Corneal Neuro-Regenerative Effect of Transcutaneous Electrical Stimulation in Rabbit Lamellar Keratectomy Model.

Purpose: This study aimed to evaluate the effect of transcutaneous electrical stimulation (TES) on corneal nerve regeneration in rabbits injured from superficial lamellar keratectomy (SLK). Methods: New Zealand White rabbits were used in this experimental study. To induce corneal nerve damage, SLK was performed using a 7.0-mm trephine. TES was applied for 28 days after the corneal nerve injury. Corneal sensitivity, Western blotting, real-time polymerase chain reaction (PCR), and immunofluorescence were performed to observe changes in the corneal tissue. Results: In the 2-Hz and 20-Hz electrical stimulation groups, the degree of corneal wound healing increased by more than 10% compared to the control group, but no significant difference was observed. Conversely, the electrical stimulation (2-Hz or 20-Hz) group showed significantly increased corneal sensitivity compared to the control group. Western blot analysis revealed that small proline-rich protein 1A (SPRR1a), a regeneration-associated protein was significantly increased in the 2-Hz group on days 1 and 7 compared to that in the other groups. Once again, nerve regeneration in the 2-Hz group was supported by the results of PCR, in which a significant increase in the nerve growth factor (NGF) on day 1 was observed compared with the other groups. Moreover, immunofluorescence after 28 days of electrical stimulation showed significant nerve regeneration in the 2-Hz group. Conclusions: TES promoted corneal nerve regeneration in rabbit SLK model. The application of electrical stimulation of 2-Hz frequency was more effective than the 20-Hz frequency, showing potential clinical applications for corneal diseases. Translational Relevance: This study shows how application of TES to the eyes that exhibit corneal nerve damage can improve corneal nerve regeneration examined by histologic analysis.

High waist circumference rather than high body mass index may be a predictive risk factor for the longer disease duration of chronic spontaneous urticaria.

In a previous study, we found that higher waist circumference (WC) and higher body mass index (BMI) both increase the risk of chronic spontaneous urticaria (CSU). The aim of this study was to determine whether WC and BMI also increase the duration of CSU. We used multivariable Cox proportional hazards models to determine the hazard ratio (HR) for longer disease duration (longer than 3 years) according to WC and BMI. A total of 52,667 subjects were enrolled and their mean age was 54.5. After adjustments for other confounding variables the high WC/high BMI group had 1.062 times higher HR (95% CI, 1.028-1.098) than the normal WC/normal BMI group. Interestingly, the high WC/normal BMI group showed a significantly higher HR (1.053; 95% CI, 1.008-1.101) than the normal WC/normal BMI group, but not the normal WC/high BMI group (0.998; 95% CI, 0.951-1.046). Taken together, our results suggest that high WC rather than high BMI is a predictive risk factor for the longer disease duration of CSU.

The KAAACI/KDA Evidence-Based Practice Guidelines for Chronic Spontaneous Urticaria in Korean Adults and Children: Part 2. Management of H1-Antihistamine-Refractory Chronic Urticaria.

Quite a few patients with chronic spontaneous urticaria (CSU) are refractory to H1-antihistamines, even though the dose of H1-antihistamines is increased up to 4-fold. CSU that is not controlled with H1-antihistamines results in increased disease burden. Several immunomodulators have been used to manage these patients. The guidelines reported herein are connected to Part 1 of the KAAACI/KDA Evidence-Based Practice Guidelines for Chronic Spontaneous Urticaria in Korean Adults and Children, and aimed to provide evidence-based recommendations for the management of H1-antihistamine-refractory CSU. Part 2 focuses on the more commonly used additional treatment options for refractory CSU, including omalizumab, cyclosporine, leukotriene receptor antagonist, dapsone, methotrexate, and phototherapy. The evidence to support their efficacy, dosing, safety, and selection of these agents is systematically reviewed. To date, for patients with refractory CSU, the methodologically sound data to evaluate the use of omalizumab has been growing; however, the evidence of other immunomodulators and phototherapy is still insufficient. Therefore, an individualized stepwise approach with a goal of achieving complete symptom control and minimizing side effects can be recommended. Larger controlled studies are needed to elevate the level of evidence to select a rational therapeutic agent for patients with refractory CSU.

