Abnormal Barrier Research Articles

Brain Barriers and Multiple Sclerosis: Novel Treatment Approaches from a Brain Barriers Perspective.

Multiple sclerosis (MS) is considered a prototypic organ specific autoimmune disease targeting the central nervous system (CNS). Blood-brain barrier (BBB) breakdown and enhanced immune cell infiltration into the CNS parenchyma are early hallmarks of CNS lesion formation. Therapeutic targeting of immune cell trafficking across the BBB has proven a successful therapy for the treatment of MS, but comes with side effects and is no longer effective once patients have entered the progressive phase of the disease. Beyond the endothelial BBB, epithelial and glial brain barriers establish compartments in the CNS that differ in their accessibility to the immune system. There is increasing evidence that brain barrier abnormalities persist during the progressive stages of MS. Here, we summarize the role of endothelial, epithelial, and glial brain barriers in maintaining CNS immune privilege and our current knowledge on how impairment of these barriers contributes to MS pathogenesis. We discuss how therapeutic stabilization of brain barriers integrity may improve the safety of current therapeutic regimes for treating MS. This may also allow for the development of entirely novel therapeutic approaches aiming to restore brain barriers integrity and thus CNS homeostasis, which may be specifically beneficial for the treatment of progressive MS.

Síndrome nefrótico congénito. Reporte de caso y revisión del enfoque diagnóstico

A nephrotic syndrome is defined as the association of massive proteinuria, hypoalbuminemia and hyperlipidemia, which may be associated with edema and hypercoagulability. It originates from an abnormality of the glomerular filtration barrier with a massive protein leak and the consequent side effects. In its primary forms, it occurs with an incidence of 1 - 3 per 100,000 children under 16 years of age. The congenital form is a rare variant of the nephrotic syndrome, which occurs at birth or within the first three months of life and is usually resistant to corticosteroid therapy. Congenital infections and most common related monogenic diseases should be tested. Finally, new generation sequencing must be used to search for mutations in other candidate genes. We present the case of a girl with congenital nephrotic syndrome difficult to control, emphasizing the diagnostic process and support management. The importance of genetic counseling to the family in all cases is highlighted.

Pathophysiology and management of sensitive skin: position paper from the special interest group on sensitive skin of the International Forum for the Study of Itch (IFSI).

The special interest group on sensitive skin of the International Forum for the Study of Itch previously defined sensitive skin as a syndrome defined by the occurrence of unpleasant sensations (stinging, burning, pain, pruritus and tingling sensations) in response to stimuli that normally should not provoke such sensations. This additional paper focuses on the pathophysiology and the management of sensitive skin. Sensitive skin is not an immunological disorder but is related to alterations of the skin nervous system. Skin barrier abnormalities are frequently associated, but there is no cause and direct relationship. Further studies are needed to better understand the pathophysiology of sensitive skin - as well as the inducing factors. Avoidance of possible triggering factors and the use of well-tolerated cosmetics, especially those containing inhibitors of unpleasant sensations, might be suggested for patients with sensitive skin. The role of psychosocial factors, such as stress or negative expectations, might be relevant for subgroups of patients. To date, there is no clinical trial supporting the use of topical or systemic drugs in sensitive skin. The published data are not sufficient to reach a consensus on sensitive skin management. In general, patients with sensitive skin require a personalized approach, taking into account various biomedical, neural and psychosocial factors affecting sensitive skin.

Use of Tape Strips to Detect Immune and Barrier Abnormalities in the Skin of Children With Early-Onset Atopic Dermatitis

