A Refractory Livedoid Vasculopathy Accompanied by Methylene Tetrahydrofolate Reductase Gene Polymorphism Successfully Treated with Hyperbaric Oxygen Therapy.

Livedoid vasculopathy (LV) is a chronic coagulation disorder characterized by recurrent, painful ulcers on the lower extremities. Methylene tetrahydrofolate reductase (MTHFR) gene polymorphism is associated with coagulopathy. Therapeutic options usually include anti-inflammatory or immunosuppressive agents. However, the condition is still highly challenging to manage and no consensus over the first-line treatment for LV exists. Furthermore, when LV is accompanied with MTHFR gene polymorphism, clinical presentations could be more severe and resistant to treatment. We report a case of refractory LV accompanied by MTHFR gene polymorphism, which was successfully treated with hyperbaric oxygen therapy (HBOT). A 63-year-old female patient presented with multiple painful ulcers, atrophie blanches, and retiform purpura on both lower legs and feet. Histopathologic findings were compatible with LV. LV was diagnosed based on these clinicopathological findings. Following the diagnosis, we treated the patient with pentoxifylline, aspirin, systemic corticosteroid, antihistamine, and antibiotics. In spite of six-month treatment, the skin lesions did not improve; hence, HBOT was performed. It was performed at 2.0 absolute atmosphere for 120 minutes each time, three times a week. After 4 sessions, the ulcers began to heal and after 13 sessions, the skin lesions almost healed. During the eight-month follow-up period, the skin ulcers did not recur and the symptoms remained stable. Additionally, it was confirmed that she had MTHFR gene polymorphism after a genetic test. In conclusion, we wish to provide evidence regarding the effectiveness of HBOT and suggest that HBOT might be a considerable treatment option in refractory LV.

Krill Oil's Protective Benefits against Ultraviolet B-Induced Skin Photoaging in Hairless Mice and In Vitro Experiments.

Krill oil (KO) shows promise as a natural marine-derived ingredient for improving skin health. This study investigated its antioxidant, anti-inflammatory, anti-wrinkle, and moisturizing effects on skin cells and UVB-induced skin photoaging in hairless mice. In vitro assays on HDF, HaCaT, and B16/F10 cells, as well as in vivo experiments on 60 hairless mice were conducted. A cell viability assay, diphenyl-1-picryhydrazyl (DPPH) radical scavenging activity test, elastase inhibition assay, procollagen content test, MMP-1 inhibition test, and hyaluronan production assay were used to experiment on in vitro cell models. Mice received oral KO administration (100, 200, or 400 mg/kg) once a day for 15 weeks and UVB radiation three times a week. L-Ascorbic acid (L-AA) was orally administered at 100 mg/kg once daily for 15 weeks, starting from the initial ultraviolet B (UVB) exposures. L-AA administration followed each UVB session (0.18 J/cm2) after one hour. In vitro, KO significantly countered UVB-induced oxidative stress, reduced wrinkles, and prevented skin water loss by enhancing collagen and hyaluronic synthesis. In vivo, all KO dosages showed dose-dependent inhibition of oxidative stress-induced inflammatory photoaging-related skin changes. Skin mRNA expressions for hyaluronan synthesis and collagen synthesis genes also increased dose-dependently after KO treatment. Histopathological analysis confirmed that krill oil (KO) ameliorated the damage caused by UVB-irradiated skin tissues. The results imply that KO could potentially act as a positive measure in diminishing UVB-triggered skin photoaging and address various skin issues like wrinkles and moisturization when taken as a dietary supplement.

Kinesiology taping and ankle foot orthosis equivalent therapeutic effects on gait function in stroke patients with foot drop: A preliminary study.

