Impact of Ae-GRD on Ivermectin Resistance and Its Regulation by miR-71-5p in Aedes aegypti.

iGABAR, a member of the Cys-loop ligand-gated ion channel superfamily, is a significant target of the insecticide ivermectin (IVM). GRD is the potential subunit of the insect iGABAR. However, little information about GRD in Ae. aegypti has been reported. In this study, we involved cloning and characterizing the iGABAR subunit GRD of Ae. aegypti (Ae-GRD). Sequence analysis indicated that Ae-GRD, as part of the cysteine-loop ligand-gated ion channel family, is similar to other insect GRD. RNA interference (RNAi) was employed to explore IVM resistance in Ae. aegypti, resulting in a significant reduction in Ae-GRD expression (p < 0.05), and the mortality of Ae. aegypti adults with Ae-GRD knockdown was significantly decreased after exposure to ivermectin. Bioinformatics prediction identified miR-71-5p as a potential regulator of Ae-GRD. In vitro, dual-luciferase reporter assays confirmed that Ae-GRD expression was regulated by miR-71-5p. Microinjection of miR-71-5p mimics upregulated miR-71-5p expression and downregulated Ae-GRD gene expression, reducing mortality by 34.52% following IVM treatment. Conversely, microinjection of a miR-71-5p inhibitor decreased miR-71-5p expression but did not affect the susceptibility to IVM despite increased Ae-GRD expression (p < 0.05). In conclusion, Ae-GRD, as one of the iGABA receptor subunits, is a potential target of ivermectin. It may influence ivermectin resistance by modulating the GABA signaling pathway. The inhibition of Ae-GRD expression by miR-71-5p decreased ivermectin resistance and consequently lowered the mortality rate of Ae. aegypti mosquitoes. This finding provides empirical evidence of the relationship between Ae-GRD and its miRNA in modulating insecticide resistance, offering novel perspectives for mosquito control strategies.

Meta-transcriptomic identification of groundnut RNA viruses in western Kenya and the novel detection of groundnut as a host for Cauliflower mosaic virus.

BACKGROUND: Groundnut (Arachis hypogaea L.) is the 13th most important global crop grown throughout the tropical and subtropical regions of the world. One of the major constraints to groundnut production is viruses, which are also the most economically important and most abundant pathogens among cultivated legumes. Only a few studies have reported the characterization of RNA viruses in cultivated groundnuts in western Kenya, most of which deployed classical methods of detecting known viruses. METHODS: We sampled twenty-one symptomatic and three asymptomatic groundnut leaf samples from farmers' fields in western Kenya. Total RNA was extracted from the samples followed by First-strand cDNA synthesis and sequencing on the Illumina HiSeq 2500 platform. After removing host and rRNA sequences, high-quality viral RNA sequences were de novo assembled and viral genomes annotated using the publicly available NCBI virus database. Multiple sequence alignment and phylogenetic analysis were done using MEGA X. RESULTS: Bioinformatics analyses using as low as ∼3.5 million reads yielded complete and partial genomes for Cauliflower mosaic virus (CaMV), Cowpea polerovirus 2 (CPPV2), Groundnut rosette assistor virus (GRAV), Groundnut rosette virus (GRV), Groundnut rosette virus satellite RNA (satRNA) and Peanut mottle virus (PeMoV) falling within the species demarcation criteria. This is the first report of CaMV and the second report of CPPV2 on groundnut hosts in the world. Confirmation of the detected viruses was further verified through phylogenetic analyses alongside reported publicly available highly similar viruses. PeMoV was the only seed-borne virus reported. CONCLUSION: Our findings demonstrate the power of Next Generation Sequencing in the discovery and identification of novel viruses in groundnuts. The detection of the new viruses indicates the complexity of virus diseases in groundnuts and would require more focus in future studies to establish the effect of the viruses as sole or mixed infections on the crop. The detection of PeMoV with potential origin from Malawi indicates the importance of seed certification and cross-boundary seed health testing.

Utilising Sentinel-1's Orbital Stability for Efficient Pre-Processing of Radiometric Terrain Corrected Gamma Nought Backscatter.

