C-reactive protein protects mice against pneumococcal infection via both phosphocholine-dependent and phosphocholine-independent mechanisms.

The mechanism of action of C-reactive protein (CRP) in protecting mice against lethal Streptococcus pneumoniae infection is unknown. The involvement of the phosphocholine (PCh)-binding property of CRP in its antipneumococcal function previously has been explored twice, with conflicting results. In this study, using three different intravenous sepsis mouse models, we investigated the role of the PCh-binding property of CRP by employing a CRP mutant incapable of binding to PCh. The ability of wild-type CRP to protect mice against infection was found to differ in the three models; the protective ability of wild-type CRP decreased when the severity of infection was increased, as determined by measuring mortality and bacteremia. In the first animal model, in which we used 25 µg of CRP and 10(7) CFU of pneumococci, both wild-type and mutant CRP protected mice against infection, suggesting that the protection was independent of the PCh-binding activity of CRP. In the second model, in which we used 25 µg of CRP and 5 × 10(7) CFU of pneumococci, mutant CRP was not protective while wild-type CRP was, suggesting that the protection was dependent on the PCh-binding activity of CRP. In the third model, in which we used 150 µg of CRP and 10(7) CFU of pneumococci, mutant CRP was as protective as wild-type CRP, again indicating that the protection was independent of the PCh-binding activity of CRP. We conclude that both PCh-dependent and PCh-independent mechanisms are involved in the CRP-mediated decrease in bacteremia and the resulting protection of mice against pneumococcal infection.

Peritoneal lavage using chlorhexidine gluconate at the end of colon surgery reduces postoperative intra-abdominal infection in mice.

BACKGROUND: The use of peritoneal lavage with antiseptic solutions after bowel surgery remains controversial. This study compared peritoneal lavage using chlorhexidine gluconate at low concentrations and normal saline in mice with cecal ligation and perforation. METHODS: A total of 180 mice were randomized to six groups. Groups A, B, and C received one-time intraperitoneal injections of normal saline, chlorhexidine gluconate 0.05%, and chlorhexidine gluconate 0.025%, respectively. Groups D, E, and F were all subject to cecal ligation and perforation, then underwent partial cecectomy and peritoneal lavage with normal saline only, chlorhexidine gluconate 0.05% followed by normal saline, and chlorhexidine gluconate 0.025% followed by normal saline, respectively. Animals were followed postoperatively then sacrificed and examined at necropsy for occurrence of intra-abdominal abscesses, adhesions, or other pathology. RESULTS: A total of 48 mice (26.7%) developed postoperative intra-abdominal abscesses. Group E mice that had chlorhexidine gluconate 0.05% lavage had significantly lower incidence of postoperative intra-abdominal abscesses compared with that of group D mice that had saline lavage only (P = 0.0113). There was no significant difference in occurrence of macroscopic adhesions among mice groups that had or did not have surgery. (P = 1 and P = 0.3728). Microscopic peritoneal fibrosis occurred significantly more among group E mice that had chlorhexidine gluconate 0.05% lavage compared with group D mice that had saline lavage only (P = <0.005). There was no significant difference in postoperative mortality between surgical groups (P = 0.8714). CONCLUSIONS: Chlorhexidine gluconate 0.05% peritoneal lavage after partial colectomy (cecectomy) in mice reduces postoperative intra-abdominal infection without significant macroscopic adhesion formation.

Distance-Based Collaborations for Assessing and Treating Challenging Behavior.

An interview-informed synthesized contingency analysis (IISCA; Hanley et al. in J Appl Behav Anal 47:16-36, 2014) and related skill-based treatment process can result in socially valid outcomes for clients exhibiting severe challenging behavior when implemented by professionals and then transferred to parents (e.g., Santiago et al. in J Autism Dev Disord 46:797-811, 2016). However, many families do not have access to professionals trained to implement functional analyses or function-based treatments (Deochand & Fuqua Behav Anal Pract 9:243-252, 2016). Experimenters in the present study coached three parents of children with autism exhibiting severe challenging behavior through implementing an IISCA and resulting skill-based treatment process through distance-based collaborative consulting. All parents achieved differentiated functional analyses, taught their children to emit functional replacement skills, and reduced challenging behavior relative to baseline.

