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Adena Rosenblatt,1 Erin F Mathes,2 Kristina W Rosbe31Department of Pediatrics, University of California, San Francisco, 2Division of Pediatric Dermatology, Departments of Dermatology and Pediatrics, University of California, San Francisco, 3Division of Pediatric Otolaryngology, Department of Otolaryngology – Head and Neck Surgery, University of California, San Francisco, CA, USAAbstract: Infantile hemangiomas (IH) are benign vascular tumors consisting of a collection of immature cells, including progenitor stem cells and disorganized blood vessels. They are the most common benign tumors in childhood. Recently, there have been significant, exciting advancements in the understanding of the pathogenesis and treatment of infantile hemangiomas, which are discussed in this review. The decision to initiate treatment for IH is based on many factors, including size and location, functional compromise, psychosocial implications, and risks and benefits of the proposed therapy. For most families of children with hemangiomas, education about the natural history of IH and reassurance are often the only "treatment" required. A minority of patients with large, complex lesions or lesions that cause functional compromise require early intervention. These patients and families benefit from a multidisciplinary approach to care in vascular birthmark centers. Ongoing multi-institutional clinical trials will provide further important data on the efficacy and safety of hemangioma treatments.Keywords: progenitor stem cell, glucose transporter 1, PHACES, LUMBAR, infantile hemangioma

Importance: The results of small studies suggest that off-label use of low-dose oral minoxidil (LDOM) may be safe and effective for patients with hair loss, but larger trials and standardized guidelines are lacking., Objective: To create an expert consensus statement for LDOM prescribing for patients with hair loss., Evidence Review: The current literature on the pharmacological properties, adverse effect profile, and use of LDOM for patients with hair loss was reviewed. Topics of interest were identified, and a modified Delphi consensus process was created. A total of 43 hair loss specialist dermatologists from 12 countries participated in a modified Delphi process. Consensus was reached if at least 70% agreed or strongly agreed on a 5-point Likert scale., Findings: Over 4 survey rounds, 180 items in the first round, 121 items in the second round, 16 items in the third round, and 11 items in the fourth round were considered and revised. A total of 76 items achieved consensus including diagnoses for which LDOM may provide direct or supportive benefit, indications for LDOM compared to topical minoxidil, dosing for adults (18 years and older) and adolescents (aged 12 to 17 years), contraindications, precautions, baseline evaluation, monitoring, adjunctive therapy, and specialty consultation. Pediatric use and dosing items for children younger than 12 years, and LDOM titration protocols fell short of consensus., Conclusions and Relevance: This international expert consensus statement regarding the off-label prescribing of LDOM for patients with hair loss can help guide clinical practice until more data emerge. Hair loss experts with experience treating pediatric patients were underrepresented on this expert panel. Future research should investigate best practices for LDOM use in pediatric patients. Other critical topics for further investigation include the comparative efficacy of topical minoxidil vs oral minoxidil, the safety of oral minoxidil for patients with a history of allergic contact dermatitis to topical minoxidil, the long-term safety of LDOM, and the use of other off-label forms of minoxidil, such as compounded formulations of oral minoxidil and sublingual minoxidil. As additional evidence-based data emerge, these recommendations should be updated.

Genetically targeted medications are emerging as important therapies for lymphatic malformations (LMs) unresponsive to sirolimus. We describe two patients with EML4::ALK-positive LMs, one with Gorham Stout disease and one with a large genitourinary (GU) LM, who were successfully treated with ALK inhibitors. This report adds ALK inhibitors to the growing toolbox of molecularly targeted therapies for LMs., (© 2024 The Author(s). Pediatric Blood & Cancer published by Wiley Periodicals LLC.)

The first annual Association of Professors of Dermatology (APD) program director (PD) survey was distributed in November 2022 and included 53 respondents from individual Accreditation Council for Graduate Medical Education (ACGME) programs. This survey included 137 in-depth questions to identify similarities and differences among programs regarding 12 broad categories: program characteristics; PD demographics; impact of the COVID-19 pandemic on residency training; available resources; quality improvement; clinical instruction; didactic instruction; research content; diversity, equity, and inclusion; wellness; evaluation systems; and graduation outcomes of postgraduate year (PGY) 4 residents. The survey provided preliminary insight to similarities and differences between programs, such as varying academic time and research resources, while also challenging norms seen in areas of diversity, equity, and inclusion. As future surveys are optimized to obtain greater response rates, these metrics can be captured in a centralized database accessible to PDs to reflect trends and identify strengths and weaknesses of dermatology residency programs.

