Syringe immersion test as in vitro bioassay against Rhipicephalus microplus: Macrocyclic lactones dose-response relationship.

Background: For the diagnosis of tick sensitivity against different acaricides, there are in vitro and in vivo methods. The main in vivo method, the stable test, is considered a defining methodology. In Uruguay, the Rhipicephalus microplus (R. microplus) strain Mozo is used as the standard susceptible strain by the regulatory authorities. In vitro techniques applied both on adult and larvae stages are validated by FAO and can serve as an orientation diagnosis of the resistance profile developed in field conditions. An alternative was proposed as a modification of the larval immersion test (LIT), where syringes were used seeking to reduce the work necessary to perform the original technique, resulting in the syringe immersion test (SIT). Aim: The aim of this study was to expand the SIT for the characterization of sensitivity to Macrocyclic Lactones (MLs) in R. microplus and provide information on field strain sensitivity of R. microplus larvae. Methods: Log-logistic dose-response model for Ivermectin (IVM), Doramectin (DRM), and Moxidectin (MOX) were performed using concentrations ranging from 0.01 to 20.0 ppm (n = 6, 3 replicates per level on each drug). Larvae sensitivity results were determined after 24 hours of incubation at 27°C/90% RH, counting live/dead larvae. The final model will be decided as the best fit according to the model selection AIC criteria for each drug. Pharmacodynamic parameters [lower limit, slope, and effective dose at different levels (ED20, ED50, ED80, and ED95)] and its 95% confidence interval were considered for drug comparison. Results: Dose-response models were fitted for IVM, DRM, and MOX. MOX had the lowest ED50 of the three drugs, implying that MOX is of higher potency (two folds) when compared to IVM and DRM on R. microplus larvae using SIT. DRM had a different slope compared to IVM and MOX (p < 0.05), while IVM and MOX showed a similar slope (p > 0.05). Conclusion: This study allowed us to standardize the technique for larvae immersion for each ML, granting a new tool for in vitro test as a screening technique for tick sensitivity.

Integration of value and action in medial prefrontal neural systems.

The rodent medial prefrontal cortex (mPFC) plays a key role in regulating cognition, emotion, and behavior. mPFC neurons are activated in diverse experimental paradigms, raising the questions of whether there are specific task elements or dimensions encoded by mPFC neurons, and whether these encoded parameters are selective to neurons in particular mPFC subregions or networks. Here, we consider the role of mPFC neurons in processing appetitive and aversive cues, outcomes, and related behaviors. mPFC neurons are strongly activated in tasks probing value and outcome-associated actions, but these responses vary across experimental paradigms. Can we identify specific categories of responses (e.g., positive or negative value), or do mPFC neurons exhibit response properties that are too heterogeneous/complex to cluster into distinct conceptual groups? Based on a review of relevant studies, we consider what has been done and what needs to be further explored in order to address these questions.

Differential Effects of Dorsal and Ventral Medial Prefrontal Cortex Inactivation during Natural Reward Seeking, Extinction, and Cue-Induced Reinstatement.

Rodent dorsal medial prefrontal cortex (mPFC), typically prelimbic cortex, is often described as promoting actions such as reward seeking, whereas ventral mPFC, typically infralimbic cortex, is thought to promote response inhibition. However, both dorsal and ventral mPFC are necessary for both expression and suppression of different behaviors, and each region may contribute to different functions depending on the specifics of the behavior tested. To better understand the roles of dorsal and ventral mPFC in motivated behavior we pharmacologically inactivated each area during operant fixed ratio 1 (FR1) seeking for a natural reward (sucrose), extinction, cue-induced reinstatement, and progressive ratio (PR) sucrose seeking in male Long-Evans rats. Bilateral inactivation of dorsal mPFC, but not ventral mPFC increased reward seeking during FR1. Inactivation of both dorsal and ventral mPFC decreased seeking during extinction. Bilateral inactivation of ventral mPFC, but not dorsal mPFC decreased reward seeking during cue-induced reinstatement. No effect of inactivation was found during PR. Our data contrast sharply with observations seen during drug seeking and fear conditioning, indicating that previously established roles of dorsal mPFC = going versus ventral mPFC = stopping are not applicable to all motivated behaviors and/or outcomes. Our results indicate that dichotomous functions of dorsal versus ventral mPFC, if they exist, may align better with other models, or may require the development of a new framework in which these multifaceted brain areas play different roles in action control depending on the behavioral context in which they are engaged.

A cross-sectional study to assess inhalation device handling and patient satisfaction in COPD.

Delivery of inhaled medications via an inhaler device underpins the effectiveness of treatment for patients with chronic obstructive pulmonary disease (COPD). Correct inhaler technique among patients is also a predictor of achieving treatment compliance and adherence. Reporting of patient satisfaction with inhalers is therefore gaining increasing attention and is now recognized as an important patient-reported outcome in clinical trials involving patients with COPD or asthma. In this cross-sectional study, we use the validated Patient Satisfaction and Preference Questionnaire (PASAPQ) to assess the handling and satisfaction for Respimat(®) Soft Mist™ Inhaler (SMI) compared with the Breezhaler(®) dry powder inhaler (DPI) among patients with COPD in Spain. Patients were already assigned to therapy with either SPIRIVA(®) (tiotropium) Respimat(®) or with Hirobriz(®)/Onbrez(®)/Oslif(®) (indacaterol) Breezhaler(®) for at least 3 but not more than 6 months before completing the PASAPQ at a single visit to the study site. The primary endpoint of the trial was the mean total PASAPQ score. Secondary endpoints were the performance score domain of the PASAPQ, the convenience score domain of the PASAPQ, and the overall satisfaction score of the PASAPQ. For the primary endpoint, the mean PASAPQ total score in the Respimat(®) and Breezhaler(®) groups was 80.7 and 79.9, respectively (difference of 0.8, 95% confidence interval [CI] -2.9 to 4.5; P=0.67). The mean total performance scores were 82.5 and 78.2 (difference of 4.3, 95% CI -0.3 to 8.9; P=0.06), and the mean total convenience scores were 78.6 and 81.9 (difference of -3.3, 95% CI -7.0 to 0.4; P=0.08) for the Respimat(®) and Breezhaler(®) groups, respectively. Patients gave the Respimat(®) SMI and the Breezhaler(®) DPI overall satisfaction PASAPQ scores of 6.0 and 5.9, respectively, which shows that patients were satisfied with these inhalers.