Background We studied whether neonatal propofol anesthesia affects development of the endocrine and neural systems. Methods Sprague-Dawley rats were anesthetized using intraperitoneal propofol for 5 h on postnatal days (P) 4, 5, or 6. Pups that received either saline or intralipid, but not those in the negative control groups, were also maternally separated for 5 h. Serum levels of corticosterone were measured immediately after anesthesia and in adulthood after prepulse inhibition (PPI) of acoustic startle testing (≥P80), followed by measurement of hippocampal neuronal activity. Results Propofol acutely increased corticosterone levels to 146.6 ± 23.5 ng/ml (n=6) vs 16.4 ± 3.5 ng/ml (n=6) and 18.4 ± 3.2 ng/ml (n=6) in saline- and intralipd-treated pups, respectively. In adulthood, the propofol group exhibited exacerbated endocrine responses to stress in a form of increased corticosterone levels (1171.58 ± 149.17 ng/ml (n=15) vs 370.02 ± 36.01 ng/ml (n=10) in the saline group). The propofol group had increased the frequency of miniature inhibitory postsynaptic currents in CA1 neurons of male and female rats, but reduced PPI of startle was detected only in males. The Na+–K+–2Cl− co-transporter inhibitor bumetanide, administered to pups prior to propofol, alleviated long-term endocrine and PPI abnormalities. Exogenous corticosterone, administered to naïve pups, induced synaptic and endocrine, but not PPI effects, similar to those of propofol. Conclusions Propofol-caused acute increases in corticosterone levels and gamma-aminobutyric acid type A receptor-mediated excitation at the time of anesthesia may play mechanistic roles in development of exacerbated endocrine responses to stress and neurobehavioral abnormalities.

Background The general anesthetics isoflurane and sevoflurane cause developmental abnormalities in neonatal animal models via incompletely understood mechanisms. Despite many common molecular targets, isoflurane and sevoflurane exhibit substantial differences in their actions. We sought to determine whether these differences can also be detected at the level of neurodevelopmental effects. Methods Postnatal day 4–6 rats were exposed to 1.2% isoflurane or 2.1% sevoflurane for 1–6 hrs and studied for immediate and delayed effects. Results Isoflurane exposure was associated with weaker seizure-like electroencephalogram patterns than sevoflurane exposure. Confronted with a new environment at a juvenile age the sevoflurane- but not isoflurane-exposed rats spent significantly more time in an “immobile” state than unexposed rats. Electroencephalographic (55.5±12.80 s vs. 14.86 ± 7.03 s, mean± SE, P = 0.014, n = 6–7) and spontaneous behavior (F(2,39)= 4.43, P=0.018) effects of sevoflurane were significantly diminished by pretreatment with the Na+–K+–2Cl– co-transporter inhibitor bumetanide, whereas those of isoflurane were not . Pretreatment with bumetanide, however, diminished isoflurane-induced activation of caspase-3 in the cerebral cortex (F(2,23)= 22.697, P=0.001) and prevented impairment in sensorimotor gating function (F(2,36)= 5.978, P= 0.006). Conclusions These findings in combination with our previously reported results suggest that isoflurane and sevoflurane produce developmental effects acting via similar mechanisms that involve an anesthetic induced increase in neuronal activity. At the same time differences in their effects suggest differences in the mediating mechanisms and in their relative safety profile for neonatal anesthesia.

Background An imbalance between excitation and inhibition in the developing central nervous system may result in a pathophysiological outcome. We investigated he mechanistic roles of endocrine activity and gamma-aminobutyric acid type A receptor (GABAAR)-mediated excitation in electroencephalographic seizures caused by the GABAAR-selective anesthetic propofol in neonatal rats. Methods Postnatal day 4–6 Sprague Dawley rats underwent a minor surgical procedure to implant electrodes to measure electroencephalographic activity for 1 h before and 1 h after intraperitoneal administration of propofol (40 mg kg−1). Various treatments were administered 15 min before administration of propofol. Results Episodes of electroencephalographic seizures and persistent low-amplitude spikes occurred during propofol anesthesia. Multifold increases in serum levels of corticosterone (t(10) = −5.062; P= 0.0005) and aldosterone (t(10) = −5.069; P= 0.0005) were detected 1 h after propofol administration in animals that underwent experimental manipulations identical to those used to study electroencephalographic activity. Pretreatment with bumetanide, the Na+–K+–2Cl– co-transporter inhibitor, which diminishes GABAAR-mediated excitation, eliminated both seizure and spike electroencephalographic activities caused by propofol. Mineralocorticoid and glucocorticoid receptor antagonists, RU 28318 and RU486, depressed electroencephalographic seizures but did not affect the spike electroencephalographic effects of propofol. Etomidate, at a dose sufficient to induce loss of righting reflex, was weak at increasing serum corticosteroid levels and eliciting electroencephalographic seizures. Etomidate given to corticosterone-pretreated rat pups further increased the total duration of electroencephalographic seizures caused by administration of exogenous corticosterone (t(21) = −2.512, P = 0.0203). Conclusions Propofol increases systemic corticosteroid levels in neonatal rats, which along with GABAAR-mediated excitation appear to be required for propofol-induced neonatal electroencephalographic seizures. Enhancement of GABAAR activity alone may not be sufficient to elicit neonatal electroencephalographic seizures.

