Microneedle-Assisted Delivery of Anti-Migraine Drugs Across Porcine Skin: Almotriptan Malate and Naratriptan Hydrochloride

Migraine is a common neurological disorder characterized by nausea, vomiting, photophobia, aching, fever, pain and chills. Triptans are selective serotonin agonists which can used to relieve migraine symptoms. Almotriptan malate and naratriptan hydrochloride are currently used for the management of migraine in the form of oral tablets. Oral tablets may be problematic for patients experiencing nausea and vomiting which are often associated with migraine. The microneedle-assisted transdermal drug delivery of these triptans may improve patient compliance. A vertical six-celled, static Franz diffusion cell system was used to conduct in vitro permeation experiments on porcine ear skin to determine the influence of microneedle-assisted transdermal delivery of both almotriptan malate and naratriptan hydrochloride. HPLC-MS analysis was performed using an Agilent 1200 series high performance liquid chromatography system in combination with an Agilent time of flight mass spectrometer (TOF-MS) system model 6230 (Agilent, Santa Clara, CA, USA). A reversed phase liquid chromatography column (Agilent Zorbax Eclipse Plus C18, 100 mm X 2.1 mm, 3.5 µm), was utilized for chromatographic separation. Confocal laser scanning microscopy was used to characterize the depth of the microchannels created after stainless-steel microneedle roller application. Transdermal flux of both triptans was calculated from the linear portion of the cumulative amount of drug permeated versus time curve. The mean passive flux of almotriptan malate was 13.044 ± 0.32 µg.cm2 .h, while the mean flux following microneedle roller application was 11.281 ± 0.22 µg.cm2 .h. The mean flux values for naratriptan hydrochloride for passive and after microneedle roller application was 0.88 ± 0.29 µg.cm2 .h and 4.18 ± 1.39 µg.cm2 .h, respectively. Statistical analysis was performed using the Student’s t-test (GradPad Prism 7). A statistically significant difference (p\u3c0.05) between microneedle-treated porcine skin samples compared to untreated skin samples was found for the transdermal flux values of naratriptan hydrochloride. Solid stainless-steel microneedle rollers enhanced the transdermal delivery of naratriptan hydrochloride. In contrast, transdermal flux values obtained for almotriptan malate indicate that differences between microneedle-treated and untreated skin samples was not statistically significant (p\u3e0.05)

The Influence of Solid Microneedles on the Transdermal Delivery of Selected Antiepileptic Drugs

The aim of this project was to examine the effect of microneedle rollers on the percutaneous penetration of tiagabine hydrochloride and carbamazepine across porcine skin in vitro. Liquid chromatography-mass spectrometric analysis was carried out using an Agilent 1200 Series HPLC system coupled to an Agilent G1969A TOF-MS system. Transdermal flux values of the drugs were determined from the steady-state portion of the cumulative amount versus time curves. Following twelve hours of microneedle roller application, there was a 6.74-fold increase in the percutaneous penetration of tiagabine hydrochloride (86.42 ± 25.66 µg/cm2/h) compared to passive delivery (12.83 ± 6.30 µg/cm2/h). For carbamazepine in 20% ethanol, passive transdermal flux of 7.85 ± 0.60 µg/cm2/h was observed compared to 10.85 ± 0.11 µg/cm2/h after microneedle treatment. Carbamazepine reconstituted in 30% ethanol resulted in only a 1.19-fold increase in drug permeation across porcine skin (36.73 ± 1.83 µg/cm2/h versus 30.74 ± 1.32 µg/cm2/h). Differences in flux values of untreated and microneedle-treated porcine skin using solid microneedles for the transdermal delivery of tiagabine were statistically significant. Although there were 1.38- and 1.19-fold increases in transdermal flux values of carbamazepine when applied as 20% and 30% ethanol solutions across microneedle-treated porcine skin, respectively, the increases were not statistically significant

