Mimicking the Impact of Infant Tongue Peristalsis on Behavior of Solid Oral Dosage Forms Administered During Breastfeeding.

An in vitro simulation system was developed to study the effect of an infant's peristaltic tongue motion during breastfeeding on oral rapidly disintegrating tablets in the mouth, for use in rapid product candidate screening. These tablets are being designed for use inside a modified nipple shield worn by a mother during breastfeeding, a proposed novel platform technology to administer drugs and nutrients to breastfeeding infants. In this study, the release of a model compound, sulforhodamine B, from tablet formulations was studied under physiologically relevant forces induced by compression and rotation of a tongue mimic. The release profiles of the sulforhodamine B in flowing deionized water were found to be statistically different using 2-way ANOVA with matching, when tongue mimic rotation was introduced for 2 compression levels representing 2 tongue strengths (p = 0.0013 and p < 0.0001 for the lower and higher compression settings, respectively). Compression level was found to be a significant factor for increasing model compound release at rotational rates representing nonnutritive breastfeeding (p = 0.0162). This novel apparatus is the first to simulate the motion and pressures applied by the tongue and could be used in future infant oral product development.This work was made possible through the generous support of the Saving Lives at Birth partners: the United States Agency for International Development (USAID), the Government of Norway, the Bill & Melinda Gates Foundation (grant number: OPP1129832), Grand Challenges Canada, and the UK Department for International Development (DFID); as well as the Gates Cambridge Trust.This is the final version of the article. It first appeared from Elsevier via http://dx.doi.org/10.1016/j.xphs.2016.08.00

Characterising the disintegration properties of tablets in opaque media using texture analysis.

Tablet disintegration characterisation is used in pharmaceutical research, development, and quality control. Standard methods used to characterise tablet disintegration are often dependent on visual observation in measurement of disintegration times. This presents a challenge for disintegration studies of tablets in opaque, physiologically relevant media that could be useful for tablet formulation optimisation. This study has explored an application of texture analysis disintegration testing, a non-visual, quantitative means of determining tablet disintegration end point, by analysing the disintegration behaviour of two tablet formulations in opaque media. In this study, the disintegration behaviour of one tablet formulation manufactured in-house, and Sybedia Flashtab placebo tablets in water, bovine, and human milk were characterised. A novel method is presented to characterise the disintegration process and to quantify the disintegration end points of the tablets in various media using load data generated by a texture analyser probe. The disintegration times in the different media were found to be statistically different (P<0.0001) from one another for both tablet formulations using one-way ANOVA. Using the Tukey post-hoc test, the Sybedia Flashtab placebo tablets were found not to have statistically significant disintegration times from each other in human versus bovine milk (adjusted P value 0.1685).This work was made possible through the generous support of the Saving Lives at Birth partners: the United States Agency for International Development (USAID), the Government of Norway, the Bill & Melinda Gates Foundation, Grand Challenges Canada and the UK Department for International Development (DFID).This is the accepted manuscript. The final version is available at http://www.sciencedirect.com/science/article/pii/S0378517315002392#

Distribution and Community Characteristics of Staging Shorebirds on the Northern Coast of Alaska

