Regional differences in the link between water exchange rate across the blood-brain barrier and cognitive performance in normal aging.

The blood-brain barrier (BBB) undergoes functional changes with aging which may contribute to cognitive decline. A novel, diffusion prepared arterial spin labeling-based MRI technique can measure the rate of water exchange across the BBB (kw) and may thus be sensitive to age-related alterations in water exchange at the BBB. However, studies investigating relationships between kw and cognition have reported different directions of association. Here, we begin to investigate the direction of associations between kw and cognition in different brain regions, and their possible underpinnings, by evaluating links between kw, cognitive performance, and MRI markers of cerebrovascular dysfunction and/or damage. Forty-seven healthy older adults (age range 61-84) underwent neuroimaging to obtain whole-brain measures of kw, cerebrovascular reactivity (CVR), and white matter hyperintensity (WMH) volumes. Additionally, participants completed uniform data set (Version 3) neuropsychological tests of executive function (EF) and episodic memory (MEM). Voxel-wise linear regressions were conducted to test associations between kw and cognitive performance, CVR, and WMH volumes. We found that kw in the frontoparietal brain regions was positively associated with cognitive performance but not with CVR or WMH volumes. Conversely, kw in the basal ganglia was negatively associated with cognitive performance and CVR and positively associated with regional, periventricular WMH volume. These regionally dependent associations may relate to different physiological underpinnings in the relationships between kw and cognition in neocortical versus subcortical brain regions in older adults.

Association of Baseline Cerebrovascular Reactivity and Longitudinal Development of Enlarged Perivascular Spaces in the Basal Ganglia.

BACKGROUND: Increasing evidence suggests that enlarged perivascular spaces (ePVS) are associated with cognitive dysfunction in aging. However, the pathogenesis of ePVS remains unknown. Here, we tested the possibility that baseline cerebrovascular dysfunction, as measured by a magnetic resonance imaging measure of cerebrovascular reactivity, contributes to the later development of ePVS. METHODS: Fifty cognitively unimpaired, older adults (31 women; age range, 60-84 years) underwent magnetic resonance imaging scanning at baseline and follow-up separated by ≈2.5 years. ePVS were counted in the basal ganglia, centrum semiovale, midbrain, and hippocampus. Cerebrovascular reactivity, an index of the vasodilatory capacity of cerebral small vessels, was assessed using carbon dioxide inhalation while acquiring blood oxygen level-dependent magnetic resonance images. RESULTS: Low baseline cerebrovascular reactivity values in the basal ganglia were associated with increased follow-up ePVS counts in the basal ganglia after controlling for age, sex, and baseline ePVS values (estimate [SE]=-3.18 [0.96]; P=0.002; [95% CI, -5.11 to -1.24]). This effect remained significant after accounting for self-reported risk factors of cerebral small vessel disease (estimate [SE]=-3.10 [1.00]; P=0.003; [CI, -5.11 to -1.09]) and neuroimaging markers of cerebral small vessel disease (estimate [SE]=-2.72 [0.99]; P=0.009; [CI, -4.71 to -0.73]). CONCLUSIONS: Our results demonstrate that low baseline cerebrovascular reactivity is a risk factor for later development of ePVS.

Electrophysiological evaluation following development of new and persistent left bundle branch block after transcatheter aortic valve replacement: A single center pilot study.

