Topical Melatonin Exerts Immunomodulatory Effect and Improves Dermatitis Severity in a Mouse Model of Atopic Dermatitis.

Oral melatonin supplement has been shown to improve dermatitis severity in children with AD, but the mechanism of the effect is unclear, and it is uncertain whether melatonin has a direct immunomodulatory effect on the dermatitis. Topical melatonin treatment was applied to DNCB-stimulated Balb/c mice, and gross and pathological skin findings, serum IgE, and cytokine levels in superficial lymph nodes were analyzed. Secretion of chemokines and cell proliferative response after melatonin treatment in human keratinocyte HaCaT cells were also studied. We found that in DNCB-stimulated Balb/c mice, topical melatonin treatment improved gross dermatitis severity, reduced epidermal hyperplasia and lymphocyte infiltration in the skin, and decreased IP-10, CCL27, IL-4, and IL-17 levels in superficial skin-draining lymph nodes. Melatonin also reduced cytokine-induced secretion of AD-related chemokines IP-10 and MCP-1 and decreased IL-4-induced cell proliferation in HaCaT cells. Melatonin seems to have an immunomodulatory effect on AD, with IP-10 as a possible target, and topical melatonin treatment is a potentially useful treatment for patients with AD.

Association of Resistin Gene Polymorphisms with Oral Squamous Cell Carcinoma Progression and Development.

Oral squamous cell carcinoma (OSCC) accounts for over 90% of malignant neoplasms of the mouth. In Taiwan, OSCC is the fourth most common male cancer and the fourth leading cause of male cancer death. Resistin (RETN) is an adipokine that is associated with obesity, inflammation, and various cancers. Here, we examine the association between four single nucleotide polymorphisms (SNPs) of the RETN gene (rs3745367, rs7408174, rs1862513, and rs3219175) and OSCC susceptibility as well as clinical outcomes in 935 patients with OSCC and in 1200 cancer-free healthy controls. We found that, in 1465 smokers, RETN polymorphisms carriers with the betel-nut chewing habit had a 6.708-10.882-fold greater risk of having OSCC compared to RETN wild-type carriers without the betel-nut chewing habit. Patients with OSCC who had A/A homozygous of RETN rs3219175 polymorphism showed a high risk for an advanced tumor size (> T2), compared to those patients with G/G homozygotes. In addition, A/T/G/G haplotype significantly increased the risks for OSCC by 1.376-fold. This study is the first to examine the risk factors associated with RETN SNPs in OSCC progression and development in Taiwan.

Sleep disorders and atopic dermatitis: A 2-way street?

Sleep disturbance is very common in patients with atopic dermatitis (AD) and is a major factor leading to impaired quality of life. Sleep disturbance is often viewed as one of the symptoms of AD and one of the measures of disease severity. In this review we describe a variety of sleep disorders associated with AD and a wide range of effect that sleep disorders have on patients with AD. We also discuss our current understanding of the mechanism of sleep disturbance in patients with AD. The relationship between sleep disorders and AD might be bidirectional and could form a vicious cycle. Therefore we suggest viewing sleep disorders as a comorbidity of AD for which regular screening and bidirectional management strategies are indicated, with equal focus on maintaining disease control and implementing specific strategies to improve sleep.

Leptin promotes VEGF-C production and induces lymphangiogenesis by suppressing miR-27b in human chondrosarcoma cells.