Radiometric Terrain Corrected (RTC) gamma nought backscatter, which was introduced around a decade ago, has evolved into the standard for analysis-ready Synthetic Aperture Radar (SAR) data. While working with RTC backscatter data is particularly advantageous over undulated terrain, it requires substantial computing resources given that the terrain flattening is more computationally demanding than simple orthorectification. The extra computation may become problematic when working with large SAR datasets such as the one provided by the Sentinel-1 mission. In this study, we examine existing Sentinel-1 RTC pre-processing workflows and assess ways to reduce processing and storage overheads by considering the satellite's high orbital stability. By propagating Sentinel-1's orbital deviations through the complete pre-processing chain, we show that the local contributing area and the shadow mask can be assumed to be static for each relative orbit. Providing them as a combined external static layer to the pre-processing workflow, and streamlining the transformations between ground and orbit geometry, reduces the overall processing times by half. We conducted our experiments with our in-house developed toolbox named wizsard, which allowed us to analyse various aspects of RTC, specifically run time performance, oversampling, and radiometric quality. Compared to the Sentinel Application Platform (SNAP) this implementation allowed speeding up processing by factors of 10-50. The findings of this study are not just relevant for Sentinel-1 but for all SAR missions with high spatio-temporal coverage and orbital stability.

CDC42-IQGAP Interactions Scrutinized: New Insights into the Binding Properties of the GAP-Related Domain.

The IQ motif-containing GTPase-activating protein (IQGAP) family composes of three highly-related and evolutionarily conserved paralogs (IQGAP1, IQGAP2 and IQGAP3), which fine tune as scaffolding proteins numerous fundamental cellular processes. IQGAP1 is described as an effector of CDC42, although its effector function yet re-mains unclear. Biophysical, biochemical and molecular dynamic simulation studies have proposed that IQGAP RASGAP-related domains (GRDs) bind to the switch regions and the insert helix of CDC42 in a GTP-dependent manner. Our kinetic and equilibrium studies have shown that IQGAP1 GRD binds, in contrast to its C-terminal 794 amino acids (called C794), CDC42 in a nucleotide-independent manner indicating a binding outside the switch regions. To resolve this discrepancy and move beyond the one-sided view of GRD, we carried out affinity measurements and a systematic mutational analysis of the interfacing residues between GRD and CDC42 based on the crystal structure of the IQGAP2 GRD-CDC42Q61L GTP complex. We determined a 100-fold lower affinity of the GRD1 of IQGAP1 and of GRD2 of IQGAP2 for CDC42 mGppNHp in comparison to C794/C795 proteins. Moreover, partial and major mutation of CDC42 switch regions substantially affected C794/C795 binding but only a little GRD1 and remarkably not at all the GRD2 binding. However, we clearly showed that GRD2 contributes to the overall affinity of C795 by using a 11 amino acid mutated GRD variant. Furthermore, the GRD1 binding to the CDC42 was abolished using specific point mutations within the insert helix of CDC42 clearly supporting the notion that CDC42 binding site(s) of IQGAP GRD lies outside the switch regions among others in the insert helix. Collectively, this study provides further evidence for a mechanistic framework model that is based on a multi-step binding process, in which IQGAP GRD might act as a 'scaffolding domain' by binding CDC42 irrespective of its nucleotide-bound forms, followed by other IQGAP domains downstream of GRD that act as an effector domain and is in charge for a GTP-dependent interaction with CDC42.

Circadian Clock Gene Period Contributes to Diapause via GABAeric-Diapause Hormone Pathway in Bombyx mori.

Diapause is a developmental transition in insects based on seasonal adaptation to adversity; it is regulated by a circadian clock system and the endocrine system. However, the molecular node and its mechanism underlying the effects of these systems are still unclear. Here, a mutant of Bombyx mori with the circadian clock gene Period (Per) knocked out was constructed, which dramatically changed the classic diapause-destined pathway. Per-knockout silkworms powerfully attenuated, but could not completely block, the predetermined effects of temperature and photoperiod on diapause determination, and this effect depended on the diapause hormone (DH) pathway. The impaired transcription-translation feedback loop of the circadian clock system lacking the Per gene caused direct up-regulation of the expression of GRD, a receptor of γ-aminobutyric acid (GABA), by changing expression level of Cycle. The synthesis of GABA in the tissue complex of brain-suboesophageal ganglion then increased and restricted the decomposition, which continuously promoted the GABAergic signal to play a role, and finally inhibiting (delaying) the release of DH to the hemolymph, and reducing the diapause-inducing effect of DH. The results provided an example to explain the regulatory mechanism of the circadian clock on endocrine hormones in the silkworm.

