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Despite its long history as a preferential cyclooxygenase-2 inhibitor, the topical application of etodolac in inflammatory disorders does not achieve the desired clinical efficiency because of its poor water solubility and poor skin permeation. In the ongoing study, phosalosomes were designed to mitigate the etodolac drawbacks and to enhance its skin localization. Hyaluronic acid was utilized to prepare a dermal gel for the alleviation of skin inflammation. Etodolac loaded hyaluronic acid phosalosomal gel had a sustainable release profile and 10.59-fold enhanced skin retention compared to free etodolac, with boosted skin tolerability on histopathological examination after acute and chronic applications. Confocal laser microscopy imaging indicated that the etodolac amounts accumulated in the liver and kidney following dermal application were 29 and 5.7-fold lower than those following the systemic dose, respectively. For in vivo studies, etodolac loaded hyaluronic acid phosalosomal gel presented superior anti-oedemic and significant anti-nociception potential. The promising homogenous localization highlighted its potential for the delivery of lipophilic drugs for the targeted treatment of other localized skin disorders.

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INTRODUCTION: In vitro methods have been widely used to assess adverse effects. Reconstructed Human Epidermis (RHE) poses as a fascinating test system employed to assess the dermal irritation hazard potential of chemicals. Although several RHE models are reported in the OECD Test Guideline No. 439, the OECD Document No. 220 encourages the scientific community to develop and validate new RHE test systems due to its relevance for socio-economic advancement. METHODS: Following the criteria documented in the OECD No. 220, a blind study for skin irritation (OECD 439) was conducted employing the Minimum List of Reference Chemicals for Determination of Reproducibility and Predictive Capacity using ES®-RHE. Structural and functional characteristics were assessed alongside the prediction model. RESULTS: The model has shown reproducibility of optical density and barrier function, similarly to internationally validated methods. Furthermore, it shows the cell layers' development and differentiation ability due to Cytokeratin14, Cytokeratin10, and filaggrin expression. The prediction model resulted in sensitivity, specificity and accuracy rates of 100, 70, and 77 %, respectively. CONCLUSIONS: The ES®-RHE demonstrated reliability and relevance, with similar structural and functional characteristics comparable to internationally validated models, in addition to the accepted predictive capacity according to OECD required minimum criteria, thus confirming the suitability of the national ES®-RHE in the hazard prediction of dermal irritation based on OECD Test Guideline No. 439.

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The importance of treating non-pulmonary vein (PV) foci is increasing with improvements in the durability of PV isolation. We describe two cases wherein non-PV foci were induced by mechanical irritation and conventional induction in the same area, which was impossible to induce after ablation, suggesting a relationship between mechanical irritation and induction of non-PV foci. In a recurrent case of non-PV foci, atrial fibrillation (AF) was induced only by mechanical irritation. No recurrence has been observed since the ablation of the area. Thus, treatment of the AF induction site with mechanical irritation could be considered an effective therapy for non-PV foci.

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PURPOSE: Wildfire occurrence is increasing worldwide, putting firefighters and general public at increased risk of eye injuries from smoke exposure. This study explored ocular symptoms and use of protective eyewear amongst wildland firefighters in Australia. METHODS: Australian wildland firefighters were invited to complete an online survey about the occurrence of eye irritation, use of protective eyewear and behaviours associated with occupational smoke exposure. Responses were analysed using logistic regression and qualitative inductive content analysis. RESULTS: 338 wildland firefighters completed the survey. Eye irritation was reported by 90% of firefighters at least sometimes during work and by 70% after work. Frequency of eye irritation was greater amongst females than males (OR 2.01, CI 1.22 - 3.31, p<0.05). Protective eyewear was used often or always by 67% of firefighters on the fireground, however 55% had to remove their protective eyewear due to sweat, fogging or another reason. Goggles were more likely to be removed compared to sunglasses and safety glasses (OR 4.28, CI 2.75 - 6.68, p<0.001). Firefighters reported that, at times smoke exposure necessitated eye closure and impaired vision on the fireground. Firefighters also reported that protective eyewear helped to reduce eye symptoms, but its consistent use on the fireground was difficult. The severity and recovery from eye symptoms varied between participants. CONCLUSION: Australian wildland firefighters frequently experience eye irritation from smoke exposure, and this can affect operational capabilities. These findings can support the development of evidence-based strategies to help protect and aid recovery of the eye surface following smoke exposure.

