Adult-specific Reelin expression alters striatal neuronal organization: implications for neuropsychiatric disorders.

In addition to neuronal migration, brain development, and adult plasticity, the extracellular matrix protein Reelin has been extensively implicated in human psychiatric disorders such as schizophrenia, bipolar disorder, and autism spectrum disorder. Moreover, heterozygous reeler mice exhibit features reminiscent of these disorders, while overexpression of Reelin protects against its manifestation. However, how Reelin influences the structure and circuits of the striatal complex, a key region for the above-mentioned disorders, is far from being understood, especially when altered Reelin expression levels are found at adult stages. In the present study, we took advantage of complementary conditional gain- and loss-of-function mouse models to investigate how Reelin levels may modify adult brain striatal structure and neuronal composition. Using immunohistochemical techniques, we determined that Reelin does not seem to influence the striatal patch and matrix organization (studied by µ-opioid receptor immunohistochemistry) nor the density of medium spiny neurons (MSNs, studied with DARPP-32). We show that overexpression of Reelin leads to increased numbers of striatal parvalbumin- and cholinergic-interneurons, and to a slight increase in tyrosine hydroxylase-positive projections. We conclude that increased Reelin levels might modulate the numbers of striatal interneurons and the density of the nigrostriatal dopaminergic projections, suggesting that these changes may be involved in the protection of Reelin against neuropsychiatric disorders.

Incorporating Alternative Polygenic Risk Scores into the BOADICEA Breast Cancer Risk Prediction Model.

BACKGROUND: The multifactorial risk prediction model BOADICEA enables identification of women at higher or lower risk of developing breast cancer. BOADICEA models genetic susceptibility in terms of the effects of rare variants in breast cancer susceptibility genes and a polygenic component, decomposed into an unmeasured and a measured component - the polygenic risk score (PRS). The current version was developed using a 313 SNP PRS. Here, we evaluated approaches to incorporating this PRS and alternative PRS in BOADICEA. METHODS: The mean, SD, and proportion of the overall polygenic component explained by the PRS (α2) need to be estimated. $\alpha $ was estimated using logistic regression, where the age-specific log-OR is constrained to be a function of the age-dependent polygenic relative risk in BOADICEA; and using a retrospective likelihood (RL) approach that models, in addition, the unmeasured polygenic component. RESULTS: Parameters were computed for 11 PRS, including 6 variations of the 313 SNP PRS used in clinical trials and implementation studies. The logistic regression approach underestimates $\alpha $, as compared with the RL estimates. The RL $\alpha $ estimates were very close to those obtained by assuming proportionality to the OR per 1 SD, with the constant of proportionality estimated using the 313 SNP PRS. Small variations in the SNPs included in the PRS can lead to large differences in the mean. CONCLUSIONS: BOADICEA can be readily adapted to different PRS in a manner that maintains consistency of the model. IMPACT: : The methods described facilitate comprehensive breast cancer risk assessment.

Lack of Helios During Neural Development Induces Adult Schizophrenia-Like Behaviors Associated With Aberrant Levels of the TRIF-Recruiter Protein WDFY1.

The role of the WDFY1 protein has been studied as a TLR3/4 scaffold/recruiting protein in the immune system and in different oncogenic conditions. However, its function in brain remains poorly understood. We have found that in mice devoid of Helios (He-/- mice), a transcription factor specifically expressed during the development of the immune cells and the central nervous system, there is a permanent and sustained increase of Wdfy1 gene expression in the striatum and hippocampus. Interestingly, we observed that WDFY1 protein levels were also increased in the hippocampus and dorsolateral prefrontal cortex of schizophrenic patients, but not in the hippocampus of Alzheimer's disease patients with an associated psychotic disorder. Accordingly, young He-/- mice displayed several schizophrenic-like behaviors related to dysfunctions in the striatum and hippocampus. These changes were associated with an increase in spine density in medium spiny neurons (MSNs) and with a decrease in the number and size of PSD-95-positive clusters in the stratum radiatum of the CA1. Moreover, these alterations in structural synaptic plasticity were associated with a strong reduction of neuronal NF-κB in the pyramidal layer of the CA1 in He-/- mice. Altogether, our data indicate that alterations involving the molecular axis Helios-WDFY1 in neurons during the development of core brain regions could be relevant for the pathophysiology of neuropsychiatric disorders such as schizophrenia.