Bacteriemia por Staphylococcus aureus con sensibilidad disminuida heterogénea a vancomicina: reporte de un caso / Staphylococcus aureus bacteremia with heterogeneous intermediate-level vancomycin resistance: a case report

Staphylococcus aureusmeticilina-resistente (SAMR)es una causa frecuente de bacteriemias intrahospitalarias. Para su tratamiento se utiliza vancomicina y han emergido cepas con sensibilidad disminuida heterogénea (h-VISA) que albergan subpoblaciones con sensibi-lidad reducida a vancomicina. Se comunica un caso de bacteriemia intra-tratamiento con vancomicina por SAMR h-VISA. El aislamiento muestra sensibilidad a vancomicina (CIMvan: 1 µg/mL), sin embargo E-test GRD sugiere h-VISA (CIMvan: 2 µg/mL y CIMtei: 8 µg/mL). El análisis del perfil poblacional - área bajo la curva (PAP-AUC) valida este hallazgo. Se rota a linezolid con resolución clínica.

Methicillin-resistant Staphylococcus aureus (SAMR) is a common cause of nosocomial bacteremia. Vancomycin, a glycopeptide, is widely employed for the therapy of SAMR infections. In recent years, heterogeneous vancomycin-intermediate strains (h-VISA) have emerged. We report a case of intra-treatment bacteremia caused by SAMR h-VISA. The isolate shows susceptibility to vancomycin (MICvan: 1 µg/mL). But the GRD E-test suggests h-VISA (MICvan: 2 µg/mL and MICtei: 8 µg/mL). The population analysis profile - area under the curve (PAP-AUC) validates SAMR h-VISA. Rotation of antibiotic therapy with linezolid is done, with good clinical outcome.

Caracterización de la productividad quirúrgica en el Hospital Regional de Arica Dr. Juan Noé Crevani, años 2015-2019 / Characterization of the surgical productivity of the Dr. Juan Noé Crevani Regional Hospital of Arica, 2015-2019

La actividad quirúrgica es una dimensión de enorme importancia en la actividad asistencial, ya que, se ha determinado que el fortalecimiento de la capacidad quirúrgica, sobre todo en los hospitales, sería un medio sumamente costo eficiente de reducir la carga mundial de morbilidad. Actualmente en Chile la productividad hospitalaria es seguida y medida mediante diferentes indicadores (compromisos de gestión y balance score card) que principalmente se enfocan en el uso eficiente de los recursos. Estos indicadores se obtienen de los diferentes sistemas de registros como REM (resumen estadístico mensual) y GRD (grupo relacionado diagnóstico). El objetivo de este estudio es describir los principales indicadores de producción quirúrgica del hospital Juan Noé Crevani entre los años 2015 al 2019. Se realizó un estudio observacional, descriptivo, longitudinal y retrospectivo de la producción quirúrgica del Hospital Juan Noé Crevani en los años 2015 al 2019. Se observa en los registros estadísticos de producción en Hospital Juan Noé Crevani según REM, una variación en el trabajo de los pabellones quirúrgicos durante los años estudiados, junto a un aumento en la dotación de pabellones quirúrgicos, específicamente un aumento en la cantidad de horas disponibles para cirugía y un aumento en el número de intervenciones en el tiempo. Además, se observa una disminución del porcentaje de suspensiones. Las estancias medias en preoperatorios de las intervenciones programadas están cercanas a 0 evidenciando una buena gestión pre quirúrgica. Se observa una mejora en la media de los días pre quirúrgicos del servicio de cirugía en comparación al servicio de traumatología. En los años 2017 y 2018 se registra una mayor frecuencia de cirugía mayor ambulatoria. Los datos obtenidos a través de GRD se diferencian de los REM por el uso de diagnósticos CIE-10 y procedimientos CIE-9. Según los expertos, estos son los datos más correctos para poder tomar medidas de gestión clínica. Ambas herramientas no son comparables, pero mediante sus indicadores se pueden utilizar los recursos quirúrgicos en su máximo potencial.

Surgical activity is a very important dimension in healthcare activity, since it has been determined that strengthening surgical capacity, especially in hospitals, would be a highly cost-efficient means of reducing the global burden of morbidity. Currently in Chile, hospital productivity is monitored and measured through different indicators (management commitments and scorecard) that mainly focus on the efficient use of resources. These indicators are obtained from the different registry systems such as REM (monthly statistical summary) and GRD (diagnostic related group). The purpose of this study is to describe the main indicators of surgical production of the Juan Noé Crevani Hospital between the years 2015 to 2019. An observational, descriptive, longitudinal and retrospective study of the surgical production of the Juan Noé Crevani Hospital was carried out in the years 2015 to 2019. Statistical records of production in Hospital Juan Noé Crevani according to REM, where the variation in the work of surgical wards is observed over the years, shows an increase in the number of surgical wards, specifically an increase in the number of hours available for surgery and thus the number of interventions has been increasing over time. In addition, the percentage of suspensions has improved, and elective major outpatient surgeries have a tendency to increase over the years. Juan Noé Crevani Hospital surgical production according to IR-GRD, between 50 and 54% of hospital discharges have surgical intervention. The preoperative MEs of the scheduled interventions are close to 0, showing good pre-surgical management. The surgery service has improved the average number of pre-surgical days compared to the trauma service. in 2017 and 2018 there was a higher frequency of major outpatient surgery. The data obtained through DRGs differ from REM data due to the use of ICD-10 diagnoses and ICD-9 procedures. According to experts, these are the most correct data to be able to take clinical management measures. Both tools are not comparable, but through their indicators, surgical resources can be used to their maximum potential.

