Tolerability of hair cleansing conditioners: a double-blind randomized, controlled trial designed to evaluate consumer complaints to the U.S. Food and Drug Administration.

Importance: Consumers have reported skin rash/irritation and hair loss/breakage with Wen by Chaz Dean Sweet Almond Mint Cleansing Conditioner (WCDSAMCC), however epidemiologic, toxicologic and clinical hair loss studies have not provided an explanation. Contact dermatitis has been hypothesized.Objective: To assess the tolerability of six products: WCDSAMCC, three other hair cleansing conditioners, and two controls [salicylic acid shampoo (SAS) and baby shampoo (BS)].Design: Double-blind, randomized, controlled trial.Setting: Single-site study.Population: General population volunteers.Intervention: Standard semi-open patch tests (SOPTs) and duration-escalation repeat open application tests (ROATs) over 5 weeks.Main Outcome Measures: Primary outcome measure was "stopping point" [ROAT total component score ≥6 (maximum 10) or global ≥4 (maximum 5)]. Secondary outcomes included "any reaction" (ROAT component score ≥1) and SOPT ≥ doubtful.Results: Two hundred of 298 volunteers were enrolled. There were no significant differences in the tolerability of WCDSAMCC and any of the other three hair cleansing conditioners as assessed by SOPT or ROAT. WCDSAMCC was significantly better tolerated than SAS ("stopping point", or "any reaction", p values<0.0001) as well as BS (p = 0.01). The frequency of doubtful SOPT reactions was lowest for WCD (2.2%) and highest for SAS (7.1%, p = 0.04).Conclusions: As assessed by both ROAT and SOPTs, WCDSAMCC was similar in tolerability to three other hair cleansing conditioners and significantly better tolerated than both controls (SAS and BS).Summary: This double-blind, randomized, controlled study found that WCDSAMCC was similar in tolerability to three other HCCs and was significantly better tolerated than both SAS and BS. This study provides critical clinical evidence on the comparative lack of cutaneous effects with use of WCDSAMCC.Trial Registration: NCT03483025 ClinicalTrials.gov.

Age-dependent differences in microglial responses to systemic inflammation are evident as early as middle age.

Whereas age increases microglial inflammatory activities and impairs their ability to effectively regulate their immune response, it is unclear at what age these exaggerated responses begin. We tested the hypotheses that augmented microglial responses to inflammatory challenge are present as early as middle age and that repeated stimulation of primed microglia in vivo would reveal microglial senescence. Microglial gene expression was investigated in a mouse model of repeated systemic inflammation induced by intraperitoneal injection of bacterial lipopolysaccharide (LPS). Following LPS, microglia from middle-aged mice (9-10 mo) displayed larger increases in Tnfα, Il-6, and Il-1ß gene expression compared with young adults (2 mo). Similar results were observed in the spleens of middle-aged mice, indicating that exaggeration of both central and peripheral immune responses are already evident at early middle age. Interestingly, despite greater proinflammatory responses to the first LPS challenge in the aged mice, there were no age-dependent differences in either microglia or spleen following a subsequent LPS dose, suggesting that animals at this age retain the ability to effectively control their immune response following repeated challenge. The exacerbated microglial immune response to systemic inflammation at early middle age suggests that the CNS may be vulnerable to age-dependent alterations earlier than previously appreciated.

Nasal reconstructive techniques following Mohs surgery or excisions: a systematic review.