INTRODUCTION: New and persistent left bundle branch block (NP-LBBB) following Transcatheter Aortic Valve Replacement (TAVR) is an ongoing concern with incidence ranging from as low as 4% to up to 65% (varying for different types of valves). Such patients are at risk of developing high-grade atrioventricular block (HAVB) warranting permanent pacemaker (PPM) implantation. However, currently, there are no consensus guidelines or large prospective studies to risk stratify these patients for safer discharge after TAVR. OBJECTIVES: To provide insight from a single center study on using modified electrophysiology (EP) study to risk stratify post-TAVR patients to outpatient monitoring for low-risk versus pacemaker implantation for high-risk patients. METHODS AND RESULTS: Between June 2020 and March 2023, all patients who underwent a TAVR procedure (324 patients) at our institution were screened for development of NP-LBBB post-operatively. Out of 26 patients who developed NP-LBBB, after a pre-specified period of observation, 18 patients were deemed eligible for a modified EP study to assess His-Ventricular (HV) interval. 11 out of 18 patients (61.1%) had normal HV interval (HV < 55 ms). Three out of 18 patients (16.7%) had HV prolongation (55 ms < HV < 70 ms) without significant HV prolongation (defined as an increase in HV interval > 30%) with intra-procedural procainamide challenge. Four out of 18 patients (22.2%) had significant HV prolongation (HV > 70 ms) warranting PPM implantation based on a multidisciplinary approach and shared decision-making with the patients. Total of 50% of patients discharged with PPM (two out of four patients) were noted to be pacemaker dependent based on serial device interrogations. All patients who did not receive PPM were discharged with ambulatory monitoring with 30-day event monitor and did not develop HAVB on serial follow-up. CONCLUSION: Normal HV interval up to 55 ms on modified EP study after TAVR and development of NP-LBBB can be utilized as a threshold for risk stratification to facilitate safe discharge. The optimal upper limit of HV interval threshold remains unclear in determining appropriate candidacy for PPM.

Plasma TDP-43 levels are associated with neuroimaging measures of brain structure in limbic regions.

Introduction: We evaluated the relationship between plasma levels of transactive response DNA binding protein of 43 kDa (TDP-43) and neuroimaging (magnetic resonance imaging [MRI]) measures of brain structure in aging. Methods: Plasma samples were collected from 72 non-demented older adults (age range 60-94 years) in the University of Kentucky Alzheimer's Disease Research Center cohort. Multivariate linear regression models were run with plasma TDP-43 level as the predictor variable and brain structure (volumetric or cortical thickness) measurements as the dependent variable. Covariates included age, sex, intracranial volume, and plasma markers of Alzheimer's disease neuropathological change (ADNC). Results: Negative associations were observed between plasma TDP-43 level and both the volume of the entorhinal cortex, and cortical thickness in the cingulate/parahippocampal gyrus, after controlling for ADNC plasma markers. Discussion: Plasma TDP-43 levels may be directly associated with structural MRI measures. Plasma TDP-43 assays may prove useful in clinical trial stratification. HIGHLIGHTS: Plasma transactive response DNA binding protein of 43 kDa (TDP-43) levels were associated with entorhinal cortex volume.Biomarkers of TDP-43 and Alzheimer's disease neuropathologic change (ADNC) may help distinguish limbic-predominant age-related TDP-43 encephalopathy neuropathologic change (LATE-NC) from ADNC.A comprehensive biomarker kit could aid enrollment in LATE-NC clinical trials.

Synergistic Detrimental Effects of Cigarette Smoke, Alcohol, and SARS-CoV-2 in COPD Bronchial Epithelial Cells.

Lung conditions such as COPD, as well as risk factors such as alcohol misuse and cigarette smoking, can exacerbate COVID-19 disease severity. Synergistically, these risk factors can have a significant impact on immunity against pathogens. Here, we studied the effect of a short exposure to alcohol and/or cigarette smoke extract (CSE) in vitro on acute SARS-CoV-2 infection of ciliated human bronchial epithelial cells (HBECs) collected from healthy and COPD donors. We observed an increase in viral titer in CSE- or alcohol-treated COPD HBECs compared to untreated COPD HBECs. Furthermore, we treated healthy HBECs accompanied by enhanced lactate dehydrogenase activity, indicating exacerbated injury. Finally, IL-8 secretion was elevated due to the synergistic damage mediated by alcohol, CSE, and SARS-CoV-2 in COPD HBECs. Together, our data suggest that, with pre-existing COPD, short exposure to alcohol or CSE is sufficient to exacerbate SARS-CoV-2 infection and associated injury, impairing lung defences.

Malondialdehyde acetaldehyde adduction of surfactant protein D attenuates SARS-CoV-2 spike protein binding and virus neutralization.