An ankle foot orthosis (AFO) is a standard type of orthosis applied to immediately treat foot drop symptoms. Kinesiology taping (KT) is a therapeutic method used in patients with neurological diseases, such as stroke, as well as in patients after orthopedic and sports injuries. This study aimed to compare outcomes of AFO treatment with those of KT to investigate the effect on gait ability in patients with foot drop after stroke. We recruited 18 patients exhibiting foot drop from stroke. Gait ability was assessed under 2 conditions: treatment with KT and that with AFO using the GAITRite system according to the following parameters: cadence, velocity, swing time, stance time, step length, and stride length. As a result, gait ability after treatment with KT and that after treatment with AFO showed no significant differences in cadence (P = .851), velocity (P = .865), swing time (P = .289 and .123), stance time (P = .255 and .711), step length (P = .955 and .975), and stride length (P = .711 and .690) of the affected and less-affected limbs. This study demonstrated that KT and AFO use have similar effects on gait function in patients with foot drop after stroke. Thus, treatment of foot drop with KT may be an alternative in patients for whom AFO use is contraindicated.

Combination of the LARS1 Inhibitor, BC-LI-0186 with a MEK1/2 Inhibitor Enhances the Anti-Tumor Effect in Non-Small Cell Lung Cancer.

PURPOSE: The mammalian target of rapamycin complex 1 (mTORC1) regulates cell growth and proliferation by growth factor coordination and amino acid availability. Leucyl-tRNA synthetase 1 (LARS1) senses the intracellular leucine concentration and mediates amino acid-induced activation of mTORC1. Thus, LARS1 inhibition could be useful in cancer treatment. However, the fact that mTORC1 can be stimulated by various growth factors and amino acids suggests that LARS1 inhibition alone has limitations in inhibiting cell growth and proliferation. We investigated the combined effects of BC-LI-0186, a LARS1 inhibitor, and trametinib, an MEK inhibitor, on non-small cell lung cancer (NSCLC). Materials and Methods: Protein expression and phosphorylation were observed by immunoblotting, and genes differentially expressed between BC-LI-0186-sensitive and -resistant cells were identified by RNA sequencing. The combined effect of the two drugs was inferred from the combination index values and a xenograft model. RESULTS: LARS1 expression was positively correlated with mTORC1 in NSCLC cell lines. BC-LI-0186 treatment of A549 and H460 cells maintained in media supplemented with fetal bovine serum revealed paradoxical phosphorylation of S6 and activation of mitogen- activated protein kinase (MAPK) signaling. Compared with BC-LI-0186-sensitive cells, -resistant cells showed enrichment of the MAPK gene set. The combination of trametinib and BC-LI-0186 inhibited the phosphorylation of S6, MEK, and extracellular signal-regulated kinase and their synergistic effects were confirmed in a mouse xenograft model. CONCLUSION: The combination of BC-LI-0186 and trametinib inhibited the non-canonical mTORC1-activating function of LARS1. Our study demonstrated a new therapeutic approach for NSCLC without targetable driver mutations.

The Effect of Apple-Derived Nanovesicles on the Osteoblastogenesis of Osteoblastic MC3T3-E1 Cells.

Osteoporosis is characterized by low bone mass and elevated structural deterioration of the bone tissue, resulting in bone weakness with an increased risk of fracture. Considering biological activities of various phytochemicals extracted from apples, we herein demonstrated the potential antiosteoporotic effects of apple-derived nanovesicles (apple NVs) using osteoblastic MC3T3-E1 cells. Apple NVs significantly stimulated the growth of MC3T3-E1 cells. The cellular alkaline phosphatase (ALP) activity was significantly upregulated in the 5 µg/mL apple NVs-treated group. In addition, the concentrarion of mineralized nodules was significantly increased in the apple NVs-treated groups. Furthermore, apple NVs increased the expression of the genes and proteins associated with osteoblast growth and differentiation, such as Runx2, ALP, OPN, and BMP2/4, which further activated ERK- and JNK-related mitogen-activated protein kinase signaling. These results demonstrate that apple NVs have a potential to prevent osteoporosis by promoting osteoblastogenesis in osteoblastic MC3T3-E1 cells through regulating the BMP2/Smad1 pathways.

New Targeted Therapy for Non-Small Cell Lung Cancer.

