Barriers and facilitators to practitioners' implementation of positive behavior support practice in social care organizations in Ireland.

In Ireland, the provision of behavior support services has developed following the introduction of Health Information and Quality Authority (2013) standards and the regulation of Positive Behavior Support (PBS) under the Health Act (2007). The purpose of this study was to explore what factors facilitate and act as barriers to implementation of behavioral recommendations in Intellectual Disability organizations from the practitioner's perspective. Twelve interviews were carried out, audio recorded, transcribed and analysed using Braun and Clarke's (2006) Thematic Analysis. One superordinate theme (administrator support), four themes (values, resources, relationships and implementation of consequences) and five sub-themes (staff turnover and burnout, training and knowledge, time and physical contact, relationships between practitioners and staff and staff and service users) were identified, all interconnected in the implementation process. A common thread reflected throughout the themes, was the practitioner's acknowledgment of barriers overpowering facilitation which resulted in a less than optimum implementation of PBS.

Developing the Parent-Coaching Assessment, Individualization, and Response to Stressors (PAIRS) Tool for Behavior Analysts.

Parent engagement in early behavioral intervention is essential to achieving meaningful intervention outcomes. However, parents may experience multiple barriers to engagement. The Parent-coaching Assessment, Individualization, and Response to Stressors (PAIRS) was developed to help practitioners assess families' barriers and facilitators, individualize their intervention, and respond to stressors using a contextual, functional approach. An expert panel of Board Certified Behavior Analysts ® (BCBAs) evaluated the content validity of the PAIRS. Average scale values (S-CVI/Ave) were 0.92 for relevance, 0.85 for effectiveness, and 0.91 for appropriateness. The PAIRS was revised, and a follow-up evaluation was conducted to rate the tool's utility. This led to the final version of the PAIRS. Clinical implications and future directions are discussed.

Breast intraductal nanoformulations for treating ductal carcinoma in situ II: Dose de-escalation using a slow releasing/slow bioconverting prodrug strategy.

Ductal carcinoma in situ (DCIS) represents approximately 20-25% of newly diagnosed breast cancers. DCIS is treated by surgery and possibly radiotherapy. Chemotherapy is only used as adjuvant or neoadjuvant therapy but not as primary therapy. The present study investigated the intraductal administration of Ciclopirox (CPX) formulated in nanosuspensions (NSs) or nanoparticles (NPs) to treat DCIS locally in a Fischer 344 rat model orthotopically implanted with 13762 Mat B III cells. Slow converting esterase responsive CPX prodrugs (CPDs) were successfully synthesized at high purity (> 95%) by directly acetylating the hydroxyl group or by appending a self-immolative linker between CPX and a phenolic ester. Direct esterification CPDs were not sufficiently stable so self-immolative CPDs were formulated in NSs and NPs. Prodrug release was evaluated from poly(lactic-co-glycolic acid) NPs, and CPD4 demonstrated the slowest release rate with the rank order of CPD2 (R = methyl) > CPD3 (R = t-butyl) > CPD4 (R = phenyl). Intraductally administered CPX NS, CPD4 NS, and an innovative mixture of CDP4 NS and NPs (at 1 mg CPX equivalent/duct) demonstrated significant (p < 0.05) in vivo anti-tumor efficacy compared with immediate release (IR) CPX NS and non-treated controls. CPX mammary persistence at 6 h and 48 h after CPD4 NS or NP administration was also greater than after the immediate release CPX NS. A strong correlation between CPX mammary persistence and efficacy is demonstrated. In conclusion, nanoformulations utilizing a slow releasing/slow bioconverting CPX prodrug delivery strategy resulted in significant dose de-escalation (~ five fold) while maintaining anti-tumor efficacy.

A Systematic Review of Family-Mediated Social Communication Interventions for Young Children with Autism.