BACKGROUND: Over 43% of the world's population regularly consumes alcohol. Although not commonly known, alcohol can have a significant impact on the respiratory environment. Living in the time of the COVID-19 pandemic, alcohol misuse can have a particularly deleterious effect on SARS-CoV-2-infected individuals and, in turn, the overall healthcare system. Patients with alcohol use disorders have higher odds of COVID-19-associated hospitalization and mortality. Even though the detrimental role of alcohol on COVID-19 outcomes has been established, the underlying mechanisms are yet to be fully understood. Alcohol misuse has been shown to induce oxidative damage in the lungs through the production of reactive aldehydes such as malondialdehyde and acetaldehyde (MAA). MAA can then form adducts with proteins, altering their structure and function. One such protein is surfactant protein D (SPD), which plays an important role in innate immunity against pathogens. METHODS AND RESULTS: In this study, we examined whether MAA adduction of SPD (SPD-MAA) attenuates the ability of SPD to bind SARS-CoV-2 spike protein, reversing SPD-mediated virus neutralization. Using ELISA, we show that SPD-MAA is unable to competitively bind spike protein and prevent ACE2 receptor binding. Similarly, SPD-MAA fails to inhibit entry of wild-type SARS-CoV-2 virus into Calu-3 cells, a lung epithelial cell line, as well as ciliated primary human bronchial epithelial cells isolated from healthy individuals. CONCLUSIONS: Overall, MAA adduction of SPD, a consequence of alcohol overconsumption, represents one mechanism of compromised lung innate defense against SARS-CoV-2, highlighting a possible mechanism underlying COVID-19 severity and related mortality in patients who misuse alcohol.

High cortical iron is associated with the disruption of white matter tracts supporting cognitive function in healthy older adults.

Aging is associated with brain iron accumulation, which has been linked to cognitive decline. However, how brain iron affects the structure and function of cognitive brain networks remains unclear. Here, we explored the possibility that iron load in gray matter is associated with disruption of white matter (WM) microstructure within a network supporting cognitive function, in a cohort of 95 cognitively normal older adults (age range: 60-86). Functional magnetic resonance imaging was used to localize a set of brain regions involved in working memory and diffusion tensor imaging based probabilistic tractography was used to identify a network of WM tracts connecting the functionally defined regions. Brain iron concentration within these regions was evaluated using quantitative susceptibility mapping and microstructural properties were assessed within the identified tracts using neurite orientation dispersion and density imaging. Results indicated that high brain iron concentration was associated with low neurite density (ND) within the task-relevant WM network. Further, regional associations were observed such that brain iron in cortical regions was linked with lower ND in neighboring but not distant WM tracts. Our results provide novel evidence suggesting that age-related increases in brain iron concentration are associated with the disruption of WM tracts supporting cognitive function in normal aging.

MRI free water as a biomarker for cognitive performance: Validation in the MarkVCID consortium.

Introduction: To evaluate the clinical validity of free water (FW), a diffusion tensor imaging-based biomarker kit proposed by the MarkVCID consortium, by investigating the association between mean FW (mFW) and executive function. Methods: Baseline mFW was related to a baseline composite measure of executive function (EFC), adjusting for relevant covariates, in three MarkVCID sub-cohorts, and replicated in five, large, independent legacy cohorts. In addition, we tested whether baseline mFW predicted accelerated EFC score decline (mean follow-up time: 1.29 years). Results: Higher mFW was found to be associated with lower EFC scores in MarkVCID legacy and sub-cohorts (p-values < 0.05). In addition, higher baseline mFW was associated significantly with accelerated decline in EFC scores (p = 0.0026). Discussion: mFW is a sensitive biomarker of cognitive decline, providing a strong clinical rational for its use as a marker of white matter (WM) injury in multi-site observational studies and clinical trials of vascular cognitive impairment and dementia (VCID).

IFN-γ transforms the transcriptomic landscape and triggers myeloid cell hyperresponsiveness to cause lethal lung injury.

Acute Respiratory Distress Syndrome (ARDS) is an inflammatory disease that is associated with high mortality but no specific treatment. Our understanding of initial events that trigger ARDS pathogenesis is limited. We have developed a mouse model of inflammatory lung injury by influenza and methicillin-resistant Staphylococcus aureus (MRSA) coinfection plus daily antibiotic therapy. Using this pneumonic ARDS model, here we show that IFN-γ receptor signaling drives inflammatory cytokine storm and lung tissue damage. By single-cell RNA sequencing (scRNA-seq) analysis, we demonstrate that IFN-γ signaling induces a transcriptional shift in airway immune cells, particularly by upregulating macrophage and monocyte expression of genes associated with inflammatory diseases. Further evidence from conditional knockout mouse models reveals that IFN-γ receptor signaling in myeloid cells, particularly CD11c+ mononuclear phagocytes, directly promotes TNF-α hyperproduction and inflammatory lung damage. Collectively, the findings from this study, ranging from cell-intrinsic gene expression to overall disease outcome, demonstrate that influenza-induced IFN-γ triggers myeloid cell hyperresponsiveness to MRSA, thereby leading to excessive inflammatory response and lethal lung damage during coinfection.

