Keep them breathing: Cystic fibrosis pathophysiology, diagnosis, and treatment.

Cystic fibrosis (CF) affects more than 30,000 people in the United States and 80,000 people worldwide. This life-threatening genetic disorder causes a buildup of thick, viscous mucus secretions in various organ systems, most commonly the gastrointestinal, pulmonary, and genitourinary systems. This article reviews the clinical manifestations, diagnosis, and monitoring of patients with CF as well as guidelines for management and emerging pharmacologic treatments.

Cysteine oxidation impairs systemic glucocorticoid responsiveness in children with difficult-to-treat asthma.

BACKGROUND: The mechanisms underlying glucocorticoid responsiveness are largely unknown. Although redox regulation of the glucocorticoid receptor (GR) has been reported, it has not been studied in asthmatic patients. OBJECTIVE: We characterized systemic cysteine oxidation and its association with inflammatory and clinical features in healthy children and children with difficult-to-treat asthma. We hypothesized that cysteine oxidation would be associated with increased markers of oxidative stress and inflammation, increased features of asthma severity, decreased clinically defined glucocorticoid responsiveness, and impaired GR function. METHODS: PBMCs were collected from healthy children (n = 16) and children with asthma (n = 118) aged 6 to 17 years. Children with difficult-to-treat asthma underwent glucocorticoid responsiveness testing with intramuscular triamcinolone. Cysteine, cystine, and inflammatory chemokines and reactive oxygen species generation were quantified, and expression and activity of the GR were assessed. RESULTS: Cysteine oxidation was present in children with difficult-to-treat asthma and accompanied by increased reactive oxygen species generation and increased CCL3 and CXCL1 mRNA expression. Children with the greatest extent of cysteine oxidation had more features of asthma severity, including poorer symptom control, greater medication use, and less glucocorticoid responsiveness despite inhaled glucocorticoid therapy. Cysteine oxidation also modified the GR protein by decreasing available sulfhydryl groups and decreasing nuclear GR expression and activity. CONCLUSIONS: A highly oxidized cysteine redox state promotes a posttranslational modification of the GR that might inhibit its function. Given that cysteine oxidation is prevalent in children with difficult-to-treat asthma, the cysteine redox state might represent a potential therapeutic target for restoration of glucocorticoid responsiveness in this population.

Embracing Neuro-Inclusivity Within Physician Assistant/Associate Education: Challenging Organizational Cultural Norms and Navigating Communication Challenges.

ABSTRACT: Effective communication in health care education is essential for creating an inclusive learning environment. This manuscript examines the crucial role of communication in physician assistant/associate (PA) education, particularly in the context of neurodiverse individuals, who constitute approximately 20% of the global population. A groundbreaking study by Nouri et al reveals a 3.1% overall disability prevalence among US practicing physicians, emphasizing the necessity for a comprehensive understanding of diversity in the health care profession. Considering the intersectionality of marginalized identities, this research sheds light on potential challenges health care providers face, underscoring the importance of promoting inclusivity and support for neurodiverse individuals in the PA profession. The increasing presence of neurodivergent students in postsecondary institutions, despite academic strengths, holds relevance for PA education. Recognizing the barriers and stigmas associated with neurodiversity is crucial for fostering inclusive environments within PA programs and sponsoring institutions. This manuscript explores the challenges faced by neurodiverse individuals in PA education and proposes strategies for cultivating a neuroinclusive culture through effective communication. With a focus on celebrating and using the strengths of all learners, regardless of neurodiversity, the overarching goal is to contribute to a paradigm shift in PA education, enriching the educational experience for students, educators, and support staff.

Addressing the Elephant in the Room: Perceptions and Treatment of Underrepresented in Medicine Physician Assistants/Associate Educators.

ABSTRACT: On Thursday, June 27, 2023, the US Supreme Court struck down race-conscious admission practices in higher education. While other demographic factors, such as the traditional Health Resources and Services Administration-disadvantaged background indicators, can be considered during the holistic admission process, explicit consideration based on race and/or ethnicity is prohibited. As a result, physician assistant/associate (PA) programs are tasked with developing novel ways to address equity, diversity, and inclusion during the admission and hiring processes. As Drumgold et al note, closing the PA workforce diversity gap is necessary to achieve health equity. Despite this, PA programs consistently struggle to attract and retain underrepresented in medicine (URiM) faculty, staff, and students. The latest PA Education Association Student Report indicates that more than 75% of applicants consider faculty and student body diversity when applying to programs. As such, addressing disparities in the recruitment, promotion, evaluation, and retention of URiM faculty is paramount. Here, the authors outline ongoing recruitment and retention challenges for URiM faculty along with institutional recommendations to ensure URiM PA faculty success and engagement.

