolism, Breast Neoplasms pathology, Neoplastic Stem Cells metabolism, Progranulins metabolism, and Tamoxifen therapeutic use

Background: The growth factor progranulin has been implicated in numerous biological processes such as wound healing, inflammation and progressive tumorigenesis. Both progranulin and its receptor sortilin are known to be highly expressed in subgroups of breast cancer and have been associated with various clinical properties including tamoxifen resistance. Recent data further suggest that progranulin, via its receptor sortilin, drives breast cancer stem cell propagation in vitro and increases metastasis formation in an in vivo breast cancer xenograft model. In this retrospective biomarker analysis, we aimed to determine whether tumor co-expression of progranulin and sortilin has prognostic and treatment predictive values for breast cancer patients.
Methods: We explored how co-expression of progranulin and sortilin was associated with established clinical markers by analyzing a tissue microarray including 560 randomized premenopausal breast cancer patients receiving either 2 years of tamoxifen treatment or no adjuvant treatment, with a median follow-up time of 28 years. Breast cancer-specific survival was analyzed using Kaplan-Meier and Cox Proportional Hazards regression models to assess the prognostic and predictive value of progranulin and sortilin in relation to known clinical markers.
Results: Co-expression of progranulin and sortilin was observed in 20% of the breast cancer samples. In untreated patients, prognostic considerations could be detailed separately from treatment prediction and the high progranulin and sortilin expressing subgroup was significantly associated with breast cancer-specific death in multivariable analyses (HR=2.188, CI: 1.317-3.637, p=0.003) along with tumor size, high tumor grade and lymph node positivity. When comparing the untreated patients with tamoxifen treated patients in the ERα positive subgroup, co-expression of progranulin and sortilin was not linked to tamoxifen resistance.
Conclusion: Data suggest that co-expression of progranulin and its receptor sortilin is a novel prognostic biomarker combination identifying a highly malignant subgroup of breast cancer. Importantly, this subpopulation could potentially be targeted with anti-sortilin based therapies.

BIOLOGICAL weed control, BIOLOGICAL pest control agents, CHRYSOMELIDAE, BEETLES, HYMENOPTERA, and EUCALYPTUS

The solitary larval endoparasitoid Eadya daenerys Ridenbaugh (Hymenoptera: Braconidae) is a proposed biocontrol agent of Paropsis charybdis Stål (Coleoptera: Chrysomelidae, Chrysomelinae), a pest of eucalypts in New Zealand. Eadya daenerys oviposition behaviour was examined in two assay types during host range testing, with the aim of improving ecological host range prediction. No‐choice sequential and two‐choice behavioural observations were undertaken against nine closely related species of New Zealand non‐target beetle larvae, including a native beetle, introduced weed biocontrol agents, and invasive paropsine beetles. No behavioural measure was significantly different between no‐choice and two‐choice tests. In sequential no‐choice assays the order of first presentation (target–non‐target) had no significant effect on the median number of attacks or the attack rate while on the plant. Beetle species was the most important factor. Parasitoids expressed significantly lower on‐plant attack rates against non‐targets compared to target P. charybdis larvae. The median number of attacks was always higher towards target larvae than towards non‐target larvae, except for the phylogenetically closest related non‐target Trachymela sloanei (Blackburn) (Coleoptera: Chrysomelidae, Chrysomelinae). Most non‐target larvae were disregarded upon contact, which suggests that the infrequent attack behaviour observed by two individual E. daenerys against Allocharis nr. tarsalis larvae in two‐choice tests and the frass of Chrysolina abchasica (Weise) was probably abnormal host selection behaviour. Results indicate that E. daenerys is unlikely to attack non‐target species apart from Eucalyptus‐feeding invasive paropsines (Chrysomelinae). Non‐lethal negative impacts upon less preferred non‐target larvae are possible if E. daenerys does attack them in the field; however, this is likely to be rare. [ABSTRACT FROM AUTHOR]

Adolescent, Animals, Child, Child, Preschool, Drosophila Proteins genetics, Drosophila melanogaster, Female, Genes, Dominant, Genetic Variation, Haploinsufficiency, Humans, Infant, Male, Microscopy, Confocal, Neuroglia metabolism, Neurons metabolism, Protein Binding, Zebrafish, Zebrafish Proteins genetics, Chromosomal Proteins, Non-Histone genetics, Developmental Disabilities genetics, Mutation, Missense, Phenotype, and Tumor Suppressor Proteins genetics

SWI/SNF-related intellectual disability disorders (SSRIDDs) are rare neurodevelopmental disorders characterized by developmental disability, coarse facial features, and fifth digit/nail hypoplasia that are caused by pathogenic variants in genes that encode for members of the SWI/SNF (or BAF) family of chromatin remodeling complexes. We have identified 12 individuals with rare variants (10 loss-of-function, 2 missense) in the BICRA (BRD4 interacting chromatin remodeling complex-associated protein) gene, also known as GLTSCR1, which encodes a subunit of the non-canonical BAF (ncBAF) complex. These individuals exhibited neurodevelopmental phenotypes that include developmental delay, intellectual disability, autism spectrum disorder, and behavioral abnormalities as well as dysmorphic features. Notably, the majority of individuals lack the fifth digit/nail hypoplasia phenotype, a hallmark of most SSRIDDs. To confirm the role of BICRA in the development of these phenotypes, we performed functional characterization of the zebrafish and Drosophila orthologs of BICRA. In zebrafish, a mutation of bicra that mimics one of the loss-of-function variants leads to craniofacial defects possibly akin to the dysmorphic facial features seen in individuals harboring putatively pathogenic BICRA variants. We further show that Bicra physically binds to other non-canonical ncBAF complex members, including the BRD9/7 ortholog, CG7154, and is the defining member of the ncBAF complex in flies. Like other SWI/SNF complex members, loss of Bicra function in flies acts as a dominant enhancer of position effect variegation but in a more context-specific manner. We conclude that haploinsufficiency of BICRA leads to a unique SSRIDD in humans whose phenotypes overlap with those previously reported.
(Copyright © 2020 American Society of Human Genetics. All rights reserved.)

High-Throughput Nucleotide Sequencing, Humans, Klebsiella pneumoniae isolation purification, Netherlands, DNA, Bacterial genetics, Klebsiella Infections microbiology, Klebsiella pneumoniae genetics, and beta-Lactamases genetics

Carbapenemase-producing Klebsiella pneumoniae emerged as a nosocomial pathogen causing morbidity and mortality in patients. For infection prevention it is important to track the spread of K. pneumoniae and its plasmids between patients. Therefore, the major aim was to recapitulate the contents and diversity of the plasmids of genetically related K. pneumoniae strains harboring the beta-lactamase gene bla KPC-2 or bla KPC-3 to determine their dissemination in the Netherlands and the former Dutch Caribbean islands from 2014 to 2019. Next-generation sequencing was combined with long-read third-generation sequencing to reconstruct 22 plasmids. wgMLST revealed five genetic clusters comprised of K. pneumoniae bla KPC-2 isolates and four clusters consisted of bla KPC-3 isolates. KpnCluster-019 bla KPC-2 isolates were found both in the Netherlands and the Caribbean islands, while bla KPC-3 cluster isolates only in the Netherlands. Each K. pneumoniae bla KPC-2 or bla KPC-3 cluster was characterized by a distinct resistome and plasmidome. However, the large and medium plasmids contained a variety of antibiotic resistance genes, conjugation machinery, cation transport systems, transposons, toxin/antitoxins, insertion sequences and prophage-related elements. The small plasmids carried genes implicated in virulence. Thus, implementing long-read plasmid sequencing analysis for K. pneumoniae surveillance provided important insights in the transmission of a KpnCluster-019 bla KPC-2 strain between the Netherlands and the Caribbean.

Anti-Bacterial Agents pharmacology, Bacterial Proteins metabolism, Carbapenem-Resistant Enterobacteriaceae drug effects, Enterobacter cloacae drug effects, Enterobacter cloacae genetics, Enterobacter cloacae isolation purification, Enterobacteriaceae Infections drug therapy, Enterobacteriaceae Infections microbiology, Escherichia coli drug effects, Escherichia coli genetics, Escherichia coli isolation purification, Humans, Interspersed Repetitive Sequences genetics, Klebsiella pneumoniae drug effects, Klebsiella pneumoniae genetics, Klebsiella pneumoniae isolation purification, Meropenem pharmacology, Microbial Sensitivity Tests, Molecular Epidemiology, Netherlands epidemiology, beta-Lactamases metabolism, Bacterial Proteins genetics, Carbapenem-Resistant Enterobacteriaceae genetics, Carbapenem-Resistant Enterobacteriaceae isolation purification, Enterobacteriaceae Infections epidemiology, and beta-Lactamases genetics

Objectives: Carbapenem resistance mediated by mobile genetic elements has emerged worldwide and has become a major public health threat. To gain insight into the molecular epidemiology of carbapenem resistance in The Netherlands, Dutch medical microbiology laboratories are requested to submit suspected carbapenemase-producing Enterobacterales (CPE) to the National Institute for Public Health and the Environment as part of a national surveillance system.
Methods: Meropenem MICs and species identification were confirmed by E-test and MALDI-TOF and carbapenemase production was assessed by the Carbapenem Inactivation Method. Of all submitted CPE, one species/carbapenemase gene combination per person per year was subjected to next-generation sequencing (NGS).
Results: In total, 1838 unique isolates were received between 2014 and 2018, of which 892 were unique CPE isolates with NGS data available. The predominant CPE species were Klebsiella pneumoniae (n = 388, 43%), Escherichia coli (n = 264, 30%) and Enterobacter cloacae complex (n = 116, 13%). Various carbapenemase alleles of the same carbapenemase gene resulted in different susceptibilities to meropenem and this effect varied between species. Analyses of NGS data showed variation of prevalence of carbapenemase alleles over time with bla OXA-48 being predominant (38%, 336/892), followed by bla NDM-1 (16%, 145/892). For the first time in the Netherlands, bla OXA-181 , bla OXA-232 and bla VIM-4 were detected. The genetic background of K. pneumoniae and E. coli isolates was highly diverse.
Conclusions: The CPE population in the Netherlands is diverse, suggesting multiple introductions. The predominant carbapenemase alleles are bla OXA-48 and bla NDM-1 . There was a clear association between species, carbapenemase allele and susceptibility to meropenem.
(Copyright © 2020 National Institute for Public Health and the Environment, Bilthoven, The Netherlands. Published by Elsevier Ltd.. All rights reserved.)

Adolescent, Adult, Aged, Child, Child, Preschool, Female, Follow-Up Studies, Humans, Infant, International Agencies, Male, Mental Disorders etiology, Middle Aged, Monocarboxylic Acid Transporters genetics, Muscular Diseases etiology, Mutation, Neurodevelopmental Disorders etiology, Prognosis, Retrospective Studies, Survival Rate, Symporters genetics, Young Adult, Biomarkers analysis, Mental Disorders pathology, Monocarboxylic Acid Transporters deficiency, Muscular Diseases pathology, Neurodevelopmental Disorders pathology, and Symporters deficiency

Background: Disordered thyroid hormone transport, due to mutations in the SLC16A2 gene encoding monocarboxylate transporter 8 (MCT8), is characterised by intellectual and motor disability resulting from cerebral hypothyroidism and chronic peripheral thyrotoxicosis. We sought to systematically assess the phenotypic characteristics and natural history of patients with MCT8 deficiency.
Methods: We did an international, multicentre, cohort study, analysing retrospective data from Jan 1, 2003, to Dec 31, 2019, from patients with MCT8 deficiency followed up in 47 hospitals in 22 countries globally. The key inclusion criterion was genetically confirmed MCT8 deficiency. There were no exclusion criteria. Our primary objective was to analyse the overall survival of patients with MCT8 deficiency and document causes of death. We also compared survival between patients who did or did not attain full head control by age 1·5 years and between patients who were or were not underweight by age 1-3 years (defined as a bodyweight-for-age Z score <-2 SDs or <5th percentile according to WHO definition). Other objectives were to assess neurocognitive function and outcomes, and clinical parameters including anthropometric characteristics, biochemical markers, and neuroimaging findings.
Findings: Between Oct 14, 2014, and Jan 17, 2020, we enrolled 151 patients with 73 different MCT8 (SLC16A2) mutations. Median age at diagnosis was 24·0 months (IQR 12·0-60·0, range 0·0-744·0). 32 (21%) of 151 patients died; the main causes of mortality in these patients were pulmonary infection (six [19%]) and sudden death (six [19%]). Median overall survival was 35·0 years (95% CI 8·3-61·7). Individuals who did not attain head control by age 1·5 years had an increased risk of death compared with patients who did attain head control (hazard ratio [HR] 3·46, 95% CI 1·76-8·34; log-rank test p=0·0041). Patients who were underweight during age 1-3 years had an increased risk for death compared with patients who were of normal bodyweight at this age (HR 4·71, 95% CI 1·26-17·58, p=0·021). The few motor and cognitive abilities of patients did not improve with age, as evidenced by the absence of significant correlations between biological age and scores on the Gross Motor Function Measure-88 and Bayley Scales of Infant Development III. Tri-iodothyronine concentrations were above the age-specific upper limit in 96 (95%) of 101 patients and free thyroxine concentrations were below the age-specific lower limit in 94 (89%) of 106 patients. 59 (71%) of 83 patients were underweight. 25 (53%) of 47 patients had elevated systolic blood pressure above the 90th percentile, 34 (76%) of 45 patients had premature atrial contractions, and 20 (31%) of 64 had resting tachycardia. The most consistent MRI finding was a global delay in myelination, which occurred in 13 (100%) of 13 patients.
Interpretation: Our description of characteristics of MCT8 deficiency in a large patient cohort reveals poor survival with a high prevalence of treatable underlying risk factors, and provides knowledge that might inform clinical management and future evaluation of therapies.
Funding: Netherlands Organisation for Health Research and Development, and the Sherman Foundation.
(Copyright © 2020 Elsevier Ltd. All rights reserved.)

Adolescent, Adult, Age of Onset, Female, Follow-Up Studies, Growth Hormone-Secreting Pituitary Adenoma genetics, Humans, Male, Pituitary Neoplasms genetics, Prognosis, Prospective Studies, Young Adult, Biomarkers analysis, Genetic Testing methods, Growth Hormone-Secreting Pituitary Adenoma diagnosis, Intracellular Signaling Peptides and Proteins genetics, Mass Screening methods, Mutation, and Pituitary Neoplasms diagnosis

Context: Germline mutations in the aryl hydrocarbon receptor-interacting protein (AIP) gene are responsible for a subset of familial isolated pituitary adenoma (FIPA) cases and sporadic pituitary neuroendocrine tumors (PitNETs).
Objective: To compare prospectively diagnosed AIP mutation-positive (AIPmut) PitNET patients with clinically presenting patients and to compare the clinical characteristics of AIPmut and AIPneg PitNET patients.
Design: 12-year prospective, observational study.
Participants & Setting: We studied probands and family members of FIPA kindreds and sporadic patients with disease onset ≤18 years or macroadenomas with onset ≤30 years (n = 1477). This was a collaborative study conducted at referral centers for pituitary diseases.
Interventions & Outcome: AIP testing and clinical screening for pituitary disease. Comparison of characteristics of prospectively diagnosed (n = 22) vs clinically presenting AIPmut PitNET patients (n = 145), and AIPmut (n = 167) vs AIPneg PitNET patients (n = 1310).
Results: Prospectively diagnosed AIPmut PitNET patients had smaller lesions with less suprasellar extension or cavernous sinus invasion and required fewer treatments with fewer operations and no radiotherapy compared with clinically presenting cases; there were fewer cases with active disease and hypopituitarism at last follow-up. When comparing AIPmut and AIPneg cases, AIPmut patients were more often males, younger, more often had GH excess, pituitary apoplexy, suprasellar extension, and more patients required multimodal therapy, including radiotherapy. AIPmut patients (n = 136) with GH excess were taller than AIPneg counterparts (n = 650).
Conclusions: Prospectively diagnosed AIPmut patients show better outcomes than clinically presenting cases, demonstrating the benefits of genetic and clinical screening. AIP-related pituitary disease has a wide spectrum ranging from aggressively growing lesions to stable or indolent disease course.
(© Endocrine Society 2020.)