Molecular profiling of skin biopsies is the criterion standard for evaluating the cutaneous atopic dermatitis (AD) phenotype. However, skin biopsies are not always feasible in children. A reproducible minimally invasive approach that can track cutaneous disease in pediatric longitudinal studies or clinical trials is lacking. To assess a minimally invasive approach using tape strips to identify skin biomarkers that may serve as a surrogate to biomarkers identified using whole-tissue biopsies. This cross-sectional study of 51 children younger than 5 years recruited children with moderate to severe AD and children without AD from the dermatology outpatient clinics at a children's hospital. Sixteen tape strips were serially collected from the nonlesional and lesional skin of 21 children who had AD and were less than 6 months from disease initiation and from the normal skin of 30 children who did not have AD between January 22, 2016, and April 20, 2018. Gene and protein expression were evaluated using quantitative real-time polymerase chain reaction and immunohistochemistry. A total of 51 children younger than 5 years were included in the study; 21 children had moderate to severe AD with less than 6 months of disease duration, and 30 children did not have AD. Of the 21 children with AD, the mean (SD) age was 1.7 (1.7) years, and most were male (15 [71.4%] and white (15 [71.4%]). Of the 30 children without AD, the mean (SD) age was 1.8 (2.0) years, and most were female (20 [66.7%]) and white (22 [73.3%]). Seventy-seven of 79 evaluated immune and barrier gene products were detected (gene detection rate, 97%) in 70 of 71 tape strips (sample detection rate, 99%), with 53 of 79 markers differentiating between children with lesional and/or nonlesional AD from children without AD. Many cellular markers of T cells (CD3), AD-related dendritic cells (Fc ε RI and OX40 ligand receptors), and key inflammatory (matrix metallopeptidase 12), innate (interleukin 8 [IL-8] and IL-6), helper T cell 2 (TH2; IL-4, IL-13, and chemokines CCL17 and CCL26), and TH17/TH22 (IL-19, IL-36G, and S100A proteins) genes were significantly increased in lesional and nonlesional AD compared with tape strips from normal skin. For example, IL-4 mean (SE) for lesional was -15.2 (0.91) and normal was -19.5 (0.48); P < .001. Parallel decreases occurred in epidermal barrier gene products (FLG, CLDN23, and FA2H) and negative immune regulators (IL-34 and IL-37). For example, the decrease for FLG lesional was mean (SE) -2.9 (0.42) and for normal was 2.2 (0.45); P < .001. Associations were found between disease severity or transepidermal water loss and TH2 (IL-33 and IL-4R) and TH17/TH22 (IL-36G and S100As) products in lesional and nonlesional AD skin (evaluated using the SCORing Atopic Dermatitis, Eczema Area and Severity Index, and Pruritus Atopic Dermatitis Quickscore tools). In this study, tape strips provide a minimally invasive alternative for serially evaluating AD-associated cutaneous biomarkers and may prove useful for tracking pediatric AD therapeutic response and predicting future course and comorbidities.

Xenobiotic Receptors and Their Mates in Atopic Dermatitis.

Atopic dermatitis (AD) is the most common inflammatory skin disease worldwide. It is a chronic, relapsing and pruritic skin disorder which results from epidermal barrier abnormalities and immune dysregulation, both modulated by environmental factors. AD is strongly associated with asthma and allergic rhinitis in the so-called ‘atopic march’. Xenobiotic receptors and their mates are ligand-activated transcription factors expressed in the skin where they control cellular detoxification pathways. Moreover, they regulate the expression of genes in pathways involved in AD in epithelial cells and immune cells. Activation or overexpression of xenobiotic receptors in the skin can be deleterious or beneficial, depending on context, ligand and activation duration. Moreover, their impact on skin might be amplified by crosstalk among xenobiotic receptors and their mates. Because they are activated by a broad range of endogenous molecules, drugs and pollutants owing to their promiscuous ligand affinity, they have recently crystalized the attention of researchers, including in dermatology and especially in the AD field. This review examines the putative roles of these receptors in AD by critically evaluating the conditions under which the proteins and their ligands have been studied. This information should provide new insights into AD pathogenesis and ways to develop new therapeutic interventions.

Severe Skin Permeability Barrier Dysfunction in Knockout Mice Deficient in a Fatty Acid ω-Hydroxylase Crucial to Acylceramide Production