Phototherapy May be a Useful Adjuvant Therapy for Retractable Chronic Spontaneous Urticaria: A Systematic Review.

The recent guideline on the management of urticaria recommends second-generation H1 antihistamine as the first-line therapy, with dose increases of up to fourfold and the addition of omalizumab or cyclosporine if inadequately controlled. However, the treatment of chronic spontaneous urticaria (CSU) is often disappointing. Therefore, a safe and effective treatment option is needed for refractory CSU. To evaluate whether phototherapy can relieve urticarial symptoms and serve as an additional treatment for CSU uncontrolled with antihistamine, we performed a qualitative systematic review. Our result suggests that NBUVB could be an effective complementary treatment modality to manage refractory CSU.

Preserved Serotonergic Activity in Early-Onset Parkinson's Disease.

BACKGROUND: Serotonergic dysfunction may play an important role in motor and nonmotor symptoms of Parkinson's disease (PD). The loudness dependence of auditory evoked potentials (LDAEP) has been used to evaluate serotonergic activity. Therefore, this study aimed to determine central serotonergic activity using LDAEP in de novo PD according to the age at onset and changes in serotonergic activity after dopaminergic treatment. METHODS: A total of 30 patients with unmedicated PD, 16 in the early-onset and 14 in the late-onset groups, were enrolled. All subjects underwent comprehensive neurological examination, laboratory tests, the Unified Parkinson's Disease Rating Scale, and LDAEP. The LDAEP was calculated as the slope of the two N1/P2 peaks measured at the Cz electrode, first at baseline conditions (pretreatment) and a second time after 12 weeks (post-treatment) following dopaminergic medications. RESULTS: The absolute values of pretreatment N1/P2 LDAEP (early-onset: late-onset, 0.99 ± 0.68: 1.62 ± 0.88, p = 0.035) and post-treatment N1 LDAEP (early-onset: late-onset, -0.61 ± 0.61: -1.26 ± 0.91, p = 0.03) were significantly lower in the early-onset group compared with those of the late-onset group. In addition, a higher value of pretreatment N1/P2 LDAEP was significantly correlated with the late-onset group (coefficient = 1.204, p = 0.044). The absolute value of the N1 LDAEP decreased after 12 weeks of taking dopaminergic medication (pretreatment: post-treatment, -1.457 ± 1.078: -0.904 ± 0.812, p = 0.0018). CONCLUSIONS: Based on the results of this study, LDAEP could be a marker for serotonergic neurotransmission in PD. Central serotonergic activity assessed by LDAEP may be more preserved in early-onset PD patients and can be altered with dopaminergic medication.

Antimelanogenic and Antimigration Properties of the Ethyl Acetate Fraction of Calendula officinalis Flowers on Melanoma Cells.

Calendula officinalis L., commonly known as marigold, is not only cultivated for ornamental purposes but is also used as a traditional medicinal herb. Its flowers have been used to treat various skin diseases, including rashes, burns, cuts and bruises, since ancient times. However, to our knowledge, the impact of C. officinalis L. on melanoma and its mechanism have not been clarified. The aim of this work was to investigate the chemical characterization and antimelanogenic and antimigration activities of the ethyl acetate fraction of C. officinalis flowers (EFC), as well as elucidate the potential mechanism. The obtained results showed that EFC markedly decreased α-MSH-induced melanin production and the cell migration ability of melanoma cells in a dose-dependent manner. Additionally, EFC significantly inhibited the activity and expression of matrix metalloproteinase 2 (MMP-2) via suppressing the mitogen-activated protein kinase (MAPK) signaling pathway. Taken together, the present study demonstrated that C. officinalis flowers can be used as a natural source of antimelanogenisis and antimigration regent to treatment or prevent skin diseases.

Anti-cancer effects of disulfiram in head and neck squamous cell carcinoma via autophagic cell death.

