Magnetic extractions and electronic microscopy observations in Jurassic remagnetized carbonates

IX Congreso Geológico de España, Huelva, 12-14 de septiembre, 2016El estudio de la remagnetización en rocas carbonatadas viene realizándose durante los últimos 40 años, tanto por medio del análisis de sus propiedades magnéticas como tratando de realizar observaciones por medio de microscopía electrónica (SEM/TEM). Los resultados obtenidos con el primer análisis han proporcionado numerosos datos y hoy en día sabemos que generalmente la remagnetización es portada por magnetita. Ésta es de tamaño nanométrico generada durante la diagénesis, correspondiéndose con una remagnetización química. Sin embargo, los numerosos intentos de observación de dichos cristales por medio de SEM/TEM siempre han sido infructuosos y los cristales observados siempre presentan tamaños dentro del rango multidominio. En un nuevo intento de observación directa de dichos cristales mediante microscopía electrónica, hemos realizado nuevos ensayos sobre extractos magnéticos en calizas jurásicas remagnetizadas de las cuencas del Alto Atlas (Marruecos), Cameros y Vasco-Cantábrica (España) según las últimas técnicas propuestas en la literatura. Las propiedades magnéticas de los diferentes subproductos provenientes del proceso de extracción indican una pérdida de material magnético durante el mismo, principalmente las partículas de grano más fino (granos de tamaño monodominio y superparamagnético). Igualmente, mediante SEM/TEM únicamente han podido observarse cristales de magnetita multidominio.Since the last 40 years the analysis of remagnetized carbonates is under debate, by studying their magnetic properties and by using electronic microscopy (SEM/TEM). Results obtained from the first analyses allowed to infer that remagnetization is carried generally by nanometric magnetite and generated during the diagenesis, therefore it corresponds to a chemical remagnetization. However, several attempts to observe these magnetites by SEM/TEM were unsuccessful and in all cases the observed magnetite was in the range of multidomain size. In a new attempt to observe these crystals by electronic microscopy we did new magnetic extracts (according the last techniques proposed in the literature) in Jurassic remagnetized limestones of the High Atlas (Morocco), Cameros and Basque-Cantabrian (Spain) basins. Magnetic properties of the different sub-products of the extracts show a lost of magnetic material during the procedure, mostly of the smallest size (superparamagnetic and single-domain size). Likewise, only multi-domain magnetite grains were observed by SEM/TEM.proyecto CGL2012-38481 de la DGICyT, MINECO y fondos FEDER de la Unión Europea, así cómo por el programa de financiación de la NSF (EEUU) al Institute for Rock Magnetis

Does gravity modelling justify a rifted "Ligurian Basin"?

The geo-historical development of the Ligurian Basin and the structure of the crust and upper mantle in this area are still being discussed. Yet it remains unclear if rifting caused continental break-up and seafloor spreading and one of the key questions is whether rifting can be identified in geophysical measurements. For our investigations we had the following updated data sets at our disposal: the new gravity maps of the AlpArray Gravity Working Group (complete Bouguer - CBA, Free air, and isostatic anomalies) the seismic results of the Lobster campaigns of our GEOMAR partners in the SPP MB4D as well as the dynamic modelling results from our own subproject. The constraining data are supplemented with seismic profile data from French and Italian offshore campaigns, as far as they are usable in publications for us. The GFZ modelling software IGMAS+ was used for an interactive 3D modelling. The resulting model contains density inhomogeneities in the crust as well as in the upper mantle down to a depth of 300 km following the results of dynamic models of our own subproject. Due to the special hybrid modelling of the crust (by polygonal structures) and the upper mantle (by voxels of recent velocity models), the individual contributions to the gravity field are clearly separable. As a further special feature, we point out that the density model used is based on the gravity modelling from the first phase of the SPP MB4D (our former subproject INTEGRATE). Thus, a largely consistent 3D density model for both the Alps and the Ligurian Sea is available for interpretation. The constrained 3D modelling of the gravity field, as well as numerical analyses of the fields (terracing, clustering, filtering, curvature), calculations of the vertical stress and Gravity Potential Energy (GPE) suggest that a rift structure in the area of the Ligurian Sea can be identified and mapped. The interactive modelling is supported by the use of geological maps in the Ligurian Sea area. By overlaying the model gravity maps and the geological maps, the good agreement becomes visible – refer to the attached figure

Age at antiretroviral therapy initiation and cell-associated HIV-1 DNA levels in HIV-1-infected children