Lung cancer ranks first in cancer mortality in Korea and cancer incidence in Korean men. More than half of Korean lung cancer patients undergo chemotherapy, including adjuvant therapy. Cytotoxic agents, targeted therapy, and immune checkpoint inhibitors are used in chemotherapy according to the biopsy and genetic test results. Among chemotherapy, the one that has developed rapidly is targeted therapy. The National Comprehensive Cancer Network (NCCN) guidelines have been updated recently for targeted therapy of multiple gene mutations, and targeted therapy is used not only for chemotherapy but also for adjuvant therapy. While previously targeted therapies have been developed for common genetic mutations, recently targeted therapies have been developed to overcome uncommon mutations or drug resistance that have occurred since previous targeted therapy. Therefore, this study describes recent, rapidly developing targeted therapies.

Canavalia gladiata Pod Extract Mitigates Ovalbumin-Induced Asthma Onset in Male BALB/c Mice via Suppression of MAPK.

Asthma is one of the most common inflammatory diseases of the lung worldwide. There has been considerable progress in recent studies to treat and prevent allergic asthma, however, various side effects are still observed in clinical practice. Six-week-old male BALB/c mice were orally administered with either sword bean pod extracts (SBP; 100 or 300 mg/kg) or dexamethasone (DEX; 5 mg/kg) once daily over 3 weeks, followed by ovalbumin sensitization (OVA/Alum.; intraperitoneal administration, 50 µg/2 mg/per mouse). Scoring of lung inflammation was performed to observe pathological changes in response to SBP treatment compared to OVA/Alum.-induced lung injury. Additionally, inflammatory cytokines were quantified in serum, bronchoalveolar lavage fluid (BALF), and lung tissue using ELISA and Western blot analyses. SBP treatment significantly reduced the infiltration of inflammatory cells, and release of histamine, immunoglobulin E, and leukotriene in serum and BALF. Moreover, the therapeutic effect of SBP was also assessed to analyze the inflammatory changes in the lung tissues. SBP markedly suppressed the activation of the MAPK signaling pathway and the expression of key inflammatory proteins (e.g., TNF-α) and Th2 type cytokines (IL-5 and IL-13). SBP was effective in ameliorating the allergic inflammation against OVA/Alum.-induced asthma by suppressing pulmonary inflammation.

Screening of Plant-Derived Natural Extracts to Identify a Candidate Extract Capable of Enhancing Lipid Synthesis in Keratinocytes.

BACKGROUND: Reduced lipid content in the stratum corneum is a major cause of skin-barrier dysfunction in various pathological conditions. Promoting lipid production is a potential strategy to improve skin-barrier function. Recent evidence supports the beneficial effects of adiponectin on lipid metabolism and senescence in keratinocytes. OBJECTIVE: This study aimed to investigate whether plant extracts can enhance skin-barrier function. METHODS: We screened fruit and herb extracts that enhance the lipid synthesis of keratinocytes via AMP-activated protein kinase (AMPK) activation and SIRT1 signaling in the adiponectin pathway. The levels of major lipid synthesis enzymes and transcription factors as well as epidermal barrier lipids involved in adiponectin-associated epidermal barrier formation were evaluated in the herbal extracts- or adiponectin-treated human epidermal keratinocyte and equivalent models. The mRNA expression of major lipid synthesis enzymes increased following treatment with Lycii Fructus , Prunus tomentosa , and Melia toosendan extracts. RESULTS: The expression of transcription factors SIRT1, liver X receptor α, peroxisome proliferator-activated receptors (PPARs), and sterol regulatory element-binding proteins (SREBPs) were upregulated. Levels of free fatty acids, cholesterol, and ceramides were elevated. The expression of keratinocyte differentiation markers increased. In particular, among fruit extracts with a detectable effect, Melia toosendan induced the highest expression of lipid synthase. CONCLUSION: These results indicate that Melia toosendan is a promising candidate for improving skin-barrier function.

Sword Bean (Canavalia gladiata) Pod Exerts Anti-Allergic and Anti-Inflammatory Effects through Modulation of Th1/Th2 Cell Differentiation.

