Treatment of Porphyromonas gulae infection and downstream pathology in the aged dog by lysine-gingipain inhibitor COR388.

COR388, a small-molecule lysine-gingipain inhibitor, is currently being investigated in a Phase 2/3 clinical trial for Alzheimer's disease (AD) with exploratory endpoints in periodontal disease. Gingipains are produced by two species of bacteria, Porphyromonas gingivalis and Porphyromonas gulae, typically associated with periodontal disease and systemic infections in humans and dogs, respectively. P. gulae infection in dogs is associated with periodontal disease, which provides a physiologically relevant model to investigate the pharmacology of COR388. In the current study, aged dogs with a natural oral infection of P. gulae and periodontal disease were treated with COR388 by oral administration for up to 90 days to assess lysine-gingipain target engagement and reduction of bacterial load and downstream pathology. In a 28-day dose-response study, COR388 inhibited the lysine-gingipain target and reduced P. gulae load in saliva, buccal cells, and gingival crevicular fluid. The lowest effective dose was continued for 90 days and was efficacious in continuous reduction of bacterial load and downstream periodontal disease pathology. In a separate histology study, dog brain tissue showed evidence of P. gulae DNA and neuronal lysine-gingipain, demonstrating that P. gulae infection is systemic and spreads beyond its oral reservoir, similar to recent observations of P. gingivalis in humans. Together, the pharmacokinetics and pharmacodynamics of COR388 lysine-gingipain inhibition, along with reduction of bacterial load and periodontal disease in naturally occurring P. gulae infection in the dog, support the use of COR388 in targeting lysine-gingipain and eliminating P. gingivalis infection in humans

Confiabilidad de un instrumento para clasificar al recién nacido de acuerdo con la complejidad de la atención

Na maioria das maternidades, a classificação, a avaliação e a definição da unidade a encaminhar o recém-nascido (RN) após o nascimento são realizadas pelo médico. A\ud avaliação ocorre na sala de parto considerando: peso ao nascer; idade gestacional;\ud condutas que definem quadro clínico e doença. Este estudo observacional teve\ud como objetivo avaliar a confiabilidade de um instrumento de classificação de RN. A pesquisa foi realizada no berçário de um hospital público, São Paulo. Nove enfermeiras\ud aplicaram o instrumento a 63 RN, sendo duas simultaneamente em cada um dos\ud cinco setores do berçário. Verificou-se que o nível de concordância Kappa entre as enfermeiras foi excelente para a maioria das áreas de cuidado (69,0%). Concluiu-se que houve consenso e concordância das enfermeiras quanto ao instrumento ser completo, de fácil entendimento e aplicável, porém despende muito tempo. As enfermeiras reconhecem a importância do instrumento para o dimensionamento dos profissionais, organização e planejamento do cuidado.In most maternity units, the physician classifies, evaluates, and determines which unit will receive the newborn (NB) after birth. Evaluation occurs in the delivery room, taking into consideration the following factors: birth weight, gestational age, and behaviors that define the clinical picture and disease. This observational study evaluates the reliability of an NB classification instrument. The study was conducted at the nursery of a public hospital in São Paulo. Nine nurses applied the instrument to 63 NB, with two of the nurses working simultaneously in each of the nursery’s fi ve sectors. The Kappa level of agreement among the nurses was found to be excellent for most care areas\ud (69.0%). It was concluded that there was a consensus and agreement among the\ud nurses that the instrument was complete, easy to understand and applicable, but was\ud very time consuming. The nurses recognize the instrument’s importance for the allocation of professionals, organization, and care planning.En la mayoría de las maternidades la clasificación, la evaluación y la definición de la unidad para referir el recién nacido (RN), son realizadas por el médico. La evaluación se realiza en la sala de parto, considerando: peso al nacer, edad gestacional y conductas que definen el cuadro clínico y la enfermedad. Este estudio observacional tuvo como objetivo evaluar la confiabilidad de un instrumento de clasificación del RN. Fue realizada en el servicio de neonatología de un hospital público en Sao Paulo. Nueve enfermeras\ud aplicaron el instrumento a 63 RN, siendo aplicados dos de forma simultánea en los cinco sectores de la unidad neonatal. El nivel de concordancia Kappa fue excelente para la mayoría de las áreas de atención (69,0%). Se concluyó que hubo consenso y\ud concordancia entre las enfermeras, quienes expresaron que el instrumento es completo, fácil de entender y de aplicar, pero se necesita mucho tempo. Las enfermeras reconocen la importancia de este instrumento para dimensionar el número de profesionales, la organización y la planificación de la atención