Social communication deficits are a core symptom of autism spectrum disorder (ASD). The present paper reviews 54 studies evaluating social communication interventions delivered by parents and siblings to children with ASD under 6 years old. Fifty studies evaluated parent-mediated intervention, and four studies evaluated sibling-mediated intervention. Fourteen studies evaluated interventions using telehealth. Treatment effects and research strength were variable across studies. Treatment modality, setting, and dosage had inconclusive impact on treatment effect. Parent-implemented intervention packages, Pivotal Response Treatment (PRT), Early Start Denver Model (ESDM), and Joint Attention, Symbolic Play, Engagement & Regulation (JASPER), qualified as established evidence-based practice for this population. Most studies reported successful generalization of skills for some, but not all, children. Telehealth and sibling-mediated intervention are promising areas of further research and clinical practice.

Teacher Characteristics, Knowledge and Use of Evidence-Based Practices in Autism Education in Ireland.

Autism evidence-based practices (EBPs) are those with demonstrated improved outcomes for students with autism across a range of skill areas, yet issues persist in adopting these in classroom settings- particularly in general education (GE) settings. This research aimed to identify teacher training, years of experience, access to allied professionals and knowledge and use of autism EBPs in GE settings in Ireland. 369 mainstream primary school teachers reported their characteristics and their knowledge and use of EBPs. Results indicated that the majority of teachers received little initial teacher education training in autism, almost no continuous professional development (CPD) before educating a child with autism, and received little support from allied professionals. Knowledge and use of EBPs differed significantly across teacher characteristics, with findings discussed in relation to teacher training.

A systematic review of training methods to increase staff's knowledge and implementation of positive behaviour support in residential and day settings for individuals with intellectual and developmental disabilities.

Behaviour support plans (BSPs), if accurately implemented, have been found to increase skills and decrease challenging behaviour of individuals with intellectual and developmental disabilities. Training is essential for staff to acquire the skills necessary for accurate implementation. The aim of this systematic literature review was to evaluate procedures used to train staff in Positive Behaviour Support (PBS), on both knowledge of PBS and implementation of BSPs. Systematic searches of 4 databases identified 18 studies as meeting criteria. Findings indicate that description alone was not consistently effective in increasing knowledge and should be used in combination with other training strategies. Staff's implementation of BSPs were increased by different combinations of the following training components: description, feedback, modelling, role-play, monitory incentive, and escape contingency. To identify evidenced based practice when training staff on BSPs, it is necessary to evaluate active and feasible training components from current training models.

A Randomized Controlled Trial of Headsprout on the Reading Outcomes in Children With Autism Using Parents as Facilitators.

Children with autism spectrum disorder (ASD) are considered an at-risk population for reading delays and challenges. In recent years, there has been emerging support for the computer-assisted instruction (CAI) Headsprout with respect to reading outcomes in children with ASD. CAI, often used within classrooms, is designed using automated and carefully sequenced instruction. A randomized controlled trial was used to explore the implementation of Headsprout by parents, including a treatment package (i.e., behavioral skills training, an online support group, and a consultative model) within the home environment, with their children with ASD. A between-groups design was used to evaluate the effects of Headsprout on the reading outcomes and print motivation of a sample of 26 children with ASD. Thirteen children were in the experimental (Headsprout) group, and thirteen were in the control group receiving treatment as usual. Supplementary online supports were provided to parents based on specific learning problems identified during the intervention. Results demonstrated that participants who received Headsprout showed greater gains in reading rate, word reading, non-word reading, and target sounds and words within Headsprout than the control group. The results of print motivation demonstrated that only Headsprout-specific print material resulted in an increase in assessed preference at posttests.

Systematic Development and Characterization of Novel, High Drug-Loaded, Photostable, Curcumin Solid Lipid Nanoparticle Hydrogel for Wound Healing.

