Perinatal Risk Factors for Asthma and Allergic Rhinitis in Children and Adolescents.

OBJECTIVES: In this study, we evaluated the associations between birth-related exposures, postnatal factors, and the risk of allergic rhinitis and asthma in children and adolescents. METHODS: We performed a comprehensive search of five literature databases up to May 2023. To quantify the associations of birth-related exposures (birth weight, delivery mode, prematurity, sex, maternal age, and parental allergy history) and postnatal factors (birth order, number of siblings, breastfeeding exclusivity, and breastfeeding duration) with allergic disease, we calculated pooled odds ratios and 95% confidence intervals. We conducted subgroup analyses for allergic disease type, birth order, number of siblings, and parental allergy history. The methodological quality of the identified studies was evaluated using the Newcastle-Ottawa Scale. RESULTS: This meta-analysis included 31 studies, encompassing 218,899 patients in total. The birth-related exposures of low birth weight, maternal age, and prematurity (less than 37 weeks gestation) were not significantly associated with the risk of asthma or allergic rhinitis during childhood or adolescence. Male sex, family history of allergy, and cesarean delivery were linked to an elevated risk of asthma or allergic rhinitis. Among postnatal factors, exclusive breastfeeding, breastfeeding for longer than 6 months, second or later birth order, and having siblings exhibited protective effects against allergic diseases in offspring. CONCLUSION: The risks of allergic rhinitis and asthma were elevated in male patients, those delivered by cesarean section, and those with a family history of allergy. Conversely, exclusive breastfeeding, breastfeeding for longer than 6 months, and having siblings corresponded to a reduced risk of respiratory allergic diseases.

Efficient production of (S)-limonene and geraniol in Saccharomyces cerevisiae through the utilization of an Erg20 mutant with enhanced GPP accumulation capability.

Monoterpenes and monoterpenoids such as (S)-limonene and geraniol are valuable chemicals with a wide range of applications, including cosmetics, pharmaceuticals, and biofuels. Saccharomyces cerevisiae has proven to be an effective host to produce various terpenes and terpenoids. (S)-limonene and geraniol are produced from geranyl pyrophosphate (GPP) through the enzymatic actions of limonene synthase (LS) and geraniol synthase (GES), respectively. However, a major hurdle in their production arises from the dual functionality of the Erg20, a farnesyl pyrophosphate (FPP) synthase, responsible for generating GPP. Erg20 not only synthesizes GPP by condensing isopentenyl pyrophosphate (IPP) with dimethylallyl pyrophosphate but also catalyzes further condensation of IPP with GPP to produce FPP. In this study, we have tackled this issue by harnessing previously developed Erg20 mutants, Erg20K197G (Erg20G) and Erg20F96W, N127W (Erg20WW), which enhance GPP accumulation. Through a combination of these mutants, we generated a novel Erg20WWG mutant with over four times higher GPP accumulating capability than Erg20WW, as observed through geraniol production levels. The Erg20WWG mutant was fused to the LS from Mentha spicata or the GES from Catharanthus roseus for efficient conversion of GPP to (S)-limonene and geraniol, respectively. Further improvements were achieved by localizing the entire mevalonate pathway and the Erg20WWG-fused enzymes in peroxisomes, while simultaneously downregulating the essential ERG20 gene using the glucose-sensing HXT1 promoter. In the case of (S)-limonene production, additional Erg20WWG-LS was expressed in the cytosol. As a result, the final strains produced 1063 mg/L of (S)-limonene and 1234 mg/L of geraniol by fed-batch biphasic fermentations with ethanol feeding. The newly identified Erg20WWG mutant opens doors for the efficient production of various other GPP-derived chemicals including monoterpene derivatives and cannabinoids.

Predictive Value of Nasal Nitric Oxide for Diagnosing Eosinophilic Chronic Rhinosinusitis: A Systematic Review and Meta-Analysis.

