Mind-body connection: metabolite 4-ethylphenyl linked to anxiety behavior and oligodendrocyte modification in autism spectrum disorder.

The connection between byproducts of digestion in the gastrointestinal (GI) tract and neurocognitive disorders is an expanding area of research that has implications for autism spectrum disorder (ASD). Needham et al. (Needham et al. Nature 602: 647-653, 2022) revealed that mice with elevated levels of 4-ethylphenyl sulfate (4EPS), a GI tract-derived metabolite previously found at increased levels in the plasma of individuals with ASD, had altered brain activity, anxiety-influenced behavior, and reduced myelination of neuronal axons. This is a monumental step forward in the study of gut-derived neuroactive compounds, like 4EPS, and advances the understanding of their role in modulating behavior and brain activity in neurocognitive disorders.

Lung fibrosis is induced in ADAR2 overexpressing mice via HuR-induced CTGF signaling.

Adenosine deaminase acting on RNA 2 (ADAR2), an RNA editing enzyme is involved in a site-selective modification of adenosine (A) to inosine (I) in double-stranded RNA (dsRNA). Its role in the lungs is unknown. The phenotypic characterization of Adarb1 mice that lacked ADAR2 auto-regulation due to the deletion of editing complementary sequence (ΔECS mice) determined the functional role of ADAR2 in the lungs. ADAR2 protein expression increased in the ΔECS mice. These mice display immune cell infiltration and alveolar disorganization. The lung wet by dry ratio indicates there is no lung edema in ΔECS mice. Bronchoalveolar lavage (BAL) analysis of ΔECS mice reveals a significant increase in neutrophils. Interestingly, ΔECS mice spontaneously develop lung fibrosis as indicated by Sirius red staining of collagen fibers in the lung sections and a significant increase in hydroxyproline level in their lungs. ADAR2 expression increased significantly in a bleomycin mouse model, implicating a role of ADAR2 in lung fibrosis. Furthermore, there is a likely possibility that the genetically modified ΔECS mice does not model the physiological or pathophysiological process of lung fibrosis. Nevertheless, this model is useful in interrogating the role of ADAR2 in the lungs. The Ctgf mRNA and connective tissue growth factor (CTGF) protein significantly increased in ΔECS lungs and occurs in bronchial epithelial cells. There is a significant increase in Human antigen R (ELAVL1; HuR) protein levels in ΔECS lungs and suggests a role in stabilizing Ctgf mRNA. Lung mechanics such as total respiratory resistance, Newtonian resistance and tissue damping were increased, whereas inspiratory capacity was decreased in the ΔECS mice. Taken together, these data indicate that overexpression of ADAR2 causes spontaneous lung fibrosis via HuR-mediated CTGF signaling and implicate a role for ADAR2 auto-regulation in lung homeostasis. The identification of ADAR2 target genes in ΔECS mice would facilitate a mechanistic understanding of the role of ADAR2 in the lungs and provide a therapeutic strategy for lung fibrosis.

Pharmacokinetic and pharmacodynamic comparison of epinephrine, administered intranasally and intramuscularly: An integrated analysis.

BACKGROUND: Manual intramuscular epinephrine injection is the standard of care for treating severe allergic reactions and anaphylaxis. Epinephrine autoinjectors were approved on the basis of the assumption that their pharmacokinetic and pharmacodynamic profiles are equivalent to manual intramuscular injection; however, although there is emerging evidence for product-related differences in pharmacokinetic profiles, very little is known about the comparative pharmacodynamic profiles. OBJECTIVE: To compare pharmacokinetic and pharmacodynamic profiles of epinephrine delivered through manual intramuscular injection, autoinjectors, and intranasal spray. METHODS: This integrated analysis was based on data from 4 randomized cross-over phase 1 trials that compared the pharmacokinetics and pharmacodynamics of epinephrine using manual intramuscular epinephrine 0.3 mg injection, epinephrine 0.3 mg autoinjectors (Symjepi and EpiPen), and epinephrine 1 mg intranasal spray (neffy). RESULTS: Data from 175 participants showed that although neffy (1.0 mg intranasal spray) resulted in a maximum concentration (258 pg/mL) that was lower than or comparable with manual epinephrine intramuscular injection (254 pg/mL), Symjepi (438 pg/mL) and EpiPen (503 pg/mL), it led to comparable increases in systolic blood pressure (maximum effect [Emax], 16.9, 10.9, 14.9, and 18.1 mm Hg, respectively). The effect of neffy on diastolic blood pressure was also markedly more pronounced than that of other products (Emax, 9.32, 5.51, 5.78, and 5.93 mm Hg, respectively). CONCLUSION: Intranasal delivery of epinephrine using neffy increases systolic blood pressure more efficiently than do manual intramuscular injection and epinephrine autoinjectors, despite lower maximum plasma concentrations.