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With the growing importance of alternative test methods that implement the 3Rs principles (Reduction, Refinement and Replacement) and the global importance of biological safety assessment data for medical devices is increasing. We have developed and optimized the 'KeraSkin™ Skin Irritation Test (KeraSkin™ SIT) for medical device' for regulatory application in biological evaluation according to ISO 10993-23. We conducted a round robin study to optimize and evaluate the performance of KeraSkin™ SIT for medical devices using KeraSkin™ Reconstructed Human Epidermis (RhE), which is developed and manufactured in Korea. This round robin study was performed to assess the transferability, reproducibility (within and between laboratories) and predictive capacity in 1 lead laboratory and 3 participating laboratories based on OECD Guidance Document 34. The predictive capacity, the results showed 83.3 % of sensitivity, 100 % of specificity and 91.6 % of accuracy. In conclusion, the results demonstrate that 'KeraSkin™ SIT for medical device' provides a robust test method for detecting irritant activity of medical device extracts and can be utilized for identifying low levels of potent irritants in medical device extracts. Therefore, it fulfills the requirements to be included as a 'me-too' test method to EpiDerm™ and SkinEthic™ skin irritation test in ISO 10993-23.

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INTRODUCTION: Here we report a child of Gullian Barre syndrome (GBS) with opisthotonic posturing and we subsequently detected Scrub typhus in him. CASE REPORT: An 11-year-old boy presented with progressive motor quadriparesis with transient bladder retention, bilateral facial weakness, diminished gag reflex, absent reflexes and his nerve conduction studies suggested Acute Motor Axonal Neuropathy (AMAN) GBS. His power gradually started recovering after one week. However, he had opisthotonus and signs of meningeal irritation. The child's CSF examination was consistent with GBS. His bacterial, fungal, tubercular microscopy and cultures and viral markers were negative. IgM for Borrelia and Leptospira and HIV ELISA were negative. IgM for scrub typhus, however, came out to be positive. Hence, we gave him azithromycin and he recovered almost completely in 3 months. CONCLUSIONS: To our knowledge there is no previous report of opisthotonic posturing in GBS patients. This could be due to radicular involvement in immune mediated etiology of GBS.

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Mental health is a serious problem among veterinarians. The aim of this study was to analyze work-related behaviors and experience (AVEM), overcommitment (OC), and cognitive and emotional irritation (IS) in different veterinary working fields. The survey included 724 German veterinarians (average age 41.0 ± 9.72 years). Validated questionnaires were used to assess overcommitment, work-related behavior and experience patterns (health-promoting pattern G or S; health-hazardous risk pattern A or B), and irritation in several working fields. A correlation analysis and a multivariate test were performed. Increased OC was observed in 35.8% of veterinarians (mixed animals vs. inspectors, p = 0.042; small vs. mixed animals, p = 0.001). A total of 66% of veterinarians exhibited AVEM risk pattern A or B. There was no significant association of AVEM risk patterns and veterinary specialty. Only the AVEM dimension "tendency toward resignation in the face of failure" differed among working fields (p = 0.04). Regardless of direct animal contact, German veterinarians showed increased psychological stress. Inadequate compensation and prolonged stress are significant factors that can lead to burnout or depression. These risks should be considered in the context of occupational healthcare.

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Background: Test methods to inform hazard characterization and labeling of pesticides to protect human health are typically conducted using laboratory animals, and for skin irritation/corrosion the rabbit Draize test is currently required by many regulatory agencies. Although the Draize test is generally regarded to provide protective classifications for human health, new approach methodologies (NAMs) have been developed that offer more human relevant models that circumvent the uncertainty associated with species differences that exist between rabbits and humans. Despite wide applicability and use of these test methods across a broad range of chemicals, they have not been widely adopted for testing pesticides and pesticidal formulations. One of the barriers to adoption of these methods in this sector is low concordance with results from the Draize rabbit test, particularly for chemicals within the mild to moderate irritation spectrum.Methods: This review compares and contrasts the extent to which available models used in skin irritation testing mimic the anatomy and physiology of human skin, and how each aligns with the known key events leading to chemically-induced adverse skin irritation and corrosion. Doing so fully characterizes the human relevance of each method.Results: As alternatives to the rabbit Draize test, several protocols using ex vivo, in chemico, and in vitro skin models are available as internationally harmonized test guidelines. These methods rely on a variety of models of human skin, including excised rodent skin, synthetic biochemical models of barrier function, cell culture systems, and reconstructed human tissue models. We find these models exhibit biological and mechanistic relevance aligned with human skin irritation responses. Further, recent retrospective analyses have shown that the reproducibility of the Draize test is less than 50% for mild and moderate responses, with many of the replicate predictions spanning more than one category (e.g., a moderate response reported in one study followed by a non-irritant response reported in another study).Conclusions: Based on this comparative evaluation, we recommend top-down and bottom-up testing strategies that use the most human relevant in vitro test methods for skin irritation and corrosion classification of pesticides and pesticide formulations. To further discriminate among mild and non-irritant formulations, optimization of a cytokine release protocol and subsequent analyses of reference formulation test results is recommended.