SESAME, BOTANICAL insecticides, INSECTICIDES, CARDIAC glycosides, INSECT mortality, HEMIPTERA, and EXTRACTS

A study was conducted to investigate the insecticidal potency of leaf and stem ethanolic extracts of white sesame (Sesamum indicum L.) on the pod-sucking bug (Clavigralla tomentosicollis Stal.) under laboratory conditions. Four different concentrations of the extracts (5.00, 10.00, 15.00 and 20.00 mg/l) of ethanolic extracts were prepared from the leaf and stem parts of the Sesame plant. Water and Cypermethrin were used as negative and positive controls. Fresh cowpea pods were treated with the various concentrations of the stem and leaf ethanolic extracts and the pod-sucking bugs were introduced into the jars containing the pods. The result obtained revealed significant differences (P≤0.05) in the effect of various concentrations in inducing mortality of the insects at different instars. The extracts were more effective in the first (1st) instars against the pod-sucking bugs. The activity is concentration dependent as it increases with increase in concentration of the extract. However, leaf ethanolic extract proved to be more effective. More so, the percentages of pods infested by the bugs were found to be lower among the 20.00 mg/l treated pods in both stem and leaf ethanolic extracts. The phytochemical result indicated the presence of certain phytochemicals such as alkaloids, carbohydrates, cardiac glycosides, diterpenoids, flavonoids, proteins, saponins, steroids, tannins and triterpenoids that were proved to be vital in the insecticidal activity of the extracts. Thus, the stem and leaf ethanolic extracts of sesame are effective botanical insecticides against C. tomentosicollis especially at 20.00 mg/l of the leaf extract. [ABSTRACT FROM AUTHOR]

Sustainable strategies such as classical or augmentative biological control are currently being evaluated for the long-term management of the alien invasive pest Halyomorpha halys (Stål) (Hemiptera: Pentatomidae). A three-year study carried out in northeastern Italy was performed to investigate the distribution and field performance of the H. halys egg parasitoid Trissolcus mitsukurii (Ashmead) (Hymenoptera: Scelionidae), in comparison with other parasitoid species. In the study area, adventive populations of T. mitsukurii were present since 2016, representing the earliest detection of this species in Europe. Trissolcus mitsukurii was the most abundant parasitoid and showed a higher "parasitoid impact" (i.e., number of parasitized eggs over the total number of field-collected eggs) compared to the other species, i.e., Anastatus bifasciatus (Geoffroy) (Hymenoptera: Eupelmidae), Trissolcus basalis (Wollaston) and Trissolcus kozlovi Rjachovskij (Hymenoptera: Scelionidae). The hyperparasitoid Acroclisoides sinicus (Huang and Liao) (Hymenoptera: Pteromalidae) was also recorded. Phylogenetic analysis of T. mitsukurii population distinguished two clades, one covering samples from Italy, Japan and China, the other from South Korea. The present study provides promising results for the biological control of a pest that is having a dramatic impact on a wide range of crops worldwide.

BROWN marmorated stink bug, STINKBUGS, HEMIPTERA, ORNAMENTAL trees, and FARM produce

The brown marmorated stink bug, Halyomorpha halys (Stål), is a polyphagous pest that feeds on a wide variety of agricultural commodities including tree fruits, berries, vegetables, field crops, and ornamental trees and shrubs. Accurate knowledge of where H. halys lays eggs is critical to optimize the potential release of Trissolcus japonicus (Ashmead), a scelionid egg parasitoid native to the same host region as H. halys. Ideally, parasitoids should be released in and around areas with high host density. In southwestern Virginia in 2017 and 2018, we searched trees for egg masses in an urban environment and nonmanaged wooded border environment. We also evaluated the effects of a commercial aggregation lure on the number of eggs being deposited. This aggregation lure, when combined with methyl (E , E , Z)-2,4,6-decatrienoate (MDT), has been shown to attract both adult and nymph H. halys and its effects on egg laying were not known. Results of this study showed no difference between the number of eggs laid on trees with and without lures. Catalpa trees, Catalpa bignonioides Walter, had the most egg masses throughout the course of the study; however, the redbud, Cercis canadensis L., had similar numbers in the late July and August. There was an overall trend with more eggs masses found on trees with fruiting structures present. This information can provide insight on where and when to make augmentative releases of egg parasitoids for H. halys. [ABSTRACT FROM AUTHOR]

Administration, Oral, Biomarkers analysis, Biopsy, Chenodeoxycholic Acid administration dosage, Chenodeoxycholic Acid therapeutic use, Double-Blind Method, Female, Humans, Liver Function Tests, Male, Middle Aged, Chenodeoxycholic Acid analogs derivatives, and Non-alcoholic Fatty Liver Disease drug therapy

Background: Non-alcoholic steatohepatitis (NASH) is a common type of chronic liver disease that can lead to cirrhosis. Obeticholic acid, a farnesoid X receptor agonist, has been shown to improve the histological features of NASH. Here we report results from a planned interim analysis of an ongoing, phase 3 study of obeticholic acid for NASH.
Methods: In this multicentre, randomised, double-blind, placebo-controlled study, adult patients with definite NASH, non-alcoholic fatty liver disease (NAFLD) activity score of at least 4, and fibrosis stages F2-F3, or F1 with at least one accompanying comorbidity, were randomly assigned using an interactive web response system in a 1:1:1 ratio to receive oral placebo, obeticholic acid 10 mg, or obeticholic acid 25 mg daily. Patients were excluded if cirrhosis, other chronic liver disease, elevated alcohol consumption, or confounding conditions were present. The primary endpoints for the month-18 interim analysis were fibrosis improvement (≥1 stage) with no worsening of NASH, or NASH resolution with no worsening of fibrosis, with the study considered successful if either primary endpoint was met. Primary analyses were done by intention to treat, in patients with fibrosis stage F2-F3 who received at least one dose of treatment and reached, or would have reached, the month 18 visit by the prespecified interim analysis cutoff date. The study also evaluated other histological and biochemical markers of NASH and fibrosis, and safety. This study is ongoing, and registered with ClinicalTrials.gov, NCT02548351, and EudraCT, 20150-025601-6.
Findings: Between Dec 9, 2015, and Oct 26, 2018, 1968 patients with stage F1-F3 fibrosis were enrolled and received at least one dose of study treatment; 931 patients with stage F2-F3 fibrosis were included in the primary analysis (311 in the placebo group, 312 in the obeticholic acid 10 mg group, and 308 in the obeticholic acid 25 mg group). The fibrosis improvement endpoint was achieved by 37 (12%) patients in the placebo group, 55 (18%) in the obeticholic acid 10 mg group (p=0·045), and 71 (23%) in the obeticholic acid 25 mg group (p=0·0002). The NASH resolution endpoint was not met (25 [8%] patients in the placebo group, 35 [11%] in the obeticholic acid 10 mg group [p=0·18], and 36 [12%] in the obeticholic acid 25 mg group [p=0·13]). In the safety population (1968 patients with fibrosis stages F1-F3), the most common adverse event was pruritus (123 [19%] in the placebo group, 183 [28%] in the obeticholic acid 10 mg group, and 336 [51%] in the obeticholic acid 25 mg group); incidence was generally mild to moderate in severity. The overall safety profile was similar to that in previous studies, and incidence of serious adverse events was similar across treatment groups (75 [11%] patients in the placebo group, 72 [11%] in the obeticholic acid 10 mg group, and 93 [14%] in the obeticholic acid 25 mg group).
Interpretation: Obeticholic acid 25 mg significantly improved fibrosis and key components of NASH disease activity among patients with NASH. The results from this planned interim analysis show clinically significant histological improvement that is reasonably likely to predict clinical benefit. This study is ongoing to assess clinical outcomes.
Funding: Intercept Pharmaceuticals.
(Copyright © 2019 Elsevier Ltd. All rights reserved.)

Animals, Female, Heteroptera physiology, Life Cycle Stages, Solanum lycopersicum parasitology, Male, Pest Control, Biological methods, Biological Control Agents classification, Moths, and Predatory Behavior

Tuta absoluta (Meyrick), a key pest of tomato, is quickly spreading over the world and biological control is considered as one of the control options. Worldwide more than 160 species of natural enemies are associated with this pest, and an important challenge is to quickly find an effective biocontrol agent from this pool of candidate species. Evaluation criteria for control agents are presented, with the advantages they offer for separating potentially useful natural enemies from less promising ones. Next, an aggregate parameter for ranking agents is proposed: the pest kill rate km. We explain why the predator's intrinsic rate of increase cannot be used for comparing the control potential of predators or parasitoids, while km can be used to compare both types of natural enemies. As an example, kill rates for males, females and both sexes combined of three Neotropical mirid species (Campyloneuropsis infumatus (Carvalho), Engytatus varians (Distant) and Macrolophus basicornis (Stål)) were determined, taking all life-history data (developmental times, survival rates, total nymphal and adult predation, sex ratios and adult lifespan) into account. Based on the value for the intrinsic rate of increase (rm) for T. absoluta and for the kill rate km of the predators, we predict that all three predators are potentially able to control the pest, because their km values are all higher than the rm of the pest. Using only km values, we conclude that E. varians is the best candidate for control of T. absoluta on tomato, with C. infumatus ranking second and M. basicornis last.

PLANT phenology, STINKBUGS, SOYBEAN farming, SOYBEAN diseases & pests, and HEMIPTERA

Stink bugs (Hemiptera: Pentatomidae) are an increasing threat to soybean (Fabales: Fabaceae) production in the North Central Region of the United States, which accounts for 80% of the country's total soybean production. Characterization of the stink bug community is essential for development of management programs for these pests. However, the composition of the stink bug community in the region is not well defined. This study aimed to address this gap with a 2-yr, 9-state survey. Specifically, we characterized the relative abundance, richness, and diversity of taxa in this community, and assessed phenological differences in abundance of herbivorous and predatory stink bugs. Overall, the stink bug community was dominated by Euschistus spp. (Hemiptera: Pentatomidae) and Chinavia hilaris (Say) (Hemiptera: Pentatomidae). Euschistus variolarius (Palisot de Beauvois) (Hemiptera: Pentatomidae), C. hilaris and Halyomorpha halys (Stål) (Hemiptera: Pentatomidae) were more abundant in the northwestern, southeastern and eastern parts, respectively, of the North Central Region of the United States. Economically significant infestations of herbivorous species occurred in fields in southern parts of the region. Species richness differed across states, while diversity was the same across the region. Herbivorous and predatory species were more abundant during later soybean growth stages. Our results represent the first regional characterization of the stink bug community in soybean fields and will be fundamental for the development of state- and region-specific management programs for these pests in the North Central Region of the United States. [ABSTRACT FROM AUTHOR]

MELIACEAE, HOST plants, HEMIPTERA, STINKBUGS, and INSECT antifeedants

Currently, the invasive brown marmorated stink bug, Halyomorpha halys (Stål) (Hemiptera: Pentatomidae), is considered an agricultural and nuisance pest in Georgia. The invasive chinaberry tree, Melia azedarach L. (Meliaceae), commonly grows in dense thickets along roadsides, and in woodlands adjacent to agricultural crops across the southeastern USA. Thus, the objective of this study was to determine the potential of M. azedarach to serve as a host plant of H. halys by examining mortality and feeding of first and second instars on M. azedarach leaves vs. carrot (i.e., a control diet), and documenting presence of H. halys on M. azedarach in woodlands at 2 locations in Georgia where this stink bug has become established. Over all sampling dates and locations, the number of H. halys in chinaberry was very low (0.1 per tree), and only 3 late instars and 1 adult were observed feeding on M. azedarach at 1 field site late in the season. Percentage feeding by second instars of H. halys was lower for individuals given M. azedarach leaves vs. those provided with carrot, most likely indicating that compounds in M. azedarach have an antifeeding effect. In fact, mortality for second instars on M. azedarach leaves was very high, and thus we conclude that M. azedarach is an unsuitable host plant for H. halys. [ABSTRACT FROM AUTHOR]

TRISSOLCUS, BROWN marmorated stink bug, PARASITOIDS, SCELIONIDAE, and WASPS

Background A parasitoid wasp, Trissolcus solocis Johnson, was recorded parasitising eggs of the invasive stink bug Halyomorpha halys (Stål), in the United States. This is the first record of this species parasitising eggs of H. halys. New information First record of Trissolcus solocis parasitising Halyomorpha halys eggs in the United States and first record of T. solocis in Alabama. [ABSTRACT FROM AUTHOR]

Diagnostic Errors statistics numerical data, Escherichia coli isolation purification, Escherichia coli Infections microbiology, Humans, Klebsiella Infections microbiology, Klebsiella pneumoniae isolation purification, Netherlands, Reproducibility of Results, Anti-Bacterial Agents pharmacology, Escherichia coli drug effects, Fosfomycin pharmacology, Klebsiella pneumoniae drug effects, and Microbial Sensitivity Tests methods

Objectives: Fosfomycin susceptibility testing is complicated and prone to error. Before using fosfomycin widely in patients with serious infections, acquisition of WT distribution data and reliable susceptibility testing methods are crucial. In this study, the performance of five methods for fosfomycin testing in the routine laboratory against the reference method was evaluated.
Methods: Ten laboratories collected up to 100 ESBL-producing isolates each (80 Escherichia coli and 20 Klebsiella pneumoniae). Isolates were tested using Etest, MIC test strip (MTS), Vitek2, Phoenix and disc diffusion. Agar dilution was performed as the reference method in a central laboratory. Epidemiological cut-off values (ECOFFs) were determined for each species and susceptibility and error rates were calculated.
Results: In total, 775 E. coli and 201 K. pneumoniae isolates were tested by agar dilution. The ECOFF was 2 mg/L for E. coli and 64 mg/L for K. pneumoniae. Susceptibility rates based on the EUCAST breakpoint of ≤32 mg/L were 95.9% for E. coli and 87.6% for K. pneumoniae. Despite high categorical agreement rates for all methods, notably in E. coli, none of the alternative antimicrobial susceptibility testing methods performed satisfactorily. Due to poor detection of resistant isolates, very high error rates of 23.3% (Etest), 18.5% (MTS), 18.8% (Vitek2), 12.5% (Phoenix) and 12.9% (disc diffusion) for E. coli and 22.7% (Etest and MTS), 16.0% (Vitek2) and 12% (Phoenix) for K. pneumoniae were found. None of the methods adequately differentiated between WT and non-WT populations.
Conclusions: Overall, it was concluded that none of the test methods is suitable as an alternative to agar dilution in the routine laboratory.

Aged, Biomarkers, Bridged-Ring Compounds administration dosage, Bridged-Ring Compounds adverse effects, Female, Humans, Kaplan-Meier Estimate, Male, Middle Aged, Molecular Targeted Therapy, Mutation, Primary Myelofibrosis diagnosis, Primary Myelofibrosis genetics, Primary Myelofibrosis mortality, Protein Kinase Inhibitors administration dosage, Protein Kinase Inhibitors adverse effects, Pyrimidines administration dosage, Pyrimidines adverse effects, Treatment Outcome, Bridged-Ring Compounds therapeutic use, Primary Myelofibrosis drug therapy, Protein Kinase Inhibitors therapeutic use, and Pyrimidines therapeutic use

Myelofibrosis (MF) is a chronic yet progressive myeloid neoplasm in which only a minority of patients undergo curative therapy, hematopoietic stem cell transplantation. Ruxolitinib, a JAK1/2 inhibitor, is the lone therapy approved for MF, offering a clear symptom and spleen benefit at the expense of treatment-related cytopenias. Pacritinib (PAC), a multi-kinase inhibitor with specificity for JAK2, FLT3, and IRAK1 but sparing JAK1, has demonstrated clinical activity in MF with minimal myelosuppression. Due to an FDA-mandated full clinical hold, the randomized phase 3 PERSIST trials were abruptly stopped and PAC was immediately discontinued for all patients. Thirty-three patients benefitting from PAC on clinical trial prior to the hold were allowed to resume therapy on an individual, compassionate-use basis. This study reports the detailed outcomes of 19 of these PAC retreatment patients with a median follow-up of 8 months. Despite a median platelet count of 49 × 10 9 /L at restart of PAC, no significant change in hematologic profile was observed. Grade 3/4 adverse events of epistaxis (n = 1), asymptomatic QT prolongation (n = 1), and bradycardia (n = 1) occurred in three patients within the first 3 months of retreatment. One death due to catheter-associated sepsis occurred. The median time to discontinuation of PAC therapy on compassionate use for all 33 patients was 12.2 (95% CI 8.3-NR) months. PAC retreatment was associated with modest improvement in splenomegaly without progressive myelosuppression and supports the continued development of this agent for the treatment of MF second line to ruxolitinib or in the setting of treatment-limiting thrombocytopenia.