Airway smooth muscle pathophysiology in asthma.

The airway smooth muscle (ASM) cell plays a central role in the pathogenesis of asthma and constitutes an important target for treatment. These cells control muscle tone and thus regulate the opening of the airway lumen and air passage. Evidence indicates that ASM cells participate in the airway hyperresponsiveness as well as the inflammatory and remodeling processes observed in asthmatic subjects. Therapeutic approaches require a comprehensive understanding of the structure and function of the ASM in both the normal and disease states. This review updates current knowledge about ASM and its effects on airway narrowing, remodeling, and inflammation in asthma.

Soluble ACE2 as a potential therapy for COVID-19.

Soluble angiotensin-converting enzyme 2 (sACE2) could be a therapeutic option to treat coronavirus disease 2019 (COVID-19) infection. Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) utilizes ACE2 receptors on cell surfaces to gain intracellular entry, making them an ideal target for therapy. High-affinity variants of sACE2, engineered using high-throughput mutagenesis, are capable of neutralizing COVID-19 infection as decoy receptors. These variants compete with native ACE2 present on cells by binding with spike (S) protein of SARS-CoV-2, making native ACE2 on cell surfaces available to convert angiotensin II to angiotensin-1,7, thus alleviating the exaggerated inflammatory response associated with COVID-19 infection. This article explores the use of sACE2 as potential therapy for COVID-19 infection.

A 48-year-old female with perioperative anaphylaxis.

Identifying the culprit medication in cases of perioperative anaphylaxis can be extremely challenging. A detailed and accurate history, coupled with the appropriate testing, plays a key role in discovering the etiology of perioperative anaphylaxis. We present the case of a 48-year-old woman with a cranial meningioma who was scheduled for surgery. Chlorhexidine, midazolam, lidocaine, propofol, fentanyl, rocuronium, and furosemide were administered during the perioperative period. She developed hypotension, urticaria, bronchospasm, and other symptoms of anaphylaxis soon after general anesthesia. The serum tryptase level obtained during anaphylaxis was 119 ng/mL (normal, <11.4 ng/mL). Epinephrine was administered, and the surgery was canceled, with no cause identified. For the next surgical attempt, she was pretreated with diphenhydramine and ranitidine, and the neuromuscular blocker was withheld. Again, she developed hypotension consistent with anaphylaxis, and epinephrine was administered. She was referred for consultation. A detailed and accurate history was obtained. The baseline serum tryptase level was 6.4 ng/mL. Skin-prick puncture tests were completed, and a diagnosis was made. The surgical team was instructed to avoid the culprit medication, and the cranial surgery was successful. Although difficult, cases of perioperative anaphylaxis can be solved with a detailed history, keen detective work, and appropriate testing.

Altered expression of p63 isoforms and expansion of p63- and club cell secretory protein-positive epithelial cells in the lung as novel features of aging.