Prioritizing choice and assent in the assessment and treatment of food selectivity.

Food selectivity affects up to 72% and 45% of individuals with and without disabilities, respectively, and there is a need for interventions that rely on positive, unrestrictive strategies. We evaluated an assessment and treatment package for food selectivity for young children with developmental disabilities that prioritized caregiver collaboration, client autonomy, and did not rely on restrictive procedures (e.g. escape extinction). The process involved: (a) collaborating with caregivers on the selection of foods and design of the children's functional analyses; (b) indirectly and directly measuring food preferences prior to treatment; (c) evaluating the sensitivity of mealtime problem behavior to environmental variables through an interview-informed synthesized contingency analysis (IISCA); and (c) incorporating the assessment results into a progressive treatment process consisting of choice-making opportunities and differential reinforcement of successive approximations to consumption. Children also had the ability to opt in and out of treatment sessions. The treatment was effective in increasing consumption of nonpreferred foods and successfully extended to caregivers. Practical implications and directions for future research are discussed.

On the generality of preference for contingent reinforcement.

Reinforcers can be delivered dependent on or independent of responding. Both human and nonhuman animals have shown a preference for contexts involving contingent reinforcement, but the generality of this phenomenon to humans and its implications have not yet been described. We present an integrative summary of studies evaluating preference for contingent versus noncontingent reinforcement, including (a) study participants, reinforcer types, response topographies, and contexts; (b) outcomes; (c) potential variables influencing preference outcomes; and (d) suggestions regarding research to expand behavior analysts' ability to design preferred contexts.

On the Reliability and Treatment Utility of the Practical Functional Assessment Process.

Saini et al. (2019) urged caution with respect to the use of practical functional assessment (PFA) procedures to inform behavioral treatment when they found that responses to an open-ended caregiver interview were only somewhat reliable and showed moderate to weak correspondence with analog functional analyses. Because the practitioner's goal in conducting any functional assessment process is to inform the successful treatment of problem behavior, we replicated and extended Saini et al. by (a) evaluating the reliability of hypotheses gleaned from two independent PFA processes for each of four children, (b) conducting treatment informed by a randomly assigned PFA, and (c) determining the extent to which potentially different levels of reliability impacted the treatment utility of the PFA process. Results indicated that the reliability of the PFA process varied depending on the stringency with which it was evaluated. However, treatments developed from randomly determined PFA processes produced efficacious outcomes on problem behavior and targeted social skills that transferred to the context designed from the other PFA process in all evaluations, suggesting that the PFA has strong treatment utility despite parts of the process having ambiguous levels of reliability. We discuss implications for practitioners tasked with treating severe problem behavior.

Understanding the effects of prompting immediately after problem behavior occurs during functional communication training.

When reported, the methods for prompting functional communication responses (FCRs) following problem behavior during functional communication training (FCT) vary. Some researchers have prompted the FCR immediately following problem behavior but doing so may inadvertently strengthen problem behavior as the first link in an undesirable response chain. This study investigated the effects of prompting FCRs following problem behavior during FCT with 4 children who exhibited severe problem behavior. Problem behavior remained low and FCR rates were near optimal when prompts were delivered immediately following problem behavior for 2 participants. Delaying prompts following problem behavior was instrumental for FCR acquisition for 1 participant but led to escalation of problem behavior for a 2nd participant. The conditions under which immediate prompts following problem behavior may improve or worsen FCT are discussed.

On the Occurrence of Dangerous Problem Behavior during Functional Analysis: An Evaluation of 30 Applications.

Functional analyses are often conducted by behavior analysts to understand the environmental variables contributing to an individual's problem behavior to better inform treatment implementation. While functional analyses are integral for designing function-based interventions, they often arrange contingencies to evoke and reinforce dangerous problem behavior. In Study 1 we reviewed 22 functional analyses with open-contingency classes including non-dangerous topographies of problem behavior and we found that participants were more likely to exhibit the non-dangerous behavior in 82% of the applications. We then conducted a single-subject comparison of closed and open-contingency classes with four additional participants in Study 2. Our results suggest that the functional analyses with the open-contingency class reduced the likelihood of observing dangerous problem behavior.