Multi-compartment diffusion magnetic resonance imaging models link tract-related characteristics with working memory performance in healthy older adults.

Multi-compartment diffusion MRI metrics [such as metrics from free water elimination diffusion tensor imaging (FWE-DTI) and neurite orientation dispersion and density imaging (NODDI)] may reflect more specific underlying white-matter tract characteristics than traditional, single-compartment metrics [i.e., metrics from Diffusion Tensor Imaging (DTI)]. However, it remains unclear if multi-compartment metrics are more closely associated with age and/or cognitive performance than single-compartment metrics. Here we compared the associations of single-compartment [Fractional Anisotropy (FA)] and multi-compartment diffusion MRI metrics [FWE-DTI metrics: Free Water Eliminated Fractional Anisotropy (FWE-FA) and Free Water (FW); NODDI metrics: Intracellular Volume Fraction (ICVF), Orientation Dispersion Index (ODI), and CSF-Fraction] with both age and working memory performance. A functional magnetic resonance imaging (fMRI) guided, white matter tractography approach was employed to compute diffusion metrics within a network of tracts connecting functional regions involved in working memory. Ninety-nine healthy older adults (aged 60-85) performed an in-scanner working memory task while fMRI was performed and also underwent multi-shell diffusion acquisition. The network of white matter tracts connecting functionally-activated regions was identified using probabilistic tractography. Diffusion metrics were extracted from skeletonized white matter tracts connecting fMRI activation peaks. Diffusion metrics derived from both single and multi-compartment models were associated with age (p s ≤ 0.011 for FA, FWE-FA, ICVF and ODI). However, only multi-compartment metrics, specifically FWE-FA (p = 0.045) and ICVF (p = 0.020), were associated with working memory performance. Our results suggest that while most current diffusion metrics are sensitive to age, several multi-compartment metrics (i.e., FWE-FA and ICVF) appear more sensitive to cognitive performance in healthy older adults.

Beyond "study skills": a curriculum-embedded framework for metacognitive development in a college chemistry course.

Background: There is a critical need for evidence-based metacognition instruction models with an ease of implementation. Three issues involved in advancing the implementation and assessment of metacognitive interventions are: (i) the lack of an operational framework for the development of metacognition; (ii) metacognition instruction models that lack a focus on explicitly engaging students' self-perceptions; (iii) a lack of metacognitive interventions that are easy to implement and require minimal training. This study describes the development and implementation of a 10-week discussion-based module to promote metacognitive development as part of a general chemistry course at a community college. This curricular metacognition instruction model involved the explicit engagement of self-efficacy beliefs in addition to introducing metacognitive awareness and regulation through individual and group reflection. This approach involves a systematic framework which allowed students to confront their beliefs about their abilities, learn various task strategies, and practice these strategies along with their peers. This case study was designed to address the following: can explicit cognitive and metacognitive instruction and discussion serve as a catalyst for students to (1) build and adapt metacognitive knowledge about cognition, and (2) incorporate effective study strategies?. Results: Students' individual and collaborative reflections were analyzed using a thematic analysis. Written journal responses indicate that the module facilitated a shared discourse about cognition where metacognitive awareness was observed shifting from a tacit to explicit awareness. In addition, the framework facilitated the formation of support networks (cognitive and emotional) where students were observed exchanging cognitive strategies and encouraging one another to persevere through challenges. Conclusions: Our findings suggest that the metacognitive instruction model described here can serve as a mechanism to encourage student reflection on their beliefs and behaviors. Instructors looking to include metacognition instruction could use the framework presented as a template. The discussion-based module is embedded in the curriculum, delivered through the course management system, and has a low barrier to implementation. Supplementary Information: The online version contains supplementary material available at 10.1186/s40594-022-00376-6.

