Haploinsufficiency of Syngap1 in striatal indirect pathway neurons alters motor and goal-directed behaviors in mice.

SYNGAP1 is a high-confidence autism spectrum disorder (ASD) risk gene and mutations in SYNGAP1 lead to a neurodevelopmental disorder (NDD) that presents with epilepsy, ASD, motor developmental delay, and intellectual disability. SYNGAP1 codes for Ras/Rap GTP-ase activating protein SynGAP (SynGAP). In mice, SynGAP is located in the postsynaptic density of glutamatergic synapses and regulates glutamate receptor trafficking in an activity-dependent manner. In addition to forebrain glutamatergic neurons, Syngap1 is highly expressed in the striatum, although the functions of SynGAP in the striatum have not been extensively studied. Here we show that Syngap1 is expressed in both direct and indirect pathway striatal projection neurons (dSPNs and iSPNs) in mice of both sexes. In a mouse model of Syngap1 haploinsufficiency, dendritic spine density, morphology, and intrinsic excitability are altered primarily in iSPNs, but not dSPNs. At the behavioral level, SynGAP reduction alters striatal-dependent motor learning and goal-directed behavior. Several behavioral phenotypes are reproduced by iSPN-specific Syngap1 reduction and, in turn, prevented by iSPN-specific Syngap1 rescue. These results establish the importance of SynGAP to striatal neuron function and pinpoint the indirect pathway as a key circuit in the neurobiology of SYNGAP1-related NDD.Significance statement SYNGAP1 mutations cause a neurodevelopmental disorder presenting with intellectual disability, motor problems, epilepsy, autism spectrum disorder, and a constellation of other behavioral and psychiatric conditions. SynGAP protein is highly expressed in the striatum but its functions in this brain region have not yet been explored. This study shows that loss of one copy of the Syngap1 gene from striatal indirect, but not direct, pathway neurons alters synaptic properties, cellular excitability, motor behaviors, and goal-directed responding in mice. This work provides a new perspective on the functions of SynGAP and suggests that altered activity in striatal circuits may be an important driver of the motor and learning alterations in people with SYNGAP1 disorder.

Reticulated pigmentary changes and Terry's nails in a patient with a TERT variant-associated telomere biology disorder.

Telomere biology disorders (TBD) are a complex set of inherited illnesses characterized by short telomeres. Dyskeratosis congenita (DC), which is now considered a severe TBD phenotype, is characterized by reticulated pigmentary changes, nail dystrophy, premalignant oral leukoplakia, and systemic involvement. This case describes a 2-year-old female with reticulated pigmentary changes and Terry's nails who was found to have a TERT variant and short telomeres; she lacked other mucocutaneous and systemic features of TBD. This report describes a unique clinical presentation of TBD and highlights the importance of upholding suspicion for TBD in individuals with limited or subtle features of classic DC.

Comparison of potential contact allergens in best-selling adult and baby cleansers.

are that the contents of this article are their own original unpublished findings. Title: Comparison of potential contact allergens in best-selling adult and baby cleansers Authors: Jayden Galamgam1 MD, Sasan D Noveir2 BA, Carol E Cheng1 MD Affiliations: 1Division of Dermatology, Department of Medicine, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, California, USA, 2 David Geffen School of Medicine, University of California Los Angeles, Los Angeles, California, USA Corresponding Author: Jayden Galamgam MD, Division of Dermatology, Department of Medicine, David Geffen School of Medicine, University of California Los Angeles, 10833 Le Conte Avenue, Los Angeles, CA 90095, Email: jgalamgam@mednet.ucla.edu.

Prevalence of potential contact allergens in best-selling baby cleansers.

Many baby cleansers are promoted as hypoallergic products; however, these claims are not typically validated. This study assessed the 50 best-selling baby cleansers from online retailer Amazon for potential allergens. We found that the presence of most marketing claims, including "hypoallergenic" or "allergy-tested," did not correlate with the number of potential allergens in a cleanser. Furthermore, the total number of marketing claims of a cleanser was positively correlated with the number of allergens, highlighting the discordance between marketing claims and allergen content in baby cleansers.