The skin permeability barrier is indispensable for maintaining water inside the body and preventing the invasion of pathogens and allergens; abnormalities lead to skin disorders such as atopic dermatitis and ichthyosis. Acylceramide is an essential lipid for skin barrier formation, and CYP4F22 is a fatty acid ω-hydroxylase involved in its synthesis. Mutations in CYP4F22 cause autosomal recessive congenital ichthyosis, although the symptoms vary among mutation sites and types. Here, we generated knockout mice deficient in Cyp4f39, the mouse ortholog of human CYP4F22, to investigate the effects of completely abrogating the function of the fatty acid ω-hydroxylase involved in acylceramide production on skin barrier formation. Cyp4f39 knockout mice died within 8 hours of birth. Large increases in transepidermal water loss and penetration of a dye from outside the body were observed, indicating severe skin barrier dysfunction. Histologic analyses of the epidermis revealed impairment of lipid lamella formation, accumulation of corneodesmosomes in the stratum corneum, and persistence of periderm. In addition, lipid analyses by mass spectrometry showed almost complete loss of acylceramide and its precursor ω-hydroxy ceramide. In conclusion, our findings provide clues to the molecular mechanisms of skin barrier abnormalities and the pathogenesis of ichthyosis caused by Cyp4f39 and CYP4F22 by association.

Gut epithelial and vascular barrier abnormalities in patients with chronic intestinal pseudo-obstruction.

Chronic intestinal pseudo-obstruction (CIPO) is a rare condition due to severe impairment of gut motility responsible for recurrent subocclusive episodes. Although neuromuscular-glial-ICC abnormalities represent the main pathogenetic mechanism, the pathophysiology of CIPO remains poorly understood. Intestinal epithelial and vascular endothelial barrier (IEVB) abnormalities can contribute to neuroepithelial changes by allowing passage of harmful substances. To test retrospectively whether IEVB defects occur in patients with CIPO, we measured the jejunal protein expression of the major tight junction (TJ) components. CIPO patients were subdivided according to gut neuromuscular histopathology: apparently normal (AN); with inflammation (INF); or with degenerative alterations (DEG). The presence of occludin/claudin oligomers (index of TJ assembly), the amount of occludin, claudin-4, and zonula occludens-1 (ZO-1), and the expression of vasoactive intestinal polypeptide (VIP) and glial fibrillary acidic protein (GFAP) immunoreactivities were evaluated on jejunal full-thickness biopsies using Western blot. Oligomers were absent in the 73% of CIPO. Total occludin decreased in CIPO with AN and INF changes. Claudin-4 was upregulated in CIPO with INF and DEG features. ZO-1 and VIP expression decreased selectively in DEG group. GFAP increased in CIPO regardless the histopathological phenotype. The absence of oligomers demonstrated in our study suggests that IEBV is altered in CIPO. The mechanism leading to oligomerization is occludin-dependent in AN and INF, whereas is ZO-1-dependent in DEG. Our study provides support to IEVB abnormalities contributing to CIPO clinical and histopathological features.

Su1048 – Intestinal Epithelial Barrier Abnormalities and Changes in Microbiome As Early Events in Diet-Induced Obesity

Su1048 – Intestinal Epithelial Barrier Abnormalities and Changes in Microbiome As Early Events in Diet-Induced Obesity

Palmar hyperlinearity in early childhood atopic dermatitis is associated with filaggrin mutation and sensitization to egg.

Palmar hyperlinearity is a typical clinical feature of Filaggrin gene (FLG) null mutations. There are reports of FLG mutations and allergic sensitization; however, reports on the relationship between palmar hyperlinearity to sensitization are limited. This study aimed to examine the association between palmar hyperlinearity and sensitization in atopic dermatitis (AD) children. This cross-sectional, case-control study included children ˂ 6years old with moderate-severe AD whose parents consented for mutation analysis and photographic documentation. Each child underwent genotyping to detect the eight most prevalent FLG mutations in the Japanese population: R501X, 3321delA, S1695X, Q1701X, S2554X, S2889X, S3296X, and K4022X. Clinical features and parameters including egg-specific IgE were examined, and palm photographs were evaluated by 12 trained dermatologists blinded to genotyping results. Of the 57 patients (age range, 2months to 5years; median, 22months), 16 were heterozygotes and three were compound heterozygotes. Palmar hyperlinearity, as recognized by more than two-thirds of dermatologists, was significantly associated with FLG mutation (P=0.002, OR=6.98, 95% CI=2.1-23.7), and this association was observed especially in children over 2years. Cross-shaped crease of the thenar eminence, as known in previous reports, also demonstrated significant correlation with FLG mutation. When the children were divided according to the presence or absence of palmar hyperlinearity, the egg white-specific IgE was significantly higher in the hyperlinearity group (55.9 vs 18.3IU/mL, P<0.05). Palmar hyperlinearity indicates possible inherited barrier abnormalities of the skin in early childhood. Its identification may help to predict a more accurate prognosis, such as sensitization.