Acceptance-enhanced behavior therapy for trichotillomania in adults: A randomized clinical trial.

Given the limited treatment options for trichotillomania (TTM), or Hair Pulling Disorder, this large randomized clinical trial evaluated the efficacy of acceptance-enhanced behavior therapy for TTM (AEBT-TTM) in reducing TTM severity relative to psychoeducation and supportive therapy (PST). Eighty-five adults (78 women) with TTM received 10 sessions (over 12 weeks) of either AEBT-TTM or PST. Independent evaluators masked to treatment assignment assessed participants at baseline (week 0), midpoint (week 6), and endpoint (week 12). Consistent with a priori hypotheses, 64% of the adults treated with AEBT-TTM were classified as clinical responders at post-treatment relative to 38% treated with PST. Clinical responders were identified by a score of 1 or 2 on the Clinical Global Impressions-Improvement (CGI-I) scale. Relative to the PST group, the AEBT-TTM group demonstrated significantly greater pre-to post-treatment reductions on the self-report Massachusetts General Hospital-Hairpulling Scale (MGH-HS) and the evaluator-rated National Institute of Mental Health Trichotillomania Severity Scale (NIMH-TSS). There were no significant post-treatment group differences on the Clinical Global Impressions-Severity (CGI-S) scale, or rate of TTM diagnoses. Results suggest AEBT-TTM provides greater treatment benefit than PST. Future research should continue to investigate AEBT-TTM along with mediators and moderators of its efficacy.

Surface Modification of Biodegradable Microparticles with the Novel Host-Derived Immunostimulant CPDI-02 Significantly Increases Short-Term and Long-Term Mucosal and Systemic Antibodies against Encapsulated Protein Antigen in Young Naïve Mice after Respiratory Immunization.

Generating long-lived mucosal and systemic antibodies through respiratory immunization with protective antigens encapsulated in nanoscale biodegradable particles could potentially decrease or eliminate the incidence of many infectious diseases, but requires the incorporation of a suitable mucosal immunostimulant. We previously found that respiratory immunization with a model protein antigen (LPS-free OVA) encapsulated in PLGA 50:50 nanoparticles (~380 nm diameter) surface-modified with complement peptide-derived immunostimulant 02 (CPDI-02; formerly EP67) through 2 kDa PEG linkers increases mucosal and systemic OVA-specific memory T-cells with long-lived surface phenotypes in young, naïve female C57BL/6 mice. Here, we determined if respiratory immunization with LPS-free OVA encapsulated in similar PLGA 50:50 microparticles (~1 µm diameter) surface-modified with CPDI-02 (CPDI-02-MP) increases long-term OVA-specific mucosal and systemic antibodies. We found that, compared to MP surface-modified with inactive, scrambled scCPDI-02 (scCPDI-02-MP), intranasal administration of CPDI-02-MP in 50 µL sterile PBS greatly increased titers of short-term (14 days post-immunization) and long-term (90 days post-immunization) antibodies against encapsulated LPS-free OVA in nasal lavage fluids, bronchoalveolar lavage fluids, and sera of young, naïve female C57BL/6 mice with minimal lung inflammation. Thus, surface modification of ~1 µm biodegradable microparticles with CPDI-02 is likely to increase long-term mucosal and systemic antibodies against encapsulated protein antigen after respiratory and possibly other routes of mucosal immunization.

Enlarged Perivascular Spaces Are Negatively Associated With Montreal Cognitive Assessment Scores in Older Adults.

Emerging evidence suggests that enlarged perivascular spaces (ePVS) may be a clinically significant neuroimaging marker of global cognitive function related to cerebral small vessel disease (cSVD). We tested this possibility by assessing the relationship between ePVS and both a standardized measure of global cognitive function, the Montreal Cognitive Assessment (MoCA), and an established marker of cSVD, white matter hyperintensity volume (WMH) volume. One hundred and eleven community-dwelling older adults (56-86) underwent neuroimaging and MoCA testing. Quantification of region-specific ePVS burden was performed using a previously validated visual rating method and WMH volumes were computed using the standard ADNI pipeline. Separate linear regression models were run with ePVS as a predictor of MoCA scores and whole brain WMH volume. Results indicated a negative association between MoCA scores and both total ePVS counts (P ≤ 0.001) and centrum semiovale ePVS counts (P ≤ 0.001), after controlling for other relevant cSVD variables. Further, WMH volumes were positively associated with total ePVS (P = 0.010), basal ganglia ePVS (P ≤ 0.001), and centrum semiovale ePVS (P = 0.027). Our results suggest that ePVS burden, particularly in the centrum semiovale, may be a clinically significant neuroimaging marker of global cognitive dysfunction related to cSVD.