BACKGROUND: Disulfiram (DSF), which is used to treat alcohol dependence, has been reported to have anti-cancer effects in various malignant tumors. In this study, we investigated the anti-cancer effects and mechanism of DSF in HNSCC. METHODS: Head and neck squamous carcinoma cell lines (FaDu and Hep2) were used to analyze the anti-cancer effects of DSF. The anti-cancer effects of DSF were confirmed in vivo using a xenograft tumor model. RESULTS: The anti-cancer effects of DSF in HNSCC were found to be copper (Cu) dependent. Specifically, DSF/Cu markedly inhibited HNSCC at a concentration of 1 µM. After DSF/Cu administration, production of reactive oxygen species (ROS) was remarkable starting at 0.5 µM, suggesting that the inhibitory effects of DSF/Cu on HNSCC are mediated through the formation of ROS. The levels of phospho-JNK, phospho-cJun and phospho-p38 were increased after DSF/Cu treatment while levels of phospho-Akt were decreased. These results suggested that the inhibitory effects of DSF/Cu on HNSCC cells involve ROS formation and down-regulation of Akt-signaling. Through these molecular mechanisms, DSF ultimately induce the inhibitory effects on HNSCC cell lines mainly through autophagic cell death, not apoptotic cell death. Lastly, we investigated the clinical relevance of DSF/Cu using a HNSCC xenograft animal model, which showed that tumor growth was remarkably decreased by DSF (50 mg/kg injection). CONCLUSION: In treating patients with HNSCC, DSF may contribute to improved HNSCC patient's survival. The characteristic anti-cancer effects of DSF on HNSCC may suggest new therapeutic potential for this medication in HNSCC patients.

Influence of Sodium Hyaluronate Concentration on Corneal Aberrations in Soft Contact Lens Wearers.

PURPOSE: This study aimed to evaluate the influence of varying concentrations of sodium hyaluronate (SH) eye drops on corneal aberrations in normal individuals wearing silicone hydrogel contact lenses. METHODS: Normal individuals wearing silicone hydrogel contact lenses were enrolled in this study. Subjects were classified into two groups depending on the concentration of the preservative-free SH used (group 1, 0.1% SH; group 2, 0.3% SH). All subjects were asked to blink five times after instillation of the SH eye drop and before the Galilei measurements. Corneal aberrations were measured over the contact lenses before and after SH eye drop instillation. Visual acuity (VA) over the contact lenses was also measured both before instillation of the SH eye drop and after the subjects completed the five blinks. RESULTS: There was no change in VA after SH instillation in group 1; however, group 2's VA significantly deteriorated after SH instillation. Changes in VA after SH instillation compared to baseline were significantly higher in group 2 than in group 1. Similarly, the increase in corneal aberrations after SH instillation was significant in group 2 but not significant in group 1. Among the significantly increased corneal aberration parameters, defocus was the main type in group 2. Changes in corneal aberrations after SH instillation compared to baseline were significantly higher in group 2 than in group 1. CONCLUSIONS: A 0.3%-concentration of SH increases corneal aberration and decreases VA in soft contact lens wearers. Defocus is the main type of aberration that increased in the 0.3% SH instillation group.

Suppression of Ultraviolet B-mediated Matrix Metalloproteinase Generation by Sorbus commixta Twig Extract in Human Dermal Fibroblasts.

Sorbus commixta is a traditional oriental medicinal plant that grows in East Asian countries such as Korea, Japan and China. The twig of S. commixta has been considered valuable for centuries to treat diseases including asthma, cough and other bronchial disorders. However, the effect of S. commixta twig extract on human skin has not been investigated well. The present study aimed at assessing the antiphotoaging effect of S. commixta twig ethanol extract (STE) on ultraviolet B (UVB)-induced matrix metalloproteinase (MMP) levels and its underlying mechanism in human dermal fibroblasts. In this study, we found that STE (12.5-50 µg mL-1 ) treatment significantly inhibited UVB-induced MMP-1, MMP-2 and MMP-3 expression, concomitant with a downregulation of intracellular ROS generation. These effects might be associated with a STE-induced inhibition of the mitogen-activated protein kinase (MAPK) pathway. Furthermore, STE also downregulated UVB-induced c-Fos expression in a concentration-dependent manner, but had no inhibitory effect on c-Jun phosphorylation. Taken together, these results indicate that STE may be an antiphotoaging agent and that its effect may occur via its inhibition of MMPs expression and MAPK pathway activation.

Antioxidative and Antiaging Activities and Component Analysis of Lespedeza cuneata G. Don Extracts Fermented with Lactobacillus pentosus.