Models Predicting Psychosis in Patients With High Clinical Risk: A Systematic Review.

OBJECTIVE: The present study reviews predictive models used to improve prediction of psychosis onset in individuals at clinical high risk for psychosis (CHR), using clinical, biological, neurocognitive, environmental, and combinations of predictors. METHODS: A systematic literature search on PubMed was carried out (from 1998 through 2019) to find all studies that developed or validated a model predicting the transition to psychosis in CHR subjects. RESULTS: We found 1,406 records. Thirty-eight of them met the inclusion criteria; 11 studies using clinical predictive models, seven studies using biological models, five studies using neurocognitive models, five studies using environmental models, and 18 studies using combinations of predictive models across different domains. While the highest positive predictive value (PPV) in clinical, biological, neurocognitive, and combined predictive models were relatively high (all above 83), the highest PPV across environmental predictive models was modest (63%). Moreover, none of the combined models showed a superiority when compared with more parsimonious models (using only neurocognitive, clinical, biological, or environmental factors). CONCLUSIONS: The use of predictive models may allow high prognostic accuracy for psychosis prediction in CHR individuals. However, only ten studies had performed an internal validation of their models. Among the models with the highest PPVs, only the biological and neurocognitive but not the combined models underwent validation. Further validation of predicted models is needed to ensure external validity.

Análisis con GRD: El egreso hospitalario indiferenciado de la maternidad no representa la complejidad de las pacientes con alto riesgo obstétrico / DRG analysis: undifferentiated hospital discharges of maternity does not represent the complexity of patients with high obstetric risk

INTRODUCCIÓN: La gestión actual de camas hospitalarias sigue un modelo de indiferenciación en el que existen camas quirúrgicas, médicas y de pacientes críticos. Las maternidades si bien no siguen este modelo, tienen egresos indiferenciados con pacientes que pueden egresar post parto o aún embarazadas (con patologías perinatales). OBJETIVO: Evaluar diferencias entre egresos con parto normal y aquellos con patologías de alto riesgo obstétrico (ARO) respecto a estancia media (EM) y el consumo de recursos cuantificado con el peso medio de los grupos relacionados con el diagnóstico (PMGRD). MÉTODO: Estudio transversal con egresos maternales periodo 2017-2018. Se usó Categoría Diagnóstica Mayor (CIE - 10) para definir dos grupos de egreso: 1. Con parto normal a término o 2. Con patología ARO. Se compararon 1.658 y 1.669 egresos del grupo 1 y 2 respectivamente. Las variables de resultado son EM y PMGRD. Se compararon variables cuantitativas con t de student y Kruskal Wallis. Se usó Odds Ratio con respectivo intervalo de confianza para evaluar asociación entre variables y regresión logística multivariada para ajustar asociación. RESULTADOS: La edad, proporción de gestantes tardías, EM y PMGRD fue mayor en los egresos ARO (p<0,05). Existe fuerte asociación de EM prolongada (>4 días) y PMGRD elevado (>0.3109) con los egresos ARO (ORa=3.75; IC95%=3.21-4.39 y ORa=1.28; IC95%=1.1-1.49 respectivamente). CONCLUSIONES: Es necesario diferenciar los egresos del servicio de maternidad porque los egresos de ARO muestran mayor complejidad. La evaluación del riesgo usando EM y PMGRD permite analizar con especificidad los egresos maternales para una mejor gestión de camas y del recurso humano.

