Abnormal Barrier Research Articles

Barriers of the CNS transfer rate dynamics in patients with vascular cognitive impairment and dementia.

Advances in in vivo MRI techniques enable cerebral barrier transfer rates (K trans ) measurement in patients with vascular cognitive impairment and dementia (VCID). However, a consensus has not been reached on the dynamic contribution and importance of cerebral barrier abnormalities to the differential diagnosis of dementia subtypes. Our goal was to investigate the dynamics of blood-brain barrier (BBB) and blood-CSF barrier (BCSFB) K trans in patients with VCID longitudinally and determine the effect of aging. We studied subjects at two time points over two years; they were 65.5 years of age (SD = 15.94, M/F = 24/14) at the first visit. We studied 38 patients, 18 of whom had two visits. We calculated the BBB and BCSFB K trans with dynamic contrast-enhanced T1 MR, and we used 1H-MR spectroscopy to measure N-acetylaspartate (NAA) levels in the white matter as a marker of injury. In addition, we measured CSF levels of active-matrix metalloproteinase-3 (MMP3) as an inflammatory biomarker to aid in patient clustering. Longitudinal BBB measurements revealed variable dynamic behavior: after two years, the BBB K trans increased in 55% of patients and decreased in the remaining 45% unpredictably. We did not find a significant linear model of BBB K trans versus age for VCID. For healthy controls, the model was K trans = 0.0014 + 0.0002 × age, which was significant (p = 0.046). VCID patients showed a reduction in BCSFB K trans compared to healthy controls (p = 0.01). Combining NAA, CSF MMP3, and K trans in a clustering analysis separated patients into groups. These results suggest that BBB K trans in VCID is dynamic and BCSFB K trans reduced by age. By combining inflammatory biomarkers with BBB K trans data, it is possible to separate VCID patients into distinct groups with different underlying pathologies.

High‐Throughput Microfluidic 3D Outer Blood‐Retinal Barrier Model in a 96‐Well Format: Analysis of Cellular Interactions and Barrier Function in Retinal Health and Disease

AbstractNumerous diseases, including age‐related macular degeneration (AMD), arise from the blood‐retinal barrier and blood vessel abnormalities in the eye; unfortunately, there is a lack of reliable in vitro models for their systematic study. This study describes a high‐throughput microphysiological system (MPS) designed to model the outer Blood‐Retinal Barrier (oBRB). The MPS platform is engineered to integrate seamlessly with high‐content screening technologies, utilizing a design with a single oBRB model incorporating RPE (retina pigment epithelial cells) and endothelial cell co‐culture to fit within a single 96‐well. Arranged in the standard 96‐well plate format, the platform allows high‐throughput assessment of barrier integrity through 3D confocal imaging (ZO‐1 staining), Trans Epithelial Electrical Resistance (TEER), and permeability measurements. The oBRB model enables the investigation of crosstalk among different cell types in co‐culture. This includes assessing changes in the barrier integrity of the Retinal Pigment Epithelium (RPE) monolayer and investigating neovascularization events resulting from endothelial cell remodeling. The platform is positioned for utility in drug discovery and development efforts targeting diseases involving oBRB damage and choroidal neovascularization, such as age‐related macular degeneration.

A prospective study evaluating the correlation between local weather conditions, pollen counts and pruritus of dogs with atopic dermatitis.