Lespedeza cuneata G. Don is a traditional herb that has been associated with multiple biological activities. In this study, we investigated the antioxidative/antiaging activities and performed an active component analysis of the non-fermented and fermented (using Lactobacillus pentosus) extracts of Lespedeza cuneata G. Don. The antioxidative activities of the fermented extract were higher than those of non-fermented extracts. The elastase inhibitory activity, inhibitory effects on UV-induced MMP-1 expression, and ability to promote type I procollagen synthesis were investigated in Hs68 human fibroblasts cells. These tests also revealed that the fermented extract had increased antiaging activities compared with the non-fermented extract. A component analysis of the ethyl acetate fractions of non-fermented and fermented extracts was performed using TLC, HPLC, and LC/ESI-MS/MS to observe changes in the components before and after fermentation. Six components that were different before and after fermentation were investigated. It was thought that kaempferol and quercetin were converted from kaempferol glucosides and quercetin glucosides, respectively, via bioconversion with the fermentation strain. These results indicate that the fermented extract of L. cuneata G. Don has potential for use as a natural cosmetic material with antioxidative and antiaging effects.

Soy Improves Cardiometabolic Health and Cecal Microbiota in Female Low-Fit Rats.

Phytoestrogen-rich soy is known to ameliorate menopause-associated obesity and metabolic dysfunction for reasons that are unclear. The gut microbiota have been linked with the development of obesity and metabolic dysfunction. We aimed to determine the impact of soy on cardiometabolic health, adipose tissue inflammation, and the cecal microbiota in ovariectomized (OVX) rats bred for low-running capacity (LCR), a model that has been previously shown to mimic human menopause compared to sham-operated (SHM) intact control LCR rats. In this study, soy consumption, without affecting energy intake or physical activity, significantly improved insulin sensitivity and body composition of OVX rats bred for low-running capacity. Furthermore, soy significantly improved blood lipid profile, adipose tissue inflammation, and aortic stiffness of LCR rats. Compared to a soy-free control diet, soy significantly shifted the cecal microbial community of LCR rats, resulting in a lower Firmicutes:Bacteroidetes ratio. Correlations among metabolic parameters and cecal bacterial taxa identified in this study suggest that taxa Prevotella, Dorea, and Phascolarctobacterium may be taxa of interest. Our results suggest that dietary soy ameliorates adiposity, insulin sensitivity, adipose tissue inflammation, and arterial stiffness and exerts a beneficial shift in gut microbial communities in a rat model that mimics human menopause.

Electrical stimulation of auricular acupressure for dry eye: A randomized controlled-clinical trial.

OBJECTIVE: To evaluate the clinical efficacy of electrical stimulation (ES) of auricular acupressure on reducing the ocular symptoms and signs before and after treatment for dry eye. METHODS: The inclusion criteria were the tear film break-up time (TFBUT) below 5 s and a Schirmer test-I below 5 mm in dry eyes with ocular symptoms for at least 6 months. Subjects were randomized into a treatment group (50 cases) with continuous low frequency ES under auricular acupressure at acupoints and a no ES under auricular acupressure (no-ES, control group, 50 cases) on the same acupoints. Auricular acupressure were stimulated with ES at 4 master points of both ears, which were performed twice a week for 4 weeks at each point for 30 s. The ocular symptoms, the TFBUT, and Schirmer test-I were evaluated before and after this procedure. RESULTS: There were significantly better scores in TFBUT (P=0.032), the Schirmer test-I (P=0.044) and ocular symptoms (P=0.029) at 3 months post-treatment in the treatment group than in the control group. The total effective rate in the treatment group was accomplished in 41 (82%) of the 50 cases of dry eye. CONCLUSIONS: Auricular acupressure with ES at auricular acupoint improves ocular symptoms and signs of dry eye for a period of at least 3 months.

Hair growth-promotion effects of different alternating current parameter settings are mediated by the activation of Wnt/ß-catenin and MAPK pathway.

