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Introduction: The role of inflammation in the pathophysiology of polycythemia vera (PV) is important. The presence of JAK2 mutations is important in the diagnosis of PV, and serum levels of erythropoietin (EPO) also play a supporting role. However, serum EPO levels show some limitations. The neutrophil‐to‐lymphocyte ratio (NLR) and platelet‐to‐lymphocyte ratio (PLR) are a readily available marker of inflammation. Thus, we examined whether NLR & PLR might diagnose PV in erythrocytosis patients. We compared NLR & PLR and EPO diagnostic values. Methods: We retrospectively reviewed clinical and laboratory data from two referral hospitals. Two hundred and eighty‐five patients with erythrocytosis who underwent a test for the JAK2 mutation were included. It wac classified as the PV group and the secondary polycythemia (SP) group. Results: The median NLR & PLR in the PV group (n = 70) was significantly higher than that in the SP group (n = 170) (NLR: 6.04 vs. 1.77, PLR: 283.18 vs. 101.56, respectively, p < 0.001). In the receiver operating characteristic analysis, the area under the curve of NLR & PLR was significantly higher than that of serum EPO (NLR vs EPO: 0.921 vs. 0.827, p = 0.003; PLR vs EPO: 0.917 vs 0.827, p = 0.003). Conclusion: In conclusion, NLR & PLR were higher in PV than in SP and showed better diagnostic value than serum EPO level, highlighting their potential as minor diagnostic criteria in patients with PV. [ABSTRACT FROM AUTHOR]

Objective: This clinical trial was conducted to investigate whether discontinuing methotrexate (MTX) for 1 week after seasonal influenza vaccination is noninferior to discontinuing for 2 weeks after vaccination in patients with rheumatoid arthritis (RA). Methods: In this multicenter, prospective, randomized, parallel‐group noninferiority trial, RA patients receiving a stable dose of MTX were randomly assigned at a ratio of 1:1 to discontinue MTX for 1 week or for 2 weeks after they received the quadrivalent 2021–2022 seasonal influenza vaccine containing H1N1, H3N2, B/Yamagata, and B/Victoria strains. The primary outcome measure was the proportion of patients with a satisfactory vaccine response, which was defined as ≥4‐fold increase in antibody titers, as determined with the hemagglutination inhibition assay, against ≥2 of the 4 vaccine strains at 4 weeks after vaccination. Results: The modified intent‐to‐treat population included 90 patients in the 1‐week MTX hold group and 88 patients in the 2‐week MTX hold group. The mean ± SD MTX doses were 12.6 ± 3.4 mg/week in the 1‐week MTX hold group and 12.9 ± 3.3 mg/week in the 2‐week MTX hold group. The proportion of satisfactory vaccine responses did not differ between the groups (68.9% versus 75.0%; P = 0.364). The rate of seroprotection and the fold increase in antibody titers for each of the 4 influenza antigens were similar between the groups. Conclusion: A temporary discontinuation of MTX for 1 week after vaccination was noninferior to a discontinuation of MTX for 2 weeks after vaccination, regarding induction of a satisfactory vaccine response to a seasonal influenza vaccine in patients with RA receiving a stable dose of MTX. [ABSTRACT FROM AUTHOR]

There is growing interest in conservative treatment of Achilles tendon rupture. However, the majority of experimental studies of Achilles tendon have been performed by open tenotomy. More appropriate model of conservative treatment of Achilles tendon rupture is required. We performed an experimental study to evaluate whether outcomes differ between open tenotomy and percutaneous tenotomy of the Achilles tendon in rats. The Achilles tendons of 48 rats were transected. The animals were divided into two groups according to surgical technique: open tenotomy or microscopy‐assisted percutaneous tenotomy. After 1, 2, and 4 weeks, functional, biomechanical, and histological analyses were performed. Western blot was performed for quantitative molecular analysis at 1 week. The Achilles functional index was superior in the percutaneous tenotomy group, compared with the open tenotomy group, at 1 week. The cross‐sectional area was significantly larger in the percutaneous tenotomy group than in the open tenotomy group at 4 weeks. Relative to the native tendons, load to failure and stiffness yielded comparable results at 2 weeks in the percutaneous tenotomy group and at 4 weeks in the open tenotomy group. The histological score was significantly better in the percutaneous tenotomy group than in the open tenotomy group at 1 week. At 1 week, interleukin‐1β expression in the open tenotomy group was higher than in the percutaneous tenotomy group. In summary, Achilles tendon healing was substantially affected by the tenotomy method. We presume that our percutaneous tenotomy method might constitute a useful experimental animal model for conservative treatment of Achilles tendon rupture. [ABSTRACT FROM AUTHOR]