Background The latent viral reservoir is the major obstacle to achieving HIV remission and necessitates life-long antiretroviral therapy (ART) for HIV-infected individuals. Studies in adults and children have found that initiating ART soon after infection is associated with a reduction in the size of the HIV-1 reservoir. Here we quantified cell-associated HIV-1 DNA in early-treated but currently older HIV-infected children suppressed on ART. Methods The study participants comprised of a cohort of 146 early-treated children with HIV-1 RNA <50 copies/ml enrolled as part of a clinical trial in Johannesburg, South Africa. A stored buffy coat sample collected after a median 4.3 years on ART and where HIV-1 RNA was <50 copies/ml was tested for cell-associated HIV-1 DNA levels. An in-house, semi-nested real-time quantitative hydrolysis probe PCR assay to detect total HIV-1 subtype C proviral DNA was used. Children were followed prospectively for up to 3 years after this measurement to investigate subsequent HIV-1 RNA rebound/failure while remaining on ART. Age at ART initiation, HIV-1 RNA decline prior to HIV-1 DNA measurement and other factors were investigated. Results A gradient between age at ART initiation and later HIV-1 DNA levels was observed. When ART was started 50 copies/ml whilst on ART within 3 years after the DNA measurement was 2.07 (95% CI: 1.352–3.167) times greater if the HIV-1 DNA level was above the median of 55 copies/106 cells. Conclusions Cell-associated HIV-1 DNA levels measured after more than 4 years on ART were lower the younger the age of the child when ART was initiated. This marker of the size of the viral reservoir also predicted subsequent viral rebound/treatment failure while ART was sustained. The results provide additional evidence of the benefits of prompt diagnosis and early ART initiation in newborns and infants

Case report: Severe central nervous system manifestations associated with aberrant efavirenz metabolism in children: the role of CYP2B6 genetic variation

Background Efavirenz, widely used as part of antiretroviral drug regimens in the treatment of paediatric human immunodeficiency virus infection, has central nervous system side effects. We describe four children presenting with serious, persistent central nervous system adverse events who were found to have elevated plasma efavirenz concentrations as a result of carrying CYP2B6 single nucleotide polymorphisms, known to play a role in the metabolism of EFV. None of the children had a CYP2B6 wildtype haplotype. We believe this is the first case of cerebellar dysfunction associated with efavirenz use to be described in children. Case presentation Four black African children, between the ages of 4 and 8 years presenting between 1 and 20 months post-efavirenz initiation, are described. Cerebellar dysfunction, generalised seizures and absence seizures were the range of presenting abnormalities. Plasma efavirenz levels ranged from 20-60 mg/L, 5–15 times the upper limit of the suggested reference range. All abnormal central nervous system manifestations abated after efavirenz discontinuation. Conclusion Efavirenz toxicity should always be considered in human immunodeficiency virus-infected children with unexplained central nervous system abnormalities. Our findings further our understanding of the impact of genetic variants on antiretroviral pharmacokinetics in children across various ethnic groups. Screening for potential EFV-toxicity based on the CYP2B6 c.516 SNP alone, may not be adequate

Sex differences in responses to antiretroviral treatment in South African HIV-infected children on ritonavir-boosted lopinavir- and nevirapine-based treatment

Background: While studies of HIV-infected adults on antiretroviral treatment (ART) report no sex differences in immune recovery and virologic response but more ART-associated complications in women, sex differences in disease progression and response to ART among children have not been well assessed. The objective of this study was to evaluate for sex differences in response to ART in South African HIV-infected children who were randomized to continue ritonavir-boosted lopinavir (LPV/r)-based ART or switch to nevirapine-based ART. Methods: ART outcomes in HIV-infected boys and girls in Johannesburg, South Africa from 2005–2010 were compared. Children initiated ritonavir-boosted lopinavir (LPV/r)-based ART before 24 months of age and were randomized to remain on LPV/r or switch to nevirapine-based ART after achieving viral suppression. Children were followed for 76 weeks post-randomization and then long-term follow up continued for a minimum of 99 weeks and maximum of 245 weeks after randomization. Viral load, CD4 count, lipids, anthropometrics, drug concentrations, and adherence were measured at regular intervals. Outcomes were compared between sexes within treatment strata. Results: A total of 323 children (median age 8.8 months, IQR 5.1-13.5), including 168 boys and 155 girls, initiated LPV/r-based ART and 195 children were randomized. No sex differences in risk of virological failure (confirmed viral load >1000 copies/mL) by 156 weeks post-randomization were observed within either treatment group. Girls switched to nevirapine had more robust CD4 count improvement relative to boys in this group through 112 weeks post-randomization. In addition, girls remaining on LPV/r had higher plasma concentrations of ritonavir than boys during post-randomization visits. After a mean of 3.4 years post-randomization, girls remaining on LPV/r also had a higher total cholesterol:HDL ratio and lower mean HDL than boys on LPV/r. Conclusions: Sex differences are noted in treated HIV-infected children even at a young age, and appear to depend on treatment regimen. Future studies are warranted to determine biological mechanisms and clinical significance of these differences. Trial registration: ClinicalTrials.gov Identifier: NCT0011772

