Ultraviolet Protection From a Patented Amino Acid Complex Technology.

OBJECTIVE:   This study aimed to investigate the ultraviolet (UV) protection/repair benefits of a patented Amino Acid Complex (AAComplex). METHODS: I) AAComplex was incubated with dermal fibroblasts, with/without UVA, and collagen I was measured with a GlasBoxPlus device. II) A lotion, with/without AAComplex (1%) was applied topically to skin explants, following UVA irradiation, and quantified for health-related biomarkers (TNFalpha, histamine, and MMP-1). III) A broad spectrum sunscreen with SPF 46 and a skincare serum containing AAComplex (2%) were assessed using epidermal equivalents, in the presence of UV irradiation, for effects on IL-1alpha, thymine dimers, Ki-67, filaggrin and Nrf2. RESULTS: I) Collagen I synthesis in dermal fibroblasts was significantly decreased after UVA compared to without UV. The presence of AAComplex prevented this decrease. II) UVA irradiation of skin explants increased histamine, TNFα, and MMP-1. Hydrocortisone aceponate cream significantly decreases all 3 biomarkers. AAComplex contained lotion also significantly decreased all 3 biomarkers, the no AAComplex control lotion only reduced histamine. III) With the regimen of sunscreen + AAComplex contained skincare serum, the significant reduction in IL-1alpha was observed along with a complete recovery of Ki-67 and stimulation of filaggrin and Nrf2T. No thymine dimer positive cell was observed indicating the most positive skin impact from the regiment.  Conclusion: This research using different human skin models demonstrated that AAComplex can provide protection and damage repair caused by UV, at the ingredient level also when formulated in a serum or lotion formula. Skin may be best protected from UV damage when the regimen is used.   J Drugs Dermatol. 2024;23(5):366-375. doi:10.36849/JDD.7916.

Histamine receptor agonist alleviates severe cardiorenal damages by eliciting anti-inflammatory programming.

Heart failure and chronic kidney disease are major causes of morbidity and mortality internationally. Although these dysfunctions are common and frequently coexist, the factors involved in their relationship in cardiorenal regulation are still largely unknown, mainly due to a lack of detailed molecular targets. Here, we found the increased plasma histamine in a preclinical mouse model of severe cardiac dysfunction, that had been cotreated with angiotensin II (Ang II), nephrectomy, and salt (ANS). The ANS mice exhibited impaired renal function accompanied with heart failure, and histamine depletion, by the genetic inactivation of histidine decarboxylase in mice, exacerbated the ANS-induced cardiac and renal abnormalities, including the reduction of left ventricular fractional shortening and renal glomerular and tubular injuries. Interestingly, while the pharmacological inhibition of the histamine receptor H3 facilitated heart failure and kidney injury in ANS mice, administration of the H3 agonist immethridine (Imm) was protective against cardiorenal damages. Transcriptome analysis of the kidney and biochemical examinations using blood samples illustrated that the increased inflammation in ANS mice was alleviated by Imm. Our results extend the pharmacological use of H3 agonists beyond the initial purposes of its drug development for neurogenerative diseases and have implications for therapeutic potential of H3 agonists that invoke the anti-inflammatory gene expression programming against cardiorenal damages.

Mast Cells Induce Ductular Reaction Mimicking Liver Injury in Mice Through Mast Cell-Derived Transforming Growth Factor Beta 1 Signaling.

