Peroxisome proliferator-activated receptor (PPAR) are nuclear hormone receptors that are activated by endogenous lipid metabolites. Previous studies have demonstrated that PPAR-alpha activation stimulates keratinocyte differentiation in vitro and in vivo, is anti-inflammatory, and improves barrier homeostasis. Recent studies have shown that PPAR-beta/delta activation induces keratinocyte differentiation in vitro. This study demonstrated that topical treatment of mice with a selective PPAR-beta/delta agonist (GW1514) in vivo had pro-differentiating effects, was anti-inflammatory, improved barrier homeostasis, and stimulated differentiation in a disease model of epidermal hyperproliferation [corrected]. In contrast to PPAR-alpha activation, PPAR-beta/deltain vivo did not display anti-proliferative or pro-apoptotic effects. The pro-differentiating effects persisted in mice lacking PPAR-alpha, but were decreased in mice deficient in retinoid X receptor-alpha, the major heterodimerization partner of PPAR. Furthermore, in vitro PPAR-beta/delta activation, aside from stimulating differentiation-related genes, additionally induced adipose differentiation-related protein (ADRP) and fasting induced adipose factor (FIAF) mRNA in cultures keratinocytes, which was paralleled by increased oil red O staining indicative of lipid accumulation, the bulk of which were triglycerides (TG). Comparison of differentially expressed genes between PPAR-beta/delta and PPAR-alpha activation revealed distinct profiles. Together, these studies indicate that PPAR-beta/delta activation stimulates keratinocyte differentiation, is anti-inflammatory, improves barrier homeostasis, and stimulates TG accumulation in keratinocytes.
Germline mutations in the fumarate hydratase gene (FH) predispose to multiple cutaneous and uterine leiomyoma syndrome (MCL) and MCL associated with renal cell cancer. MCL is inherited in an autosomal dominant pattern, manifesting as skin leiomyoma and uterine fibroids in affected individuals. Fumarate hydratase, a component of the tricarboxylic acid cycle, acts as a tumor suppressor gene in the development of cutaneous and uterine leiomyoma and renal cell cancer in this syndrome. Here we report the clinical and mutational analysis of five families with MCL, with the identification of five new mutations affecting highly conserved residues of the FH protein. These results provide further evidence for the role of the FH gene in the pathogenesis of MCL.
IMPORTANCE Potentially harmful chemicals are released when tissues are vaporized. Laser hair removal (LHR) causes heating and often vaporization of hairs, producing both a signature malodorous plume and visible particulates.OBJECTIVE To characterize the chemical composition and quantify the ultrafine particle content of the plume generated during LHR. DESIGN, SETTING, AND PARTICIPANTSIn the laser center of a large academic hospital, discarded terminal hairs from the trunk and extremities were collected from 2 adult volunteers. The hair samples were sealed in glass gas chromatography chambers and treated with a laser. The laser plume was analyzed by gas chromatography-mass spectrometry (GC-MS). During LHR treatment, two 6-L negative pressure canisters were used to capture 30 seconds of laser plume, and a portable condensation particle counter was used to measure ultrafine particulates (<1 μm). Ultrafine particle concentrations were measured within the treatment room, within the waiting room, and outside the building. MAIN OUTCOMES AND MEASURESThe chemical content of the laser plume was analyzed with GC-MS and screened for aerosolized toxins using Environmental Protection Agency-certified methods. The ambient concentration of ultrafine particles during LHR was measured by condensation particle counters.RESULTS Analysis with GC-MS identified 377 chemical compounds. Sixty-two of these compounds, of which 13 are known or suspected carcinogens and more than 20 are known environmental toxins, exhibited strong absorption peaks. During LHR, the portable condensation particle counters documented an 8-fold increase compared with the ambient room baseline level of ultrafine particle concentrations (ambient room baseline, 15 300 particles per cubic centimeter [ppc]; LHR with smoke evacuator, 129 376 ppc), even when a smoke evacuator was in close proximity (5.0 cm) to the procedure site. When the smoke evacuator was turned off for 30 seconds, there was a more than 26-fold increase in particulate count compared with ambient baseline levels (ambient baseline, 15 300 ppc; LHR without smoke evacuator for 30 seconds, 435 888 ppc). CONCLUSIONS AND RELEVANCEThese findings establish the concern that the burning-hair plume often present during LHR should be considered a biohazard, warranting the use of smoke evacuators, good ventilation, and respiratory protection, especially for health care workers with prolonged exposure to LHR plume.