Canine atopic dermatitis (cAD) is a hereditary, generally pruritic and predominantly T-cell-driven inflammatory skin disease, involving an interplay between skin barrier abnormalities, allergen sensitisation and microbial dysbiosis. The individual immunological response is predominantly against environmental allergens, including mite antigens; mould spores; and pollen from grasses, trees and weeds. Airborne pollens show fluctuating patterns during the year. The aim of this prospective study was to evaluate the influence of local pollen concentrations and weather conditions on the clinical signs of atopic dogs, and to investigate any possible correlations with the results of intradermal testing (IDT). Thirty-seven privately owned atopic dogs in Bavaria were surveyed from 1 April to 30 November 2021. Owners were asked to record pruritus using a validated Visual Analog Scale (PVAS) score and the weekly medication of their dog. Furthermore, weather data, including pollen count, rainfall, relative humidity, hours of sunshine and temperature from the dog's location were collected daily. Of the evaluated parameters, only humidity and medication scores correlated positively with the PVAS scores of the atopic dogs. There was no correlation between specific pollen counts and PVAS scores of dogs with positive IDT reactions to that pollen. The outcome of this study highlights the importance of a careful interpretation of positive IDT results in dogs with cAD and questions the validity of airborne pollen trap methodology in representing pollen exposure for dogs at ground level.

Longitudinal Correlations between Molecular Compositions of Stratum Corneum and Breast Milk Factors during Infancy: A Prospective Birth Cohort Study.

Breast milk contains numerous factors that are involved in the maturation of the immune system and development of the gut microbiota in infants. These factors include transforming growth factor-β1 and 2, immunoglobin A, and lactoferrin. Breast milk factors may also affect epidermal differentiation and the stratum corneum (SC) barrier in infants, but no studies examining these associations over time during infancy have been reported. In this single-center exploratory study, we measured the molecular components of the SC using confocal Raman spectroscopy at 0, 1, 2, 6, and 12 months of age in 39 infants born at our hospital. Breast milk factor concentrations from their mothers' breast milk were determined. Correlation coefficients for the two datasets were estimated for each molecular component of the SC and breast milk factor at each age and SC depth. The results showed that breast milk factors and molecular components of the SC during infancy were partly correlated with infant age in months and SC depth, suggesting that breast milk factors influence the maturation of the SC components. These findings may improve understanding of the pathogenesis of skin diseases associated with skin barrier abnormalities.

Immunoexpression of IL-33 in the different clinical aspects of canine atopic dermatitis

Canine atopic dermatitis (CAD) is a chronic and inflammatory skin condition with a multifaceted origin, involving genetic factors, skin barrier abnormalities, immune responses, and hypersensitivity to various allergens. Interleukin 33 (IL-33), released by keratinocytes upon cellular injury, plays a crucial role in atopic dermatitis pathogenesis by inducing Th2 lymphocyte-mediated immune responses. This study aimed to evaluate IL-33 expression in dogs with atopic dermatitis and compare it to a control group. Forty-nine dogs were included, with 39 having atopic dermatitis, subdivided into groups based on clinical characteristics, and ten in the control group. Lesion and pruritus scores were assessed, and incisional biopsies were analyzed for dermatopathological characteristics. IL-33 expression was evaluated using immunohistochemistry, the analyses were blinded, based on the measurement of immunostaining areas using Image Pro-Plus software, version 4.5, relying on a semi-automatic color segmentation method, where the tissue immunostaining area for each biomarker was artificially delimited and quantified. Statistically significant differences in IL-33 immunostaining were found among groups (P=0.0005). Lichenified dogs (group 4) exhibited higher immunostaining compared to erythema (group 3) (P=0.0006), alesional pruritus (group 2) (P=0.0261), and the control group (group 1) (P=0.0079). IL-33 immunostaining increased with lesion progression, strongly correlating with lesion scores (P<0.0001), particularly in patients with chronic lesions characterized by erythema and lichenification. These findings suggest IL-33's significant role in canine atopic dermatitis pathogenesis and its association with lesion and inflammation scores during the chronic phase. This suggests potential therapeutic interventions targeting IL-33 or its receptors, though further studies are needed to explore these possibilities.

Does sensitive skin lie in epidermal barrier impairment or abnormalities? Results from an observational study assessing biophysical parameters.

