Hidradenitis Suppurativa and 1-Carbon Metabolism: Role of Gut Microbiome, Matrix Metalloproteinases, and Hyperhomocysteinemia.

Hidradenitis suppurativa (HS) is a chronic, inflammatory skin condition characterized by painful nodules which suppurate and later develop into scar tissues followed by the development of hypodermal tracts. Although the mechanisms behind HS are not fully understood, it is known that dietary factors play important roles in flare frequency and severity. We hypothesize that the high fat diet (HFD) causes dysbiosis, systemic inflammation, and hyperhomocysteinemia (HHcy) in susceptible individuals, which subsequently elevate inflammatory cytokines such as IL-1ß, IL-6, IL-17, and tumor necrosis factor alpha (TNF-α). This increase in dysbiosis-led inflammation coupled with a dysregulation of the 1-carbon metabolism results in an increase in matrix metalloproteinases MMP-2, MMP-8, and MMP-9 along with tissue matrix remodeling in the development and maintenance of the lesions and tracts. This manuscript weaves together the potential roles played by the gut microbiome, HHcy, MMPs, and the 1-carbon metabolism toward HS disease causation in susceptible individuals.

Gene expression of sphingolipid metabolism pathways is altered in hidradenitis suppurativa.

BACKGROUND: Hidradenitis suppurativa (HS) is a debilitating skin disease characterized by painful recurrent nodules and abscesses caused by chronic inflammation. Early events in the development of HS are believed to occur in the folliculopilosebaceous unit; however, the signaling pathways behind this mechanism are unknown. Sphingolipids, such as ceramide, are essential components of the skin and appendages and have important structural and signaling roles. OBJECTIVE: We sought to explore whether the gene expression of enzymes involved in sphingolipid metabolic pathways is altered in HS. METHODS: A microarray data set including 30 samples was used to compare the expression of sphingolipid-related enzymes in inflammatory skin lesions from HS patients (n = 17) with the expression in clinically healthy skin tissue (n = 13). Differential expression of sphingolipid metabolism-related genes was analyzed using Gene Expression Omnibus 2R. RESULTS: HS lesional skin samples have significantly decreased expression of enzymes generating ceramide and sphingomyelin, increased expression of enzymes catabolizing ceramide to sphingosine, and increased expression of enzymes converting ceramide to galactosylceramide and gangliosides. LIMITATIONS: Limitations of this study include assessing the expression of sphingolipid-related enzymes without assessing the levels of the related sphingolipids. CONCLUSION: Our study suggests that sphingolipid metabolism is altered in HS lesional skin compared with normal skin.

Mutations in γ-secretase subunit-encoding PSENEN underlie Dowling-Degos disease associated with acne inversa.

Dowling-Degos disease (DDD) is an autosomal-dominant disorder of skin pigmentation associated with mutations in keratin 5 (KRT5), protein O-fucosyltransferase 1 (POFUT1), or protein O-glucosyltransferase 1 (POGLUT1). Here, we have identified 6 heterozygous truncating mutations in PSENEN, encoding presenilin enhancer protein 2, in 6 unrelated patients and families with DDD in whom mutations in KRT5, POFUT1, and POGLUT1 have been excluded. Further examination revealed that the histopathologic feature of follicular hyperkeratosis distinguished these 6 patients from previously studied individuals with DDD. Knockdown of psenen in zebrafish larvae resulted in a phenotype with scattered pigmentation that mimicked human DDD. In the developing zebrafish larvae, in vivo monitoring of pigment cells suggested that disturbances in melanocyte migration and differentiation underlie the DDD pathogenesis associated with PSENEN. Six of the PSENEN mutation carriers presented with comorbid acne inversa (AI), an inflammatory hair follicle disorder, and had a history of nicotine abuse and/or obesity, which are known trigger factors for AI. Previously, PSENEN mutations were identified in familial AI, and comanifestation of DDD and AI has been reported for decades. The present work suggests that PSENEN mutations can indeed cause a comanifestation of DDD and AI that is likely triggered by predisposing factors for AI. Thus, the present report describes a DDD subphenotype in PSENEN mutation carriers that is associated with increased susceptibility to AI.