Atopic dermatitis

Atopic dermatitis is a chronic inflammatory skin disease associated with pruritus that occurs most frecquently in children. A family history of atopy (eczema, asthma, or allergic rhinitis) and skin barrier abnormalities genetically determined are major risk factors for atopic dermatitis. The diagnosis of atopic dermatitis is clinical, based upon the history, onset, and morphology of skin lesions. The goals of treatment are to reduce symptoms, prevent exacerbations, to improve the quality of life and minimize therapeutic risks. The optimal management is based on the severity of the disease and involves the elimination of exacerbating factors, restoration of the skin barrier function, pharmacologic treatment of skin inflammation (topic and systemic agents), and patient education.

Blood-Brain Barrier Dysfunction in Small Vessel Disease Related Intracerebral Hemorrhage.

Background and Purpose: Hypertensive vasculopathy and cerebral amyloid angiopathy are the two most common forms of cerebral small vessel disease. Both forms are associated with the development of primary intracerebral hemorrhage, but the pathophysiological mechanisms underlying spontaneous vessel rupture remain unknown. This work constitutes a systematic review on blood-brain barrier dysfunction in the etiology of spontaneous intracerebral hemorrhage due to cerebral small vessel disease.Methods: We searched Medline (1946–2018) and Embase (1974–2018) for animal and human studies reporting on blood-brain barrier dysfunction associated with intracerebral hemorrhage or cerebral microbleeds.Results: Of 26 eligible studies, 10 were animal studies and 16 were in humans. The authors found indications for blood-brain barrier dysfunction in all four animal studies addressing hypertensive vasculopathy-related intracerebral hemorrhage (n = 32 hypertensive animals included in all four studies combined), and in four of six studies on cerebral amyloid angiopathy-related intracerebral hemorrhage (n = 47). Of the studies in humans, five of six studies in patients with cerebral amyloid angiopathy-related intracerebral hemorrhage (n = 117) and seven out of nine studies examining intracerebral hemorrhage with mixed or unspecified underlying etiology (n = 489) found indications for blood-brain barrier dysfunction. One post-mortem study in hypertensive vasculopathy-related intracerebral hemorrhage (n = 82) found no evidence for blood-brain barrier abnormalities.Conclusions: Signs of blood-brain barrier dysfunction were found in 20 out of 26 studies. Blood-brain barrier integrity deserves further investigation with a view to identification of potential treatment targets for spontaneous intracerebral hemorrhage.

Detection of intralabyrinthine abnormalities using post-contrast delayed 3D-FLAIR MRI sequences in patients with acute vestibular syndrome.

3D-FLAIR sequences with delayed acquisition after contrast medium injection have demonstrated new insights into blood-labyrinthine barrier (BLB) abnormalities in various diseases. The aim of this study was to assess the BLB in patients referred with unilateral acute vestibular syndrome (UAVS). In this retrospective multicenter imaging study, we performed 3D-FLAIR and steady-state free precession (SSFP) sequences 4h after contrast medium administration in 26 healthy volunteers and in 30 patients with UAVS. Two radiologists, blinded to the clinical data, independently assessed the asymmetrical enhancement of the labyrinthine structures and the vestibular nerve on 3D-FLAIR sequences, and the signal of the labyrinthine structures on SSFP sequences. Inter-reader agreement tests were performed. An asymmetrical enhancement of the semicircular canals was observed in 26 out of 30 ears (86.6%, p < 0.001) and never observed in healthy subjects. An asymmetrical enhancement of the vestibular nerve was never observed in either patients or healthy subjects. An asymmetrical enhancement of the cochlea was observed on the 3D-FLAIR sequence in 6 out of 30 ears only in the patients' group (20%, p = 0.03) and always associated with an enhancement of at least one semicircular canal. A low signal on SSFP sequences was observed only in 11 out of 30 symptomatic ears (36.7%, p < 0.001), involving the utricle in 7 ears and the superior semicircular canal in 4 ears. Patients with typical UAVS presented with semicircular canal enhancement on MRI, while an asymmetrical enhancement of the vestibular nerve was not displayed. NCT02529475 KEY POINTS: • Patients with typical vestibular neuronitis presented with semicircular canal enhancement on MRI in 87% of cases. • An enhancement of the vestibular nerve was never displayed.