Toward trauma-informed applications of behavior analysis.

Despite a growing acknowledgement of the importance of understanding the impacts of trauma on therapeutic approaches across human service disciplines, discussions of trauma have been relatively infrequent in the behavior analytic literature. In this paper, we delineate some of the barriers to discussing and investigating trauma in applied behavior analysis (ABA) and describe how the core commitments of trauma-informed care could be applied to behavior analysis. We then provide some examples of how trauma-informed care might be incorporated into ABA practice. We conclude by suggesting opportunities to approach trauma as a viable avenue for behavior analytic research and argue that omitting trauma-informed care from ABA could be detrimental not only to the public perception of ABA, but to the effectiveness of our assessment and treatment procedures.

Minimizing Escalation by Treating Dangerous Problem Behavior Within an Enhanced Choice Model.

To address dangerous problem behavior exhibited by children while explicitly avoiding physical management procedures, we systematically replicated and extended the skill-based treatment procedures described by Hanley, Jin, Vanselow, and Hanratty (2014) by incorporating an enhanced choice model with three children in an outpatient clinic and two in a specialized public school. In this model, several tactics were simultaneously added to the skill-based treatment package to minimize escalation to dangerous behavior, the most notable of which involved offering children multiple choice-making opportunities, including the ongoing options to (a) participate in treatment involving differential reinforcement, (b) "hang out" with noncontingent access to putative reinforcers, or (c) leave the therapeutic space altogether. Children overwhelmingly chose to participate in treatment, which resulted in the elimination of problem behavior and the acquisition and maintenance of adaptive skills during lengthy, challenging periods of nonreinforcement. Implications for the safe implementation of socially valid treatments for problem behavior are discussed.

Beta-arrestin 2 modulates resveratrol-induced apoptosis and regulation of Akt/GSK3ß pathways.

BACKGROUND: Resveratrol is emerging as a novel anticancer agent. However, the mechanism(s) by which resveratrol exerts its effects on endometrial cancer (EC) are unknown. We previously reported that beta-arrestin 2 plays a critical role in cell apoptosis. The role of ß-arrestin 2 in resveratrol modulation of endometrial cancer cell apoptosis remains to be established. SCOPE OF REVIEW: EC cells HEC1B and Ishikawa were transfected with either ß-arrestin 2 RNA interfering (RNAi) plasmid or beta-arrestin 2 full-length plasmid and control vector. The cells were then exposed to differing concentrations of resveratrol. Apoptotic cells were detected by TUNEL assay. Expression of total and phosphorylated Akt (p-Akt), total and phosphorylated glycogen synthase kinase 3 beta (p-GSK3ß), and caspase-3 were determined by Western blot analysis. Our data demonstrate that inhibition of ß-arrestin 2 increases the number of apoptotic cells and caspase-3 activation. Additionally ß-arrestin 2 exerted an additive effect on resveratrol-reduced levels of p-Akt and p-GSK3ß. Overexpression of ß-arrestin 2 decreased the percentage of apoptosis and caspase-3 activation and attenuated resveratrol-reduced levels of p-Akt and p-GSK3ß. Taken together, our studies demonstrate for the first time that ß-arrestin 2 mediated signaling plays a critical role in resveratrol-induced apoptosis in EC cells. MAJOR CONCLUSIONS: Resveratrol primes EC cells to undergo apoptosis by modulating beta-arrestin 2 mediated Akt/GSK3ß signaling pathways. GENERAL SIGNIFICANCE: These inspiring findings would provide a new molecular basis for further understanding of cell apoptotic mechanisms mediated by ß-arrestin 2 and may provide insights into a potential clinical relevance in EC.

ß-arrestin 2-mediated immune suppression induced by chronic stress.

