Helios expression coordinates the development of a subset of striatopallidal medium spiny neurons.

Here, we unravel the mechanism of action of the Ikaros family zinc finger protein Helios (He) during the development of striatal medium spiny neurons (MSNs). He regulates the second wave of striatal neurogenesis involved in the generation of striatopallidal neurons, which express dopamine 2 receptor and enkephalin. To exert this effect, He is expressed in neural progenitor cells (NPCs) keeping them in the G1/G0 phase of the cell cycle. Thus, a lack of He results in an increase of S-phase entry and S-phase length of NPCs, which in turn impairs striatal neurogenesis and produces an accumulation of the number of cycling NPCs in the germinal zone (GZ), which end up dying at postnatal stages. Therefore, He-/- mice show a reduction in the number of dorso-medial striatal MSNs in the adult that produces deficits in motor skills acquisition. In addition, overexpression of He in NPCs induces misexpression of DARPP-32 when transplanted in mouse striatum. These findings demonstrate that He is involved in the correct development of a subset of striatopallidal MSNs and reveal new cellular mechanisms for neuronal development.

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.

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.

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.

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.

A Survey Assessment of US Dermatologists' Perception of Biosimilars.

BACKGROUND: Biologics have transformed the treatment of psoriasis and psoriatic arthritis, but at a significant cost to payers and patients. The introduction of biosimilars into the US market could reduce costs while increasing access to biologic medications.

OBJECTIVE: We sought to identify gaps in biosimilar knowledge and perception among US dermatologists.

METHODS: An online survey was sent to dermatologists from January to April 2015.

RESULTS: Ninety-seven US dermatologists responded, of which 84% state they prescribe biologics in their practice. Only 37% of dermatologists were aware that a biosimilar is highly similar to a US-licensed reference biological product, 26% incorrectly described a biosimilar as a "generic" of a known biologic, and 10% of dermatologists stated they did not know the definition. Most dermatologists (88%) believe that substitutions from biologics to biosimilars will be made by pharmacists without consulting the physician. A total of 37% of dermatologists believed that a biosimilar with the same name as a biologic suggested they are "structurally identical." Only 25% said they would likely prescribe biosimilars to their patients, while 38% stated they would try using them on a very select, small group of patients before trying it on a majority of their patients.

LIMITATIONS: Limitations include small sample size and non-responder bias.

CONCLUSION: A biosimilars knowledge gap exists amongst dermatologists, suggesting the need for more educational initiatives.

J Drugs Dermatol. 2017;16(6):612-615.

Understanding State Regulation of Biosimilars and Effect on Prescribers.

Biologics are a mainstay of treatment for many dermatologic conditions, however the high costs can be prohibitive for many patients. A growing market of biosimilar drugs is emerging with the hope of providing patients access to more affordable medications. While the FDA has created an abbreviated licensure pathway for these drugs, states are still in the process of creating regulations regarding their substitution for reference biologics. This article looks to raise awareness of the current federal regulations and the differences among state regulations regarding the use of biosimilars. Fifty percent of states have passed legislation regarding procedures for substitution of biosimilars in the pharmacy. All states require biosimilars to have FDA-approved "interchangeable" status, however states vary on other requirements such as: prescriber and patient notification, pharmaceutical record keeping, publicly-accessible list of interchangeable products, and cost regulations. Some of the issues surrounding biosimilar regulation include difficulty obtaining interchangeability status from the FDA, resistance to the physician notification requirement, and concern for traceability of adverse reactions. Physicians must be aware of current federal and state regulations regarding biosimilars and help inform policy makers of the potential benefits and shortcoming of biosimilar legislation.

J Drugs Dermatol. 2017;16(10):995-1000.

Mast Cell Burden in a Patient With Cutaneous Disease

Mastocytosis is a disease characterized by the abnormal clonal proliferation of mast cells in skin and/or extracutaneous organs, often relating to activating mutations of c-KIT. Histopathology special stains, such as Giemsa, Leder, and Toluidine blue, are key for the diagnosis of cutaneous mastocytosis (CM). In adults, skin lesions can be associated with systemic disease. Tryptase is a diagnostic marker in mastocytosis and thought to reflect the burden of mast cell disease. In this report, we present a case of cutaneous mast cell disease with associated findings of elevated serum tryptase and mast cell infiltration of the bone marrow consistent with indolent systemic mastocytosis.