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Acrolein is considered a risk factor for indoor air health problems due to its reactivity. An objective of the study was to investigate prevalence of sensory irritation in terms of time-dependent detection and perceived intensity of symptoms in human volunteers. Another objective was to investigate individual variation in sensory irritation. Participants (n=40) were exposed twice in an exposure chamber (15 min), once to heptane and once to acrolein and heptane. Symptoms and sensory irritation thresholds were rated continuously and 70% of the participants detected eye irritation from the acrolein exposure. A significant interaction between time and exposure (ƞp2=0.19) was identified, indicating time-dependent activation. This group also reported a higher level of stress and lower self-reported health (p<0.05). The results suggest that the eye is the primary system affected by exposure to acrolein, and that duration of exposure and perceived stress play important roles in symptom reactions due to acrolein exposure.

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Malignant ascites effusion (MAE) is a common complication of advanced malignant tumors with limited treatments. Euphorbia lathyris (EL) has a long history of application in patients with edema and ascites. Herein, we reported for the first time a mode in which EL and EL Pulveratum (PEL) spontaneously formed natural microemulsions (ELM and PELM) without the addition of any carriers and excipients, and found that the protein and phospholipid contained in them encapsulated fatty oil and diterpenoid esters through non-covalent interactions. The denaturation and degradation of protein in PELM resulted in stronger binding of diterpenoid esters to the hydrophobic region of protein, which facilitated the sustained and slow release of diterpenoid esters and improved their bioavailability in vivo, thereby retaining the efficacy of preventing MAE while alleviating the irritation of intestinal mucosa. The mechanism by which PELM retained efficacy might be related to increased feces moisture and urine volume, and decreased expression of AVPR2, cAMP, PKA and AQP3 in MAE mice. And its mechanism of reducing intestinal mucosal irritation was related to decreased cell apoptosis, amelioration of oxidative stress, elevation of mitochondrial membrane potential, and up-regulation of Occludin and Claudin-1 expression in IEC-6 cells. This nano-adjuvant-free natural microemulsions may be a promising therapeutic strategy in the field of phytochemistry for promoting the application of natural and efficient nano-aggregates spontaneously formed by medicinal plants in MAE, and provide a new perspective for advancing the development of the fusion of Chinese herbal medicine and nanomedicine and its clinical translation.

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This study introduces a novel in vitro methodology that employs the 3-D reconstructed tissue model, EpiOcular, to assess the irritation and phototoxicity potential of medical devices and drugs in contact with the eye. Our study evaluated diverse test materials, including medical devices, ophthalmological solutions and an experimental drug (cemtirestat), for their potential to cause eye irritation and phototoxicity. The protocols used in this study with the EpiOcular tissue model were akin to those used in the ultra-mildness testing of cosmetic formulations, which is challenging to predict with standard in vivo rabbit tests. To design these protocols, we leveraged experience gained from the validation project on the EpiDerm skin irritation test for medical devices (ISO 10993-23:2021) and the OECD TG 498 method for photo-irritation testing. The predictions were based on the tissue viability and inflammatory response, as determined by IL-1α release. By developing and evaluating these protocols for medical devices, we aimed to expand the applicability domain of the tests referred to in ISO 10993-23. This will contribute to the standardisation and cost-effective safety evaluation of ophthalmic products, while reducing reliance on animal testing in this field. The findings obtained from the EpiOcular model in the photo-irritation test could support its implementation in the testing strategies outlined in OECD TG 498.

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Objective To evaluate the clinical behavior of different bleaching products - the hydrogen peroxide (H2O2), carbamide peroxide (CP), and titanium dioxide bleaching systems. Methods Three bleaching systems with different concentrations (H2O2 15%, 38%, CP 15%, 35%, and titanium dioxide 20% H2O2) were used. Sixty participants with discolored teeth were enrolled and equally divided into six groups. Each group was rendered the assigned bleaching protocol against the control group, which received plain dentifrice polishing. Each case was evaluated immediately, two weeks, three months, six months, and one year after the bleaching treatment. The clinical evaluation was made for color change by (shade guide and digital images with L*a*b* parameters), tooth sensitivity, gingival irritation, and participants' satisfaction. Results All bleaching systems showed color improvement after bleaching regimens with significant effect showed by in-office titanium dioxide 20% H2O2 followed by 38% H2O2 with Δ=10.26 and Δ=6.52, respectively, when compared to other bleaching techniques. Higher sensitivity was recorded in group III with 50% of the participants reporting postoperative sensitivity. Higher gingival irritation was recorded in group IV (15% CP) where 60% of the patients reported gingival irritation. Thirty-five of the 60 participants (58.5%) recorded that the treatment whitened their teeth "moderately" and "a lot" while seven participants recorded "a slight" difference. There was a highly significant difference in participants' satisfaction between all bleaching groups (p < 0.05). Conclusion It is evident that there is a development of dental sensitivity and gingival irritation irrespective of the bleaching system used. The color assessment showed that the desired result can be achieved with variable levels of patient satisfaction with excellent overall results with the titanium dioxide system.