OBJECTIVE: Stress, either physical or psychological, can modulate immune function. However, the mechanisms associated with stress-induced immune suppression remain to be elucidated. ß-Arrestin 2 serves as adaptor, scaffold, and/or signal transducer. The role of ß-arrestin 2 in stress-induced immune suppression is not known yet. METHODS/RESULTS: Here, we demonstrate that ß-arrestin 2 deficiency in mice increases the sensitivity to the chronic stress-induced reduction in the number of splenocytes. Interestingly, the stress-induced suppression of T helper-type (Th) 1 cytokines and the increased production of Th2 cytokines were greatly enhanced in ß-arrestin 2-deficient mice compared with wild-type mice. Moreover, inhibition of PI3K in ß-arrestin 2-deficient mice exerts an additive effect on the stress-induced reduction in the number of splenocytes. CONCLUSION: Our study demonstrates that a deficiency in ß-arrestin 2 augments stress-induced immune suppression.

Mand compliance as a contingency controlling problem behavior: A systematic review.

Bowman et al. (1997) described a dynamic contingency in which severe problem behavior was evoked by adult noncompliance with a variety of child mands, which occurred at high rates, and was reinforced by adult compliance with subsequent mands. They discovered this phenomenon with 2 children for whom standard functional analyses were inconclusive. In recent years, similar contingencies have been shown to influence problem behavior, but the manner in which they have been arranged and described has varied across studies. The purpose of this literature review is to (a) describe contingencies involving mand compliance and the circumstances under which they have been evaluated, (b) summarize procedural variations in analysis and treatment, and (c) discuss what is known and yet to be discovered about the contingency as it relates to problem behavior. Future research focused on improving technology for analyzing and treating problem behavior suspected to be sensitive to mand compliance is discussed.

Functional communication training: From efficacy to effectiveness.

Functional communication training (FCT; Carr & Durand, 1985) is a common function-based treatment in which an alternative form of communication is taught to reduce problem behavior. FCT has been shown to result in substantial reductions of a variety of topographically and functionally different types of problem behavior in children and adults (efficacy). The extent to which these reductions maintain in relevant contexts and result in meaningful changes in the lives of those impacted (effectiveness) is the focus of this paper. This review evaluates the degree to which FCT has been established as an evidence-based practice in psychology (EBPP) according to the definition set out by the American Psychological Association's 2005 Presidential Task Force on Evidence-Based Practice. Our review finds overwhelming evidence in support of FCT as an efficacious treatment but highlights significant limitations in support of its effectiveness. In order to also be recognized as an EBPP, future research on FCT will need to focus more closely on issues related to home, school, and community application, feasibility, consumer satisfaction, and more general and global changes for the individual.

A preference analysis of reinforcer variation and choice.

Reinforcement procedures are the cornerstone of behavioral interventions. Previous research has focused on manipulating parameters of reinforcement including quality, magnitude, and rate. In this study, we sought to better understand ways to implement reinforcer choice and variation, and to assess preference for these parameters. Across 10 participants with and without disabilities, we assessed preference for varied reinforcement conditions, as well as choice of reinforcers in a concurrent-chains arrangement. Most participants preferred varied reinforcement conditions and subsequently, choice of reinforcers, over a previously preferred varied reinforcement condition. Implications for reinforcement arrangement in teaching situations are discussed.

An Evaluation of "Balance": a Home-Based, Parent-Implemented Program Addressing Emerging Problem Behavior.

Programs that prevent the development of severe problem behavior in young children with autism spectrum disorder (ASD) are critically needed. We describe a program designed to do this, and we report on a preliminary evaluation of its effects with four 3- and 4-year-old children with ASD. Parents served as the primary implementers, with twice-weekly coaching from a Board Certified Behavior Analyst. Direct measures and Aberrant Behavior Checklist scores reflected decreases in emerging problem behavior. Direct measures also reflected increases in child communication, social, and cooperation skills, and parents rated the process as highly acceptable. A randomized controlled trial will be required to evaluate the extent to which the program prevents the development of problem behavior in young children with ASD. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1007/s40617-020-00490-3.

Does teaching an omnibus mand preclude the development of specifying mands?

