Genetic analyses unravel the causal association of cytokine levels on lichen simplex chronicus risk: insights from a mendelian randomization study.

Lichen simplex chronicus (LSC) presents a challenge in dermatology due to its elusive pathogenic mechanisms. While associations between circulating inflammatory cytokines and LSC were observed, the definitive causal dynamics remain to be elucidated. Our study used a two-sample Mendelian randomization (MR) approach to investigate causal relationships. We applied a suite of MR methodologies, including IVW, Weighted Median, MR-Egger, Weighted Mode, Simple Mode, MR-PRESSO, and the Steiger test, to ensure robust causal inference. Our analysis confirmed the causal impact of genetically determined cytokine levels on LSC risk, particularly MMP-10 (OR = 0.493, P = 0.004) and DNER (OR = 0.651, P = 0.043) in risk attenuation. We also found a positive causal correlation between GDNF levels (OR = 1.871, P = 0.007) and LSC prevalence. Notably, bidirectional causality was observed between DNER and LSC. Consistency across various MR analyses and sensitivity analyses confirmed the absence of horizontal pleiotropy, validating the causal estimates. This pioneering MR investigation unveils a novel genetically anchored causal relationship between the circulating levels of MMP-10, DNER, and GDNF and LSC risk. Although further validation is requisite, our findings augment the understanding of cytokine mediation in LSC and underscore prospective avenues for research.

Differentiating cutaneous squamous cell carcinoma and pseudoepitheliomatous hyperplasia by multiplex qRT-PCR.

Squamous cell carcinoma is the second most common cutaneous malignancy. The diagnosis can occasionally be difficult as there are many lesions that are mimics, clinically and on pathologic examination. One of the most challenging lesions to differentiate from squamous cell carcinoma is pseudoepitheliomatous hyperplasia, a reactive proliferation of the epidermis that can be encountered secondary to a variety of inflammatory and neoplastic conditions. Utilizing the data set from our previously performed DNA microarray studies on formalin-fixed and paraffin-embedded tissue, we found that the genes C15orf48 and KRT9 had a distinct and robust gene expression pattern in distinguishing squamous cell carcinoma from pseudoepitheliomatous hyperplasia. C15orf48 had higher expression than KRT9 in squamous cell carcinoma, but lower expression than KRT9 in pseudoepitheliomatous hyperplasia. We developed and blindly validated a multiplex TaqMan PCR assay that utilizes these two highly discriminatory genes, which can be performed on material extracted from formalin-fixed and paraffin-embedded tissue. The TaqMan assay was able to differentiate squamous cell carcinoma from pseudoepitheliomatous hyperplasia in 54 of 58 cases (93%). Squamous cell carcinoma was accurately identified in 27 of 28 cases (96%); pseudoepitheliomatous hyperplasia in 27 of 30 cases (90%). This multiplex TaqMan PCR assay may be used as a helpful ancillary molecular diagnostic test to accurately distinguish squamous cell carcinoma from pseudoepitheliomatous hyperplasia in challenging cases.

Alterations in the LINE-1 methylation pattern in patients with lichen simplex chronicus.

BACKGROUND: Long interspersed element-1 (LINE-1) and short interspersed element (Alu) retrotransposons have been identified to influence the human genome by modifications in gene expression. Variations in LINE-1 and Alu methylation have been shown to be associated with many diseases, predominantly malignancies and autoimmune diseases. Moreover, the degree and pattern of LINE-1 methylation are related to risk, prognosis and aggressiveness of several cancers. However, a similar study has not been performed in lichen simplex chronicus (LSC). OBJECTIVE: To evaluate DNA methylation status of repetitive sequences in LSC. RESULTS: The %mCmC of LINE-1 was significantly decreased in keratinocytes from patients with LSC (p=0.012). Moreover, the %mCuC was significantly lower in LSC than controls (p=0.029). Conversely, %uCmC was significantly higher LSC than controls (p=0.004). A receiver-operating characteristic (ROC) curve analysis demonstrated that % mCmC, % mCuC and % uCmC were highly sensitive and specific for LSC with an optimal cut-off value. There were no significant differences in Alu methylation in keratinocytes from LSC patients. METHODS: We determined the level and pattern of LINE-1 and Alu methylation in keratinocytes from patients with LSC (n=10) compared to normal controls (n=13), by the improved combined bisulfite restriction analysis of LINE-1 and Alu (COBRA-LINE-1 and Alu). COBRA-LINE-1 classifies LINE-1 loci according to the methylation patterns of two CpG dinucleotides in the 5'UTR into four categories: hypermethylated (mCmC), hypomethylated (uCuC), and two forms of partially methylated loci (uCmC and mCuC). CONCLUSION: Changes in the LINE-1 pattern were revealed in the epidermis from patients with LSC. A particular LINE-1 methylation pattern is indicative of LSC and might be used as a diagnostic tool.