Patient Awareness of Local Drug Price Variation and the Factors That Influence Pharmacy Choice: A Cross-sectional Survey Study

BACKGROUND: High out-of-pocket drug expenditures are increasingly common in dermatology. Patients may not be aware that prices vary among pharmacies and consequently may not shop for the lowest cost. OBJECTIVE: To determine what factors influence pharmacy choice and the effect of providing local prescription prices on pharmacy selection. We hypothesized that patients do not "shop around" due to lack of knowledge of price variation and would choose a pharmacy based on costs if educated on price disparity. METHODS: Between July and August 2016, we administered a cross-sectional anonymous survey to adults visiting four outpatient clinics at an academic tertiary care center in Washington, D.C. Participants answered questions before and after viewing a list of prescription drug prices from local pharmacies. RESULTS: 287 surveys were administered to a convenience sample of adults (age ≥ 18 and literate in English). Of the 287 participants, 218 fully completed the survey; 55.1% were women and 40.5% were over age 40. When considering a cost savings of $10-25, 65% would switch pharmacies if the distance were the same, and 21.3% would switch if the distance were 45-minutes further. After price education, fewer participants felt that drug price knowledge would ultimately influence pharmacy choice (P less than 0.0001). However, respondents' intended frequency of researching price online, calling a pharmacy to ask about price, and comparing price between pharmacies before filling a prescription all increased, compared to prior self-reported frequencies (P less than 0.001). Specifically, participants with $75,000-$99,999 income were more likely to compare prices than those with income below $45,000 (odds ratio [OR], 4.62; 95% confidence interval [CI], 1.24-17.28). CONCLUSION: In this study, pharmacy choice was more influenced by convenience than cost prior to drug price education. However, price education ultimately impacted intent to research prescription drug prices before selecting a pharmacy. Thus, knowledge of drug pricing may be useful in creating cost savings for patients.

Applications of the Excimer Laser: A Review.

BACKGROUND: The 308-nm excimer laser has been approved by the Food and Drug Administration for the treatment of psoriasis and vitiligo. Its ability to treat localized areas has led to many studies determining its potential in the treatment of focal diseases with inflammation or hypopigmentation. OBJECTIVE: To review the different applications of the 308-nm excimer laser for treating dermatologic conditions. METHODS AND MATERIALS: An extensive literature review was conducted by searching PubMed, MEDLINE, and ClinicalKey to find articles pertaining to dermatologic conditions treated with the 308-nm excimer laser. Articles published that contributed to new applications of the excimer laser were included, as well as initial studies utilizing the excimer laser. RESULTS: The outcomes and results were compiled for different dermatologic conditions treated with the excimer laser. CONCLUSION: The 308-nm excimer laser has a wide range of uses for focal inflammatory and hypopigmented conditions. Treatment is generally well tolerated, with few adverse reactions. Larger studies and studies evaluating the long-term effects of the 308-nm excimer laser are needed.

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.

Designing and reporting clinical trials on treatments for cutaneous leishmaniasis.

Cutaneous leishmaniasis is considered to be one of the most neglected and serious parasitic infectious skin diseases in many developing countries. We have assessed the design and reporting of randomized, controlled trials evaluating treatments included in 2 Cochrane systematic reviews on cutaneous leishmaniasis. The analysis of the methodological quality identified some potential bias that can make it difficult to determine whether truly effective therapies exist for this disease. We found important weaknesses in the adequacy and transparency of randomization, loss of participants, causative Leishmania species, outcome measures, and follow-up times. Given these distorting effects on the evidence base, we propose guidelines for authors who wish to conduct clinical trials aimed at the development of effective therapies in cutaneous leishmaniasis. The recommendations in this report will hopefully deserve the attention of the World Health Organization and assist in the planning and prioritization of global strategies for improving the interpretation and replication of clinical research on cutaneous leishmaniasis.

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.

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.

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.