INTRODUCTION: The current management of hospital beds in Chile follows an undifferentiation model in which there are surgical, medical and critical patient bed. Maternity hospitals although they do not follow this model, have undifferentiated discharges with patients who may leave poatpartum or still pregnant (with perinatal pathologies) OBJECTIVE: To assess differences between discharges with normal delivery and those with high obstetric risk pathologies (HOR) with respect to mean stay (MS) and the resource spending quantified with the average weight of the diagnosis related group (AWDRG). METHOD: Cross-sectional study with maternal discharges between 2017-2018 period. Major Diagnostic Category (ICD - 10) was used to define two discharge groups: 1. With normal term birth or 2. With HOR pathology. 1,658 and 1,669 egress from group 1 and 2 were compared respectively. The outcome variables are EM and AWDRG. Quantitative variables were compared with student t and Kruskal Wallis. Odds Ratio and respective confidence interval were used to evaluate association between variables and multivariate logistic regression to adjust association. RESULTS: Age, proportion of late pregnant women, MS and AWDRG was higher in HOR discharges (p <0.05). There is a strong association of prolonged MS (> 4 days) and elevated AWDRG (> 0.3109) with HOR discharges (ORa = 3.75; 95% CI 3.21-4.39 and ORa = 1.28; 95% CI 1.1-1.49 respectively). CONCLUSIONS: It is necessary to differentiate medical discharge of the maternity service because the HOR egress show greater complexity. The risk assessment using MS and AWDRG allows to analyze with specificity the maternal discharge for a better management of beds and human resources.

Grаdiеnt HPLC Mеthоd fоr Simultаnеоus Dеtеrminаtiоn оf Еight Sаrtаn аnd Stаtin Drugs in Thеir Purе аnd Dоsаgе Fоrms.

А grаdiеnt HPLC mеthоd was dеvеlоpеd аnd vаlidаtеd fоr rаpid simultаnеоus sеpаrаtiоn аnd dеtеrminаtiоn оf the following eight drugs оf sаrtаn аnd stаtin clаssеs in thеir purе аnd dоsаgе fоrms within 15 minutes: irbеsаrtаn (IRB), lоsаrtаn (LОS), vаlsаrtаn (VАL), оlmеsаrtаn (ОLM), rоsuvаstаtin (RОS), аtоrvаstаtin (АTR), lоvаstаtin (LОV), аnd simvаstаtin (SIM). Sеpаrаtiоn wаs cаrriеd оut оn а Kinеtеx C18 100А cоlumn (2.60 m, 4.60 mm × 100 mm) using а grаdiаnt binаrу mоbilе phаsе оf 0.05M pоtаssium dihуdrоgеn phоsphаtе buffеr (pH 3.50 аdjustеd bу оrthо-phоsphоric аcid) аnd аcеtоnitrilе аt rооm tеmpеrаturе. Thе flоw rаtе wаs 1.00 mL/min аnd mаximum аbsоrptiоn wаs mеаsurеd using a DАD dеtеctоr аt 280 nm. Thе rеtеntiоn timеs оf IRB, LОS, RОS, VАL, АTR, LОV, ОLM, аnd SIM wеrе rеcоrdеd tо bе 4.72, 5.32, 6.06, 7.19, 7.96, 9.30, 11.91, аnd 14.66 minutеs, rеspеctivеlу. Limits оf dеtеctiоn wеrе rеpоrtеd tо bе 2.01, 1.32, 1.10, 0.76, 0.21, 1.50, 0.38, аnd 0.55 mM fоr thе sаmе sеquеncе оf drugs, rеspеctivеlу, shоwing а high dеgrее оf mеthоd sеnsitivitу. Thе mеthоd wаs thеn vаlidаtеd аccоrding tо the intеrnаtiоnаl cоnfеrеncе оf hаrmоnizаtiоn (ICH) guidеlinеs fоr thе dеtеrminаtiоn оf thе drugs in thеir dоsаgе fоrms with highlу prеcisе rеcоvеriеs. Аlsо, a stаtisticаl cоmpаrisоn with rеfеrеncе mеthоds wаs pеrfоrmеd shоwing nо significаnt diffеrеncеs bеtwееn thе prоpоsеd mеthоd аnd rеpоrtеd оnеs in tеrms оf prеcisiоn аnd аccurаcу.

An Operational Tool for the Automatic Detection and Removal of Border Noise in Sentinel-1 GRD Products.

The presence of border noise in Sentinel-1 Ground Range Detected (GRD) products is an undesired processing artifact that limits their full exploitation in a number of applications. All of the Sentinel-1 GRD products generated before March 2018-more than 800,000-are affected by this particular type of noise. In March 2018, an official fix was deployed that solved the problem for a large portion of the newly generated products, but it did not cover the entire range of products, hence the need for an operational tool that is able to effectively and consistently remove border noise in an automated way. Currently, a few solutions have been proposed that try to address the problem, but all of them have limitations. The scope of this paper is therefore to present a new method based on mathematical morphology for the automatic detection and masking of border noise in Sentinel-1 GRD products that is able to overcome the existing limitations. To evaluate the performance of the method, a detailed numerical assessment was carried out, using, as a benchmark, the 'Remove GRD Border Noise' module integrated in ESA's Sentinel Application Platform. The results showed that the proposed method is capable of very accurately removing the undesired noisy pixels from GRD images, regardless of their acquisition mode, polarization, or resolution and can cope with challenging features within the image scenes that typically affect other approaches.

