Melanocyte transplantation to skin prepared by controlled PUVA-induced sunburn-like blistering for vitiligo treatment - A pilot clinical trial.

Vitiligo is a common acquired disease of pigment loss. In lesions recalcitrant to non-invasive treatment, transplantation of cultured autologous melanocytes is an emerging choice. Conventionally, the recipient site is often prepared by laser-mediated or mechanical dermabrasion. Such preparation procedures have disadvantages including prolonged transplantation duration, long period for reepithelialization and potential scarring. We propose a method of preparing recipient sites by psoralen and controlled ultraviolet A (PUVA)-induced blistering followed by transplanting suspended melanocytes. We introduced this method in 10 patients with segmental vitiligo on their recipient site 3 to 5 days before transplantation and blistering developed in 2 to 3 days afterwards. On the day of transplantation, the blister roof could be peeled off easily without bleeding and the recipient site preparation could be completed in 20 min. The recipient site became reepithelialized within 1 week. Progressive repigmentation was observed for up to 6 months, with an average of 65.06% repigmentation in the recipient site without scarring at the end of follow-up. Hence, preparation of the recipient site by controlled PUVA-induced sunburn-like blistering can potentially facilitate melanocyte transplantation and prevent scarring.

Prognostic importance and determinants of uremic pruritus in patients receiving peritoneal dialysis: A prospective cohort study.

BACKGROUND: Uremic pruritus is a common and frustrating symptom among patients receiving peritoneal dialysis (PD). This study aimed to examine the prognostic importance of uremic pruritus and to identify the determinants for higher pruritus intensity in PD patients. METHODS: We conducted a prospective cohort study of patients receiving maintenance PD. A visual analogue scale (VAS) score was used to measure the intensity of uremic pruritus. The composite endpoint of PD technique failure or all-cause death was assessed using a multivariable Cox proportional hazards model. The determinants for the VAS score of uremic pruritus was assessed using a multivariable linear regression model. RESULTS: Among the 85 PD patients, 24 (28%) had uremic pruritus. During a median follow-up of 28.0 months, 12 patients experienced technique failure, and 7 died. We found that a higher VAS score of pruritus intensity was an independent risk factor for technique failure or death (hazard ratio, 1.64; 95% confidence interval, 1.18 to 2.28; P = 0.003) after adjusting for a variety of confounding factors. We also found that a weekly total Kt/V of less than 1.88, a longer duration of dialysis, a higher dietary protein intake, and higher blood levels of intact parathyroid hormone and high-sensitivity C-reactive protein were independent determinants of higher VAS scores of pruritus intensity. CONCLUSIONS: Our results show that uremic pruritus is an independent risk factor of technique failure and death in patients receiving PD. We also found that a weekly total Kt/V < 1.88 is associated with higher intensity of uremic pruritus in PD patients.

Differential activation behavior of dermal dendritic cells underlies the strain-specific Th1 responses to single epicutaneous immunization.

BACKGROUND: Epicutaneous immunization with allergens is an important sensitization route for atopic dermatitis. We recently showed in addition to the Th2 response following single epicutaneous immunization, a remarkable Th1 response is induced in B6 mice, but not in BALB/c mice, mimicking the immune response to allergens in human non-atopics and atopics. OBJECTIVE: We investigated the underlying mechanisms driving this differential Th1 response between BALB/c and B6 mice. METHODS: We characterized dermal dendritic cells by flow cytometric analysis. We measured the induced Th1/Th2 responses by measuring the IFN-γ/IL-13 contents of supernatants of antigen reactivation cultures of lymph node cells. RESULTS: We demonstrate that more dermal dendritic cells with higher activation status migrate into draining lymph nodes of B6 mice compared to BALB/c mice. Dermal dendritic cells of B6 mice have a greater ability to capture protein antigen than those of BALB/c mice. Moreover, increasing the activation status or amount of captured antigen in dermal dendritic cells induced a Th1 response in BALB/c mice. Further, differential activation behavior, but not antigen-capturing ability of dermal dendritic cells between BALB/c and B6 mice is dendritic cell-intrinsic. CONCLUSION: These results show that the differential activation behavior of dermal dendritic cells underlies the strain-specific Th1 responses following single epicutaneous immunization. Furthermore, our findings highlight the potential differences between human atopics and non-atopics and provide useful information for the prediction and prevention of atopic diseases.

A Comparison of Uremic Pruritus in Patients Receiving Peritoneal Dialysis and Hemodialysis.

