Dexamethasone sodium phosphate loaded nanoparticles for prevention of nitrogen mustard induced corneal injury.

Nitrogen mustard (NM) is a potent vesicating chemical warfare agent that is primarily absorbed through skin, inhalation, or ocular surface. Ocular exposure of NM can cause acute to chronic keratopathy which can eventually lead to blindness. There is a current lack of effective countermeasures against ocular exposure of NM despite their imperative need. Herein, we aim to explore the sustained effect of Dexamethasone sodium phosphate (DSP)-loaded polymeric nanoparticles (PLGA-DSP-NP) following a single subconjunctival injection in the management and prevention of corneal injury progression upon exposure to NM. DSP is an FDA approved corticosteroid with proven anti-inflammatory properties. We formulated PLGA-DSP-NP with zinc chelation ion bridging method using PLGA polymer, with particles of approximately 250 nm and a drug loading of 6.5 wt%. Under in vitro sink conditions, PLGA-DSP-NP exhibited a sustained drug release for two weeks. Notably, in NM injured cornea, a single subconjunctival (SCT) injection of PLGA-DSP-NP outperformed DSP eyedrops (0.1%), DSP solution, placebo NP, and saline, significantly mitigating corneal neovascularization, ulceration, and opacity for the two weeks study period. Through PLGA-DSP-NP injection, sustained DSP release hindered inflammatory cytokine recruitment, angiogenic factors, and endothelial cell proliferation in the cornea. This strategy presents a promising localized corticosteroid delivery system to effectively combat NM-induced corneal injury, offering insights into managing vesicant exposure.

Suppression of the caspase-1/GSDMD-mediated pyroptotic signaling pathway through dexamethasone alleviates corneal alkali injuries.

The pathological mechanism of corneal injuries mediated by alkali burns are associated with Nucleotide-binding oligomerization domain (NOD)-like receptor (NLR) family pyrin domain containing 3 protein (NLRP3)-related corneal sterile inflammation. Whether the executive protein gasdermin D (GSDMD) of pyroptosis mediated by the NLRP3 inflammasome is present in alkali-induced corneal lesions remains unclear. Dexamethasone (Dex) is a commonly used drug for ocular surface diseases that can maintain corneal transparency and anti-inflammatory effects by topical administration. Here, we presented evidence that the effect of Dex on the pyroptosis-related caspase-1/GSDMD pathway in corneal alkali burns (CABs). We assessed the clinical manifestations and histological characteristics of the placebo group, 0.05% Dex group, 0.1% Dex group on day 3 or day 7 postburn and the control group (healthy corneas). The expression of factors (including NLRP3, caspase-1, cleaved-caspase-1, GSDMD, GSDMD-N termini, pro-interleukin(IL)-1ß, IL-1ß, pro-IL-18 and IL-18) involved in the pyroptosis related caspase-1/GSDMD signaling pathway was demonstrated by molecular experiments in CAB. Alkali burns can upregulate the originally relatively dim expression of NLRP3, caspase-1, cleaved-caspase-1, GSDMD, GSDMD-N, pro-IL-1ß, pro-IL-18, IL-1ß and IL-18 in the healthy corneal epithelium and stroma. However, Dex can reverse the enhanced expression at the two timepoints. Corneal sterile inflammation can activate the NLRP3 inflammasome through the innate immune response mechanism and then activate the pyroptosis-related caspase-1/GSDMD signaling pathway. In addition, Dex can inhibit pyroptosis through this pathway.

Protective roles of the TIR/BB-loop mimetic AS-1 in alkali-induced corneal neovascularization by inhibiting ERK phosphorylation.