Type I IFN Signaling Is Essential for Preventing IFN-γ Hyperproduction and Subsequent Deterioration of Antibacterial Immunity during Postinfluenza Pneumococcal Infection.

Postinfluenza bacterial pneumonia is a significant cause of hospitalization and death in humans. The mechanisms underlying this viral and bacterial synergy remain incompletely understood. Recent evidence indicates that influenza-induced IFNs, particularly type I IFN (IFN-I) and IFN-γ, suppress antibacterial defenses. In this study, we have investigated the relative importance and interplay of IFN-I and IFN-γ pathways in influenza-induced susceptibility to Streptococcus pneumoniae infection. Using gene-deficient mouse models, as well as in vivo blocking Abs, we show that both IFN-I and IFN-γ signaling pathways contribute to the initial suppression of antibacterial immunity; however, IFN-γ plays a dominant role in the disease deterioration, in association with increased TNF-α production and alveolar macrophage (AM) depletion. We have previously shown that IFN-γ impairs AM antibacterial function and thereby acute bacterial clearance. The findings in this study indicate that IFN-γ signaling also impairs AM viability and αß T cell recruitment during the progression of influenza/S. pneumoniae coinfection. Macrophages insensitive to IFN-γ mice express a dominant-negative mutant IFN-γR in mononuclear phagocytes. Interestingly, macrophages insensitive to IFN-γ mice exhibited significantly improved recovery and survival from coinfection, despite delayed bacterial clearance. Importantly, we demonstrate that IFN-I receptor signaling is essential for preventing IFN-γ hyperproduction and animal death during the progression of postinfluenza pneumococcal pneumonia.

Within-sibship genome-wide association analyses decrease bias in estimates of direct genetic effects.

Estimates from genome-wide association studies (GWAS) of unrelated individuals capture effects of inherited variation (direct effects), demography (population stratification, assortative mating) and relatives (indirect genetic effects). Family-based GWAS designs can control for demographic and indirect genetic effects, but large-scale family datasets have been lacking. We combined data from 178,086 siblings from 19 cohorts to generate population (between-family) and within-sibship (within-family) GWAS estimates for 25 phenotypes. Within-sibship GWAS estimates were smaller than population estimates for height, educational attainment, age at first birth, number of children, cognitive ability, depressive symptoms and smoking. Some differences were observed in downstream SNP heritability, genetic correlations and Mendelian randomization analyses. For example, the within-sibship genetic correlation between educational attainment and body mass index attenuated towards zero. In contrast, analyses of most molecular phenotypes (for example, low-density lipoprotein-cholesterol) were generally consistent. We also found within-sibship evidence of polygenic adaptation on taller height. Here, we illustrate the importance of family-based GWAS data for phenotypes influenced by demographic and indirect genetic effects.

Instrumental validation of free water, peak-width of skeletonized mean diffusivity, and white matter hyperintensities: MarkVCID neuroimaging kits.

Introduction: To describe the protocol and findings of the instrumental validation of three imaging-based biomarker kits selected by the MarkVCID consortium: free water (FW) and peak width of skeletonized mean diffusivity (PSMD), both derived from diffusion tensor imaging (DTI), and white matter hyperintensity (WMH) volume derived from fluid attenuation inversion recovery and T1-weighted imaging. Methods: The instrumental validation of imaging-based biomarker kits included inter-rater reliability among participating sites, test-retest repeatability, and inter-scanner reproducibility across three types of magnetic resonance imaging (MRI) scanners using intra-class correlation coefficients (ICC). Results: The three biomarkers demonstrated excellent inter-rater reliability (ICC >0.94, P-values < .001), very high agreement between test and retest sessions (ICC >0.98, P-values < .001), and were extremely consistent across the three scanners (ICC >0.98, P-values < .001). Discussion: The three biomarker kits demonstrated very high inter-rater reliability, test-retest repeatability, and inter-scanner reproducibility, offering robust biomarkers suitable for future multi-site observational studies and clinical trials in the context of vascular cognitive impairment and dementia (VCID).