Clinical characteristics and NF1 gene mutation analysis of three successive generations in three different Indian families with neurofibromatosis type 1 and peripheral nerve sheath tumours.

Neurofibromatosis type 1 (NF1) is a rare autosomal-dominant disorder caused by inactivation of NF1 tumour suppressor gene, which associates in the development of peripheral nerve tumours. NF1 is an important regulator of GAP and RAS proteins, mutations in NF1 results in the impairment in this function causing specific osseous lesions in any organ of the human body. In the present study, we investigated the clinical characteristics and NF1 gene mutation analysis of 3 unrelated Indian families with neurofibromatosis type 1. All the exons of NF1 gene was PCR amplified and sequenced. The structural and functional analysis was performed using molecular modelling tools. The sequence analysis of NF1 gene revealed; in family I five novel mutations p.R103K, p.D105N, p.M108I, p.L114M, p.E116X and p.A131S was observed in exon 4. In family II one missense p.A131S mutation and one silent p.L234L mutation was detected in exon 4. While, in family III one novel frame shift p.E225Rfs∗6 mutation was identified in exon 7 resulting in the truncated protein formation. Further, the structural analysis revealed all these mutations fall in the protein kinase C domain of NF1 gene causing loss of functional GRD and CSRD domains. In conclusion, novel mutations in the exon 4 and exon 7 of NF1 gene in these families correlating with genotype-phenotype characters explaining the neurofibromatosis type 1 and peripheral nerve sheath tumours condition in these patients.

Unravelling Swedish informal caregivers' Generalised Resistance Deficits.

In salutogenic theory, individual/contextual, immaterial/material characteristics enabling movements towards health are labelled Specific and Generalised Resistance Resources, SRRs/GRRs, and characteristics counteracting such movements Specific and Generalised Resistance Deficits, SRDs/GRDs. The aim of this paper was to present SRDs and GRDs described by caregivers as stemming from themselves and their care recipient. Guided by salutogenic theory, an explorative design was used to collect data through interviews with 32 Swedish informal caregivers. During the theory-driven analysis, SRDs were unravelled using within-case approaches. To be able to unite them as GRDs across cases, a serviceable GRD definition was developed from the existing theoretical GRR definition. In findings, SRDs are visualised in citations and GRDs described in detail. Caregivers' experiences of SRDs/GRDs are presented as themes: 'Experiencing personal deficiencies', when stemming from themselves; and 'Struggling with an uncooperative co-worker', when stemming from their care recipients. Findings indicate that if these themes dominate a caregiver's view of life, she/he seems to have reached the 'breaking point' when caregiving ends due to lack of usable SRRs/GRRs. To prolong the time until this occurs, support, making otherwise unusable SRRs/GRRs usable, is needed. When designing this type of 'salutogenic' support, it seems essential to involve the target group (e.g. caregivers, care recipients), to ascertain what their SRRs/GRRs and SRDs/GRDs may consist of. Such knowledge regarding SRRs/SRDs could be used to design individualised support, and regarding GRRs/GRDs to design generalised support at group level. This study suggests how such new knowledge regarding resistance resources and deficits could be acquired.

Estudio epidemiológico descriptivo de pacientes hospitalizados en el Servicio de ORL del Hospital Clínico de la Universidad de Chile entre los años 2007 y 2014 / Descriptive epidemiological study of patients hospitalized in the ENT Department of the Hospital Clínico de la Universidad de Chile between the years 2007 and 2014

Introducción: Las enfermedades de origen otorrinolaringológico (ORL) tienen una elevada prevalencia en atención primaria de salud, sin embargo, la información epidemiológica en pacientes hospitalizados es bastante escasa. Objetivo: Obtener características demográficas y prevalencia de enfermedades en los pacientes hospitalizados del Servicio de ORL del Hospital Clínico de la Universidad de Chile (HCUCh). Material y método: Estudio de tipo descriptivo y retrospectivo, llevado a cabo en el Servicio de ORL del HCUCh, donde se revisaron los registros electrónicos, existentes de grupos relacionados a diagnóstico (GRD) de egresos, entre los años 2007 y 2014. Resultados: Se incluyeron 7.353 egresos, con un promedio de edad de los pacientes de 28,24 años. La causa de hospitalización más frecuente fue la patología de faringe. Del total de los egresos 87,88% presentaron una intervención quirúrgica donde la amigdalectomía con adenoidectomía alcanzó el 15,7% de las cirugías realizadas. Conclusión: Este estudio nos entrega información epidemiológica sobre los pacientes hospitalizados en un servicio de ORL de un hospital de referencia a nivel nacional.