Numerous reconstructive techniques for nasal defects following skin cancer removal have been described; however, the literature lacks a comprehensive systematic review. Our objective was to systematically review nasal reconstruction methods after tumor removal, correlate the use of specific techniques to the nasal subunits involved, assess the quality of the available evidence, and set the stage for future research on this topic. Eight databases were searched for studies published in English from January 2004 to December 2018 containing repair data for nasal defects following Mohs or excision for four or more subjects. Recorded data included author specialties, study design, subject number, demographics, defect characteristics, procedure type, reconstructive methods, outcome measures, and complications. One-hundred and eleven studies were included. Study types included case series (73%), observational cohort studies (25%), and clinical trials (2%). Most authors were dermatologic surgeons (61%). Resection was most commonly performed via Mohs (82%). Flaps (42%), linear closures (28%) and grafts (25%) were most utilized for reconstruction. In Zones I and II, transposition flaps were the most common followed by advancement flaps. In Zone III, full thickness skin grafts were the most common repair. Most studies were case series or small cohort studies, representing low level evidence. Flaps are the most common method described in the literature for nasal reconstruction. The overall quality of the evidence available on this topic is low.

Allergic Contact Dermatitis to Pramoxine (Pramocaine).

Prescription and over-the-counter topical anesthetics are commonly used. Although allergy to amide and ester anesthetics is known, little has been reported on the nonamide, nonester pramoxine (pramocaine). This article briefly reviews allergy to topical anesthetics, provides detailed information on pramoxine, and describes characteristics of multiple patients with positive, relevant reactions to pramoxine.

Patch Testing: The Patient Experience.

BACKGROUND: Data regarding patient-reported symptoms during patch testing are limited. OBJECTIVE: To provide frequency of symptoms (pain, sleep difficulty, medication need, site itching, itch elsewhere, and worsening rash) experienced by patients undergoing extensive patch testing and to determine association of these symptoms with patient characteristics. METHODS: This was a retrospective chart review of patients who underwent patch testing at a tertiary referral, contact dermatitis clinic over 15 months. Demographics, number of patches placed, patch location(s), and number of reactions (total and ++/+++) were extracted by chart review. Frequency of symptoms reported on a questionnaire administered at the 48-hour (48H) and final (F) visits was tabulated, and associations were evaluated using χ2 and Fisher exact tests. RESULTS: Six hundred forty-one patient records were accessed. The most common symptom was patch site itching (48H, 77.4%; F, 76.5%). Frequency of pain and sleep difficulty were significantly higher at 48H compared with F (P < 0.0001). Worsening of rash was significantly higher at F compared with 48H (P < 0.0001). The number of patches was significantly associated with all symptoms except sleep difficulty (P ≤ 0.0141). Patch location was significantly associated with pain, medication need, itch elsewhere, and worsening rash but not sleep difficulty or site itch (P ≤ 0.0257). The number of reactions (total and ++/+++) was significantly associated with all symptoms except itch elsewhere (total P ≤ 0.0316; ++/+++: P ≤ 0.0445). CONCLUSIONS: Most patients reported symptoms during patch testing, most commonly itching (at patch site and elsewhere), sleep difficulty, and need for medication. The number of positive patch test reactions (total and ++/+++) was the most common characteristic associated with the symptoms.

Isothiazolinone Detection in Dish Soap and Personal Care Products: Comparison of Lovibond Isothiazolinone Test Kit and Ultrahigh-Performance Liquid Chromatography-Tandem Mass Spectrometry.

BACKGROUND: Isothiazolinones are commonly used preservatives, which may cause allergic contact dermatitis. The Lovibond Isothiazolinone Test Kit (LITK) has been reported to successfully identify clinically relevant, occult isothiazolinones in patient personal care products. OBJECTIVE: The aim of the study was to analyze dish soaps and personal care products that do not declare isothiazolinones ("no-ISO") for the presence of isothiazolinones via 2 methods: LITK and ultrahigh-performance liquid chromatography-tandem mass spectrometry (UHPLC-MS/MS). METHODS: No-ISO dish soaps (n = 9), a convenience sample of patient products (n = 6), and controls (positive [isothiazolinone declared], n = 5; negative, n = 2) were tested with LITK (X3) and UHPLC-MS/MS. RESULTS: Several no-ISO dish soaps and personal products were positive for isothiazolinones (LITK, n = 12; UHPLC-MS/MS, n = 3). Ultrahigh-performance liquid chromatography-tandem mass spectrometry specifically identified methylisothiazolinone alone in 1 no-ISO dish soap, methylchloroisothiazolinone in another, and both in a third. Using UHPLC-MS/MS as the criterion standard, we observed the accuracy of LITK for 9 dish soaps was poor (sensitivity, 66.7%; specificity, 20%) and very poor for 6 personal care products (sensitivity, 0%; specificity, 0%). CONCLUSIONS: Personal products may contain undeclared isothiazolinones. The current study found that LITK had poor accuracy for testing dish soap and personal care products. Clinicians should be aware of these factors when managing patients with contact allergy to isothiazolinones.