The pathophysiology of sensitive skin is largely unknown and no univocal data on the role of the epidermal barrier impairment have been identified. The aim of this study was to assess whether subjects with or without sensitive skin differ for some biophysical skin parameters, which reflect skin barrier integrity or skin hyperactivity. This observational, cross-sectional study included adult volunteers not affected with chronic inflammatory skin diseases who attended the Unit of Dermatology and the Center of Cosmetology of the University of Ferrara, Ferrara, Italy, between March 2021 and November 2022. All subjects, subdivided into those with or without sensitive skin, based on either Lactic Acid Stinging Test (LAST) result or a questionnaire-based skin sensitivity score ≥4, were tested for transepidermal water loss (TEWL), skin elasticity and hydrations and dermographism. One hundred and eighty-seven subjects were included. No significant differences in terms of TEWL, elasticity and hydration levels were recorded between subjects with sensitive skin and those without, subdivided according to both the LAST result and the questionnaire score. Dermographism was elicited more in subjects with sensitive skin than in the others, although without statistical significance. The study failed to find significant biophysical differences between sensitive and non-sensitive skin. Therefore, the role of skin barrier impairment does not appear to be a necessary condition in determining an abnormal skin sensitivity to potentially unpleasant and irritating stimuli. These findings indirectly support the relevance of a peripheral sensory neural hyperactivity in the pathophysiology of sensitive skin.

Targeting IL-13 with tralokinumab normalizes type 2 inflammation in atopic dermatitis both early and at 2 years.

Tralokinumab is a monoclonal antibody that specifically neutralizes interleukin (IL)-13, a key driver of skin inflammation and barrier abnormalities in atopic dermatitis (AD). This study evaluated early and 2-year impacts of IL-13 neutralization on skin and serum biomarkers following tralokinumab treatment in adults with moderate-to-severe AD. Skin biopsies and blood samples were evaluated from a subset of patients enrolled in the Phase 3 ECZTRA 1 (NCT03131648) and the long-term extension ECZTEND (NCT03587805) trials. Gene expression was assessed by RNA sequencing; protein expression was assessed by immunohistochemistry and immunoassay. Tralokinumab improved the transcriptomic profile of lesional skin by Week 4. Mean improvements in the expression of genes dysregulated in AD were 39% at Week 16 and 85% at 2 years with tralokinumab, with 15% worsening at Week 16 with placebo. At Week 16, tralokinumab significantly decreased type 2 serum biomarkers (CCL17/TARC, periostin, and IgE), reduced epidermal thickness versus placebo, and increased loricrin coverage versus baseline. Two years of tralokinumab treatment significantly reduced expression of genes in the Th2 (IL4R, IL31, CCL17, and CCL26), Th1 (IFNG), and Th17/Th22 (IL22, S100A7, S100A8, and S100A9) pathways as well as increased expression of epidermal differentiation and barrier genes (CLDN1 and LOR). Tralokinumab also shifted atherosclerosis signaling pathway genes (SELE, IL-37, and S100A8) toward non-lesional expression. Tralokinumab treatment improved epidermal pathology, reduced systemic markers of type 2 inflammation, and shifted expression of key AD biomarkers in skin towards non-lesional levels, further highlighting the key role of IL-13 in the pathogenesis of AD. NCT03131648, NCT03587805.

Sweat Protects against Contact Hypersensitivity: Transient Sweat Suppression Compromises Skin Barrier Function in Mice

Although subtle barrier defects may facilitate allergen penetration, thereby enabling allergic sensitization, the relationship between sweating disturbance and skin barrier function is unknown. However, many studies on contact hypersensitivity in mice examined ear skin, which does not sweat, instead of the footpad, where sweating is uniquely present. In this study, we assessed whether sweat suppression in the footpad before hapten application provoked a skin barrier abnormality and reduced inflammatory thresholds to topical haptens. Mice without any genetic skin barrier dysfunction displayed markedly reduced inflammatory thresholds to haptens under transient sweat suppression before hapten application. Epicutaneously applied haptens penetrated the skin more robustly in the presence of sweat suppression compared with that in its absence, although this increase was abolished by exposure to high-humidity conditions. These mice displayed a subtle atopic dermatitis-like inflammation mediated by type 2 response-dominant inflammation and increased IgE responses, mimicking some events occurring in nonlesional atopic dermatitis skin in humans and in murine models. These lesions were dramatically attenuated by exposure to high-humidity conditions. In our model, hapten sensitization does not require mechanical injury, explaining why sensitization occurs through nonlesional atopic dermatitis skin. Awareness of the importance of preserving sweating responses is essential to prevent occupational contact dermatitis and atopic dermatitis.

