Effect of excess weight and insulin resistance on DNA methylation in prepubertal children.

Epigenetic mechanisms, such as DNA methylation, regulate gene expression and play a role in the development of insulin resistance. This study evaluates how the BMI z-score (BMIz) and the homeostatic model assessment of insulin resistance (HOMA-IR), alone or in combination, relate to clinical outcomes and DNA methylation patterns in prepubertal children. DNA methylation in peripheral blood mononuclear cells (PBMCs) and clinical outcomes were measured in a cohort of 41 prepubertal children. Children with higher HOMA-IR had higher blood pressure and plasma lactate levels while children with higher BMIz had higher triglycerides levels. Moreover, the DNA methylation analysis demonstrated that a 1 unit increase in the BMIz was associated with a 0.41 (95% CI: 0.29, 0.53) increase in methylation of a CpG near the PPP6R2 gene. This gene is important in the regulation of NF-kB expression. However, there was no strong evidence that the BMIz and the HOMA-IR were synergistically related to any clinical or DNA methylation outcomes. In summary, the results suggest that obesity and insulin resistance may impact metabolic health both independently in prepubertal children. In addition, obesity also has an impact on the DNA methylation of the PPP6R2 gene. This may be a novel underlying starting point for the systemic inflammation associated with obesity and insulin resistance, in this population.

Pulmonary Procedures During the COVID-19 Pandemic: A Work Group Report of the AAAAI Asthma Diagnosis and Treatment (ADT) Interest Section.

The COVID-19 pandemic has placed increased demands on the ability to safely perform pulmonary procedures in keeping with Centers for Disease Control and Prevention (CDC), American Thoracic Society (ATS), and the Occupational Safety and Health Administration (OSHA) recommendations. Accordingly, the American Academy of Allergy, Asthma & Immunology (AAAAI) Asthma Diagnosis and Treatment convened this work group to offer guidance. The work group is composed of specialist practitioners from academic and both large and small practices. Individuals with special expertise were assigned sections on spirometry, fractional exhaled nitric oxide, nebulized treatments, and methacholine challenge. The work group met periodically to achieve consensus. This resulting document has recommendations for the allergy/asthma/immunology health care setting based on available evidence including reference documents from the CDC, ATS, and OSHA.

Anti-PD-1/L1 lead-in before MAPK inhibitor combination maximizes antitumor immunity and efficacy.

Rationally sequencing and combining PD-1/L1-and MAPK-targeted therapies may overcome innate and acquired resistance. Since increased clinical benefit of MAPK inhibitors (MAPKi) is associated with previous immune checkpoint therapy, we compare the efficacies of sequential and/or combinatorial regimens in subcutaneous murine models of melanoma driven by BrafV600, Nras, or Nf1 mutations as well as colorectal and pancreatic carcinoma driven by KrasG12C. Anti-PD-1/L1 lead-in preceding MAPKi combination optimizes response durability by promoting pro-inflammatory polarization of macrophages and clonal expansion of interferon-γhi, and CD8+ cytotoxic and proliferative (versus CD4+ regulatory) T cells that highly express activation genes. Since therapeutic resistance of melanoma brain metastasis (MBM) limits patient survival, we demonstrate that sequencing anti-PD-1/L1 therapy before MAPKi combination suppresses MBM and improves mouse survival with robust T cell clonal expansion in both intracranial and extracranial metastatic sites. We propose clinically testing brief anti-PD-1/L1 (± anti-CTLA-4) dosing before MAPKi co-treatment to suppress therapeutic resistance.

The challenge of asthma in adolescent athletes: exercise induced bronchoconstriction (EIB) with and without known asthma.

Exercise induced bronchconstriction (EIB) is defined as a transient increase in airway resistance reflected as at least a 10% decline in FEV1 following at least 6-8 minutes of strenuous exercise. Up to 90% of asthmatics, 45% of individuals with allergic rhinitis, 50% of Olympic athletes, and 12% of the general population have EIB. EIB in adolescence may be either under- or over-diagnosed because of denial of symptoms or misperception of dyspnea or other respiratory symptoms. Diagnosis cannot always rely on history alone and may require an objective exercise challenge or surrogate measure. Management of EIB may require reduction in the exercise provoking the asthma but it can usually be successfully managed with training and the appropriate use of medications, including inhaled beta-agonists, inhaled steroids, and/or leukotriene antagonists. Nonpharmacologic therapy with face masks, warming up and down, and calisthenics may also be an effective adjunct in reducing medication needs. For most adolescents, proper pharmacotherapy will provide complete control of the airway and a normal healthy lifestyle without exercise restrictions.

An update on exercise-induced bronchoconstriction with and without asthma.

Exercise-induced bronchoconstriction (EIB) is defined as transient, reversible bronchoconstriction that develops after strenuous exercise. It is a heterogeneous syndrome made up of a spectrum of phenotypes ranging from the asymptomatic military recruit whose condition is detected by diagnostic exercise challenge to the athlete with known asthma to the elite athlete for whom EIB represents an overuse or injury syndrome. If exercise is the only identified trigger for bronchoconstriction, it is called EIB. However, when it is associated with known asthma, then it is defined as EIB with asthma. This review discusses the pathogenesis, presentation, diagnosis, and management of EIB and EIB with asthma.

Changes in NGF and NT-3 protein species in the superior cervical ganglion following axotomy of postganglionic axons.