Adolescent, Cell Count, Child, Collagen metabolism, Cytokines biosynthesis, Cytokines genetics, Female, Gene Expression Regulation, Humans, Male, Muscle Fibers, Skeletal pathology, RNA, Ribosomal genetics, Real-Time Polymerase Chain Reaction, Ribosomes genetics, Ribosomes pathology, Satellite Cells, Skeletal Muscle pathology, Brain Injuries pathology, Cerebral Palsy pathology, Extracellular Matrix pathology, Muscle, Skeletal pathology, and RNA, Ribosomal biosynthesis

Introduction: Children with cerebral palsy (CP) and acquired brain injury (ABI) commonly develop muscle contractures with advancing age. An underlying growth defect contributing to skeletal muscle contracture formation in CP/ABI has been suggested.
Methods: The biceps muscles of children and adolescents with CP/ABI (n = 20) and typically developing controls (n = 10) were investigated. We used immunohistochemistry, quantitative real-time polymerase chain reaction, and Western blotting to assess gene expression relevant to growth and size homeostasis.
Results: Classical pro-inflammatory cytokines and genes involved in extracellular matrix (ECM) production were elevated in skeletal muscle of children with CP/ABI. Intramuscular collagen content was increased and satellite cell number decreased and this was associated with reduced levels of RNA polymerase I transcription factors, 45s pre-rRNA and 28S rRNA.
Discussion: The present study provides novel data suggesting a role for pro-inflammatory cytokines and reduced ribosomal production in the development/maintenance of muscle contractures, possibly underlying stunted growth and perimysial ECM expansion. Muscle Nerve 58: 277-285, 2018.
(© 2018 Wiley Periodicals, Inc.)

The work's aims were to identify both harmful and helpful insect species for safflower crop and to study their distribution along time in relation to plant phenological state. The insect species identified as harmful were: Uroleucon jaceae L., Capitophorus elaeagni, Frankliniella occidentalis P., Dichelops furcatus (F.), Athaumasthus haematicus (Stál), Nezara viridula (L.), Nysius simulans Stál, Edessa meditabunda (F.), Piezodorus guildinii (W.), Helicoverpa zea B., Epicauta adspersa K., Spodoptera frugiperda (J. E. Smith), Chauliognathus scriptus (Germ.), Pantomorus auripes H. and Rachiplusia nu (G.). Regarding aphids, their highest density was observed at the beginning of November, when crop was in the state of branching, with invasion mainly of the upper third of plants: leaves, young shoots and flower heads. Among all harmful true bugs found in the crop, red bug - Athaumastus haematicus (Stál)- comprised the highest proportion and was detected before aphids attacks, when stem elongation of plants was just beginning. As for beneficial species, the six insects detected in sufflower crop were Hippodamia convergens G., Eriopis connexa G., Harmonia axyridis (P.), Nabis sp., Ophion sp. and Apis melifera L., besides various spider species. The coccinellids- Hippodamia convergens; Eriopis connexa and Harmonia axydiris performed as the main natural control agents at crop. KE [ABSTRACT FROM AUTHOR]

Bacterial Infections drug therapy, Bacterial Infections epidemiology, Drug Resistance, Bacterial, Humans, Netherlands epidemiology, Recurrence, Risk Factors, Anti-Bacterial Agents pharmacology, Bacteria drug effects, and Bacterial Infections microbiology

Background: Direct health effects of antibiotic resistance are difficult to assess. We quantified the risk of recurrent bacteremia associated with resistance.
Methods: We extracted antimicrobial susceptibility testing data on blood isolates from the Dutch surveillance system for antimicrobial resistance between 2008 and 2017. First and first recurrent (4-30 days) bacteremia episodes were categorized as susceptible, single nonsusceptible, or co-nonsusceptible to third-generation cephalosporins without or with carbapenems (Enterobacteriaceae), ceftazidime without or with carbapenems (Pseudomonas species), aminopenicillins without or with vancomycin (Enterococcus species), or as methicillin-sensitive/-resistant S. aureus (MSSA/MRSA). We calculated risks of recurrent bacteremia after nonsusceptible vs susceptible first bacteremia, estimated the crude population attributable effect of resistance for the Netherlands, and calculated risks of nonsusceptible recurrent bacteremia after a susceptible first episode.
Results: Risk ratios for recurrent bacteremia after a single- and co-nonsusceptible first episode, respectively, vs susceptible first episode, were 1.7 (95% confidence interval [CI], 1.5-2.0) and 5.2 (95% CI, 2.1-12.4) for Enterobacteriaceae, 1.3 (95% CI, 0.5-3.1) and 5.0 (95% CI, 2.9-8.5) for Pseudomonas species, 1.4 (95% CI, 1.2-1.7) and 1.6 (95% CI, 0.6-4.2) for Enterococcus species, and 1.6 (95% CI, 1.1-2.4) for MRSA vs MSSA. The estimated population annual number of recurrent bacteremias associated with nonsusceptibility was 40. The risk of nonsusceptible recurrent bacteremia after a susceptible first episode was at most 0.4% (Pseudomonas species).
Conclusions: Although antibiotic nonsusceptibility was consistently associated with higher risks of recurrent bacteremia, the estimated annual number of additional recurrent episodes in the Netherlands (40) was rather limited.

Adolescent, Adult, Aged, Aged, 80 and over, Breast Neoplasms mortality, Breast Neoplasms pathology, Breast Neoplasms therapy, Disease-Free Survival, Female, Genotype, Humans, Middle Aged, Mutation, Neoplasm Staging, Prognosis, Proportional Hazards Models, Receptor, ErbB-2 metabolism, Receptors, Estrogen metabolism, Survival Rate, Young Adult, Breast Neoplasms genetics, and Class I Phosphatidylinositol 3-Kinases genetics

Purpose Phosphatidylinositol-4, 5-bisphosphate 3-kinase catalytic subunit alpha ( PIK3CA) mutations are frequently observed in primary breast cancer. We evaluated their prognostic relevance by performing a pooled analysis of individual patient data. Patients and Methods Associations between PIK3CA status and clinicopathologic characteristics were tested by applying Cox regression models adjusted for age, tumor size, nodes, grade, estrogen receptor (ER) status, human epidermal growth factor receptor 2 (HER2) status, treatment, and study. Invasive disease-free survival (IDFS) was the primary end point; distant disease-free survival (DDFS) and overall survival (OS) were also assessed, overall and by breast cancer subtypes. Results Data from 10,319 patients from 19 studies were included (median OS follow-up, 6.9 years); 1,787 patients (17%) received chemotherapy, 4,036 (39%) received endocrine monotherapy, 3,583 (35%) received both, and 913 (9%) received none or their treatment was unknown. PIK3CA mutations occurred in 32% of patients, with significant associations with ER positivity, increasing age, lower grade, and smaller size (all P < .001). Prevalence of PIK3CA mutations was 18%, 22%, and 37% in the ER-negative/HER2-negative, HER2-positive, and ER-positive/HER2-negative subtypes, respectively. In univariable analysis, PIK3CA mutations were associated with better IDFS (HR, 0.77; 95% CI, 0.71 to 0.84; P < .001), with evidence for a stronger effect in the first years of follow-up (0 to 5 years: HR, 0.73; 95% CI, 0.66 to 0.81; P < .001; 5 to 10 years: HR, 0.82; 95% CI, 0.68 to 0.99; P = .037); > 10 years: (HR, 1.15; 95% CI, 0.84 to 1.58; P = .38; P heterogeneity = .02). In multivariable analysis, PIK3CA genotype remained significant for improved IDFS ( P = .043), but not for the DDFS and OS end points. Conclusion In this large pooled analysis, PIK3CA mutations were significantly associated with a better IDFS, DDFS, and OS, but had a lesser prognostic effect after adjustment for other prognostic factors.

Biodiversity and Conservation of Natural Resources

MIRIDAE, EGGS as food, PREDATORY animals, TEMPERATURE effect, and MEDITERRANEAN flour moth

Three Neotropical predators Campyloneuropsis infumatus (Carvalho), Engytatus varians (Distant) and Macrolophus basicornis (Stål) (Hemiptera: Miridae) are considered in Brazil as potential biological control agents of Tuta absoluta Meyrick (Lepidoptera: Gelechiidae) and other tomato pests. This study evaluated the effect of five constant temperatures (16, 20, 24, 28 and 32°C, all ±1°C) on the reproduction, population growth and longevity of these predatory mirids. Adults freshly emerged from nymphs reared at each temperature, were separated in couples and kept in 1.7 l glass pots with tobacco plant seedlings (Nicotiana tabacum L., cv. TNN) as oviposition substrate and ad libitum Ephestia kuehniella (Zeller) (Lepidoptera: Pyralidae) eggs as food. The shortest pre-oviposition and the longest oviposition periods were observed at 24°C and 28°C in all three mirid species. At 24°C all three species showed the highest daily and total fecundities. The population growth parameters represented by the intrinsic rate of increase (rm) and the finite rate of increase (λ) were highest at 24°C and 28°C, and the net reproductive rate (R0) was highest at 24°C for all three species. Longevities of both males and females were longest at 24°C and 28°C in all three mirids. The size of tibia and adult weight in the three species were greatest at 20°C and 28°C, respectively. Differences in values for all above variables were small and often statistically non-significant for the three mirid species at the same temperature. Also, not a single significant difference was found for any of the growth parameters at each of the temperatures, including rm. The results indicate that temperatures in the range from 24-28°C are best for reproduction and population growth of C. infumatus, E. varians and M. basicornis. The factitious prey E. kuehniella is an excellent food source and tobacco plants provide a good rearing substrate for these mirids. The obtained results may assist in developing a mass rearing method for C. infumatus, E. varians and M. basicornis, in determining optimal timing and frequency of mirid releases in the crop, and in determining whether they are active at the temperature spectrum observed during tomato production in the field or greenhouse. [ABSTRACT FROM AUTHOR]

Female, Genes, Recessive, Humans, Male, Pregnancy, Congenital Abnormalities genetics, Genetic Diseases, Inborn diagnosis, Parents, Prenatal Diagnosis methods, and Exome Sequencing

Objective: Rare genetic disorders resulting in prenatal or neonatal death are genetically heterogeneous, but testing is often limited by the availability of fetal DNA, leaving couples without a potential prenatal test for future pregnancies. We describe our novel strategy of exome sequencing parental DNA samples to diagnose recessive monogenic disorders in an audit of the first 50 couples referred.
Method: Exome sequencing was carried out in a consecutive series of 50 couples who had 1 or more pregnancies affected with a lethal or prenatal-onset disorder. In all cases, there was insufficient DNA for exome sequencing of the affected fetus. Heterozygous rare variants (MAF < 0.001) in the same gene in both parents were selected for analysis. Likely, disease-causing variants were tested in fetal DNA to confirm co-segregation.
Results: Parental exome analysis identified heterozygous pathogenic (or likely pathogenic) variants in 24 different genes in 26/50 couples (52%). Where 2 or more fetuses were affected, a genetic diagnosis was obtained in 18/29 cases (62%). In most cases, the clinical features were typical of the disorder, but in others, they result from a hypomorphic variant or represent the most severe form of a variable phenotypic spectrum.
Conclusion: We conclude that exome sequencing of parental samples is a powerful strategy with high clinical utility for the genetic diagnosis of lethal or prenatal-onset recessive disorders. © 2017 The Authors Prenatal Diagnosis published by John Wiley & Sons Ltd.
(© 2017 The Authors Prenatal Diagnosis published by John Wiley & Sons Ltd.)

BIODIVERSITY, VERTEBRATES, HABITATS, GLACIATION, and PLIOCENE Epoch

It is now rare to find a semi-aquatic organism group with which to vigorously test whether their diversification model and distribution pattern are closely related to the Cenozoic temperature variation. This hypothesis is explored for water striders of the genera Aquarius Schellenberg, Gerris Fabricius and Limnoporus Stål, which comprise a monophyletic clade with primarily Holarctic distribution. We sample almost 90% of the currently recognized Aquarius, Gerris and Limnoporus species. Five DNA fragments from 62 species are used to reconstruct a phylogram. Divergence time is estimated using Bayesian relaxed-clock method and three fossil calibrations. We investigate diversification dynamics, biogeography and ancestral state reconstruction by using maximum-likelihood, Bayesian and parsimony approaches. Our results showed that the crown of the three genera originated and underwent an initial diversification in Asia at 72 Ma (HPD: 59-86 Ma) in the Late Cretaceous, subsequently expanding into other regions via dispersal. The Bering Land Bridge was the major migration route between Eurasia and North America but was interrupted before the early Oligocene (34 Ma). Ancestors most likely used lentic habitats, and a minimum of two independent shifts to lotic habitats occurred in the initial diversification. Cenozoic temperature variation regulated the evolutionary history of Holarctic water striders of the genera Aquarius, Gerris and Limnoporus. Temperature warming during Stage I (52-66 Ma) was associated with the disappearance of shallow lentic habitats; this phenomenon forced certain lentic lineages to colonize new lotic habitats and promoted the diversification of lineages. Temperature cooling during Stage II (after 34 Ma) was associated with the fragmentation of water habitats of the 'mixed-mesophytic' belt, resulting in the extinction of historical taxa and influencing close lineages that shaped the present disjunct Eurasian-North American distribution. [ABSTRACT FROM AUTHOR]

ZOOLOGICAL nomenclature, LEAFHOPPERS, PARROTFISHES, BURSA fabricii, and ANNOTATIONS

A synoptic, annotated catalogue is provided, documenting the long history of vacillated nomenclature usages between leafhopper family-group names Gyponidae Stål 1870c and Scaridae Amyot & Serville 1843a (nec Scaridae Rafinesque 1810b), between genus-group names Gypona Germar 1821a and Scaris Le Peletier & Serville 1828a (nec Scaris Chaudoir 1879), synonyms, and use of Docalidia ferruginea (Fabricius) in the literature for Iassus ferrugineus, beginning at the formation of each taxon and ending at the present. Authors' annotations, where applicable, follow each citation. A photograph of the lectotype of Iassus ferrugineus Fabricius (Coelidiinae) and a misidentified specimen (Gyponinae) by Germar are shown for comparative purposes. [ABSTRACT FROM AUTHOR]

Animals, Housing, Seasons, Chemotaxis, Heteroptera physiology, Insect Control, and Pheromones pharmacology

The brown marmorated stink bug, Halyomorpha halys (Stål), is an invasive species from Asia capable of causing severe agricultural damage. It can also be a nuisance pest when it enters and exits anthropogenic overwintering sites. In recent years, pheromone lures and traps for H. halys have been developed and used to monitor populations in field studies. To date, no study has investigated the applicability of these monitoring tools for use indoors by building residents during the overwintering period. Herein, we 1) assessed when in late winter (diapause) and spring (postdiapause) H. halys begins to respond to its pheromone (10,11-epoxy-1-bisabolen-3-ol), 2) evaluated whether pheromone-based tools can be used reliably for monitoring H. halys adults in unheated and heated buildings, and 3) elucidated the potential for indoor management using pheromone-baited traps. A 2-yr trapping study suggested that H. halys began to respond reliably to pheromone-baited traps after a critical photoperiod of 13.5 h in the spring. Captures before that point were not correlated with visual counts of bugs in buildings despite robust populations, suggesting currently available pheromone-baited traps were ineffective for surveillance of diapausing H. halys. Finally, because baited traps captured only 8-20% of the adult H. halys known to be present per location, they were not an effective indoor management tool for overwintering H. halys. Our study contributes important knowledge about the capacity of H. halys to perceive its pheromone during overwintering, and the ramifications thereof for building residents with nuisance problems.
(Published by Oxford University Press on behalf of Entomological Society of America 2017. This work is written by US Government employees and is in the public domain in the US.)