Aging is a key contributor for subclinical progression of late-onset lung diseases. Basal, club, and type II alveolar epithelial cells (AECs) are lung epithelial progenitors whose capacities of differentiation are extensively studied. The timely transition of these cells in response to environmental changes helps maintain the intricate organization of lung structure. However, it remains unclear how aging affects their behavior. This paper demonstrates that the protein expression profiles of a type II AEC marker, prosurfactant protein C (pro-SPC), and a basal cell marker, p63, are altered in the lungs of 14-mo-old versus 7- to 9-wk-old mice. Expression of NH2-terminal-truncated forms of p63 (ΔNp63), a basal cell marker, and claudin-10, a club cell marker, in cytoplasmic extracts of lungs of 14-mo-old mice was upregulated. In contrast, nuclear expression of full-length forms of p63 (TAp63) decreases with age. These alterations in protein expression profiles coincide with dramatic changes in lung functions including compliance. Whole tissue lysates of middle-aged versus aged rhesus monkey lungs display similar age-associated alterations in pro-SPC expression. An age-associated decrease of TAp63 in nuclear lysates was observed in aged monkey group. Moreover, the lungs of 14-mo-old versus 7- to 9-wk-old mice display a wider spreading of ΔNp63-positive CCSP-positive bronchiolar epithelial cells. This expansion did not involve upregulation of Ki67, a representative proliferation marker. Collectively, it is postulated that 1) this expansion is secondary to a transition of progenitor cells committed to club cells from ΔNp63-negative to ΔNp63-positive status, and 2) high levels of cytoplasmic ΔNp63 expression trigger club cell migration.

Effect of grass sublingual tablet immunotherapy is similar in children and adults: A Bayesian approach to design pediatric sublingual immunotherapy trials.

BACKGROUND: Large sample sizes are needed for sublingual immunotherapy (SLIT) trials because of inherent data variability secondary to inconsistent allergen exposure. Obtaining large sample sizes for pediatric SLIT trials is challenging, but a Bayesian approach using prior adult data can reduce the necessary sample size. OBJECTIVE: We sought to describe how a Bayesian framework using prior information from adult trials can be used to improve pediatric SLIT clinical development. METHODS: Data were compiled by using a frequentist approach (conventional clinical trial approach independent of prior data) from trials conducted during the clinical development of timothy grass SLIT-tablets. RESULTS: The treatment effect of timothy grass SLIT-tablets was considered similar between pediatric (n = 795) and adult (n = 2299) data pools, with relative total combined symptom plus medication score improvement versus placebo of 21% (95% CI, 11.0% to 30.4%) and 20% (95% CI, 14.6% to 24.4%), respectively. Phleum pratense-specific IgG4 and IgE-blocking factor increased from baseline in both children and adults treated with timothy grass SLIT-tablets. Given the reasonable assumption in similarity of treatment response between adults and children, a Bayesian approach is described to demonstrate rigorous efficacy criteria for pediatric trials incorporating information from prior adult trials and thereby reduce the sample size. CONCLUSIONS: Data support the similarity of efficacy and immunologic changes between children and adults treated with SLIT for allergic rhinoconjunctivitis. Therefore it is appropriate to use data from adult trials to design feasible trials in children, which might reduce unsafe off-label use by promoting more quickly proper labeling of approved products.

Epigenetics of Mucus Hypersecretion in Chronic Respiratory Diseases.

Asthma, chronic obstructive pulmonary disease, and cystic fibrosis are three chronic pulmonary diseases that affect an estimated 420 million individuals across the globe. A key factor contributing to each of these conditions is mucus hypersecretion. Although management of these diseases is vastly studied, researchers have only begun to scratch the surface of the mechanisms contributing to mucus hypersecretion. Epigenetic regulation of mucus hypersecretion, other than microRNA post-translational modification, is even more scarcely researched. Detailed study of epigenetic mechanisms, such as DNA methylation and histone modification, could not only help to better the understanding of these respiratory conditions but also reveal new treatments for them. Because mucus hypersecretion is such a complex event, there are innumerable genes involved in the process, which are beyond the scope of a single review. Therefore, the purpose of this review is to narrow the focus and summarize specific epigenetic research that has been conducted on a few aspects of mucus hypersecretion in asthma, chronic obstructive pulmonary disease, cystic fibrosis, and some cancers. Specifically, this review emphasizes the contribution of DNA methylation and histone modification of particular genes involved in mucus hypersecretion to identify possible targets for the development of future therapies for these conditions. Elucidating the role of epigenetics in these respiratory diseases may provide a breath of fresh air to millions of affected individuals around the world.

A mitochondrial delicacy: dynamin-related protein 1 and mitochondrial dynamics.