Uremic pruritus is common and bothersome in patients receiving either peritoneal dialysis (PD) or hemodialysis (HD). To date, the preferred dialysis modality regarding the alleviation of uremic pruritus remains controversial. We conducted this cross-sectional study to compare the prevalence, intensity, and characteristics of uremic pruritus between PD and HD patients. Patients receiving maintenance dialysis at a referral medical center in Taiwan were recruited. Dialysis modality, patient demographic, clinical characteristics, and laboratory data were recorded. The intensity of uremic pruritus was measured using visual analogue scale (VAS) scores. Multivariate linear regression analysis was conducted to compare the severity of uremic pruritus between PD and HD patients. Generalized additive models were applied to detect nonlinear effects between pruritus intensity and continuous covariates. A total of 380 patients completed this study, with a mean age of 60.3 years and 49.2% being female. Uremic pruritus was presented in 24 (28.6%) of the 84 PD patients and 113 (38.2%) of the 296 HD patients (P = .12). The VAS score of pruritus intensity was significantly lower among the PD patients than the HD patients (1.32 ±â€Š2.46 vs 2.26 ±â€Š3.30, P = .04). Multivariate linear regression analysis showed that PD was an independent predictor for lower VAS scores of pruritus intensity compared with HD (ß-value -0.88, 95% confidence interval -1.62 to -0.13). The use of active vitamin D was also an independent predictor for a lower intensity of uremic pruritus, whereas hyperphosphatemia and higher serum levels of triglyceride and aspartate transaminase were significantly associated with higher pruritus intensity. There was a trend toward a less affected body surface area of uremic pruritus in the PD patients than in the HD patients, but the difference did not reach statistical significance (P = .13).In conclusion, the severity of uremic pruritus was lower among PD patients than HD patients, and PD may provide better alleviation of pruritus symptoms. The result provides a valuable reference for clinicians and patients when choosing a dialysis modality.

Insulin-Like Growth Factor II mRNA-Binding Protein 3 Expression Correlates with Poor Prognosis in Acral Lentiginous Melanoma.

Insulin-like growth factor-II mRNA-binding protein 3 (IMP-3) is an RNA-binding protein expressed in multiple cancers, including melanomas. However, the expression of IMP-3 has not been investigated in acral lentiginous melanoma (ALM). This study sought to elucidate its prognostic value in ALMs. IMP-3 expression was studied in 93 patients diagnosed with ALM via immunohistochemistry. Univariate and multivariate analyses for survival were performed, according to clinical and histologic parameters, using the Cox proportional hazard model. Survival curves were graphed using the Kaplan-Meier method. IMP-3 was over-expressed in 70 out of 93 tumors (75.3%). IMP-3 expression correlated with thick and high-stage tumor and predicted poorer overall, melanoma-specific, recurrence-free and distant metastasis-free survivals (P = 0.002, 0.006, 0.008 and 0.012, respectively). Further analysis showed that patients with tumor thickness ≤ 4.0 mm and positive IMP-3 expression had a significantly worse melanoma-specific survival than those without IMP-3 expression (P = 0.048). IMP-3 (hazard ratio 3.67, 95% confidence intervals 1.35-9.97, P = 0.011) was confirmed to be an independent prognostic factor for melanoma-specific survival in multivariate survival analysis. Positive IMP-3 expression was an important prognostic factor for ALMs.

Dermal dendritic cells, but not Langerhans cells, are critical in murine single epicutaneous sensitization.

A murine repeated protein-patch model has been established to study epicutaneous sensitization in atopic dermatitis. This model has shown a predominant Th2 and a weak Th1 response in both BALB/c and C57BL/6 mice. However, Th responses induced in the repeated model are not consistent with the generally accepted theory that BALB/c and C57BL/6 mice are Th2 and Th1 prone and are representatives of human atopy and non-atopy, respectively. In this study, a single protein-patch model was established, which showed in addition to the Th2 response, a remarkable Th1 response in C57BL/6 mice, but not in BALB/c mice. Moreover, using muLangerin-DTR mice, we demonstrated that dermal dendritic cells, but not Langerhans cells, are critical in single epicutaneous sensitization in both strains of mice.

IMP-3 promotes migration and invasion of melanoma cells by modulating the expression of HMGA2 and predicts poor prognosis in melanoma.