Burning Mouth Syndrome and Contact Dermatitis.

: Burning mouth syndrome (BMS) is a condition that remains a diagnostic challenge and is frequently difficult to treat. Rather than being a singular entity, more recent research has suggested that the diagnosis of BMS encompasses a family of syndromes. Of this family, type 3 has been identified as being related to contact dermatitis. Although this subtype has been most commonly associated with dental allergens, several food, cosmetic, and pharmaceutical products have also been identified as allergens related to the onset of BMS. Failure to identify these allergens prevents timely diagnosis and initiation of treatment for patients with BMS related to contact dermatitis. This article identifies the allergens most relevant to this type 3 and describes the commercially available allergy panels needed to ensure that all relevant allergens are included during patch testing. This study also describes approaches to diagnosis of BMS and discusses approaches to treatment based on subtypes of the condition.

Helios modulates the maturation of a CA1 neuronal subpopulation required for spatial memory formation.

Currently, molecular, electrophysiological and structural studies delineate several neural subtypes in the hippocampus. However, the precise developmental mechanisms that lead to this diversity are still unknown. Here we show that alterations in a concrete hippocampal neuronal subpopulation during development specifically affect hippocampal-dependent spatial memory. We observed that the genetic deletion of the transcription factor Helios in mice, which is specifically expressed in developing hippocampal calbindin-positive CA1 pyramidal neurons (CB-CA1-PNs), induces adult alterations affecting spatial memory. In the same mice, CA3-CA1 synaptic plasticity and spine density and morphology in adult CB-CA1-PNs were severely compromised. RNAseq experiments in developing hippocampus identified an aberrant increase on the Visinin-like protein 1 (VSNL1) expression in the hippocampi devoid of Helios. This aberrant increase on VSNL1 levels was localized in the CB-CA1-PNs. Normalization of VSNL1 levels in CB-CA1-PNs devoid of Helios rescued their spine loss in vitro. Our study identifies a novel and specific developmental molecular pathway involved in the maturation and function of a CA1 pyramidal neuronal subtype.

Síndrome de Down por mosaico, reporte de caso Ecuador / Mosaic Down syndrome, case report Ecuador

El síndrome de Down, es una de las principales causas de discapacitada intelectual relacionada a alteraciones en los cromosomas humanos, el síndrome de Down por mosaísmo es uno de los tres tipos de alteración cromosómica que se presentan en estos pacientes, encontrándose en 1% al 4% de los casos reportados de este síndrome, en los cuales las características físicas son casi imperceptibles a una simple valoración. Presentamos el caso clínico de paciente masculino de 9 meses de edad que acudió a valoración médica por retraso leve madurativo e infecciones respiratorias a repetición.

Down syndrome is one of the main causes of intellectual disability related to alterations in human chromosomes. Mosaic Down syndrome is one of the three types of chromosomal alteration that occurs in these patients, being 1% at 4% of the reported cases of this syndrome, in any of the physical characteristics are almost imperceptible to a simple assessment. We present the clinical case of a 9-month-old male patient who attended a medical evaluation for mild maturational delay and repeated respiratory infections.

Emerging Nonsteroid-Based Procedural Therapies for Alopecia Areata: A Systematic Review.

BACKGROUND: Alopecia areata (AA) is a common form of patchy, nonscarring hair loss. Although intralesional steroid injections are currently the mainstay procedural therapy for AA, other nonsteroid-based procedural therapies, including platelet-rich plasma (PRP), ultraviolet radiation (UVR), and laser-based modalities, are emerging as practical options. OBJECTIVE: To systematically review nonsteroid-based procedural therapies for AA and recapitulate the available clinical data. MATERIALS AND METHODS: A systematic review of the literature was performed searching PubMed/MEDLINE databases identifying studies investigating PRP, UVR, and laser-based modalities for AA treatment. RESULTS: Literature search yielded 644 articles encompassing PRP, UVR, and laser treatment modalities for AA. Of the 644 articles, 46 met inclusion criteria. Although numerous reports demonstrate strong potential for PRP, UVR, and laser modalities in treating AA, high-quality evidence supporting their efficacy is still lacking. CONCLUSION: There is an abundance of evidence for nonsteroid-based procedural therapies in the treatment of AA. Randomized control trials comparing these treatment options head-to-head should be performed to better understand the true efficacy of these treatments.