Electrical stimulation is being used in variable skin therapeutic conditions. There have been clinical studies demonstrating the positive effect of electrical stimuli on hair regrowth. However, the underlying exact mechanism and optimal parameter settings are not clarified yet. To investigate the effects of different parameter settings of electrical stimuli on hair growth by examining changes in human dermal papilla cells (hDPCs) in vitro and by observing molecular changes in animal tissue. In vitro, cultured hDPCs were electrically stimulated with different parameter settings at alternating current (AC). Cell proliferation was measured by MTT assay. The Ki67 expression was measured by immunofluorescence. Hair growth-related gene expressions were measured by RT-PCR. In animal model, different parameter settings of AC were applied to the shaved dorsal skin of rabbit for 8 weeks. Expression of hair-related genes in the skin of rabbit was examined by RT-PCR. At low voltage power (3.5 V) and low frequency (1 or 2 MHz) with AC, in vitro proliferation of hDPCs was successfully induced. A significant increase in Wnt/ß-catenin, Ki67, p-ERK and p-AKT expressions was observed under the aforementioned settings. In animal model, hair regrowth was observed in the entire stimulated areas under individual conditions. Expression of hair-related genes in the skin significantly increased on the 6th week of treatment. There are optimal conditions for electrical stimulated hair growth, and they might be different in the cells, animals and human tissues. Electrical stimuli induce mechanisms such as the activation of Wnt/ß-catenin and MAPK pathway in hair follicles.

Disease awareness and management behavior of patients with atopic dermatitis: a questionnaire survey of 313 patients.

BACKGROUND: Patients with atopic dermatitis (AD) should be relatively well informed about the disorder to control their condition and prevent flare-ups. Thus far, there is no accurate information about the disease awareness levels and therapeutic behavior of AD patients. OBJECTIVE: To collect data on patients' knowledge about AD and their behavior in relation to seeking information about the disease and its treatment. METHODS: We performed a questionnaire survey on the disease awareness and self-management behavior of AD patients. A total of 313 patients and parents of patients with AD who had visited the The Catholic University of Korea, Catholic Medical Center between November 2011 and October 2012 were recruited. We compared the percentage of correct answers from all collected questionnaires according to the demographic and disease characteristics of the patients. RESULTS: Although dermatologists were the most frequent disease information sources and treatment providers for the AD patients, a significant proportion of participants obtained information from the Internet, which carries a huge amount of false medical information. A considerable number of participants perceived false online information as genuine, especially concerning complementary and alternative medicine treatments of AD, and the adverse effects of steroids. Some questions on AD knowledge had significantly different answers according to sex, marriage status, educational level, type of residence and living area, disease duration, disease severity, and treatment history with dermatologists. CONCLUSION: Dermatologists should pay more attention to correcting the common misunderstandings about AD to reduce unnecessary social/economic losses and improve treatment compliance.

Mycophenolate antagonizes IFN-γ-induced catagen-like changes via ß-catenin activation in human dermal papilla cells and hair follicles.

Recently, various immunosuppressant drugs have been shown to induce hair growth in normal hair as well as in alopecia areata and androgenic alopecia; however, the responsible mechanism has not yet been fully elucidated. In this study, we investigate the influence of mycophenolate (MPA), an immunosuppressant, on the proliferation of human dermal papilla cells (hDPCs) and on the growth of human hair follicles following catagen induction with interferon (IFN)-γ. IFN-γ was found to reduce ß-catenin, an activator of hair follicle growth, and activate glycogen synthase kinase (GSK)-3ß, and enhance expression of the Wnt inhibitor DKK-1 and catagen inducer transforming growth factor (TGF)-ß2. IFN-γ inhibited expression of ALP and other dermal papillar cells (DPCs) markers such as Axin2, IGF-1, and FGF 7 and 10. MPA increased ß-catenin in IFN-γ-treated hDPCs leading to its nuclear accumulation via inhibition of GSK3ß and reduction of DKK-1. Furthermore, MPA significantly increased expression of ALP and other DPC marker genes but inhibited expression of TGF-ß2. Therefore, we demonstrate for the first time that IFN-γ induces catagen-like changes in hDPCs and in hair follicles via inhibition of Wnt/ß-catenin signaling, and that MPA stabilizes ß-catenin by inhibiting GSK3ß leading to increased ß-catenin target gene and DP signature gene expression, which may, in part, counteract IFN-γ-induced catagen in hDPCs.

Efficacy and safety of human placental extract for alcoholic and nonalcoholic steatohepatitis: an open-label, randomized, comparative study.