The Function of Necroptosis and Its Treatment Target in IBD.

Inflammatory bowel disease (IBD), which encompasses Crohn's disease (CD) and ulcerative colitis (UC), is a complicated illness whose exact cause is yet unknown. Necroptosis is associated with IBD pathogenesis, leading to intestinal barrier abnormalities and uncontrolled inflammation. Molecules involved in necroptosis, however, exhibit different expression levels in IBD and its associated colorectal cancer. Multiple studies have shown that inhibiting these molecules alleviates necroptosis-induced IBD. Moreover, due to the severe scarcity of clinical medications for treating IBD caused by necroptosis, we review the various functions of crucial necroptosis molecules in IBD, the stimuli regulating necroptosis, and the current emerging therapeutic strategies for treating IBD-associated necroptosis. Eventually, understanding the pathogenesis of necroptosis in IBD will enable the development of additional therapeutic approaches for the illness.

Minipuberty period of children with atopic dermatitis compared to healthy children.

Atopic dermatitis (AD) is an inflammatory, pruritic, noncontagious, chronic relapsing skin disease. Skin barrier abnormalities, excessive T helper 2 activity, and immune dysregulation are held responsible. Androgens have a negative effect on the integrity of the epidermal skin barrier, while estrogen has a positive effect. We aimed to investigate whether hormones make a difference between healthy children and children with AD during minipuberty. A total of 96 infants (postnatal 4-13 weeks), 48 diagnosed with AD and 48 controls, were included. Each group consisted of 23 girls (47.9%) and 25 boys (52.1%). Anthropometric examinations and hormone measurements were compared. The two groups, having similar age, sex, body mass index, and weight-for-length standard deviation scores, were compared. Serum free thyroxine (FT4) levels were found to be lower and insulin-like growth factor binding protein-3 (IGFBP3) levels were found to be higher in children with AD (p < 0.001 and p = 0.038, respectively). In girls with AD, estradiol, FT4, and insulin-like growth factor-1 (IGF-1) levels were found to be lower, but thyroid-stimulating hormone (TSH) levels were found to be higher (p = 0.023, p < 0.001, p = 0.038, and p = 0.034, respectively). In boys with AD, the FT4 level was found to be lower (p = 0.023). Serum FT4 and TSH levels were within normal reference ranges in all comparisons. Especially in girls with AD, decreased estradiol and IGF-1 levels were observed compared to the controls during minipuberty. In the logistic regression model, decreased levels of serum estradiol, dehydroepiandrosterone sulfate, FT4, and IGF-1, and increased levels of IGFBP3 were associated with an increased likelihood of exhibiting atopic dermatitis.

Comparison of skin barrier abnormalities and epidermal ceramide profiles among three ω-O-acylceramide synthesis-deficient mouse strains