Chondrosarcoma is the second most frequently occurring type of bone malignancy that is characterized by the distant metastasis propensity. Vascular endothelial growth factor-C (VEGF-C) is the chief lymphangiogenic mediator, and makes crucial contributions to tumor lymphangiogenesis. Leptin is an adipocytokine and has been indicated to facilitate tumorigenesis, angiogenesis and metastasis. However, the effect of leptin on VEGF-C regulation and lymphangiogenesis in human chondrosarcoma has hugely remained a mystery. Our results showed a clinical correlation between leptin and VEGF-C as well as tumor stage in human chondrosarcoma tissues. We further demonstrated that leptin promoted VEGF-C production and secretion in human chondrosarcoma cells. The conditioned medium from leptin-treated chondrosarcoma cells induced lymphangiogenesis of human lymphatic endothelial cells. We also found that leptin-induced VEGF-C is mediated by the FAK, PI3K and Akt signaling pathway. Furthermore, the expression of microRNA-27b was negatively regulated by leptin via the FAK, PI3K and Akt cascade. Our study is the first to describe the mechanism of leptin-promoted lymphangiogenesis by upregulating VEGF-C expression in chondrosarcomas. Thus, leptin could serve as a therapeutic target in chondrosarcoma metastasis and lymphangiogenesis.

Mechanism of Sleep Disturbance in Children with Atopic Dermatitis and the Role of the Circadian Rhythm and Melatonin.

Sleep disturbance is common in children with atopic dermatitis (AD). It is a major factor leading to impaired quality of life in these patients and could have negative effects on neurocognitive function and behavior. However, the pathophysiology of sleep disturbance in children with AD is poorly understood, and there is no consensus on how to manage sleep problems in these patients. Pruritus and scratching could lead to sleep disruption but is unlikely the sole etiology. The circadian rhythm of cytokines, the immune system, and skin physiology such as transcutaneous water loss and skin blood flow might also play a role. Recent studies have suggested that melatonin could also be involved due to its multiple effects on sleep, immunomodulation, and anti-oxidant ability. Environmental factors should also be considered. In this review, we summarize the current understanding of the pathophysiology of sleep disturbance in children with AD, and discuss possible therapeutic implications.

Synbiotics for Prevention and Treatment of Atopic Dermatitis: A Meta-analysis of Randomized Clinical Trials.

IMPORTANCE: Atopic dermatitis (AD) is a highly prevalent condition that may be associated with an altered gastrointestinal microbiota that promotes an immune environment more susceptible to allergic disease. Synbiotics, a mixture of prebiotics and probiotics, have been used for the prevention and treatment of AD. OBJECTIVE: To investigate the efficacy of synbiotics for primary prevention and treatment of AD. DATA SOURCES: PubMed/MEDLINE, EMBASE, the Cochrane Central Register of Controlled Trials, and the CAB Abstracts Archive searchable database were searched from the inception of all databases to October 15, 2015, with no language restrictions. STUDY SELECTION: We included all published randomized clinical trials of synbiotics for prevention and/or treatment of AD. To be included, a publication needed to clearly define the intervention as oral administration of synbiotics (combination of probiotics and prebiotics) and must have included an assessment of AD disease severity, such as the Severity Scoring of Atopic Dermatitis (SCORAD) index, or the incidence of AD as an outcome measure. Only 8 of 257 initially identified studies (3%) met selection criteria. DATA EXTRACTION AND SYNTHESIS: Data extraction was independently done by multiple observers and cross-checked to avoid errors. The quality of the selected studies was critically examined following the Cochrane guidelines. Data were pooled using a random-effects model. MAIN OUTCOMES AND MEASURES: The primary outcomes were the SCORAD index (treatment studies) and the relative risk of AD (prevention studies). The hypothesis was formulated before data collection. RESULTS: A total of 257 abstracts were screened to identify 6 treatment studies (369 children enrolled; aged 0 months to 14 years) and 2 prevention studies (1320 children enrolled; up to age 6 months in one study and term neonates aged <3 days in the other). From the 6 treatment studies included for random-effects meta-analysis, the overall pooled change in SCORAD index in those treated with synbiotics at 8 weeks of treatment was -6.56 (95% CI, -11.43 to -1.68; P = .008). Heterogeneity was significant (I(2) = 77.1%; P = .001). Subgroup analysis showed that the beneficial effect was significant only when using mixed strains of bacteria (weighted mean difference, -7.32; 95% CI, -13.98 to -0.66; P = .03) and when used in children aged 1 year or older (weighted mean difference, -7.37; 95% CI, -14.66 to -0.07; P = .048). From the 2 prevention studies included, the pooled relative risk ratio of AD in those treated with synbiotics compared with placebo was 0.44 (95% CI, 0.11 to 1.83; P = .26). CONCLUSIONS AND RELEVANCE: This meta-analysis shows evidence that supports the use of synbiotics for the treatment of AD, particularly synbiotics with mixed strains of bacteria and for children aged 1 year or older. Further studies are needed to evaluate the effectiveness of synbiotics for primary prevention of AD.