Avian studies conducted in the 1970s on Alaska’s Arctic Coastal Plain (ACP) indicated that coastal littoral habitats are important to Arctic-breeding shorebirds for staging prior to fall migration. However, relatively little recent, broad-scale, or quantitative information exists on shorebird use of staging areas in this region. To locate possible shorebird concentration areas in the littoral zone of the ACP, we conducted aerial surveys from the southwest end of Kasegaluk Lagoon on the Chukchi Sea to Demarcation Point on the Beaufort Sea during the summers of 2005–07. These surveys identified persistent within- and between-year concentrations of staging shorebirds at Peard Bay, Point Barrow/Elson Lagoon, Cape Simpson, and Smith Bay to Cape Halkett. Among river deltas in the Beaufort Sea, the Sagavanirktok and Kongakut deltas had large concentrations of staging shorebirds. We also collected data on shorebird community characteristics, staging phenology, and habitat use in 2005 and 2006 by conducting land-based surveys at six camps: Kasegaluk Lagoon, Peard Bay, Point Barrow/Elson Lagoon, Colville Delta, Sagavanirktok Delta, and Okpilak Delta. The shorebird community was more even and diverse (evenness E and Shannon Weiner H’) along the Beaufort Sea compared to the Chukchi Sea and in 2005 versus 2006. Staging phenology varied by species and location and differed for several species from that reported in previous studies. Our results suggest the existence of three foraging habitat guilds among the shorebird species observed in this study: gravel beach, mudflat, and salt marsh/pond edge. A comparison to data collected in the mid-1970s suggests that these foraging associations are conserved through time. Results from this research will be useful to land managers for monitoring the effects of changing environmental conditions and human activity on shorebirds and their habitats in Arctic Alaska.Des études aviaires réalisées dans les années 1970 sur la plaine côtière de l’Arctique en Alaska ont permis de constater que les habitats du littoral côtier revêtent de l’importance pour les oiseaux de rivage nicheurs de l’Arctique en halte migratoire avant la migration d’automne. Cependant, relativement peu d’information récente, à grande échelle ou quantitative existe à propos de l’utilisation que font les oiseaux de rivage des haltes migratoires de cette région. Afin de localiser des zones de concentration possibles d’oiseaux de rivage dans la région littorale de la plaine côtière de l’Arctique, nous avons effectué des levés aériens du sud-ouest de la lagune Kasegaluk dans la mer des Tchouktches jusqu’à Demarcation Point dans la mer de Beaufort au cours des étés allant de 2005 à 2007. Ces levés ont permis de repérer des concentrations durables d’oiseaux de rivage en halte migratoire au cours d’une même année ainsi que d’une année à l’autre à la baie Peard, à pointe Barrow et à la lagune Elson, au cap Simpson de même que de la baie Smith jusqu’au cap Halkett. Parmi les deltas de rivières de la mer de Beaufort, les deltas Sagavanirktok et Kongakut comptaient de fortes concentrations d’oiseaux de rivage en halte migratoire. Nous avons également recueilli des données sur les caractéristiques des populations d’oiseaux de rivage, sur la phénologie des haltes migratoires de même que sur l’utilisation des habitats en 2005 et en 2006 au moyen de levés terrestres effectués à six camps, soit celui de la lagune Kasegaluk, de la baie Peard, de la pointe Barrow et de la lagune Elson, du delta Colville, du delta Sagavanirktok et du delta Okpilak. La population d’oiseaux de rivage était plus homogène et diverse (homogénéité E et Shannon Weiner H’) le long de la mer de Beaufort comparativement à la mer des Tchouktches, ainsi qu’en 2005 par rapport à 2006. La phénologie en halte migratoire variait selon les espèces et les emplacements, et différait pour plusieurs espèces de celles signalées dans le cadre d’études ultérieures. Nos résultats laissent croire à l’existence de trois guildes d’habitats de fourrage chez les espèces d’oiseaux de rivage observées dans cette étude : plage de gravier, vasière et marais salant ou bordure d’étang. La comparaison des données recueillies au milieu des années 1970 laisse entendre que ces associations de fourrage se sont conservées au fil du temps. Les résultats découlant de cette recherche seront utiles aux gestionnaires de terres dans le cadre de la surveillance des effets des conditions environnementales changeantes et de l’activité humaine sur les oiseaux de rivage et leurs habitats de l’Arctique alaskien

Quinoa, potatoes, and llamas fueled emergent social complexity in the Lake Titicaca Basin of the Andes

The Lake Titicaca basin was one of the major centers for cultural development in the ancient world. This lacustrine environment is unique in the high, dry Andean altiplano, and its aquatic and terrestrial resources are thought to have contributed to the florescence of complex societies in this region. Nevertheless, it remains unclear to what extent local aquatic resources, particularly fish, and the introduced crop, maize, which can be grown in regions along the lakeshores, contributed to facilitating sustained food production and population growth, which underpinned increasing social political complexity starting in the Formative Period (1400 BCE to 500 CE) and culminating with the Tiwanaku state (500 to 1100 CE). Here, we present direct dietary evidence from stable isotope analysis of human skeletal remains spanning over two millennia, together with faunal and floral reference materials, to reconstruct foodways and ecological interactions in southern Lake Titicaca over time. Bulk stable isotope analysis, coupled with compound-specific amino acid stable isotope analysis, allows better discrimination between resources consumed across aquatic and terrestrial environments. Together, this evidence demonstrates that human diets predominantly relied on C(3) plants, particularly quinoa and tubers, along with terrestrial animals, notably domestic camelids. Surprisingly, fish were not a significant source of animal protein, but a slight increase in C(4) plant consumption verifies the increasing importance of maize in the Middle Horizon. These results underscore the primary role of local terrestrial food resources in securing a nutritious diet that allowed for sustained population growth, even in the face of documented climate and political change across these periods