Hydrocinnamoyl-L-valylpyrrolidine (AS-1), a synthetic low-molecule mimetic of myeloid differentiation primary response gene 88 (MyD88), inhibits inflammation by disrupting the interaction between the interleukin-1 receptor (IL-1R) and MyD88. Here, we describe the effects of AS-1 on injury-induced increases in inflammation and neovascularization in mouse corneas. Mice were administered a subconjunctival injection of 8 µL AS-1 diluent before or after corneal alkali burn, followed by evaluation of corneal resurfacing and corneal neovascularization (CNV) by slit-lamp biomicroscopy and clinical assessment. Corneal inflammation was assessed by whole-mount CD45+ immunofluorescence staining, and corneal hemangiogenesis and lymphangiogenesis following injury were evaluated by immunostaining for the vascular markers isolectin B4 (IB4) and the lymphatic vascularized marker lymphatic vessel endothelial hyaluronan receptor 1 (LYVE1), respectively. Additionally, corneal tissues were collected to determine the expression of 35 cytokines, and we detected activation of IL-1RI, MyD88, and mitogen-activated protein kinase (MAPK). The results showed that alkali conditions increased the number of CD45+ cells and expression of vascular endothelial growth factor (VEGF)-A, VEGF-C, and LYVE1 in corneas, with these levels decreased in the AS-1-treated group. Moreover, AS-1 effectively prevented alkali-induced cytokine production, blocked interactions between IL-1RI and MyD88, and inhibited MAPK activation post-alkali burn. These results indicated that AS-1 prevented alkali-induced corneal hemangiogenesis and lymphangiogenesis by blocking IL-1RI-MyD88 interaction, as well as extracellular signal-regulated kinase phosphorylation, and could be efficacious for the prevention and treatment of corneal alkali burn.

Quemadura con cloroformiato de etilo en ocasión de la respuesta a una emergencia química. A propósito de un caso / Burning by Ethyl chloroformate in response to a chemical emergency. A case report

Resumen Se describe un caso de quemadura causada por cloroformiato de etilo en ocasión de la respuesta a un incidente que requirió el trasvase del producto desde contenedores defectuosos a otros seguros. La investigación del evento puso en evidenciala necesidad de mantener un protocolo de registro de materiales que ingresan a la zona caliente, que debe ser tenido en cuentaal momento del retiro de los mismos, procediendo a su correcta descontaminación bajo la fiscalización del oficial de seguridad.

Abstract A burn by Ethyl chloroformate in occasion of response to a chemical emergency which required to transfer products from defective containers to safe containers is described. The investigation of the event highlighted the need to maintain aprotocol for the registration of materials to be entered in the hot zone, which must be considered al the moment of remove andproceeding to the proper decontamination under the supervision of the security officer.

Rapamycin ameliorates corneal injury after alkali burn through methylation modification in mouse TSC1 and mTOR genes.

Alkali burn to the cornea is one of the most intractable injuries to the eye due to the opacity resulting from neovascularization (NV) and fibrosis. Numerous studies have focused on studying the effect of drugs on alkali-induced corneal injury in mouse, but fewer on the involvement of alkali-induced DNA methylation and the PI3K/AKT/mTOR signaling pathway in the mechanism of alkali-induced corneal injury. Thus, the aim of this study was to determine the involvement of DNA methyltransferase 3 B-madiated DNA methylation and PI3K/AKT/mTOR signaling modulation in the mechanism of alkali-induced corneal injury in a mouse model. To this end, we used bisulfite sequencing polymerase chain reaction and Western blot analysis, to study the effects of 5-aza-2'-deoxycytidine and 2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one, which inhibit methyltransferase and PI3K respectively, on DNA methylation and expression of downstream effectors of PI3K related to corneal NV, including TSC1 and mTOR genes. The results showed that, after an intraperitoneal injection of rapamycin (2 mg/kg/day) for seven days, the alkali-induced opacity and NV were remarkably decreased mainly by suppressing the infiltration of immune cells into injured corneas, angiogenesis, VEGF expression and myofibroblasts differentiation; as well as by promoting corneal cell proliferation and PI3K/AKT/mTOR signaling. More significantly, these findings showed that epigenetic regulatory mechanisms by DNA methylation played a key role in corneal NV, including in corneal alkali burn-induced methylation modification and rapamycin-induced DNA demethylation which involved the regulation of the PI3K/AKT/mTOR signaling pathway at the protein level. The precise findings of morphological improvement and regulatory mechanisms are helpful to guide the use of rapamycin in the treatment of corneal angiogenesis induced by alkaline-burn.

Nuclear magnetic resonance-based plasma metabolomics revealed the protective effect of tea polyphenols on sulfur mustard-induced injury in rats.