Airway TGF-ß1 and oxidant stress in children with severe asthma: association with airflow limitation.

BACKGROUND: TGF-ß1 is thought to play a role in airway remodeling in asthmatic subjects. TGF-ß1 expression might be mediated by an excessive burden of reactive oxygen species and oxidant stress. OBJECTIVE: Given the profound airway oxidant stress we have previously observed in children with severe asthma, we sought to (1) quantify TGF-ß1 protein and mRNA gene expression in the airways of children with mild-to-moderate and severe atopic asthma and (2) determine the relationship of airway TGF-ß1 concentrations to oxidant burden (ie, lipid peroxidation), T(H)2-mediated eosinophilic inflammation, and airflow limitation. METHODS: Bronchoalveolar lavage fluid was collected from 68 atopic children with asthma (severe asthma, n = 28) and 12 atopic adult control subjects. Airway TGF-ß1 expression and activation were assessed in relation to airway IL-13, 8-isoprostane, and malondialdehyde concentrations. The relationship of airway TGF-ß1 expression to airflow limitation in children with asthma was also assessed. RESULTS: Children with severe asthma had higher total airway concentrations of TGF-ß1 that were associated with increased protein and mRNA expression of TGF-ß1 in airway macrophages and an increase in concentrations of the lipid peroxidation biomarkers 8-isoprostanes and malondialdehyde. TGF-ß1 activation was also greater in children with severe asthma and was associated with higher airway 8-isoprostane, malondialdehyde, and IL-13 concentrations. Total airway TGF-ß1 concentrations were further associated with airflow limitation. CONCLUSIONS: Children with severe asthma have increased airway TGF-ß1 expression and activation associated with an increased airway oxidant burden. Oxidant stress might mediate the effects of TGF-ß1 and promote airway remodeling in children with severe asthma.

Ethanol (EtOH)-induced TGF-ß1 and reactive oxygen species production are necessary for EtOH-induced alveolar macrophage dysfunction and induction of alternative activation.

BACKGROUND: Previous studies have shown that chronic ethanol (EtOH) ingestion results in impaired alveolar macrophage function, increased TGF-ß(1) production, and decreased antioxidant availability. Similarly, alternative activation (M2 activation) of alveolar macrophages also induces TGF-ß(1) production and impairs macrophage function. However, the potential links between EtOH-induced alveolar macrophage derangements, M2 activation, TGF-ß(1) production signaling, and oxidant stress have yet to be examined. We hypothesized that EtOH-induced oxidant stress and induction of TGF-ß(1) signaling result in alternative activation which subsequently impairs the phagocytic capacity of alveolar macrophages. METHODS: Primary rat alveolar macrophages and the alveolar macrophages cell line NR8383 were treated with 0.08% EtOH ± the antioxidant glutathione (GSH) or a TGF-ß(1) neutralizing antibody for 5 days. Outcome measures included TGF-ß(1) production, reactive oxygen species (ROS) production, phagocytic capacity, and expression of markers of M2 activation. RESULTS: Chronic EtOH treatment greatly decreased alveolar macrophage phagocytic function, increased ROS production, increased TGF-ß(1) , and increased expression of markers of M2 activation. GSH supplementation and inhibition of TGF-ß(1) signaling during EtOH treatment prevented these alterations. CONCLUSIONS: EtOH treatment increased oxidant stress, TGF-ß(1) production, and alternative activation in NR8383 cells. However, GSH supplementation and ablation of TGF-ß(1) signaling prevented these effects. This suggested that the EtOH-induced switch to an M2 phenotype was a result of decreased antioxidant availability and increased TGF-ß(1) signaling. Preventing EtOH-induced induction of alternative activation may improve alveolar macrophage function in alcoholic subjects and decrease the risk of respiratory infections.

Utilizing Supplemental Online Modules for Physician Assistant Student Electrocardiogram Interpretation Training.