A Head-to-Head Comparison of Topical Collagen Powder to Primary Closure for Acute Full-Thickness Punch Biopsy-Induced Human Wounds: An Internally Controlled Pilot Study

Background: Collagen-based products have been implemented in wound healing due to collagen's hemostatic properties, low antigenicity, and poor culture ability. Objective: To compare the rate and quality of full-thickness wound healing for topical collagen powder and primary closure. Methods: Eight volunteers received one 4 mm punch biopsy on each thigh. One wound was managed with primary closure while the other received daily collagen powder. Wounds were biopsied at four weeks for histopathological analysis. Subjects rated itch, pain, and treatment preferences at weeks 1, 2, 4, 6, and 12. Results: Six out of eight collagen-treated wounds were completely healed 4 weeks after initial wounding. Histologic analysis of the wounds revealed epidermal re-epithelization in both groups. More organized granulation tissue was noted in collagen-treated wounds and confirmed using Masson trichrome and CD31 staining for collagen and neoangiogenesis, respectively. Subjects reported similar itch and pain metrics between wounds. Both subjects and blinded dermatologists preferred the early cosmetic appearance of collagen-treated wounds over primarily closed wounds. Limitations: Small sample size, absence of negative control. Conclusion: These data suggest that collagen powder is non-inferior to primary closure at the macro- and microscopic levels, while possibly leading to superior early cosmetic outcomes and accelerated histologic wound maturation. Ethics/Clinical Trials Registration: Study was approved by the George Washington University Institutional Review Board (IRB protocol #121745). ClinicalTrials.gov: NCT03481907. J Drugs Dermatol. 2019;18(7):667-673.

Psychological Therapies in Management of Psoriatic Skin Disease: A Systematic Review.

BACKGROUND: Psoriasis is a chronic, immune-mediated skin disease shown to have a multifaceted relationship with psychological factors. Because these factors have been shown to both worsen and result from psoriasis, an increasing number of studies have sought to investigate the efficacy of various psychological interventions in psoriasis management. METHODS: A systematic review of PubMed® and Scopus® databases was performed for studies investigating psychological interventions in psoriasis management published from 1 January 1990 through 4 November 2018. Primary articles published in English and conveying physical treatment outcomes were included, whereas articles not describing clinical outcomes were excluded. Studies supporting intervention efficacy were graded with a level of evidence according to the Scottish Intercollegiate Guidelines Network levels of evidence. RESULTS: A total of 28 reports studying 27 unique sets of patients receiving psychological therapies in psoriasis management were identified, including three case reports and series and 24 clinical trials, investigating 1522 patients in total. Cognitive behavioral therapy and its variants, biofeedback, meditation and mindfulness-based therapies, hypnosis, music resonance therapy, motivational interviewing, emotional disclosure, and educational and multidisciplinary approaches have been studied in the treatment of psoriasis. Although 16 randomized controlled trials were included in this review, literature is limited by heterogeneity of methodology, analyses, and outcomes. Only 4 of 27 studies (three of which investigated cognitive behavioral therapy) were rated a level of evidence of 1+ or greater. Studies, overall, have sample sizes often < 50 patients, lack follow-up past 12 months, and have attrition rates > 20%. CONCLUSIONS: Based on assigned levels of evidence, the most promising methods of psychological intervention in psoriasis include cognitive behavioral therapy, mindfulness-based therapies, motivational interviewing, and educational and interdisciplinary interventions. Further study is needed to determine the efficacy, practicality, and economic feasibility of these treatment options for patients with psoriasis.

Dermatologic Surgical Care for Transgender Individuals.