Imposter Syndrome.

This self-portrait, done in bold colors, depicts the experience of "imposterhood" in medicine.

Time and dose-dependent impairment of neonatal respiratory motor activity after systemic inflammation.

Neonatal respiratory impairment during infection is common, yet its effects on respiratory neural circuitry are not fully understood. We hypothesized that the timing and severity of systemic inflammation is positively correlated with impairment in neonatal respiratory activity. To test this, we evaluated time- and dose-dependent impairment of in vitro fictive respiratory activity. Systemic inflammation (induced by lipopolysaccharide, LPS, 5 mg/kg, i.p.) impaired burst amplitude during the early (1 h) inflammatory response. The greatest impairment in respiratory activity (decreased amplitude, frequency, and increased rhythm disturbances) occurred during the peak (3 h) inflammatory response in brainstem-spinal cord preparations. Surprisingly, isolated medullary respiratory circuitry within rhythmic slices showed decreased baseline frequency and delayed onset of rhythm only after higher systemic inflammation (LPS 10 mg/kg) early in the inflammatory response (1 h), with no impairments at the peak inflammatory response (3 h). Thus, different components of neonatal respiratory circuitry have differential temporal and dose sensitivities to systemic inflammation, creating multiple windows of vulnerability for neonates after systemic inflammation.

Evaluation of Patch Test Findings in Patients With Anogenital Dermatitis.

Importance: Contact dermatitis in the anogenital area is associated with sleep disturbance and dyspareunia and can profoundly affect quality of life. The literature on anogenital contact dermatitis and culprit allergens is limited. The last large-scale study on common, relevant allergens in patients with anogenital dermatitis was published in 2008. Objectives: To characterize patients with anogenital dermatitis referred for patch testing by the North American Contact Dermatitis Group, to identify common allergens, and to explore sex-associated differences between anogenital dermatitis and allergens. Design, Setting, and Participants: A retrospective, cross-sectional analysis was conducted of the North American Contact Dermatitis Group database among 28 481 patients who underwent patch testing from January 1, 2005, to December 31, 2016, at outpatient referral clinics in the United States and Canada. Exposure: Patch testing for allergens. Main Outcomes and Measures: Currently relevant allergic patch test reactions in patients with anogenital dermatitis. Results: Of 28 481 patients tested during the study period, 832 patients (336 men and 496 women; mean [SD] age, 50.1 [26.5] years) had anogenital involvement and 449 patients (177 men and 272 women; mean [SD] age, 49.6 [17.4] years) had anogenital dermatitis only. Compared with those without anogenital involvement, there were significantly more male patients in the group with anogenital dermatitis (177 [39.4%] vs 8857 of 27 649 [32.0%]; relative risk, 1.37; 95% CI, 1.14-1.66; P < .001). In the group with anogenital involvement, female patients were significantly less likely than male patients to have allergic contact dermatitis as a final diagnosis (130 [47.8%] vs 107 [60.5%]; relative risk, 0.78; 95% CI, 0.64-0.94; P = .01), whereas a final diagnosis of other dermatoses (eg, lichen planus, lichen sclerosus, or lichen simplex chronicus) was more frequent for female patients than for male patients (67 [24.6%] vs 28 [15.8%]; relative risk, 1.54; 95% CI, 1.02-2.31; P = .03). Of the 449 patients in the group with anogenital involvement only, 227 (50.6%) had 1 or more relevant reaction with patch testing. Allergens that were statistically significantly more common in patients with anogenital involvement compared with those without anogenital involvement included medicaments such as dibucaine (10 of 250 patients tested [4.0%] vs 32 of 17 494 patients tested [0.2%]; relative risk, 22.74; 95% CI, 11.05-46.78; P < .001) and preservatives such as methylchloroisothiazolinone and methylisothiazolinone (30 of 449 patients tested [6.7%] vs 1143 of 27 599 patients tested [4.1%]; relative risk, 1.61; 95% CI, 1.14-2.41; P = .008). A total of 152 patients met the definition for anogenital allergic contact dermatitis, which is defined as anogenital involvement only, allergic contact dermatitis as the only diagnosis, and 1 or more positive reaction of current clinical relevance. Conclusions and Relevance: For patients with anogenital involvement only who were referred for patch testing, male patients were more likely to have allergic contact dermatitis, whereas female patients were more likely to have other dermatoses. Common allergens or sources consisted of those likely to contact the anogenital area. For individuals with anogenital involvement suspected of having allergic contact dermatitis, reactions to preservatives, fragrances, medications (particularly topical anesthetics), and topical corticosteroids should be tested.

