Parasympathetic Airway Hyperreactivity Is Enhanced in Acute but Not Chronic Eosinophilic Asthma Mouse Models.

Airway hyperreactivity in asthma is mediated by airway nerves, including sensory nerves in airway epithelium and parasympathetic nerves innervating airway smooth muscle. Isolating the function of these two nerve populations in vivo, to distinguish how each is affected by inflammatory processes and contributes to hyperreactivity in asthma, has been challenging. In this study, we used optogenetic acti-vation of airway nerves in vivo to study parasympathetic contributions to airway hyperreactivity in two mouse models of asthma: 1) acute challenge with house dust mite antigen, and 2) chronic airway hy-pereosinophilia due to genetic IL-5 overexpression in airways.

Association between emergency department disposition and mortality in patients with COVID-19 acute respiratory distress syndrome.

Objectives: Patients hospitalized for COVID-19 frequently develop hypoxemia and acute respiratory distress syndrome (ARDS) after admission. In non-COVID-19 ARDS studies, admission to hospital wards with subsequent transfer to intensive care unit (ICU) is associated with worse outcomes. We hypothesized that initial admission to the ward may affect outcomes in patient with COVID-19 ARDS.

Cardiovascular collapse and McConnell's sign as early manifestations of leucostasis.

A man in his late 70s with chronic myelomonocytic leukaemia presented for evaluation of acute leukaemic transformation and initiation of cytoreductive therapy after being found to have asymptomatic hyperleucocytosis. Within 24 hours, the patient developed vasopressor-refractory shock, severe lactic acidosis and multiorgan failure. Serial echocardiographic assessments revealed interval enlargement of the right ventricle with development of the McConnell's sign, and abdominal CT showed diffuse bowel wall thickening, likely due to ischaemia.

Grandmaternal allergen sensitization reprograms epigenetic and airway responses to allergen in second-generation offspring.

Asthma susceptibility is influenced by environmental, genetic, and epigenetic factors. DNA methylation is one form of epigenetic modification that regulates gene expression and is both inherited and modified by environmental exposures throughout life. Prenatal development is a particularly vulnerable time period during which exposure to maternal asthma increases asthma risk in offspring.

Unique Allergic Asthma Phenotypes in Offspring of House Dust Mite-exposed Mice.

Asthma is a heterogeneous inflammatory airway disease that develops in response to a combination of genetic predisposition and environmental exposures. Patients with asthma are grouped into phenotypes with shared clinical features and biomarker profiles to help tailor specific therapies. However, factors driving development of specific phenotypes are poorly understood.

Multicolor labeling of airway neurons and analysis of parasympathetic heterogeneity.

We report subpopulations of airway parasympathetic neurons expressing substance P, neuronal nitric oxide synthase, and tyrosine hydroxylase, highlighting unexplored heterogeneity in this population. These neurotransmitter-specific subpopulations did not form intraganglionic interneurons, but rather, extended outside the ganglia, into the airways, to distant innervation targets. Our experiments demonstrate the utility of multicolor labeling to characterize airway innervation, allowing us to confirm the extensive heterogeneity of postganglionic parasympathetic neurons.

Inflammatory mechanisms linking maternal and childhood asthma.

Asthma is a chronic inflammatory airway disease characterized by airway hyperresponsiveness, inflammation, and remodeling. Asthma often develops during childhood and causes lifelong decrements in lung function and quality of life. Risk factors for childhood asthma are numerous and include genetic, epigenetic, developmental, and environmental factors.

IL-5 Exposure Increases Lung Nerve Density and Airway Reactivity in Adult Offspring.

Asthma is characterized by airway hyperreactivity and inflammation. In the lungs, parasympathetic and sensory nerves control airway tone and induce bronchoconstriction. Dysregulation of these nerves results in airway hyperreactivity.

Toll-Like Receptor 7-Targeted Therapy in Respiratory Disease.

Allergic asthma and allergic rhinitis are inflammatory diseases of the respiratory tract characterized by an excessive type-2 T helper cell (Th2) immune response. Toll-like receptor 7 (TLR7) is a single-stranded viral RNA receptor expressed in the airway that initiates a Th1 immune response and has garnered interest as a novel therapeutic target for treatment of allergic airway diseases. In animal models, synthetic TLR7 agonists reduce airway hyperreactivity, eosinophilic inflammation, and airway remodeling while decreasing Th2-associated cytokines.

The influences of parental diet and vitamin E intake on the embryonic zebrafish transcriptome.

The composition of the typical commercial diet fed to zebrafish can dramatically vary. By utilizing defined diets we sought to answer two questions: 1) How does the embryonic zebrafish transcriptome change when the parental adults are fed a commercial lab diet compared with a sufficient, defined diet (E+)? 2) Does a vitamin E-deficient parental diet (E-) further change the embryonic transcriptome? We conducted a global gene expression study using embryos from zebrafish fed a commercial (Lab), an E+ or an E- diet. To capture differentially expressed transcripts prior to onset of overt malformations observed in E- embryos at 48h post-fertilization (hpf), embryos were collected from each group at 36hpf.