IGF II mRNA-binding protein 3 (IMP-3) has been reported to be a marker of melanoma progression. However, the mechanisms by which it impacts melanoma are incompletely understood. In this study, we investigate the clinical significance of IMP-3 in melanoma progression and also its underlying mechanisms. We found that IMP-3 expression was much higher in advanced-stage/metastatic melanomas and that it was associated with a poor prognosis (P=0.001). Univariate analysis showed that IMP-3 expression was associated with stage III/IV melanomas (odds ratio=5.40, P=0.031) and the acral lentiginous subtype (odds ratio=3.93, P=0.0034). MeWo cells with overexpression of IMP-3 showed enhanced proliferation and migration and significantly increased tumorigenesis and metastatic ability in nude mice. We further demonstrated that IMP-3 could bind and enhance the stability of the mRNA of high mobility group AT-hook 2 (HMGA2). It was also confirmed that IMP-3 had an important role in melanoma invasion and metastasis through regulating HMGA2 mRNA expression. IMP-3 expression was positively correlated with HMGA2 expression in melanoma cells and also in melanoma tissues. Our results show that IMP-3 expression is a strong prognostic factor for melanoma, especially acral lentiginous melanoma.

Interleukin-31 is associated with uremic pruritus in patients receiving hemodialysis.

BACKGROUND: Interleukin (IL)-31 induces severe pruritus and dermatitis in transgenic mice, and is associated with many itching skin diseases. OBJECTIVE: We sought to investigate the association of serum IL-31 levels with uremic pruritus in patients undergoing hemodialysis. METHODS: Patients receiving maintenance hemodialysis in a referral medical center were recruited. Serum IL-31 levels were determined by the enzyme-linked immunosorbent assay methodology. The various characteristics of pruritus were assessed using an interview questionnaire. RESULTS: Among the 178 study participants, 34.8% had uremic pruritus. The patients with pruritus had higher serum IL-31 levels than those without pruritus symptoms (median 8.68 [first quartile 0.43, third quartile 35.04] vs 4.91 [0, 15.78], P = .04). A multivariate linear regression analysis showed that higher serum levels of IL-31, high-sensitivity C-reactive protein, and alanine transaminase, and a lower dialysis dose assessed by Kt/V, were independent predictors for higher pruritus intensity. The generalized additive model also showed a positive exposure-response relationship between serum levels of IL-31 and visual analog scale scores of pruritus intensity. LIMITATIONS: The cause-effect relationship between IL-31 and uremic pruritus could not be assessed by the cross-sectional study design. CONCLUSION: IL-31 may play an important role in the pathophysiology of uremic pruritus.

Postprandial blood glucose is associated with generalized pruritus in patients with type 2 diabetes.

BACKGROUND: Although pruritus is a common complaint in patients with diabetes, little is known about its relation with glycemic control. OBJECTIVES: We investigated whether generalized pruritus is associated with glycemic control in patients with type 2 diabetes. MATERIALS AND METHODS: A total of 385 patients with type 2 diabetes who attended the diabetes care system underwent cutaneous examination by a dermatologist at a teaching hospital in Taiwan. A detailed interview questionnaire including visual analogue scale was used to assess various characteristics and the intensity of pruritus. Multivariate logistic regression was used to assess the association between postprandial blood glucose, preprandial blood glucose, and glycosylated hemoglobin with generalized pruritus. RESULTS: Generalized pruritus was noted in 27.5% of the patients. As a result of pruritus, 24.5% of the patients had difficulties in falling asleep, 15.1% had disturbance of sleep, and 9.5% needed soporifics. Patients who had a higher postprandial glucose level had a higher probability of having generalized pruritus [OR = 1.41 (95% C.I.: 1.05-1.90), P = 0.02] in type 2 diabetic patients. CONCLUSIONS: This study showed positive associations between postprandial blood glucose and generalized pruritus and suggested that a better control of postprandial glucose might be beneficial to relieve generalized pruritus in diabetic patients.

Uremic pruritus, dialysis adequacy, and metabolic profiles in hemodialysis patients: a prospective 5-year cohort study.