Recurrent amebic liver abscesses despite metronidazole treatment: A rare case report.

Amebic liver abscesses should be considered in adult males with a liver abscess and a history of travel to endemic areas. Effective treatment includes metronidazole, followed by paromomycin.

Patterns and determinants of pediatric dermatologic care in the United States: An evaluation of the National Ambulatory Medical Care Survey from 2009 to 2015.

BACKGROUND: Dermatologists and other providers play essential roles in managing the dermatologic care of pediatric patients. This study aims to identify patterns and elucidate factors associated with receiving dermatologic care in the United States. METHODS: The National Ambulatory Medical Care Survey (NAMCS) was used to identify pediatric patients with dermatologic diagnoses from 2009 to 2015. Clinical and demographic information were evaluated, and visit diagnoses were stratified based on provider type (dermatologists vs. non-dermatologists). Multivariate logistic regression analysis was used to identify key predictors of outpatient dermatology care for pediatric patients. National estimates of diagnoses were procured using weights provided within the NAMCS database to project disease incidence. RESULTS: A total of 85,217,557 pediatric patients (survey-weighted) were observed during the study period. Of the sampled patients, 29.3% were evaluated by dermatologists, while 70.7% were seen by non-dermatology providers. Atopic dermatitis was the most common diagnosis encountered by dermatologists in ages 0-3 years, while unspecified contact dermatitis was the most common diagnosis reported by non-dermatologists in all age groups. On multivariable logistic regression, ≥1 year of age, Caucasian race, private insurance versus Medicaid, residence in a metropolitan area, referral from another provider, and longer appointment wait time were associated with an increased likelihood of being evaluated by a dermatologist compared to a non-dermatologist. CONCLUSIONS: Non-dermatologists are responsible for the majority of pediatric dermatologic care. For pediatric patients, health disparities by race, insurance status, and rurality present significant challenges to being evaluated by a dermatologist.

Effect of the ABCA1 agonist CS-6253 on amyloid-ß and lipoprotein metabolism in cynomolgus monkeys.

BACKGROUND: Inducing brain ATP-binding cassette 1 (ABCA1) activity in Alzheimer's disease (AD) mouse models is associated with improvement in AD pathology. The purpose of this study was to investigate the effects of the ABCA1 agonist peptide CS-6253 on amyloid-ß peptides (Aß) and lipoproteins in plasma and cerebrospinal fluid (CSF) of cynomolgus monkeys, a species with amyloid and lipoprotein metabolism similar to humans. METHODS: CS-6253 peptide was injected intravenously into cynomolgus monkeys at various doses in three different studies. Plasma and CSF samples were collected at several time points before and after treatment. Levels of cholesterol, triglyceride (TG), lipoprotein particles, apolipoproteins, and Aß were measured using ELISA, ion-mobility analysis, and asymmetric-flow field-flow fractionation (AF4). The relationship between the change in levels of these biomarkers was analyzed using multiple linear regression models and linear mixed-effects models. RESULTS: Following CS-6253 intravenous injection, within minutes, small plasma high-density lipoprotein (HDL) particles were increased. In two independent experiments, plasma TG, apolipoprotein E (apoE), and Aß42/40 ratio were transiently increased following CS-6253 intravenous injection. This change was associated with a non-significant decrease in CSF Aß42. Both plasma total cholesterol and HDL-cholesterol levels were reduced following treatment. AF4 fractionation revealed that CS-6253 treatment displaced apoE from HDL to intermediate-density- and low density-lipoprotein (IDL/LDL)-sized particles in plasma. In contrast to plasma, CS-6253 had no effect on the assessed CSF apolipoproteins or lipids. CONCLUSIONS: Treatment with the ABCA1 agonist CS-6253 appears to favor Aß clearance from the brain.