BACKGROUND AND AIMS: Following liver injury, mast cells (MCs) migrate into the liver and are activated in patients with cholestasis. Inhibition of MC mediators decreases ductular reaction (DR) and liver fibrosis. Transforming growth factor beta 1 (TGF-ß1) contributes to fibrosis and promotes liver disease. Our aim was to demonstrate that reintroduction of MCs induces cholestatic injury through TGF-ß1. APPROACH AND RESULTS: Wild-type, KitW-sh (MC-deficient), and multidrug resistance transporter 2/ABC transporter B family member 2 knockout mice lacking l-histidine decarboxylase were injected with vehicle or PKH26-tagged murine MCs pretreated with 0.01% dimethyl sulfoxide (DMSO) or the TGF-ß1 receptor inhibitor (TGF-ßRi), LY2109761 (10 µM) 3 days before sacrifice. Hepatic damage was assessed by hematoxylin and eosin (H&E) and serum chemistry. Injected MCs were detected in liver, spleen, and lung by immunofluorescence (IF). DR was measured by cytokeratin 19 (CK-19) immunohistochemistry and F4/80 staining coupled with real-time quantitative PCR (qPCR) for interleukin (IL)-1ß, IL-33, and F4/80; biliary senescence was evaluated by IF or qPCR for p16, p18, and p21. Fibrosis was evaluated by sirius red/fast green staining and IF for synaptophysin 9 (SYP-9), desmin, and alpha smooth muscle actin (α-SMA). TGF-ß1 secretion/expression was measured by enzyme immunoassay and qPCR. Angiogenesis was detected by IF for von Willebrand factor and vascular endothelial growth factor C qPCR. In vitro, MC-TGF-ß1 expression/secretion were measured after TGF-ßRi treatment; conditioned medium was collected. Cholangiocytes and hepatic stellate cells (HSCs) were treated with MC-conditioned medium, and biliary proliferation/senescence was measured by 3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium and qPCR; HSC activation evaluated for α-SMA, SYP-9, and collagen type-1a expression. MC injection recapitulates cholestatic liver injury characterized by increased DR, fibrosis/TGF-ß1 secretion, and angiogenesis. Injection of MC-TGF-ßRi reversed these parameters. In vitro, MCs induce biliary proliferation/senescence and HSC activation that was reversed with MCs lacking TGF-ß1. CONCLUSIONS: Our study demonstrates that reintroduction of MCs mimics cholestatic liver injury and that MC-derived TGF-ß1 may be a target in chronic cholestatic liver disease.

Bovine ß-lactoglobulin-induced passive systemic anaphylaxis model using humanized NOG hIL-3/hGM-CSF transgenic mice.

Food allergy is a common disease caused by intake of allergen-containing foods, such as milk, eggs, peanuts and wheat. Systemic anaphylaxis is a severe hypersensitive allergic reaction resulting from degranulation of mast cells or basophils after cross-linking of surface high-affinity IgE receptors (Fcε-RI) with allergen-specific IgE and allergens. In this study, we developed a novel human mast cell/basophil-engrafted mouse model that recapitulates systemic anaphylaxis triggered by ß-lactoglobulin (BLG), a major allergen found in cow's milk. Human CD34+ hematopoietic stem cells were transferred into NOG (non-Tg) or NOG hIL-3/hGM-CSF transgenic (Tg) mice. After 14-16 weeks, bovine BLG-specific human IgE was intravenously injected into humanized mice, followed by intravenous or oral bovine BLG exposure 1 day later. Body temperature in Tg, but not in non-Tg, mice gradually decreased within 10 min, and 80% of Tg mice died within 1 h by intravenous BLG exposure. Serum histamine levels and anaphylaxis scores in Tg mice were markedly increased compared to non-Tg mice. Furthermore, these allergic symptoms were significantly inhibited by epinephrine treatment of the Tg mice. Therefore, the current NOG hIL-3/hGM-CSF Tg mouse model may be useful for development of novel anaphylaxis drugs for treatment of food allergies and for safety assessment of low-allergenicity extensively hydrolyzed cow's milk whey protein-based infant formulas.

Type I interferon limits mast cell-mediated anaphylaxis by controlling secretory granule homeostasis.

