Providing multimedia information to children and young people increases recruitment to trials: pre-planned meta-analysis of SWATs.

BACKGROUND: Randomised controlled trials are often beset by problems with poor recruitment and retention. Information to support decisions on trial participation is usually provided as printed participant information sheets (PIS), which are often long, technical, and unappealing. Multimedia information (MMI), including animations and videos, may be a valuable alternative or complement to a PIS. The Trials Engagement in Children and Adolescents (TRECA) study compared MMI to PIS to investigate the effects on participant recruitment, retention, and quality of decision-making. METHODS: We undertook six SWATs (Study Within A Trial) within a series of host trials recruiting children and young people. Potential participants in the host trials were randomly allocated to receive MMI-only, PIS-only, or combined MMI + PIS. We recorded the rates of recruitment and retention (varying between 6 and 26 weeks post-randomisation) in each host trial. Potential participants approached about each host trial were asked to complete a nine-item Decision-Making Questionnaire (DMQ) to indicate their evaluation of the information and their reasons for participation/non-participation. Odds ratios were calculated and combined in a meta-analysis. RESULTS: Data from 3/6 SWATs for which it was possible were combined in a meta-analysis (n = 1758). Potential participants allocated to MMI-only were more likely to be recruited to the host trial than those allocated to PIS-only (OR 1.54; 95% CI 1.05, 2.28; p = 0.03). Those allocated to combined MMI + PIS compared to PIS-only were no more likely to be recruited to the host trial (OR = 0.89; 95% CI 0.53, 1.50; p = 0.67). Providing MMI rather than PIS did not impact on DMQ scores. Once children and young people had been recruited to host trials, their trial retention rates did not differ according to intervention allocation. CONCLUSIONS: Providing MMI-only increased the trial recruitment rate compared to PIS-only but did not affect DMQ scores. Combined MMI + PIS instead of PIS had no effect on recruitment or retention. MMIs are a useful tool for trial recruitment in children and young people, and they could reduce trial recruitment periods.

What assessments are currently used to investigate and diagnose cerebral visual impairment (CVI) in children? A systematic review.

PURPOSE: Cerebral visual impairment (CVI) is the leading cause of childhood visual impairment in the developed world. Despite this, there are no agreed clinical guidelines for the investigation and diagnosis of the condition. Before development of such guidelines can commence, it is important to recognise which approaches are currently employed. This systematic review evaluated the literature to identify which methods of assessment are currently used to investigate and diagnose childhood CVI. METHODS: Medline, Embase, CINAHL, Scopus and the Cochrane Library databases were systematically searched in January 2020 using defined search terms. Articles were included if they: (i) were research papers, conference abstracts or research protocols published in peer-reviewed scientific journals, or relevant textbooks; (ii) included a clinical investigation of CVI in children; (iii) provided an explanation or criteria to diagnose CVI and (iv) were specifically investigating cerebral/cortical visual impairment. Methods used to a) assess and b) diagnose CVI were extracted from included articles. 'Assessment scores' were assigned for each method employed by researchers to investigate and diagnose CVI to quantify and compare approaches between articles. A quality grading was also applied to each article. RESULTS: Of 6454 identified articles, 45 met the inclusion criteria. From these, 10 categories of assessment utilised within included articles were identified: (1) Medical history, (2) Vision assessment/ophthalmologic examination, (3) Neuroimaging, (4) Visual behaviour and direct observation, (5) Structured history-taking, (6) Visual perception tests, (7) Ocular movement and posture assessment, (8) Intelligence/IQ assessment, (9) Clinical electrophysiology and (10) Neurodevelopmental tests. In terms of diagnostic criteria, the most commonly reported approach was one of exclusion, i.e., CVI was diagnosed when visual dysfunction could not be attributed to abnormalities detected in the anterior visual pathway. CONCLUSION: There is a lack of common practice in the approaches used by clinicians to investigate and diagnose CVI in children. At present, a 'diagnosis of exclusion' remains the most common means to diagnose CVI. Development of clinical guidelines for assessment and diagnosis are necessary to ensure consistency in the diagnosis of CVI and the timely implementation of support to alleviate the impact of CVI on the child's daily living.