Introduction: Diseases ofotolaryngology (ENT) origin have a high prevalence in primary health care, however, the epidemiological information on hospitalized patients is almost null. Aim: To obtain demographic and disease prevalence information in hospitalized patients of the ENT Department at the Hospital Clínico de la Universidad de Chile (HCUCh). Material and method: A descriptive and retrospective study, was carried out at the ENT department of the HCUCh, reviewing existing records of diagnostic related groups (GRD) for discharges between 2007 and 2014. Results: We review a total of 7353 discharges, with an average age of patients of 28.24 years. The most frequent cause of hospitalization was pharynx pathology. An 87.88% of discharges had surgery performed, where tonsillectomy with adenoidectomy reached 15,7% of the total. Conclusion: This study provides us with epidemiological information on patients hospitalized in an ENT department in a nationwide referral hospital.

Going mainstream: How is the body axis of plants first initiated in the embryo?

Vascular plants have an open body plan and continuously generate new axes of growth, such as shoot or root branches. Apical-to-basal transport of the hormone auxin is a hallmark of every axis, and the resulting pattern of auxin distribution affects plant development across scales, from overall architecture to cellular differentiation. How the first axis is initiated in the early embryo is a long-standing question. While our knowledge is still sparse, some of the key players of axialization have emerged, and recent work points to specific models for connecting cellular polarity to the asymmetric division of the zygote and domain specific gene expression to the organization of basipetal auxin flux.

Anti-tubercular drug development: computational strategies to identify potential compounds.

InhA is an attractive target to combat tuberculosis (TB), which is targeted by many pro-drugs (isoniazid, etc.) and drugs such as triclosan. However, triclosan is less useful as an antitubercular drug due to its low bioavailability and therefore, in order to overcome this difficulty, many derivatives of triclosan were prepared. Here, we have combined various computational techniques to virtually screen out four potential triclosan derivatives. Molecular docking methods have been employed to screen out 32 out of 62 triclosan derivatives considering the mode of binding and the top re-rank scores. A comparative study on the chemical properties of triclosan and some of its derivatives has been performed using density functional theory (DFT) calculations. DFT based global reactivity descriptors (GRD), such as hardness, chemical potential, chemical softness, electrophilicity index, Fukui function, and local philicity calculated at the optimized geometries were used to investigate the usefulness of these descriptors for understanding the reactive nature and sites of the molecules. QSAR equations were built using these descriptors considering these 32 compounds. Four common compounds showing the best correlation and the best docking scores were considered for the ADMET property calculations and their dynamical movements have been studied using molecular dynamics simulations. Our results showed that these four compounds are chemically more active than triclosan and have the potential to inhibit the Mycobacterium tuberculosis enoyl acyl carrier protein reductase. This work shows that combination of different computational techniques may help to screen out potential drug candidates from a list of possible ones.

Gut microbes and adverse food reactions: Focus on gluten related disorders.

Immediately following birth, the gastrointestinal tract is colonized with a complex community of bacteria, which helps shape the immune system. Under conditions of health, the immune system is able to differentiate between innocuous antigens, including food protein and commensals, and harmful antigens such as pathogens. However, patients with celiac disease (CD) develop an intolerance to gluten proteins which results in a pro-inflammatory T-cell mediated immune response with production of anti-gluten and anti-tissue transglutaminase antibodies. This adaptive immune response, in conjunction with activation of innate inflammatory cells, lead to destruction of the small intestinal mucosa. Overall 30% of the global population has genetic risk to develop CD. However, only a small proportion develop CD, suggesting that additional environmental factors must play a role in disease pathogenesis. Alterations in small intestinal microbial composition have recently been associated with active CD, indicating a possible role for the microbiota in CD. However, studies demonstrating causality are lacking. This review will highlight the recent data on the potential role of the microbiota in CD pathogenesis, the potential mechanisms, and discuss future research directions.

Pomegranate extract protects against cerebral ischemia/reperfusion injury and preserves brain DNA integrity in rats.