BACKGROUND: Uremic pruritus is a common and intractable symptom in patients on chronic hemodialysis, but factors associated with the severity of pruritus remain unclear. This study aimed to explore the associations of metabolic factors and dialysis adequacy with the aggravation of pruritus. METHODS: We conducted a 5-year prospective cohort study on patients with maintenance hemodialysis. A visual analogue scale (VAS) was used to assess the intensity of pruritus. Patient demographic and clinical characteristics, laboratory parameters, dialysis adequacy (assessed by Kt/V), and pruritus intensity were recorded at baseline and follow-up. Change score analysis of the difference score of VAS between baseline and follow-up was performed using multiple linear regression models. The optimal threshold of Kt/V, which is associated with the aggravation of uremic pruritus, was determined by generalized additive models and receiver operating characteristic analysis. RESULTS: A total of 111 patients completed the study. Linear regression analysis showed that lower Kt/V and use of low-flux dialyzer were significantly associated with the aggravation of pruritus after adjusting for the baseline pruritus intensity and a variety of confounding factors. The optimal threshold value of Kt/V for pruritus was 1.5 suggested by both generalized additive models and receiver operating characteristic analysis. CONCLUSIONS: Hemodialysis with the target of Kt/V ≥1.5 and use of high-flux dialyzer may reduce the intensity of pruritus in patients on chronic hemodialysis. Further clinical trials are required to determine the optimal dialysis dose and regimen for uremic pruritus.

Induction of chemokine receptor CXCR4 expression by transforming growth factor-ß1 in human basal cell carcinoma cells.

BACKGROUND: Higher CXCR4 expression enhances basal cell carcinoma (BCC) invasion and angiogenesis. The underlying mechanism of increased CXCR4 expression in invasive BCC is still not well understood. OBJECTIVE: To investigate the mechanisms involved in the regulation of CXCR4 expression in invasive BCC. METHODS: We used qRT-PCR, RT-PCR, Western blot, and flow cytometric analyses to examine different CXCR4 levels among the clinical samples, co-cultured BCC cells and BCC cells treated with recombinant transforming growth factor-ß1 (TGF-ß1) and connective tissue growth factor (CTGF). Immunohistochemical studies were used to demonstrate the correlation between TGF-ß1 and CXCR4 expressions. The signal transduction pathway and transcriptional regulation were confirmed by treatments with chemical inhibitors, neutralizing antibodies, or short interfering RNAs, as well as luciferase reporter activity. RESULTS: Invasive BCC has higher TGF-ß1 and CTGF levels compared to non-invasive BCC. Non-contact dermal fibroblasts co-culture with human BCC cells also increases the expression of CXCR4 in BCC cells. Treatment with recombinant human TGF-ß1, but not CTGF, enhanced the CXCR4 levels in time- and dose-dependent manners. The protein level and surface expression of CXCR4 in human BCC cells was increased by TGF-ß1 treatment. TGF-ß1 was intensely expressed in the surrounding fibroblasts of invasive BCC and was positively correlated with the CXCR4 expression of BCC cells. The transcriptional regulation of CXCR4 by TGF-ß1 is mediated by its binding to the TGF-ß receptor II and phosphorylation of the extracellular signal-related kinase 1/2 (ERK1/2)-ETS-1 pathway. CONCLUSION: TGF-ß1 induces upregulation of CXCR4 in human BCC cells by phosphorylation of ERK1/2-ETS-1 pathway.

Long-term sequelae of drug reaction with eosinophilia and systemic symptoms: a retrospective cohort study from Taiwan.

BACKGROUND: The development of autoimmune sequelae is one of the characteristic features of drug reaction with eosinophilia and systemic symptoms (DRESS) or drug-induced hypersensitivity syndrome; however, the incidence of sequelae and prognosis of patients with DRESS are unknown. OBJECTIVE: We sought to investigate the incidence of sequelae, including less well-known sequelae, and long-term prognosis in patients with DRESS/drug-induced hypersensitivity syndrome. METHODS: A retrospective cohort study was conducted at a medical center in northern Taiwan using a DRESS/drug-induced hypersensitivity syndrome database. Patients who were followed up for at least 1 year were included in the study. RESULTS: Nine patients died before interview, whereas 43 patients completed a specially designed questionnaire. The overall cumulative incidence of long-term sequelae was 11.5% (6 of 52 patients). Four patients developed autoimmune diseases, specifically Graves disease (n = 2), type 1 diabetes mellitus (n = 1), and autoimmune hemolytic anemia (n = 1). Alopecia areata was also noted in 1 of the 2 patients with Graves disease. The other 2 patients developed renal failure after visceral involvement and required lifetime hemodialysis. LIMITATIONS: Our study included a small number of patients. Further, viral studies were not performed. CONCLUSION: The sequelae of DRESS can be divided into 2 major types that appear to occur in different age groups: young patients tend to develop autoimmune diseases, whereas elderly patients are more vulnerable to end-organ failure.