Airborne Allergic Contact Dermatitis: Management and Responsible Allergens on the American Contact Dermatitis Society Core Series.

Airborne allergic contact dermatitis occurs when allergen particles suspended in the air deposit on the skin. Many allergens can result in an airborne distribution if presented in an aerosolized form. This review summarizes the allergens in the American Contact Dermatitis Society Core Allergen Series that have been documented to cause airborne allergic contact dermatitis. In addition to responsible allergens, this article also reviews management and treatment options.

Antinociceptive and respiratory effects following application of transdermal fentanyl patches and assessment of brain µ-opioid receptor mRNA expression in ball pythons.

OBJECTIVE To quantify plasma fentanyl concentrations (PFCs) and evaluate antinociceptive and respiratory effects following application of transdermal fentanyl patches (TFPs) and assess cerebrospinal µ-opioid receptor mRNA expression in ball pythons (compared with findings in turtles). ANIMALS 44 ball pythons (Python regius) and 10 turtles (Trachemys scripta elegans). PROCEDURES To administer 3 or 12 µg of fentanyl/h, a quarter or whole TFP (TFP-3 and TFP-12, respectively) was used. At intervals after TFP-12 application in snakes, PFCs were measured by reverse-phase high-pressure liquid chromatography. Infrared heat stimuli were applied to the rostroventral surface of snakes to determine thermal withdrawal latencies after treatments with no TFP (control [n = 16]) and TFP-3 (8) or TFP-12 (9). Breathing frequency was measured in unrestrained controls and TFP-12-treated snakes. µ-Opioid receptor mRNA expression in brain and spinal cord tissue samples from snakes and turtles (which are responsive to µ-opioid receptor agonist drugs) were quantified with a reverse transcription PCR assay. RESULTS Mean PFCs were 79, 238, and 111 ng/mL at 6, 24, and 48 hours after TFP-12 application, respectively. At 3 to 48 hours after TFP-3 or TFP-12 application, thermal withdrawal latencies did not differ from pretreatment values or control treatment findings. For TFP-12-treated snakes, mean breathing frequency significantly decreased from the pretreatment value by 23% and 41% at the 24- and 48-hour time points, respectively. Brain and spinal cord tissue µ-opioid receptor mRNA expressions in snakes and turtles did not differ. CONCLUSIONS AND CLINICAL RELEVANCE In ball pythons, TFP-12 application resulted in high PFCs, but there was no change in thermal antinociception, indicating resistance to µ-opioid-dependent antinociception in this species.

Microglial numbers attain adult levels after undergoing a rapid decrease in cell number in the third postnatal week.