Understanding temporal and spatial distribution of intestinal nematodes of horses using faecal egg counts and DNA metabarcoding.

This study reports the spatial and temporal distribution of ascarid and strongylid nematodes in Thoroughbred horses by age category across different climatic zones in Australia over an 18-month period. Faecal samples (n = 2046) from individual horses were analysed using the modified McMaster technique for faecal egg counts (FECs). Strongylids were identified using PCR-directed next-generation sequencing of the second internal transcribed spacer (ITS-2) of the nuclear ribosomal DNA. Yearlings had the highest prevalence (82%) of strongyle eggs followed by weanlings (79%), foals (58%), wet mares (49%) and dry mares (46%). For Parascaris spp., foals had the highest prevalence (35%) followed by weanlings (21%) and yearlings (10%). The highest mean FECs for Parascaris spp. were observed in foals (525 eggs per gram [EPG] of faeces) while those for strongyles were in yearlings (962 EPG). Among horses that were classified as adults at the time of sampling, 77% (860 of 1119) of mares were low (i.e., <250 EPG) strongyle egg-shedders. Mean strongyle FEC counts were highest in the Mediterranean (818 EPG) followed by summer (599 EPG), winter (442 EPG), and non-seasonal (413 EPG) rainfall zones. Twenty-six nematode species were detected, with Cylicostephanus longibursatus (26.5%), Cylicocyclus nassatus (23.7%) and Coronocyclus coronatus (20.5%) being the most frequently detected species. Their richness and relative abundance varied with horse age, season and climatic zone. In addition, Strongylus equinus and Triodontophorus spp. (T. brevicauda and T. serratus) were also detected. This comprehensive study elucidates spatial (climatic zone) and temporal (i.e., seasonal) trends in prevalence and burdens of intestinal nematodes in Australian horses using non-invasive conventional and molecular methods. The information presented in this study is crucial for developing integrated management strategies to control horse parasites in farmed horses.

A national survey of anthelmintic resistance in ascarid and strongylid nematodes in Australian Thoroughbred horses.

This study quantified the extent of anthelmintic resistance (AR) in ascarid and strongylid nematodes against commonly used anthelmintics in Australian Thoroughbred horses. Faecal egg count reduction tests (FECRTs, n = 86) and egg reappearance period (ERP) tests were conducted on 22 farms across Australia. Faecal egg counts (FECs) were determined using the modified McMaster technique, and percent faecal egg count reduction (%FECR) was calculated using the Bayesian hierarchical model and hybrid Frequentist/Bayesian analysis method. The results were interpreted using old (published in 1992) and new (2023) research guidelines of the World Association for the Advancement of Veterinary Parasitology (WAAVP). The species composition of strongylid nematodes was detected utilising a DNA-metabarcoding method using pre- and post-treatment samples. Resistance was observed in strongylid nematodes to commonly used single-active and combination anthelmintics, including ivermectin (IVM %FECR range: 82%-92%; 95% lower credible interval (LCI) range: 80%-90%), abamectin (ABM: 73%-92%; 65%-88%), moxidectin (MOX: 89%-91%; 84%-89%), oxfendazole (OFZ: 0%-56%; 0%-31%) and its combination with pyrantel (OFZ + PYR: 0%-82%; 0%-78%). Resistance in Parascaris spp. was observed to IVM (10%-43%; 0%-36%), ABM (0%; 0%) and MOX (0%; 0%). When the new thresholds recommended by the WAAVP were used, AR was detected in six additional FECRTs for strongylids and three more tests for Parascaris spp., introducing resistance to OFZ and OFZ + PYR in the latter. Shortened ERPs (4-6 weeks) of strongylids were observed in 31 FECRTs in which AR was not detected at 2 weeks post-treatment for all the anthelmintics tested. Among cyathostomins, Cylicocyclus nassatus, Cylicostephanus longibursatus and Coronocyclus coronatus were the most prevalent species at 2 weeks post-treatment, whereas the main species appearing at five weeks following treatments with macrocyclic lactones were Cylicocyclus nassatus, Cylicostephanus longibursatus and Cylicocyclus ashworthi. After treatment with OFZ + PYR, the latter three, plus Coronocyclus coronatus and Cyathostomum catinatum, were detected at 5 weeks post-treatment. Overall, the study highlights the prevalence of AR in both ascarids and strongylid nematodes against commonly used anthelmintic products to control worms in Australian horses. The results indicate that ML combination products provided acceptable efficacy at 2 weeks. However, ERP calculations suggest that products work less effectively than previously measured. It is suggested to regularly monitor the efficacy of the anthelmintics and consider changing the worm control practices to better manage worms and AR in Australian horses.