The constant physiological flux of mitochondrial fission and fusion is inextricably tied to the maintenance of cellular bioenergetics and the fluidity of mitochondrial networks. Yet, the intricacies of this dynamic duo remain unclear in diseases that encompass mitochondrial dysregulation. Particularly, the role of the GTPase fission protein dynamin-related protein 1 (Drp1) is of profound interest. Studies have identified that Drp1 participates in complex signaling pathways, suggesting that the function of mitochondria in pathophysiology may extend far beyond energetics alone. Research indicates that, in stressed conditions, Drp1 translocation to the mitochondria leads to elevated fragmentation and mitophagy; however, despite this, there is limited knowledge about the mechanistic regulation of Drp1 in disease conditions. This review highlights literature about fission, fusion, and, more importantly, discusses Drp1 in cardiac, neural, carcinogenic, renal, and pulmonary diseases. The therapeutic desirability for further research into its contribution to diseases that involve mitochondrial dysregulation is also discussed.

Thyroid hormone: a resurgent treatment for an emergent concern.

The story of thyroid hormone in human physiology is one of mixed emotions. Studying past literature on its use leads one to believe that it serves only a few functions in a handful of diseases. In reality, the pathophysiological role of thyroid hormone is an uncharted expanse. Over the past few decades, research on thyroid hormone has been understandably monopolized by studies of hypo- and hyperthyroidism and cancers. However, in our focused pursuit, we have neglected to observe its role in systems that are not so easily relatable. Recent evidence in lung disease suggests that the thyroid hormone is capable of preserving mitochondria in an indirect manner. This is an exciting revelation given the profound implications of mitochondrial dysfunction in several lung diseases. When paired with known links between thyroid hormone and fibrotic pathways, thyroid hormone-based therapies become more enticing for research. In this article, we inspect the sudden awareness surrounding thyroid hormone and discuss why it is of paramount importance that further studies scrutinize the potential of thyroid hormone, and/or thyromimetics, as therapies for lung diseases.

Akap1 genetic deletion increases the severity of hyperoxia-induced acute lung injury in mice.

Critically ill patients are commonly treated with high levels of oxygen, hyperoxia, for prolonged periods of time. Unfortunately, extended exposure to hyperoxia can exacerbate respiratory failure and lead to a high mortality rate. Mitochondrial A-kinase anchoring protein (Akap) has been shown to regulate mitochondrial function. It has been reported that, under hypoxic conditions, Akap121 undergoes proteolytic degradation and promotes cardiac injury. However, the role of Akap1 in hyperoxia-induced acute lung injury (ALI) is largely unknown. To address this gap in our understanding of Akap1, we exposed wild-type ( wt) and Akap1-/- mice to 100% oxygen for 48 h, a time point associated with lung damage in the murine model of ALI. We found that under hyperoxia, Akap1-/- mice display increased levels of proinflammatory cytokines, immune cell infiltration, and protein leakage in lungs, as well as increased alveolar capillary permeability compared with wt controls. Further analysis revealed that Akap1 deletion enhances lung NF-κB p65 activity as assessed by immunoblotting and DNA-binding assay and mitochondrial autophagy-related markers, PINK1 and Parkin. Ultrastructural analysis using electron microscopy revealed that Akap1 deletion was associated with remarkably aberrant mitochondria and lamellar bodies in type II alveolar epithelial cells. Taken together, these results demonstrate that Akap1 genetic deletion increases the severity of hyperoxia-induced acute lung injury in mice.

Recombinant human C1 esterase inhibitor for prophylaxis of hereditary angio-oedema: a phase 2, multicentre, randomised, double-blind, placebo-controlled crossover trial.