Hypertension is a leading risk factor for cardiovascular events and death. Despite differences in clinical implications of hypertension between men and women, guidelines establishing optimal blood pressure (BP) targets are still debated. The aim of this study was to investigate sex differences in the BP level associated with increased risks of major adverse cardiac and cerebral events (MACCEs) among antihypertensive-treated patients. Using data from the Korean National Health Insurance Service-National Sample Cohort, we enrolled antihypertensive-treated patients and divided them into four categories: Group 1: SBP < 120 and DBP < 80 mm Hg; Group 2: 120 ≤ SBP < 130 and DBP < 80 mm Hg; Group 3: 130 ≤ SBP < 140 or 80 ≤ DBP < 90 mm Hg; and Group 4: SBP ≥ 140 or DBP ≥ 90 mm Hg. We performed time-dependent cox regression analysis to investigate sex differences in the BP levels that increased the risk of MACCEs. Most of the 98 267 patients fell into Group 3 (53.2% men and 52.8% women) and Group 4 (30.5% men and 28.1% women). During 8.34 ± 2.07 years, there were 8,813 MACCEs and 791 deaths. The incidences of MACCEs and death tended to increase as the BP increased in both sexes. Compared to Group 1, the risk of MACCEs significantly increased only in Group 4 for men, while it significantly increased in Groups 3 and 4 for women. This study shows that there are sex differences in the BP level at which the risk of MACCEs increases. Our finding suggests that sex should be significantly considered when determining the optimal BP target in patients undergoing hypertension treatment. [ABSTRACT FROM AUTHOR]

Background and Purpose: Charcot-Marie-Tooth (CMT) disease is the most common hereditary peripheral neuropathy. CMT type 1A (CMT1A) accounts for approximately 50% of CMT patients and is linked to PMP22 gene duplication. Histone deacetylase-6 (HDAC6) has pleiotropic effects, such as regulating lipid homeostasis and cellular stress. Although HDAC6 has been regarded as a promising drug target for neurodegenerative diseases, its inhibition has not yet been tested in CMT1A. Here we have tested the therapeutic potential of CKD-504, a clinical stage HDAC6 inhibitor, in a mouse model of CMT1A EXPERIMENTAL APPROACH: The potency and selectivity of CKD-504 was evaluated, using a HDAC enzyme panel assay and western blots. The therapeutic potential of CKD-504 was evaluated using behavioural testing and electrophysiological assessments in the C22 mouse model of CMT1A. PMP22 protein expression and aggregation were analysed in mesenchymal stem cell-derived Schwann cells from CMT1A patients and sciatic nerves from C22 mice.Key Results: The HDAC6 inhibitor, CKD-504, modulated molecular chaperon proteins such as HSP90 and HSP70, which are involved in the folding/refolding of proteins such as PMP22. CKD-504 treatment restored myelination in both mesenchymal stem cell-derived Schwann cells from CMT1A patients and sciatic nerves of C22 mice and improved the axonal integrity of the sciatic nerve, leading to behavioural, electrophysiological, and histological improvements in C22 mice.Conclusion and Implications: A novel HDAC6 inhibitor, CKD-504, has potent therapeutic efficacy for CMT1A. [ABSTRACT FROM AUTHOR]