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Surfactants are amphiphilic substances that induce surface tension reduction, washing, and emulsification and are used for various purposes. Recently, biosurfactants manufactured from renewable resources and with high biocompatibility have gained increasing attention. Sophorolipid (SL), a type of biosurfactant derived from Starmerella bombicola, possesses detergency and emulsification properties, making it suitable for household and personal care applications. However, there are limited toxicological data on SLs. In this study, we conducted cytotoxicity and skin-irritation tests using SLs, revealing that cytotoxicity and skin irritation induced by SLs were extremely low (logIC 50 = 4.76 mg/L) and equivalent to those of solvents and oils used in personal care products.

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OBJECTIVE: To assess the level of agreement on various prevention and management strategies for irritation caused by topical retinoids in facial and trunk acne in an attempt to alleviate it and minimize treatment discontinuations as much as possible. METHOD: After reviewing the scientific medical literatura currently available, 4 different areas of uncertainty in the management of irritation caused by topical retinoids in acne were identified. A questionnaire with 34 recommendations was created and evaluated by a group of 133 dermatologists (Delphi methodology). RESULTS: In 82.3% of the recommendations (28 out of 34), some level of agreement was reached (≥85% agreement in 22 recommendations and≥70% agreement in 6). The results with the highest level of agreement focused on specific patient education strategies (explaining that irritation is an expected reaction at the beginning of treatment and tends to decrease over time), gradual and/or spaced application of topical retinoids (at night time to prevent and/or reduce skin irritation), and the importance of using adjuvant products, specific for acne-prone skin, hydration, photoprotection, and skin cleansing. These recommendations reflect a comprehensive approach to managing irritation associated with topical retinoids and promoting long-term adherence. CONCLUSIONS: Skin irritation caused by topical retinoids in facial and trunk acne is an expected, mild, and controllable reaction if proper prevention and management guidelines are followed, meaning that it should not be a reason for treatment discontinuation.

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This study explores the synthesis and characterization of superabsorbent hydrogels derived from chemically modified gum Arabic, designed for controlled folic acid release. The synthesis involves a two-step process: carboxymethylation followed by grafting with 2-hydroxyethyl methacrylate via gamma irradiation. The resulting hydrogels exhibit enhanced mechanical strength and controlled diffusivity, essential for nutrient delivery systems. Key factors such as copolymer composition and irradiation dose are investigated, affecting the synthesis process. Systematic studies of swelling behaviors reveal that the hydrogel achieves a maximum swelling of 888.1% at 40 °C. The hydrogels are loaded with folic acid, and in vitro, sustained release profiles are examined under various pH conditions. The maximum release of 83.3% is observed after 24 h at pH 7.0, following a Korsmeyer-Peppas release mechanism. Different characterization techniques, confirm the successful synthesis and unique properties of the superabsorbent hydrogels. Rheological behavior analysis, scanning electron microscopy, and biocompatibility assessments provide a comprehensive understanding of the hydrogel structures. Gamma irradiation ensures a homogeneous network structure, crucial for optimal swelling behavior and mechanical properties. This research highlights the potential of eco-friendly biopolymer hydrogels in precise drug delivery applications, leveraging the safety and process control benefits of gamma irradiation.

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The skin of newborns is classified as sensitive, with a higher risk of skin barrier disruption and irritation of a diapered area. Despite dermatologist recommendations to use only water and a cloth for cleaning, most of the population still relies on the comforts of modern parenting, which includes intensive daily usage of baby wet wipes. Novel baby formulations are designed following the concept of infant skin health, containing a gentle cleanser, suitable emollient, and buffer system enabling a slightly acidic pH value and they are free of ethyl alcohol. Thus, it is important to understand the chemical background of such a complex liquid formulation, with emphasis on its safety. In line with this, the present paper discusses the scientific background of various chemical compounds found in baby wipe formulations to improve the understanding of wet wipe designs and direct them toward more skin-friendly solutions.