BACKGROUND: Transgender individuals experience common and unique dermatologic concerns from severe acne associated with testosterone therapy in transmen to complications due to illicit silicone injections in transwomen. Currently, 2 survey studies and 4 reviews have addressed the dermatologic care of transgender individuals. However, none of them provide a focus on the dermatologic surgeon. OBJECTIVE: To assess the dermatologic considerations in transgender individuals and the role of dermatologic surgeon in their care. METHODS: The PubMed and MEDLINE databases were reviewed in June 2018 using keywords, such as transgender, procedures, hair removal, laser, and hormone therapy. RESULTS: In total, 48 relevant publications addressing dermatologic care in transgender patients were reviewed. According to the literature, there are several critical dermatologic considerations in transgender patients, including hair growth and removal, acne vulgaris, facial procedures to masculinize and feminize the face, scar removal, and sexually transmitted infections. CONCLUSION: As dermatologic surgeons have the privilege to improve the health care of transgender patients, they must understand the common and unique concerns of transgender individuals. Given the considerable spectrum of physical goals expressed by transmen and transwomen, individual patient preference must ultimately guide his/her/their dermatologic care.

Augmented Zika and Dengue Neutralizing Antibodies Are Associated With Guillain-Barré Syndrome.

The role of neutralizing antibodies in Zika-induced Guillain-Barré syndrome (GBS) has not yet been investigated. We conducted a case-control study using sera from the 2016 Zika epidemic in Colombia to determine the neutralizing antibody activity against Zika virus (ZIKV) and dengue virus serotype 2 (DENV2). We observed increased neutralizing antibody titers against DENV2 in ZIKV-infected individuals compared with uninfected controls and higher titers to both ZIKV and DENV2 in ZIKV-infected patients diagnosed with GBS compared with non-GBS ZIKV-infected controls. These data suggest that high neutralizing antibody titers to DENV and to ZIKV are associated with GBS during ZIKV infection.

A Case-control Study to Evaluate the Prevalence of Nonalcoholic Fatty Liver Disease Among Patients with Moderate-to-severe Psoriasis.

Objective: International case-control studies have demonstrated that psoriasis is associated with an increased prevalence of nonalcoholic fatty liver disease (NAFLD). The purpose of the present study was to establish an association of psoriasis and NAFLD in patients attending a dermatology clinic center in the United States. Design: This was an observational, case-control study. Setting: The study setting was an outpatient dermatology clinic of the George Washington Medical Faculty Associates in Washington DC. Participants: One hundred fifty-one adult patients with psoriasis and 51 control subjects were recruited. Measurements: NAFLD was diagnosed by ultrasonography after excluding secondary causes of liver disease. Regression analysis was used to assess the associations between: 1) NAFLD and psoriasis and 2) metabolic syndrome components and NAFLD among psoriasis patients. Results: NAFLD was more prevalent in patients with psoriasis (21.2% vs. 7.8%, p<0.04). However, psoriasis was not associated with NAFLD when matching for age, sex, and body mass index (BMI) (odds ratio: 2.63, 95% confidence interval [CI]: 0.51-13.6; p=0.25). As compared to patients with psoriasis but without NAFLD, those with NAFLD were more likely to have obesity (BMI: 34.9 vs. 27.2, 95% CI: 32.4-37.5 vs. 25.9-28.5; p<0.01). NAFLD in patients with psoriasis was also associated with select components of metabolic syndrome, including hyperglycemia and hyperlipidemia. Conclusion: Our findings show there is an association of psoriasis with NAFLD. Our findings also suggest an increased presence of metabolic syndrome components in patients with psoriasis and NAFLD. Trial registry: NCT00930384.

Kv7 channels are upregulated during striatal neuron development and promote maturation of human iPSC-derived neurons.