Measurement of the biomechanical function and structure of ex vivo drying skin using raman spectral analysis and its modulation with emollient mixtures.

An important aspect of the biomechanical behaviour of the stratum corneum (SC) is the drying stresses that develop with water loss. These stresses act as a driving force for damage in the form of chapping and cracking. Betasitosterol is a plant sterol with a structure similar to cholesterol, a key component in the intercellular lipids of the outermost layer of human skin, the SC. Cholesterol plays an important role in stabilizing the SC lipid structure, and altered levels of cholesterol have been linked with SC barrier abnormalities. Betasitosterol is currently applied topically to skin for treatment of wounds and burns. However, it is unknown what effect betasitosterol has on the biomechanical barrier function of skin. Here, by analysing the drying stress profile of SC generated during a kinetics of dehydration, we show that betasitosterol, in combination with two emollient molecules, isocetyl stearoyl stearate (ISS) and glyceryl tri-2-ethylhexanoate (GTEH), causes a significant modulation of the drying stress behaviour of the SC by reducing both the maximal peak stress height and average plateau of the drying stress profile. Raman spectra analyses demonstrate that the combination of betasitosterol with the two emollients, ISS and GTEH, allows a high water retention capacity within the SC, while the lipid conformational order by increasing the amount of trans conformers. Our study highlights the advantage of combining a biomechanical approach together with Raman spectroscopy in engineering a suitable combination of molecules for alleviating dryness and dry skin damage.

Using the Reduced Uterine Perfusion Pressure model of preeclampsia to study the blood brain barrier permeability

***Using the Reduced Uterine Perfusion Pressure model of preeclampsia to study the blood brain barrier permeability***AIMS: To use the Reduced Uterine Perfusion Pressure (RUPP) model for preeclampsia to describe and evaluate the blood brain barrier permeability in pregnant rats.METHODS: Forty-one pregnant Wistar rats were divided into different intervention groups between 13 to 15 days of gestation: Pregnant-Control (PC; n=12), Reduced Uterine Perfusion Pressure (RUPP; n=15), Invasive Blood Pressure-Control (IBP; n=7) and Reduced Uterine Perfusion Pressure and Invasive Blood Pressure (RUPP-IBP; n=7). The 14 rats of groups IBP and RUPP-IBP had their mean arterial pressure measured at day 21. All animals were then sacrificed, administered Evans Blue dye through the tail vein and perfused with paraformaldehyde 4%. Brains were removed and evaluated by a blinded pathologist. Results are presented as means and standard errors. Comparisons between the groups were performed using Student's t-test for continuous variables and Fisher’s exact test for categorical variables. Statistical significance was set as a p value less than 0.05.RESULTS: Mean arterial pressure averaged 85.4±2.2 mmHg in the IPB group and 102.5±8.3 mmHg in the RUPP-IPB group (p=0.002). Among all the RUPP rats (RUPP and RUPP-IBP groups), 82% had a positive staining with Evans Blue dye for at least one of the brain hemispheres, while none of the pregnant control rats (PC and IBP groups) had brain staining (p&lt;0.001).CONCLUSIONS: In this study, altered permeability of the blood brain barrier was successfully reproduced in pregnant rats exposed to the RUPP protocol. Therefore, we concluded that the RUPP model is a valid surrogate to study blood brain barrier abnormalities.

The Unique Molecular Signatures of Contact Dermatitis and Implications for Treatment.