BackgroundThe epidermis contains many structurally diverse ceramides, which form the skin permeability barrier (skin barrier). Mutations in genes involved in the synthesis of ω-O-acylceramides (acylceramides) and protein-bound ceramides cause ichthyosis. ObjectiveWe aimed to elucidate the relationship between the degree of skin barrier impairment and changes in epidermal ceramide profiles caused by mutations in acylceramide synthesis genes. MethodsKnockout (KO) mice of three genes—fatty acid (FA) ω-hydroxylase Cyp4f39 (human CYP4F22 ortholog), FA elongase Elovl1, and acyl-CoA synthetase Fatp4—were subjected to transepidermal water loss measurement, toluidine blue staining, and epidermal ceramide profiling via liquid chromatography coupled with tandem mass spectrometry. ResultsTransepidermal water loss was highest in Cyp4f39 KO mice, followed by Elovl1 KO and Fatp4 KO mice, and Cyp4f39 KO mice also showed the strongest degree of toluidine blue staining. In Cyp4f39 KO, Elovl1 KO, and Fatp4 KO mice, acylceramide levels were 0.6%, 1.6%, and 12%, respectively, of those in wild-type mice. Protein-bound ceramide levels were 0.2%, 30%, and 33%, respectively, of those in wild-type mice. We also observed a near-complete absence of ω-hydroxy ceramides in Cyp4f39 KO mice, reduced total ceramide levels and shortened FA moieties in Elovl1 KO mice, and increased hydroxylated ceramide levels and slightly shortened FA moieties in Fatp4 KO mice. ConclusionsThe degree of reduction in protein-bound ceramide levels is probably related to the severity of skin barrier defects in these three strains. However, reduced acylceramide levels and other changes in ceramide composition unique to each KO strain are also involved.

Barrier Abnormalities in Type 1 Diabetes Mellitus: The Roles of Inflammation and Ceramide Metabolism

Xerosis is a common sign of both type 1 and type 2 diabetes mellitus (DM), and patients with DM and mouse models for DM show a compromised epidermal permeability barrier. Barrier defects then allow the entry of foreign substances into the skin, triggering inflammation, infection, and worsening skin symptoms. Characterizing how barrier abnormalities develop in DM could suggest treatments for xerosis and other skin disease traits. Because the proper ratio, as well as proper bulk amounts, of heterogeneous ceramide species are keys to forming a competent barrier, we investigated how ceramide metabolism is affected in type 1 DM using a mouse model (induced by streptozotocin). Chronic inflammation, evident in the skin of mice with DM, leads to (i) decreased de novo ceramide production through serine racemase activation-mediated attenuation of serine palmitoyl transferase activity by D-serine; (ii) changes in ceramide synthase activities and expression that modify the ratio of ceramide molecular species; and (iii) increased ceramide-1-phosphate, a proinflammatory lipid mediator, that stimulates inflammatory cytokine expression (TNFα and IFN-γ). Together, chronic inflammation affects ceramide metabolism, which attenuates epidermal permeability barrier formation, and ceramide-1-phosphate could amplify this inflammation. Alleviation of chronic inflammation is a credible approach for normalizing barrier function and ameliorating diverse skin abnormalities in DM.

Surgery-induced gut microbial dysbiosis promotes cognitive impairment via regulation of intestinal function and the metabolite palmitic amide

BackgroundPerioperative neurocognitive disorders (PND) are the most common postoperative complications with few therapeutic options. Gut microbial dysbiosis is associated with neurological diseases; however, the mechanisms by which the microbiota regulates postoperative gastrointestinal and cognitive function are incompletely understood.MethodsBehavioral testing, MiSeq 16S rRNA gene sequencing, non-target metabolism, intestinal permeability detection, protein assays, and immunofluorescence staining were employed to discern the impacts of surgery on microbial profiles, intestinal barriers, serum metabolism, and the brain. Interventions in mice included fecal microbiota transplantation, the anti-inflammatory agent dexamethasone, Lactobacillus supplementation, indole propionic acid supplementation, and palmitic amide administration.ResultsSurgery-induced cognitive impairment occurs predominantly in aged mice, and surgery-induced alterations in the microbiota composition profile exacerbate intestinal barrier disruption in aged mice. These adverse effects can be mitigated by transferring microbiota from young donors or by bolstering the intestinal barrier function using dexamethasone, Lactobacillus, or indole propionic acid. Moreover, microbiota composition profiles can be restored by transplanting feces from young mice to aged surgical mice, improving neuropathology and cognitive function, and these effects coincide with increased intestinal permeability. Metabolomic screening identified alterations in metabolites in mouse serum after surgery, especially the increase in palmitic amide. Palmitic amide levels in serum and brain can be decreased by transplanting feces from young mice to aged surgical mice. Oral palmitic amide exacerbates cognitive impairment and neuropathological changes in mice.ConclusionsGut microbial dysbiosis in mice after surgery is a key mechanism leading to cognition dysfunction, which disrupts the intestinal barrier and metabolic abnormalities, resulting in neuroinflammation and dendritic spine loss. Intestinal barrier damage and high level of palmitic amide in old mice may be the cause of high incidence of PND in the elderly. Preoperative microbiota regulation and intestinal barrier restoration may be of therapeutic benefit in preventing PND.9Ey9teFKZKXmrKtD72aS7bVideo