During postnatal development, microglia, CNS resident innate immune cells, are essential for synaptic pruning, neuronal apoptosis and remodeling. During this period microglia undergo morphological and phenotypic transformations; however, little is known about how microglial number and density is regulated during postnatal CNS development. We found that after an initial increase during the first 14 postnatal days, microglial numbers in mouse brain began declining in the third postnatal week and were reduced by 50% by 6weeks of age; these "adult" levels were maintained until at least 9months of age. Microglial CD11b levels increased, whereas CD45 and ER-MP58 declined between P10 and adulthood, consistent with a maturing microglial phenotype. Our data indicate that both increased microglial apoptosis and a decreased proliferative capacity contribute to the developmental reduction in microglial numbers. We found no correlation between developmental reductions in microglial numbers and brain mRNA levels of Cd200, Cx3Cl1, M-Csf or Il-34. We tested the ability of M-Csf-overexpression, a key growth factor promoting microglial proliferation and survival, to prevent microglial loss in the third postnatal week. Mice overexpressing M-Csf in astrocytes had higher numbers of microglia at all ages tested. However, the developmental decline in microglial numbers still occurred, suggesting that chronically elevated M-CSF is unable to overcome the developmental decrease in microglial numbers. Whereas the identity of the factor(s) regulating microglial number and density during development remains to be determined, it is likely that microglia respond to a "maturation" signal since the reduction in microglial numbers coincides with CNS maturation.

Repetitive acute intermittent hypoxia does not promote generalized inflammatory gene expression in the rat CNS.

Modest protocols of repetitive acute intermittent hypoxia (rAIH) enhance motor function in patients with chronic incomplete spinal injury. Since chronic intermittent hypoxia (CIH) elicits neuroinflammation, there is potential for rAIH to have similar effects. Thus, we tested the hypothesis that rAIH has minimal impact on microglial inflammatory gene expression, but up-regulates key neurotrophic factor expression in a CNS region-specific manner. Using real time PCR, we evaluated mRNA levels of inflammatory and neurotrophic factors in immunomagnetically-isolated microglia from rat frontal cortex, brainstem and upper and lower cervical spinal cord following rAIH (ten, 5-min episodes, thrice weekly, 4 weeks). In agreement with our hypothesis, rAIH had no significant impact on microglial inflammatory gene expression in any region studied. On the other hand, neurotrophic factor expression was altered in a gene- and region-specific pattern. These results have important implications for the safety of rAIH as a potential therapy to enhance neuroplasticity and motor function in patients with spinal injury or other neurologic disorders.

Cell-type-specific Jumonji histone demethylase gene expression in the healthy rat CNS: detection by a novel flow cytometry method.

Our understanding of how histone demethylation contributes to the regulation of basal gene expression in the brain is largely unknown in any injury model, and especially in the healthy adult brain. Although Jumonji genes are often regulated transcriptionally, cell-specific gene expression of Jumonji histone demethylases in the brain remains poorly understood. Thus, in the present study we profiled the mRNA levels of 26 Jumonji genes in microglia (CD11b+), neurons (NeuN+) and astrocytes (GFAP+) from the healthy adult rat brain. We optimized a method combining a mZBF (modified zinc-based fixative) and FCM (flow cytometry) to simultaneously sort cells from non-transgenic animals. We evaluated cell-surface, intracellular and nuclear proteins, including histones, as well as messenger- and micro-RNAs in different cell types simultaneously from a single-sorted sample. We found that 12 Jumonji genes were differentially expressed between adult microglia, neurons and astrocytes. While JMJD2D was neuron-restricted, PHF8 and JMJD1C were expressed in all three cell types although the expression was highest in neurons. JMJD3 and JMJD5 were expressed in all cell types, but were highly enriched in microglia; astrocytes had the lowest expression of UTX and JHDM1D. Levels of global H3K27 (H3 lysine 27) methylation varied among cell types and appeared to be lowest in microglia, indicating that differences in basal gene expression of specific Jumonji histone demethylases may contribute to cell-specific gene expression in the CNS (central nervous system). This multiparametric technique will be valuable for simultaneously assaying chromatin modifications and gene regulation in the adult CNS.