Aldehyde Trapping by ADX-102 Is Protective against Cigarette Smoke and Alcohol Mediated Lung Cell Injury.

Most individuals diagnosed with alcohol use disorders smoke cigarettes. Large concentrations of malondialdehyde and acetaldehyde are found in lungs co-exposed to cigarette smoke and alcohol. Aldehydes directly injure lungs and form aldehyde protein adducts, impacting epithelial functions. Recently, 2-(3-Amino-6-chloroquinolin-2-yl)propan-2-ol (ADX-102) was developed as an aldehyde-trapping drug. We hypothesized that aldehyde-trapping compounds are protective against lung injury derived from cigarette smoke and alcohol co-exposure. To test this hypothesis, we pretreated mouse ciliated tracheal epithelial cells with 0-100 µM of ADX-102 followed by co-exposure to 5% cigarette smoke extract and 50 mM of ethanol. Pretreatment with ADX-102 dose-dependently protected against smoke and alcohol induced cilia-slowing, decreases in bronchial epithelial cell wound repair, decreases in epithelial monolayer resistance, and the formation of MAA adducts. ADX-102 concentrations up to 100 µM showed no cellular toxicity. As protein kinase C (PKC) activation is a known mechanism for slowing cilia and wound repair, we examined the effects of ADX-102 on smoke and alcohol induced PKC epsilon activity. ADX-102 prevented early (3 h) activation and late (24 h) autodownregulation of PKC epsilon in response to smoke and alcohol. These data suggest that reactive aldehydes generated from cigarette smoke and alcohol metabolism may be potential targets for therapeutic intervention to reduce lung injury.

IFN-γ Attenuates Eosinophilic Inflammation but Is Not Essential for Protection against RSV-Enhanced Asthmatic Comorbidity in Adult Mice.

The susceptibility to respiratory syncytial virus (RSV) infection in early life has been associated with a deficient T-helper cell type 1 (Th1) response. Conversely, healthy adults generally do not exhibit severe illness from RSV infection. In the current study, we investigated whether Th1 cytokine IFN-γ is essential for protection against RSV and RSV-associated comorbidities in adult mice. We found that, distinct from influenza virus, prior RSV infection does not induce significant IFN-γ production and susceptibility to secondary Streptococcus pneumoniae infection in adult wild-type (WT) mice. In ovalbumin (OVA)-induced asthmatic mice, RSV super-infection increases airway neutrophil recruitment and inflammatory lung damage but has no significant effect on OVA-induced eosinophilia. Compared with WT controls, RSV infection of asthmatic Ifng-/- mice results in increased airway eosinophil accumulation. However, a comparable increase in eosinophilia was detected in house dust mite (HDM)-induced asthmatic Ifng-/- mice in the absence of RSV infection. Furthermore, neither WT nor Ifng-/- mice exhibit apparent eosinophil infiltration during RSV infection alone. Together, these findings indicate that, despite its critical role in limiting eosinophilic inflammation during asthma, IFN-γ is not essential for protection against RSV-induced exacerbation of asthmatic inflammation in adult mice.

Proof of Concept Study of an Oral Orthotic in Reducing Tic Severity in Tourette Syndrome.

The use of an oral orthotic, called an occlusal splint, has gained recognition for the potential to reduce the frequency of tics for individuals with Persistent Tic Disorders. The purpose of this study was to assess the feasibility of a fully blinded, randomized controlled trial (RCT) to assess the safety, tolerability and initial efficacy of the oral orthotic in youth with chronic tics. Thirteen youth were randomly assigned to wear an active or sham orthotic in a two week double-blind RCT, with a 4-6 week unblinded follow up period. A statistically significant difference was found for change in tic severity between participants wearing the active and sham orthotic. However, this difference was not replicated during the follow up period. The oral orthotic is a promising intervention for the reduction of tics in youth with Tourette's Syndrome and is worthy of continued study to establish intervention efficacy and mechanism of action.