Molecular diagnostics for gastrointestinal helminths in equids: Past, present and future.

This review is aimed to (i) appraise the literature on the use of molecular techniques for the detection, quantification and differentiation of gastrointestinal helminths (GIH) of equids, (ii) identify the knowledge gaps and, (iii) discuss diagnostic prospects in equine parasitology. Following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines for systematic reviews, we retrieved 54 studies (horses: 50/54; donkeys and zebras: 4/54) from four databases. Polymerase chain reaction (PCR) was employed in all of the studies whereas PCR amplicons were sequenced in only 18 of them. Other techniques used (including modifications of PCR) were reverse line blot, quantitative (q)PCR, restriction fragment length polymorphism, nested-PCR, PCR-directed next-generation sequencing, Southern blotting, single strand conformation polymorphism, PCR-enzyme linked immunosorbent assay, matrix-assisted laser desorption/ionisation-time of flight and random amplification of polymorphic DNA. Most of the studies (53/54) used nuclear ribosomal RNA (including the internal transcribed spacers, intergenic spacer, 5.8 S, 18 S, 28 S and 12 S) as target loci while cytochrome c oxidase subunit 1 and random genomic regions were targeted in only three and one studies, respectively. Overall, to date, the majority of molecular studies have focused on the diagnosis and identification of GIHs of equids (i.e. species of Anoplocephala, Craterostomum, cyathostomins, Oesophagodontus, Parascaris, Strongylus, Strongyloides and Triodontophorus), with a recent shift towards investigations on anthelmintic resistance and the use of high-throughput nemabiome metabarcoding. With the increasing reports of anthelmintic resistance in equid GIHs, it is crucial to develop and apply techniques such as advanced metabarcoding for surveillance of parasite populations in order to gain detailed insights into their diversity and sustainable control. To the best of our knowledge, this is the first systematic review that evaluates molecular investigations published on the diagnosis and quantification of equid GIHs and provides useful insights into important knowledge gaps and future research directions in equid molecular parasitology.

Prevalence and diversity of ascarid and strongylid nematodes in Australian Thoroughbred horses using next-generation sequencing and bioinformatic tools.

The study presents the results of a cross-sectional survey to describe the epidemiology of ascarid and strongylid nematodes in horses, the impact of diverse climatic conditions on parasite diversity and the levels of faecal egg shedding in different age groups of managed Thoroughbred horses. Individual faecal samples (n = 1377) collected from 62 Thoroughbred farms across four climatic zones in Australia were analysed using the modified McMaster technique for faecal egg counts (FECs) and strongylid nematodes were identified utilising PCR-directed next-generation sequencing (NGS) of the second internal transcribed spacer of the nuclear ribosomal DNA (ITS-2). Across all age groups, the prevalence of ascarid and strongylid nematodes was 12% (95% confidence interval 10-14%) and 72% (70-74%), respectively. Based on strongylid FECs, yearlings had the highest prevalence (89%) followed by weanlings (83%), foals (79%), wet mares (61%), dry mares (59%) and stallions (54%). However, for Parascaris spp., foals had the highest prevalence (46%) followed by weanlings (32%) and yearlings (13%). The highest mean FECs for Parascaris spp. were observed in foals (418 eggs per gram [EPG] of faeces) while those for strongylids were in yearlings (1002 EPG). Of the adult horses (mares and stallions), 67% (489 of 729) and 11% (77 of 729) were low (i.e., ≤250 EPG) and moderate (i.e., 251-500 EPG) strongylid egg-shedders, respectively. Strongylid egg shedding varied across climatic zones, with the highest mean FECs in the summer rainfall (723 EPG) followed by non-seasonal rainfall (629 EPG), winter rainfall (613 EPG), and Mediterranean (606 EPG) rainfall zones. Twenty-three nematode species were detected using NGS, with Cylicostephanus longibursatus (28%), Cylicocyclus nassatus (23%) and Coronocyclus coronatus (23%), being the most abundant species. Three species of Strongylus (i.e., S. vulgaris, S. equinus and S. edentatus) were also detected. The nemabiome composition, species richness and relative abundance varied within horse age and between climatic zones. These empirical findings provide a comprehensive understanding of the prevalence of parasites within horse populations and the multifaceted factors that influence their occurrence, thereby allowing for the formulation of tailored strategies aimed at parasite control in domestic horses.