The study aims to develop high drug-loaded (about 15% lipid matrix) curcumin solid lipid nanoparticles (CSLNs) for wound healing. CSLNs prepared by hot, high-pressure homogenization, without using organic solvents, were optimized using the Taguchi design followed by the central composite design. The optimized CSLNs exhibited a high assay/drug content (0.6% w/w), solubility (6 × 105 times), and EE (75%) with a particle size < 200 nm (PDI-0.143). The CSLNs were safe (in vitro and in vivo), photostable, autoclavable, stable up to one year at 30 °C and under refrigeration and exhibited a controlled release (zero-order; 5 days). XRD, FTIR, and DSC confirmed solubilization and entrapment of the curcumin within the SLNs. TEM and FESEM revealed a smooth and spherical shape. The CSLNs showed a significant antimicrobial effect (MIC of 64 µg/mL for planktonic cells; 512 µg/mL for biofilm formation; and 2 mg/mL for mature biofilm) against Staphylococcus aureus 9144, while free curcumin dispersion did not exhibit any effect. This is the first report on the disruption of mature biofilms by curcumin solid lipid nanoparticles (CSLNs). The cell proliferation potential of CSLNs was also evaluated in vitro while the wound healing potential of CSLNs (incorporated in a hydrogel) was assessed in vivo. In (i) nitrogen mustard gas and (ii) a full-thickness excision wound model, CSLNs exhibited (a) significantly faster wound closure, (b) histologically and immunohistochemically better healing, (c) lower oxidative stress (LPO) and (d) inflammation (TNFα), and (e) increased angiogenesis (VEGF) and antioxidant enzymes, i.e., catalase and GSH levels. CSLNs thus offer a promising modern wound therapy especially for infected wounds, considering their effects in mature biofilm disruption.

An Evaluation of Assistive Technology in Determining Job-Specific Preference for Adults With Autism and Intellectual Disabilities.

The transition to employment can be difficult for adults with autism spectrum disorders (ASDs) and intellectual disabilities (IDs). Currently, a limited number of ASD-specific career-planning tools exist within the literature, creating a challenge in terms of accurately identifying jobs that match individual preferences and strengths. This study evaluated the effects of a technology-based prework assessment on job performance among 3 adults with ASD and ID, aged 20-21 years prior to beginning supported employment. Three job conditions were established: a high-preference, high-skill-match job; a high-preference, low-skill-match job; and a low-preference, low-skill-match job. The 3 job conditions were evaluated using an alternating-treatments design with supported-employment sessions counterbalanced across a 6-week period. The results indicated that the high-preference job conditions produced higher levels of job performance irrespective of skill match. Implications for future research and practice are discussed.

Breast intraductal nanoformulations for treating ductal carcinoma in situ I: Exploring metal-ion complexation to slow ciclopirox release, enhance mammary persistence and efficacy.

INTRODUCTION: Ductal Carcinoma In Situ (DCIS) represents a significant fraction (~20-25%) of all newly diagnosed breast cancer cases and, if left untreated, a significant fraction of patients will progress to invasive disease. Surgery is the only treatment option. Ciclopirox (CPX), an FDA-approved antifungal drug, has exhibited promising antitumor activity by down-regulating the expression of vital antiapoptotic cellular proteins and inhibiting the genetic expression of several oncogenic pathways. In this study, the feasibility of using nanoscale delivery systems to control release and prolong mammary tissue persistence of a lipophilic metal complex of CPX and Zinc (CPXZn) after intraductal administration was investigated. METHODS: CPX and CPX-Zn nanosuspensions (NSs) were prepared using an evaporative nanoprecipitation-ultra-sonication method. Flash nanoprecipitation was used to prepare PLGA nanoparticles (NPs) loaded with CPXZn. Our established orthotopic DCIS rat model was used to evaluate efficacy. Briefly, two days after 13762 Mat B III cell intraductal inoculation, rats were divided into treatment groups and a single intraductal injection of CPX NS, CPX-Zn NS or CPX-Zn NPs was administered. In the first study arm, the efficacy of CPX NS (1, 3, 5 mg/duct) was evaluated. In the second arm, the in vivo efficacy of CPX NS, CPX-Zn NS and CPX-Zn loaded NPs was evaluated and compared at equivalent CPX doses. The mammary persistence of CPX from CPX NS, CPX-Zn NS, and CPX-Zn PLGA NPs was also assessed. RESULTS: CPX-Zn complex was successfully synthesized and characterized by several spectral analyses. CPX release was slowed from the CPX-Zn NS and further slowed by incorporating CPX-Zn into PLGA NPs as compared to the CPX NS with release half times following the order: CPX NS < CPX-Zn NS << CPX-Zn NP. Intraductal CPX NS administration was dose and time dependent in suppressing tumor initiation suggesting prolonged mammary exposure may improve efficacy. In the second arm, mammary tissue persistence of CPX followed the rank order CPX NS < CPX-Zn NS << CPX-Zn NP at 6 h and 48 h post-administration. Prolonged mammary CPX exposure was highly correlated to improved efficacy. Prolonged CPX tissue persistence, attributed to slower release from the zinc complex and the PLGA NPs, resulted in a 5-fold dose reduction compared to the CPX NS. CONCLUSIONS: The current results demonstrate that slowing drug release in the mammary duct after intraductal administration overcomes the rapid ductal clearance of CPX, prolongs mammary tissue persistence, improves efficacy against DCIS lesions in vivo, and requires 5-fold less CPX to achieve equivalent efficacy. The studies also provide a strategic path forward for developing a locally administered drug delivery system for treating DCIS, for which no primary chemotherapy option is available.