Kv7 channels determine the resting membrane potential of neurons and regulate their excitability. Even though dysfunction of Kv7 channels has been linked to several debilitating childhood neuronal disorders, the ontogeny of the constituent genes, which encode Kv7 channels (KNCQ), and expression of their subunits have been largely unexplored. Here, we show that developmentally regulated expression of specific KCNQ mRNA and Kv7 channel subunits in mouse and human striatum is crucial to the functional maturation of mouse striatal neurons and human-induced pluripotent stem cell-derived neurons. This demonstrates their pivotal role in normal development and maturation, the knowledge of which can now be harnessed to synchronise and accelerate neuronal differentiation of stem cell-derived neurons, enhancing their utility for disease modelling and drug discovery.

Genital Allergic Contact Dermatitis.

Genital allergic contact dermatitis (ACD) is an uncommon disorder, yet it severely impairs the quality of life for both men and women. Because of cultural taboos, many patients self-treat and delay proper diagnosis before presenting to a provider. Diagnosis is further confounded by irritant contact dermatitis and other genital dermatoses, which can predispose to skin barrier dysfunction and allergen penetration. Genital ACD can present acutely with erythematous erosions and pruritus or chronically with lichenification. Patch testing helps determine the diagnosis and provide relief for the patient. Topical medications, including local anesthetics and corticosteroids, are the most common genital allergens. Other typical allergens include fragrances, preservatives, adhesives, dyes, and rubber products. Less commonly considered allergens include herbs, spices, and topical vehicle components. Here, we review the most common allergens for both men and women, discuss important patch-testing panels, and recommend safe products for patients with genital ACD.

Optimal Adherence to a Mediterranean Diet and High Muscular Fitness Are Associated with a Healthier Cardiometabolic Profile in Collegiate Students.

The aim of the study was to investigate the combined association of adherence to a Mediterranean diet (MedDiet) and muscular fitness (MF) with cardiometabolic health in collegiate students. The present cross-sectional analysis consisted of 1248 (714 females) healthy collegiate students (20.1 ± 2.7 years old). Adherence to a MedDiet was assessed by a KIDMED (Mediterranean Diet Quality Index) questionnaire. Standing broad jump, standing vertical jump, and isometric handgrip dynamometry were used as indicators of MF. The cardiometabolic profile was assessed using the following components: triglycerides, blood pressure, triglycerides, high-density lipoprotein (HDL)-cholesterol, glucose, and waist circumference. Analysis of covariance shows a significant difference in the cardiometabolic profile of both genders between the high MF/low MedDiet and high MF/optimal MedDiet groups, and the low MF/low MedDiet and low MF/optimal MedDiet groups (p < 0.001). No difference was found on cardiometabolic profile between high MF/optimal MedDiet and high MF/low MedDiet, both in males and females. Additionally, logistic regression shows that both female (odds ratio (OR) = 2.01; 95% confidence interval (CI): (1.8⁻3.7); p = 0.02) and male (OR = 3.38; 95% CI: (1.9⁻5.8); p < 0.001) participants in the optimal MedDiet/high MF group had the highest odds of expressing a healthier cardiometabolic profile as compared to those in the low MF/low MedDiet group. In conclusion, a combination of high MF levels and optimal adherence to a MedDiet is associated with a healthier cardiometabolic profile; however, high MF levels seem to circumvent the deleterious effects of having a low adherence to a MedDiet.

Profile of dupilumab and its potential in the treatment of inadequately controlled moderate-to-severe atopic dermatitis.

Atopic dermatitis (AD) is a common inflammatory skin disorder that manifests as eczematous lesions, often associated with allergic rhinitis and asthma. Historically, moderate-to-severe disease has been managed with systemic immunosuppression, such as oral corticosteroids, which result in relapse and limiting side effects. Due to recent advancements in the identification of interleukin (IL)-4 and IL-13 as key mediators in AD, new biological agents have been developed for treatment. Dupilumab is a recently approved monoclonal antibody that targets the alpha subunit of the IL-4 receptor and, thus, downregulates activity of IL-4 and IL-13. This review discusses the profile of dupilumab and its potential for efficacy and safety in treating moderate-to-severe AD by reviewing data from Phase I-III clinical trials. Results suggest that dupilumab shows great therapeutic promise for AD. Further studies investigating extended use of dupilumab and dupilumab in comparison to other agents are needed to establish long-term efficacy and safety.