Genomic profiling of human vascular cells identifies TWIST1 as a causal gene for common vascular diseases.

Genome-wide association studies have identified multiple novel genomic loci associated with vascular diseases. Many of these loci are common non-coding variants that affect the expression of disease-relevant genes within coronary vascular cells. To identify such genes on a genome-wide level, we performed deep transcriptomic analysis of genotyped primary human coronary artery smooth muscle cells (HCASMCs) and coronary endothelial cells (HCAECs) from the same subjects, including splicing Quantitative Trait Loci (sQTL), allele-specific expression (ASE), and colocalization analyses. We identified sQTLs for TARS2, YAP1, CFDP1, and STAT6 in HCASMCs and HCAECs, and 233 ASE genes, a subset of which are also GTEx eGenes in arterial tissues. Colocalization of GWAS association signals for coronary artery disease (CAD), migraine, stroke and abdominal aortic aneurysm with GTEx eGenes in aorta, coronary artery and tibial artery discovered novel candidate risk genes for these diseases. At the CAD and stroke locus tagged by rs2107595 we demonstrate colocalization with expression of the proximal gene TWIST1. We show that disrupting the rs2107595 locus alters TWIST1 expression and that the risk allele has increased binding of the NOTCH signaling protein RBPJ. Finally, we provide data that TWIST1 expression influences vascular SMC phenotypes, including proliferation and calcification, as a potential mechanism supporting a role for TWIST1 in CAD.

Cutaneous Keratocyst With D2-40 Immunoreactivity in Basal Cell Nevus Syndrome.

ABSTRACT: Although not a diagnostic criterion for basal cell nevus syndrome (BCNS, OMIM#109400), cutaneous cysts, particularly epidermoid cysts, are common in this condition. Cutaneous keratocysts, on the other hand, are extremely rare in general and have been identified in only 5 patients with BCNS. Here, we describe a BCNS patient with a cutaneous keratocyst that demonstrated D2-40 (podoplanin) immunoreactivity, which has been detected in odontogenic keratocysts but not cutaneous keratocysts. This finding suggests that cutaneous keratocysts may be developmentally homologous to odontogenic keratocysts and may behave similarly in terms of invasion and growth pattern.

At the dinner table with Adam and Eve.

Parents of children with atopic dermatitis often believe that dietary factors influence the course of a child's eczema. This is not a new phenomenon. In this paper, we examine two old documents that explore the relationships between diet and health. The first document is 125-years-old and real; the second document is a fictional one that we composed in the style of Mark Twain's Extracts from Adam's Diary, which Twain humorously suggested was from the time of Genesis.

Modification of footed pajamas to confirm arthropod bites: The Modified Onesie Biting Bug Assessment suit.

When children present with features of bed bug bites, many parents are reluctant to accept the diagnosis. Furthermore, standard methods to detect arthropods in or around one's home can be expensive, time-consuming, and frustrating. We developed a simple, inexpensive way to provide evidence that the lesions are in fact due to arthropod bites. The Modified Onesie Biting Bug Assessment (MOBBA) suit utilizes simple alterations to a full-body onesie-type footed pajama, exposing some body surfaces to insect predators while protecting other areas.

Use of psoralen therapies obtained abroad in two children with Vitiligo.

We describe two American-born children with vitiligo, each of whom travelled to their family's ancestral home (India and Ethiopia), where their skin conditions were treated with PUVAsol, which involves the use of topical or oral psoralens followed by exposure to natural sunlight. Both children experienced modest repigmentation and were subsequently seen in our dermatology clinics. PUVAsol may be an attractive treatment option for some families, but there are potentially serious side effects including phototoxicity and cutaneous malignancy. Dermatologists should be aware of the existence of this treatment modality as well as its complications.

Outlier detection for improved differential splicing quantification from RNA-Seq experiments with replicates.

Motivation: A key component in many RNA-Seq-based studies is contrasting multiple replicates from different experimental conditions. In this setup, replicates play a key role as they allow to capture underlying biological variability inherent to the compared conditions, as well as experimental variability. However, what constitutes a 'bad' replicate is not necessarily well defined. Consequently, researchers might discard valuable data or downstream analysis may be hampered by failed experiments. Results: Here we develop a probability model to weigh a given RNA-Seq sample as a representative of an experimental condition when performing alternative splicing analysis. We demonstrate that this model detects outlier samples which are consistently and significantly different compared with other samples from the same condition. Moreover, we show that instead of discarding such samples the proposed weighting scheme can be used to downweight samples and specific splicing variations suspected as outliers, gaining statistical power. These weights can then be used for differential splicing (DS) analysis, where the resulting algorithm offers a generalization of the MAJIQ algorithm. Using both synthetic and real-life data, we perform an extensive evaluation of the improved MAJIQ algorithm in different scenarios involving perturbed samples, mislabeled samples, same condition groups, and different levels of coverage, showing it compares favorably to other tools. Overall, this work offers an outlier detection algorithm that can be combined with any splicing pipeline, a generalized and improved version of MAJIQ for DS detection, and evaluation metrics with matching code and data for DS algorithms. Availability and implementation: Software and data are accessible via majiq.biociphers.org/norton_et_al_2017/. Contact: yosephb@upenn.edu. Supplementary information: Supplementary data are available at Bioinformatics online.