Selenoether oxytocin analogues have analgesic properties in a mouse model of chronic abdominal pain

Poor oral availability and susceptibility to reduction and protease degradation is a major hurdle in peptide drug development. However, drugable receptors in the gut present an attractive niche for peptide therapeutics. Here we demonstrate, in a mouse model of chronic abdominal pain, that oxytocin receptors are significantly upregulated in nociceptors innervating the colon. Correspondingly, we develop chemical strategies to engineer non-reducible and therefore more stable oxytocin analogues. Chemoselective selenide macrocyclization yields stabilized analogues equipotent to native oxytocin. Ultra-high-field nuclear magnetic resonance structural analysis of native oxytocin and the seleno-oxytocin derivatives reveals that oxytocin has a pre-organized structure in solution, in marked contrast to earlier X-ray crystallography studies. Finally, we show that these seleno-oxytocin analogues potently inhibit colonic nociceptors both in vitro and in vivo in mice with chronic visceral hypersensitivity. Our findings have potentially important implications for clinical use of oxytocin analogues and disulphide-rich peptides in general

The macroecology of phylogenetically structured hummingbird-plant networks

Aim To investigate the association between species richness, species' phylogenetic signal, insularity and historical and current climate with hummingbird-plant network structure. Location 54 communities along a c. 10,000 kilometer latitudinal gradient across the Americas (39ºN - 32ºS), ranging from sea level to c. 3700 m asl, located on the mainland and on islands, and covering a wide range of climate regimes. Methods We measured null-modeled corrected complementary specialization and bipartite modularity (compartmentalization) in networks of quantitative interactions between hummingbird and plant species. Using an ordinary least squares multi-model approach, we examined the influence of species richness, phylogenetic signal, insularity, and current and historical climate conditions on network structure. Results Phylogenetically-related species, especially plants, showed a tendency to interact with a similar array of partners. The spatial variation in network structure exhibited a constant association with species' phylogeny (R2=0.18-0.19). Species richness and environmental factors showed the strongest associations with network structure (R2=0.20-0.44; R2138 =0.32-0.45, respectively). Specifically, higher levels of complementary specialization and modularity were associated to species-rich communities and communities in which closely-related hummingbirds visited distinct sets of flowering species. On the mainland, warmer temperatures and higher historical temperature stability associated to higher levels of complementary specialization. Main conclusions Previous macroecological studies of interaction networks have highlighted the importance of environment and species richness in determining network structure. Here, for the first time, we report an association between species phylogenetic signal and network structure at macroecological scale. Specifically, null model corrected complementary specialization and modularity exhibited a positive association with species richness and a negative association with hummingbird phylogenetic signal, indicating that both high richness and high inter-specific competition among closely-related 150 hummingbirds exhibit important relationships with specialization in hummingbird-plant networks. Our results document how species richness, phylogenetic signal and climate associate with network structure in complex ways at macroecological scale

Differential Patterns of Food Appreciation during Consumption of a Simple Food in Congenitally Anosmic Individuals: An Explorative Study

Food is evaluated for various attributes. One of the key food evaluation domains is hedonicity. As food is consumed, its hedonic valence decreases (due to prolonged sensory stimulation) and hedonic habituation results. The aim of the present study was to investigate changes in food pleasantness ratings during consumption of a simple food by individuals without olfactory experience with food as compared to normosmics. 15 congenital anosmics and 15 normosmic controls were each presented with ten 10 g banana slices. Each was visually inspected, then smelled and chewed for ten seconds and subsequently rated for hedonicity on a 21-point scale. There was a significant difference in pleasantness ratings between congenital anosmics and controls (F(1, 26) = 6.71, p = .02) with the anosmics exhibiting higher ratings than the controls, a significant main repeated-measures effect on the ratings (F(1.85, 48) = 12.15, p<.001), which showed a decreasing trend over the course of consumption, as well as a significant portion*group interaction (F(1.85, 48) = 3.54, p = .04), with the anosmic participants experiencing a less pronounced decline. The results of the present explorative study suggest that over the course of consumption of a simple food, congenitally anosmic individuals experience differential patterns of appreciation of food as compared to normosmics. In this particular case, the decrease of hedonic valence was less pronounced in congenital anosmics