COMPARING ESTIMATION PROCEDURES FOR DOSE-RESPONSE FUNCTIONS

The dose-response design is often used in agricultural research when it is necessary to measure a biological response at various levels of an experimental factor. This type of problem is common in chemical and pesticide research, however, it can also occur in other disciplines such as plant, animal, soil, and environmental sciences. While the analysis of dose-response data usually involves fitting a regression curve, the primary objective often centers on the estimation of dose related percentiles such as the LD50 or LC50. These measures are useful for comparing the relative efficacy of various treatments, however, the estimation of the specified percentiles is not always straightforward. Traditional methodology has relied on inverted solutions or asymptotic theory for statistical inference. More recently, computer intensive methods have been used to model dose-response relationships and can be more appropriate than traditional methods in some situations. This paper examines both the traditional and modem approaches to estimating doseresponse functions as they apply to binomial data. The techniques will be demonstrated using mortality data collected on black vine weevil eggs exposed to an organic pesticide treatment

Molecular Characterization of NRXN1 Deletions from 19,263 Clinical Microarray Cases Identifies Exons Important for Neurodevelopmental Disease Expression

PURPOSE: The purpose of the current study was to assess the penetrance of NRXN1 deletions. METHODS: We compared the prevalence and genomic extent of NRXN1 deletions identified among 19,263 clinically referred cases to that of 15,264 controls. The burden of additional clinically relevant copy-number variations (CNVs) was used as a proxy to estimate the relative penetrance of NRXN1 deletions. RESULTS: We identified 41 (0.21%) previously unreported exonic NRXN1 deletions ascertained for developmental delay/intellectual disability that were significantly greater than in controls (odds ratio (OR) = 8.14; 95% confidence interval (CI): 2.91-22.72; P \u3c 0.0001). Ten (22.7%) of these had a second clinically relevant CNV. Subjects with a deletion near the 3\u27 end of NRXN1 were significantly more likely to have a second rare CNV than subjects with a 5\u27 NRXN1 deletion (OR = 7.47; 95% CI: 2.36-23.61; P = 0.0006). The prevalence of intronic NRXN1 deletions was not statistically different between cases and controls (P = 0.618). The majority (63.2%) of intronic NRXN1 deletion cases had a second rare CNV at a prevalence twice as high as that for exonic NRXN1 deletion cases (P = 0.0035). CONCLUSIONS: The results support the importance of exons near the 5\u27 end of NRXN1 in the expression of neurodevelopmental disorders. Intronic NRXN1 deletions do not appear to substantially increase the risk for clinical phenotypes.Genet Med 19 1, 53-61

Nuclear Energy Research Initiative Project No. 02 103 Innovative Low Cost Approaches to Automating QA/QC of Fuel Particle Production Using On Line Nondestructive Methods for Higher Reliability Final Project Report

This Nuclear Energy Research Initiative (NERI) project was tasked with exploring, adapting, developing and demonstrating innovative nondestructive test methods to automate nuclear coated particle fuel inspection so as to provide the United States (US) with necessary improved and economical Quality Assurance and Control (QA/QC) that is needed for the fuels for several reactor concepts being proposed for both near term deployment [DOE NE & NERAC, 2001] and Generation IV nuclear systems. Replacing present day QA/QC methods, done manually and in many cases destructively, with higher speed automated nondestructive methods will make fuel production for advanced reactors economically feasible. For successful deployment of next generation reactors that employ particle fuels, or fuels in the form of pebbles based on particles, extremely large numbers of fuel particles will require inspection at throughput rates that do not significantly impact the proposed manufacturing processes. The focus of the project is nondestructive examination (NDE) technologies that can be automated for production speeds and make either: (I) On Process Measurements or (II) In Line Measurements. The inspection technologies selected will enable particle “quality” qualification as a particle or group of particles passes a sensor. A multiple attribute dependent signature will be measured and used for qualification or process control decisions. A primary task for achieving this objective is to establish standard signatures for both good/acceptable particles and the most problematic types of defects using several nondestructive methods