Background: Initial propranolol recommendations for infantile hemangioma published in 2013 were intended as provisional best practices to be updated as evidence-based data emerged., Methods: A retrospective multicenter study was performed to evaluate utility of prolonged monitoring after first propranolol dose and escalation(s). Inclusion criteria included diagnosis of hemangioma requiring propranolol of greater than or equal to 0.3 mg/kg per dose, younger than 2 years, and heart rate monitoring for greater than or equal to 1 hour. Data collected included demographics, dose, vital signs, and adverse events., Results: A total of 783 subjects met inclusion criteria; median age at initiation was 112 days. None of the 1148 episodes of prolonged monitoring warranted immediate intervention or drug discontinuation. No symptomatic bradycardia or hypotension occurred during monitoring. Mean heart rate change from baseline to 1 hour was -8.19/min (±15.54/min) and baseline to 2 hours was -9.24/min (±15.84/min). Three preterm subjects had dose adjustments because of prescriber concerns about asymptomatic vital sign changes. No significant difference existed in pretreatment heart rate or in heart rate change between individuals with later adverse events during treatment and those without., Conclusion: Prolonged monitoring for initiation and escalation of oral propranolol rarely changed management and did not predict future adverse events. Few serious adverse events occurred during therapy; none were cardiovascular., (Copyright © 2021. Published by Elsevier Inc.)

Importance: Oral propranolol is widely considered to be first-line therapy for complicated infantile hemangioma, but its use in patients with PHACE (posterior fossa malformations, hemangioma, arterial anomalies, cardiac defects, eye anomalies) syndrome has been debated owing to concerns that the cardiovascular effects of the drug may increase the risk for arterial ischemic stroke., Objective: To assess the incidence of adverse events among patients with PHACE syndrome receiving oral propranolol for infantile hemangioma., Design, Setting, and Participants: This multicenter retrospective cohort study assessed the incidence of adverse events among 76 patients with PHACE syndrome receiving oral propranolol for infantile hemangioma at 11 tertiary care, academic pediatric dermatology practices. Medical records from January 1, 2010, through April 25, 2017, were reviewed., Exposures: Patients received oral propranolol, 0.3 mg/kg/dose or more., Main Outcomes and Measures: The main outcome was the rate and severity of adverse events occurring throughout the course of treatment with oral propranolol, as documented in the medical records. Adverse events were graded from 1 to 5 using a scale derived from the Common Terminology Criteria for Adverse Events and were considered to be serious if they were grade 3 or higher., Results: A total of 76 patients (59 girls and 17 boys; median age at propranolol initiation, 56 days [range, 0-396 days]) met the inclusion criteria. There were no reports of serious adverse events (ie, stroke, transient ischemic attack, or cardiovascular events) during treatment with oral propranolol. A total of 46 nonserious adverse events were reported among 29 patients (38.2%); the most commonly reported nonserious adverse events were sleep disturbances and minor gastrointestinal tract and respiratory tract symptoms. In a comparison with 726 infants who received oral propranolol for hemangioma but did not meet criteria for PHACE syndrome, there was no significant difference in the rate of serious adverse events experienced during treatment (0 of 76 patients with PHACE syndrome and 3 of 726 patients without PHACE syndrome [0.4%])., Conclusions and Relevance: This study found that oral propranolol was used to treat infantile hemangioma in 76 patients with PHACE syndrome and that no serious adverse events were experienced. These data provide support for the safety of oral propranolol in this patient population.