Zinc penetration through the skin barrier in atopic dermatitis and rosacea using reflectance confocal microscopy.

Atopic dermatitis (AD) is a chronic, recurrent eczematous disorder with a complex pathophysiology caused by skin barrier abnormalities. Rosacea is a common chronic immune-mediated inflammatory disorder that results in diminished skin barrier function. Reflectance confocal microscopy (RCM) is a non-invasive method for visualizing the dynamic status of epidermal and upper dermal structures. In this study, we compared skin barrier permeability among normal, AD and rosacea groups. To assess skin barrier permeability, zinc was applied to lesional skin and the RCM reflectance intensity of zinc penetration was measured. Reflectance confocal microscopy revealed that the intensity in patients with rosacea and AD was higher than that in the normal group at depths of 8-24 μm in both the face and forearm, which were considered as the stratum corneum (SC) and tight junction (TJ) level (p < 0.0001). When comparing AD and rosacea, the intensity of rosacea was higher than that of AD at a depth of 8 μm in the face (p < 0.0001). The intensity of AD was higher than that of rosacea at a depth of 24 μm (p = 0.009). This suggests that skin barrier permeability is increased in the upper epidermis of patients with AD and rosacea. On the face, patients with rosacea had more SC weakness than did those with AD, whereas patients with AD had more TJ weakness than those with rosacea.

Adipokine-Enriched Adipose Extract Restores Skin Barrier and Ameliorates Inflammatory Dysregulation in Atopic Dermatitis Mice.

Atopic dermatitis (AD) is a chronic dermatosis with high incidence worldwide characterized by skin barrier abnormalities and immune dysregulation. Conventional therapies are usually limited by side effects and high cost. Given the antiinflammatory and repairing properties, adipokines are increasingly considered as promising therapeutic agents for dermatoses. Adipose collagen fragments (ACF), a novel adipokine-enriched product, may alleviate AD through modulating immune microenvironment and restoring skin barrier. ACF was extracted from adipose tissue by means of high-speed homogenization (10,000 rpm/min for 1 minute) and centrifugation (3000 g for 3 minutes). Ovalbumin-induced AD female BALB/c mice (6-week-old) were intradermally injected with 0.2 mL of ACF or phosphate-buffered saline (negative control), with normal mice being set as normal control ( n = 6). Dermatitis severity, inflammatory metrics (epidermal thickness, infiltrated mast cells, T helper cell [Th]-type cytokine expression), and skin barrier-related metrics (transepidermal water loss, skin barrier-related proteins expression) were evaluated after the AD induction period (day 50). ACF-derived bioactive components were also evaluated using proteomic analysis. ACF-derived adipokines contained antiinflammatory, skin barrier- and lipid biosynthesis-related components. ACF treatment decreased dermatitis severity (6.2 ± 1.8 [ P < 0.0001]), epidermal thickness (25.7 ± 12.8 μm [ P = 0.0045]), infiltrated mast cells (31.3 ± 12.4 cells/field [ P = 0.0475]), and expression of Th-type cytokines (interferon-γ, tumor necrosis factor-α, interleukin [IL]-4, IL-4R, IL-13, and IL-17A [ P < 0.05]) in AD skins. Transepidermal water loss (29.8 ± 13.8 g/m 2 per hour [ P = 0.0306]) and skin barrier-related protein expression (filaggrin, 14,258 ± 4375 [ P = 0.0162]; loricrin, 6037 ± 1728 [ P = 0.0010]; claudin-1, 20,043 ± 6406 [ P = 0.0420]; and zonula occludens-1, 4494 ± 1114 [ P = 0.0134]) were also improved. ACF improved AD in a murine model by ameliorating inflammatory dysregulation and skin barrier defects. Further validation is needed in more advanced animal models. ACF is an injectable, adipose-derived collagen scaffold prepared from autologous harvested fat using fast and simple mechanical methods. ACF may reduce the limitations associated with health care regulatory issues and serve as a promising autologous therapeutic agent for skin disorders in clinics.