"Slime" dermatitis, a fad-associated chronic hand dermatitis.

"Slime" is the colloquial name for a non-Newtonian viscoelastic putty-like substance that is currently a popular plaything among pre-teens and adolescents. Several ingredients in homemade slime recipes may cause irritant or allergic contact dermatitis. We report two children who developed slime-associated chronic hand dermatitis, more prominently on their dominant hand. We review the potential for irritant and allergic contact dermatoses as the causes of dermatitis associated with homemade slime.

Postinjection abscesses and granulomas in children adopted from Russia.

Up to 1.3 million children from the former Soviet Union (fSU) and Eastern Europe have been placed in institutional care worldwide. With the hope of ensuring the child's health in the immediate post-adoption period, these children are known to receive many injections of vaccines, vitamins, and medications, many unnecessary and often administered with unsafe technique. This practice can lead to formation of suppurative granulomas in these children. Though rare, dermatologists should be aware of these conditions in adoptees from Eastern Europe.

Erythema ab igne in patients with sickle cell disease.

Erythema ab igne (EAI) is an asymptomatic dermatosis caused by prolonged exposure to localized heat. Affected areas have net-like hyperpigmentation that may resemble more serious conditions such as livedo racemosa or vasculitis. We report three cases of EAI in pediatric sickle cell disease (SCD) patients who were initially suspected of having a more severe, life-threatening disorder before Dermatology was consulted. Clinicians caring for pediatric SCD patients who regularly use heating pads/devices for pain relief should consider EAI in the differential diagnosis of large areas of net-like hyperpigmentation. This paper aims to increase recognition of EAI and patient education on safe practices while using heating pads.

The effect of climate change on skin disease in North America.

Global temperatures continue to rise, reaching new records almost every year this decade. Although the causes are debated, climate change is a reality. Consequences of climate change include melting of the arctic ice cap, rising of sea levels, changes in precipitation patterns, and increased severe weather events. This article updates dermatologists about the effects of climate change on the epidemiology and geographic ranges of selected skin diseases in North America. Although globalization, travel, and trade are also important to changing disease and vector patterns, climate change creates favorable habitats and expanded access to immunologically naïve hosts. Endemic North American illnesses such as Lyme disease, leishmaniasis, and dimorphic fungal infections have recently expanded the geographic areas of risk. As temperatures increase, epidemic viral diseases such as hand-foot-and-mouth disease may develop transmission seasons that are longer and more intense. Chikungunya and dengue are now reported within the southern United States, with Zika on the horizon. Cutaneous injuries from aquatic and marine organisms that have expanding habitats and longer durations of peak activity include jellyfish envenomation, cercarial dermatitis, and seabather eruption, among others. Skin cancer rates may also be affected indirectly by changes in temperature and associated behaviors.

Painful subcutaneous nodules on the thigh.

Osteoma cutis is the presence of bone within the dermis or subcutaneous tissue. This condition may occur sporadically or secondary to other dermatologic or genetic conditions. We present a 12-year-old girl with pseudohypoparathyroidism type-Ia who developed osteoma cutis on the right thigh.

MixMir: microRNA motif discovery from gene expression data using mixed linear models.

microRNAs (miRNAs) are a class of ∼22nt non-coding RNAs that potentially regulate over 60% of human protein-coding genes. miRNA activity is highly specific, differing between cell types, developmental stages and environmental conditions, so the identification of active miRNAs in a given sample is of great interest. Here we present a novel computational approach for analyzing both mRNA sequence and gene expression data, called MixMir. Our method corrects for 3' UTR background sequence similarity between transcripts, which is known to correlate with mRNA transcript abundance. We demonstrate that after accounting for kmer sequence similarities in 3' UTRs, a statistical linear model based on motif presence/absence can effectively discover active miRNAs in a sample. MixMir utilizes fast software implementations for solving mixed linear models, which are widely used in genome-wide association studies (GWASs). Essentially we use 3' UTR sequence similarity in place of population cryptic relatedness in the GWAS problem. Compared to similar methods such as miReduce, Sylamer and cWords, we found that MixMir performed better at discovering true miRNA motifs in three mouse Dicer-knockout experiments from different tissues, two of which were collected by our group. We confirmed these results on protein and mRNA expression data obtained from miRNA transfection experiments in human cell lines. MixMir can be freely downloaded from https://github.com/ldiao/MixMir.