Parents and teachers of children in special education settings value in-school eyecare and written reports of visual status.

OBJECTIVES: To evaluate parent and teacher opinion of the provision of in-school eyecare and jargon-free written reporting of visual status for children in special educational settings. PARTICIPANTS AND METHODS: A nationally-agreed, in-school eyecare framework for children attending special schools which recommends a full eye examination, dispensing of spectacles and provision of a jargon-free written report of visual outcomes to parents and teachers, was provided to 200 children (mean age 10 years, 9 months; 70% male) attending a special school in the UK. The written 'Vision Report' detailed, in lay-language, results from the eye examination and provided practical advice to alleviate the impact of vision difficulties both at home and in the classroom. Following implementation of the framework, parents and teachers completed a feedback questionnaire to determine their opinion of the in-school eye examination and utility of the Vision Report. RESULTS: Parents of 123 participants returned a feedback questionnaire. Eighty-eight participants were represented by the 23 teachers who returned a questionnaire. The in-school eyecare was rated positively for children in special education by 82.4% of parents and 80.9% of teachers. Key benefits included the familiarity of the in-school setting (81.3% of parents and 100% of teachers agree), the convenience of the setting for parents (74.0% of parents and 100% of teachers agree), and the opportunity for teachers to speak directly to eyecare providers regarding a child's visual needs (82.6% of teachers agree). The information provided by the Vision Report was deemed useful day-to-day by 78.3% of parents and 100% of teachers. The majority (80%) of teachers implemented classroom modifications suggested in the report, whereas only 47.9% of parents reported implementation of modifications at home. CONCLUSIONS: Provision of in-school eyecare is valued by parents and teachers of children in special education settings. Jargon-free, written reports of visual status are valued and utilised by parents and teachers. Further support is required to aid parents in implementing vision modifications at home.

Investigation of the relationship between macular pigment levels and rod-mediated dark adaptation in intermediate age-related macular degeneration.

BACKGROUND: It has been shown that rod-mediated dark adaptation is significantly delayed in ageing, a change which is exacerbated in age-related macular degeneration (AMD). Levels of lutein and zeaxanthin, the two main constituents of macular pigment have been found in rod outer segments, indicating that the macular pigment may have an influence on rod-mediated dark adaptation. The aim of this study was to determine if rod-mediated dark adaptation is associated with central macular pigment levels in individuals with intermediate stage AMD. METHODS: A cross-sectional observational study included individuals with acuity better than 6/15 Snellen and intermediate stage AMD based on graded fundus photographs using an internationally accepted grading scale. Rod-mediated dark adaptation was assessed at five degrees eccentricity in the superior retina (inferior visual field) using the rod intercept time measure from the MacuLogix AdaptDx. Macular pigment optical density was measured at 0.5 degrees eccentricity using a heterochromatic flicker photometry-based method. RESULTS: Twenty-seven individuals (mean age 76.7 years) with intermediate stage AMD and 23 age-matched normal controls (mean age 74.0 years) were recruited. Rod-mediated dark adaptation was significantly delayed in intermediate stage AMD compared with healthy controls (32.9 minutes versus 10.7 minutes, p < 0.01). There was no statistically significant correlation between the rod intercept time and the level of macular pigment in those with intermediate AMD (r = -0.04, p = 0.85). CONCLUSION: The results did not support the hypothesis that higher macular pigment is associated with improved rod-mediated performance or that higher levels of macular pigment protect rod-mediated function in intermediate AMD.

Mucoadhesion and the gastrointestinal tract.