Type I interferon (IFN-I) is a family of multifunctional cytokines that modulate the innate and adaptive immunity and are used to treat mastocytosis. Although IFN-I is known to suppress mast cell function, including histamine release, the mechanisms behind its effects on mast cells have been poorly understood. We here investigated IFN-I's action on mast cells using interferon-α/ß receptor subunit 1 (Ifnar1)-deficient mice, which lack a functional IFN-I receptor complex, and revealed that IFN-I in the steady state is critical for mast cell homeostasis, the disruption of which is centrally involved in systemic anaphylaxis. Ifnar1-deficient mice showed exacerbated systemic anaphylaxis after sensitization, which was associated with increased histamine in the circulation, even though the mast cell numbers and high affinity immunoglobulin E receptor (FcεRI) expression levels were similar between Ifnar1-deficient and wild-type (WT) mice. Ifnar1-deficient mast cells showed increased secretory granule synthesis and exocytosis, which probably involved the increased transcription of Tfeb. Signal transducer and activator of transcription 1(Stat1) and Stat2 were unexpectedly insufficient to mediate these IFN-I functions, and instead, Stat3 played a critical role in a redundant manner with Stat1. Our findings revealed a novel regulation mechanism of mast cell homeostasis, in which IFN-I controls lysosome-related organelle biogenesis.

Exposure of ovalbumin during pregnancy prevents the development of allergic rhinitis in offspring through the induction of mast cell autophagy.

Most allergic disease studies have focused on postnatal chemical or microbial exposure. Recent studies have indicated that allergic diseases are associated with the immunological interaction between the mother and her offspring, but the relevant mechanisms are unclear. The aim of this study was to assess whether maternal exposure to allergens during pregnancy could affect allergic rhinitis (AR) in the offspring. Compared with offspring of naïve mothers, offspring of ovalbumin (OVA)-exposed mothers exhibited a significant reduction in AR clinical symptoms and levels of histamine, IgE, T helper type-2(Th2) cytokines, thymic stromal lymphopoietin, cyclooxygenase-2, chemokines, infiltration of inflammatory cell, and activity of caspase-1. Interestingly, we observed that offspring of OVA-exposed mothers regulated OVA-induced Th2 responses by inducing autophagy in mast cells. Our data demonstrated that maternal exposure to OVA during pregnancy decreased allergic sensitivity in offspring, suggesting that the vertical transmission of maternal immune responses may be involved. These findings have important implications in the regulation of AR. Furthermore, we propose that the autophagy of mast cells may be a potential target for AR prevention or treatment.

Changes of microbial and metabolome of the equine hindgut during oligofructose-induced laminitis.

BACKGROUND: Laminitis is a common and serve disease which caused by inflammation and pathological changes of the laminar junction. However, the pathologic mechanism remains unclear. In this study we aimed to investigate changes of the gut microbiota and metabolomics in oligofructose-induced laminitis of horses. RESULTS: Animals submitted to treatment with oligofructose had lower fecal pH but higher lactic acid, histamine, and Lipopolysaccharide (LPS) in serum. Meanwhile, oligofructose altered composition of the hindgut bacterial community, demonstrated by increasing relative abundance of Lactobacillus and Megasphaera. In addition, the metabolome analysis revealed that treatment with oligofructose decreased 84 metabolites while 53 metabolites increased, such as dihydrothymine, N3,N4-Dimethyl-L-arginine, 10E,12Z-Octadecadienoic acid, and asparagine. Pathway analysis revealed that aldosterone synthesis and secretion, regulation of lipolysis in adipocytes, steroid hormone biosynthesis, pyrimidine metabolism, biosynthesis of unsaturated fatty acids, and galactose metabolism were significantly different between healthy and laminitis horses. Furthermore, correlation analysis between gut microbiota and metabolites indicated that Lactobacillus and/or Megasphaera were positively associated with the dihydrothymine, N3,N4-Dimethyl-L-arginine, 10E,12Z-Octadecadienoic acid, and asparagine. CONCLUSIONS: These results revealed that disturbance of gut microbiota and changes of metabolites were occurred during the development of equine laminitis, and these results may provide novel insights to detect biomarkers for a better understanding of the potential mechanism and prevention strategies for laminitis in horses.