Distribution of Breeding Shorebirds on the Arctic Coastal Plain of Alaska

Available information on the distribution of breeding shorebirds across the Arctic Coastal Plain of Alaska is dated, fragmented, and limited in scope. Herein, we describe the distribution of 19 shorebird species from data gathered at 407 study plots between 1998 and 2004. This information was collected using a single-visit rapid area search technique during territory establishment and early incubation periods, a time when social displays and vocalizations make the birds highly detectable. We describe the presence or absence of each species, as well as overall numbers of species, providing a regional perspective on shorebird distribution. We compare and contrast our shorebird distribution maps to those of prior studies and describe prominent patterns of shorebird distribution. Our examination of how shorebird distribution and numbers of species varied both latitudinally and longitudinally across the Arctic Coastal Plain of Alaska indicated that most shorebird species occur more frequently in the Beaufort Coastal Plain ecoregion (i.e., closer to the coast) than in the Brooks Foothills ecoregion (i.e., farther inland). Furthermore, the occurrence of several species indicated substantial longitudinal directionality. Species richness at surveyed sites was highest in the western portion of the Beaufort Coastal Plain ecoregion. The broad-scale distribution information we present here is valuable for evaluating potential effects of human development and climate change on Arctic-breeding shorebird populations.Les renseignements qui existent en matière de répartition des oiseaux de rivage en reproduction sur la plaine côtière de l’Arctique en Alaska sont anciens, fragmentés et restreints. Ici, nous décrivons la répartition de 19 espèces d’oiseaux de rivage à partir de données recueillies à 407 lieux de recherche entre 1998 et 2004. Cette information a été recueillie grâce à une technique de recherche consistant en une seule visite rapide durant les périodes d’établissement du territoire et de début d’incubation, périodes pendant lesquelles les comportements sociaux et les vocalisations permettent de bien repérer les oiseaux. Nous décrivons la présence ou l’absence de chaque espèce, de même que le nombre général d’espèces, ce qui procure une perspective régionale de la répartition des oiseaux de rivage. Nous comparons et contrastons nos cartes de répartition des oiseaux de rivage à celles d’études antérieures, en plus de décrire les tendances les plus marquées en matière de répartition des oiseaux de rivage. Notre examen de la variation latitudinale et longitudinale en matière de répartition et de nombre d’espèces d’oiseaux de rivage à l’échelle de la plaine côtière arctique de l’Alaska nous a permis de constater que la plupart des espèces d’oiseaux de rivage se manifestaient plus souvent dans la région écologique de la plaine côtière de Beaufort (c’est-à-dire plus proche de la côte) que dans la région écologique des contreforts de Brooks (c’est-à-dire plus à l’intérieur des terres). Par ailleurs, l’occurrence de plusieurs espèces indiquait une directionalité longitudinale substantielle. La richesse des espèces aux sites à l’étude était à son meilleur dans la partie ouest de la région écologique de la plaine côtière de Beaufort. Les renseignements sur la répartition à grande échelle que nous présentons ici jouent un rôle dans l’évaluation des effets éventuels des travaux de mise en valeur par l’être humain et du changement climatique sur les populations d’oiseaux de rivage en reproduction de l’Arctique

Fiber optic Raman spectroscopy for the evaluation of disease state in Duchenne muscular dystrophy:An assessment using the mdx model and human muscle

INTRODUCTION/AIMS: Raman spectroscopy is an emerging technique for the evaluation of muscle disease. In this study we evaluate the ability of in vivo intramuscular Raman spectroscopy to detect the effects of voluntary running in the mdx model of Duchenne muscular dystrophy (DMD). We also compare mdx data with muscle spectra from human DMD patients. METHODS: Thirty 90‐day‐old mdx mice were randomly allocated to an exercised group (48‐hour access to a running wheel) and an unexercised group (n = 15 per group). In vivo Raman spectra were collected from both gastrocnemius muscles and histopathological assessment subsequently performed. Raman data were analyzed using principal component analysis–fed linear discriminant analysis (PCA‐LDA). Exercised and unexercised mdx muscle spectra were compared with human DMD samples using cosine similarity. RESULTS: Exercised mice ran an average of 6.5 km over 48 hours, which induced a significant increase in muscle necrosis (P = .03). PCA‐LDA scores were significantly different between the exercised and unexercised groups (P < .0001) and correlated significantly with distance run (P = .01). Raman spectra from exercised mice more closely resembled human spectra than those from unexercised mice. DISCUSSION: Raman spectroscopy provides a readout of the biochemical alterations in muscle in both the mdx mouse and human DMD muscle