BACKGROUND: Hereditary angio-oedema is a recurrent, oedematous disorder caused by deficiency of functional C1 inhibitor. Infusions of plasma-derived C1 esterase inhibitor deter attacks of hereditary angio-oedema, but the prophylactic effect of recombinant human C1 esterase inhibitor has not been rigorously studied. We aimed to assess the efficacy of recombinant human C1 esterase inhibitor for prophylaxis of hereditary angio-oedema. METHODS: We conducted this phase 2, multicentre, randomised, double-blind, placebo-controlled crossover trial at ten centres in Canada, the Czech Republic, Israel, Italy, Macedonia, Romania, Serbia, and the USA. We enrolled patients aged 13 years or older with functional C1-inhibitor concentrations of less than 50% of normal and a history of four or more attacks of hereditary angio-oedema per month for at least 3 months before study initiation. Patients were randomly assigned centrally (1:1:1:1:1:1), via an interactive response technology system with fixed allocation, to receive one of six treatment sequences. During each sequence, patients received intravenous recombinant human C1 esterase inhibitor (50 IU/kg; maximum 4200 IU) twice weekly, recombinant human C1 esterase inhibitor once weekly and placebo once weekly, and placebo twice weekly, each for 4 weeks with a 1 week washout period between crossover. All patients, investigators, and study personnel who participated in patient care were masked to group allocation during the study. The primary efficacy endpoint was the number of attacks of hereditary angio-oedema observed in each 4 week treatment period. Attack symptoms were recorded daily. The primary efficacy analysis was done in the intention-to-treat population. Safety was assessed in all patients who received at least one injection of study medication. This study is registered with ClinicalTrials.gov, number NCT02247739. FINDINGS: Between Dec 29, 2014, and May 3, 2016, we enrolled 35 patients, of whom 32 (91%) underwent randomisation (intention-to-treat population) and 26 (81%) completed the study. The mean number of attacks of hereditary angio-oedema over 4 weeks was significantly reduced with recombinant human C1 esterase inhibitor twice weekly (2·7 attacks [SD 2·4]) and once weekly (4·4 attacks [3·2]) versus placebo (7·2 attacks [3·6]), with mean differences of -4·4 attacks (p<0·0001) and -2·8 attacks (p=0·0004), respectively. We recorded adverse events in ten (34%) of 29 patients given twice-weekly recombinant human C1 esterase inhibitor, 13 (45%) of 29 patients given the once-weekly regimen, and eight (29%) of 28 patients given placebo. Headache (twice-weekly treatment) and nasopharyngitis (once-weekly treatment) were the most common adverse events. Two (7%) adverse events (fatigue and headache) were deemed possibly related to treatment with recombinant human C1 esterase inhibitor, but both resolved without additional treatment. No thrombotic or thromboembolic events, systemic allergic reactions (including anaphylaxis), or neutralising antibodies were reported. INTERPRETATION: Prophylaxis with recombinant human C1 esterase inhibitor provided clinically relevant reductions in frequency of hereditary angio-oedema attacks and was well tolerated. In view of the pharmacokinetic profile of recombinant human C1 esterase inhibitor, our results suggest that efficacy of C1-inhibitor replacement therapy might not be a direct function of plasma trough concentrations of C1 inhibitor. FUNDING: Pharming Technologies.

Acute asthma, prognosis, and treatment.

Asthma affects about 300 million people globally and accounts for 1 in every 250 deaths in the world. Approximately 12 million people in the United States each year experience an acute exacerbation of their asthma, a quarter of which require hospitalization. Acute asthma should be differentiated from poor asthma control. Patients with acute asthma will exhibit increasing shortness of breath, chest tightness, coughing, and/or wheezing. In contrast, poor asthma control typically presents with a diurnal variability in airflow and is a characteristic that is usually not seen during an acute exacerbation. The history should include a review of comorbidities, adherence to medications, previous episodes of near-fatal asthma, and whether the patient has experienced multiple emergency department visits or hospitalizations, particularly those requiring admission to an intensive care unit involving respiratory failure, intubation, and mechanical ventilation. Patient education is important to ensure that the patient understands that asthma is mostly a chronic disease and necessitates the avoidance of allergens, prevention of infections, adherence with routine vaccinations, management of comorbid conditions, and adherence to treatment regimens. This article is a structured review of the available literature regarding the diagnosis and management of acute asthma.

Pollen used to produce allergen extracts.