Tea polyphenols (TP) are the major antioxidant components from tea, which could be beneficial to oxidative stress injury, such as sulfur mustard (SM) exposure. However, the holistic efficacy of TP on SM poisoning remains unexplored and needs further investigation. In this study, Nuclear magnetic resonance(NMR)-based metabolomics along with multivariate statistical analysis was used to explore the metabolic alteration after SM injury and the protective mechanism of TP. Thirteen potential plasma biomarkers of SM injury were identified, which primarily related to synthesis of ketone bodies, arginine and proline metabolism, butanoate metabolism and alanine aspartate and glutamate metabolism. After TP pre-treatment, the biomarkers were mostly restored to normal levels, which suggested that TP provided effective protection against SM injury and might play its role by rebalancing disordered metabolism pathways. This work enhanced our comprehension of the metabolic profiling of SM injury and revealed the protective mechanism of TP.

Epidemiology of isolated adult lower limb burns over 15 years with a focus on preventable work-related injuries.

Our aim was to describe the epidemiology of isolated adult lower limb burns presenting to the Pinderfields Regional Burns Centre, Wakefield, United Kingdom between 2003 and 2018. Data was obtained using our local records of the international Burn Injury Database (iBID). 6059 patients were treated in our department during this period. 18.7% presented with isolated lower limb burns (n = 1133). 65.4% of patients were male (n = 741). Scald was the most common mechanism of injury. Work-related burns accounted for 23.4% of the injuries (n = 265). 36% of patients were admitted (n = 408), and 11.7% underwent surgical intervention (n = 133). Isolated lower limb burns are common in patients in the working age group. Work-related injuries are preventable. Targeted education to highlight the risks, reduce the incidence, and improve awareness of first aid measures are recommended.

Ocular chemical burns in the workplace: Epidemiological characteristics.

BACKGROUND: Epidemiological studies focusing on occupational pathologies can be an important medium through which to bring about change with respect to workplace accidents, both in terms of prevention planning and management as well as the appropriate care following an accident. Ocular chemical burns benefit from urgent attention as, if not treated early and appropriately, the tissue of the eye and its functionality can be seriously compromised. The objective of this study was to collate epidemiological data on workplace ocular chemical burns which could in turn serve to identify key action points in terms of occupational health. METHODS: Cohort study with 604 cases of chemical burns to the eye occurring in the workplace between 2014 and 2015. Criteria inclusion were diagnosis of chemical burn, patient seen at the medical centre of the mutual society, workplace acquired ophthalmic pathology leading to the issuing of a sickness certificate. No exclusion criteria were defined. RESULTS: Ocular chemical burns were the second most common workplace eye injury (12.68%) behind foreign bodies in the eye (43.42%). Men accounted for 68.54% of cases of ocular chemical burns. In around 75% of cases, sickness certification was for less than 7 days, although 6 patients suffered permanent disability. The occupational sector which was most affected particularly the industry service industry. The economic costs with these workplace injuries were extracted. CONCLUSIONS: Appropriate early medical assistance is essential. The production and distribution of clinical guides for health care workers could optimise first line assistance and mitigate possible training deficiencies.

Cosmetic-Related Pediatric Exposures Are a Main Source of Calls to Poison Centers.

Storage precautions like those for medications are recommended.

Efficacy of Sunitinib, Sunitinib-Hesperetin, and Sunitinib-Doxycycline Combinations on Experimentally-Induced Corneal Neovascularization.

Purpose: To investigate the preventive effects of topical sunitinib, sunitinib-hesperetin and sunitinib-doxycycline combinations on corneal neovascularization (CNV), apoptosis and fibrosis in a corneal alkali burn model. Materials and Methods: The corneas of 32 Wistar albino rats were cauterized with silver nitrate to induce CNV. Four groups were created receiving artificial tears (sham), sunitinib (0.5 mg/ml), sunitinib-hesperetin (0.5 mg/ml-0.2 mg/ml), and sunitinib-doxycycline (0.5 mg/ml-20 mg/ml) treatments. Corneal photographs were taken on days 0, 7 and 15 . Photographs of the cornea were digitally analyzed to measure the size of the neovascularization area in comparison to the total corneal surface area. On the 15th day, the animals were euthanized, and the eyes were enucleated for immunohistochemical staining to investigate neovascularization, apoptosis, and fibrosis. Results: CNV areas on the 7th day in the sunitinib (4.8% ± 0.07%) and sunitinib-hesperetin (1.1% ± 0.03%) groups were smaller than those in the sham group (33.9% ± 0.12%) (p = 0.001 and, p < 0.001 respectively). On the 15th day, the CNV area in the sunitinib-hesperetin (20.8% ± 0.37%) group was significantly smaller than that of the sham group (74.6% ± 0.32%) (p = 0.039). The combination groups had lower levels of VEGF, TUNEL and α-SMA positivity than the sunitinib monotherapy group. TUNEL positivity was lowest in the sunitinib-hesperetin and sunitinib-doxycycline groups, and α-SMA positivity was lowest in the sunitinib-hesperetin group. Conclusion: Topical sunitinib-hesperetin was more effective than sunitinib alone and the sunitinib-doxycycline combination in the treatment of CNV. The combination of sunitinib and hesperetin seems to be a promising treatment for preventing corneal fibrosis and apoptosis.