GDU-952, a novel AhR agonist ameliorates skin barrier abnormalities and immune dysfunction in DNFB-induced atopic dermatitis in mice

The aryl hydrocarbon receptor (AhR) is widely expressed in the skin. It controls immune-mediated skin responses to various external environmental signals, promote terminal differentiation of epidermal keratinocytes and participates the maintenance of the skin barrier function. As a therapeutic target, AhR activation modulates many diseases progression driven by immune/inflammatory processes such as atopic dermatitis (AD) and psoriasis. In this study, we revealed that GDU-952 is a novel AhR agonist, which is able to decreases IgE serum levels, to inhibit pro-inflammatory cytokines such as IL-6 and TNF-α and to induce immunoregulatory effects through restoring Th1/Th2 immune balance and promoting CD4+FOXP3+regulatory T (Treg) populations in AD skin lesions. Furthermore, GDU-952 can strengthen the skin barrier function through upregulating epidermal differentiation-related and tight junction proteins. This may alleviate AD symptoms, such as dermatitis scores, epidermal hyperplasia and mast cell infiltration. These results offer a rationale for further preclinical/clinical studies to evaluate the possible use of GDU-952 in the management of AD.

Curcumin reduces blood-nerve barrier abnormalities and cytotoxicity to endothelial cells and pericytes induced by cisplatin.

Cisplatin is a platinum-based antineoplastic agent used to treat cancers of solid organs. Neuropathy is one of its major side effects, necessitating dose reduction or cessation. Previous studies suggested that cisplatin causes microvascular toxicity, including pericyte detachment. This study aimed to clarify whether these alterations occurred in the blood-nerve barrier (BNB) of capillaries after cisplatin treatment. Electron microscopic analysis of rat sciatic nerves with cisplatin neuropathy showed increased frequency and severity of pericyte detachment. Moreover, the vascular basement membrane did not tightly encircle around the endothelial cells and pericytes. Cultured human umbilical vein endothelial cells and human brain vascular pericytes showed reduced viability, increased caspase-3 activity and enhanced oxidative stress following cisplatin treatment. In addition, cisplatin decreased transendothelial electrical resistance (TEER) and the expression of the tight junction proteins occludin and zonula occludens-1. Curcumin, a polyphenol found in the root of Curcuma longa, had favourable effects on cisplatin neuropathy in previous work. Therefore, curcumin was tested to determine whether it had any effect on these abnormalities. Curcumin alleviated pericyte detachment, cytotoxicity, oxidative stress, TEER reduction and tight junction protein expression. These data indicate that cisplatin causes BNB disruption in the nerves and might result in neuropathy. Curcumin might improve neuropathy via the restoration of BNB. Whether alterations in the BNB occur and curcumin is effective in patients with cisplatin neuropathy remain to be investigated.