Allergy is an immunoglobulin E (IgE)-mediated process, and its incidence and prevalence have increased worldwide in recent years. Therapeutic agents for allergic diseases are continuously being developed, but side effects follow when used for a long-term use. Therefore, treatments based on natural products that are safe for the body are urgently required. Sword bean (Canavalia gladiata) pod (SBP) has been traditionally used to treat inflammatory diseases, but there is still no scientific basis for its anti-allergic effect. Accordingly, this study investigates the anti-allergic effect and its mechanism of SBP in vitro and in vivo. SBP reduced the nitric oxide production and decreased mRNA and protein expression of inflammatory mediates (inducible nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2)), and inhibited the phosphorylation of nuclear factor kappa B (NF-κB), a major signaling molecule in the inflammatory response. Additionally, SBP extract treatment inhibited phosphatidylinositol-3-kinase/mammalian target of rapamycin (PI3K/mTOR) signaling activity to further inhibit degranulation and allergy mediator generation and control the balance of Th1/Th2 cells, which can induce an allergic reaction when disrupted. Furthermore, the SBP extract exhibited anti-allergic effects in anti-dinitrophenyl IgE-induced RBL-2H3 cells and ovalbumin-treated mice. These findings have potential clinical implications for the treatment as well as prevention of allergic diseases.

High Dose Intramuscular Vitamin D3 Supplementation Impacts the Gut Microbiota of Patients With Clostridioides Difficile Infection.

Background and Aim: Current therapeutic strategies for Clostridioides difficile infections (CDI), including oral vancomycin, metronidazole and fecal microbial transplantation, have limited efficacy and treatment failure may occur in as many as one- third of cases. Recent studies have reported that lower concentrations of 25-hydroxyvitamin D are associated with CDI severity and recurrence. However, there have been no studies on microbiota composition after the administration of vitamin D in patients with CDI. Therefore, our study aimed to compare the microbiota composition between the two groups, including eight CDI-positive patients with vitamin D supplementation and ten CDI-positive patients without vitamin D supplementation by using 16S rRNA microbial profiling. Methods: Twenty subjects were enrolled in this prospective randomized controlled study. One subject dropped out due to lack of contact with the guardian after discharge and one subject dropped out due to withdrawal of consent. Thus, 18 patients with CDI and vitamin D insufficiency (vitamin D level < 17 ng/mL) were divided into two groups: CDI with vitamin D supplementation (n = 8) and CDI without vitamin D supplementation (control: n = 10). Subjects with vitamin D insufficiency were randomized to receive 200,000 IU intramuscular cholecalciferol whereas patients in the control group received only oral vancomycin. Stool samples were obtained twice before vancomycin was administered and eight weeks after treatment; the V3-V4 16S rRNA metagenomic sequencing was performed using EzBioCloud. Results: The alpha diversity of the gut microbiota in the recovery state was significantly higher than that in the CDI state. Analysis of bacterial relative abundance showed significantly lower Proteobacteria and higher Lachnospiraceae, Ruminococcaceae, Akkermansiaceae, and Bifidobacteriaceae in the recovery state. When comparing the control and vitamin D treatment groups after eight weeks, increase in alpha diversity and, abundance of Lachnospiraceae, and Ruminococcaceae exhibited the same trend in both groups. A significant increase in Bifidobacteriaceae and Christensenellaceae was observed in the vitamin D group; Proteobacteria abundance was significantly lower in the vitamin D treatment group after eight weeks than that in the control group. Conclusion: Our study confirmed that the increase in the abundance of beneficial bacteria such as Bifidobacteriaceae, and Christensenellaceae were prominently evident during recovery after administration of a high dose of cholecalciferol. These findings indicate that vitamin D administration may be useful in patients with CDI, and further studies with larger sample sizes are required.

Evaluation of the Relationship Between Bioactive Components in Seaweeds and Advanced Glycation End-Products Inhibitory Activities Using Principal Component Analysis.