Plasma histamine concentrations in horses administered sodium penicillin, guaifenesin-xylazine-ketamine and isoflurane with morphine or butorphanol.

OBJECTIVE: Various drugs administered to horses undergoing surgical procedures can release histamine. Histamine concentrations were evaluated in horses prepared for surgery and administered butorphanol or morphine intraoperative infusions. STUDY DESIGN: Prospective studies with one randomized. ANIMALS: A total of 44 client-owned horses. METHODS: In one study, anesthesia was induced with xylazine followed by ketamine-diazepam. Anesthesia was maintained with guaifenesin-xylazine-ketamine (GXK) during surgical preparation. For surgery, isoflurane was administered with intravenous (IV) morphine (group M: 0.15 mg kg-1 and 0.1 mg kg-1 hour-1; 15 horses) or butorphanol (group B: 0.05 mg kg-1 and 0.01 mg kg-1 hour-1; 15 horses). Histamine and morphine concentrations were measured using enzyme-linked immunoassay before opioid injection (time 0), and after 1, 2, 5, 30, 60 and 90 minutes. In a subsequent study, plasma histamine concentrations were measured in 14 horses before drug administration (baseline), 15 minutes after IV sodium penicillin and 15 minutes after starting GXK IV infusion. Statistical comparison was performed using anova for repeated measures. Pearson correlation compared morphine and histamine concentrations. Data are presented as mean ± standard deviation. Significance was assumed when p ≤ 0.05. RESULTS: With histamine, differences occurred between baseline (3.2 ± 2.4 ng mL-1) and GXK (5.2 ± 7.1 ng mL-1) and between baseline and time 0 in group B (11.9 ± 13.4 ng mL-1) and group M (11.1 ± 12.4 ng mL-1). No differences occurred between baseline and after penicillin or between groups M and B. Morphine concentrations were higher at 1 minute following injection (8.1 ± 5.1 ng mL-1) than at 30 minutes (4.9 ± 3.1 ng mL-1) and 60 minutes (4.0 ± 2.5 ng mL-1). Histamine correlated with morphine at 2, 30 and 60 minutes. CONCLUSIONS AND CLINICAL RELEVANCE: GXK increased histamine concentration, but concentrations were similar with morphine and butorphanol.

Increased Basal Blood Histamine Levels in Patients with Self-Reported Hypersensitivity to Non-Steroidal Anti-Inflammatory Drugs.

BACKGROUND: Non-steroidal anti-inflammatory drugs (NSAIDs) represent one of the most prevalent causes of drug hypersensitivity reactions (DHRs), yet the underlying processes are far from clear. Despite the established role of histamine in allergic reactions, its precise implication in DHRs is elusive. OBJECTIVES: This study aimed to explore the connection of basal blood histamine levels to the reported NSAID hypersensitivity. METHODS: Sixteen patients reporting hypersensitivity reactions to a single or multiple NSAIDs and/or paracetamol and 18 healthy volunteers serving as the normal control group enrolled in the study. The medical history was recorded and histamine was quantified spectrophotofluorometrically in whole peripheral blood and plasma. RESULTS: Compared to the normal group, plasma but not whole blood histamine levels were significantly higher in patients (p < 0.001), mainly in the subgroup reporting hypersensitivity to a single agent (p < 0.001). Plasma histamine levels were significantly correlated with the culprit drug selectivity for cyclooxygenase (COX) isozymes (p < 0.001), with higher levels being obtained in patients reporting reactions to COX-1 than to COX-2 selective inhibitors (p < 0.05). CONCLUSIONS: The findings provide first evidence connecting basal blood histamine levels to the reported NSAID-triggered DHRs. Prospective studies are expected to decipher the contribution of histamine-associated parameters to the mechanisms underlying DHRs.

A simpler potentiometric method for histamine assessment in blood sera.