Protective Effect of TLR4 Ablation against Corneal Neovascularization following Chemical Burn in a Mouse Model.

PURPOSE: To determine whether Toll-like receptor 4 knockout protects mice from corneal neovascularization following chemical injury compared to wild-type (WT) mice. METHODS: A chemical burn (75% silver nitrate, 25% potassium nitrate) was created under anesthesia in the central right cornea of 32 WT and 31 Toll-like receptor 4 knockout mice. Corneal neovascularization was evaluated at 3, 4, 6, 8, 10, and 35 days after injury using digital photography, fluorescein angiography, gelatin perfusion with fluorescence vascular imaging, immunofluorescence staining, and molecular analysis. RESULTS: There was no significant between-group difference in relative corneal burn area at 10 days after injury (39.0 ± 2.4% vs. 38.8 ± 9.8%, respectively). Neovascularization was detected in all corneas in vivo and perfusion was detected by fluorescence vascular imaging, reaching maximum area on day 10. The relative area of neovascularization was significantly smaller in the knockout than the WT mice on days 6 (33.3 ± 4.2% vs. 46.8 ± 7.4%, respectively, p = 0.005) and 8 (36.6 ± 1.1% vs. 52.2 ± 6.4%, respectively, p = 0.027), although neovascularization was intensive in both groups. In line with the immunostaining findings of angiogenesis and inflammatory infiltration of damaged corneas, molecular analysis (performed on day 3) revealed elevated expression levels of angiogenesis-related genes (vascular endothelial growth factor, VEGFR2, VEGFR1) and inflammation-related genes (CD45 and TGFß1) in the WT mice. The knockout mice had higher TNF-α expression than the WT mice. CONCLUSION: In a mouse corneal chemical burn model, lack of Toll-like receptor 4 expression did not completely inhibit angiogenesis, but did have a relative effect to reduce neovascularization as compared to the WT.

Prevention of Corneal Neovascularization by Adenovirus Encoding Human Vascular Endothelial Growth Factor Soluble Receptor (s-VEGFR1) in Lacrimal Gland.

Purpose: The aims of this study were (1) to determine the efficacy of adenovirus vector serotype 5 (Ad) encoding human soluble VEGF receptor 1 (s-VEGFR1) gene transfer to the lacrimal gland (LG); (2) to investigate whether expression of s-VEGFR1 prevents corneal neovascularization (CNV) induced by alkali burns; and (3) to evaluate the safety of the procedure. Methods: AdVEGFR1 vectors (25 µL, 1 × 1010 pfu/mL) were injected in the right LGs of rats and were compared with AdNull vector (25 µL, 1 × 1010 pfu/mL) or 25 µL of saline (Control) before cornea alkali burns with 1 M NaOH. After 7 days, CNV was documented at the slit lamp. Tear secretion was measured with phenol red threads. The animals were tested for s-VEGFR1 mRNA and protein in the LG by quantitative (q)PCR and immunohistochemistry staining, respectively. qPCR was used to compare the mRNA levels of IL-1ß, IL-6, and TNF-α in the LG and ipsilateral trigeminal ganglion (TG). Results: Ad-VEGFR1 transfected 83% (10/12) of the rats. VEGFR1 was present in LG acinar cells. CNV was prevented in 9 of 12 animals in the Ad-VEGFR1 group, compared with the Ad-Null (3:10) and Control groups (1:10) (P = 0.0317). The tear secretion and cytokine mRNA levels in the LG and TG were similar in all three groups (P > 0.05). Conclusions: Adenoviral vector gene transfer was safe for LG structure and function. The LG as the target tissue showed local expression of human s-VEGFR1, and CNV was prevented in most of the eyes exposed to alkali burns.