PURPOSE: The literature suggests that graduating medical and physician assistant (PA) students lack competency in electrocardiogram (ECG) interpretation. This project aimed to determine whether use of perceptual adaptive learning modules (PALMs) would improve PA students' ECG interpretation, alter self-perceptions of their ECG education, or both. METHODS: PALMs were incorporated into the PA curriculum after lecture-based ECG learning. Students' pretest, posttest, and delayed-posttest scores were then compared. Students' ability to correctly interpret ECGs (accuracy) and the percentage of ECGs accurately interpreted within 15 seconds or less (fluency) also were evaluated. Finally, students' perceptions of PALMs and overall ECG training were assessed. RESULTS: PALM training improved ECG interpretation accuracy and fluency (p < .0001), as well as delayed-posttest accuracy and fluency (p < .0001). The majority of student respondents felt supplemental training enhanced their learning. CONCLUSION: These perception results combined with data on ECG interpretation improvement supports continued use of supplemental PALMs in ECG interpretation training.

Determining the Best Time to Integrate Opioid Use Disorder Training into the Curriculum Based on Student Perceptions.

PURPOSE: The clinical phase of physician assistant (PA) education has been reported to be the best time period to deliver opioid prescribing education (OPE) and opioid addiction education (OAE); however, there are no current published studies that evaluate the timing of OPE and OAE instruction in PA curricula. METHODS: This pilot study compared didactic and clinical phase cohorts' perceived confidence in their ability to evaluate patients with opioid use disorder (OUD) after receiving identical training at different time points within the curriculum. RESULTS: As expected, clinical phase students displayed high confidence levels in their abilities both before and after implementation of OUD-focused patient simulations. Interestingly, didactic phase students' confidence levels were comparable to clinical phase students' confidence levels after participating in the patient simulations. CONCLUSIONS: Our findings suggest that students can benefit from this training in both phases of the curriculum, which may encourage and help PA programs to insert this important and timely information into their curriculum.

The effect of age on a visual learning task in the American cockroach.

Neuronal modifications that accompany normal aging occur in brain neuropils and might share commonalities across phyla including the most successful group, the Insecta. This study addresses the kinds of neuronal modifications associated with loss of memory that occur in the hemimetabolous insect Periplaneta americana. Among insects that display considerable longevity, the American cockroach lives up to 64 wk and reveals specific cellular alterations in its mushroom bodies, higher centers that have been shown to be associated with learning and memory. The present results describe a vision-based learning paradigm, based on a modified Barnes maze, that compares memory in young (10-wk old), middle-aged (30-wk old), and aged adults (50-wk old). We show that not only is the performance of this task during the 14 training trials significantly decremented in aged cockroaches, but that aged cockroaches show significant impairment in successfully completing a crucial test involving cue rotation. Light and electron microscopical examination of the brains of these different age groups reveal major changes in neuron morphology and synaptology in the mushroom body lobes, centers shown to underlie place memory in this taxon.

Impaired terminal differentiation of pulmonary macrophages in a Guinea pig model of chronic ethanol ingestion.

BACKGROUND: Alcoholic patients have an increased risk of respiratory infections, which is partially due to an impaired immune response of alveolar macrophages. The mechanisms by which alcohol impairs alveolar macrophage function are poorly understood. In this study, we demonstrated in a guinea pig model that chronic ethanol ingestion significantly impaired alveolar macrophage differentiation and function. METHODS: Isolated alveolar macrophages were separated into 4 different subpopulations with varying densities and levels of maturation. RESULTS: Compared to control values, chronic ethanol ingestion decreased the percentage of alveolar macrophages in the mature fractions by approximately 60%. Alveolar macrophage function in each subpopulation was determined by measuring phagocytosis of fluorescein isothiocyanate-labeled Staphylococcus aureus. Alveolar macrophages from ethanol-fed animals had approximately 80% decrease in the phagocytic index. Western blot and immunohistochemical analysis of the differential markers granulocyte/macrophage colony-stimulating factor (GM-CSF) receptor alpha (GM-CSFR-alpha), PU.1, CD11c, and CD11b verified that alcoholic macrophages displayed impaired terminal differentiation. While oral supplementation with the glutathione precursor S-adenosyl-methionine (SAM) did not alter the maturational status of control animals, SAM supplementation shifted the distribution of macrophages to more mature fractions, normalized the phagocytic index; as well as normalized expression of CD11c, CD11b, PU.1, and GM-CSFR-alpha. Chronic ethanol ingestion also impaired the differentiation status of interstitial macrophages which was normalized by SAM supplementation. CONCLUSION: This improvement in the maturational status suggested that ethanol-induced oxidant stress is a central feature in impaired terminal differentiation of macrophages in the interstitial and alveolar space. Therefore, strategies targeting pulmonary oxidant stress may restore macrophage differentiation and function even after chronic ethanol ingestion.