Background: The opioid epidemic in the United States has resulted in a significant increase in fentanyl-related overdoses nationwide since 2013. Because of an increased rate of fentanyl-related overdoses seen in Jefferson Parish, LA, the Jefferson Parish Coroner's Office (JPCO) hypothesized that the opioid epidemic, specifically related to fentanyl, had reached this region. To test this hypothesis, JPCO analyzed fentanyl overdose deaths to determine if the deaths had increased during a 6-year period and if the change met the definition of an epidemic. Methods: In the toxicology laboratory at JPCO, enzyme-linked immunosorbent assay screening and gas chromatography/mass spectrometry are used in-house to determine the presence of drugs. Drug-positive samples are sent to National Medical Services (NMS) Labs to quantify the analyte concentration in each sample. Data for each decedent were extracted from the Medicolegal Death Investigation Log (MDILog) database for the years 2013 through 2018. Results: A slow increase in fentanyl-related deaths during the first 3 years of the study period was followed by a near doubling of cases in 2016, a tripling of cases in 2017, and a 6-fold increase in incidence in 2018. During the 6-year study period, fentanyl-related deaths increased from 6 in 2013, to 8 in 2014, to 14 in 2015. Twenty-five deaths in 2016 spiked to 66 in 2017 and increased to 78 fentanyl-related overdose deaths in 2018. The percentage of fentanyl-related overdose deaths increased from 4% of all drug deaths in 2013 to 45% in 2018. Conclusion: The data validate the hypothesis that the fentanyl epidemic has affected Jefferson Parish in southeast Louisiana., (©2019 by the author(s); Creative Commons Attribution License (CC BY).)

Background/objectives: Infantile hemangiomas are common vascular tumors. Identifying sites of predilection may provide insight into pathogenesis. Previous studies have suggested a predilection for the boundary of facial metameres. The objective was to observe patterns of localized hemangiomas on the face and scalp, determine sites of predilection, and place these patterns in a developmental context., Methods: A retrospective review of photographic archives at 10 Hemangioma Investigator Group pediatric dermatology centers identified localized infantile hemangiomas of the face and scalp. Heat map software was used to identify areas of predilection. Dot maps were used to assess frequency, and densities of infantile hemangiomas were compared between facial units using t-testing. The scalp was divided into quintiles to assess relative frequencies., Results: Four thousand one hundred fifty-three focal face and scalp infantile hemangiomas were mapped, of which 2962 (71%) were mapped to a frontal facial template. On the face, 73.8% (2186/2962) of hemangiomas occurred along the midline axis or perpendicularly across the ocular axis in a cross-shaped area of predilection intersecting at the glabella. Scalp hemangiomas show a predilection for the midline, with 149/295 (50.5%) noted on the top of the scalp at the midline (P < 0.001). Localized hemangiomas do not demonstrate a preferential laterality., Conclusion: The distribution of localized infantile hemangiomas of the face and scalp is not random. There is preferential involvement of the midline face and scalp and the ocular axis. The regions corresponding to the boundaries between the embryonic facial segments, including the maxillary and mandibular metameres, are not accentuated in the distribution of infantile hemangiomas., (© 2018 Wiley Periodicals, Inc.)

Background: There has been a dramatic increase in the off-label use of ophthalmic timolol maleate, a β-blocker used for infantile hemangioma (IH) treatment as a topical counterpart to oral propranolol. Its safety and efficacy in a pediatric population with IH have not been evaluated in a large cohort. Our goal was to retrospectively assess timolol's effectiveness, discern characteristics associated with response, and document reported adverse events., Methods: A multicenter retrospective cohort study of 731 patients treated with topical timolol was completed at 9 centers. Inclusion required an IH suitable for timolol in the treating physician's judgment and access to clinical details including photographs. Logistic regression analysis and descriptive statistics were performed. Primary outcome measures were efficacy assessed by using visual analog scales for color and for size, extent, and volume from review of digital photographs taken as standard of care., Results: Most IHs were localized (80.1%) and superficial (55.3%). Risk of disfigurement was the most common indication for therapy (74.3%). Duration of therapy (P < .0001), initial thinness (P = .008), and subtype (P = .031) were significant predictors of response. Best response occurred in superficial IHs <1 mm thick. Fifty-three (7.3%) required subsequent therapy with systemic β-blocker. Adverse events were mild, occurring in 25 (3.4%) patients. No cardiovascular side effects were documented., Conclusions: Timolol seems to be a well-tolerated, safe treatment option with moderate to good effectiveness, demonstrating best response in thin, superficial IHs regardless of pretreatment size. Timolol can be recommended as an alternative to systemic β-blockers and watchful waiting for many patients., (Copyright © 2016 by the American Academy of Pediatrics.)

Giant cell fibroblastoma (GCF) is a rare pediatric soft tissue tumor, which exists on a spectrum with dermatofibrosarcoma protuberans (DFSP). Histologic features are well established for these entities; however, cytologic findings have not been well characterized. We report for the first time a case of GCF, confirmed by cytogenetics, with mixed DFSP features. In this case of an 8-month-old boy, a fine needle aspiration specimen showed a low-grade spindle cell tumor, with oval to spindled cells dispersed singly and in patternless groups, and with occasional giant cells. Subsequent histologic features were consistent with GCF, which is an uncommon, CD34 positive, soft tissue neoplasm with a distinct molecular aberration. This case emphasizes the differential diagnosis in pediatric soft tissue tumors and stresses the unique features of GCF., (© 2014 Wiley Periodicals, Inc.)