This study comprehensively presents the relationship between the bioactive substance of 70% (v/v) aqueous ethanol extract of 38 species of seaweeds (SWEs), and anti-glycation activities. The contents of bioactive substance of SWEs, such as total phenolic, total flavonoid and condensed tannins, were determined through a colorimetric analysis. Among the tested species, Ecklonia bicyclis, Ishige foliacea, and Cladophora urightiana var. minor had the highest amount of total phenolic (255.75 mg GAE/g DW), total condensed tannins (63.36 mg CE/g DW), and total flavonoid content (85.26 mg CE/g DW), respectively. Anti-glycation properties of SWEs were evaluated through advanced glycation end-products (AGEs) formation, AGEs-collagen cross-link formation, and AGEs-collagen cross-link breaking assay. Brown algae species exhibited a more prominent inhibitory activity on AGEs formation and AGEs-collagen cross-links, and the breaking of AGEs-collagen cross-links compared to that exhibited by aminoguanidine and ALT-711 (positive controls). Using principal component analysis, we confirmed that the AGEs formation inhibitory property and AGEs-collagen cross-links breaking activity were closely correlated with total phenolic and the condensed tannin contents contained in SWEs. Therefore, the bioactive substances such as phenolics and condensed tannins in seaweeds can be used as predictive indices in selecting compounds for the development of a therapeutic agent that prevents diabetic complications related to the AGEs. In addition, our results suggest that brown algae species, which contains more bioactive substances than green and red algae species, can be utilized as a promising natural resource for the prevention and alleviation of AGEs-related diabetic complications as AGE inhibitor and cross-links breaker.

Characterization, prebiotic and immune-enhancing activities of rhamnogalacturonan-I-rich polysaccharide fraction from molokhia leaves.

Plant-derived polysaccharides possess potential health benefits that improve intestinal health and the immune system. Molokhia leaves have a large amount of mucilage polysaccharide; in the present study, crude polysaccharide extract was prepared from molokhia leaves. The molecular weight of molokhia leaf polysaccharide fraction (MPF) was estimated to be 51.2 × 103 Da. Polysaccharide was methylated and the structure of MPF was mainly composed of rhamnogalacturonan-I structure with side chains, such as galactans and linear glucan (starch), as shown by GC-MS analysis. To study the biofunctional effects of MPF, its prebiotic and intestinal immune-enhancing activities were assayed in vitro. MPF exhibited good prebiotic activity, as shown by its high prebiotic scores, and increased contents of total short-chain fatty acids on five probiotic strains. In addition, MPF showed immune-enhancing activity on Peyer's patches, as revealed by the high bone marrow cell proliferating activity and production of immunoglobulin A and cytokines. These results demonstrate that MPF may be a potential beneficial prebiotic and intestinal immune-enhancer, which may have wide implications in the food industry.

Sex difference in long-term clinical outcomes after percutaneous coronary intervention: A propensity-matched analysis of National Health Insurance data in Republic of Korea.

OBJECTIVE: We investigated the gender difference in the 5-year outcome after percutaneous coronary intervention (PCI) using an unselected population data. BACKGROUND: Sex-specific outcome after percutaneous coronary intervention (PCI) is not consistent among studies. METHODS: A total of 48,783 patients were enrolled from a Korean nationwide cohort of PCI in year 2011. Outcomes adjusted with age and propensity for clinical characteristics were compared. Primary outcome was 5-year cumulative incidence of all-cause death. Nonfatal major adverse clinical event (MACE) consisting of revascularization, shock, or stroke was also assessed. RESULTS: In unadjusted analysis, women were older and had higher frequency of comorbidities including hypertension, hyperlipidemia, and diabetes compared to men (p < .001, all). Women had higher 5-year death risk than men (21.8 vs. 17.3%; hazard ratio [HR] 1.29, 95% confidential interval [CI] 1.23-1.34). In propensity score-matched analysis (N = 28,924), women had lower 5-year death risk (20.2 vs. 26.1%, HR 0.75, 95% CI 0.71-0.78). This lower death risk in women was consistent in subgroup analyses of age, risk factors, and clinical diagnosis including angina or acute myocardial infarction (p < .05, all). CONCLUSIONS: Older age and more common comorbidities in women contributed to the apparent worse outcome after PCI in women. After adjusting these disadvantages, women had better outcome after PCI than men.

The long-term risk of lymphoma and skin cancer did not increase after topical calcineurin inhibitor use and phototherapy in a cohort of 25,694 patients with vitiligo.