OBJECTIVES: The primary aim of this study was to assess disparities in nasal nitric oxide (NO) levels between individuals diagnosed with eosinophilic chronic rhinosinusitis (ECRS) and those without ECRS. The second aim was to ascertain the comparative predictive efficacy of these nasal NO levels for the presence of ECRS. METHODS: A systematic analysis was conducted on relevant studies that compared nasal NO levels in individuals with ECRS and those without. Furthermore, the discriminatory capacity of nasal NO in distinguishing ECRS from non-ECRS cohorts was quantified. The risk of bias across studies was evaluated utilizing the Newcastle-Ottawa scale. RESULTS: The comprehensive review encompassed a total of 5 studies involving 470 participants. Findings revealed that patients diagnosed with ECRS exhibited significantly higher levels of nasal NO, as measured in parts per billion (ppb), compared to their non-ECRS patients. The mean difference was 130.03 ppb (95% confidence interval: [66.30, 193.75], I2 = 58.7%). The diagnostic odds ratio for nasal NO in identifying ECRS was 9.29 ([5.85, 14.75], I2 = 26.4%). The area under the summary receiver operating characteristic curve was 0.82. The correlation between sensitivity and false positive rate was 0.53, suggesting a lack of heterogeneity. Sensitivity, specificity, negative predictive value, and positive predictive value were 69% ([0.55, 0.79], I2 = 77.0%), 83% ([0.73, 0.90], I2 = 68.5%), 77% ([0.69, 0.83], I2 = 50.1%), and 75% ([0.67, 0.82], I2 = 41.5%), respectively. CONCLUSION: Nasal NO has the potential as a noninvasive diagnostic measure and endotype tool for ECRS.

A comparison of doxycycline and conventional treatments of refractory chronic rhinosinusitis with nasal polyps: a systematic review and meta-analysis.

PURPOSE: To compare the effects of doxycycline (DOX) and conventional management in patients with refractory chronic rhinosinusitis and nasal polyps (CRSwNP). METHODS: Six databases were searched to September 2023. We retrieved studies that compared improvements in refractory chronic sinusitis-related symptoms between DOX-treated and control groups. RESULTS: DOX significantly reduced the Lund-Kennedy (LK) score [- 0.3670 (range - 0.6173; - 0.1166); I2 = 92.8%], the nasal polyposis score [- 0.9484 (- 1.2287; - 0.6680); I2 = 92.5%], the patient-reported Sinonasal Outcome Test (SNOT) score [- 0.3141 (- 0.4622; - 0.1660); I2 = 91.2%], and the nasal obstruction score [- 0.1813 (- 0.3382; - 0.0243); I2 = 86.2%]. On subgroup analyses by the measurement timepoints, the extent of nasal polyposis was significantly lower in the DOX group during treatment, at the end of treatment, and 4 and 8 weeks later. The LK scores also indicated improvements during treatment and at the end of treatment. The SNOT score tended to decrease with time in the treatment group. Nasal obstruction symptoms improved during treatment and 4 weeks later. CONCLUSION: DOX enhances the postoperative endoscopic outcomes of refractory CRSwNP patients by reducing recurrent polyposis and inflammation.

Occurrences of benzalkonium chloride in streams near a pharmaceutical manufacturing complex in Korea and associated ecological risk.

Benzalkonium chloride (BKC) is a commonly used preservative in personal care products and pharmaceutical preparations. However, its ecological risks are not well understood because of lack of monitoring data and ecotoxicological information. In the present study, occurrence of BKC was investigated in the waters near a pharmaceutical manufacturing complex of South Korea and its acute and chronic ecotoxicities were evaluated using Daphnia magna and Japanese medaka (Oryzias latipes). Associated ecological risks were estimated by calculating hazard quotients (HQs). In addition, endocrine disruption potency of BKC was compared with those of other frequently used preservatives using human adrenal (H295R) and rat pituitary (GH3) cells. High concentration of BKC was detected at locations near the pharmaceutical manufacturing plants, i.e., 35.8 µg/L for dodecyl benzyl dimethyl ammonium chloride (BKC-C12), and 21.6 µg/L tetradecyl benzyl dimethyl ammonium chloride (BKC-C14). In Daphnia, 48 h immobilization EC50 and 21 d reproduction NOEC were determined at 41.1 µg/L and ≥10.8 µg/L, respectively. For O. latipes, 96 h LC50 was determined at 246 µg/L while the growth inhibition NOEC was ≥113.4 µg/L following early life stage exposure. BKC significantly up-regulated vitellogenin gene of juvenile fish, indicating its endocrine disrupting potential in fish. Exposure to BKC increased steroid hormone level in H295R cells, and induced cytotoxicity in GH3 cells. HQ values of BKC were determined at greater than one in the ambient water near pharmaceutical manufacturing facilities. Considering high ecological risk and endocrine disrupting potential, long-term consequences of BKC contamination in aquatic ecosystem need to be examined.