Down-regulated expression of transient receptor potential ankyrin 1 in lichen simplex chronicus.

BACKGROUND: Lichen simplex chronicus (LSC) is an acquired chronic dermatosis that is often accompanied by severe paroxysmal pruritus, and its pathogenesis to date is still unclear. Transient receptor potential channel A1 (TRPA1) is a non-selective cation channel. TRPA1 is widely expressed in skin, sensory neurons, and various other tissues, along with various biological functions and activation mechanisms. This study aimed to explore the changes in TRPA1 expression in human LSC and provide evidence for further research on the role of TRPA1 in chronic pruritus. METHODS: A total of 21 skin lesion specimens from LSC patients with skin pruritus lasting more than 6 weeks, and 28 normal skin tissue specimens through the skin biopsy from June 2018 to February 2019 were collected. The expression of TRPA1 in these skin tissues was evaluated through western blotting, quantitative reverse transcription PCR (qRT-PCR), and immunohistochemical analysis. The changes of inflammatory mediators, including interleukin (IL)-6, IL-13, endothelin-1 (ET-1), and thymic stromal lymphopoietin (TSLP), as well as substance P, are also analyzed by qRT-PCR. TRPA1 was detected using immunohistochemistry for all skin layers, the basal layer, and around the blood vessels of the dermis. RESULTS: The expression of TRPA1 in LSC specimens was significantly decreased as compared with that in the normal specimens (P<0.05). Also, TRPA1 protein levels were consistently decreased in LSC specimens (P<0.05). Simultaneously, the mRNA expressions of TRPA1, IL-6, IL-13, ET-1, TSLP, and substance P presented with no significant differences between LSC and normal specimens. CONCLUSIONS: TRPA1 expression is proved downregulated in skin lesions of LSC patients with skin pruritus, indicating that TRPA1 serves as a crucial role in the pathogenesis of human LSC.

A family of McLeod syndrome, masquerading as chorea-acanthocytosis.

A man, aged 52, is reported to show (1) adult onset, (2) progressive orofacial dyskinesia and choreic movements of the extremities, (3) tongue biting, (4) denervation of the peripheral nerves, (5) acanthocytosis, and (6) increased serum creatine kinase, which are characteristic of chorea-acanthocytosis. The Kell blood group examination on erythrocytes disclosed that the propositus had McLeod phenotype, and his mother and one of his sisters were carriers of the McLeod phenotype. Thus, he was diagnosed as having McLeod syndrome. A criterion of exclusion of McLeod phenotype on erythrocytes should be added to the diagnostic criteria of chorea-acanthocytosis. Moreover, chronic neurogenic changes instead of myogenic changes were electromyographically and histopathologically verified in the muscle.

Lichen simplex chronicus.

A review of the literature for the last 20 years shows no monumental advances in the diagnosis or treatment of the disease; however, there have been some very intriguing insights into the causes. The physical and emotional aspect of the skin condition is well known but the genetic, vascular, and neurogenic implications are of interest.

Modelling patterns of agreement for nominal scales.

The measurement of agreement of repeat rating is the usual method of assessing the reliability of categorical scales. Measurement of agreement is also important in genetic twin studies based on categorical scales. One of the most commonly used methods of analysis for both types of study is the kappa coefficient. For scales with more than two categories, one approach is to use a single summary kappa coefficient. While this may be sufficient for many studies, in some instances investigation of heterogeneity in the pattern of agreement may give additional insights as there may be greater agreement for some pairs of categories than for others. In this paper, kappa-type coefficients are used to model heterogeneity in the pattern of agreement. Constraints are added to the heterogeneous model to obtain simplified models. Procedures for estimation, confidence intervals, and inference for these coefficients are described for the case of two ratings per subject for a single sample and for the comparison of two independent samples. Formulae for sample size and power calculation are derived using the non-central chi-squared distribution. Two simulation studies are carried out to check the empirical test size and power. Methods are illustrated by two examples involving nominal scales with three categories.

Association of serotonin transporter gene-linked polymorphic region and variable number of tandem repeat polymorphism of the serotonin transporter gene in lichen simplex chronicus patients with psychiatric status.