BACKGROUND: Topical calcineurin inhibitors have been used to treat vitiligo, either alone or in combination with phototherapy; however, the long-term safety of these agents remains controversial. OBJECTIVE: To investigate the risk of lymphoma and skin cancer in vitiligo patients who received topical calcineurin inhibitors or phototherapy. METHODS: A multicenter retrospective cohort study of 25,694 vitiligo patients who received topical calcineurin inhibitors or phototherapy for 6 weeks or more between 2001 and 2019 was performed. Cumulative doses of topical calcineurin inhibitors and total phototherapy sessions were determined. Outcomes were the development of lymphoma or skin cancer after enrollment, confirmed through chart review and pathology reports. RESULTS: During 95,203 person-years, 13 cases of lymphoma, 22 of actinic keratosis, 15 of nonmelanoma skin cancer, and 5 of melanoma were observed. The risk of lymphoma and skin cancer was not significantly increased by topical calcineurin inhibitor dose or phototherapy sessions. The interaction between the topical calcineurin inhibitors and phototherapy was not associated with an increased risk of skin cancer. LIMITATIONS: Retrospective study, individual follow-up duration less than 4 years, and no adjustment for comorbidities and medication history. Not generalizable to other races. CONCLUSION: The long-term risk of skin cancer or lymphoma was not associated with the use of topical calcineurin inhibitors, phototherapy, and both treatments in combination in patients with vitiligo.

The efficacy of fractional carbon dioxide laser combined with narrow-band ultraviolet B phototherapy for non-segmental vitiligo: a systematic review and meta-analysis.

Fractional carbon dioxide (CO2) laser has been used with conventional treatments for vitiligo, demonstrating more effectiveness compared with conventional treatments alone. Especially, fractional CO2 laser combined with narrow-band ultraviolet B (NB-UVB) was shown to induce more improvement compared with NB-UVB monotherapy for treating stable non-segmental vitiligo. However, the effectiveness of fractional CO2 laser plus NB-UVB for the treatment of non-segmental vitiligo remains controversial. Therefore, this study aimed to confirm the safety and efficacy of fractional CO2 laser combined with NB-UVB compared with NB-UVB monotherapy in stable non-segmental vitiligo. We searched the data from different databases, including Cochrane, Embase, and PubMed up to January 2020. Four randomized controlled trials (RCTs) for comparison between fractional CO2 laser plus NB-UVB and NB-UVB monotherapy in patients with stable non-segmental vitiligo were included. We performed meta-analyses for repigmentation improvement and patient satisfaction as well as subgroup analyses based on acral or non-acral vitiligo, according to the PRISMA guidelines. The combination treatment showed more superior results than NB-UVB monotherapy (≥ 75% repigmentation, RR 4.60, 95% CI 1.19-17.74; ≥ 50% repigmentation, RR 2.24, 95% CI 0.45-11.17; < 25% repigmentation, RR 0.81, 95% CI 0.60-1.08). Also, fractional CO2 laser plus NB-UVB significantly improved acral and non-acral vitiligo compared with NB-UVB monotherapy (standard mean difference (SMD) 1.24, 95% CI 0.66-1.82; SMD 1.14, 95% CI 0.67-1.60, respectively), while it increased markedly patient satisfaction compared with NB-UVB monotherapy (SMD 1.12, 95% CI 0.66-1.58). Collectively, this meta-analysis suggested that fractional CO2 laser combined with NB-UVB might be more effective for treating non-segmental vitiligo than NB-UVB monotherapy.

Development of evidence-based consensus on critical issues in the management of patients with vitiligo: A modified Delphi study.

BACKGROUND/PURPOSE: Vitiligo remains a major challenge in dermatology. However, much of the treatment remains unclear, because little evidence is available. We sought to answer some critical questions pertaining to management of vitiligo patients. METHODS: A modified Delphi process among 31 vitiligo experts was conducted. A total of 12 clinical vitiligo treatment questions without clear answers were collected via a vote. To address each question, two members performed systematic literature reviews and prepared draft statements along with the levels of evidence and strength of recommendation. After reviewing the draft, all expressed their extent of agreement from 1 (strong disagreement) to 9 (strong agreement) for each item. The drafts were revised to reflect suggested comments. Discussion continued until all members agreed with the ultimate decision. RESULTS: The consensus process was completed after five rounds. We identified the best answers to 12 key questions, including issues on long-term phototherapy, systemic and topical corticosteroids, topical calcineurin inhibitors, immunosuppressants, excimer laser treatment, and surgical interventions. CONCLUSION: This consensus would complement current guidelines and aid both physician and patient decision-making in the treatment of vitiligo.