Comparison of clinical bracket point registration with 3D laser scanner and coordinate measuring machine

OBJECTIVE: The aim of the present study was to assess the diagnostic value of a laser scanner developed to determine the coordinates of clinical bracket points and to compare with the results of a coordinate measuring machine (CMM). METHODS: This diagnostic experimental study was conducted on maxillary and mandibular orthodontic study casts of 18 adults with normal Class I occlusion. First, the coordinates of the bracket points were measured on all casts by a CMM. Then, the three-dimensional coordinates (X, Y, Z) of the bracket points were measured on the same casts by a 3D laser scanner designed at Shahid Beheshti University, Tehran, Iran. The validity and reliability of each system were assessed by means of intraclass correlation coefficient (ICC) and Dahlberg's formula. RESULTS: The difference between the mean dimension and the actual value for the CMM was 0.0066 mm. (95% CI: 69.98340, 69.99140). The mean difference for the laser scanner was 0.107 ± 0.133 mm (95% CI: -0.002, 0.24). In each method, differences were not significant. The ICC comparing the two methods was 0.998 for the X coordinate, and 0.996 for the Y coordinate; the mean difference for coordinates recorded in the entire arch and for each tooth was 0.616 mm. CONCLUSION: The accuracy of clinical bracket point coordinates measured by the laser scanner was equal to that of CMM. The mean difference in measurements was within the range of operator errors. .

OBJETIVO: o objetivo do presente estudo foi avaliar o valor diagnóstico de um scanner a laser desenvolvido para determinar as coordenadas dos pontos de colagem de braquetes, comparando seus resultados aos resultados obtidos com uma máquina de medição coordenada (MMC). MÉTODOS: esse estudo experimental diagnóstico foi conduzido com modelos ortodônticos obtidos a partir da arcada superior de 18 pacientes adultos, com oclusão normal de Classe I. Inicialmente, as coordenadas dos pontos de colagem de braquetes de todos os modelos foram mensuradas por uma MMC. Em seguida, as coordenadas tridimensionais (X, Y, Z) dos pontos foram mensuradas nos mesmos modelos por um scanner a laser 3D, desenvolvido na Universidade de Shahid Beheshti. A eficácia e confiabilidade dos dois sistemas foram avaliadas pelo Coeficiente de Correlação Intraclasse (CCI) e pela fórmula de Dahlberg. RESULTADOS: a diferença entre a média da dimensão mensurada pela MMC e o valor real obtido foi de 0,0066mm (IC 95%: 69,98340 - 69,99140). A diferença média para o scanner a laser foi de 0,107 ± 0,133 (95% IC: -0,002 - 0,24). Em cada método, as diferenças não foram significativas. Ao comparar os dois métodos, o CCI gerou um valor de 0,998 para a coordenada X e de 0,996 para a coordenada Y. A diferença média para as coordenadas registradas em cada dente da arcada foi de 0,616mm. CONCLUSÃO: a precisão das coordenadas do ponto de colagem dos braquetes foi a mesma no scanner a laser e na MMC. A diferença média entre as medições manteve-se dentro dos limites de erros operacionais. .

Tumour necrosis factor-alpha and matrix metalloproteinase-2 are expressed strongly in hidradenitis suppurativa.

Hidradenitis suppurativa is a chronic skin condition, characterized clinically by painful, recurrent, deep- seated nodules and suppuration, and histologically by hyper-trophic scarring of apocrine gland bearing skin and sinus tracts. The overall consequence of the disease is considerable tissue remodelling and the underlying alterations in innate immunity are poorly understood. The aim of this study was to evaluate the expression of human beta-defensin 2, tumour necrosis factor (TNF)-α and matrix metalloproteinase-2 in skin lesions of patients with hidradenitis suppurativa. A total of 14 skin samples from patients and 2 skin samples from healthy volunteers were evaluated by immunohistochemistry. Human beta-defensin 2 was negative in 12/14 specimens. Elevated expression of metalloproteinase-2 was observed in keratinocytes, fibroblasts and inflammatory cells in dermis, sweat glands, hair follicles and sinus tracts, suggesting a key role for hidradenitis suppurativa pathogenesis. Decreased human beta-defensin 2 in the presence of inflammatory (TNF-α-containing) cells suggests a decreased innate immunity in hidradenitis suppurativa-affected skin.

Gamma-secretase gene mutations in familial acne inversa.

Acne inversa (AI), also known as hidradenitis suppurativa, is a chronic, recurrent, inflammatory disease of hair follicles that often runs in families. We studied six Chinese families with features of AI as well as additional skin lesions on back, face, nape, and waist and found independent loss-of-function mutations in PSENEN, PSEN1, or NCSTN, the genes encoding essential components of the γ-secretase multiprotein complex. Our results identify the γ-secretase component genes as the culprits for a subset of familial AI, implicate the γ-secretase-Notch pathway in the molecular pathogenesis of AI, and demonstrate that familial AI can be an allelic disorder of early-onset familial Alzheimer's disease.