A Novel Bivalent Mannosylated Targeting Ligand Displayed on Nanoparticles Selectively Targets Anti-Inflammatory M2 Macrophages.

Persistent activation of macrophages (MP)s into a proinflammatory M1 or anti-inflammatory M2 phenotype plays a role in several pathological conditions, including autoimmune diseases, fibrosis, infections, atherosclerosis and tumor development. The mannose receptor (MR, CD206), expressed at low levels on resting MPs and absent on M1 MPs, is highly expressed on M2 MPs, making it a potential target and drug delivery portal. Recently, we developed a novel, highly selective MR targeting ligand (MRTL), consisting of two mannose molecules separated by a monodisperse 12 unit poly(ethylene glycol) linker, to enhance the cellular uptake of polymeric nanocarriers. The feasibility of using the MRTL ligand for selectively targeting M2 MPs for intracellular delivery of nanoparticles (NPs) was investigated. Rat peritoneal MPs were differentiated into an M1 or M2 phenotype using IFN-γ and IL-4/IL-13, respectively. Expression of the M1 marker, inducible nitric oxide synthase (iNOS), and the M2 markers arginase (Arg)-1 and MR (at both the mRNA and protein levels) confirmed MP phenotypic activation. Resting, M1 and M2 MPs were treated with fluorescein isothiocyanate (FITC)-labeled MRTL or NPs displaying FITC-labeled MRTL at two surface densities (1 and 10%) and examined by confocal microscopy. Intracellular fluorescence was also quantified. Uptake of the MRTL was 2.4- and 11.8-fold higher in M2 MPs when compared to resting or M1 MPs, respectively, consistent with marker expression levels. Mannan, a competitive inhibitor of the MR, abrogated MRTL uptake. MRTL also co-localized with a fluid-phase endocytosis marker, further suggesting that uptake was mediated by MR-mediated endocytosis. Intracellular NP fluorescence was confirmed by flow cytometry and by confocal microscopy. MRTL-NPs accumulated intracellularly with no significant cell surface binding, suggesting efficient translocation. NPs displaying a low surface density (1%) of the MRTL exhibited significantly higher (2.3-fold) uptake into M2 MPs, relative to resting and M1 MPs. The 10% MRTL-NPs displayed greater uptake by M2 MPs when compared to resting and M1 MPs, but less uptake than 1% MRTL-NPs into M2 MPs. Control FITC-labeled plain NPs did not exhibit selective MP uptake. These studies demonstrate that M2 MPs are selectively targeted by NPs displaying a novel bivalent ligand that utilizes the MR as a target/portal for cell entry. This study also establishes the feasibility of the approach allowing for further investigation in vivo.

An evaluation of parents as behavior change agents in the Preschool Life Skills program.