AIM: Interruption to blood flow causes ischemia and infarction of brain tissues with consequent neuronal damage and brain dysfunction. Pomegranate extract is well tolerated, and safely consumed all over the world. Interestingly, pomegranate extract has shown remarkable antioxidant and anti-inflammatory effects in experimental models. Many investigators consider natural extracts as novel therapies for neurodegenerative disorders. Therefore, this study was carried out to investigate the protective effects of standardized pomegranate extract against cerebral ischemia/reperfusion-induced brain injury in rats. MAIN METHODS: Adult male albino rats were randomly divided into sham-operated control group, ischemia/reperfusion (I/R) group, and two other groups that received standardized pomegranate extract at two dose levels (250, 500 mg/kg) for 15 days prior to ischemia/reperfusion (PMG250+I/R, and PMG500+I/R groups). After I/R or sham operation, all rats were sacrificed and brains were harvested for subsequent biochemical analysis. KEY FINDINGS: Results showed reduction in brain contents of MDA (malondialdehyde), and NO (nitric oxide), in addition to enhancement of SOD (superoxide dismutase), GPX (glutathione peroxidase), and GRD (glutathione reductase) activities in rats treated with pomegranate extract prior to cerebral I/R. Moreover, pomegranate extract decreased brain levels of NF-κB p65 (nuclear factor kappa B p65), TNF-α (tumor necrosis factor-alpha), caspase-3 and increased brain levels of IL-10 (interleukin-10), and cerebral ATP (adenosine triphosphate) production. Comet assay showed less brain DNA (deoxyribonucleic acid) damage in rats protected with pomegranate extract. SIGNIFICANCE: The present study showed, for the first time, that pre-administration of pomegranate extract to rats, can offer a significant dose-dependent neuroprotective activity against cerebral I/R brain injury and DNA damage via antioxidant, anti-inflammatory, anti-apoptotic and ATP-replenishing effects.

Eucommia ulmoides Oliv.: ethnopharmacology, phytochemistry and pharmacology of an important traditional Chinese medicine.

ETHNOPHARMACOLOGICAL RELEVANCE: Eucommia ulmoides Oliv. (Family Eucommiaceae), also known as Dù-zhòng (Chinese: ), Tuchong (in Japanese), is the sole species of the genus Eucommia. The leaf, stem, and bark as well as staminate flower of Eucommia ulmoides have been traditionally used to cure many diseases in China, Japan, Korea, among others. The aim of this review is to comprehensively outline the botanical description, ethnopharmacology, phytochemistry, biological activities, and toxicology of Eucommia ulmoides and to discuss possible trends for further study of Eucommia ulmoides. MATERIALS AND METHODS: Information on Eucommia ulmoides was gathered via the internet (using Pub Med, Elsevier, Baidu Scholar, Google Scholar, Medline Plus, ACS, CNKI, and Web of Science) and from books in local libraries. RESULTS: One-hundred twelve compounds of Eucommia ulmoides, including the main active constituents, lignans and iridoids, have been isolated and identified. In vitro and in vivo studies indicated that monomer compounds and extracts from Eucommia ulmoides possess wide-ranging pharmacological actions, especially in treating hypertension, hyperlipemia, diabetes, obesity, sexual dysfunction, osteoporosis, Alzheimer's disease, aging, lupus-like syndrome, and immunoregulation. CONCLUSIONS: Eucommia ulmoides has been used as a source of traditional medicine and as a beneficial health food. Phytochemical and pharmacological studies of Eucommia ulmoides have received much interest, and extracts and active compounds continue to be isolated and proven to exert various effects. Further toxicity and clinical studies are warranted to establish more detailed data on crude extracts and pure compounds, enabling more convenient preparations for patients. Therefore, this review on the ethnopharmacology, phytochemistry, biological activities, and toxicity of Eucommia ulmoides will provide helpful data for further studies as well as the commercial exploitation of this traditional medicine.

Evaluation of subchronic toxicity of GRD081, a dual PI3K/mTOR inhibitor, after 28-day repeated oral administration in Sprague-Dawley rats and beagle dogs.

GRD081, a newly developed dual PI3K/mTOR inhibitor, is now being considered for evaluation in phase I clinical trial. In this work, the subchronic toxicity of GRD081 in Sprague-Dawley (SD) rats and beagle dogs has been characterized. Rats and dogs received GRD081 orally (2, 5, 10 and 1, 2, 4 mg/kg/day, respectively) on a consecutive daily dosing schedule for 28 days following a 14 days of recovery period. The treatment resulted in unscheduled mortality in rats receiving 5 mg/kg/day and 10 mg/kg/day. The adverse effects of GRD081 on rats and dogs mainly included myelosuppression, immunosuppression, hematological toxicity, and moderate liver, pancreas and kidney toxicity. These observations are consistent with pharmacologic perturbations of physiologic processes associated with the intended molecular targets for this class of PI3K/mTOR signaling inhibitors. Most of the treatment-induced effects were reversible upon discontinuation of treatment. The no-observed-adverse-effect level (NOAEL) of GRD081 was 1mg/kg/day for beagle dogs and less than 2 mg/kg/day for SD rats.