Histamine intolerance results from a disequilibrium of accumulated histamine and the capacity for histamine degradation. An impaired histamine degradation based on reduced DAO activity and the resulting histamine excess may cause numerous symptoms mimicking an allergic reaction. For that, the determination of histamine in blood or in food products has great importance to identify risk factors. A new histamine-selective electrode is proposed using cucurbit[6]uril (CB[6]), as ionophore, in the analysis of biological samples. The selection of this smart supramolecular organic framework was based on its apparent stability constant of histamine-CB[6] (log ß) of 4.33. The optimized electrode based on a polymeric membrane (PVC) combines the histamine-selective ionophore with 2-nitrophenyl octyl ether as solvent mediator and potassium tetrakis(4-chlorophenyl)borate as anionic additive. Furthermore, multi-walled carbon nanotubes particles were included in the membrane composition to partly lower the detection limit of the method, while improving stability and lowering the response drift (± 4 mV). The electrodes showed a rapid response (≃ 13 s) in the pH operational range of 2.7-5.4, with a Nernstian slope of 30.9 ± 1.2 mV/dec, a detection limit of (3.00 ± 0.61) × 10-7 mol/L, and a lower limit of the linear range of (3.00 ± 0.00) × 10-7 mol/L. After miniaturization, the electrode was used as a detector in a sequential-injection lab-on-valve flow setup. The optimized flow conditions were achieved for sample injection volumes of 197 µL propelled towards the cell under detection, at a flow rate of 30 µL/s during 100 s, making the analysis of 30 samples per hour possible. The developed system was used to analyze spiked blood serum samples previously cleaned by using solid-phase extraction. The sample pretreatment of the serum samples using Oasis MCX cartridges showed outstanding efficiency for histamine determination. The recovery values for three different levels of histamine concentration (1 × 10-4 mol/L, 1 × 10-5 mol/L, and 1 × 10-6 mol/L) were (97 ± 6)%, (103 ± 1)%, and (118 ± 9)%, respectively, showing that this method was suitable for biological samples.

Viridicatol Isolated from Deep-Sea Penicillium Griseofulvum Alleviates Anaphylaxis and Repairs the Intestinal Barrier in Mice by Suppressing Mast Cell Activation.

Viridicatol is a quinoline alkaloid isolated from the deep-sea-derived fungus Penicillium griseofulvum. The structure of viridicatol was unambiguously established by X-ray diffraction analysis. In this study, a mouse model of ovalbumin-induced food allergy and the rat basophil leukemia (RBL)-2H3 cell model were established to explore the anti-allergic properties of viridicatol. On the basis of the mouse model, we found viridicatol to alleviate the allergy symptoms; decrease the levels of specific immunoglobulin E, mast cell protease-1, histamine, and tumor necrosis factor-α; and promote the production of interleukin-10 in the serum. The treatment of viridicatol also downregulated the population of B cells and mast cells (MCs), as well as upregulated the population of regulatory T cells in the spleen. Moreover, viridicatol alleviated intestinal villi injury and inhibited the degranulation of intestinal MCs to promote intestinal barrier repair in mice. Furthermore, the accumulation of Ca2+ in RBL-2H3 cells was significantly suppressed by viridicatol, which could block the activation of MCs. Taken together, these data indicated that deep-sea viridicatol may represent a novel therapeutic for allergic diseases.

Untargeted Metabolomics Differentiates l-Carnitine Treated Septic Shock 1-Year Survivors and Nonsurvivors.