Parental involvement in intervention can support intervention efficacy, improve generalization, and increase accessibility. The Preschool Life Skills (PLS) program is designed to teach 13 preschool life skills and prevent problem behavior. The current study explores the utility of the PLS program as delivered by parents. In Experiment 1, 6 parents were taught to use the PLS program at home with their typically developing children (3 years 3 months to 4 years 11 months). This application of the PLS program led to an increase in preschool life skills and a decrease in problem behavior and supported some generalization of the target preschool life skills from the home to preschool settings. In Experiment 2, 7 parents were taught to use the PLS program with their children with autism spectrum disorder (ASD; 3 years 11 months to 6 years 9 months). Results overall supported the parent implementation of the program and highlighted modifications required to support positive outcomes for children with ASD.

Increasing appropriate conversation skills using a behavioral skills training package for adults with intellectual disability and autism spectrum disorder.

The current research evaluates the effectiveness of a behavioral skills training (BST) package used to increase appropriate conversation interactions for six adults with autism spectrum disorder (ASD). Deficits in the area of social skills can become a significant feature for individuals with disabilities and in particular for those with ASD. A multiple probe design across participant dyads was employed to examine the effects of the intervention on conversation interactions. The BST package was delivered in small group instruction and included (i) instructions about having a conversation, (ii) modeling a conversation, (iii) practicing a conversation, and (iv) feedback on performance during each session. Results indicated that BST was effective for increasing appropriate conversation interactions for all six participants, and maintenance was evident 4 weeks post intervention. The findings were discussed in relation to the importance of social interactions and communication amongst this population.

An investigation of the effects of a parent delivered stimulus-stimulus pairing intervention on vocalizations of two children with Autism Spectrum Disorder.

Communication deficits in children with Autism Spectrum Disorder (ASD) can manifest in a myriad of lifelong social and educational challenges. Many children with ASD fail to learn vocal verbal behavior and may require intensive individualized intervention to learn early verbal operants. The current research aimed to evaluate the effects of a parent delivered stimulus-stimulus pairing (SSP) procedure on target vocalizations of two young children with ASD who did not present with vocal verbal behavior. Results indicated the intervention was successful in increasing the frequency of the target vocalizations for both participants. Social validity results indicated that parents were satisfied with the intervention and their own implementation of these procedures. These results are discussed in terms of their implications for parent delivered interventions.

The Use of Differential Reinforcement of Other Behaviours to Establish Inhibitory Stimulus Control for the Management of Vocal Stereotypy in Children with Autism.

OBJECTIVE: This study examined the efficacy of an inhibitory stimulus control procedure (ISCP) for the management of vocal stereotypy in three children with autism. METHOD: During discrimination training, implemented within a changing criterion design, participants were taught that there were no consequences for vocal stereotypy in the absence of an inhibitory stimulus but that differential reinforcement procedures were in effect in the presence of the stimulus. Functional control of the inhibitory stimulus was subsequently assessed within a reversal design. RESULTS: Inhibitory stimulus control was established during discrimination training, with participants inhibiting vocal stereotypy for 30 min periods in the presence of the inhibitory stimulus. Reductions in vocal stereotypy were maintained in the presence of the inhibitory stimulus and in the absence of further programmed consequences. DISCUSSION: This study extends current knowledge by demonstrating the efficacy of ISCPs paired with reinforcement only, and illustrating the functional control of the inhibitory stimulus.

Evaluation of intraductal delivery of poly(ethylene glycol)-doxorubicin conjugate nanocarriers for the treatment of ductal carcinoma in situ (DCIS)-like lesions in rats.