Persistent disruption of an established morphine conditioned place preference.

In human addicts, craving and relapse are frequently evoked by the recall of memories connected to a drug experience. Established memories can become labile if recalled and can then be disrupted by several interfering events and pharmacological treatments, including inhibition of protein synthesis. Thus, reactivation of mnemonic traces provides an opportunity for disrupting memories that contribute to pathological states. Here, we tested whether the memory of a drug experience can be weakened by inhibiting protein synthesis after the reactivation of its trace. We found that an established morphine conditioned place preference (mCPP) was persistently disrupted if protein synthesis was blocked by either anisomycin or cycloheximide after the representation of a conditioning session. Unlike other types of memories, an established mCPP did not become labile after contextual recall, but required the concomitant re-experience of both the conditioning context and the drug. An established mCPP was disrupted after the conditioning session if protein synthesis was blocked selectively in the hippocampus, basolateral amygdala, or nucleus accumbens but not in the ventral tegmental area. This disruption seems to be permanent, because the preference did not return after further conditioning. Thus, established memories induced by a drug of abuse can be persistently disrupted after reactivation of the conditioning experience.

Development-dependent and -independent ubiquitin expression in divisions of the cockroach mushroom body.

It has been proposed that the alpha and beta divisions of the mushroom bodies support intermediate and long-term memory whereas the gamma lobes support short-term memory. Here we investigate developmentally dependent versus developmentally independent alterations of mushroom body structure with special emphasis on its lobes. We show that in the cockroach mushroom bodies there are two types of plastic remodeling. One is developmental, in which episodic addition of new circuitry to the alpha and beta lobes is accomplished by newly born Kenyon cells. The second is revealed as a persistent alteration of structure within the gamma lobe. In the alpha/beta lobes, newly generated Kenyon cell axons extend glutamate-immunoreactive collaterals across layers of the axons of mature Kenyon cells. At specific times in each developmental episode (instar) these collaterals express ubiquitin, undergo localized degeneration, and are scavenged by glial cells. In contrast, the mature Kenyon cells that comprise the gamma lobe express detectable ubiquitin throughout each developmental episode. This pattern of ubiquitin expression suggests that the gamma lobe circuitry undergoes continuous modification independent of development.

Stereological analysis reveals striking differences in the structural plasticity of two readily identifiable glomeruli in the antennal lobes of the adult worker honeybee.

The primary antennal sensory centers (antennal lobes) in the brain of the honeybee are highly compartmentalized into discrete spheres of synaptic neuropil called glomeruli, many of which can be identified according to their predictable size and location. Glomeruli undergo significant changes in volume during the lifetime of the adult worker bee, at least some of which are activity dependent. This study tests the commonly expressed assumption that increases in neuropil volume are accompanied by an underlying increase in the number of synapses present in the tissue. A combination of light and electron microscopy was used to determine total synapse number within two glomeruli, T1-44 and T4-2(1). The Cavalieri direct estimator of volume was applied to 1.5 microm sections of resin-embedded brains. Selected sections were then re-embedded and prepared for transmission electron microscopy. Synapse densities were determined using the physical disector method on electron micrographs. Synapse density and glomerulus volume were combined to give an unbiased estimate of the total number of synapses. In glomerulus T1-44, a significant increase in volume was accompanied by a significant increase in the total number of synapses. In contrast, synapse counts in T4-2(1) remained unchanged, despite a significant increase in the volume of this glomerulus. These results demonstrate that synapse proliferation in antennal lobes of the adult worker bee is highly site specific. Although volumetric changes and changes in synapse number both contribute to the structural plasticity of the antennal lobes, these two components of plasticity appear to be independent processes.

Poor asthma control in obese children may be overestimated because of enhanced perception of dyspnea.