Melatonin Supplementation for Children With Atopic Dermatitis and Sleep Disturbance: A Randomized Clinical Trial.

IMPORTANCE: Sleep disturbance is common in children with atopic dermatitis (AD), but effective clinical management for this problem is lacking. Reduced levels of nocturnal melatonin were found to be associated with sleep disturbance and increased disease severity in children with AD. Melatonin also has sleep-inducing and anti-inflammatory properties and therefore might be useful for the management of AD. OBJECTIVE: To evaluate the effectiveness of melatonin supplementation for improving the sleep disturbance and severity of disease in children with AD. DESIGN, SETTING, AND PARTICIPANTS: This randomized clinical trial used a double-blind, placebo-controlled crossover design to study 73 children and adolescents aged 1 to 18 years with physician-diagnosed AD involving at least 5% of the total body surface area. The study was conducted at the pediatric department of a large tertiary care hospital in Taiwan from August 1, 2012, through January 31, 2013. Forty-eight children were randomized 1:1 to melatonin or placebo treatment, and 38 of these (79%) completed the cross-over period of the trial. Final follow-up occurred on April 13, 2013, and data were analyzed from January 27 to April 25, 2014. Analyses were based on intention to treat. INTERVENTIONS: Melatonin, 3 mg/d, or placebo for 4 weeks followed by a 2-week washout period and then crossover to the alternate treatment for 4 weeks. MAIN OUTCOMES AND MEASURES: The primary outcome was AD severity evaluated using the Scoring Atopic Dermatitis (SCORAD) index, with scores ranging from 0 to 103 and greater scores indicating worse symptoms. Secondary outcomes included sleep variables measured by actigraphy, subjective change in sleep and dermatitis, sleep variables measured by polysomnography, nocturnal urinary levels of 6-sulfatoxymelatonin, and serum IgE levels. RESULTS: After melatonin treatment among the 48 children included in the study, the SCORAD index decreased by 9.1 compared with after placebo (95% CI, -13.7 to -4.6; P < .001), from a mean (SD) of 49.1 (24.3) to 40.2 (20.9). Moreover, the sleep-onset latency shortened by 21.4 minutes after melatonin treatment compared with after placebo (95% CI, -38.6 to -4.2; P = .02). The improvement in the SCORAD index did not correlate significantly with the change in sleep-onset latency (r = -0.04; P = .85). No patient withdrew owing to adverse events, and no adverse event was reported throughout the study. CONCLUSIONS AND RELEVANCE: Melatonin supplementation is a safe and effective way to improve the sleep-onset latency and disease severity in children with AD. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT01638234.

Leptin increases VEGF expression and enhances angiogenesis in human chondrosarcoma cells.

