Delivery of Brain-Derived Neurotrophic Factor via Nose-to-Brain Pathway

Purpose  

To investigate the plausibility of delivering brain-derived neurotrophic factor (BDNF) to brain via nose-to-brain pathway using chitosan as barrier-modulating agent.     

Network structure and dynamics of the mental workspace

The conscious manipulation of mental representations is central to many creative and uniquely human abilities. How does the human brain mediate such flexible mental operations? Here, multivariate pattern analysis of functional MRI data reveals a widespread neural network that performs specific mental manipulations on the contents of visual imagery. Evolving patterns of neural activity within this mental workspace track the sequence of informational transformations carried out by these manipulations. The network switches between distinct connectivity profiles as representations are maintained or manipulated.Albert Einstein described the elements of his scientific thought as “certain signs and more or less clear images which can be ‘voluntarily’ reproduced or combined” (1). Creative thought in science as well as in other domains such as the visual arts, mathematics, music, and dance requires the capacity to manipulate mental representations flexibly. Cognitive scientists refer to this capacity as a “mental workspace” and suggest that it is a key function of consciousness (2) involving the distribution of information among widespread, specialized subdomains (3).How does the human brain mediate these flexible mental operations? Behavioral studies of the mental workspace, such as Shepard and Metzler’s work on mental rotation (4), have found that many mental operations closely resemble their corresponding physical operations. This finding supports the view that the mental workspace can simulate the physical world. Recent work in neuroscience has focused on mental representations instead of operations, showing that the contents of visual perception (5), visual imagery (6), and even dreams (7) can be decoded from activity in visual cortex. These results suggest that the same regions that mediate representations in sensory perception also are involved in mental imagery. However, how the mind can manipulate these representations remains unknown. Many studies have found increased activity in frontal and parietal regions associated with a range of high-level cognitive abilities (8, 9) including mental rotation (10), analogical reasoning (11), working memory (12), and fluid intelligence (13). Together, these findings suggest that a frontoparietal network may form the core of the mental workspace. We therefore hypothesized that operations on visual representations in the mental workspace are realized through the coordinated activity of a distributed network of regions that spans at least the frontal, parietal, and occipital cortices. A strong test of this hypothesis would be to ask whether patterns of neural activity in these regions contain information about specific mental operations and whether these patterns evolve over time as mental representations are manipulated.In the present study, we tested this hypothesis by asking 15 participants to engage in either maintenance or manipulation of visual imagery while we collected functional MRI (fMRI) measurements of their neural activity. As stimuli, we developed 100 abstract parts that could be combined into 2 × 2 figures (Fig. 1 A and C). In a series of trials, participants mentally maintained a set of parts or a whole figure, mentally constructed a set of four parts into a figure, or mentally deconstructed a figure into its four parts (Fig. 1B). Stimuli were presented briefly at the beginning of each trial, followed by a task prompt and a 6-s delay during which the participant performed the indicated mental operation. At the end of the delay, the target output of the operation was presented along with three similar distractors, and the participant indicated the correct target (Fig. 1D). Adjusting the complexity of the stimuli allowed us to equate for task difficulty by maintaining an accuracy of two out of three correct responses for each participant in each of the four conditions (chance would be 1 out of 4 correct; Fig. 1E).Open in a separate windowFig. 1.Experimental design. (A) Parts could be constructed into 2 × 2 figures, and figures could be deconstructed into parts. (B) Participants performed four mental operations on stimuli: construct parts into figure, deconstruct figure into parts, maintain parts, or maintain figure. (C) The stimulus set of 100 abstract parts, ordered from simple to complex. (D) Example of figures. Parts and figures ranged from simple to complex according to an index, d. This index allowed the difficulty of the task to be equated across conditions. (E) Trial schematic. Trials begin with a figure and four unrelated parts presented for 2 s, followed by a task prompt for 1 s consisting of an arrow indicating the figure or the parts and a letter indicating the task. In this case, the participant is instructed to maintain the figure in memory. The task prompt is followed by a 5-s delay period during which no stimulus is shown and the participant performs the indicated operation. Finally, a test screen appears for 2.5 s. Depending on the task, four figures or four sets of parts are presented, and the participant indicates the correct output of the operation.     

A study on the effect of inorganic salts in transungual drug delivery of terbinafine

Objectives The poor success rate of topical therapy in nail disorders is mainly because of the low permeability of keratinized nail plates. This can be overcome by utilizing potent perungual drug penetration enhancers that facilitate the drug permeation across the nail plate. This study evaluated the efficacy of inorganic salts in enhancing the trans‐nail permeation using a model potent antifungal agent, terbinafine hydrochloride. Methods Permeation studies were carried out across human cadaver nail in a Franz diffusion cell using terbinafine solution (1 mg/ml; pH 3). Preliminary studies were carried out to assess the effect of salts (0.5 m ) on the terbinafine permeation into and through the nail. Further, the influence of salt concentration (0.25–3 m ) on permeation, the mechanism for the enhancement and the suitability of developing a formulation were also studied. Key findings Terbinafine permeation (3–5 fold) through the nail and drug load (4–7 fold) in the nail were enhanced significantly when salts were used at 0.5 m concentration. Increase in salt concentration up to 1 m increased the permeation, which decreased with further increase in salt concentration (>1 m ). Mechanistic studies revealed that the enhanced permeation by salts was mainly due to their ability to increase the nail hydration and also to increase the thermodynamic activity of the drug. The cumulative amount of terbinafine permeated at 24 h from the formulated gel (9.70 ± 0.93 μg/cm²) was comparable with that of a solution (11.45 ± 1.62 μg/cm2 ). Conclusions Given the promising results from the permeation and drug load studies, it was concluded that inorganic salts could be used as potent transungual permeation enhancers.     