BROWN marmorated stink bug, HEMIPTERA, INTRODUCED insects, INSECT pests, PHEROMONES, INSECT traps, INSECT population density, and ECONOMICS

Halyomorpha halys Stål (Hemiptera: Pentatomidae) is an invasive insect that causes severe economic damage to multiple agricultural commodities. Several monitoring tools, including pheromone and light-baited black pyramid traps, have been developed to monitor H. halys. Here, we evaluated the attractiveness of these traps baited with only light, only pheromone, or the combination in comparison with unbaited traps throughout the growing season in regions with high and low H. halys population densities. In regions with high population densities in the Mid-Atlantic, all traps baited with pheromone or lights performed better than control traps. During mid-season, traps containing lights captured more H. halys adults, whereas pheromone-baited traps captured greater numbers during the late season. In low density regions in the Pacific Northwest, traps with lights or pheromone captured more H. halys adults than control traps. In addition, we evaluated the influence of competing light sources associated with anthropogenic structures. When light traps were deployed next to these additional light sources, H. halys captures in pyramid traps baited with light were not significantly reduced. Overall, our results indicate that both light and pheromone traps can be used to detect H. halys activity in low and high density populations. [ABSTRACT FROM AUTHOR]

HIGGS bosons, SCALAR field theory, SUPERSYMMETRY, STANDARD model (Nuclear physics), DARK matter, and MATHEMATICAL models

The goal of this report is to summarize the current situation and discuss possible search strategies for charged scalars, in non-supersymmetric extensions of the Standard Model at the LHC. Such scalars appear in Multi-Higgs-Doublet models, in particular in the popular Two-Higgs-Doublet model, allowing for charged and additional neutral Higgs bosons. These models have the attractive property that electroweak precision observables are automatically in agreement with the Standard Model at the tree level. For the most popular version of this framework, Model II, a discovery of a charged Higgs boson remains challenging, since the parameter space is becoming very constrained, and the QCD background is very high. We also briefly comment on models with dark matter which constrain the corresponding charged scalars that occur in these models. The stakes of a possible discovery of an extended scalar sector are very high, and these searches should be pursued in all conceivable channels, at the LHC and at future colliders. [ABSTRACT FROM AUTHOR]

NEISSERIA gonorrhoeae, SEXUALLY transmitted diseases, ANTIBIOTICS, CHLAMYDIA trachomatis, GYNECOLOGISTS, DIAGNOSIS, CHLAMYDIA infection diagnosis, GENITOURINARY disease diagnosis, GONORRHEA diagnosis, CLINICS, GENITOURINARY diseases, GONORRHEA, DISEASES in men, NEISSERIA, PHARYNGEAL diseases, PHYSICIANS, GENERAL practitioners, CROSS-sectional method, and RECTAL diseases

Background: Gonorrhoea, caused by Neisseria gonorrhoeae (NG), can cause reproductive morbidity, is increasingly becoming resistant to antibiotics and is frequently asymptomatic, which shows the essential role of NG test practice. In this study we wanted to compare NG diagnostic testing procedures between different STI care providers serving a defined geographic Dutch region (280,000 inhabitants).Methods: Data on laboratory testing and diagnosis of urogenital and extragenital (i.e. anorectal and oropharyngeal) NG were retrieved from general practitioners (GPs), an STI clinic, and gynaecologists (2006-2010). Per provider, we assessed their contribution regarding the total number of tests performed and type of populations tested, the proportion of NG positives re-tested (3-12 months after treatment) and test-of-cure (TOC, within 3 months post treatment).Results: Overall, 17,702 NG tests (48.7% STI clinic, 38.2% GPs, 13.1% gynaecologists) were performed during 15,458 patient visits. From this total number of tests, 2257 (12.7%) were extragenital, of which 99.4% were performed by the STI clinic. Men were mostly tested at the STI clinic (71%) and women by their GP (43%). NG positivity per visit was 1.6%; GP 1.9% (n = 111), STI clinic 1.7% (n = 131) and gynaecology 0.2% (n = 5). NG positivity was associated with Chlamydia trachomatis positivity (OR: 2.06, 95% confidence interval: 1.46-2.92). Per anatomical location, the proportion of NG positives re-tested were: urogenital 20.3% (n = 36), anorectal 43.6% (n = 17) and oropharyngeal 57.1% (n = 20). NG positivity among re-tests was 16.9%. Proportions of NG positives with TOC by anatomical location were: urogenital 10.2% (n = 18), anorectal 17.9% (n = 7) and oropharyngeal 17.1% (n = 6).Conclusions: To achieve best practice in relation to NG testing, we recommend that: 1) GPs test at extragenital sites, especially men who have sex with men (MSM), 2) all care providers consider re-testing 3 to 12 months after NG diagnosis and 3) TOC is performed following oropharyngeal NG diagnosis in settings which provide services to higher-risk men and women (such as STI clinics). [ABSTRACT FROM AUTHOR]

Adult, Aged, Biomarkers blood, Fatty Acids blood, Female, Fibrosis, Glycerophospholipids blood, Humans, Liver pathology, Liver Cirrhosis etiology, Logistic Models, Male, Middle Aged, Multivariate Analysis, Prospective Studies, Risk Factors, Severity of Illness Index, Surveys and Questionnaires, Sweden, Young Adult, Alcohol Drinking, Liver Cirrhosis pathology, Non-alcoholic Fatty Liver Disease complications, and Non-alcoholic Fatty Liver Disease pathology

Background and Aim: Moderate alcohol consumption has been associated with a lower risk of disease severity in non-alcoholic fatty liver disease (NAFLD). It is unclear if this reflects current or lifetime drinking, or can be attributed to confounders such as diet and exercise. We evaluated the impact of lifetime alcohol consumption on fibrosis severity in NAFLD.
Methods: We prospectively enrolled 120 subjects with biopsy-proven NAFLD and through detailed questionnaires examined lifetime alcohol consumption, diet and physical activity. Main outcome measures were odds ratios (OR) for fibrosis stage, calculated through ordinal regression after adjustment for body mass index, diabetes mellitus type 2, smoking and age at biopsy. A biomarker for recent alcohol consumption, phosphatidyl ethanol (PEth) was sampled.
Results: An increase in median weekly alcohol consumption to a maximum of 13 drinks per week was associated with lower fibrosis stage (adjusted OR for each incremental unit, 0.86; 95% CI, 0.76-0.97; p = .017). The lowest risk for fibrosis was found with the lowes`t odds seen in the top quartile of alcohol consumption (aOR 0.23; 95% CI 0.08-0.66; p = .006). Adding soft drink and coffee consumptions, and physical activity to the model did not change the estimates. Subjects with PEth ≥0.3 μmol/L had higher ORs for a higher fibrosis stage (aOR 2.77; 95% CI 1.01-7.59; p = .047).
Conclusion: Lifetime alcohol consumption with up to 13 units per week is associated with lower fibrosis stage in NAFLD. Elevated PEth is associated with higher stages of fibrosis.

Adult, Aged, Aged, 80 and over, Breast Neoplasms drug therapy, Breast Neoplasms metabolism, Cohort Studies, Female, Follow-Up Studies, Humans, Immunoenzyme Techniques, Lymphatic Metastasis, Middle Aged, Neoplasm Grading, Neoplasm Recurrence, Local drug therapy, Neoplasm Recurrence, Local metabolism, Neoplasm Staging, Prognosis, Receptor, ErbB-2 metabolism, Receptors, Estrogen metabolism, Receptors, Progesterone metabolism, Survival Rate, Antineoplastic Combined Chemotherapy Protocols therapeutic use, Biomarkers, Tumor metabolism, Breast Neoplasms classification, Breast Neoplasms pathology, and Neoplasm Recurrence, Local pathology

Background: The St Gallen surrogate definition of the intrinsic subtypes of breast cancer consist of five subgroups based on estrogen receptor (ER), progesterone receptor (PgR), human epidermal growth factor receptor type 2 (HER2), and Ki-67. PgR and Ki-67 are used for discriminating between the 'Luminal A-like' and 'Luminal B-like (HER2-negative)' subtypes. Histological grade (G) has prognostic value in breast cancer; however, its relationship to the St Gallen subtypes is not clear. Based on a previous pilot study, we hypothesized that G could be a primary discriminator for ER-positive/HER2-negative breast cancers that were G1 or G3, whereas Ki-67 and PgR could provide additional prognostic information specifically for patients with G2 tumors. To test this hypothesis, a larger patient cohort was examined.
Patients and Methods: Six hundred seventy-one patients (≥35 years of age, pT1-2, pN0-1) with ER-positive/HER2-negative breast cancer and complete data for PgR, Ki-67, G, lymph node status, tumor size, age, and distant disease-free survival (DDFS; median follow-up 9.2 years) were included.
Results: 'Luminal A-like' tumors were mostly G1 or G2 (90%) whereas 'Luminal B-like' tumors were mostly G2 or G3 (87%) and corresponded with good and poor DDFS, respectively. In 'Luminal B-like' tumors that were G1 (n = 23), no metastasis occurred, whereas 14 of 40 'Luminal A-like' tumors that were G3 metastasized. In the G2 subgroup, low PgR and high Ki-67 were associated with an increased risk of distant metastases, hazard ratio (HR) and 95% confidence interval (CI) 1.8 (0.95-3.4) and 1.5 (0.80-2.8), respectively.
Conclusions: Patients with ER-positive/HER2-negative/G1 breast cancer have a good prognosis, similar to that of 'Luminal A-like', while those with ER-positive/HER2-negative/G3 breast cancer have a worse prognosis, similar to that of 'Luminal B-like', when assessed independently of PgR and Ki-67. Therapy decisions based on Ki-67 and PgR might thus be restricted to the subgroup G2.

RICE diseases & pests, NILAPARVATA lugens, LOCUS (Genetics), GENETIC markers in plants, and RICE breeding

Brown planthopper ( BPH), Nilaparvata lugens Stål ( Hemiptera: Delphacide), is a destructive insect pest of rice, Oryza sativa L. ( Poaceae), in rice-producing areas worldwide. Host plant resistance is a major aspect of managing this pest. In this study, a mapping population consisting of 150 F3 lines, derived from a cross of MR276 and Rathu Heenati, was used to detect and analyse quantitative trait loci ( QTLs) for the resistance to BPH. Composite Interval Mapping ( CIM) was used for QTL detection. In total 10 QTLs controlling BPH resistance were mapped on chromosomes 1, 3, 6, 7, 9, 10, and 12. Four QTLs - qBph-1-1, qBph-3-1, qBph-6-1, and qBph-7-1 - were mapped on chromosomes 1, 3, 6, and 7 in the standard seedbox screening test, explaining 41% of the phenotypic variance. Two QTLs, qBph-6-1 and qBph-9-1, were detected on chromosomes 6 and 9 in the honeydew test, accounting for 32% of the total phenotypic variance. Moreover, four QTLs - qBph-3-1, qBph-6-1, qBph-10-1, and qBph-12-1 - were identified on chromosomes 3, 6, 10, and 12 expressing antixenosis to BPH and explaining 41% of the phenotypic variance. QTL qBph-3-1 was located in the chromosomal region between markers RM231 and RM3872 on chromosome 3, and QTL qBph-6-1 was located in the region between RM588 and RM204 on chromosome 6, indicating that these regions have a major effect in controlling the resistance to BPH in the population studied. The molecular markers linked to QTLs that are identified will be useful in the development of varieties resistant to BPH. Our study contributes to the development of genetic material for breeding programmes and marker-assisted selection ( MAS) in rice to improve BPH resistance. [ABSTRACT FROM AUTHOR]

BROWN marmorated stink bug, PODISUS, and INSECT pest control

Stink bugs (Hemiptera: Heteroptera: Pentatomidae) are an emerging threat to soybean and corn production in the midwestern United States. An invasive species, the brown marmorated stink bug, Halyomorpha halys (Stål), is spreading through the region. However, little is known about the complex of stink bug species associated with corn and soybean in the midwestern United States. In this region, particularly in the more northern states, stink bugs have historically caused only infrequent impacts to these crops. To prepare growers and agricultural professionals to contend with this new threat, we provide a review of stink bugs associated with soybean and corn in the midwestern United States. Descriptions and images of common stink bug species are provided as a diagnostic aid. The biologies and impacts of stink bugs to crops are discussed, with particular attention to differences among species. Based primarily on information from southern states, scouting, thresholds, and insecticide-based management of these pests are discussed. It is hoped that this review will provide stakeholders sufficient information for management of these pests, until more region-specific research can be performed on stink bugs in soybean and corn in the midwestern United States. [ABSTRACT FROM AUTHOR]

SOYBEAN diseases & pests, BROWN marmorated stink bug, and STINKBUGS

Sampling soybean fields for the brown marmorated stink bug, Halyomorpha halys Stål (Hemiptera: Pentatomidae), can be challenging. Both adults and nymphs have a "startle response" and drop to the ground with even the slightest disturbance. This behavior could reduce the effectiveness of the traditional sweep net and ground cloth sampling methods. In 2013 and 2014, in Virginia, Delaware, and Maryland, we evaluated a visual plant inspection method that consisted of counting the number of brown marmorated stink bug nymphs and adults seen on soybean plants in a 2-min inspection period while walking carefully between two rows. After a 30-min interval, which allowed the stink bugs to reposition in the canopy, the area was resampled using 15 sweeps with a 38-cm-diameter sweep net. In total, 76 soybean fields and 2,042 paired comparisons were used to determine a strong linear relationship between sampling methods (y = 0.984x + 0.4359, R2 = 0.6934, where y = brown marmorated stink bugs/2-min visual count and x = brown marmorated stink bugs/15 sweeps). An average visual count of 5.4 brown marmorated stink bugs in 2 min was estimated as being equivalent to the current economic threshold of 5 stink bugs per 15 sweeps. Visual inspection appears to be an effective method for assessing brown marmorated stink bug populations in soybeans. [ABSTRACT FROM AUTHOR]

A crude rice extract caused a higher probing response than did the control in the green rice leafhopper, Nephotettix nigropictus . Bioassay-guided separation led to the isolation of four active compounds, isoscoparin 2″- O -glucoside, isoscoparin 2″- O -(6‴-( E )-feruloyl)glucoside, isoscoparin 2″- O -(6‴-( E )- p -coumaroyl)glucoside, and isovitexin 2″- O -(6‴-( E )-feruloyl)glucoside from ODS 40% methanol in water faction. Each of the compounds, or any combination without one of the four compounds, caused weaker probing responses than the crude rice extract. The activity was recovered only when all the compounds were combined.