The concept of mucoadhesion is one that has the potential to improve the highly variable residence times experienced by drugs and dosage forms at various sites in the gastrointestinal tract, and consequently, to reduce variability and improve efficacy. Intimate contact with the mucosa should enhance absorption or improve topical therapy. A variety of approaches have been investigated for mucoadhesion in the gastrointestinal tract, particularly for the stomach and small intestine. Despite interesting results in these sites, mucoadhesive approaches have not yet shown success in humans. The potential of the lower gut for these applications has been largely neglected, although the large intestine in particular may benefit, and the colon has several factors that suggest mucoadhesion could be successful there, including lower motility and the possibility of a lower mucus turnover and thicker mucus layer. In vitro studies on colonic mucoadhesion show promise, and rectal administration has shown some positive results in vivo. This review considers the background to mucoadhesion with respect to the physiological conditions of the gastrointestinal tract as well as the principles that underlie this concept. Mucoadhesive approaches to gastrointestinal drug delivery will be examined, with particular attention given to the lower gut.

Gut instincts: explorations in intestinal physiology and drug delivery.

We need to look beyond our gut instincts to use information on "simple" intestinal physiological parameters as they have been presented to us in the past. Here we present a discussion on such parameters, old and new, and ask how much we really understand them. Behaviour of drugs and delivery systems in the intestine depends on many physiological factors including fluid volume, fluid composition, transit, motility, bacteria and pH, which are further influenced by food, gender and age. These are often considered well understood, but their true variability and idiosyncrasies are not fully appreciated or utilised in intestinal dosage form design or in vitro testing. There are still many unknowns in these areas. The distal gut especially has been neglected, and the influence of disease is often ignored. As pharmaceutics moves forward into the molecular era an understanding of the role of cellular mechanisms of transporters and metabolic enzymes is important, but the basics must not be forgotten. This discussion on intestinal physiology is utilised to address those areas which require further research and understanding, and new technologies are highlighted. Better understanding of the fundamental information available can open new avenues for research and pave the way for the future of gastrointestinal drug delivery.

Measurements of rat and mouse gastrointestinal pH, fluid and lymphoid tissue, and implications for in-vivo experiments.

To use rodent models effectively in in-vivo investigations on oral drug and vaccine delivery, the conditions in the gastrointestinal tract must be understood. Some fundamental information is currently unavailable or incomplete. We have investigated the pH, water content and lymphoid tissue distribution along the gastrointestinal tract, as well as the stomach volume, as these were critical to our investigations on pH-responsive drug delivery and colonic vaccination. The observed values were compared with those in man as an indication of the validity of the rodent model. The mouse stomach pH was 3.0 (fed) and 4.0 (fasted), and the corresponding values in the rat were 3.2 (fed) and 3.9 (fasted). The mean intestinal pH was lower than that in man (

What do the data show? Knowledge map development for comprehensive environmental assessment.

Environmental and human health risk assessments benefit from using data that cross multiple scientific domains. Although individual data points may often be readily understood, the total picture can be difficult to envision. This is especially true with gaps in the data (e.g., with emerging substances such as engineered nanomaterials [ENM]), such that simply presenting only known information can result in a skewed picture. This study describes a method for building knowledge maps (KM) to visually summarize factors relevant to risk assessment in a relatively easy to interpret format. The KMs were created in the context of the comprehensive environmental assessment (CEA) approach for research planning and risk management of environmental contaminants. Recent applications of CEA to emerging substances such as engineered nanomaterials that have numerous data gaps have suggested that a more visually based depiction of information would improve the approach. We developed KM templates as a pilot project, to represent pertinent aspects of conceptual domains, and to highlight gaps in available information for one particular portion of a specific CEA application: the comparison of environmental transport, transformation, and fate of multiwalled carbon nanotubes (MWCNTs) and decabromodiphenyl ether as flame retardants. The results are 3 KM templates representing Physical Properties, Transport, and Transformation. The 3 templates were applied to both substances, resulting in a total of 6 KMs. In addition to presenting the KMs, this paper details the process used to generate them, to aid KM development for other sections of CEA applied to MWCNTs, or to apply the process to new CEA applications.

Systematic Omics Analysis Review (SOAR) tool to support risk assessment.

