Both cardiovascular and cerebrovascular events are decreased following long-term narrowband ultraviolet B phototherapy in patients with vitiligo: a propensity score matching analysis.

BACKGROUND: Systemic effects of long-term narrowband ultraviolet B (NB-UVB) phototherapy have not been well studied in vitiligo patients. An 11-year nationwide population-based retrospective cohort study was conducted using the Korean National Health Insurance claims database (2007-2017). OBJECTIVES: To investigate the effects of long-term NB-UVB phototherapy on the risk of cardiovascular and cerebrovascular events in vitiligo patients. METHODS: This study included vitiligo patients with ≥100 phototherapy sessions (phototherapy group, n = 3229) and <3 phototherapy sessions (no phototherapy group, n = 9687), in which covariables with age, sex, insurance type and comorbidities such as diabetes, hypertension and hyperlipidemia were matched by 1 : 3 propensity score matching. The outcomes of interest were cardiovascular (ischaemic heart disease and myocardial infarction) and cerebrovascular events (cerebrovascular infraction and haemorrhage). Cox proportional hazards models were used to assess the associations between NB-UVB phototherapy and each event. RESULTS: The risk of cardiovascular or cerebrovascular events was significantly decreased in the phototherapy group compared with the no phototherapy group [hazard ratio (HR) 0.637, 95% confidence interval (CI) 0.523-0.776]. Subgroup analysis revealed that the risk of cardiovascular (HR: 0.682, 95% CI: 0.495-0.940) and cerebrovascular events (HR: 0.601, 95% CI: 0.470-0.769) were significantly lower in the phototherapy group than the no phototherapy group, respectively. CONCLUSIONS: Our findings suggest that long-term NB-UVB phototherapy could decrease the risk of cardiovascular and cerebrovascular events in patients with vitiligo.

Pain, xerostomia, and younger age are major determinants of fatigue in Korean patients with primary Sjögren's syndrome: a cohort study.

OBJECTIVES: Fatigue is a common clinical manifestation in patients with primary Sjögren's syndrome (pSS). The aims of this study were to investigate the association between fatigue severity and other clinical characteristics in pSS patients and to determine the factors contributing to fatigue. METHOD: We analysed 257 participants from the Korean Initiative of pSS (KISS), a prospective pSS cohort. Fatigue was assessed according to the fatigue domain of the European League Against Rheumatism (EULAR) Sjögren's Syndrome Patient-Reported Index (ESSPRI). Health-related quality of life (HRQoL) was evaluated using the EuroQol-5 dimensions (EQ-5D) questionnaire. Multiple linear regression analysis was used to estimate the effect of each variable on fatigue severity. RESULTS: The median total ESSPRI score was 5 [interquartile range (IQR) 4-6]. Thirty-four per cent of patients reported a fatigue score > 5. Younger and premenopausal patients presented with more fatigue (p = 0.013 and p < 0.001, respectively). Higher Xerostomia Inventory (XI) scale (p < 0.001) and Ocular Surface Dryness Index (OSDI) (p < 0.001) scores were observed in patients with a fatigue score > 5. Pain, xerostomia, and age were determined to be significantly associated with fatigue severity after adjusting for depression/anxiety, OSDI score, and the presence of fibromyalgia using a multivariate general linear model. The ESSPRI fatigue score was correlated with the EQ-5D by time trade-off (TTO) values and visual analogue scale (VAS) scores. CONCLUSIONS: In Korean patients with pSS, younger age, xerostomia, and pain were correlated significantly with fatigue, and fatigue was associated with HRQoL.

Neural transdifferentiation of human bone marrow mesenchymal stem cells on hydrophobic polymer-modified surface and therapeutic effects in an animal model of ischemic stroke.