STIMULANTS, LEAFHOPPERS, RICE diseases & pests, BIOLOGICAL assay, and METHANOL

A crude rice extract caused a higher probing response than did the control in the green rice leafhopper, Nephotettix nigropictus. Bioassay-guided separation led to the isolation of four active compounds, isoscoparin 2"-O-glucoside, isoscoparin 2"-O-(6"'-(E)-feruloyl)glucoside, isoscoparin 2"-O-(6"'-(E)-p-coumaroyl)glucoside, and isovitexin 2"-O-(6"'- (E)-feruloyl)glucoside from ODS 40% methanol in water faction. Each of the compounds, or any combination without one of the four compounds, caused weaker probing responses than the crude rice extract. The activity was recovered only when all the compounds were combined. [ABSTRACT FROM AUTHOR]

Adenoma genetics, Adolescent, Adult, Female, Gene Frequency, Growth Hormone-Secreting Pituitary Adenoma genetics, Humans, Male, Mexico, Mutation, Young Adult, Acromegaly genetics, Gigantism genetics, and Intracellular Signaling Peptides and Proteins genetics

Although aryl hydrocarbon receptor-interacting protein (AIP) mutations are rare in sporadic acromegaly, their prevalence among young patients is nonnegligible. The objectives of this study were to evaluate the frequency of AIP mutations in a cohort of Mexican patients with acromegaly with disease onset before the age of 30 and to search for molecular abnormalities in the AIP gene in teeth obtained from the "Tampico Giant". Peripheral blood DNA from 71 patients with acromegaly (51 females) with disease onset <30 years was analysed (median age of disease onset of 23 years) and correlated with clinical, biochemical and imaging characteristics. Sequencing was also carried out in DNA extracted from teeth of the Tampico Giant. Five patients (7 %) harboured heterozygous, germline mutations of the AIP gene. In two of them (a 9-year-old girl with gigantism and a young man with symptoms of GH excess since age 14) the c.910C>T (p.Arg304Ter), well-known truncating mutation was identified; in one of these two cases and her identical twin sister, the mutation proved to be a de novo event, since neither of their parents were found to be carriers. In the remaining three patients, new mutations were identified: a frameshift mutation (c.976_977insC, p.Gly326AfsTer), an in-frame deletion (c.872_877del, p.Val291_Leu292del) and a nonsense mutation (c.868A > T, p.Lys290Ter), which are predicted to be pathogenic based on in silico analysis. Patients with AIP mutations tended to have an earlier onset of acromegaly and harboured larger and more invasive tumours. A previously described genetic variant of unknown significance (c.869C > T, p.Ala299Val) was identified in DNA from the Tampico Giant. The prevalence of AIP mutations in young Mexican patients with acromegaly is similar to that of European cohorts. Our results support the need for genetic evaluation of patients with early onset acromegaly.

Tuta absoluta (Meyrick) has quickly developed into a significant tomato pest worldwide. While the recently found mirid predators Macrolophus basicornis (Stal), Engytatus varians (Distant) and Campyloneuropsis infumatus (Carvalho) of this pest are able to establish and reproduce on tomato, biological knowledge of these mirids is still limited. Here we describe the functional response of the three mirid predators of the tomato pest T. absoluta when offered a range of prey densities (four, eight, 16, 32, 64, 128 and 256 eggs) during a 24 h period inside cylindrical plastic cages in the laboratory. Engytatus varians and M. basicornis showed a type III functional response, whereas C. infumatus showed a type II functional response. At the highest prey densities, C. infumatus consumed an average of 51.0 eggs, E. varians 91.1 eggs, and M. basicornis 100.8 eggs. Taking all information into account that we have collected of these three Neotropical mirid species, we predict that M. basicornis might be the best candidate for control of the tomato borer in Brazil: it has the highest fecundity, the largest maximum predation capacity, and it reacts in a density-dependent way to the widest prey range.
Competing Interests: The authors declare no conflict of interest. The founding sponsors had no role in the design of the study; in the collection, analyses, or interpretation of data; in the writing of the manuscript, and in the decision to publish the results.

CHLAMYDIA, CHLAMYDIA infections, SEXUALLY transmitted diseases, CHLAMYDIA trachomatis, DIAGNOSIS of genitalia diseases, DIAGNOSIS of bacterial diseases, CHLAMYDIA infection diagnosis, SEXUALLY transmitted disease diagnosis, ANUS, BACTERIAL diseases, CERVIX uteri, DEMOGRAPHY, MULTIVARIATE analysis, POISSON distribution, RECTUM, URETHRA, VAGINA, LOGISTIC regression analysis, SOCIOECONOMIC factors, CROSS-sectional method, BACTERIURIA, and OROPHARYNX

Objectives: To evaluate and compare Chlamydia trachomatis (CT) diagnostic test practices of different sexually transmitted infection (STI) care providers in 16-29 year olds from one defined geographic Dutch region (280,000 inhabitants). Both number and proportion of positive CT tests (ie, test positivity) were assessed, and factors associated with these outcomes.Methods: Data on laboratory testing and diagnosis of urogenital, anorectal and oropharyngeal CT between 2006 and 2010 were retrieved from general practitioners (GPs), gynaecologists, an STI clinic and a population-based chlamydia screening programme. Multivariable regression analyses explored associations between age, sex, test year, socio-economic status (SES) and STI care provider and the outcomes being the number of tests and test positivity.Results: Overall, 22,831 tests were performed (1868 positive; 8.2%). Extragenital (ie, anorectal and oropharyngeal) tests accounted for 4% of all tests (7.5% positive) and were almost exclusively (99%) performed by the STI clinic. STI clinics tested most men (37.2% of all tested men), whereas GPs tested most women (29.9% of all tested women). GPs and STI clinics accounted for 73.3% (1326/1808) of urogenital CT diagnoses. In women, the number of tests increased with age, whereas test positivity decreased for all STI care providers. Lower SES was associated with higher test positivity in GP and gynaecology patients.Conclusions: STI clinics performed most CT tests in men, whereas GPs performed most CT tests in women. GPs and STI clinics accounted for the majority of positives. Extragenital CT testing is rarely performed outside the STI clinic and needs to be promoted, especially in men who have sex with men. [ABSTRACT FROM AUTHOR]

Adenoma genetics, Adenoma pathology, Adolescent, Adult, Aged, Aged, 80 and over, Child, Child, Preschool, Female, Genetic Testing, Germ-Line Mutation, Growth Hormone-Secreting Pituitary Adenoma genetics, Growth Hormone-Secreting Pituitary Adenoma pathology, Humans, Longitudinal Studies, Male, Middle Aged, Mutation, Pituitary Neoplasms genetics, Pituitary Neoplasms pathology, Prospective Studies, Young Adult, Adenoma diagnosis, Growth Hormone-Secreting Pituitary Adenoma diagnosis, Intracellular Signaling Peptides and Proteins genetics, and Pituitary Neoplasms diagnosis

Context: Familial isolated pituitary adenoma (FIPA) due to aryl hydrocarbon receptor interacting protein (AIP) gene mutations is an autosomal dominant disease with incomplete penetrance. Clinical screening of apparently unaffected AIP mutation (AIPmut) carriers could identify previously unrecognized disease.
Objective: To determine the AIP mutational status of FIPA and young pituitary adenoma patients, analyzing their clinical characteristics, and to perform clinical screening of apparently unaffected AIPmut carrier family members.
Design: This was an observational, longitudinal study conducted over 7 years.
Setting: International collaborative study conducted at referral centers for pituitary diseases.
Participants: FIPA families (n 216) and sporadic young-onset (30 y) pituitary adenoma patients (n 404) participated in the study.
Interventions: We performed genetic screening of patients for AIPmuts, clinical assessment of their family members, and genetic screening for somatic GNAS1 mutations and the germline FGFR4 p.G388R variant.
Main Outcome Measure(s): We assessed clinical disease in mutation carriers, comparison of characteristics of AIPmut positive and negative patients, results of GNAS1, and FGFR4 analysis.
Results: Thirty-seven FIPA families and 34 sporadic patients had AIPmuts. Patients with truncating AIPmuts had a younger age at disease onset and diagnosis, compared with patients with nontruncating AIPmuts. Somatic GNAS1 mutations were absent in tumors from AIPmut-positive patients, and the studied FGFR4 variant did not modify the disease behavior or penetrance in AIPmut-positive individuals. A total of 164 AIPmut-positive unaffected family members were identified; pituitary disease was detected in 18 of those who underwent clinical screening.
Conclusions: A quarter of the AIPmut carriers screened were diagnosed with pituitary disease, justifying this screening and suggesting a variable clinical course for AIPmut-positive pituitary adenomas.

Adult, Aged, Aged, 80 and over, Antibodies, Monoclonal, Humanized, Carcinoma, Hepatocellular mortality, Carcinoma, Hepatocellular pathology, Confidence Intervals, Disease-Free Survival, Dose-Response Relationship, Drug, Double-Blind Method, Drug Administration Schedule, Female, Follow-Up Studies, Humans, Kaplan-Meier Estimate, Liver Neoplasms mortality, Liver Neoplasms pathology, Male, Middle Aged, Niacinamide therapeutic use, Patient Selection, Proportional Hazards Models, Remission Induction, Sorafenib, Survival Analysis, Time Factors, Treatment Outcome, Antibodies, Monoclonal therapeutic use, Carcinoma, Hepatocellular drug therapy, Liver Neoplasms drug therapy, Niacinamide analogs derivatives, and Phenylurea Compounds therapeutic use

Background: VEGF and VEGF receptor-2-mediated angiogenesis contribute to hepatocellular carcinoma pathogenesis. Ramucirumab is a recombinant IgG1 monoclonal antibody and VEGF receptor-2 antagonist. We aimed to assess the safety and efficacy of ramucirumab in advanced hepatocellular carcinoma following first-line therapy with sorafenib.
Methods: In this randomised, placebo-controlled, double-blind, multicentre, phase 3 trial (REACH), patients were enrolled from 154 centres in 27 countries. Eligible patients were aged 18 years or older, had hepatocellular carcinoma with Barcelona Clinic Liver Cancer stage C disease or stage B disease that was refractory or not amenable to locoregional therapy, had Child-Pugh A liver disease, an Eastern Cooperative Oncology Group performance status of 0 or 1, had previously received sorafenib (stopped because of progression or intolerance), and had adequate haematological and biochemical parameters. Patients were randomly assigned (1:1) to receive intravenous ramucirumab (8 mg/kg) or placebo every 2 weeks, plus best supportive care, until disease progression, unacceptable toxicity, or death. Randomisation was stratified by geographic region and cause of liver disease with a stratified permuted block method. Patients, medical staff, investigators, and the funder were masked to treatment assignment. The primary endpoint was overall survival in the intention-to-treat population. This study is registered with ClinicalTrials.gov, number NCT01140347.
Findings: Between Nov 4, 2010, and April 18, 2013, 565 patients were enrolled, of whom 283 were assigned to ramucirumab and 282 were assigned to placebo. Median overall survival for the ramucirumab group was 9·2 months (95% CI 8·0-10·6) versus 7·6 months (6·0-9·3) for the placebo group (HR 0·87 [95% CI 0·72-1·05]; p=0·14). Grade 3 or greater adverse events occurring in 5% or more of patients in either treatment group were ascites (13 [5%] of 277 patients treated with ramucirumab vs 11 [4%] of 276 patients treated with placebo), hypertension (34 [12%] vs ten [4%]), asthenia (14 [5%] vs five [2%]), malignant neoplasm progression (18 [6%] vs 11 [4%]), increased aspartate aminotransferase concentration (15 [5%] vs 23 [8%]), thrombocytopenia (13 [5%] vs one [<1%]), hyperbilirubinaemia (three [1%] vs 13 [5%]), and increased blood bilirubin (five [2%] vs 14 [5%]). The most frequently reported (≥1%) treatment-emergent serious adverse event of any grade or grade 3 or more was malignant neoplasm progression.
Interpretation: Second-line treatment with ramucirumab did not significantly improve survival over placebo in patients with advanced hepatocellular carcinoma. No new safety signals were noted in eligible patients and the safety profile is manageable.
Funding: Eli Lilly and Co.
(Copyright © 2015 Elsevier Ltd. All rights reserved.)

BIOLOGICAL control of plant parasites, LEPIDOPTERA, ENTOMOPHAGOUS insects, PREDATORY insects, and HORTICULTURE

Pest suppression through biological control seeks to maximize the action of the pest's natural enemies with the goal of reducing pesticide use. We present a summary of published studies and original findings on several entomophagous species as biocontrol agents of Tuta absoluta (Meyrick, 1917) (Lepidoptera: Gelechiidae), a key pest of tomato crops in Argentina, with the aim to select potential candidates for its management. Spontaneously occurring T. absoluta egg parasitism was lower than that inflicted by the larval parasitoids Dineulophus phthorimaeae (De Santis, 1983) (Hymenoptera: Eulophidae) and Pseudapanteles dignus (Muesebeck, 1938) (Hymenoptera: Braconidae). These parasitoids exhibit important life history traits in laboratory conditions and produce relevant amounts of T. absoluta mortality in the field. Surveys carried out in Tucumán and Buenos Aires provinces, Argentina, revealed that D. phthorimaeae and P. dignus coexist in tomato and eggplant crops; T. absoluta- P. dignus interaction is also found on other non-cultivated solanaceous species present in horticultural farms. In addition, studies are currently under way to determine the predation ability of Zelus obscuridorsis (Stål, 1860) (Hemiptera: Reduviidae) on both larvae and adults of the pest. Finally, we discuss the prospects for implementing experimental augmentative releases of P. dignus to control the pest, a candidate selected considering various positive biological traits and because of its simple mass production and manipulation compared with other antagonists of T. absoluta. [ABSTRACT FROM AUTHOR]

Adenoma epidemiology, Adrenal Gland Neoplasms epidemiology, Adult, Cohort Studies, Female, Genetic Association Studies, Genetic Testing, Humans, Male, Middle Aged, Paraganglioma epidemiology, Pheochromocytoma epidemiology, Pituitary Neoplasms epidemiology, Young Adult, Adenoma genetics, Adrenal Gland Neoplasms genetics, Genetic Heterogeneity, Genetic Predisposition to Disease, Paraganglioma genetics, Pheochromocytoma genetics, and Pituitary Neoplasms genetics

Context: Pituitary adenomas and pheochromocytomas/paragangliomas (pheo/PGL) can occur in the same patient or in the same family. Coexistence of the two diseases could be due to either a common pathogenic mechanism or a coincidence.
Objective: The objective of the investigation was to study the possible coexistence of pituitary adenoma and pheo/PGL.
Design: Thirty-nine cases of sporadic or familial pheo/PGL and pituitary adenomas were investigated. Known pheo/PGL genes (SDHA-D, SDHAF2, RET, VHL, TMEM127, MAX, FH) and pituitary adenoma genes (MEN1, AIP, CDKN1B) were sequenced using next generation or Sanger sequencing. Loss of heterozygosity study and pathological studies were performed on the available tumor samples.
Setting: The study was conducted at university hospitals.
Patients: Thirty-nine patients with sporadic of familial pituitary adenoma and pheo/PGL participated in the study.
Outcome: Outcomes included genetic screening and clinical characteristics.
Results: Eleven germline mutations (five SDHB, one SDHC, one SDHD, two VHL, and two MEN1) and four variants of unknown significance (two SDHA, one SDHB, and one SDHAF2) were identified in the studied genes in our patient cohort. Tumor tissue analysis identified LOH at the SDHB locus in three pituitary adenomas and loss of heterozygosity at the MEN1 locus in two pheochromocytomas. All the pituitary adenomas of patients affected by SDHX alterations have a unique histological feature not previously described in this context.
Conclusions: Mutations in the genes known to cause pheo/PGL can rarely be associated with pituitary adenomas, whereas mutation in a gene predisposing to pituitary adenomas (MEN1) can be associated with pheo/PGL. Our findings suggest that genetic testing should be considered in all patients or families with the constellation of pheo/PGL and a pituitary adenoma.