l-Carnitine is a candidate therapeutic for the treatment of septic shock, a condition that carries a ≥40% mortality. Responsiveness to l-carnitine may hinge on unique metabolic profiles that are not evident from the clinical phenotype. To define these profiles, we performed an untargeted metabolomic analysis of serum from 21 male sepsis patients enrolled in a placebo-controlled l-carnitine clinical trial. Although treatment with l-carnitine is known to induce changes in the sepsis metabolome, we found a distinct set of metabolites that differentiated 1-year survivors from nonsurvivors. Following feature alignment, we employed a new and innovative data reduction strategy followed by false discovery correction, and identified 63 metabolites that differentiated carnitine-treated 1-year survivors versus nonsurvivors. Following identification by MS/MS and database search, several metabolite markers of vascular inflammation were determined to be prominently elevated in the carnitine-treated nonsurvivor cohort, including fibrinopeptide A, allysine, and histamine. While preliminary, these results corroborate that metabolic profiles may be useful to differentiate l-carnitine treatment responsiveness. Furthermore, these data show that the metabolic signature of l-carnitine-treated nonsurvivors is associated with a severity of illness (e.g., vascular inflammation) that is not routinely clinically detected.

Plasma histamine elevation in a large cohort of sickle cell disease patients.

The role of mast cells has been questioned in sickle cell disease (SCD). We performed a prospective study evaluating plasma histamine and tryptase levels in a cohort of paediatric and adult patients, in steady state (n = 132) and during vaso-occlusive crisis (VOC) (n = 121). Histamine level was elevated in 18% of patients in steady state and in 61% during VOC. Median histamine level was significantly higher during VOC than in steady state (24·1 [7·0-45·0] vs 9·6 [6·2-14·4] nmol/l, P < 0·0001). Tryptase level was slightly increased during VOC without reaching pathological values. These results suggest a role of mast cell activation in SCD pathophysiology.

Vibratory Urticaria Associated with a Missense Variant in ADGRE2.

Patients with autosomal dominant vibratory urticaria have localized hives and systemic manifestations in response to dermal vibration, with coincident degranulation of mast cells and increased histamine levels in serum. We identified a previously unknown missense substitution in ADGRE2 (also known as EMR2), which was predicted to result in the replacement of cysteine with tyrosine at amino acid position 492 (p.C492Y), as the only nonsynonymous variant cosegregating with vibratory urticaria in two large kindreds. The ADGRE2 receptor undergoes autocatalytic cleavage, producing an extracellular subunit that noncovalently binds a transmembrane subunit. We showed that the variant probably destabilizes an autoinhibitory subunit interaction, sensitizing mast cells to IgE-independent vibration-induced degranulation. (Funded by the National Institutes of Health.).

Massive release of the histamine-degrading enzyme diamine oxidase during severe anaphylaxis in mastocytosis patients.

BACKGROUND: Histaminolytic activity mediated by diamine oxidase (DAO) is present in plasma after induction of severe anaphylaxis in rats, guinea pigs, and rabbits. Heparin released during mast cell degranulation in the gastrointestinal tract might liberate DAO from heparin-sensitive storage sites. DAO release during anaphylaxis has not been demonstrated in humans. METHODS: Plasma DAO, tryptase, and histamine concentrations of four severe anaphylaxis events were determined at multiple serial time points in two patients with systemic mastocytosis. The histamine degradation rates were measured in anaphylaxis samples and in pregnancy sera and plasma with comparable DAO concentrations. RESULTS: Mean DAO (132 ng/mL) and tryptase (304 ng/mL) concentrations increased 187- and 4.0-fold, respectively, over baseline values (DAO 0.7 ng/mL, tryptase 76 ng/mL) during severe anaphylaxis. Under non-anaphylaxis conditions, DAO concentrations were not elevated in 29 mastocytosis patients compared to healthy volunteers and there was no correlation between DAO and tryptase levels in mastocytosis patients. The histamine degradation rate of DAO in plasma from mastocytosis patients during anaphylaxis is severely compromised compared to DAO from pregnancy samples. CONCLUSION: During severe anaphylaxis in mastocytosis patients, DAO is likely released from heparin-sensitive gastrointestinal storage sites. The measured concentrations can degrade histamine, but DAO activity is compromised compared to pregnancy samples. For accurate histamine measurements during anaphylaxis, DAO inhibition is essential to inhibit further histamine degradation after blood withdrawal. Determination of DAO antigen levels might be of clinical value to improve the diagnosis of mast cell activation.