Irritant contact dermatitis (ICD) and allergic contact dermatitis (ACD) are common skin disorders that are characterized by inflammation, oozing, crusting, and pruritus. Atopic dermatitis (AD) is an inflammatory skin disease characterized by immune and barrier abnormalities and is additionally a risk factor for acquiring ICD and ACD. New work on allergic sensitization to common allergens (e.g., nickel and fragrance) in human skin has shown that different allergens have distinct molecular fingerprinting. For example, nickel promotes strong Th1/Th17 polarization, whereas fragrance allergy causes Th2/Th22 skewing, which is similar to the phenotype of AD. While ACD has previously been considered to be constant across all allergens, largely based on mouse models involving strong sensitizers, these new data suggest that ACD differs mechanistically according to allergen. Further, ACD in the setting of concurrent AD shows a different and attenuated phenotype as compared to healthy individuals with ACD, which influences the way AD patients respond to vaccination and other treatment modalities. As in contact sensitization, skin challenged by food patch testing shows that common food allergens (e.g., peanut and barley) also cause distinct immune polarizations in the skin. Additionally, house dust mite reactions in human skin have been profiled to show unique Th2, Th9, and Th17/22 activation as compared to controls, which are similar to the phenotype of psoriasis and contact responses to nickel. Given this information, ACD patients should be treated based on their unique allergen polarity. Refined understanding of the molecular behavior of contact dermatitis and related diseases translates to improved methods of inducing tolerance in sensitized allergic patients, such as with targeted drug therapy and epicutaneous immunotherapy.

648 The barrier abnormality of early-onset pediatric atopic dermatitis results from abnormalities in tight junctions and epidermal lipids, but not differentiation proteins

648 The barrier abnormality of early-onset pediatric atopic dermatitis results from abnormalities in tight junctions and epidermal lipids, but not differentiation proteins

Cellular and Metabolic Basis for the Ichthyotic Phenotype in NIPAL4 (Ichthyin)–Deficient Canines

Mutations in several lipid synthetic enzymes that block fatty acid and ceramide production produce autosomal recessive congenital ichthyoses (ARCIs) and associated abnormalities in permeability barrier homeostasis. However, the basis for the phenotype in patients with NIPAL4 (ichthyin) mutations (among the most prevalent ARCIs) remains unknown. Barrier function was abnormal in an index patient and in canines with homozygous NIPAL4 mutations, attributable to extensive membrane stripping, likely from detergent effects of nonesterified free fatty acid. Cytotoxicity compromised not only lamellar body secretion but also formation of the corneocyte lipid envelope (CLE) and attenuation of the cornified envelope (CE), consistent with a previously unrecognized, scaffold function of the CLE. Together, these abnormalities result in failure to form normal lamellar bilayers, accounting for the permeability barrier abnormality and clinical phenotype in NIPA-like domain-containing 4 (NIPAL4) deficiency. Thus, NIPAL4 deficiency represents another lipid synthetic ARCI that converges on the CLE (and CE), compromising their putative scaffold function. However, the clinical phenotype only partially improved after normalization of CLE and CE structure with topical ω-O-acylceramide because of ongoing accumulation of toxic metabolites, further evidence that proximal, cytotoxic metabolites contribute to disease pathogenesis.

Genetic Signature of Skin Aging: A Pilot Study

The sun plays a major role in prematurely aging our skin. Our skin is at the mercy of many forces as we age: sun, harsh weather, and bad habits. But we can take steps to help our skin stay supple and fresh-looking. Sunlight is a major cause of skin aging. The increasing knowledge of the genetic bases of several common multifactorial diseases paves the way to personalized medicine that means preventive and therapeutic interventions that are tailored to individuals on the basis of their genetic profiles. The aging process, as well as multi factorial diseases, depends on a complex crosstalk between intrinsic (genetic and hormonal) andextrinsic (nutrition, lifestyle etc.) factors. Skin changes are the most visible signs of senescence process, and a field of increasing interest ina society that places more and more interest in appearance and beauty. skin disease characterized by increased trans-epidermal water loss and skin barrier abnormalities and disruption. On this subject, numerous environmental events such as: chemical injuries, traumatic wounds, UV exposure and genomic characteristics can compromise the barrier activity. To date, the mutational spectrum of FLG gene comprises different variations that show an ethno-specific distribution profile, especially among north European and Mediterranean populations. The study was conducted in 100 Italian volunteers, with an age between 21 and 66 years old (23 males and 77 females). All selected patients were Caucasian (people with European origin), belonging to Fitzpatrick skin type 2 and 3. Subjects underwent medical history and clinical examination; exclusion criteria included systemic diseases or presence of genetic diseases which were clinically evident. All patients signed written informed consent. The examination of each subject was conducted using a lifestyle questionnaire and, to evaluate the impact of lifetime sun exposure (LSE), using the Sun Exposure and Behavior Inventory (SEBI). For the aging process, like to multi-factorial and polygenic diseases, is known that single genetic polymorphism has only a modest effect since the interaction of each gene and its polymorphism with other ones (gene-gene interaction) and with environmental factors (gene-environment interaction) has a crucial role in the development of the pathology. Moreover, the diversity of ethnic background may be a possible bias in such research. In the light of these considerations we selected Caucasian, Italian subjects only, and we constructed a literature based genetic risk score for skin aging with the aim to evaluate the contribution of individual genetic variability to skin aging. Prior skin aging studies have analyzed intrinsic and extrinsic skin aging parameters, believed to reflect genetic and environmental factors contributing to skin aging feature. Heritability analyses in twins have shown that genetic component of skin deterioration process accounts for about 60% [3]. In recent years, research on genetic polymorphisms indicate that Genetic Risk Scores (GRSs) allow the composite assessment of genetic risk in complex traits. Although some authors have expressed doubts as to whether a candidate gene approach can ever add significantly to risk prediction, because of the modest impact on risk, and the apparent inconsistency of effect, other authors demonstrate that, depending on the prevalence and heritability of the disease, few genetic variants may have a strong predictive power. Our results indicate that the use of the genetic risk score including 8single nucleotide polymorphisms This work is partly presented at International Conference on Aesthetic Medicine and Cosmetology, May 21-22 2018A¢Â”‚Singapore Vol.4 No.2 Extended Abstract Skin Diseases & Skin Care 2019 involved in aging process aspreviously described in literature, could be promising to predict skinproperties evolution and address antiA¢Â€Âaging and skin treatment againstspecific metabolic target. Keywords:

The Occurrence of Antibodies Against Gluten in Children with Autism Spectrum Disorders Does Not Correlate with Serological Markers of Impaired Intestinal Permeability.

There is evidence that children with autism spectrum disorders (ASDs) display an increased immune reactivity against gluten, which is supposed to be the effect of intestinal barrier abnormalities. The aim of study was to evaluate the relation of antibody induced by gluten to zonulin and intestinal fatty acid binding proteins (I-FABP), that is, serological markers of an impaired gut barrier. The study included 77 patients with ASDs. Zonulin, I-FABP, celiac-specific antibodies, anti-gliadin antibodies (AGA), and antibodies against neural transglutaminase 6 (TG6) of immunoglobulin (Ig) A and IgG classes were detected in sera. Celiac-specific antibodies were negative in all ASD children, four children (5.2%) had positive anti-TG6 antibodies, and increased AGA-IgG production was found in 21 patients (27.3%). Mean levels of zonulin and I-FABP in ASD patients were similar to those found in healthy controls and revealed a negative correlation with age, whereas regression analysis revealed a significant positive relationship between antibody production and the age. Serum concentrations of zonulin and I-FABP showed no statistically significant association with antibody positivity. An increased production of antibodies related to gliadin and neural TG6 in ASD children is not related to serological markers of an impaired intestinal barrier.

Enhanced Expression of Genes Related to Xenobiotic Metabolism in the Skin of Patients with Atopic Dermatitis but Not with Ichthyosis Vulgaris

Previous transcriptome analyses underscored the importance of immunological and skin barrier abnormalities in atopic dermatitis (AD). We sought to identify pathogenic pathways involved in AD by comparing the transcriptomes of AD patients stratified for filaggrin (FLG)-null mutations to those of both healthy donors and patients with ichthyosis vulgaris. We applied RNA sequencing to analyze the whole transcriptome of nonlesional skin. We found that 607 genes (476 up-regulated and 131 down-regulated by >2-fold) and 193 genes (172 up-regulated and 21 down-regulated by >2-fold) were differentially expressed when all AD or ichthyosis vulgaris patients were compared with healthy donors, respectively. Expression of genes involved in RNA/protein turnover and adenosine triphosphate synthesis, as well as genes involved in cell death, response to oxidative stress, DNA damage/repair, and autophagy, were significantly enriched in AD skin and, to a lesser extent, in ichthyosis vulgaris skin. FLG-null mutations appear to hardly interfere with current observations. Genes related to xenobiotic metabolism were up-regulated in AD skin only, as were genes related to arachidonic, linoleic, and α-linolenic acid metabolism. Thus, this work newly links AD pathogenesis to aberrant expression of genes related to xenobiotic metabolism.