Adult, Aged, Blood Chemical Analysis, Case-Control Studies, Enzyme-Linked Immunosorbent Assay, Female, Hepcidins genetics, Humans, Kidney Failure, Chronic blood, Limit of Detection, Liver metabolism, Liver Diseases blood, Male, Middle Aged, RNA, Messenger metabolism, Tandem Mass Spectrometry, Young Adult, and Hepcidins blood

Background: Hepcidin-25 is a potential marker for iron disorders with a demand for accessible assays. This study aimed to evaluate a commercial competitive enzyme-linked immunosorbent assay (cELISA) for hepcidin quantitation.
Methods: Serum samples; 95 healthy subjects (HS), six patients with iron deficiency (ID), 84 patients with liver disorders (LD) and 220 hemodialysis patients (HD), were analyzed. Controls were used for imprecision, while accuracy was evaluated by quantitating hepcidin-25 with LC-MS/MS in 149 samples. Cross-reactivity for hepcidin-20 and hepcidin-22 was tested. Hepcidin-mRNA expression in 37 liver biopsies was measured.
Results: S-hepcidin ranged from 8-76 and 2-31 μg/L in healthy men and women. Levels in ID, LD and HD significantly differed from HS. Total coefficients of variation (CV) for controls were 24% and 22%. Within-sample CV was 10%. Despite a good correlation with LC-MS/MS (r = 0.89), the cELISA showed higher values and detected hepcidin-20 and hepcidin-22. Hepcidin-mRNA correlated well with S-hepcidin using cELISA and LC-MS/MS (r = 0.69 and 0.64).
Conclusions: The correlation with LC-MS/MS is good and the examined kit can differentiate between patient groups although it is not specific for hepcidin-25. Considering ELISA's capacity to readily be set up, the investigated kit can be applied. Specific reference ranges are required.

The aim of this paper is to report the differential diagnosis undertaken in a 47-year-old patient who was admitted for severe pancytopenia at the Department of Internal Medicine, Tomas Bata Regional Hospital in Zlín in August 2012. As the initial examinations regarding inflammation, tumours, infections and systemic diseases were negative, myelodysplastic syndrome was suspected. Trephine biopsy was performed, but myelodysplastic syndrome was not confirmed. The patient quickly became dependent on transfusions and suffered from recurrent infections. The differential diagnostic process was further complicated by the patient's repeated refusal to be hospitalized at the department of Internal Medicine. Repeated CT scans showed increasing splenomegaly and eventually multiple osteoplastic and mixed deposits in the pelvic bone appeared, pointing to a probable malignancy. The patient was referred for further investigation to the Department of Internal Medicine, Haematology and Oncology Clinic, University Hospital Brno-Bohunice. The indicated whole-body PET/CT found extensive deposits of viable tumour tissue in the chest wall. Histological samples were taken and corticosteroid treatment was started. However, this resulted in tumour lysis syndrome followed by kidney failure. The patient developed multiple organ failure with disseminated intravascular coagulopathy and died on the day that the histological diagnosis of undifferentiated sarcoma was made. [ABSTRACT FROM AUTHOR]

Aldehydes chemistry, Benzamides chemistry, Catalysis, Cyclohexanones chemistry, Hydrophobic and Hydrophilic Interactions, Naphthalimides chemistry, Proline chemistry, Spectrometry, Fluorescence, Stereoisomerism, Water chemistry, Nanoparticles chemistry, and Polymers chemistry

Here, a modular approach is reported to introduce a specific function into single-chain polymeric nanoparticles (SCPNs). Hereto, an amphiphilic polymer with pendant benzene-1,3,5-tricarboxamide (BTA) units is mixed with a "free" BTA that contains a functional group, either a fluorescent naphthalimide or a catalytically active l-proline. Taking advantage of hydrophobic interactions and self-recognition properties of the BTA units, the "free" BTAs are captured into the interior of the SCPN in water as evidenced by fluorescence studies. To illustrate that function can be readily introduced using a modular approach, l-proline-based BTAs are incorporated to procure a catalytically active SCPN in water. The aldol reaction between p-nitrobenzaldehyde and cyclohexanone shows good conversions at low catalyst loadings and substrate concentrations, and high stereoselectivities are obtained (de = 91% and ee = 98%).
(© 2014 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.)

ESSENTIAL oils, REPELLENTS, STINKBUGS, HEMIPTERA, LEMONGRASS oil, SPEARMINT oil, and METHYL benzoate

The brown marmorated stink bug ( BMSB), Halyomorpha halys ( Stål), native to Northeastern Asia, is a serious invasive pest in the United States, Canada, Switzerland, Germany and France. Several common essential oils and their compositions were tested against BMSBs as potential repellents. All the tested individual essential oils and a ternary oil blend showed significant repellency to both BMSB nymphs and adults. Clove oil, lemongrass oil, spearmint oil, ylang-ylang oil, and the ternary oil mixture (clove, lemongrass and spearmint) almost completely blocked attraction of BMSBs to the stink bug attractant-baited traps; whereas wintergreen oil, geranium oil, pennyroyal oil and rosemary oil resulted in 60-85% trap catch reductions. Over 20 BMSB antennally active compounds were identified from SPME headspace samples of the eight repellent essential oils using GC- EAD and GC- MS techniques. Among the synthetic EAD-active compounds tested in the field, eugenol, l-carvone, p/l-menthone, pulegone, methyl salicylate, trans/ cis-citral, methyl benzoate and β-caryophyllene significantly reduced trap catches of BMSBs by 72-99%; these compounds are likely responsible for the repellency of their corresponding essential oils. Surprisingly, a synthetic mixture of the predacious spined soldier bug ( SSB) [ Podisus maculiventris (Say)] aggregation pheromone ( trans-2-hexenal, α-terpineol and benzyl alcohol) also showed a significant inhibition of BMSB response to its attractants. These repellent essential oils and their active compounds, as well as the synthetic SSB pheromone, are potentially useful as part of an efficient, environmentally sound semiochemical-based IPM programme to combat this serious invasive stink bug. [ABSTRACT FROM AUTHOR]

Aged, Female, Genome, Human, Genome-Wide Association Study, Hemochromatosis complications, Hemochromatosis pathology, Hemochromatosis Protein, Homozygote, Humans, Iron metabolism, Male, Middle Aged, Polymorphism, Single Nucleotide, Risk Factors, Hemochromatosis genetics, Histocompatibility Antigens Class I genetics, Liver Cirrhosis genetics, Membrane Proteins genetics, and Subtilisins genetics

Genome-wide association studies (GWAS) have revealed genetic determinants of iron metabolism, but correlation of these with clinical phenotypes is pending. Homozygosity for HFE C282Y is the predominant genetic risk factor for hereditary hemochromatosis (HH) and may cause liver cirrhosis. However, this genotype has a low penetrance. Thus, detection of yet unknown genetic markers that identify patients at risk of developing severe liver disease is necessary for better prevention. Genetic loci associated with iron metabolism (TF, TMPRSS6, PCSK7, TFR2 and Chr2p14) in recent GWAS and liver fibrosis (PNPLA3) in recent meta-analysis were analyzed for association with either liver cirrhosis or advanced fibrosis in 148 German HFE C282Y homozygotes. Replication of associations was sought in additional 499 Austrian/Swiss and 112 HFE C282Y homozygotes from Sweden. Only variant rs236918 in the PCSK7 gene (proprotein convertase subtilisin/kexin type 7) was associated with cirrhosis or advanced fibrosis (P = 1.02 × 10(-5)) in the German cohort with genotypic odds ratios of 3.56 (95% CI 1.29-9.77) for CG heterozygotes and 5.38 (95% CI 2.39-12.10) for C allele carriers. Association between rs236918 and cirrhosis was confirmed in Austrian/Swiss HFE C282Y homozygotes (P = 0.014; ORallelic = 1.82 (95% CI 1.12-2.95) but not in Swedish patients. Post hoc combined analyses of German/Swiss/Austrian patients with available liver histology (N = 244, P = 0.00014, ORallelic = 2.84) and of males only (N = 431, P = 2.17 × 10(-5), ORallelic = 2.54) were consistent with the premier finding. Association between rs236918 and cirrhosis was not confirmed in alcoholic cirrhotics, suggesting specificity of this genetic risk factor for HH. PCSK7 variant rs236918 is a risk factor for cirrhosis in HH patients homozygous for the HFE C282Y mutation.
(© The Author 2014. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.)

In Arabidopsis thaliana, seven cyclin-dependent kinase (CDK) inhibitors have been identified, designated interactors of CDKs or Kip-related proteins (KRPs). Here, the function of KRP6 was investigated during cell cycle progression in roots infected by plant-parasitic root-knot nematodes. Contrary to expectations, analysis of Meloidogyne incognita-induced galls of KRP6-overexpressing lines revealed a role for this particular KRP as an activator of the mitotic cell cycle. In accordance, KRP6-overexpressing suspension cultures displayed accelerated entry into mitosis, but delayed mitotic progression. Likewise, phenotypic analysis of cultured cells and nematode-induced giant cells revealed a failure in mitotic exit, with the appearance of multinucleated cells as a consequence. Strong KRP6 expression upon nematode infection and the phenotypic resemblance between KRP6 overexpression cell cultures and root-knot morphology point toward the involvement of KRP6 in the multinucleate and acytokinetic state of giant cells. Along these lines, the parasite might have evolved to manipulate plant KRP6 transcription to the benefit of gall establishment.
(© 2014 American Society of Plant Biologists. All rights reserved.)

Androstadienes therapeutic use, Antineoplastic Agents, Hormonal pharmacology, Aromatase Inhibitors therapeutic use, Biomarkers, Tumor genetics, Breast pathology, Breast Neoplasms genetics, Breast Neoplasms pathology, Cell Line, Tumor, Cell Proliferation drug effects, Cell Survival drug effects, Enzyme Activators pharmacology, ErbB Receptors antagonists inhibitors, Erlotinib Hydrochloride, Estrogen Receptor alpha antagonists inhibitors, Estrogen Receptor alpha genetics, Female, Gene Expression Regulation, Neoplastic, Genetic Association Studies, Genetic Variation, Humans, Letrozole, MCF-7 Cells, Nitriles therapeutic use, Protein Kinase Inhibitors pharmacology, Quinazolines pharmacology, RNA Interference, RNA, Small Interfering, Tamoxifen pharmacology, Tamoxifen therapeutic use, Toremifene pharmacology, Toremifene therapeutic use, Triazoles therapeutic use, Breast Neoplasms drug therapy, Drug Resistance, Neoplasm genetics, Estrogen Receptor alpha metabolism, Indazoles pharmacology, and Proto-Oncogene Proteins c-vav genetics

Introduction: Endocrine therapies targeting cell proliferation and survival mediated by estrogen receptor α (ERα) are among the most effective systemic treatments for ERα-positive breast cancer. However, most tumors initially responsive to these therapies acquire resistance through mechanisms that involve ERα transcriptional regulatory plasticity. Herein we identify VAV3 as a critical component in this process.
Methods: A cell-based chemical compound screen was carried out to identify therapeutic strategies against resistance to endocrine therapy. Binding to ERα was evaluated by molecular docking analyses, an agonist fluoligand assay and short hairpin (sh)RNA-mediated protein depletion. Microarray analyses were performed to identify altered gene expression. Western blot analysis of signaling and proliferation markers, and shRNA-mediated protein depletion in viability and clonogenic assays, were performed to delineate the role of VAV3. Genetic variation in VAV3 was assessed for association with the response to tamoxifen. Immunohistochemical analyses of VAV3 were carried out to determine its association with therapeutic response and different tumor markers. An analysis of gene expression association with drug sensitivity was carried out to identify a potential therapeutic approach based on differential VAV3 expression.
Results: The compound YC-1 was found to comparatively reduce the viability of cell models of acquired resistance. This effect was probably not due to activation of its canonical target (soluble guanylyl cyclase), but instead was likely a result of binding to ERα. VAV3 was selectively reduced upon exposure to YC-1 or ERα depletion, and, accordingly, VAV3 depletion comparatively reduced the viability of cell models of acquired resistance. In the clinical scenario, germline variation in VAV3 was associated with the response to tamoxifen in Japanese breast cancer patients (rs10494071 combined P value = 8.4 × 10-4). The allele association combined with gene expression analyses indicated that low VAV3 expression predicts better clinical outcome. Conversely, high nuclear VAV3 expression in tumor cells was associated with poorer endocrine therapy response. Based on VAV3 expression levels and the response to erlotinib in cancer cell lines, targeting EGFR signaling may be a promising therapeutic strategy.
Conclusions: This study proposes VAV3 as a biomarker and a rationale for its use as a signaling target to prevent and/or overcome resistance to endocrine therapy in breast cancer.

Biomarkers, Tumor metabolism, Breast Neoplasms genetics, Breast Neoplasms metabolism, Cadherins metabolism, Colorectal Neoplasms genetics, Colorectal Neoplasms metabolism, Epithelial-Mesenchymal Transition genetics, Gene Expression Regulation, Neoplastic genetics, Homeodomain Proteins metabolism, Humans, Immunohistochemistry, In Situ Hybridization, Laser Capture Microdissection, Liver Neoplasms secondary, Real-Time Polymerase Chain Reaction, Reverse Transcriptase Polymerase Chain Reaction, Survival Analysis, Transcription Factors metabolism, Zinc Finger E-box-Binding Homeobox 1, Breast Neoplasms physiopathology, Colorectal Neoplasms physiopathology, Epithelial-Mesenchymal Transition physiology, Gene Expression Regulation, Neoplastic physiology, Liver Neoplasms metabolism, MicroRNAs metabolism, and Signal Transduction physiology

The role of the epithelial-mesenchymal transition (EMT) in cancer has been studied extensively in vitro, but involvement of the EMT in tumorigenesis in vivo is largely unknown. We investigated the potential of microRNAs as clinical markers and analyzed participation of the EMT-associated microRNA-200-ZEB-E-cadherin pathway in cancer progression. Expression of the microRNA-200 family was quantified by real-time RT-PCR analysis of fresh-frozen and microdissected formalin-fixed paraffin-embedded primary colorectal tumors, normal colon mucosa, and matched liver metastases. MicroRNA expression was validated by in situ hybridization and after in vitro culture of the malignant cells. To assess EMT as a predictive marker, factors considered relevant in colorectal cancer were investigated in 98 primary breast tumors from a treatment-randomized study. Associations between the studied EMT-markers were found in primary breast tumors and in colorectal liver metastases. MicroRNA-200 expression in epithelial cells was lower in malignant mucosa than in normal mucosa, and was also decreased in metastatic compared to non-metastatic colorectal cancer. Low microRNA-200 expression in colorectal liver metastases was associated with bad prognosis. In breast cancer, low levels of microRNA-200 were related to reduced survival and high expression of microRNA-200 was predictive of benefit from radiotheraphy. MicroRNA-200 was associated with ER positive status, and inversely correlated to HER2 and overactivation of the PI3K/AKT pathway, that was associated with high ZEB1 mRNA expression. Our findings suggest that the stability of microRNAs makes them suitable as clinical markers and that the EMT-related microRNA-200-ZEB-E-cadherin signaling pathway is connected to established clinical characteristics and can give useful prognostic and treatment-predictive information in progressive breast and colorectal cancers.

Introduction. Current curative treatment of acute myeloid leukemia is based on intensive chemotherapy and hematopoietic stem cell transplantation with a significant risk of severe adverse effects, including leukemogenic and cancerogenic ones. Objectives. The study is aimed at assessing of incidence and types of malignant tumours in successfully treated acute myeloid leukemia patients. Methods. A retrospective analysis consists of 256 patients diagnosed with acute myeloid leukemia at the Department of Hemato-Oncology in Olomouc in 1996-2008 who were treated with intensive chemotherapy and achieved complete remission of the disease. Results. Second malignancy occurred in 11 individuals (4.3%) after successful treatment of acute myeloid leukemia. Observed age-standardized incidence of these tumours, 8.29/1,000 person-years, 95% Cl = (2.99; 13.58), was not significantly different from the incidence in population. Five patients died of the second malignancy. [ABSTRACT FROM AUTHOR]

Animals, Bacillus thuringiensis Toxins, Binding Sites, Insect Control, Insect Proteins metabolism, Microvilli metabolism, Peptide Hydrolases metabolism, Proteolysis, Bacterial Proteins metabolism, Endotoxins metabolism, Hemiptera metabolism, and Hemolysin Proteins metabolism

To understand the low toxicity of Cry toxins in planthoppers, proteolytic activation of Cry1Ab in Nilaparvata lugens was studied. The proteolytic processing of Cry1Ab protoxin by N. lugens midgut proteases was similar to that by trypsin activated Cry1Ab. The Cry1Ab processed with N. lugens midgut proteases was highly insecticidal against Plutella xylostella. However, Cry1Ab activated either by trypsin or the gut proteases of the brown planthopper showed low toxicity in N. lugens. Binding analysis showed that activated Cry1Ab bound to brush border membrane vesicles (BBMV) from N. lugens at a significantly lower level than to BBMV from P. xylostella.
(Copyright © 2013 Elsevier Inc. All rights reserved.)