The role of the individual difference variables of mate value, short-term and long-term mating preferences, and life history strategy along with the manipulated variable of life expectancy were used to predict differences in the willingness to engage in sexually coercive behaviors. Short-term preferences and long-term preferences were correlated with the willingness to engage in sexual coercion at all life expectancies. Life history strategy was correlated with the willingness to engage in sexual coercion at only the shortest and longest life expectancies. Most importantly short-term and long-term mating preferences interacted with life expectancy to predict the willingness to engage in sexually coercive behaviors. Short life expectancies increased willingness in individuals with high short-term and low long-term preferences. The results are discussed in terms of the varying theories of sexual coercion with emphasis put on a life history approach.

Homeostatic regulation of NF-κB requires the continuous synthesis of IκBα and its rapid degradation by the proteasome through a ubiquitin-independent pathway. We previously showed that the ubiquitin-independent degradation signal of unbound IκBα was located in the C-terminal PEST region, and we have now identified a single tyrosine, Tyr-289, and determined that the hydrophobic character of the tyrosine is important for the rapid turnover of IκBα. The sequence composition of the PEST peptide surrounding this Tyr-289 imposes a distinct polyproline II conformation. Enhancing the polyproline II helix formation correlates with slower degradation rates of unbound IκBα. We have further identified a degradation signal located within the 5th ankyrin repeat that is functional once the C terminus is removed. Both the C-terminal and 5th ankyrin repeat degradation signals have inherent flexibility and specific hydrophobic residue(s), which together constitute the ubiquitin-independent degradation signal for IκBα.

Following a model that is inclusive of both dispositional and situational influences on life-history behaviors and attitudes, the effect of life expectancies on aggression and generativity was examined. Consistent with the hypotheses it was found that shorter life expectancies led to an increase in the desire to aggress and a decrease in the desire to engage in generative behaviors. The results are discussed in terms of how life history theory can be used to frame research on person-situation interactions.

Transcription complex components frequently show coupled folding and binding but the functional significance of this mode of molecular recognition is unclear. IkappaBalpha binds to and inhibits the transcriptional activity of NF-kappaB via its ankyrin repeat (AR) domain. The beta-hairpins in ARs 5-6 in IkappaBalpha are weakly-folded in the free protein, and their folding is coupled to NF-kappaB binding. Here, we show that introduction of two stabilizing mutations in IkappaBalpha AR 6 causes ARs 5-6 to fold cooperatively to a conformation similar to that in NF-kappaB-bound IkappaBalpha. Free IkappaBalpha is degraded by a proteasome-dependent but ubiquitin-independent mechanism, and this process is slower for the pre-folded mutants both in vitro and in cells. Interestingly, the pre-folded mutants bind NF-kappaB more weakly, as shown by both surface plasmon resonance and isothermal titration calorimetry in vitro and immunoprecipitation experiments from cells. One consequence of the weaker binding is that resting cells containing these mutants show incomplete inhibition of NF-kappaB activation; they have significant amounts of nuclear NF-kappaB. Additionally, the weaker binding combined with the slower rate of degradation of the free protein results in reduced levels of nuclear NF-kappaB upon stimulation. These data demonstrate clearly that the coupled folding and binding of IkappaBalpha is critical for its precise control of NF-kappaB transcriptional activity.

IkappaB proteins are known as the regulators of NF-kappaB activity. They bind tightly to NF-kappaB dimers, until stimulus-responsive N-terminal phosphorylation by IKK triggers their ubiquitination and proteasomal degradation. It is known that IkappaBalpha is an unstable protein whose rapid degradation is slowed upon binding to NF-kappaB, but it is not known what dynamic mechanisms control the steady-state level of total IkappaBalpha. Here, we show clearly that two degradation pathways control the level of IkappaBalpha. Free IkappaBalpha degradation is not controlled by IKK or ubiquitination but intrinsically, by the C-terminal sequence known as the PEST domain. NF-kappaB binding to IkappaBalpha masks the PEST domain from proteasomal recognition, precluding ubiquitin-independent degradation; bound IkappaBalpha then requires IKK phosphorylation and ubiquitination for slow basal degradation. We show the biological requirement for the fast degradation of the free IkappaBalpha protein; alteration of free IkappaBalpha degradation dampens NF-kappaB activation. In addition, we find that both free and bound IkappaBalpha are similar substrates for IKK, and the preferential phosphorylation of NF-kappaB-bound IkappaBalpha is due to stabilization of IkappaBalpha by NF-kappaB.