Multiple cutaneous and uterine leiomyomata syndrome (MCL) is an autosomal dominant disease characterized by the presence of concurrent benign tumors of smooth muscle origin (leiomyoma) in the skin and uterus of affected females, and in the skin of affected males. MCL can also be associated with type II papillary renal cell cancer (HLRCC). The genetic locus for MCL and HLRCC was recently mapped to chromosome 1q42.3-43 and subsequently, dominantly inherited mutations in the fumarate hydratase gene ( FH ) were identified. Importantly, analysis of the FH gene in tumors of MCL patients revealed a second mutation inactivating the wild-type allele in some tumors. Based on these findings, it has been suggested that FH may function as a tumor suppressor gene in MCL. Here, we report the analysis of the FH gene in a group of 11 MCL families, with the identification of 8 different mutations accounting for the disease in all families. One of the mutations, 905-1G>A, has been identified in 4 families of Iranian origin. The analysis of highly polymorphic markers in the vicinity of the FH gene showed a shared haplotype in these 4 families, suggesting that 905-1G>A represents a founder mutation. Collectively, identification of 5 novel and 3 recurrent mutations further supports the role of FH in the pathogenesis of MCL.
BackgroundOccupational exposures to ultrafine particles in the plume generated during laser hair removal procedures, the most commonly performed light based cosmetic procedure, have not been thoroughly characterized. Acute and chronic exposures to ambient ultrafine particles have been associated with a number of negative respiratory and cardiovascular health effects. Thus, the aim of this study was to measure airborne concentrations of particles in a diameter size range of 10 nm to 1 μm in procedure rooms during laser hair removal procedures.MethodsTSI Model 3007 Condensation Particle Counters were used to quantify the particle count concentrations in the waiting and procedure rooms of a dermatology office. Particle concentrations were sampled before, during, and after laser hair removal procedures, and characteristics of each procedure were noted by the performing dermatologist.ResultsTwelve procedures were sampled over 4 days. Mean ultrafine particle concentrations in the waiting and procedure rooms were 14,957.4 particles/cm3 and 22,916.8 particles/cm3 (p < 0.0001), respectively. Compared to background ultrafine particle concentrations before the procedure, the mean concentration in the procedure room was 2.89 times greater during the procedure (p = 0.009) and 2.09 times greater after the procedure (p = 0.007). Duration of procedure (p = 0.006), body part (p = 0.013), and the use of pre-laser lotion/type of laser (p = 0.039), were the most important predictors of ultrafine particle concentrations. Use of a smoke evacuator (a recommended form of local exhaust ventilation) positioned at 30.5 cm from the source, as opposed to the recommended 1–2 in., lowered particle concentrations, but was not a statistically significant predictor (p = 0.49).ConclusionsLaser hair removal procedures can generate high exposures to ultrafine particles for dermatologists and other individuals performing laser hair removal, with exposure varying based on multiple determinants.
Abbreviations: COL7A1, COL7A1 gene; DEB, dystrophic epidermolysis bullosa; DDEB, dominant dystrophic epidermolysis bullosa; EB, epidermolysis bullosa; PCR, polymerase chain reaction. Keywords: COL7A1 gene, epidermolysis bullosa pruriginosa, mutation AbstractEpidermolysis bullosa (EB) pruriginosa is a subtype of dominant dystrophic epidermolysis bullosa (DDEB), characterized by severe pruritus and blistering localized to the extensor surface of the extremities. EB pruriginosa exhibits extensive clinical heterogeneity with variable expressivity and delayed age of onset. Mutations in the COL7A1 gene, especially in glycine residues within of Gly-X-Y repeats, have been shown to cause this form of DDEB. Here, we report a novel COL7A1 mutation in a Taiwanese pedigree with EB pruriginosa. Using polymerase chain reaction amplification and direct sequence analysis, we have identified a G-to-T transversion at nucleotide 7097 within exon 92 of COL7A1, converting a glycine residue to valine (G2366V). The mutation resides within a consecutive, uninterrupted 17 Gly-X-Y of the triple-helical domain of type VII collagen.Interestingly, the proband in our family also displayed elevated IgE levels, previously reported in some patients with this disorder. Our finding further implicates COL7A1 mutation in the pathogenesis of EB pruriginosa and underscores the heterogeneous clinical symptoms of glycine mutations in DDEB. Here, we have identified a two-generation EB pruriginosa kindred of Taiwanese descent (Fig. 1a). The proband is a 52-year old woman (II-8) who developed intense pruritic blisters in her lower extremities and extensor surface of both arms in her twenties. ReportA detailed clinical description of her symptoms was reported previously in the Chinese literature.13 Briefly, histology of biopsy showed a subepidermal cleft and mild perivascular mononuclear infiltration in the upper dermis. Upon electron microscopic examination, the anchoring fibrils were found to be decreased in number and thinner than in normal control skin. Neither the parents nor the six other siblings of the index case developed any similar symptoms. Recently, at the age of 25 years, the son (III-1) of the proband developed similar pruritic blisters on both shins and extensor arms (Fig. 2b).Although the 22 year-old daughter of the proband (III-2) lacked blistering lesions, nail dystrophy, and other symptoms of the disease, she had reported localized pruritus on pretibial skin and not yet reached the age of onset of her mother and brother.After obtaining informed consent, DNA was isolated from peripheral blood highlighting the importance of residue G2366 (Fig. 2). Similarly, a heterozygous glycineto-serine missense mutation (G2369S) in the adjacent Gly-X-Y repeat causes dominant EB pruriginosa (Fig. 2). 4 This observation is consistent with the notion that the specific position of a glycine substitution within a particular helical block, rather than its position along the entire collagenous domain, might be more critical in determining its impact on the ov...