Background: Rectal preservation against medical advice after neoadjuvant chemoradiotherapy for rectal cancer may increase oncologic uncertainty. This study aimed to compare the oncologic outcomes of patients undergoing rectal preservation as intended by the surgeon, and the outcomes of patients refusing rectal resection against medical advice. Methods: The study population consisted of patients in whom the rectum was preserved after neoadjuvant chemoradiotherapy for clinical stage I–III mid or low rectal cancer between May 2003 and August 2017 (n = 2883); these patients were divided into those in whom rectal preservation was intended by their surgeon (intended rectal preservation, group A, n = 41) and those in whom the rectum was not resected against medical advice (unintended rectal preservation, group B, n = 101), defined as non-operative management or local excision. Results: The tumor distance, age, and performance status of patients were not significantly different between the groups, while the clinical T stage before chemoradiotherapy was lower in group A than in group B (P < 0.001). During the median follow-up period of 34 months (interquartile range 18.0–72.0 months), the 3-year overall survival in group B (59.7%) was worse than that in group A (90.1%; P < 0.001), and 80.2% of group B patients had residual or unknown disease status. Conclusions: This study showed that unintended rectal preservation increases oncologic risk after neoadjuvant chemoradiotherapy for rectal cancer regardless of short-term follow-up. Therefore, these findings could be shared with rectal cancer patients who choose to ignore medical advice after chemoradiotherapy to preserve their rectum. [ABSTRACT FROM AUTHOR]

Background: The association between diabetes mellitus (DM) and bone diseases is acknowledged. However, the mechanistic pathways leading to the alveolar bone (AB) destruction remain unclear. This study aims to elucidate the mechanical forces (MF)-induced AB destruction in DM and its underlying mechanism.Methods: In vivo periodontal tissue responses to MF were evaluated in rats with diabetes. In vitro human periodontal ligament (PDL) cells were either treated with advanced glycation end products (AGEs) alone or with AGEs and MF.Results: In vivo, the transcription of VEGF-A, colony stimulating factor-1 (CSF-1), and Ager was upregulated in diabetes, whereas changes in DDOST and Glo1 mRNAs were negligible. DM induced VEGF-A protein in the vascular cells of the PDL and subsequent angiogenesis, but DM itself did not induce osteoclastogenesis. MF-induced AB resorption was augmented in DM, and such augmentation was morphologically substantiated by the occasional undermining resorption as well as the frontal resorption of the AB by osteoclasts. The mRNA levels of CSF-1 and vascular endothelial growth factor (VEGF) during MF application were highly elevated in diabetes, compared with those of the normal counterparts. In vitro, AGEs treatment elevated Glut-1 and CSF-1 mRNA levels via the p38 and JNK pathways, whereas OGT and VEGF levels remained unchanged. Compressive MF especially caused upregulation of VEGF, CSF-1, and Glut-1 levels, and such upregulation was further enhanced by AGEs treatment.Conclusions: Overloaded MF and AGEs metabolites may synergistically aggravate AB destruction by upregulating CSF-1 and VEGF. Therefore, regulating the compressive overloading of teeth, as well as the levels of diabetic AGEs, may prove to be an effective therapeutic modality for managing DM-induced AB destruction. [ABSTRACT FROM AUTHOR]

Background and Purpose: Kazinol U is a prenylated flavan isolated from an extract of Broussonetia kazinoki Sieb (Moraceae). Kazinol U has shown cytoprotective effects against cytokine-induced apoptotic cell death and induces AMP kinase (AMPK) activation through LKB1 activation. However, kazinol U has not been tested as a regulator of melanogenesis, although bark extract of B. kazinoki has been used as a cosmetic ingredient for skin conditioning.Experimental Approach: We cultured mouse, human melanoma cells and normal human melanocytes to demonstrate anti-melanogenic effects of kazinol U. A tyrosinase activity assay, Western blot, RT-qPCR and a luciferase reporter gene assay were performed to determine the anti-melanogenic mechanisms of kazinol U. We confirmed its effect on melanogenesis in vivo using zebrafish.Key Results: Kazinol U inhibited the expression and activity of tyrosinase, the rate-limiting enzyme in melanogenesis, and reduced tyrosinase expression and activity in response to cAMP-inducing agents. Kazinol U reduced the expression of other melanogenic enzymes, such as tyrosinase-related protein (Tyrp) 1 and Tyrp2, and down-regulated microphthalmia-associated transcription factor (MITF), the master regulator of the tyrosinase gene family. Moreover, kazinol U induced phosphorylation of AMPK and MAPK proteins, which are MITF inhibitors. It also exhibited anti-melanogenic effects in zebrafish, a recently developed in vivo model.Conclusions and Implications: Our findings suggest that kazinol U reduces melanogenesis via its inhibitory effect on MITF and its downstream target genes, tyrosinase, Tyrp1 and Tyrp2. This work may provide a basis for the application of kazinol U for the treatment of hyperpigmentation skin disorders. [ABSTRACT FROM AUTHOR]