Ductal carcinoma in situ is the most commonly diagnosed early stage breast cancer. The efficacy of intraductally delivered poly(ethylene glycol)-doxorubicin (PEG-DOX) nanocarriers, composed of one or more DOX conjugated to various PEG polymers, was investigated in an orthotopic ductal carcinoma in situ-like rat model. In vitro cytotoxicity was evaluated against 13762 Mat B III cells using MTT assay. The orthotopic model was developed by inoculating cancer cells into mammary ducts of female Fischer 344 retired breeder rats. The ductal retention and in vivo antitumour efficacy of two of the six nanocarriers (5 kDa PEG-DOX and 40 kDa PEG-(DOX)4) were investigated based on in vitro results. Mammary retention of DOX and PEG-DOX nanocarriers was quantified using in vivo imaging. Histopathologic effects of DOX and PEG-DOX nanocarriers on mammary ductal structure were also investigated. Cytotoxicities of small linear PEG-DOX nanocarriers (5 and 10 kDa) were not different from DOX whereas larger PEG-DOX nanocarriers showed reduced potency. The order of mammary retention was 40 kDa PEG-(DOX)4 > 5 kDa PEG-DOX >> DOX, in normal and tumour-bearing rats. Intraductally administered PEG-DOX nanocarriers and DOX were effective in reducing tumour incidence and increasing survival rate, with no significant differences found among the three treatment groups. However, nanocarriers administered intravenously at the same doses were not effective, and intraductally administered free DOX caused severe local toxicity. Intraductal administration of PEG-DOX nanocarriers is effective and less toxic than that of free DOX, as well as IV DOX/PEG-DOX. Furthermore, PEG-DOX nanocarriers demonstrate the added benefit of prolonging DOX ductal retention, which would necessitate less frequent dosing.

The effect of size and polymer architecture of doxorubicin-poly(ethylene) glycol conjugate nanocarriers on breast duct retention, potency and toxicity.

Although systemic administration of chemotherapeutic agents is routinely used for treating invasive breast cancer, the only therapeutic options for ductal carcinoma in situ (DCIS) are surgery and radiation. Treating DCIS by delivering drugs locally to the affected milk duct offers significant advantages over systemic administration, including reduced systemic and breast toxicities, as well as a greatly reduced need for surgery and radiation. In this study, mammary gland retention and toxicity of intraductally administered poly(ethylene) glycol-doxorubicin (PEG-DOX) polymeric conjugate nanocarriers of varying molecular sizes and architectures were investigated. Nanocarriers were formed by conjugating one or more copies of doxorubicin to PEG polymers, of varying molecular weights (5, 10, 20, and 40 kDa) and architectures (linear, four-arm and eight-arm). Cytotoxicity against MCF7 cells, a human breast cancer cell line, was assessed, and IC50 values were calculated. The nanocarriers were intraductally administered into the mammary glands of female retired breeder Sprague-Dawley rats. Whole body images were captured using in vivo optical imaging, and changes in ductal structure as well local inflammation were monitored. Fluorescence intensities were monitored, over time, to evaluate nanocarrier mammary gland retention half-lives (t1/2). The IC50 values of PEG-DOX nanocarriers against MCF7 cells were 40 kDa PEG-(DOX)4 (1.23 µM) < 5 kDa PEG-DOX (1.76 µM) < 40 kDa PEG-(DOX)8 (3.49 µM) < 10 kDa PEG-DOX (3.86 µM) < 20 kDa PEG-DOX (8.96 µM) < 40 kDa PEG-DOX (18.11 µM), whereas the IC50 of free DOX was only 0.14 µM. The t1/2 of linear 5, 20, and 40 kDa nanocarriers were 2.2 ±â€¯0.3, 3.6 ±â€¯0.6, and 13.1 ±â€¯3.4 h, whereas the retention t1/2 of 4- and 8-arm 40 kDa nanocarriers were 14.9 ±â€¯5.6 h and 11.9 ±â€¯2.9 h, respectively. The retention t1/2 of free doxorubicin was 2.0 ±â€¯0.4 h, which was significantly shorter than that of the linear and branched 40 kDa PEG-DOX nanocarriers. Increased molecular weight and decreased branching both demonstrated a strong correlation to enhanced mammary gland retention. Intraductally administered free doxorubicin resulted in ductal damage, severe inflammation and generation of atypical cell neoplasms, whereas PEG-DOX nanocarriers induced only minor and transient inflammation (i.e., damaged epithelial cells and detached cellular debris). The 40 kDa 4-arm PEG-DOX nanocarrier demonstrated the longest ductal retention half-life, the lowest IC50 (i.e., most potent), and minimal ductal damage and inflammation. The current results suggest that PEG-DOX nanocarriers with prolonged ductal retention may present the best option for intraductal treatment of DCIS, due to their low local toxicity and potential for sustained therapeutic effect.