The influence of alkalosis on repeated high-intensity exercise performance and acid–base balance recovery in acute moderate hypoxic conditions

Purpose Exacerbated hydrogen cation (H⁺) production is suggested to be a key determinant of fatigue in acute hypoxic conditions. This study, therefore, investigated the effects of NaHCO3 ingestion on repeated 4 km TT cycling performance and post-exercise acid–base balance recovery in acute moderate hypoxic conditions. Methods Ten male trained cyclists completed four repeats of 2 × 4 km cycling time trials (TT1 and TT2) with 40 min passive recovery, each on different days. Each TT series was preceded by supplementation of one of the 0.2 g kg⁻¹ BM NaHCO3 (SBC2), 0.3 g kg⁻¹ BM NaHCO3 (SBC3), or a taste-matched placebo (0.07 g kg⁻¹ BM sodium chloride; PLA), administered in a randomized order. Supplements were administered at a pre-determined individual time to peak capillary blood bicarbonate concentration ([HCO3⁻]). Each TT series was also completed in a normobaric hypoxic chamber set at 14.5% FiO2 (~ 3000 m). Results Performance was improved following SBC3 in both TT1 (400.2 ± 24.1 vs. 405.9 ± 26.0 s; p = 0.03) and TT2 (407.2 ± 29.2 vs. 413.2 ± 30.8 s; p = 0.01) compared to PLA, displaying a very likely benefit in each bout. Compared to SBC2, a likely and possible benefit was also observed following SBC3 in TT1 (402.3 ± 26.5 s; p = 0.15) and TT2 (410.3 ± 30.8 s; p = 0.44), respectively. One participant displayed an ergolytic effect following SBC3, likely because of severe gastrointestinal discomfort, as SBC2 still provided ergogenic effects. Conclusion NaHCO3 ingestion improves repeated exercise performance in acute hypoxic conditions, although the optimal dose is likely to be 0.3 g kg⁻¹ BM

Sodium bicarbonate supplementation improves severe-intensity intermittent exercise under moderate acute hypoxic conditions

Acute moderate hypoxic exposure can substantially impair exercise performance, which occurs with a concurrent exacerbated rise in hydrogen cation (H+) production. The purpose of this study was therefore, to alleviate this acidic stress through sodium bicarbonate (NaHCO3) supplementation and determine the corresponding effects on severe intensity intermittent exercise performance. Eleven recreationally active individuals participated in this randomised, double-blind, crossover study performed under acute normobaric hypoxic conditions (FiO2% = 14.5%). Pre-experimental trials involved the determination of time to attain peak bicarbonate anion concentrations ([HCO3-]) following NaHCO3 ingestion. The intermittent exercise tests involved repeated 60 s work in their severe intensity domain and 30 s recovery at 20 W to exhaustion. Participants ingested either 0.3 g·kg bm-1 of NaHCO3 or a matched placebo of 0.21 g·kg bm-1 of sodium chloride prior to exercise. Exercise tolerance (+110.9 ± 100.6 s; 95% CI: 43.3 to 178 s; g = 1.0) and work performed in the severe intensity domain (+5.8 ± 6.6 kJ; 95% CI: 1.3 to 9.9 kJ; g = 0.8) were enhanced with NaHCO3 supplementation. Furthermore, a larger post-exercise blood lactate concentration was reported in the experimental group (+4 ± 2.4 mmol·l-1; 95% CI: 2.2 to 5.9; g = 1.8), while blood [HCO3-] and pH remained elevated in the NaHCO3 condition throughout experimentation. In conclusion, this study reported a positive effect of NaHCO3 under acute moderate hypoxic conditions during intermittent exercise and therefore, may offer an ergogenic strategy to mitigate hypoxic induced declines in exercise performance