Human bone marrow-derived mesenchymal stem cells (MSCs) have multi-lineage differentiation potential and can become cells of mesodermal and neural lineages. These stem cells thus hold considerable clinical promise for the treatment of neurodegenerative diseases. For successful regeneration of damaged neural tissues, directed differentiation of neural or neuronal precursor cells from MSCs and integration of transplanted cells are pivotal factors. We induced MSCs into neurogenesis using a modified protocol. The therapeutic potency of the resulting neural progenitor cells in a rat model of ischemic stroke was analyzed. Using a highly hydrophobic diphenylamino-s-triazine-bridged p-phenylene (DTOPV)-coated surface and adopting a procedure for propagation of neural stem cells, we efficiently converted MSCs into neurosphere-like cellular aggregates (NS-MSCs). The spherical cells were subsequently induced to differentiate into neural cells expressing neuroectodermal markers. To determine whether these cells had neuronal fates and induced neuro-protective effects in vivo, NS-MSCs were intra-cerebrally administered to rats 48h after permanent middle cerebral artery occlusion (pMCAo). The results showed a remarkable attenuation of ischemic damage with significant functional recovery, although the cells were not fully incorporated into the damaged tissues on post-operative day 26. Improvement in the NS-MSC-transplanted rats was faster than in the MSC group and suppression of inflammation was likely the key factor. Thus, our culture system using the hydrophobic surface of a biocompatible DTOPV coating efficiently supported neural cell differentiation from MSCs. Neural-primed MSCs exhibited stronger therapeutic effects than MSCs in rat brains with pMCAo.

Expression of CCL1 and CCL18 in atopic dermatitis and psoriasis.

BACKGROUND: Recent studies have shown that chemoattractive proteins play an important role in the organization of the innate and adaptive immune responses. There are some reports that chemokine (C-C motif) ligand (CCL)1 and CCL18, members of a family of chemoattractive proteins, have increased expression in atopic dermatitis (AD). AIM: To evaluate the quantity and pattern of CCL1 and CCL18 expression in lesions and blood of patients with AD, and compare them with those of patients with psoriasis. METHODS: Biopsy specimens were taken from atopic skin and normal-appearing skin of patients with AD and from the psoriatic skin only of patients with psoriasis. Quantitative real-time PCR analysis and immunohistochemistry of CCL1 and CCL18 expression were performed, and the quantities of expressed CCL1 and CCL18 in acute AD were compared with those of normal-appearing atopic skin and psoriatic skin. The serum level of CCL1 and CCL18 was assessed by ELISA. RESULTS: Expression of CCL1 mRNA and protein was significantly higher in the acute lesional skin of patients with AD than in their nonlesional skin or in the lesional skin of patients with psoriasis. Both CCL18 mRNA and protein were abundant in acute AD lesions and in psoriatic lesions, but were lower in the nonlesional skin of patients with AD. The serum levels of CCL1 and CCL18 were not different in patients with AD and patients with psoriasis. CONCLUSIONS: CCL1 is a chemokine that is associated with AD. Both CCL1 and CCL18 may play important roles in the initiation and progression of atopic skin inflammation.

Corticotropin-releasing hormone enhances the invasiveness and migration of Ishikawa cells, possibly by increasing matrix metalloproteinase-2 and matrix metalloproteinase-9.

Corticotropin-releasing hormone (CRH), synthesized in the hypothalamus, is also produced at several extrahypothalamic sites and in normal endometrial cells. CRH exerts antiproliferative activity on oestrogen-dependent tumour cell lines (Ishikawa cells and breast cancer cells) via the CRH receptor-1. This study investigated the potential role of CRH as a factor affecting endometrial migration and invasion in Ishikawa cells, and the possible mechanisms involved in this process. Increasing concentrations of CRH (1, 10 and 100 nM) significantly reduced the proliferation of Ishikawa cells but increased the invasiveness these cells compared with the control group. All three concentrations of CRH significantly increased matrix metalloproteinase (MMP)-2 and MMP-9 levels in Ishikawa cells. In conclusion, CRH inhibited the growth of Ishikawa cells but enhanced their invasiveness, possibly by increasing MMP-2 and MMP-9 levels. These findings suggest that CRH might induce invasion and migration by upregulating MMP-2 and MMP-9 in endometrial cancer.

Feasibility of second hematopoietic stem cell transplantation using reduced-intensity conditioning with fludarabine and melphalan after a failed autologous hematopoietic stem cell transplantation.