Follicular helper T cells are required for systemic autoimmunity

Production of high-affinity pathogenic autoantibodies appears to be central to the pathogenesis of lupus. Because normal high-affinity antibodies arise from germinal centers (GCs), aberrant selection of GC B cells, caused by either failure of negative selection or enhanced positive selection by follicular helper T (TFH) cells, is a plausible explanation for these autoantibodies. Mice homozygous for the san allele of Roquin, which encodes a RING-type ubiquitin ligase, develop GCs in the absence of foreign antigen, excessive TFH cell numbers, and features of lupus. We postulated a positive selection defect in GCs to account for autoantibodies. We first demonstrate that autoimmunity in Roquinsan/san (sanroque) mice is GC dependent: deletion of one allele of Bcl6 specifically reduces the number of GC cells, ameliorating pathology. We show that Roquinsan acts autonomously to cause accumulation of TFH cells. Introduction of a null allele of the signaling lymphocyte activation molecule family adaptor Sap into the sanroque background resulted in a substantial and selective reduction in sanroque TFH cells, and abrogated formation of GCs, autoantibody formation, and renal pathology. In contrast, adoptive transfer of sanroque TFH cells led to spontaneous GC formation. These findings identify TFH dysfunction within GCs and aberrant positive selection as a pathway to systemic autoimmunity

Global maps of soil temperature

Research in global change ecology relies heavily on global climatic grids derived from estimates of air temperature in open areas at around 2 m above the ground. These climatic grids do not reflect conditions below vegetation canopies and near the ground surface, where critical ecosystem functions occur and most terrestrial species reside. Here, we provide global maps of soil temperature and bioclimatic variables at a 1-km2 resolution for 0–5 and 5–15 cm soil depth. These maps were created by calculating the difference (i.e. offset) between in situ soil temperature measurements, based on time series from over 1200 1-km2 pixels (summarized from 8519 unique temperature sensors) across all the world\u27s major terrestrial biomes, and coarse-grained air temperature estimates from ERA5-Land (an atmospheric reanalysis by the European Centre for Medium-Range Weather Forecasts). We show that mean annual soil temperature differs markedly from the corresponding gridded air temperature, by up to 10°C (mean = 3.0 ± 2.1°C), with substantial variation across biomes and seasons. Over the year, soils in cold and/or dry biomes are substantially warmer (+3.6 ± 2.3°C) than gridded air temperature, whereas soils in warm and humid environments are on average slightly cooler (−0.7 ± 2.3°C). The observed substantial and biome-specific offsets emphasize that the projected impacts of climate and climate change on near-surface biodiversity and ecosystem functioning are inaccurately assessed when air rather than soil temperature is used, especially in cold environments. The global soil-related bioclimatic variables provided here are an important step forward for any application in ecology and related disciplines. Nevertheless, we highlight the need to fill remaining geographic gaps by collecting more in situ measurements of microclimate conditions to further enhance the spatiotemporal resolution of global soil temperature products for ecological applications

Global maps of soil temperature

Research in global change ecology relies heavily on global climatic grids derived from estimates of air temperature in open areas at around 2 m above the ground. These climatic grids do not reflect conditions below vegetation canopies and near the ground surface, where critical ecosystem functions occur and most terrestrial species reside. Here, we provide global maps of soil temperature and bioclimatic variables at a 1-km² resolution for 0–5 and 5–15 cm soil depth. These maps were created by calculating the difference (i.e., offset) between in-situ soil temperature measurements, based on time series from over 1200 1-km² pixels (summarized from 8500 unique temperature sensors) across all the world’s major terrestrial biomes, and coarse-grained air temperature estimates from ERA5-Land (an atmospheric reanalysis by the European Centre for Medium-Range Weather Forecasts). We show that mean annual soil temperature differs markedly from the corresponding gridded air temperature, by up to 10°C (mean = 3.0 ± 2.1°C), with substantial variation across biomes and seasons. Over the year, soils in cold and/or dry biomes are substantially warmer (+3.6 ± 2.3°C) than gridded air temperature, whereas soils in warm and humid environments are on average slightly cooler (-0.7 ± 2.3°C). The observed substantial and biome-specific offsets emphasize that the projected impacts of climate and climate change on near-surface biodiversity and ecosystem functioning are inaccurately assessed when air rather than soil temperature is used, especially in cold environments. The global soil-related bioclimatic variables provided here are an important step forward for any application in ecology and related disciplines. Nevertheless, we highlight the need to fill remaining geographic gaps by collecting more in-situ measurements of microclimate conditions to further enhance the spatiotemporal resolution of global soil temperature products for ecological applications

Global maps of soil temperature.