CRABPII is a small, cytosolic protein that solubilizes and transfers retinoic acid (RA) to the nucleus while also enhancing its transcriptional activity. We have determined the first high-resolution structure of apo-wild type (WT) CRABPII at 1.35 A. Using three different data sets collected on apo-WT CRABPII we have shown that apo- and holo-CRABPII share very similar structures. Binding of RA appears to increase the overall rigidity of the structure, although the induced structural changes are not as pronounced as previously thought. The enhanced structural rigidity may be an important determinant for the enhanced nuclear localization of the RA-bound protein. Comparison of our apo-WT with a mutant apo-CRABPII structure shows that mutation of Arg111, a conserved residue of CRABPII and a key residue in RA binding, causes structural changes in the molecule. We further investigated the structural importance of conserved residues by determining the structure of the F15W mutant CRABPII (F15W-CRABPII). Our structures also demonstrate structural changes induced by crystal packing and show that a crystal can harbor demonstrative structural differences in the asymmetric unit.

The purpose of this research was to test the hypothesis that when an individual's romantic partner is sexually unfaithful the individual will be more angry with and aggressive toward the partner than the third party. 40 college men and women participated in this study. Each subject rated how angry and aggressive he or she would be toward him- or herself, the partner, and the third party if the partner were unfaithful. Intensity of love, degree of commitment, and mode of anger/aggression expression were also investigated. Support was found for the hypothesis.

The purpose of this research was to test the hypothesis that the individual who believes death is the end and who expects to experience more displeasure than pleasure over the remainder of his life will choose suicide. College students (N = 272) completed questionnaires measuring their beliefs about after-life, expectations of pleasure and displeasure should certain negative events happen to them, and expectations of suicide should these negative events happen to them. Support was not found for the hypothesis. The students who believed that death was the end stated that they would choose to live even if negative events promised them a life of greater displeasure than pleasure.

The hypotheses that physical attractiveness is positively correlated with happiness, psychological health, and self-esteem was tested with 211 men and women undergraduates. Physical attractiveness was measured by judges' ratings, while happiness, psychological health (neuroticism), and self-esteem were measured by self-report inventories. Physical attractiveness was found to correlate positively with happiness (r equals .37), negatively with neuroticism (r equals minus.22), and positively with self-esteem (r equals .24) for women but not for men (corresponding rs equals .09, .03, and minus.04, respectively). These results were accounted for by the suggestion that physical attractiveness "buys" more for women than for men, and the most prominent outcomes obtained by physical attractiveness--friends and dates--are of greater value to women undergraduates than men. The superior outcomes obtained by the attractive women made them happy, psychologically healthy, and proud of themselves.

White's (1981) theory of romantic jealousy states that the loss (or anticipated loss) of a romantic partner to a rival causes two kinds of suffering: loss (or anticipated loss) of relationship rewards and loss (or anticipated loss) of self-esteem. Elaborating this theory, we proposed that loss of relationship rewards causes depression, whereas loss of self-esteem causes anxiety and anger. General support was found for White's theory and the elaborations, but not for the hypothesis that the loss of self-esteem causes anxiety. Anxiety may be a product of both loss of self-esteem and loss of relationship rewards.

To test the hypotheses that people believe that certain kinds and styles of clothing are indicative of liberal sexual attitudes and behavior and these beliefs are correct, questionnaires were filled out by 259 subjects. These questionnaires asked each subject for the frequencies with which he wore various items and styles of clothing, his attitude toward premarital sexual relations, the number of persons with whom he had had sexual relations, the frequencies with which he believed sexually liberal men and women wore various items and styles of clothing, and the frequencies with which he felt sexually conservative men and women wore various items and styles of clothing. Correlations showed that, although subjects believed that a large number of items and styles of clothing are indicative of liberal sexual attitudes and behavior, only a few items and styles actually were associated with liberal sexual attitudes and reported behavior.