P17 Pseudomonas infection causing acute painful flexural exacerbation in a child with IFAP syndrome

Abstract Ichthyosis follicularis alopecia and photophobia (IFAP) syndrome is a rare, X-linked inherited disorder caused by pathogenic mutations in the MBTPS2 gene. Seventy cases have been reported previously. The phenotypic spectrum varies, but IFAP consistently causes noninflammatory follicular keratoses, nonscarring alopecia and progressive corneal scarring. A 7-year-old boy, with IFAP syndrome associated with neurodevelopmental delay, chorioretinal coloboma and poor growth requiring gastrostomy, presented with a 4-week history of worsening flexural erythema and pain. Trials of topical steroids with fucidic acid, nystatin and oral penicillin had proven ineffective. On initial evaluation he had florid painful flexural erythema with surrounding crusting and scale. The Nikolsky sign was negative. He was systemically unwell with fever, dehydration and malaise requiring hospital admission. Laboratory evaluation demonstrated leucocytosis with neutrophilia and peak CRP of 100. He was treated empirically for bacterial superinfection including Staphylococcus scalded skin syndrome with intravenous clindamycin. With no appreciable improvement after 48 h, antimicrobial therapy was extended to include fluconazole and aciclovir. After 5 days, he continued to be febrile and systemically unwell with extensive yellow-brown crusting most marked at the flexural areas, and clindamycin was switched to piperacillin/tazobactam to provide antipseudomonal coverage. Skin swab cultures subsequently confirmed heavy growth of Pseudomonas aeruginosa. Within 48 h there was marked clinical improvement. He was discharged home to complete a course of oral antibiotics. This case highlights the importance of early consideration of Pseudomonas infection as a cause of subacute flexural exacerbations, particularly in those with skin barrier abnormalities, including inherited ichthyoses.

Mechanism of Qingchang Suppository on repairing the intestinal mucosal barrier in ulcerative colitis.

Ulcerative colitis (UC) is a refractory inflammatory bowel disease, and the outcomes of conventional therapies of UC, including 5-aminosalicylic acid, glucocorticoids, immunosuppressants, and biological agents, are not satisfied with patients and physicians with regard to adverse reactions and financial burden. The abnormality of the intestinal mucosal barrier in the pathogenesis of UC was verified. Qingchang Suppository (QCS) is an herbal preparation and is effective in treating ulcerative proctitis. The mechanism of QCS and its active ingredients have not been concluded especially in mucosal healing. This review elucidated the potential mechanism of QCS from the intestinal mucosal barrier perspective to help exploring future QCS research directions.

Intrapatient comparison of atopic dermatitis skin transcriptome shows differences between tape-strips and biopsies.

Our knowledge of etiopathogenesis of atopic dermatitis (AD) is largely derived from skin biopsies, which are associated with pain, scarring and infection. In contrast, tape-stripping is a minimally invasive, nonscarring technique to collect skin samples. To construct a global AD skin transcriptomic profile comparing tape-strips to whole-skin biopsies, we performed RNA-seq on tape-strips and biopsies taken from the lesional skin of 20 moderate-to-severe AD patients and the skin of 20 controls. Differentially expressed genes (DEGs) were defined by fold-change (FCH) ≥2.0 and false discovery rate <0.05. We detected 4104 (2513 Up; 1591 Down) and 1273 (546 Up; 727 Down) DEGs in AD versus controls, in tape-strips and biopsies, respectively. Although both techniques captured dysregulation of key immune genes, tape-strips showed higher FCHs for innate immunity (IL-1B, IL-8), dendritic cell (ITGAX/CD11C, FCER1A), Th2 (IL-13, CCL17, TNFRSF4/OX40), and Th17 (CCL20, CXCL1) products, while biopsies showed higher upregulation of Th22 associated genes (IL-22, S100As) and dermal cytokines (IFN-γ, CCL26). Itch-related genes (IL-31, TRPV3) were preferentially captured by tape-strips. Epidermal barrier abnormalities were detected in both techniques, with terminal differentiation defects (FLG2, PSORS1C2) better represented by tape-strips and epidermal hyperplasia changes (KRT16, MKI67) better detected by biopsies. Tape-strips and biopsies capture overlapping but distinct features of the AD molecular signature, suggesting their respective utility for monitoring specific AD-related immune, itch, and barrier abnormalities in clinical trials and longitudinal studies.