Escherichia coli isolation purification, Escherichia coli Infections microbiology, Humans, Microbial Sensitivity Tests methods, Microbial Sensitivity Tests standards, Sepsis microbiology, beta-Lactam Resistance, Amoxicillin pharmacology, Anti-Bacterial Agents pharmacology, Clavulanic Acid pharmacology, and Escherichia coli drug effects

Objectives: The CLSI recommends a fixed 2 : 1 ratio of co-amoxiclav for broth microdilution susceptibility testing of Enterobacteriaceae, while EUCAST recommends a fixed 2 mg/L clavulanate concentration. The aims of this study were: (i) to determine the influence of a switch from CLSI to EUCAST methodology on Escherichia coli susceptibility rates; (ii) to compare susceptibility results obtained using EUCAST-compliant microdilution with those from disc diffusion and the Etest; and (iii) to evaluate the clinical outcome of patients with E. coli sepsis treated with co-amoxiclav in relation to the susceptibility results obtained using either method.
Methods: Resistance rates were determined in three laboratories that switched from CLSI to EUCAST cards with the Phoenix system (Becton Dickinson) as well as in 17 laboratories that continued to use CLSI cards with the VITEK 2 system (bioMérieux). In one laboratory, isolates were simultaneously tested by both the Phoenix system and either disc diffusion (n = 471) or the Etest (n = 113). Medical and laboratory records were reviewed for E. coli sepsis patients treated with co-amoxiclav monotherapy.
Results: Only laboratories that switched methodology showed an increase in resistance rates - from 19% in 2010 to 31% in 2011 (P < 0.0001). All isolates that tested susceptible by microdilution were also susceptible by disc diffusion or the Etest, but of 326 isolates that tested resistant by microdilution, 43% and 59% tested susceptible by disc diffusion and the Etest, respectively. Among the 89 patients included there was a better correlation between clinical response and measured MICs using the Phoenix system than the Etest.
Conclusions: EUCAST methodology resulted in higher co-amoxiclav E. coli resistance rates than CLSI methodology, but correlated better with clinical outcome. EUCAST-compliant microdilution and disc diffusion provided discrepant results.

Animals, Bacterial Proteins genetics, Chi-Square Distribution, DNA, Bacterial analysis, DNA, Bacterial genetics, Drug Resistance, Bacterial, Escherichia coli genetics, Escherichia coli isolation purification, Escherichia coli Infections microbiology, Humans, Microbial Sensitivity Tests, beta-Lactamases metabolism, Anti-Bacterial Agents pharmacology, Escherichia coli drug effects, Escherichia coli enzymology, Meat microbiology, Poultry microbiology, and beta-Lactamases genetics

The concurrent presence of bla CTX-M-1 and bla TEM-52 genes on similar plasmids of Escherichia coli isolated from poultry, chicken meat and humans supports the occurrence of food-borne transmission of extended-spectrum beta-lactamase (ESBL) genes. ESBL-producing E. coli (ESBL-E. coli) are most frequently detected in hospitalised patients and are known to spread in healthcare settings. We hypothesised that poultry-associated (PA) ESBL genes are predominant in the community, where acquisition is fuelled by food contamination, whereas non-PA ESBL genes are predominant in hospitals, with acquisition fuelled by cross-transmission. Then, differences in antimicrobial selective pressure in hospitals and poultry would create differences in co-resistance between PA and non-PA ESBL-E. coli. We, therefore, determined the prevalence and co-resistance of PA and non-PA ESBL-E. coli in community-acquired and nosocomial urinary tract infections in humans and bla CTX-M-1 and bla TEM-52 isolates from poultry. A total of 134 human ESBL-E. coli urine isolates were included in this study. Isolates containing bla CTX-M-1 or bla TEM-52 were considered to be PA, with the remainder being non-PA. Also, 72 poultry ESBL-E. coli were included. Minimum inhibitory concentration (MIC) values were determined by broth microdilution. The prevalence of PA ESBL genes in isolates obtained in general practice and hospitals was 28 % versus 30 % (n.s.). Human PA ESBL-E. coli were more frequently susceptible to ciprofloxacin (51 % vs. 25 %; p = 0.0056), gentamicin (86 % vs. 63 %; p = .0.0082), tobramycin (91 % vs. 34 %; p = 0.0001) and amikacin (98 % vs. 67 %; p = 0.0001) compared to human non-PA ESBL-E. coli. PA ESBL-E. coli are not more prevalent in community acquired than nosocomial urine samples, but are more often susceptible to ciprofloxacin and aminoglycosides than non-PA ESBL-E. coli. This does not support the existence of different reservoirs of ESBL genes.

Biomarkers, Tumor metabolism, Female, Humans, Middle Aged, Phosphorylation, Postmenopause, Predictive Value of Tests, Receptors, Estrogen metabolism, Retrospective Studies, Serine metabolism, Treatment Outcome, Antineoplastic Agents, Hormonal pharmacology, Breast Neoplasms drug therapy, Breast Neoplasms metabolism, Proto-Oncogene Proteins c-akt metabolism, TOR Serine-Threonine Kinases metabolism, and Tamoxifen pharmacology

The frequent alterations of the PI3K/Akt/mTOR-growth signaling pathway are proposed mechanisms for resistance to endocrine therapy in breast cancer, partly through regulation of estrogen receptor α (ER) activity. Reliable biomarkers for treatment prediction are required for improved individualized treatment. We performed a retrospective immunohistochemical analysis of primary tumors from 912 postmenopausal patients with node-negative breast cancer, randomized to either tamoxifen or no adjuvant treatment. Phosphorylated (p) Akt-serine (s) 473, p-mTOR-s2448, and ER phosphorylations-s167 and -s305 were evaluated as potential biomarkers of prognosis and tamoxifen treatment efficacy. High expression of p-mTOR indicated a reduced response to tamoxifen, most pronounced in the ER+/progesterone receptor (PgR) + subgroup (tamoxifen vs. no tamoxifen: hazard ratio (HR), 0.86; 95 % confidence interval (CI), 0.31-2.38; P = 0.78), whereas low p-mTOR expression predicted tamoxifen benefit (HR, 0.29; 95 % CI, 0.18-0.49; P = 0.000002). In addition, nuclear p-Akt-s473 as well as p-ER at -s167 and/or -s305 showed interaction with tamoxifen efficacy with borderline statistical significance. A combination score of positive pathway markers including p-Akt, p-mTOR, and p-ER showed significant association with tamoxifen benefit (test for interaction; P = 0.029). Cross-talk between growth signaling pathways and ER-signaling has been proposed to affect tamoxifen response in hormone receptor-positive breast cancer. The results support this hypothesis, as an overactive pathway was significantly associated with reduced response to tamoxifen. A clinical pre-treatment test for cross-talk markers would be a step toward individualized adjuvant endocrine treatment with or without the addition of PI3K/Akt/mTOR pathway inhibitors.

Biota, DNA Primers genetics, Databases, Genetic, Ecology methods, Microsatellite Repeats, and Polymorphism, Single Nucleotide

This article documents the addition of 473 microsatellite marker loci and 71 pairs of single-nucleotide polymorphism (SNP) sequencing primers to the Molecular Ecology Resources Database. Loci were developed for the following species: Barteria fistulosa, Bombus morio, Galaxias platei, Hematodinium perezi, Macrocentrus cingulum Brischke (a.k.a. M. abdominalis Fab., M. grandii Goidanich or M. gifuensis Ashmead), Micropogonias furnieri, Nerita melanotragus, Nilaparvata lugens Stål, Sciaenops ocellatus, Scomber scombrus, Spodoptera frugiperda and Turdus lherminieri. These loci were cross-tested on the following species: Barteria dewevrei, Barteria nigritana, Barteria solida, Cynoscion acoupa, Cynoscion jamaicensis, Cynoscion leiarchus, Cynoscion nebulosus, Cynoscion striatus, Cynoscion virescens, Macrodon ancylodon, Menticirrhus americanus, Nilaparvata muiri and Umbrina canosai. This article also documents the addition of 116 sequencing primer pairs for Dicentrarchus labrax.
(© 2012 Blackwell Publishing Ltd.)

Animals, Brazil, DNA, Bacterial analysis, Hemiptera classification, Insect Vectors classification, Phytoplasma classification, Phytoplasma genetics, Phytoplasma isolation purification, Polymerase Chain Reaction, Population Density, Sequence Analysis, DNA, Species Specificity, Citrus microbiology, Hemiptera microbiology, Insect Vectors microbiology, Phytoplasma physiology, Plant Diseases microbiology, and Plant Weeds growth development

Huanglongbing (HLB) is a severe citrus (Citrus spp.) disease associated with the bacteria genus Candidatus Liberibacter, detected in Brazil in 2004. Another bacterium was found in association with HLB symptoms and characterized as a phytoplasma belonging to the 16SrIX group. The objectives of this study were to identify potential leafhopper vectors of the HLB-associated phytoplasma and their host plants. Leafhoppers were sampled every other week for 12 mo with sticky yellow cards placed at two heights (0.3 and 1.5 m) in the citrus tree canopy and by using a sweep net in the ground vegetation of two sweet orange, Citrus sinensis (L.) Osbeck, groves infected by the HLB-phytoplasma in São Paulo state. Faunistic analyses indicated one Agalliinae (Agallia albidula Uhler) and three Deltocephalinae [Balclutha hebe (Kirkaldy), Planicephalus flavicosta (Stål), and Scaphytopius (Convelinus) marginelineatus (Stål)] species, as the most abundant and frequent leafhoppers (Hemiptera: Cicadellidae). Visual observations indicated an association of leafhopper species with some weeds and the influence of weed species composition on leafhopper abundance in low-lying vegetation. S. marginelineatus and P. flavicosta were more frequent on Sida rhombifolia L. and Althernantera tenella Colla, respectively, whereas A. albidula was observed more often on Conyza bonariensis (L.) Cronq. and B. hebe only occurred on grasses. DNA samples of field-collected S. marginelineatus were positive by polymerase chain reaction and sequencing tests for the presence of the HLB-phytoplasma group, indicating it as a potential vector. The association of leafhoppers with their hosts may be used in deciding which management strategies to adopt against weeds and diseases in citrus orchards.

Adolescent, Adult, Aged, Bacterial Proteins genetics, Bacterial Typing Techniques, Child, Child, Preschool, Enterobacteriaceae classification, Humans, Infant, Infant, Newborn, Microbial Sensitivity Tests, Middle Aged, Netherlands, Young Adult, Anti-Bacterial Agents pharmacology, Cephalosporin Resistance genetics, Cephalosporins pharmacology, Enterobacteriaceae drug effects, Enterobacteriaceae genetics, and beta-Lactamases genetics

There is a global increase in infections caused by Enterobacteriaceae with plasmid-borne β-lactamases that confer resistance to third-generation cephalosporins. The epidemiology of these bacteria is not well understood, and was, therefore, investigated in a selection of 636 clinical Enterobacteriaceae with a minimal inhibitory concentration >1 mg/L for ceftazidime/ceftriaxone from a national survey (75% E. coli, 11% E. cloacae, 11% K. pneumoniae, 2% K. oxytoca, 2% P. mirabilis). Isolates were investigated for extended-spectrum β-lactamases (ESBLs) and ampC genes using microarray, PCR, gene sequencing and molecular straintyping (Diversilab and multi-locus sequence typing (MLST)). ESBL genes were demonstrated in 512 isolates (81%); of which 446 (87%) belonged to the CTX-M family. Among 314 randomly selected and sequenced isolates, bla(CTX-M-15) was most prevalent (n = 124, 39%), followed by bla(CTX-M-1) (n = 47, 15%), bla(CTX-M-14) (n = 15, 5%), bla(SHV-12) (n = 24, 8%) and bla(TEM-52) (n = 13, 4%). Among 181 isolates with MIC ≥16 mg/L for cefoxitin plasmid encoded AmpCs were detected in 32 and 27 were of the CMY-2 group. Among 102 E. coli isolates with MIC ≥16 mg/L for cefoxitin ampC promoter mutations were identified in 29 (28%). Based on Diversilab genotyping of 608 isolates (similarity cut-off >98%) discriminatory indices of bacteria with ESBL and/or ampC genes were 0.994, 0.985 and 0.994 for E. coli, K. pneumoniae and E. cloacae, respectively. Based on similarity cut-off >95% two large clusters of E. coli were apparent (of 43 and 30 isolates) and 21 of 21 that were typed by belonged to ST131 of which 13 contained bla(CTX-M-15). Our findings demonstrate that bla(CTX-M-15) is the most prevalent ESBL and we report a larger than previously reported prevalence of ampC genes among Enterobacteriaceae responsible for resistance to third-generation cephalosporins.

Animals, Argentina, Enzyme-Linked Immunosorbent Assay, Female, Hemiptera physiology, Insect Vectors physiology, Male, Microscopy, Electron, Polymerase Chain Reaction, Spiroplasma physiology, Zea mays physiology, Hemiptera microbiology, Insect Vectors microbiology, Plant Diseases microbiology, and Zea mays microbiology

"Corn stunt" caused by the mollicute Spiroplasma kunkelii (Whitcomb) is potentially one of the most severe diseases affecting the corn (Zea mays L.) crop in the Americas, and the leafhopper Dalbulus maidis (DeLong & Wolcott) is considered its most important vector. However, other insects seen quite frequently in corn crops might well be its vectors in Argentina To identify any leafhoppers species other than D. maidis that can transmit S. kunkelii, transmission assays were conducted, using individuals of Exitianus obscurinervis (Stål) collected in field and reared under controlled conditions. S. kunkelii was transmitted to corn plants by E. obscurinervis. The pathogen was transmitted to seven of the 11 plants, which showed characteristic corn stunt symptoms, and the presence of the pathogen was confirmed by DAS-ELISA. The presence of S. kunkelii in the E. obscurinervis individuals used in transmission experiments was confirmed by polymerase chain reaction and electron microscopy. The current study shows the existence of a new experimental vector of S. kunkelii, the leafhopper E. obscurinervis, which acquired spiroplasmas from infected plants and inoculated it to healthy plants.

Animals, Brazil, Circadian Rhythm, Climate, Demography, Ecosystem, Genetic Variation, Species Specificity, Temperature, Arecaceae genetics, Arecaceae parasitology, and Rhodnius genetics

This work evaluated the occurrence and genetic structure of Rhodnius nasutus sampled in two sites using morphometry and microsatellites. These sites, presented distinct abiotic features and palm trees: (i) nine Attalea speciosa palm trees, so called babaçu, were sampled from the Meruoca Mountain Ridge, a sloping region of reminiscent forest in the state of Ceará, Brazil, and (ii) 17 Copernicia prunifera palm trees, so called carnaúba, were sampled in the scrub savanna region (Sobral district) that surrounds the mountain ridge. Of the twenty-six palm trees dissected, 70.6% of carnauba and 88.9% of babaçu were infested by R. nasutus. The micro-climatic data where R. nasutus were sheltered demonstrated that the babaçu and carnaúba palm trees presented significant differences (p < 0.05) in relation to the external environment, except for temperature and relative humidity regulation, suggesting that the architecture of the babaçu crown keeps a more stable micro-environment. The morphometric studies of the F1 generation demonstrated that insects from the babaçu (A. speciosa) were significantly larger (p = 0.000) than those collected in carnaúba (C. prunifera) palm trees. Also, microsatellite analysis demonstrated a high genetic differentiation between the two groups of R. nasutus (R(st) = -0.77). Our results suggest that the difference in size between the populations is probably related to an incipient process of genetic drift in populations associated to each palm tree, probably also driven by the different climatic features observed in these micro-environments.
(Copyright © 2011 Elsevier B.V. All rights reserved.)