Research in global change ecology relies heavily on global climatic grids derived from estimates of air temperature in open areas at around 2 m above the ground. These climatic grids do not reflect conditions below vegetation canopies and near the ground surface, where critical ecosystem functions occur and most terrestrial species reside. Here, we provide global maps of soil temperature and bioclimatic variables at a 1-km2 resolution for 0-5 and 5-15 cm soil depth. These maps were created by calculating the difference (i.e. offset) between in situ soil temperature measurements, based on time series from over 1200 1-km2 pixels (summarized from 8519 unique temperature sensors) across all the world's major terrestrial biomes, and coarse-grained air temperature estimates from ERA5-Land (an atmospheric reanalysis by the European Centre for Medium-Range Weather Forecasts). We show that mean annual soil temperature differs markedly from the corresponding gridded air temperature, by up to 10°C (mean = 3.0 ± 2.1°C), with substantial variation across biomes and seasons. Over the year, soils in cold and/or dry biomes are substantially warmer (+3.6 ± 2.3°C) than gridded air temperature, whereas soils in warm and humid environments are on average slightly cooler (-0.7 ± 2.3°C). The observed substantial and biome-specific offsets emphasize that the projected impacts of climate and climate change on near-surface biodiversity and ecosystem functioning are inaccurately assessed when air rather than soil temperature is used, especially in cold environments. The global soil-related bioclimatic variables provided here are an important step forward for any application in ecology and related disciplines. Nevertheless, we highlight the need to fill remaining geographic gaps by collecting more in situ measurements of microclimate conditions to further enhance the spatiotemporal resolution of global soil temperature products for ecological applications

Estrogens: Properties, Behaviors, and Fate in Dairy Manure-Amended Soils

In 2012 there were 63% fewer dairies in the United States than there were in 1997 as a result of conglomeration of the dairy industry into concentrated animal feeding operations at the expense of smaller farms. Today, 60% of all milk produced in the United States comes from 5% of the nation’s dairies (operations with ≥ 500 cows). Concentrated animal feeding operations are touted as economically efficient agricultural business models, hailed for their increased milk yields. Yet, with an average daily manure production of over 27 000 kg for a 500-head dairy farm, manure storage and disposal are serious management and environmental concerns. A common economical mode of manure disposal is application to nearby agricultural fields. However, a major concern with land application of dairy manure is the fate of manure-borne hormones, compounds considered chemicals of emerging concern, and the potential threat these hormones pose to humans and the environment. The fate of these chemicals in the soil environment is complicated by multiple edaphic variables including pH, mineralogy, organic matter, microbial activity, and redox status. Estrogens are sorbed by soil organic matter and transformed to nonbioactive, highly soluble conjugated forms or to metabolites that exhibit yet additional properties distinct from their parent compounds. However, deconjugation frequently occurs, regenerating endocrine-disrupting free estrogen compounds. It is challenging to fully understand the behavior and predict the fate of estrogenic compounds from dairy manure in soils because of variable and complex interactions with soil factors, as well as possible interactions among the different chemicals of emerging concern. This review focuses on the behavior of naturally occurring estrogen hormones present in dairy manure in the soil environment. Heightened understanding of the fate of these compounds in soil will enhance our ability to reduce their potential risks.The accepted manuscript in pdf format is listed with the files at the bottom of this page. The presentation of the authors' names and (or) special characters in the title of the manuscript may differ slightly between what is listed on this page and what is listed in the pdf file of the accepted manuscript; that in the pdf file of the accepted manuscript is what was submitted by the author