BACKGROUND: Leptin, 16kDa product of obese gene, is adipocytokine playing critical role in regulation of body weight. In recent years, leptin is also defined as potent angiogenic factor involving in tumorigenesis, angiogenesis, and metastasis. However, it is unknown whether leptin regulates VEGF production in human chondrosarcoma and contributing the tumor-associated angiogenesis. METHODS: We analyzed protein level of leptin and VEGF in human chondrosarcoma tissues. Effects of leptin on chondrosarcoma cells were examined by in vitro and in vivo assays. In addition, intracellular signal pathways were investigated by pharmacological and genetic approaches. RESULTS: We found that both leptin and VEGF are highly expressed in human chondrosarcoma tissues, and positively correlated with tumor stage. Leptin increases VEGF production by activating OBRl receptor and MAPKs (p38, ERK, and JNK), which in turn enhances binding of AP-1 transcription factor to VEGF promoter, resulting in the transactivation of VEGF expression and subsequently promoting migration and tube formation in endothelial progenitor cells (EPCs). In vivo, knockdown leptin significantly reduces angiogenesis and tumor growth. CONCLUSION: Leptin may be a therapeutic target of angiogenesis and metastasis in chondrosarcoma. GENERAL SIGNIFICANCE: These findings provide better understanding of pathogenesis of chondrosarcoma and can utilize this knowledge to design new therapeutic strategy.

Leptin induces oncostatin M production in osteoblasts by downregulating miR-93 through the Akt signaling pathway.

Inflammatory response and articular destruction are common symptoms of osteoarthritis (OA) and rheumatoid arthritis (RA). Leptin, an adipocyte-secreted hormone that centrally regulates weight control, may exert proinflammatory effects in the joint, depending on the immune response. Yet, the mechanism of leptin interacting with the arthritic inflammatory response is unclear. This study finds that leptin increased expression of oncostatin M (OSM) in human osteoblasts in a concentration- and time-dependent manner. In addition, OBRl, but not OBRs receptor antisense oligonucleotide, abolished the leptin-mediated increase of OSM expression. On the other hand, leptin inhibited miR-93 expression; an miR-93 mimic reversed leptin-increased OSM expression. Stimulation of osteoblasts with leptin promoted Akt phosphorylation, while pretreatment of cells with Akt inhibitor or siRNA reversed leptin-inhibited miR-93 expression. Our results showed that leptin heightened OSM expression by downregulating miR-93 through the Akt signaling pathway in osteoblasts, suggesting leptin as a novel target in arthritis treatment.

Atopic dermatitis, melatonin, and sleep disturbance.

BACKGROUND AND OBJECTIVES: Sleep disturbance is common in patients with atopic dermatitis (AD). However, studies have largely been questionnaire-based, and the pathophysiology remains unclear. The aims of this study were to determine objective characteristics of sleep disturbance in children with AD and explore contributing factors and clinical predictors. METHODS: Sleep parameters were measured by actigraphy and polysomnography in 72 patients with AD and 32 controls ages 1 to 18 years. Urinary 6-sulfatoxymelatonin levels, serum cytokines, and total and allergen-specific immunoglobulin E (IgE) levels were also measured. RESULTS: The patients with AD had significantly reduced sleep efficiency, longer sleep onset latency, more sleep fragmentation, and less nonrapid eye movement sleep. Results from actigraphy correlated well with those from polysomnography. The AD disease severity was associated with sleep disturbance (r = 0.55-0.7), and a Scoring Atopic Dermatitis index of ≥48.7 predicted poor sleep efficiency with a sensitivity of 83.3% and a specificity of 75% (area under the curve = 0.81, P = .001). Lower nocturnal melatonin secretion was significantly associated with sleep disturbance in the patients with AD. Other correlates of sleep disturbance included pruritus, scratching movements, higher total serum IgE levels, and allergic sensitization to dust mite and staphylococcal enterotoxins. CONCLUSIONS: Poor sleep efficiency is common in children with AD and can be predicted by the Scoring Atopic Dermatitis index. Melatonin and IgE might play a role in the sleep disturbance. Further studies are required to explore the mechanisms and clinical implications, and actigraphy could serve as a useful evaluating tool.

Efficacy of leukotriene receptor antagonist with anti-H1 receptor antagonist plus anti-H2 receptor antagonist for treatment of refractory chronic idiopathic urticaria.