[How to improve the prevention and treatment of ocular chemical burns in China: important elements].

Ocular chemical burns are common and serious ocular emergencies which require immediate and intensive evaluation and treatment. Loss of vision and disfigurement affect the victims, bringing great sufferings to themselves and their families. China is the biggest developing country in the world with a large number of such cases. The prevention of ocular chemical burns is emphasized in different aspects. After emergency treatment, proper care of chemical burns is started by control of inflammation with corticosteroids. Topical and systemic ascorbic acid supplement is important. Re-epithelialization is critical to stabilize the ocular surface and to prevent corneal ulceration and melting. The goal of treatment is mainly to restore the ocular structure and function. Neuroprotection is important during the treatment course for control of both glaucoma and inflammation. Prognosis depends on the degree of limbal, corneal and conjunctival involvement at the time of injury as well as the management. Medical treatments only or with combination of surgical procedures, including amniotic membrane transplantation, epithelial or limbal stem cell transplantation, tenonplasty, keratoplasty and keratoprosthesis, are according to the classification of ocular chemical burns and the phases. Further investigations should be done in the future in both prevention and management of ocular chemical burns in China. (Chin J Ophthalmol, 2018, 54: 401-405).

A Chemical-Biological-Radio-Nuclear (CBRN) Filter can be Added to the Air-Outflow Port of a Ventilator to Protect a Home Ventilated Patient From Inhalation of Toxic Industrial Compounds.

OBJECTIVES: Chemical-biological-radio-nuclear (CBRN) gas masks are the standard means for protecting the general population from inhalation of toxic industrial compounds (TICs), for example after industrial accidents or terrorist attacks. However, such gas masks would not protect patients on home mechanical ventilation, as ventilator airflow would bypass the CBRN filter. We therefore evaluated in vivo the safety of adding a standard-issue CBRN filter to the air-outflow port of a home ventilator, as a method for providing TIC protection to such patients. METHODS: Eight adult patients were included in the study. All had been on stable, chronic ventilation via a tracheostomy for at least 3 months before the study. Each patient was ventilated for a period of 1 hour with a standard-issue CBRN filter canister attached to the air-outflow port of their ventilator. Physiological and airflow measurements were made before, during, and after using the filter, and the patients reported their subjective sensation of ventilation continuously during the trial. RESULTS: For all patients, and throughout the entire study, no deterioration in any of the measured physiological parameters and no changes in measured airflow parameters were detected. All patients felt no subjective difference in the sensation of ventilation with the CBRN filter canister in situ, as compared with ventilation without it. This was true even for those patients who were breathing spontaneously and thus activating the ventilator's trigger/sensitivity function. No technical malfunctions of the ventilators occurred after addition of the CBRN filter canister to the air-outflow ports of the ventilators. CONCLUSIONS: A CBRN filter canister can be added to the air-outflow port of chronically ventilated patients, without causing an objective or subjective deterioration in the quality of the patients' mechanical ventilation. (Disaster Med Public Health Preparedness. 2018;12:739-743).

Evaluación de lesiones esofágicas secundarias a la ingesta de sustancias cáusticas no rotuladas: Serie de casos pediátricos / Evaluation of esophageal injuries secondary to ingestion of unlabeled corrosive substances: pediatric case series

Las lesiones esofágicas o gástricas secundarias a la ingesta de sustancias cáusticas siguen siendo un problema importante en los países en vías de desarrollo. El espectro clínico puede variar desde la ausencia de una lesión en la mucosa hasta complicaciones tales como quemaduras graves, estenosis y perforación. El examen físico y la evaluación endoscópica inicial son sumamente importantes para el diagnóstico. El objetivo de este estudio es presentar los casos de 154 niños sometidos a una endoscopía digestiva alta debido a la ingesta de sustancias cáusticas, entre otras, desincrustante químico, desengrasante, lavandina no rotulada, limpiador de tuberías de desagüe, limpiador de superficies, abrillantador de vajilla y ácido clorhídrico. Se observaron signos orofaríngeos positivos en 69 niños. Con la endoscopía inicial, se hallaron quemaduras en 63 niños; en 40, las quemaduras eran graves. Durante el seguimiento, se produjo estenosis en 20 niños, que fueron incluidos en el programa de dilatación. Entre ellos, fue posible dilatar e inyectar corticoides intralesionales satisfactoriamente a 14 niños. Sin embargo, tres niños fueron sometidos a una interposición de colon, y otros tres, a una gastroduodenostomía y gastroyeyunostomía.

