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BACKGROUND. Hyaluronan (HA), an extracellular matrix glycosaminoglycan, has been implicated in the pathophysiology of COVID-19 infection, pulmonary hypertension, pulmonary fibrosis, and other diseases, but is not targeted by any approved drugs. We asked whether hymecromone (4-methylumbelliferone [4-MU]), an oral drug approved in Europe for biliary spasm treatment that also inhibits HA in vitro and in animal models, could be repurposed as an inhibitor of HA synthesis in humans. METHODS. We conducted an open-label, single-center, dose-response study of hymecromone in healthy adults. Subjects received hymecromone at 1200 (n = 8), 2400 (n = 9), or 3600 (n = 9) mg/d divided into 3 doses daily, administered orally for 4 days. We assessed safety and tolerability of hymecromone and analyzed HA, 4-MU, and 4-methylumbelliferyl glucuronide (4-MUG; the main metabolite of 4-MU) concentrations in sputum and serum. RESULTS. Hymecromone was well tolerated up to doses of 3600 mg/d. Both sputum and serum drug concentrations increased in a dose-dependent manner, indicating that higher doses lead to greater exposures. Across all dose arms combined, we observed a significant decrease in sputum HA from baseline after 4 days of treatment. We also observed a decrease in serum HA. Additionally, higher baseline sputum HA levels were associated with a greater decrease in sputum HA. CONCLUSION. After 4 days of exposure to oral hymecromone, healthy human subjects experienced a significant reduction in sputum HA levels, indicating this oral therapy may have potential in pulmonary diseases where HA is implicated in pathogenesis. TRIAL REGISTRATION. ClinicalTrials.gov NCT02780752. FUNDING. Stanford Medicine Catalyst, Stanford SPARK, Stanford Innovative Medicines Accelerator program, NIH training grants 5T32AI052073-14 and T32HL129970., Introduction Hyaluronan (HA), an extracellular matrix glycosaminoglycan, plays an important role in inflammation (1, 2). Within injured and infected tissues, HA is produced by stromal cells in response to inflammatory [...]

California uses a unique method to screen newborns for cystic fibrosis (CF) that includes gene scanning and DNA sequencing after only one California-40 cystic fibrosis transmembrane conductance regulator (CFTR) panel mutation has been identified in hypertrypsinogenemic specimens. Newborns found by sequencing to have one or more additional mutations or variants (including novel variants) in the CFTR gene are systematically followed, allowing for prospective assessment of the pathogenic potential of these variants. During the first 3 years of screening, 55 novel variants were identified. Six of these novel variants were discovered in five screen-negative participants and three were identified in multiple unrelated participants. Ten novel variants (c.2554_2555insT, p.F1107L, c.-152G>C, p.L323P, p.L32M, c.2883_2886dupGTCA, c.2349_2350insT, p.K114del, c.-602A>T, and c.2822delT) were associated with a CF phenotype (42% of participants were diagnosed at 4 to 25 months of age), whereas 26 were associated with CFTR-related metabolic syndrome to date. Associations with the remaining novel variants were confounded by the presence of other diseases or other mutations in cis or by inadequate follow-up. These findings have implications for how CF newborn screening and follow-up is conducted and will help guide which genotypes should, and which should not, be considered screen positive for CF in California and elsewhere.

Multiciliated cell loss is a hallmark of airway epithelial remodeling in chronic inflammatory airway diseases including cystic fibrosis (CF), asthma, and chronic obstructive pulmonary disease. It disrupts mucociliary clearance, which fuels disease progression. Effective clearance requires an optimal proportion of multiciliated and secretory cells. This is controlled by Notch signaling such that between two adjacent cells the one that activates Notch becomes a secretory cell and the one that avoids Notch activation becomes a multiciliated cell. Consequently, blocking Notch by a small molecule inhibitor of the γ-secretase enzyme that cleaves the Notch receptor for signal activation directs differentiation toward the multiciliated lineage. Thus, γ-secretase inhibitor (GSI) treatment may alleviate multiciliated cell loss in lung disease. Here, we demonstrate the therapeutic restoration of multiciliated cells by the GSI LY450139 (semagacestat). LY450139 increased multiciliated cell numbers in a dose-dependent manner in healthy primary human nasal epithelial cells (HNECs) during differentiation and in mature cultures, but not when applied during early epithelialization of progenitors. LY450139 did not impact stem cell proliferation. Basal and apical administration were equally effective. In healthy adult mice, LY450139 increased multiciliated cell numbers without detectible toxicity. LY450139 also increased multiciliated cells and decreased excess mucus secretory cells in CF HNECs and IL-13 remodeled healthy HNECs. LY450139 normalized multiciliated cell numbers in CF HNECs without interfering with the activity of CFTR modulator compounds. In summary, we demonstrate that GSI administration is a promising therapeutic to restore multiciliated cells and potentially improve epithelial function in a wide range of chronic lung diseases. [ABSTRACT FROM AUTHOR]