Mature sympathetic neurons in the superior cervical ganglion (SCG) are regulated by target-derived neurotrophins such as nerve growth factor (NGF) and neurotrophin-3 (NT-3). High molecular weight NGF species and mature NT-3 are the predominant NGF and NT-3 protein isoforms in the SCG, yet it is unknown whether the presence of these species is dependent on intact connection with the target tissues. In an attempt to determine the role of peripheral targets in regulating the neurotrophin species found in the SCG, we investigated the NGF and NT-3 protein species present in the SCG following axotomy (transection) or injury of the post-ganglionic axons. Following a 7 day axotomy, the 22-24 kDa NGF species and the mature 14 kDa NT-3 species in the SCG were significantly reduced by 99% and 66% respectively, suggesting that intact connection with the target is necessary for the expression of these protein species. As expected, tyrosine hydroxylase (TH) protein in the SCG was significantly reduced by 80% at 7 days following axotomy. In order to distinguish between the effects of injury and loss of target connectivity, the SCG was examined following compression injury to the post-ganglionic nerves. Following injury, no reduction in the 22-24 kDa NGF or 14 kDa mature NT-3 species was observed in the SCG. TH protein was slightly, yet significantly, decreased in the SCG following injury. The findings of this study suggest that the presence of the 22-24 kDa NGF and mature 14 kDa NT-3 species in the SCG is dependent on connection with peripheral targets and may influence, at least in part, TH protein expression in adult sympathetic neurons.

Exercise-induced bronchospasm in children.

This review will encompass definition, history, epidemiology, pathogenesis, diagnosis, and management of exercise -induced bronchospasm in the pediatric individual with and without known asthma. Exercise induced asthma is the conventional term for transient airway narrowing in a known asthma in association with strenuous exercise usually lasting 5-10 minutes with a decline in pulmonary function by at least 10%. Exercise induced asthma will be referred to as exercise induced bronchospasm in an asthmatic. Exercise-induced bronchospasm (EIB ) is the same phenomenon in an individual without known asthma. EIB can be seen in healthy individuals including children as well as defense recruits and competitive or elite athletes. The diagnosis with objective exercise challenge methods in conjunction with history is delineated. Management is characterized with pharmacotherapy and non pharmacotherapeutic measures for underlying asthma as well as exercise induced bronchospasm and inhalant allergy. Children can successfully participate in all sports if asthma is properly managed.

Regulation of NGF and NT-3 protein expression in peripheral targets by sympathetic input.

Nerve growth factor (NGF) and neurotrophin-3 (NT-3) are target-derived proteins that regulate innervating sympathetic neurons. Here, we used western blot analysis to investigate changes in NGF and NT-3 protein in several peripheral tissues following loss of sympathetic input. Following removal of the superior cervical ganglion (SCG), large molecular weight (MW) NGF species, including proNGF-A, were increased in distal intracranial SCG targets, such as pineal gland and extracerebral blood vessels (bv). Mature NGF was a minor species in these tissues and unchanged following sympathectomy. Large MW NGF species also were increased when sympathectomy was followed by in vivo NGF administration. Mature NT-3, which was abundant in controls, was significantly decreased in these targets following sympathetic denervation. The decrease in mature NT-3 was enhanced following NGF administration. The trigeminal ganglion, which provides sensory input to these targets, showed increased NGF, but decreased NT-3, in these treatments, demonstrating that decreased NT-3 at the targets did not result from enhanced NT-3 uptake. Unlike pineal gland and extracerebral bv, the external carotid artery, an extracranial proximal SCG target, showed no change in NGF following denervation, and mature NT-3 was significantly increased. Following NGF administration, NT-3 was significantly decreased. We provide evidence for sympathetic regulation of NGF and NT-3 in peripheral targets and that elevated NGF can depress NT-3. The differential response in distal and proximal adult targets is consistent with the idea that neurons innervating proximal and distal targets may serve different roles in regulating neurotrophin protein. In addition, we conclude that previous ELISA results showing increased NGF protein following sympathetic denervation may have resulted from increases in large MW species, rather than an increase in mature NGF.

Making the diagnosis of asthma in the athlete.

This article encompasses a discussion of the clinical presentation and features as various diagnostic modalites of bronchoprovocation and differential diagnosis used in screening for asthma in the athlete. A comparative analysis of these modalities, including questionnaire, treadmill, eucapneic hyperventilation, as well as field challenge, is provided with sensitivities and specificities, predictive value, and application to clinical practice. The indication and mechanics of each diagnostic modality is discussed, providing the clinician with a comprehensive understanding of the principles and procedures used to diagnosis asthma in the athlete.

The syndrome of thyroid autoimmunity and idiopathic chronic urticaria and angioedema presenting as anaphylaxis.

Previous observations have shown that the syndrome of thyroid autoimmunity and idiopathic urticaria and angioedema (ICUA) can be associated with a marked worsening of reactive airway disease. Possibly, mediators released in this syndrome may contribute to acute bronchospasm and associated respiratory symptoms in some patients. In this study, two patients presenting with overlapping clinical presentations of the syndrome of thyroid immunity and ICUA are described in whom a diagnosis of anaphylaxis to food and antibiotics, respectively, was initially suspected but ruled out by testing and challenges. These cases illustrate clinical overlap between presentations of ICUA and anaphylaxis. We suggest that patients with idiopathic anaphylaxis be evaluated for the presence of antithyroid microsomal (peroxidase) antibodies or antithyroglobulin antibodies, particularly because the diagnosis of thyroid antibody-positive ICUA may suggest additional therapeutic options.