Environmental health risk assessors are challenged to understand and incorporate new data streams as the field of toxicology continues to adopt new molecular and systems biology technologies. Systematic screening reviews can help risk assessors and assessment teams determine which studies to consider for inclusion in a human health assessment. A tool for systematic reviews should be standardized and transparent in order to consistently determine which studies meet minimum quality criteria prior to performing in-depth analyses of the data. The Systematic Omics Analysis Review (SOAR) tool is focused on assisting risk assessment support teams in performing systematic reviews of transcriptomic studies. SOAR is a spreadsheet tool of 35 objective questions developed by domain experts, focused on transcriptomic microarray studies, and including four main topics: test system, test substance, experimental design, and microarray data. The tool will be used as a guide to identify studies that meet basic published quality criteria, such as those defined by the Minimum Information About a Microarray Experiment standard and the Toxicological Data Reliability Assessment Tool. Seven scientists were recruited to test the tool by using it to independently rate 15 published manuscripts that study chemical exposures with microarrays. Using their feedback, questions were weighted based on importance of the information and a suitability cutoff was set for each of the four topic sections. The final validation resulted in 100% agreement between the users on four separate manuscripts, showing that the SOAR tool may be used to facilitate the standardized and transparent screening of microarray literature for environmental human health risk assessment.

Evaluation of microelectrode array data using Bayesian modeling as an approach to screening and prioritization for neurotoxicity testing.

The need to assess large numbers of chemicals for their potential toxicities has resulted in increased emphasis on medium- and high-throughput in vitro screening approaches. For such approaches to be useful, efficient and reliable data analysis and hit detection methods are also required. Assessment of chemical effects on neuronal network activity using microelectrode arrays (MEAs) has been proposed as a screening tool for neurotoxicity. The current study examined a Bayesian data analysis approach for assessing effects of a 30 chemical training set on activity of primary cortical neurons grown in multi-well MEA plates. Each well of the MEA plate contained 64 microelectrodes and the data set contains the number of electrical spikes registered by each electrode over the course of each experiment. A Bayesian data analysis approach was developed and then applied to several different parsings of the data set to produce probability determinations for hit selection and ranking. This methodology results in an approach that is approximately 74% sensitive in detecting chemicals in the training set known to alter neuronal function (23 expected positives) while being 100% specific in detecting chemicals expected to have no effect (7 expected negatives). Additionally, this manuscript demonstrates that the Bayesian approach may be combined with a previously published weighted mean firing rate approach in order to produce a more robust hit detection method. In particular, when combined with the weighted mean firing rate approach, the joint analysis produces a sensitivity of approximately 96% and a specificity of 100%. These results demonstrate the utility of a novel approach to analysis of MEA data and support the use of neuronal networks grown on MEAs as a for neurotoxicity screening approach.

Decoupling the role of image size and calorie intake on gastric retention of swelling-based gastric retentive formulations: pre-screening in the dog model.

Gastric retention is postulated as an approach to improve bioavailability of compounds with narrow absorption windows. To elucidate the role of image size on gastric retention and pharmacokinetics, formulations with different image sizes and swelling kinetics but similar dissolution rates were designed and imaged in dogs. Diet had a clear effect, with increasing calorific intake prolonging retention in the dog model. In contrast to clinical observations, no obvious effect of image size on gastric retention was observed in the dog, with the larger gastric retentive (GR) and smaller controlled release (CR) formulations both demonstrating similar gastric emptying. Comparable pharmacokinetic profiles were observed for the two formulations, corroborating the imaging data and providing evidence of similar in vivo dissolution rates and dosage form integrity in the dog. Food, specifically meal composition, resulted in comparable enhancements in exposure in the dog and clinic due to prolonged gastric retention. However, differentiating retention based on image size in the dog was not feasible due to the smaller pyloric aperture compared to humans. This work illustrates that the dog is capable of determining the pharmacokinetic advantage of gastric retention relative to immediate release (IR) or CR formulations, however, has limited value in differentiating between CR and GR formulations.

Evaluation of multi-well microelectrode arrays for neurotoxicity screening using a chemical training set.