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Biliary ascites due to spontaneous biliary duct perforation is a rare case presentation usually seen in the paediatric age group of 6-36 months. We are presenting the case of a 14-month-old baby with abdominal distention associated with abdominal pain, vomiting, fever, and a history of no passage of stools. Upon examination, the abdomen was tense and tender. On radiological investigations, gross free fluid was present in the abdominal cavity along with bowel obstruction and partial situs inversus of the spleen and stomach. The bowel obstruction was relieved by rectal stimulation, after which oral feeds were well tolerated. Bilious fluid was found on diagnostic paracentesis, confirming the diagnosis. The patient was managed further by broad-spectrum antibiotics and drainage of the free fluid. The management ranges from conservative treatment to Roux-en-Y anastomosis. A non-surgical diagnosis is uncommonly seen and helps improve the patient's prognosis if detected early. This case report highlights the importance of early diagnosis and non-surgical treatment modality in critical patients.

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Personal lubricants intended for local or systemic delivery via the vaginal route can induce vaginal irritation, damage the vaginal epithelial barrier which can enhance microbial entry, induce inflammation, and alter the microbiome of the vaginal ecosystem. Therefore, manufacturers of personal lubricants and medical devices are required to show biocompatibility and safety assessment data to support regulatory decision-making within a specified context of use. Furthermore, due to ethical concerns and the introduction of the 7th amendment of the European Council Directive which bans animal testing for cosmetic ingredients and products coupled with the Food and Drug Administration modernization Act 2.0 guidelines, there is a wave of drive to develop alternative test methods to predict human responses to chemical or formulation exposure. In this framework, there is a potential to use three-dimensional organotypic human vaginal-ectocervical tissue models as a screening tool to predict the vaginal irritation potential of personal lubricants and medicaments. To be physiologically relevant, the in vitro tissue models need to be reconstructed using primary epithelial cells of the specific organ or tissue and produce organ-like structure and functionality that recapitulate the in vivo-like responses. Through the years, progress has been made and vaginal tissue models are manufactured under controlled conditions with a specified performance criterion, which leads to a high level of reproducibility and reliability. The utility of vaginal tissue models has been accelerated in the last 20 years with an expanded portfolio of applications ranging from toxicity, inflammation, infection to drug safety, and efficacy studies. This article provides an overview of the state of the art of diversified applications of reconstructed vaginal tissue models and highlights their utility as a tool to predict vaginal irritation potential of feminine care products.

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Polyacrylamide hydrogel (PAAG) is widely regarded as a safe soft tissue filler and has been extensively utilized for cosmetic enhancements, such as breast and facial augmentation in China from 1997 until its ban in 2006. Common complications associated with its use include inflammation, infection, granulomas, fibrosis, gel migration, and facial and soft tissue deformities. This case report describes a 45-year-old Chinese woman who experienced PAAG migration into her mandible 24 years after facial augmentation, causing irritation of the mandibular alveolar nerve - apparently the first documented instance of this occurrence. Surgical intervention was necessary to remove the migrated gel and associated calcifications. A literature review explored adverse events and management strategies for PAAG complications in cosmetic procedures. While generally considered safe, this report underscores the importance of meticulous injection techniques and careful anatomical site selection to prevent such severe complications.

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Following the publication of the above article, the authors contacted the Editorial Office to explain that they had identified a pair of duplicate images in the control (Vehicle) group of mouse images in Fig. 1A on p. 1792. Specifically, the same image (corresponding correctly to the 'Day 5' experiment) was inadvertently chosen to represent the cutaneous manifestations of mice in the Vehicle group on 'Day 3' and 'Day 5' in Fig. 1A. This error arose as a consequence of repetitive application and duplication procedures within the image set, resulting in the inadvertent reuse of the same photo. Additionally, due to minimal alterations observed in the skin condition of mice from the control group following treatment, each mouse exhibited a similar appearance; this similarity further contributed to the delayed identification of this error during the paper revision stage. Consequently, this duplication of the same image was made as a result of insufficient scrutiny. The revised version of Fig. 1, showing the correct image for the 'Day 3' experiment in Fig. 1A, is shown on the next page. The authors can confirm that the error associated with the assembly of this figure did not have any significant impact on either the results or the conclusions reported in this study, and all the authors agree with the publication of this Corrigendum. The authors are grateful to the Editor of International Journal of Molecular Medicine for allowing them the opportunity to publish this; furthermore, they apologize to the readership of the Journal for any inconvenience caused. [International Journal of Molecular Medicine 43: 1789­1805, 2019; DOI: 10.3892/ijmm.2019.4098].