Addisonian-Like Hyperpigmentation as an Indicator of Uncontrolled Congenital Adrenal Hyperplasia.

A 20-year-old man of Indo-Malaysian ancestry presented with a complaint of increased facial pigmentation that he first noticed at age 13. He had congenital adrenal hyperplasia (21-hydroxylase deficiency, salt-wasting variant; OMIM 201910), diagnosed during infancy. Glucocorticoid and mineralocorticoid therapy was started at that time, but he had several episodes of salt craving during adolescence. During the past 7 years, the degree of facial pigmentation waxed and waned but never returned to baseline of early adolescence. Progressive skin darkening was also observed in annual family photos, which also showed a vast difference in skin tones between the patient and other members of his immediate family.

Zinc deficiency-associated dermatitis in infants during a nationwide shortage of injectable zinc - Washington, DC, and Houston, Texas, 2012-2013.

Injectable zinc, a vital component of parenteral nutrition (PN) formulations, has been in short supply in the United States since late 2012. In December 2012, three premature infants with cholestasis hospitalized in Washington, DC, experienced erosive dermatitis in the diaper area and blisters on their extremities, a condition that can be associated with zinc deficiency. All three infants were receiving PN because they had extreme cholestasis and were unable to be fed by mouth or tube. The PN administered to each infant was zinc deficient. Injectable zinc normally is added to PN for premature or medically compromised infants (e.g., those with cholestasis) by the hospital pharmacy because the amount of zinc needed by each patient differs; however, the pharmacy had run out of injectable zinc. No alternatives were available; other preparations of parenteral trace elements either contained insufficient zinc to meet infants' requirements or had the potential to cause trace element toxicity in infants with cholestasis (2). The dermatitis of one infant resolved after the patient was able to take nutrition by mouth. The other two infants were found to have low serum zinc levels. In January 2013, CDC was notified of four additional cases of zinc deficiency among infants with cholestasis who received zinc-deficient PN in a hospital in Houston, Texas. In collaboration with the Food and Drug Administration (FDA), the two hospitals obtained emergency shipments of injectable zinc. No additional cases were reported. Current injectable zinc supplies have been increasing as FDA collaborates with pharmaceutical companies to import emergency supplies. FDA is working to establish temporary backup sources should future shortages occur.

Nonsyndromic whorled eyebrows in a healthy 6-year-old girl.

Whorled eyebrows are an unusual and rarely described finding of unknown clinical significance. We present such a case in a 6-year-old healthy girl.

Metoposcopy redux.

Phrenology is the pseudoscience in which practitioners claim that they can discern one's character and personality traits by studying the structure of the skull. Long before "head bumps" were viewed as determinants of character, skin lines were analyzed to provide similar information and to divine one's future. Palmistry, also called chiromancy, is the interpretation of the lines of the palms and is one of the oldest forms of divination. A similar pseudoscience, metoposcopy, suggests that facial lines and marks, mainly forehead lines, can reveal one's personality and foretell events in one's future. Metoposcopy was first practiced by the ancient Chinese and was popularized during the Renaissance by Girolamo Cardano and later by Richard Saunders. Metoposcopy is a largely forgotten form of skin-based pseudoscience that is no longer practiced today, unlike palmistry.

Characterization of enhancer activity in early human neurodevelopment using Massively Parallel Reporter Assay (MPRA) and forebrain organoids.

Regulation of gene expression through enhancers is one of the major processes shaping the structure and function of the human brain during development. High-throughput assays have predicted thousands of enhancers involved in neurodevelopment, and confirming their activity through orthogonal functional assays is crucial. Here, we utilized Massively Parallel Reporter Assays (MPRAs) in stem cells and forebrain organoids to evaluate the activity of ~ 7000 gene-linked enhancers previously identified in human fetal tissues and brain organoids. We used a Gaussian mixture model to evaluate the contribution of background noise in the measured activity signal to confirm the activity of ~ 35% of the tested enhancers, with most showing temporal-specific activity, suggesting their evolving role in neurodevelopment. The temporal specificity was further supported by the correlation of activity with gene expression. Our findings provide a valuable gene regulatory resource to the scientific community.