Comparison of thyroid hormone disruption potentials by bisphenols A, S, F, and Z in embryo-larval zebrafish.

Several structural analogues of bisphenol A (BPA), e.g., bisphenol F (BPF), bisphenol S (BPS), and bisphenol Z (BPZ), have been used as its substitutes in many applications and consequently detected in the environment, and human specimen such as urine and serum. While BPA has been frequently reported for thyroid hormone disruption in both experimental and epidemiological studies, less is known for the BPA analogues. In the present study, thyroid hormone disrupting effects of BPF, BPS and BPZ, were investigated, and compared with those of BPA, using embryo-larval zebrafish (Danio rerio). At 120 hpf, significant increases in T3 and/or T4 were observed in the larval fish following exposure to BPA, BPF, or BPS. Moreover, transcriptional changes of the genes related to thyroid development (hhex and tg), thyroid hormone transport (ttr) and metabolism (ugt1ab) were observed as well. Thyroid hormone (T4) disruption by BPF was observed even at the concentration (2.0 mg/L) lower than the effective concentration determined for BPA (>2.0 mg/L). Delayed hatching was observed by all tested bisphenols. Our results clearly show that these BPA analogues can disrupt thyroid function of the larval fish, and their thyroid hormone disruption potencies could be even greater than that of BPA. The concentrations which disrupt thyroid function of the larval fish were orders of magnitude higher than those occurring in the ambient environment. However, thyroid hormone disruption by longer term exposure and its consequences in the fish population, deserve further investigation.

Cell-SELEX-Based Identification of a Human and Mouse Cross-Reactive Endothelial Cell-Internalizing Aptamer.

Increased interest and insights gained by researchers on the roles of endothelial cells in the pathophysiology of cancer, inflammatory, and cardiovascular diseases have led to the design of pharmacological interventions aimed at the endothelium lining in the diseased sites. Toward this end, we used established brain microvascular endothelial cell lines mouse (bEND3), human (hCMEC/D3), and Toggle Cell-SELEX to identify a species cross-reactive, endothelial cell-internalizing aptamer R11-3. This 2'F-modified RNA aptamer is specific for endothelial cells as no internalization was seen with cells of nonendothelial origin. R11-3 was truncated in size, and its potential in endothelial targeted therapeutics was established using VEGFR2 targeting long interfering RNA (liRNA) aptamer chimera. Due to its specificity for both mouse and human endothelial cells, we believe that this aptamer not only fits for development of endothelial targeted drug development for human diseases but is also suitable for preclinical evaluation in mice.

Searching for novel modes of toxic actions of oil spill using E. coli live cell array reporter system - A Hebei Spirit oil spill study.

Oil is a complex mixture of numerous compounds. Therefore, oil spills near shore can cause various adverse effects on coastal ecosystems. However, most toxicological assessments conducted on oil spill sites have focused on limited modes of toxic actions. In the present study, we utilized the Escherichia coli (E. coli) live cell array system (LCA) to identify novel modes of toxicities of the oil spill-affected sediments. For this purpose, sediment samples were collected from an area heavily polluted by Hebei Spirit oil spill (HSOS) incident of 2007. A total of 93 E. coli reporter genes were used to study responses to the chemicals in the mixture. E. coli K12 strains were exposed to extracts of oil or the sediment, and changes in gene expression were measured. Exposure to extracts of crude and weathered oil resulted in decreased expression in ∼30% of tested genes. However, changes in expression observed after exposure to sediment extracts varied. Sediment extracts containing large concentrations of polycyclic aromatic hydrocarbons (PAH) caused down-regulation of >70% of the genes, while extracts containing lesser total concentrations of PAHs exhibited different trends: genes involved in drug resistance were generally up-regulated, while genes responsive to DNA damage were up-regulated in only two extracts. Results suggest that oil pollution can modulate several toxic response pathways related to DNA repair and antibiotic responses. Results from LCA obtained from the sediment and oil samples were different from those observed in the H4IIE-luc assay. Toxicological implications of such observations deserve further examination. Overall, LCA is a promising tool for screening samples and identifying potential modes of toxicities of environmental samples associated with oil spills.