Background Subcutaneous immunotherapy (SCIT) has been used for treating local allergic rhinitis (LAR) patients. However, the clinical efficacy and safety were still questioned. Objective This study was designed to estimate the efficacy and safety of SCIT for treating LAR patients through meta-analysis. Methods We systemically searched MEDLINE, Cochrane Library, and Embase publications. Randomized, double-blind, clinical trials for the efficacy and safety of Allergen Immunotherapy (AIT) for LAR were included. A meta-analysis of 4 clinical endpoints (combined symptom and medication scores [CSMS], symptom scores [SS], medication scores [MS] and rhinoconjunctivitis quality of life questionnaire [RQLQ]) and adverse events (AEs)) was performed after bias and heterogeneity assessments. The immunologic response results were summarized. Results Four RCTs with 134 patients were included. Four studies for analyzing primary outcomes (CSMS, SS, MS) and AEs, three for RQLQ results. The results indicated an important significant difference between SCIT and placebo groups, list as follows: CSMS (SMD = −2.42, 95% CI: −3.60 to −1.25, P < .0001), SS (SMD = −2.08, 95% CI −3.68 to −0.48, P = .01), MS (SMD = −1.43, 95% CI: −2.65 to −0.21, P = 0.02), RQLQ (SMD = −0.70, 95% CI −1.29 to −0.12, P = .02), Local AEs (RR = 4.13, 95% CI 1.08 to 15.77, P = .04). For immunologic response, significantly increased serum sIgG4 levels and improvements of allergen tolerance was observed after SCIT. Conclusions Our meta-analysis suggests that SCIT has a significant effect on improving symptoms and reducing medicine consumption for LAR patients. Larger and multicenter clinical trials are needed to clarify the safety and long-term efficacy.

Background BALB/c and C57BL/6 mouse strains are commonly used in allergy research. The current study investigated the immunological differences between these two mouse strains with a locally allergic rhinitis model. Methods Eighteen BALB/c and eighteen C57BL/6 mice received different doses of ovalbumin (OVA) intranasally for eight weeks (each mouse strain has three subgroups, 25 mg/mL group, 0.25 mg/mL group, and the PBS group). The allergic symptoms, OVA-specific serum antibody (IgE, IgG1, IgG2a), cytokines (IL-4, IFN-γ, IL-10) in the splenic culture supernatant, infiltrating eosinophils and goblet cells in local nasal mucosa were measured. RNA-seq technology was applied to detect differential gene expression in the local nasal mucosa. Results With the same dose of OVA stimulation, the exacerbation of allergic symptoms was more pronounced in C57BL/6 than in BALB/c. BALB/c serum IgE, IgG1, and IgG2a gradually increased, and C57BL/6 produced fewer serum antibodies IgE and IgG1, while IgG2a never increased. BALB/c spleen cell culture supernatant IL-4 and IL-10 increased with increasing dose, and IFN-γ increased significantly in the intermediate dose group, while IL-4, IL-10, and IFN-γ did not increase in C57BL/6. The infiltration of eosinophils and goblet cells in both mice was proportional to the dose, while C57BL/6 was elevated more than BALB/c. RNA-seq suggested that the innate immune response, immune system process function, Jun kinase (JNK) pathway, and MAPKK pathway were upregulated in C57BL/6 compared to BALB/c. The core genes responsible for the differential immune response in both mice with allergic rhinitis were Kng2, Kng1, Gnb3, Lpar3, Lpar1, Pik3r1, Pf4, Apob, Rps9, and Fbxo2. Conclusion There are significant differences in the immunologic responses between BALB/c mice and C57BL/6 mice. BALB/c mice developed mild local allergic inflammatory reactions and strong systemic immune responses. In contrast, C57BL/6 mice had stronger local allergic inflammatory responses and relatively mild systemic immune responses. Different mice strains can be selected according to the research purpose.

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Background: It has been reported that when DCs are exposed to high-dose antigens, they can induce Th0 cells into regulatory cells (Treg) and Th1 cells. When DCs are subjected to low-dose allergen, they can drive to Th2 cells. However, the mechanisms of such dose-effect relationship are poorly understood so far. Methods: Bone marrow immature DCs (imDCs) were generated from mice and stimulated with OVA of different concentrations (0, 10, 100, 1000, 10000 μg/ml, respectively). The mDCs were then seeded and cocultured with naïve T cells for 3 days, and then the markers of different T cell subgroups were flow cytometrically tested. RNA-seq detection and DNA methylation of DCs were performed. Results: When DCs were stimulated with low-dose (10ug/ml), 77 genes were up-regulated and 87 genes down-regulated. Most activated genes were related to ribosome synthesis and ion channel inhibition but not to the immune responses and Th2 activation. At the medium-dose (100μg/ml), 339 genes were up-regulated and 168 genes down-regulated. Most activated genes involved cytokine synthesis and regulation of immune responses. At high-dose (10000μg/ml), 2794 genes were up-regulated and 1156 genes down-regulated. Tumor necrosis factor signaling pathway, MAPK signaling pathway, antigen processing and presentation signaling pathway were mostly up-regulated. The related co-stimulators, co-inhibitory molecules, inhibitory cytokines, negative regulating enzymes were highly expressed. The monocarbate, coenzyme, fatty acid, glucolipid, starch, sucrose and other metabolism-related signaling pathways were down-regulated. Conclusion: The profiles of DNA methylation and RNA synthesis of DCs varied with different doses of OVA, which serves to induce T cells to differentiate in various directions.