Non-IgE-mediated hypersensitivity induced by multivitamins containing Tween-80.

Multivitamins have been widely used for years. Adverse reactions, especially hypersensitivity, to multivitamins are becoming noteworthy. However, the classification of hypersensitivity is confusing, and the trigger is unknown. Multivitamins consist of two vials labelled vial 1 containing Tween-80 and vial 2. Multivitamins without Tween-80 were used as a contrast. Behaviouristics, histamine, IgE, and blood pressure of beagle dogs and guinea-pigs were investigated by observation, ELISA and sphygmomanometer, and degranulation and apoptotic of RBL-2H3 cells were assayed by spectrophotometry and flow cytometry. The results showed that dogs suffered from multiorgan anaphylactoid symptoms, and dramatically decreased blood pressure, and high plasma concentrations of histamine after the first administration of multivitamins and multivitamins vial 1, which contains Tween-80, compared to the control, multivitamins vial 2 or multivitamins without Tween-80. In anaphylaxis assay, guinea-pigs did not display any anaphylaxis symptoms and there were no changes in plasma histamine and IgE concentrations in the multivitamins and multivitamins vial 1 groups or in the multivitamins vial 2 and multivitamins without Tween-80 groups except ovalbumin. Compared to the control, the release of ß-hexosaminidase and histamine, and the apoptosis of non-antigen-sensitized RBL-2H3 cells significantly increased in the Tween-80 and multivitamins and multivitamins vial 1 groups in a concentration-dependent manner. However, there was no alteration in multivitamins vial 2 and multivitamins without Tween-80 groups. The results indicate that the hypersensitivity induced by multivitamins may be anaphylactoid reaction, but not anaphylaxis. Multivitamin-induced release of inflammatory factors is triggered by Tween-80 through a non-IgE-mediated pathway.

Anti-Inflammatory Effects of Cold Thermal Therapy on Allergic Skin Inflammation Induced by Trimellitic Anhydride in BALB/c Mice.

Cold and hot thermal therapies are widely used as a traditional therapy in many cultures and are often prescribed in the treatment of various musculoskeletal and neurological conditions which present themselves to primary care physicians. However, there are no reports that investigated either the effects of cold and hot thermal therapies on the skin inflammation of trimellitic anhydride- (TMA-) induced dermatitis-like contact hypersensitivity (CHS) mouse model, or the mechanism of thermal therapy on allergic skin inflammation. Therefore, in this study, to reveal the anti-inflammatory effect of thermal therapy and its mechanism on TMA-induced CHS, we analyzed ear-swelling response (ear edema), vascular permeability, serum IgE levels, histological examination, and histamine and Th2 cytokine levels. Cold thermal therapy reduced the ear-swelling response, the vascular permeability, the serum IgE levels, and the infiltration of eosinophils and mast cells as well as the mast cell degranulation. To determine the mechanism by which cold thermal therapy inhibits allergic skin inflammation, detailed studies were carried out revealing that cold thermal therapy suppressed IL-4 and IL-5 secretion and mast cell activation. These results indicated that cold thermal therapy cures skin inflammation of TMA-induced CHS by decreasing Th2 cytokine release, especially IL-4 and IL-5, and mast cell activation. These data suggest that new insight into the mechanism of robust therapeutic effects of cold thermal therapy against allergic dermatitis, and cold thermal therapy may prove to be a useful therapeutic modality on allergic inflammatory diseases as traditional use as well as Th2- or mast cell-mediated allergic responses.

Screening anaphylactoid components of Shuang Huang Lian Injection by analyzing spectrum-effect relationships coupled with UPLC-TOF-MS.