Dermal Drug Levels of Antibiotic (Cephalexin) Determined by Electroporation and Transcutaneous Sampling (ETS) Technique

The purpose of this project was to assess the validity of a novel Electroporation and transcutaneous sampling (ETS) technique for sampling cephalexin from the dermal extracellular fluid (ECF). This work also investigated the plausibility of using cephalexin levels in the dermal ECF as a surrogate for the drug levels in the synovial fluid. In vitro and in vivo studies were carried out using hairless rats to assess the workability of ETS. Cephalexin (20 mg/kg) was administered (i.v.) through tail vein and the time course of drug concentration in the plasma was determined. In the same rats, cephalexin concentration in the dermal ECF was determined by ETS and microdialysis techniques. In a separate set of rats, only intraarticular microdialysis was carried out to determine the time course of cephalexin concentration in synovial fluid. The drug concentration in the dermal ECF determined by ETS and microdialysis did not differ significantly from each other and so as were the pharmacokinetic parameters. The results provide validity to the ETS technique. Further, there was a good correlation (~ 0.9) between synovial fluid and dermal ECF levels of cephalexin indicating that dermal ECF levels could be used as a potential surrogate for cephalexin concentration in the synovial fluid.     

Whole exome and whole genome sequencing with dried blood spot DNA without whole genome amplification

Newborn screening (NBS) for rare conditions is performed in all 50 states in the USA. We have partnered with the California Department of Public Health Genetic Disease Laboratory to determine whether sufficient DNA can be extracted from archived dried blood spots (DBS) for next‐generation sequencing in the hopes that next‐generation sequencing can play a role in NBS. We optimized the DNA extraction and sequencing library preparation protocols for residual infant DBS archived over 20 years ago and successfully obtained acceptable whole exome and whole genome sequencing data. This sequencing study using DBS DNA without whole genome amplification prior to sequencing library preparation provides evidence that properly stored residual newborn DBS are a satisfactory source of DNA for genetic studies.     

Selection of Solid-State Plasticizers as Processing Aids for Hot-Melt Extrusion

The objective of the study was to select solid-state plasticizers for hot-melt extrusion (HME) process. The physical and mechanical properties of plasticizers, in selected binary (polymer:plasticizer) and ternary (active pharmaceutical ingredient:polymer:plasticizer) systems, were evaluated to assess their effectiveness as processing aids for HME process. Indomethacin and Eudragit^® E PO were selected as model active pharmaceutical ingredient and polymer, respectively. Solubility parameters, thermal analysis, and rheological evaluation were used as assessment tools. Based on comparable solubility parameters, stearic acid, glyceryl behenate, and polyethylene glycol 8000 were selected as solid-state plasticizers. Binary and ternary physical mixtures were evaluated as a function of plasticizer concentration for thermal and rheological behavior. The thermal and rheological assessments also confirmed the miscibility predictions from solubility parameters. The understanding of thermal and rheological properties of the various mixtures helped in predicating plasticization efficiency of stearic acid, glyceryl behenate, and polyethylene glycol 8000. The evaluation also provided insight into the properties of the final product. An empirical model was also developed correlating rheological property of physical mixtures to actual HME process. Based on plasticizer efficiency, solid-state plasticizers and processing conditions can be selected for a HME process.     

In vitro and in vivo evaluation of a hydrogel-based prototype transdermal patch system of alfuzosin hydrochloride

The first-line therapy for moderate to severe benign prostatic hyperplasia is the oral therapy by alfuzosin hydrochloride. Unfortunately, the oral therapy of alfuzosin is associated with several route-specific systemic side-effects. The current study was aimed to develop a prototype transdermal patch system for alfuzosin using a hydrogel polymer and optimize the drug delivery through the skin for systemic therapy. The prospective of different chemical enhancers (polyethylene glycol (PEG 400), isopropyl myristate, propylene glycol, menthol and L-methionine; 5% w/v) and iontophoresis (0.3 mA/cm(2)) in the alfuzosin delivery across the full thickness rat skin was assessed in vitro. In vivo iontophoretic studies were carried out using selected patch system (PEG 400) for a period of 6 h in Sprague-Dawley rats. Passive permeation studies indicated that the incorporation of chemical agents have moderate effect (~4- to 7-fold) on the alfuzosin skin permeability and reduced the lag time. Combined approach of iontophoresis with chemical enhancers significantly augmented the drug transport (~ 43- to 72-fold). In vivo pharmacokinetic parameters revealed that the iontophoresis (transdermal patch with PEG 400) significantly enhanced the C(max) (~ 3-fold) and AUC(0-α) (~ 4-fold), when compared to control. The current study concludes that the application of iontophoresis (0.3 mA/cm(2)) using the newly developed agaorse-based prototype patch with PEG 400 could be utilized for the successful delivery of alfuzosin by transdermal route.     

Getting to the Heart of the Story: Using Talanoa to Explore Pacific Mental Health

Talanoa is an established format for generating discussion about complex topics used throughout the Pacific. Pacific researchers use talanoa to gather data with migrant Pacific Island populations, in countries such as the United States of America, Australia, and Aotearoa/New Zealand (A/NZ). Using talanoa in this way, changes the way that the approach is used as, on the one hand it is out of its original context, and on the other hand, extends its use to gather data with Pacific Islanders. In this article, we discuss the implementation of talanoa in an explorative qualitative research project, and discuss its effectiveness and usefulness for getting to the heart of the story about Tongan interpretations of mental illness and distress.