This study was performed to determine the feasibility of second hematopoietic stem cell transplantation (HSCT) using reduced-intensity conditioning (RIC) with fludarabine and melphalan in patients with relapsed hematologic malignancies after a prior autologous HSCT. Twelve patients (multiple myeloma [n = 7], non-Hodgkin lymphoma [n = 3], and acute myeloid leukemia [n = 2] received allogeneic HSCT using RIC with fludarabine (25 mg/m(2) for 5 days) and melphalan (140 mg/m(2) for 1 day) after a failed autologous HSCT. The graft-versus-host disease (GVHD) prophylaxis consisted of cyclosporine plus a minidose of methotrexate. All patients achieved a neutrophil and platelet engraftment in a median 13.5 days and 17.5 days, respectively. The transplant-related mortality was 2 patients (16.7%). Grade II-IV acute GVHD and chronic extensive GVHD were noted in 4 (33.3%) and 1 patient (11.1%), respectively. Over a median follow-up duration of 376 days, 5 patients were alive without evidence of disease. The estimated nonrelapse mortality at 1 year was 28.4%. The estimated overall survival rate at 1 year was 58.3%, and the estimated event-free survival rate at 1 year was 41.7%. Allogeneic HSCT using RIC with fludarabine and melphalan appears to be feasible for a second HSCT in patients with relapsed hematologic malignancies after a failed autologous HSCT.

Induction of striatal neurogenesis enhances functional recovery in an adult animal model of neonatal hypoxic-ischemic brain injury.

While intraventricular administration of epidermal growth factor (EGF) expands the proliferation of neural stem/progenitor cells in the subventricular zone (SVZ), overexpression of brain-derived neurotrophic factor (BDNF) is particularly effective in enhancing striatal neurogenesis. We assessed the induction of striatal neurogenesis and consequent functional recovery after chronic infusion of BDNF and EGF in an adult animal model of neonatal hypoxic-ischemic (HI) brain injury. Permanent brain damage was induced in CD-1 (ICR) mice (P7) by applying the ligation of unilateral carotid artery and hypoxic condition. At 6 weeks of age, the mice were randomly assigned to groups receiving a continuous 2-week infusion of one of the following treatments into the ventricle: BDNF, EGF, BDNF/EGF, or phosphate buffered saline (PBS). Two weeks after treatment, immunohistochemical analysis revealed an increase in the number of BrdU(+) cells in the SVZ and striata of BDNF/EGF-treated mice. The number of new neurons co-stained with BrdU and betaIII-tubulin was also significantly increased in the neostriata of BDNF/EGF-treated mice, compared with PBS group. In addition, the newly generated cells were expressed as migrating neuroblasts labeled with PSA-NCAM or doublecortin in the SVZ and the ventricular side of neostriata. The new striatal neurons were also differentiated as mature neurons co-labeled with BrdU(+)/NeuN(+). When evaluated post-surgical 8 weeks, BDNF/EGF-treated mice exhibited significantly longer rotarod latencies at constant speed (48 rpm) and under accelerating condition (4-80 rpm), relative to PBS and untreated controls. In the forelimb-use asymmetry test, BDNF/EGF-treated mice showed significant improvement in the use of the contralateral forelimb. In contrast, this BDNF/EGF-associated functional recovery was abolished in mice receiving a co-infusion of 2% cytosine-b-d-arabinofuranoside (Ara-C), a mitotic inhibitor. Induction of striatal neurogenesis by the intraventricular administration of BDNF and EGF promoted functional recovery in an adult animal model of neonatal HI brain injury. The effect of Ara-C to completely block functional recovery indicates that the effect may be the result of newly generated neurons. Therefore, this treatment may offer a promising strategy for the restoration of motor function for adults with cerebral palsy (CP).

Immune regulatory effects of simvastatin on regulatory T cell-mediated tumour immune tolerance.

Statins are potent inhibitors of hydroxyl-3-methylglutaryl co-enzyme A (HMG-CoA) reductase, and have emerged as potential anti-cancer agents based on preclinical evidence. In particular, compelling evidence suggests that statins have a wide range of immunomodulatory properties. However, little is known about the role of statins in tumour immune tolerance. Tumour immune tolerance involves the production of immunosuppressive molecules, such as interleukin (IL)-10, transforming growth factor (TGF)-beta and indoleamine-2,3-dioxygenase (IDO) by tumours, which induce a regulatory T cell (T(reg)) response. In this study, we investigated the effect of simvastatin on the production of IL-10, TGF-beta and IDO production and the proliferation of T(regs) using several cancer cell lines, and Lewis lung cancer (3LL) cells-inoculated mouse tumour model. Simvastatin treatment resulted in a decrease in the number of cancer cells (3LL, A549 and NCI-H292). The production of the immune regulatory markers IL-10, TGF-beta in 3LL and NCI-H292 cells increased after treatment with simvastatin. The expression of IDO and forkhead box P3 (FoxP3) transcription factor was also increased in the presence of simvastatin. In a murine 3LL model, there were no significant differences in tumour growth rate between untreated and simvastatin-treated mice groups. Therefore, while simvastatin had an anti-proliferative effect, it also exhibited immune tolerance-promoting properties during tumour development. Thus, due to these opposing actions, simvastatin had no net effect on tumour growth.