Human placental extract (HPE) is a traditional medicine that has been used for the symptomatic treatment of liver disease without any verifying clinical evidence. This study aimed to evaluate the efficacy and safety of HPE in patients with alcoholic or nonalcoholic steatohepatitis (ASH or NASH). We designed this clinical trial as a multicenter, open-label, randomized, comparative noninferiority study to improve the reliability of analyses. The enrollment criteria were limited to ASH or NASH patients with serum alanine aminotransferase (ALT) 1.5-fold higher than the normal level. Patients in the control group were treated with a commercially available mixture of liver extract and flavin adenine dinucleotide (LE­FAD). Intention-to-treat (ITT) analysis was applied to 194 patients, and per-protocol (PP) analysis was available for 154 patients. The rate of primary goal achievement of treatment efficacy was arbitrarily defined as 20% or greater improvement in ALT level compared with the pretreatment level and did not differ significantly between the HPE and control groups [62.9% (44/70) vs. 48.8% (41/84); p=0.0772]. ITT and modified ITT analysis showed results similar to those of PP analysis. Adverse drug reactions (ADRs) of minimal to moderate degree occurred in 3.1% of patients. The ADR and treatment compliance rates were similar in both groups. In conclusion, the clinical value of HPE in the treatment of ASH and NASH is equivalent to that of LE­FAD.

Relationship between SSRI-induced sexual dysfunction and central serotonergic activity based on the loudness dependence of auditory evoked potentials.

RATIONALE: It has been hypothesized that selective serotonin reuptake inhibitor (SSRI)-induced sexual dysfunction can occur more frequently in patients with higher central serotonergic activity, and that this higher serotonergic activity can induce inhibition of sexual desire, ejaculation, and orgasm. Thus, the aim of this study was to determine the relationship between SSRI-induced sexual dysfunction and increased serotonin. METHOD: Event-related potentials for the loudness dependence of auditory evoked potentials (LDAEP) were measured in 46 patients at a single time point. The subjects' scores on the Hamilton Depression Rating Scale and Antidepressant Side-Effect Checklist were also determined by the investigators at the same time point. All patients had received SSRI monotherapy. RESULTS: Overall, 37 % (17/46) of the patients experienced some form of SSRI-induced sexual dysfunction: lack of sexual desire, impotence, orgasm, and menstrual abnormality or mastalgia were experienced by 21.7, 8.3, 15.2, and 20.6 % of the patients, respectively. The subjects were thus divided into two groups-those with and without sexual dysfunction-and their data were compared. There was a tendency for the LDAEP to be lower in the group with sexual dysfunction (1.04 ± 0.77 µV) than the group without sexual dysfunction (1.45 ± 0.86 µV), although the difference was not statistically significant (p = 0.086). Furthermore, the distribution of the frequency of SSRI-induced sexual dysfunction differed marginally significantly between patients with low and high LDAEP, dichotomized according to the median LDAEP on the Cz electrode (χ (2) = 3.664, p = 0.056). CONCLUSIONS: There was a relatively high frequency of SSRI-induced sexual dysfunction in patients with low LDAEP.

Secondary mania in a patient with delayed anoxic encephalopathy after carbon monoxide intoxication caused by a suicide attempt.

We report herein a female patient presenting with delayed anoxic encephalopathy after carbon monoxide (CO) intoxication. Five months after she attempted suicide in her car using burning charcoal, she showed manic symptoms including aggressive behaviors, irritability, decreased total sleep time, increased energy and sexual interest, and hyperactivity, as well as illusions and visual hallucinations related to bugs, certain animals, monsters and her ex-husband. Fluid-attenuated inversion recovery and T2-weighted images in brain magnetic resonance imaging showed white-matter hyperintensity in the frontal lobe and periventricular area. Her manic symptoms and psychotic features improved following daily administration of valproate (600 mg) and olanzapine (10 mg). These observations indicate that clinicians should monitor for delayed neuropsychiatric symptoms in patients with CO intoxication.

Perverted head-shaking and positional downbeat nystagmus in pregabalin intoxication.

Dizziness and ataxia are known adverse effects of pregabalin, but characteristic oculomotor signs in pregabalin intoxication have not been reported. Here we describe a patient who displayed perverted head-shaking and positional downbeat nystagmus after prescription of a high dosage of pregabalin. Since pregabalin reduces excitatory neurotransmitter secretion in the central nervous system, decreased excitatory inputs from the brainstem may lead to cerebellar dysfunction, causing perverted head-shaking and positional downbeat nystagmus.