Animals, Bacterial Typing Techniques, Carrier State microbiology, Cluster Analysis, Escherichia coli isolation purification, Genotype, Humans, Molecular Epidemiology, Molecular Typing, Multilocus Sequence Typing, Netherlands, Plasmids analysis, Polymerase Chain Reaction, Zoonoses microbiology, Carrier State veterinary, Escherichia coli enzymology, Escherichia coli genetics, Escherichia coli Infections microbiology, Meat microbiology, Poultry microbiology, and beta-Lactamases genetics

Intestinal carriage of extended-spectrum beta-lactamase (ESBL) -producing bacteria in food-producing animals and contamination of retail meat may contribute to increased incidences of infections with ESBL-producing bacteria in humans. Therefore, distribution of ESBL genes, plasmids and strain genotypes in Escherichia coli obtained from poultry and retail chicken meat in the Netherlands was determined and defined as 'poultry-associated' (PA). Subsequently, the proportion of E. coli isolates with PA ESBL genes, plasmids and strains was quantified in a representative sample of clinical isolates. The E. coli were derived from 98 retail chicken meat samples, a prevalence survey among poultry, and 516 human clinical samples from 31 laboratories collected during a 3-month period in 2009. Isolates were analysed using an ESBL-specific microarray, sequencing of ESBL genes, PCR-based replicon typing of plasmids, plasmid multi-locus sequence typing (pMLST) and strain genotyping (MLST). Six ESBL genes were defined as PA (bla(CTX-M-1) , bla(CTX-M-2) , bla(SHV-2) , bla(SHV-12) , bla(TEM-20) , bla(TEM-52) ): 35% of the human isolates contained PA ESBL genes and 19% contained PA ESBL genes located on IncI1 plasmids that were genetically indistinguishable from those obtained from poultry (meat). Of these ESBL genes, 86% were bla(CTX-M-1) and bla(TEM-52) genes, which were also the predominant genes in poultry (78%) and retail chicken meat (75%). Of the retail meat samples, 94% contained ESBL-producing isolates of which 39% belonged to E. coli genotypes also present in human samples. These findings are suggestive for transmission of ESBL genes, plasmids and E. coli isolates from poultry to humans, most likely through the food chain.
(2011 The Authors. Clinical Microbiology and Infection; 2011 European Society of Clinical Microbiology and Infectious Diseases.)

RHODNIUS, CONENOSES, CLASSIFICATION of insects, and SPECIES diversity

Tribe Rhodniini includes Rhodnius Stål and Psammolestes Bergroth. Enzymatic and molecular evidence suggest the tribe is monophyletic. Most species are wild, living in palms and bird nests. Traditionally both genera were considered related; nevertheless, molecular studies don't support the Rhodnius monophyly. The goal was to phylogenetically analyze morphometric variation in wing architecture in support of Rhodniini taxonomy and systematics. We photographed 524 wings of five representatives of Rhodniini: Psammolestes arthuri (Pinto) (n = 89), Rhodnius pictipes Stål (n = 21), R. robustus Larrousse (n = 24), R. prolixus Stål (n = 16), and R. neivai Lent (n = 22). As outgroups we studied four representatives of Triatomini: Eratyrus mucronatus Stål (n = 15), Panstrongylus rufotuberculatus (Champion) (n = 45), P. geniculatus (Latreille) (n = 183), and Triatoma maculata (Erichson) (n = 109). Landmark coordinate (x, y) configurations were registered and aligned by Generalized Procrustes Analysis. Covariance Analyses were implemented with proportions of re-classified groups and MANOVA. Then, wing shape variables (confidence intervals from relative warps) and centroid size were cladistically analysed. Statistical analyses of variance found not significant differences in wing isometric size (Kruskal-Wallis) among P. arthuri-R. neivai-R. pictipes; R. robustus-R. prolixus-T. maculata and between P. rufotuberculatus-P. geniculatus. The a posteriori re-classification was perfect in E. mucrunatus 100% and R. pictipes, followed by T. maculata 96%, R. neivai 95%, P arthuri 93.2%; R. prolixus 87.5%, P. geniculatus 87.4%, P. rufotuberculatus 84.4%, and R. robustus 76%. Cladistic analyses under parsimony selected two most parsimonious trees (L=4.461 IC=0.973 and IR=0.979), where the strict consensus showed a monophyletic group with Panstrongylus (rufotuberculatus + geniculatus) and Triatoma + Rhodniini (Rhodinus + Psammolestes), but internally it shows the paraphyly of Rhodnius regarding Psammolestes. The congruence between these results and previous molecular analyses in Rhodniini, reveal the phylogenetic information of our morphometric characters as support to systematic studies, allowing the combination of geometric morphometrics and phylogenetic methods for the first time in this group. [ABSTRACT FROM AUTHOR]

COMPARTMENT syndrome, THERAPEUTICS, ANALYSIS of variance, CAPILLARIES, CHI-squared test, COMPUTER software, EXERCISE, IMMUNOHISTOCHEMISTRY, LEG, LONGITUDINAL method, MICROCIRCULATION, MUSCLES, RESEARCH funding, STRIATED muscle, T-test (Statistics), DATA analysis, CASE-control method, ANALYTICAL chemistry, PATHOLOGY, DONOR blood supply, and FASCIAE surgery

There is a paucity of data regarding the pathogenesis of chronic exertional compartment syndrome (CECS), its consequences for the muscles and the effects of treatment with fasciotomy. We analyzed biopsies from the tibialis anterior muscle, from nine patients, obtained during a decompressing fasciotomy and during follow-up 1 year later. Control biopsies were obtained from nine normal subjects. Muscle capillarity, fiber-type composition and fiber area were analyzed with enzyme- and immunohistochemistry and morphometry. At baseline, CECS patients had lower capillary density (273 vs 378 capillaries/mm, P=0.008), lower number of capillaries around muscle fibers (4.5 vs 5.7, P=0.004) and lower number of capillaries in relation to the muscle fiber area (1.1 vs 1.5, P=0.01) compared with normal controls. The fiber-type composition and fiber area did not differ, but focal signs of neuromuscular damage were observed in the CECS samples. At 1-year follow-up after fasciotomy, the fiber area and the number of fibers containing developmental myosin heavy chains were increased, but no enhancement of the capillary network was detected. Thus, morphologically, patients with CECS seemed to have reduced microcirculation capacity. Fasciotomy appeared to trigger a regenerative response in the muscle, however, without any increase in the capillary bed. [ABSTRACT FROM AUTHOR]

Computational Biology, Cyclin-Dependent Kinases metabolism, Cyclins metabolism, DNA Replication, Luciferases metabolism, Mitosis, Models, Biological, Multiprotein Complexes metabolism, Protein Binding, Protein Interaction Mapping, Reproducibility of Results, Arabidopsis cytology, Arabidopsis metabolism, Arabidopsis Proteins metabolism, Cell Cycle, and Cell Cycle Proteins metabolism

Cell proliferation is the main driving force for plant growth. Although genome sequence analysis revealed a high number of cell cycle genes in plants, little is known about the molecular complexes steering cell division. In a targeted proteomics approach, we mapped the core complex machinery at the heart of the Arabidopsis thaliana cell cycle control. Besides a central regulatory network of core complexes, we distinguished a peripheral network that links the core machinery to up- and downstream pathways. Over 100 new candidate cell cycle proteins were predicted and an in-depth biological interpretation demonstrated the hypothesis-generating power of the interaction data. The data set provided a comprehensive view on heterodimeric cyclin-dependent kinase (CDK)-cyclin complexes in plants. For the first time, inhibitory proteins of plant-specific B-type CDKs were discovered and the anaphase-promoting complex was characterized and extended. Important conclusions were that mitotic A- and B-type cyclins form complexes with the plant-specific B-type CDKs and not with CDKA;1, and that D-type cyclins and S-phase-specific A-type cyclins seem to be associated exclusively with CDKA;1. Furthermore, we could show that plants have evolved a combinatorial toolkit consisting of at least 92 different CDK-cyclin complex variants, which strongly underscores the functional diversification among the large family of cyclins and reflects the pivotal role of cell cycle regulation in the developmental plasticity of plants.

Adult, Alternative Splicing genetics, Amino Acid Sequence, Animals, Cell Line, Cyclic AMP metabolism, Cyclic AMP-Dependent Protein Kinases metabolism, Family, Female, Gene Expression Regulation, Neoplastic, Humans, Intracellular Signaling Peptides and Proteins chemistry, Intracellular Signaling Peptides and Proteins metabolism, Male, Middle Aged, Molecular Sequence Data, Mutant Proteins genetics, Mutant Proteins metabolism, Mutation, Missense genetics, Pedigree, Pituitary Neoplasms enzymology, Promoter Regions, Genetic genetics, RNA Splice Sites genetics, RNA, Messenger genetics, RNA, Messenger metabolism, Rats, Signal Transduction, Intracellular Signaling Peptides and Proteins genetics, Mutation genetics, and Pituitary Neoplasms genetics

Familial isolated pituitary adenoma (FIPA) is an autosomal dominant condition with variable genetic background and incomplete penetrance. Germline mutations of the aryl hydrocarbon receptor interacting protein (AIP) gene have been reported in 15-40% of FIPA patients. Limited data are available on the functional consequences of the mutations or regarding the regulation of the AIP gene. We describe a large cohort of FIPA families and characterize missense and silent mutations using minigene constructs, luciferase and beta-galactosidase assays, as well as in silico predictions. Patients with AIP mutations had a lower mean age at diagnosis (23.6+/-11.2 years) than AIP mutation-negative patients (40.4+/-14.5 years). A promoter mutation showed reduced in vitro activity corresponding to lower mRNA expression in patient samples. Stimulation of the protein kinase A-pathway positively regulates the AIP promoter. Silent mutations led to abnormal splicing resulting in truncated protein or reduced AIP expression. A two-hybrid assay of protein-protein interaction of all missense variants showed variable disruption of AIP-phosphodiesterase-4A5 binding. In summary, exonic, promoter, splice-site, and large deletion mutations in AIP are implicated in 31% of families in our FIPA cohort. Functional characterization of AIP changes is important to identify the functional impact of gene sequence variants.

BIOLOGICAL pest control, LANTANA camara, PREDICTION theory, BIOCLIMATOLOGY, SPATIAL variation, BIOLOGICAL mathematical modeling, and CHRYSOMELIDAE

Abstract: Understanding the effects of different types and quality of data on bioclimatic modeling predictions is vital to ascertaining the value of existing models, and to improving future models. Bioclimatic models were constructed using the CLIMEX program, using different data types – seasonal dynamics, geographic (overseas) distribution, and a combination of the two – for two biological control agents for the major weed Lantana camara L. in Australia. The models for one agent, Teleonemia scrupulosa Stål (Hemiptera: Tingidae) were based on a higher quality and quantity of data than the models for the other agent, Octotoma scabripennis Guérin-Méneville (Coleoptera: Chrysomelidae). Predictions of the geographic distribution for Australia showed that T. scrupulosa models exhibited greater accuracy with a progressive improvement from seasonal dynamics data, to the model based on overseas distribution, and finally the model combining the two data types. In contrast, O. scabripennis models were of low accuracy, and showed no clear trends across the various model types. These case studies demonstrate the importance of high quality data for developing models, and of supplementing distributional data with species seasonal dynamics data wherever possible. Seasonal dynamics data allows the modeller to focus on the species response to climatic trends, while distributional data enables easier fitting of stress parameters by restricting the species envelope to the described distribution. It is apparent that CLIMEX models based on low quality seasonal dynamics data, together with a small quantity of distributional data, are of minimal value in predicting the spatial extent of species distribution. [Copyright &y& Elsevier]

The marine filamentous nonheterocystous nitrogen-fixing cyanobacterium Lyngbya aestuarii (F. K. Mert.) Liebman ex Gomont CCY 9616 was grown under diazotrophic and nondiazotrophic conditions and under an alternating 16:8 light:dark (L:D) regime. Nitrogenase activity appeared just before the onset of the dark period, reaching its maximum 1-2 h in the dark, subsequently decreasing to zero at the beginning of the following light period. Nitrogenase activity was only detected at low levels of O2 (5%) and when the culture was grown in the absence of combined nitrogen. Quantitative reverse transcriptase-PCR (RT-PCR) analysis of one of the structural genes encoding nitrogenase, nifK, showed that the highest levels of transcription preceded the maximum activity of nitrogenase by 2-4 h. nifK transcription was not completely abolished during the remaining time of the 24 h cycle. Even in the presence of nitrate, when nitrogenase activity was undetectable, nifK was still transcribed. The H2 -uptake activity seemed to follow the nitrogenase, but the transcription of hupL (gene encoding the large subunit of uptake hydrogenase) preceded the nifK transcription. However, H2 -uptake and hupL transcription occurred throughout the 24 h cycle as well as under nondiazotrophic conditions, albeit at much lower levels. The hoxH transcript levels (a structural gene coding for the bidirectional hydrogenase) were similar under diazotrophic or nondiazotrophic conditions but slightly higher during the dark period. All three enzymes investigated are involved in H2 metabolism. It is concluded that the uptake hydrogenase is mainly responsible for H2 uptake. Nevertheless, uptake hydrogenase and nitrogenase do not seem to be coregulated.
(© 2009 Phycological Society of America.)

Breast Neoplasms pathology, Breast Neoplasms radiotherapy, Chemotherapy, Adjuvant, Combined Modality Therapy, Female, Follow-Up Studies, Gene Frequency, Humans, Immunohistochemistry, Neoplasm Recurrence, Local epidemiology, Prognosis, Randomized Controlled Trials as Topic, Retinoblastoma Protein genetics, Time Factors, Antineoplastic Combined Chemotherapy Protocols therapeutic use, Breast Neoplasms drug therapy, Breast Neoplasms genetics, Cyclin E genetics, and Gene Expression Regulation, Neoplastic

Cyclin E and the retinoblastoma protein (Rb) are both important regulators of the G1 phase in the cell cycle. Overexpression of cyclin E and lost expression of Rb has previously been observed in breast tumours at frequencies of 10-50% and 20-30%, respectively. We explored the prognostic role of cyclin E and Rb in breast cancer patients randomised for tamoxifen (TAM), CMF (cyclophosphamide, metotrexate, 5-fluorouracil) chemotherapy and radiotherapy (RT) and how their expression affects the patients' response to treatment. Protein expression was assessed with immunohistochemistry. We found overexpression of cyclin E in 32.1% (71/221) of the tumours and loss of Rb expression in 25.0% (59/236). Increased expression of cyclin E correlated to dysfunctional p53 (P=0.003) while loss of Rb correlated to normal p53 status (P=0.001). Our results suggest that patients with high cyclin E tumours have less benefit from tamoxifen (ER+, TAM vs. no TAM; RR=0.97; 95% CI, 0.36-2.60) than patients whose tumours show low expression (ER+, TAM vs. no TAM; RR =0.41; 95% CI, 0.24-0.72). Cyclin E also tended to predict the benefit from radiotherapy with a local recurrence rate of 0.31 (RT vs. CMF; 95% CI, 0.12-0.83) for patients with low expression and 0.68 (RT vs. CMF; 95% CI, 0.2-2.32) for patients with high expression of cyclin E. When the p53 status was taken in consideration the results showed that patients with both normal p53 and normal Rb expression had considerably lower locoregional recurrence rate when treated with radiotherapy instead of CMF (RR=0.17; 95% CI, 0.052-0.58) as compared to patients with either altered Rb or p53 or both (RR=0.70; 95% CI, 0.28-1.73).