Generation of functionally mature dendritic cells from elutriated monocytes using polyinosinic : polycytidylic acid and soluble CD40 ligand for clinical application.

Despite the increasing use of dendritic cell (DC) vaccination in clinical trials, optimal conditions for the generation of functionally mature DCs remain to be established. The current standard DC maturation protocol for clinical trials has been used as an inflammatory cytokine cocktail [tumour necrosis factor (TNF)-alpha, interleukin (IL)-1beta, IL-6 and prostaglandin E(2)], but this cocktail induced insufficient maturation of DCs derived from elutriated monocytes when cultured in X-VIVO 15. The aim of this study was to define effective combinations of stimulators for generating functionally mature DCs from elutriated monocytes under current good manufacturing practice conditions. We compared the functional capacity of DCs in response to all possible pairwise combinations of four different classes of stimuli: TNF-alpha, peptidoglycan, polyinosinic : polycytidylic acid [poly(I:C)] and soluble CD40 ligand (CD40L). Maturation status of DCs stimulated with combination of four stimuli was similar to that of the cytokine cocktail as assessed by the cell surface phenotype. However, only the combination of poly(I:C) + CD40L induced complete functional activation of the whole DC population, assessing IL-12p70 production, allostimulatory activity, migratory response to CCL19 and T helper 1-polarizing capacity. Thus, the protocol based on the combination of poly(I:C) and CD40L is more effective for the induction of clinical-grade DCs from elutriated monocytes than the standard cytokine cocktail.

Post-thaw viable CD34(+) cell count is a valuable predictor of haematopoietic stem cell engraftment in autologous peripheral blood stem cell transplantation.

BACKGROUND AND OBJECTIVES: In peripheral blood stem cell transplantation, the number of CD34(+) cells infused is considered a predictor of haematopoietic engraftment. However, the currently accepted minimal threshold of CD34(+) cells/kg was determined by counting CD34(+) cells before freezing, and the loss of viable CD34(+) cells during freezing, cryopreservation or thawing prior to reinfusion has not been assessed. MATERIALS AND METHODS: Total and viable CD34(+) cells were quantified using single platform flow cytometry and viability dye, 7-amino actinomycin D (7-ADD), at the time of collection and prior to reinfusion in 46 peripheral haematopoietic stem cell grafts from 36 patients. The time to engraftment of neutrophil and platelet was assessed by routine peripheral blood cell counts performed daily. RESULTS: The median number of viable CD34(+) cells harvested was 3.6 x 10(6)/kg (range 0.05-21.2), and the median viability was 98% (range 70-100%) before freezing. After thawing, the median number of viable CD34(+) cells was reduced to 2.2 x 10(6)/kg (range 0.04-14.8) and the median viability was reduced to 71% (range 31-89%). The number of viable CD34(+) cells/kg before freezing and after thawing significantly correlated with engraftment of neutrophils (P < 0.0001 both) and platelets (P = 0.007 and 0.006, respectively). Although the minimum dose for engraftment (2.0 x 10(6) CD34(+) cells/kg) was harvested in 37 of 46 cases (85%), only 25 cases (54%) met this threshold at the time of reinfusion. For platelet engraftment, determination of viable CD34(+) cells prior to reinfusion was more important than enumeration at the time of collection. CONCLUSION: Quantification of post-thaw viable CD34(+) cells better represents the actual composition of the graft and may be a more accurate predictor of haematopoietic engraftment than post-thaw total CD34(+) cell counts, or prefreeze determinations, especially for platelet engraftment. It is necessary to develop good quality controls for freezing and thawing procedures to minimize variance in cell viability.

Targeted RNA interference of phosphatidylinositol 3-kinase p110-beta induces apoptosis and proliferation arrest in endometrial carcinoma cells.