Microelectrode array (MEA) approaches have been proposed as a tool for detecting functional changes in electrically excitable cells, including neurons, exposed to drugs, chemicals or particles. However, conventional single well-MEA systems lack the throughput necessary for screening large numbers of uncharacterized compounds. Recently, multi-well MEA (mwMEA) formats have become available to address the need for increased throughput. The current experiments examined the effects of a training set of 30 chemicals on spontaneous activity in networks of cortical neurons grown on mwMEA plates. Each plate contained 12 wells with 64 microelectrodes/well, for a total of 768 channels. Of the 30 chemicals evaluated, 23 were known to alter neuronal function in vivo ("positives"), including 6 GABAergic and 3 glutamatergic antagonists/agonists, 4 pyrethroids, 3 metals, 2 cholinesterase inhibitors, 2 nicotinic acetylcholine receptor agonists, valproic acid, verapamil, and fluoxetine. Seven compounds expected to have no effect on neuronal function were tested as "negatives" (glyphosate, acetaminophen, salicylic acid, paraquat, saccharin, d-sorbitol and amoxicillin). Following collection of 33 min of baseline activity, chemical effects (50 µM or highest soluble concentration) were recorded for 33 min. Twenty of the positives altered the mean network spike rate by more than the 14% threshold (two standard deviations from the mean for DMSO control). The three positives without effect were bifenthrin, nicotine and imidacloprid. None of the negative compounds caused a change in activity beyond the threshold. Based on these results, the mwMEA assay has both high sensitivity (87% identification of positive compounds) and specificity (100% identification of negative compounds). These experiments demonstrate the capacity of mwMEAs to screen compounds for neurotoxic effects mediated by a broad variety of mechanisms.

Assessment of gastrointestinal pH, fluid and lymphoid tissue in the guinea pig, rabbit and pig, and implications for their use in drug development.

Laboratory animals are often used in drug delivery and research. However, basic information about their gastrointestinal pH, fluid volume, and lymphoid tissue is not completely known. We have investigated these post-mortem in healthy guinea pigs, rabbits and pigs, to assess their suitability for pre-clinical studies by comparing the results with reported human literature. The mean gastric pH (fed ad libitum) was 2.9 and 4.4 in guinea pig and pig, respectively. In contrast, a very low pH (1.6) was recorded in the rabbits. The small intestinal pH was found in the range of 6.4-7.4 in the guinea pigs and rabbits, whereas lower pH (6.1-6.7) was recorded in the pig, which may have consequences for ionisable or pH responsive systems when tested in pig. A relatively lower pH than in the small intestine was found in the caecum (6.0-6.4) and colon (6.1-6.6) of the guinea pig, rabbit and the pig. The water content in the gastrointestinal tract of guinea pig, rabbit and pig was 51g, 153g and 1546g, respectively. When normalized to the body weight, the guinea pig, had larger amounts of water compared to the rabbit and the pig (guinea pig>rabbit>pig); in contrast, a reverse order was found when normalized to per unit length of the gut (guinea pig

Colonic treatments and targets: issues and opportunities.

The colon provides a plethora of therapeutic opportunities. There are multiple disease targets, drug molecules, and colon-specific delivery systems to be explored. Clinical studies highlight the potential for systemic delivery via the colon, and the emerging data on the levels of cell membrane transporters and metabolic enzymes along the gut could prove advantageous for this. Often efflux transporters and metabolic enzyme levels are lower in the colon, suggesting a potential for improved bioavailability of drug substrates at this site. The locoregional distribution of multiple metabolic enzymes (including cytochromes), efflux transporters (including P-glycoprotein and breast cancer resistance proteins), and influx transporters (including the solute carrier family) along the intestine is summarized. Local delivery to the colonic mucosa remains a valuable therapeutic option. New therapies that target inflammatory mediators could improve the treatment of inflammatory bowel disease, and old and new anticancer molecules could, when delivered topically, prove to be beneficial adjuncts to the current systemic or surgical treatments. New issues such as pharmacogenomics, chronotherapeutics, and the delivery of prebiotics and probiotics are also discussed in this review. Targeting drugs to the colon utilizes various strategies, each with their advantages and flaws. The most promising systems are considered in the light of the physiological data which influence their in vivo behavior.