When problem behavior is controlled by a synthesized reinforcement contingency, a simple omnibus mand that yields access to all reinforcers simultaneously has been shown to effectively replace problem behavior. The question arises as to whether teaching an omnibus mand will preclude the acquisition of specifying mands for each of the combined reinforcers. In this study, after 3 students diagnosed with autism acquired an omnibus mand ("My way, please") that yielded all identified reinforcers simultaneously, specifying mands (e.g., "All done," "May I have my toys?" "Play with me") were taught to yield each individual reinforcer (e.g., escape, tangibles, attention). Problem behavior was immediately eliminated for all children, and the omnibus mand was acquired quickly. Teaching an omnibus mand did not preclude acquisition of specifying mands for any learner and instead allowed for the acquisition of specifying mands once problem behavior had been effectively reduced.

Randomized controlled trial of seminar-based training on accurate and general implementation of practical functional assessments.

General and long-term outcomes of functional analysis training have not yet been reported. Within a randomized control trial, we trained 18 behavior analytic practitioners to interview caregivers, design and then conduct a personalized analysis as a part of a practical functional assessment (PFA). Participants were randomly assigned to groups, and those who experienced the seminar prior to conducting PFA with a confederate demonstrated more component skills than those who were provided the same materials but did not experience the seminar (mean scores: 87%, 36% respectively). Participants who experienced the seminar considered the training valuable and reported greater confidence in their ability to achieve control in an analysis. Several participants then conducted a PFA with a client who engaged in SPB. Results showed that skills transferred to these authentic applications. Results suggest that a seminar-based training can increase practitioners' ability to functionally analyze problem behavior and leads to subsequent analytic activity.

ß-arrestin 2 regulates Toll-like receptor 4-mediated apoptotic signalling through glycogen synthase kinase-3ß.

Toll-like receptor 4 (TLR4), a key member of the TLR family, has been well characterized by its function in the induction of inflammatory products of innate immunity. However, the involvement of TLR4 in a variety of apoptotic events by an unknown mechanism has been the focus of great interest. Our investigation found that TLR4 promoted apoptotic signalling by affecting the glycogen synthase kinase-3beta (GSK-3beta) pathway in a serum-deprivation-induced apoptotic paradigm. Serum deprivation induces GSK-3beta activation in a pathway that leads to subsequent cell apoptosis. Intriguingly, this apoptotic cascade is amplified in presence of TLR4 but greatly attenuated by beta-arrestin 2, another critical molecule implicated in TLR4-mediated immune responses. Our data suggest that the association of beta-arrestin 2 with GSK-3beta contributes to the stabilization of phospho-GSK-3beta, an inactive form of GSK-3beta. It becomes a critical determinant for the attenuation of TLR4-initiated apoptosis by beta-arrestin 2. Taken together, we demonstrate that the TLR4 possesses the capability of accelerating GSK-3beta activation thereby deteriorating serum-deprivation-induced apoptosis; beta-arrestin 2 represents an inhibitory effect on the TLR4-mediated apoptotic cascade, through controlling the homeostasis of activation and inactivation of GSK-3beta.

Toll-like receptor 2 is required for opioids-induced neuronal apoptosis.

Toll-like receptor 2 (TLR2), a key immune receptor in the TLR family, is widely expressed in various systems, including the immune and nervous systems and plays a critical role in controlling innate and adaptive immune responses. We previously reported that opioids inhibit cell growth and trigger apoptosis. However, the underlying mechanism by which TLR2 mediates apoptosis in response to opioids is not yet known. Here we show that chronic morphine treatment in primary neurons dramatically increased the expression of TLR2 at both the messenger RNA and protein levels. In addition, TLR2 deficiency significantly inhibited chronic morphine-induced apoptosis in primary neurons. Activation of caspase-3 after morphine treatment is impaired in TLR2 deficient primary neurons. Moreover, morphine treatment failed to induce an increased level of phosphorylated glycogen synthase kinase 3 beta (GSK3beta) in TLR2 deficient primary neurons, suggesting an involvement of GSK3beta in morphine-mediated TLR2 signaling. These results thus demonstrate that opioids prime neurons to undergo apoptosis by inducing TLR2 expression. Our data suggest that inhibition of TLR2 is capable of preventing opioids-induced damage to neurons.