Differences in efficacy of monepantel, derquantel and abamectin against multi-resistant nematodes of sheep

Drug resistance has become a global phenomenon in gastrointestinal nematodes of sheep, particularly resistance to macrocyclic lactones. New anthelmintics are urgently needed for both the control of infections with multi-resistant nematodes in areas where classical anthelmintics are no longer effective, and the prevention of the spread of resistance in areas where the problem is not as severe. Recently, two new active ingredients became commercially available for the treatment of nematode infections in sheep, monepantel (Zolvix®) and derquantel, the latter used only in a formulated combination with the macrocyclic lactone, abamectin (Startect®). In order to assess the potential of the new actives for the control and prevention of spread of anthelmintic resistance, two characterized multi-resistant field isolates from Australia were used in a GLP (good laboratory practice) conducted efficacy study in sheep. Eight infected sheep in each group were treated orally according to the product labels with 2.5 mg/kg body weight monepantel, 0.2 mg/kg abamectin, or with the combination of 2.0 mg/kg derquantel and 0.2 mg/kg abamectin. The results demonstrate that monepantel was fully effective against multi-resistant species, Trichostrongylus colubriformis and Haemonchus contortus (99.9%). In contrast, the combination of derquantel and abamectin was effective against T. colubriformis (99.9%), but was not effective against larval stages of the barber's pole worm H. contortus (18.3%)

Performance of Polymerase Chain Reaction Techniques Detecting Perforin in the Diagnosis of Acute Renal Rejection: A Meta-Analysis

BACKGROUND: Studies in the past have shown that perforin expression is up-regulated during acute renal rejection, which provided hopes for a non-invasive and reliable diagnostic method to identify acute rejection. However, a systematic assessment of the value of perforin as a diagnostic marker of acute renal rejection has not been performed. We conducted this meta-analysis to document the diagnostic performance of perforin mRNA detection and to identify potential variables that may affect the performance. METHODOLOGY/PRINCIPAL FINDINGS: Relevant materials that reported the diagnostic performance of perforin mRNA detection in acute renal rejection patients were extracted from electronic databases. After careful evaluation of the studies included in this analysis, the numbers of true positive, true negative, false positive and false negative cases of acute renal rejection identified by perforin mRNA detection were gathered from each data set. The publication year, sample origin, mRNA quantification method and housekeeping gene were also extracted as potential confounding variables. Fourteen studies with a total of 501 renal transplant subjects were included in this meta-analysis. The overall performance of perforin mRNA detection was: pooled sensitivity, 0.83 (95% confidence interval: 0.78 to 0.88); pooled specificity, 0.86 (95% confidence interval: 0.82 to 0.90); diagnostic odds ratio, 28.79 (95% confidence interval: 16.26 to 50.97); and area under the summary receiver operating characteristic curves value, 0.9107±0.0174. The univariate analysis of potential variables showed some changes in the diagnostic performance, but none of the differences reached statistical significance. CONCLUSIONS/SIGNIFICANCE: Despite inter-study variability, the test performance of perforin mRNA detected by polymerase chain reaction was consistent under circumstances of methodological changes and demonstrated both sensitivity and specificity in detecting acute renal rejection. These results suggest a great diagnostic potential for perforin mRNA detection as a reliable marker of acute rejection in renal allograft recipients

AAPS Workshop Report: Strategies to Address Therapeutic Protein–Drug Interactions during Clinical Development

Therapeutic proteins (TPs) are increasingly combined with small molecules and/or with other TPs. However preclinical tools and in vitro test systems for assessing drug interaction potential of TPs such as monoclonal antibodies, cytokines and cytokine modulators are limited. Published data suggests that clinically relevant TP-drug interactions (TP-DI) are likely from overlap in mechanisms of action, alteration in target and/or drug-disease interaction. Clinical drug interaction studies are not routinely conducted for TPs because of the logistical constraints in study design to address pharmacokinetic (PK)- and pharmacodynamic (PD)-based interactions. Different pharmaceutical companies have developed their respective question- and/or risk-based approaches for TP-DI based on the TP mechanism of action as well as patient population. During the workshop both company strategies and regulatory perspectives were discussed in depth using case studies; knowledge gaps and best practices were subsequently identified and discussed. Understanding the functional role of target, target expression and their downstream consequences were identified as important for assessing the potential for a TP-DI. Therefore, a question-and/or risk-based approach based upon the mechanism of action and patient population was proposed as a reasonable TP-DI strategy. This field continues to evolve as companies generate additional preclinical and clinical data to improve their understanding of possible mechanisms for drug interactions. Regulatory agencies are in the process of updating their recommendations to sponsors regarding the conduct of in vitro and in vivo interaction studies for new drug applications (NDAs) and biologics license applications (BLAs)