An Evaluation of a Social Skills Intervention for Adults with Autism Spectrum Disorder and Intellectual Disabilities preparing for Employment in Ireland: A Pilot Study.

Individuals with autism spectrum disorder (ASD) are faced with significant barriers relating to employment opportunities and workplace participation. This study evaluated the effectiveness of the Walker social skills curriculum: the ACCESS program and video modeling to increase social communication skills necessary for workplace inclusion. Participants attended two sessions (i.e., 3 h) per week across a period of 20 weeks. A multiple-probe design was used to demonstrate social skills outcomes across three broad curricular areas (i.e., peer-related, adult-related, and self-related social skills). Pre-and post-intervention standardized assessments were also taken. Results showed significant increases in target social skills and a significant decrease in problem behaviors following intervention. Evidence of maintenance and generalization were also demonstrated. Implications for practice and research are discussed.

Adjunctive Phosphodiesterase-4 Inhibitor Therapy Improves Antibiotic Response to Pulmonary Tuberculosis in a Rabbit Model.

OBJECTIVES: Adjunctive host-directed therapy is emerging as a new potential approach to improve the outcome of conventional antimicrobial treatment for tuberculosis (TB). We tested the ability of a phosphodiesterase-4 inhibitor (PDE4i) CC-11050, co-administered with the first-line anti-TB drug isoniazid (INH), to accelerate bacillary killing and reduce chronic inflammation in the lungs of rabbits with experimental Mycobacterium tuberculosis (Mtb) infection. METHODS: A rabbit model of pulmonary TB that recapitulates the pathologic manifestations seen in humans was used. Rabbits were infected with virulent Mtb by aerosol exposure and treated for eight weeks with INH with or without CC-11050, starting at four weeks post infection. The effect of CC-11050 treatment on disease severity, pathology, bacillary load, T cell proliferation and global lung transcriptome profiles were analyzed. RESULTS: Significant improvement in bacillary clearance and reduced lung pathology and fibrosis were noted in the rabbits treated for eight weeks with INH + CC-11050, compared to those treated with INH or CC-11050 only. In addition, expression of host genes associated with tissue remodeling, tumor necrosis factor alpha (TNF-α) regulation, macrophage activation and lung inflammation networks was dampened in CC-11050-treated, compared to the untreated rabbits. CONCLUSIONS: Adjunctive CC-11050 therapy significantly improves the response of rabbits with experimental pulmonary TB to INH treatment. We propose that CC-11050 may be a promising candidate for host directed therapy of patients with pulmonary TB, reducing the duration and improving clinical outcome of antibiotic treatment.

Etanercept exacerbates inflammation and pathology in a rabbit model of active pulmonary tuberculosis.

Treatment of chronic inflammatory diseases with tumor necrosis factor alpha (TNF-α) antagonists has been associated with increased risk of tuberculosis (TB). We examined the usefulness of the rabbit model of active pulmonary TB for studying the impact of the human immune modulatory reagent etanercept on the host immune response. Control of Mycobacterium tuberculosis (Mtb) infection, disease pathology, and the global transcriptional response in Mtb-infected lungs of rabbits were studied. Etanercept treatment exacerbated disease pathology and reduced bacillary control in the lungs, compared with infected untreated animals. Reduced collagen and fibrin deposition in the granulomas was associated with significant downregulation of the collagen metabolism and fibrosis network genes and upregulation of genes in the inflammatory response and cell recruitment networks in the lungs of etanercept treated, compared with untreated rabbits. Our results suggest that targeting the TNF-α signaling pathway disrupts the tissue remodeling process, which is required for the formation and maintenance of well-differentiated granulomas and for control of Mtb growth in the lungs. These results validate the use of the rabbit model for investigating the impact of selected human immune modulatory drugs, such as a TNF-α antagonist, on the host immune response and pathogenesis in TB.