Interactions between α-tocopherol, polyunsaturated fatty acids, and lipoxygenases during embryogenesis.

α-Tocopherol is a lipid-soluble antioxidant that is specifically required for reproduction and embryogenesis. However, since its discovery, α-tocopherol's specific biologic functions, other than as an antioxidant, and the mechanism(s) mediating its requirement for embryogenesis remain unknown. As an antioxidant, α-tocopherol protects polyunsaturated fatty acids (PUFAs) from lipid peroxidation.

Chronic vitamin E deficiency promotes vitamin C deficiency in zebrafish leading to degenerative myopathy and impaired swimming behavior.

We hypothesized that zebrafish (Danio rerio) undergoing long-term vitamin E deficiency with marginal vitamin C status would develop myopathy resulting in impaired swimming. Zebrafish were fed for 1 y a defined diet without (E-) and with (E+) vitamin E (500 mg α-tocopherol/kg diet). For the last 150 days, dietary ascorbic acid concentrations were decreased from 3500 to 50 mg/kg diet and the fish sampled periodically to assess ascorbic acid concentrations.

The α-tocopherol transfer protein is essential for vertebrate embryogenesis.

The hepatic α-tocopherol transfer protein (TTP) is required for optimal α-tocopherol bioavailability in humans; mutations in the human TTPA gene result in the heritable disorder ataxia with vitamin E deficiency (AVED, OMIM #277460). TTP is also expressed in mammalian uterine and placental cells and in the human embryonic yolk-sac, underscoring TTP's significance during fetal development. TTP and vitamin E are essential for productive pregnancy in rodents, but their precise physiological role in embryogenesis is unknown.

Urinary α-carboxyethyl hydroxychroman can be used as a predictor of α-tocopherol adequacy, as demonstrated in the Energetics Study.

Background: Other than the in vitro erythrocyte hemolysis test, no valid biomarkers of vitamin E status currently exist.

Objective: We hypothesized that the urinary vitamin E metabolite α-carboxyethyl hydroxychroman (α-CEHC) could serve as a biomarker.

Design: The relations between urinary α-CEHC, plasma α-tocopherol, and vitamin E intakes were assessed by using a previously validated multipass, Web-based, 24-h self-administered dietary recall, and we concurrently collected plasma and 24-h urine samples from 233 participants of both sexes.

Poor lysosomal membrane integrity in proximal tubule cells of haptoglobin 2-2 genotype mice with diabetes mellitus.

The haptoglobin (Hp) genotype is a major determinant of progression of nephropathy in individuals with diabetes mellitus (DM). The major function of the Hp protein is to bind and modulate the fate of extracorpuscular hemoglobin and its iron cargo. We have previously demonstrated an interaction between the Hp genotype and the DM on the accumulation of iron in renal proximal tubule cells.

Vitamin C deficiency activates the purine nucleotide cycle in zebrafish.

Vitamin C (ascorbic acid, AA) is a cofactor for many important enzymatic reactions and a powerful antioxidant. AA provides protection against oxidative stress by acting as a scavenger of reactive oxygen species, either directly or indirectly by recycling of the lipid-soluble antioxidant, α-tocopherol (vitamin E). Only a few species, including humans, guinea pigs, and zebrafish, cannot synthesize AA.

'Tocol-omic' diversity in wild barley, short communication.

Hordeum spontaneum, wild barley, is the direct progenitor of domestic barley, Hordeum vulgare, an economically important ingredient of animal feed, beer, soy sauce, and more recently, of nutraceuticals. Domestic barley has also been used in the past as a medicine. Barley is a rich source of tocotrienols, with α-tocotrienol being the most prevalent.

Vitamin E deficiency decreases long-chain PUFA in zebrafish (Danio rerio).

α-Tocopherol is a required, lipid-soluble antioxidant that protects PUFA. We hypothesized that α-tocopherol deficiency in zebrafish compromises PUFA status. Zebrafish were fed for 1 y either an α-tocopherol-sufficient (E+; 500 mg α-tocopherol/kg) or -deficient (E-; 1.

α-Tocopherol injections in rats up-regulate hepatic ABC transporters, but not cytochrome P450 enzymes.

The role of hepatic xenobiotic regulatory mechanisms in modulating hepatic α-tocopherol concentrations during excess vitamin E administration remains unclear. We hypothesized that increased hepatic α-tocopherol would cause a marked xenobiotic response. Thus, we assessed cytochrome P450 oxidation systems (phase I), conjugation systems (phase II), and transporters (phase III) after daily α-tocopherol injections (100mg/kg body wt) for up to 9days in rats.

Zebrafish (Danio rerio) fed vitamin E-deficient diets produce embryos with increased morphologic abnormalities and mortality.

Vitamin E (α-tocopherol) is required to prevent fetal resorption in rodents. To study α-tocopherol's role in fetal development, a nonplacental model is required. Therefore, the zebrafish, an established developmental model organism, was studied by feeding the fish a defined diet with or without added α-tocopherol.