Multiple cutaneous and uterine leiomyomata (MCL) is an autosomal dominant disorder characterized by the development of benign smooth muscle tumours (leiomyomas) in the skin and uterus of affected women, and in the skin of affected men. In rare cases, MCL has been associated with a predisposition to the rare type II papillary renal cell cancer, also known as hereditary leiomyomatosis and renal cell cancer. The genetic locus for MCL has been mapped to chromosome 1q42.3-43 and subsequently, germline mutations in the fumarate hydratase (FH) gene have been identified. In addition, analysis of FH in some tumours of MCL patients revealed a second mutation inactivating the wild-type allele, suggesting that FH may function as a tumour suppressor gene. Here, we report two cases of MCL patients with FH mutations, designated as T287P and R190L. T287P represents a novel mutation of a highly conserved amino acid of the FH protein. In addition, a patient with an unusual clinical presentation of MCL was found to have the recurrent mutation, R190L, raising the possibility of incorporating FH sequencing as a diagnostic tool. Our findings extend the allelic series of mutations in FH and support its status as the underlying cause of MCL.
Background Squamous cell carcinoma (SCC) in situ (SCCIS) is often treated without any pathologic confirmation of tumor clearance. It is unclear how often an invasive SCC is harbored within a lesion in which the initial biopsy demonstrated SCCIS because of inadequate sampling. This study examines the final histologic diagnosis of cases in which the initial biopsies were diagnosed as SCCIS and evaluates factors that may correlate with a histologic upstaging of the diagnosis. Methods We prospectively recruited 29 consecutive patients with biopsy‐proven SCCIS sent for Mohs micrographic surgery (MMS). Each tumor underwent MMS, and the central blocks of the Mohs debulking specimens were horizontally sectioned at 30‐μm intervals until exhausted. A fellowship‐trained Mohs surgeon and a board‐certified dermatopathologist processed and examined these sections to determine the final histologic diagnosis of the tumor. Results Of the 29 subjects with biopsy‐proven SCCIS, nine were found to harbor invasive SCC on final histology. Of the remaining lesions, seven had residual SCCIS, whereas the rest exhibited only actinic keratoses or scars. Approximately 31% of lesions showed evidence of invasive SCC. Correlating the clinical characteristics of the lesions with their corresponding final histologic diagnoses, the lesions harboring invasive SCC were more likely to demonstrate clinical signs of residual tumor (scales and papular changes) and be larger than 1.4 cm in diameter. Limitations Our experience at a single institution in the northeastern United States may not be reflective of a wider population. There is also a possible referral bias, because only lesions with high clinical suspicion for invasive SCC were referred for MMS. Conclusion Although biopsy‐proven SCCIS is often treated with modalities that are best suited for superficial disease and do not involve a final pathologic confirmation of clearance (e.g., cryotherapy, electrodesiccation and curettage), this study demonstrated that up to 31% of biopsy‐proven SCCIS lesions may harbor invasive SCC. Clinical signs of residual tumor and a diameter larger than 1.4 cm are statistically significant predictors of underlying invasive SCC. These data suggest that treatment modalities that include histologic control of tumor removal should also be strongly considered for the treatment of select biopsy‐proven SCCIS meeting the above criteria.
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