The contribution of spinal glial cells to chronic pain behaviour in the monosodium iodoacetate model of osteoarthritic pain

<p>Abstract</p> <p>Background</p> <p>Clinical studies of osteoarthritis (OA) suggest central sensitization may contribute to the chronic pain experienced. This preclinical study used the monosodium iodoacetate (MIA) model of OA joint pain to investigate the potential contribution of spinal sensitization, in particular spinal glial cell activation, to pain behaviour in this model. Experimental OA was induced in the rat by the intra-articular injection of MIA and pain behaviour (change in weight bearing and distal allodynia) was assessed. Spinal cord microglia (Iba1 staining) and astrocyte (GFAP immunofluorescence) activation were measured at 7, 14 and 28 days post MIA-treatment. The effects of two known inhibitors of glial activation, nimesulide and minocycline, on pain behaviour and activation of microglia and astrocytes were assessed.</p> <p>Results</p> <p>Seven days following intra-articular injection of MIA, microglia in the ipsilateral spinal cord were activated (p < 0.05, compared to contralateral levels and compared to saline controls). Levels of activated microglia were significantly elevated at day 14 and 21 post MIA-injection. At day 28, microglia activation was significantly correlated with distal allodynia (p < 0.05). Ipsilateral spinal GFAP immunofluorescence was significantly (p < 0.01) increased at day 28, but not at earlier timepoints, in the MIA model, compared to saline controls. Repeated oral dosing (days 14-20) with nimesulide attenuated pain behaviour and the activation of microglia in the ipsilateral spinal cord at day 21. This dosing regimen also significantly attenuated distal allodynia (p < 0.001) and numbers of activated microglia (p < 0.05) and GFAP immunofluorescence (p < 0.001) one week later in MIA-treated rats, compared to vehicle-treated rats. Repeated administration of minocycline also significantly attenuated pain behaviour and reduced the number of activated microglia and decreased GFAP immunofluorescence in ipsilateral spinal cord of MIA treated rats.</p> <p>Conclusions</p> <p>Here we provide evidence for a contribution of spinal glial cells to pain behaviour, in particular distal allodynia, in this model of osteoarthritic pain. Our data suggest there is a potential role of glial cells in the central sensitization associated with OA, which may provide a novel analgesic target for the treatment of OA pain.</p

The Meta-Position of Phe4 in Leu-Enkephalin Regulates Potency, Selectivity, Functional Activity, and Signaling Bias at the Delta and Mu Opioid Receptors

This work is licensed under a Creative Commons Attribution 4.0 International License.As tool compounds to study cardiac ischemia, the endogenous δ-opioid receptors (δOR) agonist Leu5-enkephalin and the more metabolically stable synthetic peptide (d-Ala2, d-Leu5)-enkephalin are frequently employed. However, both peptides have similar pharmacological profiles that restrict detailed investigation of the cellular mechanism of the δOR’s protective role during ischemic events. Thus, a need remains for δOR peptides with improved selectivity and unique signaling properties for investigating the specific roles for δOR signaling in cardiac ischemia. To this end, we explored substitution at the Phe4 position of Leu5-enkephalin for its ability to modulate receptor function and selectivity. Peptides were assessed for their affinity to bind to δORs and µ-opioid receptors (µORs) and potency to inhibit cAMP signaling and to recruit β-arrestin 2. Additionally, peptide stability was measured in rat plasma. Substitution of the meta-position of Phe4 of Leu5-enkephalin provided high-affinity ligands with varying levels of selectivity and bias at both the δOR and µOR and improved peptide stability, while substitution with picoline derivatives produced lower-affinity ligands with G protein biases at both receptors. Overall, these favorable substitutions at the meta-position of Phe4 may be combined with other modifications to Leu5-enkephalin to deliver improved agonists with finely tuned potency, selectivity, bias and drug-like properties