BACKGROUND: The efficacy of the combination of leukotriene receptor antagonist (LRA) and H1 antihistamine was similar to the synergistic regimen of H1 and H2 antihistamine for treatment of chronic idiopathic urticaria (CIU). However, the effective rates of these two regimens were only 53.3% and 63.3%, respectively. METHOD: A total of 50 with two combined therapeutic regimens treatment ineffective patients were evaluated. Patients were single blinded and randomly assigned to one of two medication groups that received the following regimens for 4 weeks: Group A (n = 30), combination of LRA, H1 antihistamine and H2 antihistamine. Group B (n = 20) continued with the previously taken two combination regimens. The treatment efficacy was measured by daily urticaria activity score (UAS) of wheal and itch. A positive therapeutic response was defined as a reduction to <25% of baseline weekly UAS, while a relapse was a return to >75% of baseline weekly UAS. RESULTS: At the end of 4 weeks, the UAS response to treatment of Group A was decreased from 35.2% to 21.2%, and the Group B was persisted with 33.9% as before the treatment. CONCLUSION: The combination of LRA, H2 antihistamine and H1 antihistamine is promising for the refractory CIU cases, which were refractory for two combined therapeutic regimens.

Leptin induces IL-6 expression through OBRl receptor signaling pathway in human synovial fibroblasts.

BACKGROUND: Leptin, an adipocyte-secreted hormone that centrally regulates weight control, may exert proinflammatory effects in the joint, depending on the immune response. Leptin is abundantly expressed in osteoarthritis (OA) cartilage and synovium. However, the relationship between leptin and interleukin-6 (IL-6) in OA synovial fibroblasts (OASFs) remains obscure. METHODOLOGY/PRINCIPAL FINDINGS: Stimulation of OASFs with leptin induced IL-6 expression in a concentration- and time-dependent manner. OASFs expressed the long (OBRl) and short (OBRs) isoforms of the leptin receptor. However, OBRl, but not OBRs, antisense oligonucleotide (AS-ODN) abolished the leptin-mediated increase of IL-6 expression. Transfection with insulin receptor substrate (IRS)-1 siRNA decreased leptin-induced IL-6 production. In addition, pretreatment of cells with PI3K, Akt, or AP-1 inhibitor also inhibited the potentiating action of leptin. Leptin-induced AP-1 activation was inhibited by OBRl, IRS-1, PI3K, or Akt inhibitors and siRNAs. CONCLUSIONS/SIGNIFICANCE: Our results showed that leptin activates the OBRl receptor, which in turn activates IRS-1, PI3K, Akt, and AP-1 pathway, leading to up-regulation of IL-6 expression.

An unexpected cause of a subcutaneous nodule: a case report of dirofilaria infection.

Humans are not natural hosts of Dirofilaria; however, pulmonary or subcutaneous infections may occur through mosquitoes transmission. Patients presenting with simple subcutaneous nodules may not seek early medical attention, and hence systemic involvement through hematogenous spread may occur. Definitive diagnosis of Dirofilaria infection is made by histopathological examinations of the infected tissues. We report a patient with an incidental diagnosis of Dirofilaria infection confirmed by histopathological findings of a subcutaneous nodule on the right thigh. The source of infection remains unknown.

Neonatal Behçet's disease without maternal history.

A neonate presented with frequent vomiting since 10 days old, followed by severe diarrhea. Multiple oral ulcers and recurrent genital ulcers subsequently appeared. Colonoscopy showed multiple shallow round ulcerations in the colon. The symptoms responded well to a short course of oral prednisolone. There was a brief recurrence of vomiting, diarrhea, and oral ulcers at 2 months old. The mother has never had any symptoms of Behçet's disease to date. This is the first reported case in literature of neonatal Behçet's disease without a maternal history of Behçet's disease, which raises doubts about the assumed role of maternal antibodies in the pathogenesis of neonatal Behçet's disease. A literature review of neonatal Behçet's disease shows that oral ulcers, skin lesions, fever, and leukocytosis are common features. However, only half of the patients fulfill the classical diagnostic criteria based on adult studies. A treatment consensus for neonatal cases is also lacking.