Shuang Huang Lian Injection (SHLI) has been used in China for over 30 years as an effective and widely used Chinese herbal prescription to treat acute respiratory infectious. SHLI has, however, caused many severe anaphylactoid reactions. It is important to identify the potential anaphylactoid components of SHLI. Spectrum-effect relationships were used to explore potentially anaphylactoid components. Based on the original herbal formula, honeysuckle, Fructus Forsythiae and Radix Scutellariae extracts were prepared and combined in appropriate proportions. The preparations were then injected into the caudal vein of rats to obtain in vivo serum samples for pharmacological evaluation and fingerprint analysis. The release rate of ß-hexosaminidase from RBL-2H3 cells and plasma histamine level was used as the pharmacological index. Chromatographic fingerprint analysis identified 22 common peaks. Regression analysis and correlation analysis were used to calculate the relationships between the peaks and the pharmacological effects and identified peaks 5, 6, 11, 12 and 17 as likely anaphylactoid agents. The correlated peaks were identified by comparing the fingerprints with in vitro samples and reference standard samples and the structure was identified by UPLC-TOF-MS. This study established a prospective method to clarify the anaphylactoid components in SHLI, which would provide guidances for screening anaphylactoid components in other traditional Chinese medicine injections.

Histamine food poisoning: a sudden, large outbreak linked to fresh yellowfin tuna from Reunion Island, France, April 2017.

On 20 April 2017, an outbreak of histamine food poisoning occurred in a French military unit located near Paris. A total of 40 cases were identified (attack rate: 16.6%). We conducted a case-control study on 31 cases and 63 controls. Multivariate analysis pointed to cooked yellowfin tuna fillet as the very likely source of food poisoning (odds ratio = 156.8; 95% confidence interval: 18.4-1,338.4). The fresh yellowfin tuna was from Reunion Island and was supplied vacuum-sealed and packed with ice at the principal food market of Paris. No cold chain issues could be established in the upstream and downstream supply chains. Histamine concentration was found to be 1,720 mg/kg in leftover raw tuna, and 3,720 mg/kg in control cooked tuna, well above the threshold limit values defined by European regulations (200 mg/kg). The presence of Klebsiella variicola and Pantoea agglomerans, microorganisms of the Enterobacterales order that have been reported to produce histamine, was confirmed in the leftover raw tuna. This type of food poisoning is rarely recognised and confirmed. We describe the outbreak to highlight the specific key points of this type of investigation.

[Establishment of new evaluation standards for systemic anaphylactoid reactions using mouse model].

The detection of drug-induced anaphylactoid reactions remains a global challenge,still lacking mature and reliable animal models or test methods. Therefore,the purpose of this paper is to explore and establish the test methods and evaluation standards for anaphylactoid reactions that apply to injection drugs. Based on the anaphylactoid reaction symptoms of mice induced by intravenous injection drugs C48/40 and Tween 80,a list of systemic anaphylactoid reaction symptoms in mice was sorted out and an evaluation standard of anaphylactoid reactions symptoms was established by applying symptom intensity coefficient K( that can represent these verity of anaphylactoid reaction symptoms) and its calculation formula Accordingly,histamine,tryptase,and Ig E were selected as blood indicators of anaphylactoid reactions,so that a test method combining symptoms evaluation and blood makers detection was established.This test method could be used to evaluate the characteristics of anaphylactoid reactions: coefficient K,blood histamine levels were highly and positively correlated with C48/80 and Tween 80 dose; The log value of histamine was highly and positively correlated with K; tryptase level may rise,or remain steady,or drop,possibly associated with the characteristics of the tested object and time for blood taking; and Ig E level would drop or remain steady,but it would not rise,which can be clearly distinguished from type I allergic reactions. On this basis,tiohexol,iopromide,paclitaxel,Xuesaitong Injection,Shuanghuanglian Injection and Shengmai Injection were used to investigate the applicability. The testing results showed a high degree of consistency with the actual clinical situation. The results suggest that the method of systemic anaphylaxis test in mice has high sensitivity,specificity and good consistency with clinical practice.It is suggested to be further validated and popularized.