BACKGROUND: The serotonin (5-hydroxytryptamine; 5-HT) is a key neurotransmitter in the central nervous system and a responsible mediator for the itch. Dysregulation of serotonergic pathways has been implicated in the pathogenesis of many complex neuropsychiatric diseases. OBJECTIVES: The purpose of this study was to evaluate the relationship between lichen simplex chronicus and dysfunction and serotonin transporter (5-HTT) gene polymorphism. METHODS: Thirty-nine patients with lichen simplex chronicus and 61 healthy control subjects were examined. RESULTS: The results for the patients and control subjects were not significantly different (P > 0.05) in long/long (L/L) and long/short (L/S) genotypes of 5-HTT gene-linked polymorphic region (HTTLPR) polymorphism, but short/short S/S genotype was lower in lichen simplex chronicus patients (17.9%) than in controls (42.6%). This difference was statistically significant (P = 0.028). The results for the patients and control subjects were not significantly different in 12/12, 10/12 and 10/10 genotypes of variable number of tandem repeat (VNTR) polymorphism (P > 0.05). Beck depression inventory (BDI) scores and symptom checklist-90-revised (SCL-90) psychotic subscale were overrepresented significantly in the 12/12 genotypes than 10/12 genotypes. State and Trait Anxiety Inventory tests (STAI-I and -II) point averages were not statistically significant (P > 0.05) CONCLUSION: S/S genotypes of HTTLPR polymorphism in the 5-HTT gene may be related to lichen simplex chronicus and that patients who have 12/12 genotypes of VNTR polymorphism may be affected psychiatrically.

[Hypothyroid iodine deficiency struma in 2 siblings as a sequela of alternative nutrition]. / Hypothyreote Jodmangelstruma bei 2 Geschwistern als Folge einer alternativen Ernährung.

Two siblings aged 4 and 7 years presented with a goitre and growth retardation. Laboratory data revealed hypothyroidism with elevated TSH, low T4 und T3, and a decreased urinary iodine excretion. Both children suffered from neurodermitis and because of that for already two years on a vegetarian diet free of any milk products; their nutrition contained sufficient calories but not enough iodine or vitamin B.

[Early appearing neurofibromatosis (author's transl)]. / Neurofibromatosis de aparición precoz. Nuestra casuística

Six cases of neurofibromatosis in children under seven years of age with other members of the family affected are reported. Mental retardation was observed in five patients, and one had convulsive crises. Growth and bone maturation retardation, without HGH deficiency after glucagon stimulation were observed.

Neurotic excoriations. A controlled psychiatric examination.

The investigation covers 68 patients with the primary form of neurotic excoriations (n.ex.) who within a 5 year period, 1974-78 had contact with the dermatology department, Odense University Hospital. The diagnosis was ascertained clinically - anamnestically, and by various laboratory examinations. The first 25 typical patients were matched with neurotic control patients (control group) who were homogeneous with regard to sex, age, level of intelligence, main personality traits (self-esteem, orderliness in a broad sense, hysterical traits), and level of invalidity. The primary psychiatric investigation contained a semistructured biographic interview lasting about 3 hours. N.ex. patients were on an average 42 years old at the time of reference to the dermatology department and most frequently in their 20s, 30s, and 40s. About 90% were women and only about 1/2 were married. Occupationally pensioners and workers dominated. Childhood seems on many levels to have been more discordant for n.ex. patients than for the control patients. Father and steady partners tended to have a lower social status in the n.ex. group than in the control group. A predominance of n.ex. patients lacked self-confidence (though possibly managed to mask it), were hypersensitive, meticulous or perfectionistic, suffered from sexual dysfunction. They were more reserved in contact situations than patients in the control group and often revealed no manifest need of psychiatric treatment. Significantly more in the n.ex. group than in the control group had a high level of energy and activity. There was a dominant tendency to depressive/dysphoric moods in the n.ex. group. Management of aggression was seldom without problems in both the n.ex. group and in the control group but aggressive explosions occurred with significantly greater frequency in the n.ex. group. A number of the patients in the n.ex. group described how their spouse's phlegmatism could violently irritate them. The same frequency for suicidal behaviour was found for both groups. The onset of the skin disease occurred at the average age of 30 years approximately; for 40% the outbreak could be described as "fresh" on approach to the dermatology department. Distressing factors preceding onset or recidivation after healing that were of significance for the patient were registered for about 90%.(ABSTRACT TRUNCATED AT 400 WORDS)