Evaluation of an effectiveness and safety of the electroacupuncture in the management of intractable neuropathic pain: A prospective, open-labeled, randomized, cross-over clinical trial.

BACKGROUND: There is no sufficient evidence on the effectiveness of acupuncture for neuropathic pain. This protocol describes a study that aims to evaluate the effectiveness and safety of electroacupuncture combined with conventional medicine for patients with intractable neuropathic pain, when compared with conventional medicine alone. METHODS/DESIGN: This study is a prospective, open-labeled, randomized, cross-over clinical trial. A total of 40 patients with neuropathic pain who had a numeric rating scale (NRS) score of over 4 despite receiving conventional treatment for more than 3 months will be enrolled. Participants will receive conventional treatment for neuropathic pain (treatment C) or treatment C combined with 12 additional sessions of electroacupuncture treatment (treatment A) for 6 weeks. Participants will be randomly assigned to 1 of the 2 sequence groups (AC and CA group) with a 1:1 allocation. The differences of responder in the composite efficacy outcomes, which consist of the NRS, Brief Pain Inventory-Short Form (BPI-SF) pain subscale, and global assessment at 6 weeks after randomization will be examined as the primary outcome. Secondary outcomes include differences in the NRS, the Short-Form McGill Pain Questionnaire, BPI-SF, Fatigue Severity Scale, Hospital Anxiety and Depression Scale, Medical Outcomes Study Sleep Scale, global assessment, EQ-5D, and incremental cost-effective ratio at 6 and 15 weeks after randomization. Adverse events, vital signs, and physical examinations will be recorded to evaluate safety. DISCUSSION: The study protocol for this trial will provide up-to-date evidence on the effectiveness and safety of electroacupuncture for patients with intractable neuropathic pain. The results will be disseminated through a peer-reviewed journal and conference presentations. TRIAL REGISTRATION: Clinical Research Information Service, ID: KCT0003615. Registered on March 12, 2019. https://cris.nih.go.kr/cris/search/search_result_st01_kren.jsp?seq=13410& ltype=&rtype=.

Impaired Odor Identification of Culturally Familiar Odorants Associated with Dementia in South Korean Older Adults.

Among olfactory functions, odor identification is the most studied predictor of dementia. We aimed to verify whether patients with dementia are less aware of specific odors than cognitively normal individuals using an odor identification test, which includes odorants that are culturally familiar to South Koreans. We divided 139 older adults aged 57-79 years into the dementia and normal cognition groups. Odor identification function was assessed in all participants. We conducted hierarchical logistic regression analyses with the diagnosis of dementia as a dependent variable and three demographic characteristics, as well as 12 odor identification items, as independent variables. Impaired odor identification for herbal medicine (odds ratio (OR) = 9.420; p = 0.012) and Korean grilled meat (OR = 5.361; p = 0.019) and older age (OR = 1.176; p = 0.005) were significant predictors of dementia. Impaired odor identification of culturally familiar odorants was associated with dementia risk. This may be explained by the fact that compared with culturally non-specific universal odorants, familiar odorants are more related to episodic memory, which is impaired in the early stages of dementia. Thus, an optimal combination of odor identification items should be used for screening individuals with cognitive decline requiring further neurocognitive function tests.

Resolvin D3 controls mouse and human TRPV1-positive neurons and preclinical progression of psoriasis.