Objective. Nutritional status is associated with pulmonary health and survival in children with cystic fibrosis (CF). This study evaluated the weight gain pattern of children with CF in relation to the longitudinal trends of their pulmonary function. Our hypothesis was that children who experience continuous weight gain at a given rate will have better average forced expiratory volume in 1 second (FE[V.sub.1]) and change in FE[V.sub.1] than children who have weight gain patterns that deviate from this rate, even when total weight gain seems adequate. Methods. Prospectively collected data were examined in 319 children, aged 6 to 8, who were routinely followed at the Minnesota Cystic Fibrosis Center. One to 67 measurements of weight (kg), height (cm), and FE[V.sub.1] (mL) were taken per child during this 2-year period. The data were analyzed by repeated measure regression analysis and by growth pattern analysis. Results. At baseline, a 1-kg higher initial weight was associated with a 55-mL higher average FE[V.sub.1]. During the follow-up period, a 1-kg gain in weight was associated with an increase in FE[V.sub.1] by 32 mL. Children who had a steady weight gain tended to experience greater increases in FE[V.sub.1] than children who experienced periodic losses in weight. Conclusions. We established that children who weigh more and who gain weight at an appropriate and uninterrupted rate have a better FE[V.sub.1] trajectory. Aggressive nutritional support to maintain growth in these children may therefore improve FE[V.sub.1], which can be taken as a surrogate for better lung health, and may ultimately lead to better survival. Pediatrics 2003;112:588-592; cystic fibrosis, growth, pulmonary, function, longitudinal studies., Cystic fibrosis (CF) is the most common life-shortening disease in white individuals and is characterized by multiorgan involvement with primarily pulmonary and gastrointestinal manifestations, as well as abnormally high levels [...]

Objective. In recent years, continuous intravenous propofol infusion has been widely used in pediatric intensive care units. Several case reports have raised concerns about its safety. The objective of this study was to report our experience with continuous intravenous propofol in consecutive patients during an 18-month period. Methods. The study design was a retrospective review of a case series. Case was defined as a critically ill child who was treated with continuous intravenous propofol. The attending physician staff agreed to prescribe propofol via continuous intravenous infusion at a dose not to exceed 50/ [micro]g/kg/min. The protocol allowed for each patient to receive an additional intravenous bolus of propofol at a dose of 1 mg/kg no more than once per hour. The study entailed data collection from consecutive patients who were prescribed a continuous infusion of propofol in either the pediatric intensive care unit or bone marrow transplant unit. Results. Data from 142 patients were analyzed. Each patient enrolled was adequately sedated. Administration of propofol via continuous intravenous infusion was not associated with metabolic acidosis or hemodynamic compromise. No patient in the study group was inadvertently extubated or had a central venous catheter accidentally discontinued. Conclusions. Propofol can be safely and effectively used to provide sedation to critically ill infants and children. We speculate that continuous infusion of propofol for extended periods of time should not exceed 67 [micro]g/kg/min. Pediatrics 2002;110:1177-1181; sedation, metabolic acidosis, mechanical ventilation., ABBREVIATIONS. PICU, pediatric intensive care unit; BMT, bone marrow transplantation; FDA, US Food and Drug Administration. Providing effective and safe sedation for young children in the pediatric intensive care unit [...]

A study was conducted to investigate the effects of K+-channel inhibition, cyclic nucleotide-dependent kinase inhibition, and Ca2+-release on inhaled nitric oxide-induced perinatal pulmonary vasodilation. Experiments were done on acutely prepared, late-gestation fetal lambs which were treated with N-nitro-L-arginine, an inhibitor of nitric oxide synthase. This was done to prevent the production of endogenous nitric oxide. Findings revealed that nitric oxide causes perinatal pulmonary vasodilation.