OBJECTIVE: To review the use of pollen for the production of allergen extracts to diagnose and treat allergic diseases, examine the associated regulations, and highlight candidate areas for improvement. DATA SOURCES: A PubMed search was performed using focused keywords combined with a review of regulatory documents and industry guidelines. STUDY SELECTIONS: The information obtained through literature, documents, and industry was scrutinized and used with personal experience and expertise to write this article. RESULTS: Both genetic and environmental factors affect the allergenic composition of pollen because it is a biologically active pharmaceutical ingredient obtained from nature. The potential effect of airborne contaminants in pollen requires major attention but can be properly addressed through careful collection practices, combined with a proper interpretation of the data on purity obtained for each pollen lot. The regulations associated with pollen used to manufacture allergen extracts in the United States and Europe and the numbers of pollen allergen extracts commercially available in both areas of the world differ. A critical parameter to select the appropriate extracts for diagnosis and allergen immunotherapy is to understand the phenomenon of cross-reactivity among pollen families, genera, and species. CONCLUSION: Physicians should be aware of the factors responsible for the qualitative and quantitative composition of pollen allergen extracts and the associated regulations to produce suitable extracts to diagnose and treat allergic diseases. Collaboration and cooperation among allergen manufacturing companies and regulatory agencies are necessary.

Deletion of P2X7 attenuates hyperoxia-induced acute lung injury via inflammasome suppression.

Increasing evidence shows that hyperoxia is a serious complication of oxygen therapy in acutely ill patients that causes excessive production of free radicals leading to hyperoxia-induced acute lung injury (HALI). Our previous studies have shown that P2X7 receptor activation is required for inflammasome activation during HALI. However, the role of P2X7 in HALI is unclear. The main aim of this study was to determine the effect of P2X7 receptor gene deletion on HALI. Wild-type (WT) and P2X7 knockout (P2X7 KO) mice were exposed to 100% O2 for 72 h. P2X7 KO mice treated with hyperoxia had enhanced survival in 100% O2 compared with the WT mice. Hyperoxia-induced recruitment of inflammatory cells and elevation of IL-1ß, TNF-α, monocyte chemoattractant protein-1, and IL-6 levels were attenuated in P2X7 KO mice. P2X7 deletion decreased lung edema and alveolar protein content, which are associated with enhanced alveolar fluid clearance. In addition, activation of the inflammasome was suppressed in P2X7-deficient alveolar macrophages and was associated with suppression of IL-1ß release. Furthermore, P2X7-deficient alveolar macrophage in type II alveolar epithelial cells (AECs) coculture model abolished protein permeability across mouse type II AEC monolayers. Deletion of P2X7 does not lead to a decrease in epithelial sodium channel expression in cocultures of alveolar macrophages and type II AECs. Taken together, these findings show that deletion of P2X7 is a protective factor and therapeutic target for the amelioration of hyperoxia-induced lung injury.

Symptomatic Primary Selective Immunoglobulin M Deficiency with Nonprotective Pneumococcal Titers Responsive to Subcutaneous Immunoglobulin Treatment.

Selective immunoglobulin M deficiency (SIgMD) is a rare disorder with varying clinical features. The prevalence of SIgMD is 0.03-3%. Patients may be asymptomatic or else present with recurrent infection, autoimmunity, atopic disease and/or malignancy. About 50% of patients with symptomatic SIgMD also have impaired antibody responses to the pneumococcal polysaccharide vaccine. We report on an adult who presented with symptomatic SIgMD with impaired pneumococcal polysaccharide antibody responses and lymphopenia, who experienced a significant clinical improvement in the frequency of infections after subcutaneous immunoglobulin replacement therapy.

Asthma and chronic obstructive pulmonary disease inhalers: Techniques for proper use.

BACKGROUND: Asthma and chronic obstructive pulmonary disease (COPD) affect millions of Americans. Inhalers are necessary to manage these diseases, but physicians and patients often struggle to use them correctly. OBJECTIVE: To simplify inhaler use for patients and physicians. METHODS: This article compares the various inhalers used to treat asthma and COPD, their techniques for use, and the steps necessary to prime the inhaler if required. The authors provide a suggested standardized technique for the use of metered-dose inhalers, dry powder inhalers, and soft-mist inhalers to provide for a more universal approach for the use of these medications and summarizes how each product is to be used per the U.S. Food and Drug Administration approved package insert. RESULTS AND CONCLUSIONS: The simplified techniques proposed in this article for the use of metered-dose inhalers, dry powder inhalers, and soft mist inhalers used to treat asthma and COPD may limit inhaler misuse and aid in proper medication delivery and treatment.