Rationale: Psoriasis is a chronic inflammatory disease caused by a complex interplay between the immune and nervous systems with recurrent scaly skin plaques, thickened stratum corneum, infiltration and activation of inflammatory cells, and itch. Despite an increasing availability of immune therapies, they often have adverse effects, high costs, and dissociated effects on inflammation and itch. Activation of sensory neurons innervating the skin and TRPV1 (transient receptor potential vanilloid 1) are emerging as critical components in the pathogenesis of psoriasis, but little is known about their endogenous inhibitors. Recent studies have demonstrated that resolvins, endogenous lipid mediators derived from omega-3 fatty acids, are potent inhibitors of TRP channels and may offer new therapies for psoriasis without known adverse effects. Methods: We used behavioral, electrophysiological and biochemical approaches to investigate the therapeutic effects of resolvin D3 (RvD3), a novel family member of resolvins, in a preclinical model of psoriasis consisting of repeated topical applications of imiquimod (IMQ) to murine skin, which provokes inflammatory lesions that resemble human psoriasis. Results: We report that RvD3 specifically reduced TRPV1-dependent acute pain and itch in mice. Mechanistically, RvD3 inhibited capsaicin-induced TRPV1 currents in dissociated dorsal root ganglion (DRG) neurons via the N-formyl peptide receptor 2 (i.e. ALX/FPR2), a G-protein coupled receptor. Single systemic administration of RvD3 (2.8 mg/kg) reversed itch after IMQ, and repeated administration largely prevented the development of both psoriasiform itch and skin inflammation with concomitant decreased in calcitonin gene-related peptide (CGRP) expression in DRG neurons. Accordingly, specific knockdown of CGRP in DRG was sufficient to prevent both psoriasiform itch and skin inflammation similar to the effects following RvD3 administration. Finally, we elevated the translational potential of this study by showing that RvD3 significantly inhibited capsaicin-induced TRPV1 activity and CGRP release in human DRG neurons. Conclusions: Our findings demonstrate a novel role for RvD3 in regulating TRPV1/CGRP in mouse and human DRG neurons and identify RvD3 and its neuronal pathways as novel therapeutic targets to treat psoriasis.

Electroacupuncture May Improve Burning and Electric Shock-Like Neuropathic Pain: A Prospective Exploratory Pilot Study.

Objective: To test the effectiveness of electroacupuncture (EA) for managing intractable neuropathic pain (NeP) and assess the protocol for a larger confirmatory trial. Design: A prospective, multicenter, single-armed, add-on, pilot study. Settings/location: At two tertiary university-based hospitals in Seoul, Republic of Korea. Subjects: Patients with chronic peripheral NeP, who have received conventional oral medications but complained of moderate to severe pain. Interventions: Two Korean medicine doctors conducted 12 sessions of EA (2 sessions per week for 4 weeks, followed by 1 session per week for the second month) in addition to conventional treatment. Outcome measures: During the 8-week treatment period, pain intensity, pain natures such as burning, electric shock-like, temperature or mechanical hyperalgesia, and numbness, Short Form of the McGill Pain Questionnaire (SF-MPQ) and the Brief Pain Inventory (BPI-SF), the EuroQol five dimensions questionnaire, patients' satisfaction, and adverse events were evaluated. The primary endpoint was a change in pain intensity (%) at 4 weeks from the baseline. Results: Among 22 patients, 19 finished the protocol. The eight EA sessions over a month reduced pain intensity from 6.0 ± 1.6 at baseline to 3.2 ± 0.9 at 4 weeks, which was a 46.7% reduction (p < 0.001). The incidences of severe burning, electric shock-like pain, and mechanical hyperalgesia reduced at 8 weeks [36%-16% (p = 0.04), 53%-21% (p = 0.009), and 53%-26% (p = 0.03), respectively]. The affective dimensions in the SF-MPQ (p = 0.007) and the pain interference parameters, including mood (p = 0.02), relations with other people (p = 0.03), and enjoyment of life (p = 0.002) in the BPI-SF, were improved at 4 and 8 weeks. The majority of patients (68%) responded that their pain was "much or somewhat improved." Overall, 84.2% expressed "satisfaction" with their multidisciplinary management. Conclusions: EA might decrease the intensity of NeP, in particular, such as burning, electric shock-like pain, and mechanical hyperalgesia, which was accompanied by psychosocial and functional improvement. A larger study is warranted to prove the effectiveness of EA for managing refractory NeP. Trial registration: ClinicalTrials.gov: NCT03315598. Retrospectively registered on October 20, 2017.