Phosphatidylinositol 3-kinase (PI3K) signalling plays a pivotal role in intracellular signal transduction pathways involved in cell growth, cellular transformation, and tumourigenesis. PI3K is overexpressed in many human cancers, including endometrial carcinomas, one of the most common female genital tract malignancies. Here, we used small interfering RNA (siRNA) targeted to PI3K p110-beta to determine whether inhibition of the beta isoform could be a potential therapeutic target for endometrial carcinoma. In this study, treatment of HEC-1B endometrial cancer cells with PI3K p110-beta-specific siRNA resulted in increased apoptosis and decreased tumour cell proliferation. Depletion of PI3K p110-beta decreased the protein levels of AKT1, AKT2, pAKT, and mTOR-downstream targets of PI3K. Knock-down of PI3K p110-beta by siRNA also induced decreased expression of cyclin E and Bcl-2, suggesting that PI3K p110-beta stimulates tumour growth, at least in part by regulating cyclin E and Bcl-2. Thus, our results indicate that siRNA-mediated gene silencing of PI3K p110-beta may be a useful therapeutic strategy for endometrial cancers overexpressing PI3K p110-beta.

Possible role of Fas/Fas ligand-mediated apoptosis in the pathogenesis of fixed drug eruption.

BACKGROUND: Although epidermal and dermal T cells play roles in the pathogenesis of fixed drug eruption (FDE), not much is known about keratinocyte death and its precise mechanism in FDE. OBJECTIVES: Our aim is to elucidate the mechanism that underlies keratinocyte death in FDE, that is, the role of apoptosis and its signalling pathway. METHODS: We first examined the involvement of apoptosis in the active FDE lesions by terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate nick end-labelling (TUNEL) assay and immunohistochemical analysis of caspase-3. We then examined the expressions of Fas and Fas ligand (FasL) to deduce the possible upstream signalling pathway of apoptosis, if apoptosis were involved. We finally characterized the infiltrated T-cell subpopulations in the active FDE lesions. RESULTS: In the active FDE lesions, TUNEL positivity was strongly observed in the basal keratinocytes, and also weakly observed in the upper dermal infiltrates as well as in a few keratinocytes in the granular layer. The distribution of TUNEL-positive cells was similar to that of the strong staining of active capase-3. Fas was found mainly in the keratinocytes and some infiltrated dermal cells, whereas FasL was identified predominantly in the intraepidermal and dermal infiltrated cells and in some basal keratinocytes. Overlapping expression of Fas and FasL was accompanied by apoptosis in the FDE lesions. Many of the infiltrated mononuclear cells were CD8+. Perforin was rarely observed in the FDE lesions. CONCLUSIONS: These findings suggest that apoptosis of the keratinocyte is highly likely to be involved in the pathogenesis of FDE, and this cytotoxicity might be predominantly mediated by the FasL of the infiltrating CD8+ T cells, possibly also playing an inflammatory role.

Naringin supplementation lowers plasma lipids and enhances erythrocyte antioxidant enzyme activities in hypercholesterolemic subjects.

BACKGROUND AND AIMS: Preliminary studies have shown that naringin has a potent lipid-lowering effect and antioxidant capacity in high-cholesterol diet fed animals. Accordingly, the present study was conducted to investigate the effect of naringin on hypercholesterolemic subjects. METHODS: A hypercholesterolemic group (n=30) and healthy control group (n=30) were established based on the plasma cholesterol levels in the subjects, then all subjects received naringin (400mg/capsule/day) with regular meals for a period of 8 weeks. RESULTS: In the hypercholesterolemic subjects, naringin supplementation was found to lower the plasma total cholesterol by 14% and low-density lipoprotein cholesterol concentrations by 17%, while the plasma triglyceride and high-density lipoprotein cholesterol concentrations remained unaffected. The apolipoprotein B levels in the hypercholesterolemic subjects were significantly lowered after naringin treatment, yet no change was observed in the apolipoprotein A-1 levels. The erythrocyte superoxide dismutase and catalase activities in the hypercholesterolemic group were significantly increased, whereas the glutathione peroxidase activity and plasma TBARS levels were not different from the baseline measurements. Meanwhile, naringin supplementation had no affect on plasma lipids, apolipoproteins, and TBARS levels or antioxidant enzyme activities in the control group. CONCLUSIONS: Therefore, these data suggest that naringin may play an important role in lowering plasma cholesterol and regulating the antioxidant capacity in hypercholesterolemic subjects.