Esophageal or gastric injuries secondary to caustic substance ingestion is still an important issue in developing countries. Its clinical spectrum can vary from absence of mucosal injury to complications such as severe burns, strictures and perforation. Physical examination and first endoscopic evaluation are very important in the diagnosis. The objective of this study is to present 154 children who were undergone upper gastrointestinal endoscopy because of caustic substance ingestion including descaler, degreaser, unlabeled bleach, drain opener, surface cleaner, dishwasher rinse aid, hydrochloric acid. Sixty-nine children had positive oropharyngeal findings. Sixty-three children were found to have burns in the first endoscopic examination and forty of these burns were severe burn. In the follow-up, twenty children developed strictures that were undergone dilatation program. Fourteen children in the dilatation program had successful dilatation and intralesional steroid injection. However three children had undergone colonic interposition and three undergone laparoscopic gastroduodenostomy and gastrojejunostomy.

Evaluation of esophageal injuries secondary to ingestion of unlabeled corrosive substances: pediatric case series. / Evaluación de lesiones esofágicas secundarias a la ingesta de sustancias cáusticas no rotuladas: Serie de casos pediátricos.

Esophageal or gastric injuries secondary to caustic substance ingestion is still an important issue in developing countries. Its clinical spectrum can vary from absence of mucosal injury to complications such as severe burns, strictures and perforation. Physical examination and first endoscopic evaluation are very important in the diagnosis. The objective of this study is to present 154 children who were undergone upper gastrointestinal endoscopy because of caustic substance ingestion including descaler, degreaser, unlabeled bleach, drain opener, surface cleaner, dishwasher rinse aid, hydrochloric acid. Sixty-nine children had positive oropharyngeal findings. Sixtythree children were found to have burns in the first endoscopic examination and forty of these burns were severe burn. In the follow-up, twenty children developed strictures that were undergone dilatation program. Fourteen children in the dilatation program had successful dilatation and intralesional steroid injection. However three children had undergone colonic interposition and three undergone laparoscopic gastroduodenostomy and gastrojejunostomy.

Las lesiones esofágicas o gástricas secundarias a la ingesta de sustancias cáusticas siguen siendo un problema importante en los países en vías de desarrollo. El espectro clínico puede variar desde la ausencia de una lesión en la mucosa hasta complicaciones tales como quemaduras graves, estenosis y perforación. El examen físico y la evaluación endoscópica inicial son sumamente importantes para el diagnóstico. El objetivo de este estudio es presentar los casos de 154 niños sometidos a una endoscopía digestiva alta debido a la ingesta de sustancias cáusticas, entre otras, desincrustante químico, desengrasante, lavandina no rotulada, limpiador de tuberías de desagüe, limpiador de superficies, abrillantador de vajilla y ácido clorhídrico. Se observaron signos orofaríngeos positivos en 69 niños. Con la endoscopía inicial, se hallaron quemaduras en 63 niños; en 40, las quemaduras eran graves. Durante el seguimiento, se produjo estenosis en 20 niños, que fueron incluidos en el programa de dilatación. Entre ellos, fue posible dilatar e inyectar corticoides intralesionales satisfactoriamente a 14 niños. Sin embargo, tres niños fueron sometidos a una interposición de colon, y otros tres, a una gastroduodenostomía y gastroyeyunostomía.

Avoiding Chlorhexidine Burns in Preterm Infants.

Chlorhexidine is a skin antiseptic agent frequently used for off-label indications in NICUs. Changes to the safety labeling of chlorhexidine products for use in preterm infants were recently made because of the risk of severe chemical burns. We provide tips for a safer use of chlorhexidine to prevent injury in newborns and to help health care professionals protect themselves against burn injury claims.