BACKGROUND: Although studies in adults have shown a non-TH2 obese asthma phenotype, whether a similar phenotype exists in children is unclear. OBJECTIVE: We hypothesized that asthmatic children with obesity, defined as a body mass index above the 95th percentile for age and sex, would have poorer asthma control as well as decreased quality of life, increased health care utilization, and decreased pulmonary function measures as a function of increased TH1 versus TH2 polarization. METHODS: This study involved a post hoc analysis of cross sectional data from 269 children 6 to 17 years of age enrolled in the National Heart, Lung, and Blood Institute Severe Asthma Research Program. Children answered questionnaires and underwent spirometry, plethysmography, exhaled nitric oxide determination, and venipuncture for TH1/TH2 cytokine determination. Asthma control was defined according to national asthma treatment guidelines that are based on prespecified thresholds for lung function and symptom frequency. RESULTS: Fifty-eight children (22%) were overweight and 67(25%) were obese. Obese children did not have poorer asthma control but were more likely to report nonspecific symptoms such as dyspnea and nocturnal awakenings. Obese children did have decreased asthma-related quality of life and increased health care utilization, but this was not associated with airflow limitation. Instead, obese children had decreased functional residual capacity. A unique pattern of TH1 or TH2 polarization was not observed. CONCLUSIONS: Poor asthma control in obese children with asthma may be overestimated because of enhanced perception of nonspecific symptoms such as dyspnea that results from altered mechanical properties of the chest wall. Careful assessment of physiologic as well as symptom-based measures is needed in the evaluation of obese children with respiratory symptoms.

Fine structural organization of the hemiellipsoid body of the land hermit crab, Coenobita clypeatus.

Electron microscopical observations of the hemiellipsoid bodies of the land hermit crab Coenobita clypeatus resolve microglomerular synaptic complexes that are comparable to those observed in the calyces of insect mushroom bodies and which characterize olfactory inputs onto intrinsic neurons. In an adult hermit crab, intrinsic neurons and one class of efferent neurons originate from neuronal somata of globuli cells covering the hemiellipsoid bodies. Counts of their nucleoli show that about 120,000 globuli cells supply each hemiellipsoid body in an adult hermit crab. This number is comparable to the number of globuli cells supplying mushroom bodies of certain insects, such as honey bees and cockroaches. Counts of axons in tracts leading from the olfactory lobes to the hemiellipsoid bodies resolve 20,000 afferent axons, however, an order of magnitude greater than known for any insect. These afferent axons provide numerous swollen varicosities, each presynaptic to many small profiles, and thus comparable to the microglomeruli that characterize insect mushroom body calyces. Also, common to mushroom bodies and hemiellipsoid bodies are arrangements of intrinsic neurons, afferent neurons containing dense core vesicles, and systems of serial synaptic complexes that relate to postsynaptic profiles of efferent neurons. Together, the ultrastructural organization of the hemiellipsoid bodies of C. clypeatus supports the proposition that this center may share a common origin with the insect mushroom body despite obvious divergent evolution of overall shape.

The minute brain of the copepod Tigriopus californicus supports a complex ancestral ground pattern of the tetraconate cerebral nervous systems.

Copepods are a diverse and ecologically crucial group of minute crustaceans that are relatively neglected in terms of studies on nervous system organization. Recently, morphological neural characters have helped clarify evolutionary relationships within Arthropoda, particularly among Tetraconata (i.e., crustaceans and hexapods), and indicate that copepods occupy an important phylogenetic position relating to both Malacostraca and Hexapoda. This taxon therefore provides the opportunity to evaluate those neural characters common to these two clades likely to be results of shared ancestry (homology) versus convergence (homoplasy). Here we present an anatomical characterization of the brain and central nervous system of the well-studied harpacticoid copepod species Tigriopus californicus. We show that this species is endowed with a complex brain possessing a central complex comprising a protocerebral bridge and central body. Deutocerebral glomeruli are supplied by the antennular nerves, and a lateral protocerebral olfactory neuropil corresponds to the malacostracan hemiellipsoid body. Glomeruli contain synaptic specializations comparable to the presynaptic "T-bars" typical of dipterous insects, including Drosophila melanogaster. Serotonin-like immunoreactivity pervades the brain and ventral nervous system, with distinctive deutocerebral distributions. The present observations suggest that a suite of morphological characters typifying the Tigriopus brain reflect a ground pattern organization of an ancestral Tetraconata, which possessed an elaborate and structurally differentiated nervous system.

Vitamin D and asthma.

Asthma, one of the most prevalent diseases affecting people worldwide, is a chronic respiratory disease characterized by heightened airway inflammation, airway hyperresponsiveness and airflow obstruction in response to specific triggers. While the specific mechanisms responsible for asthma are not well understood, changing environmental factors associated with urban lifestyles may underlie the increased prevalence of the disorder. Vitamin D is of particular interest in asthma since vitamin D concentrations decrease with increased time spent indoors, decreased exposure to sunlight, less exercise, obesity, and inadequate calcium intake. Additionally, a growing body of literature suggests that there is a relationship between vitamin D status and respiratory symptoms, presumably through immunomodulatory effects of vitamin D. This review discusses vitamin D as it relates to asthma across the age spectrum, with a focus on human studies.