There is growing public interest in alternative approaches to addiction treatment and scientific interest in elucidating the neurobiological underpinnings of acupuncture. Our previous studies showed that acupuncture at a specific Shenmen (HT7) points reduced dopamine (DA) release in the nucleus accumbens (NAc) induced by drugs of abuse. The present study was carried out to evaluate the effects of HT7 acupuncture on γ-aminobutyric acid (GABA) neuronal activity in the ventral tegmental area (VTA) and the reinstatement of cocaine-seeking behavior. Using microdialysis and in vivo single-unit electrophysiology, we evaluated the effects of HT7 acupuncture on VTA GABA and NAc DA release and VTA GABA neuronal activity in rats. Using a within-session reinstatement paradigm in rats self-administering cocaine, we evaluated the effects of HT7 stimulation on cocaine-primed reinstatement. Acupuncture at HT7 significantly reduced cocaine suppression of GABA release and GABA neuron firing rates in the VTA. HT7 acupuncture attenuated cocaine-primed reinstatement, which was blocked by VTA infusions of the selective GABAB receptor antagonist 2-hydroxysaclofen. HT7 stimulation significantly decreased acute cocaine-induced DA release in the NAc, which was also blocked by 2-hydroxysaclofen. HT7 acupuncture also attenuated cocaine-induced sensitization of extracellular DA levels in the NAc. Moreover, HT7 acupuncture reduced both locomotor activity and neuronal activation in the NAc induced by acute cocaine in a needle-penetration depth-dependent fashion. These results suggest that acupuncture may suppress cocaine-induced DA release in the NAc and cocaine-seeking behavior through activation of VTA GABA neurons. Acupuncture may be an effective therapy to reduce cocaine relapse by enhancing GABAergic inhibition in the VTA. [ABSTRACT FROM AUTHOR]

Aim: The aim of the present study was to evaluate the clinical characteristics, including floor characteristics and factors, related to severe injury from outdoor falls in older adults. Methods: Patients were divided into two groups based on injury severity: the severe group and non‐severe group. The clinical and general characteristics were compared between the two groups, and factors associated with severe injury were investigated. Results: Approximately 5% (364/7635) of older people involved in outdoor falls were classified into severe injury. The proportion of men and the rate of alcohol ingestion were higher in the severe group compared with that in the non‐severe group. Falling from stairs was a more frequent mechanism of fall in the severe group compared with that in the non‐severe group. Non‐slippery floor condition had a higher proportion in the severe group than that in the non‐severe group. Head and neck were the predominantly injured regions in both groups. Discharge was the most common result of emergency department treatment in the non‐severe group, whereas admission to intensive care unit was the main result in the severe group. Multivariate logistic analysis showed that male sex and falls from stairs rather than slipping down on the same level were associated with severe injury. Conclusions: Floor characteristics did not influence injury severity; however, the risk of severe injury from outdoor falls in older adults was high in men and those who fell from stairs. Geriatr Gerontol Int 2018; 18: 80–87. [ABSTRACT FROM AUTHOR]

Background: Cytopenia occurs frequently during cytotoxic chemotherapy. Little is known about the optimal timing of influenza vaccination for patients receiving chemotherapy. This study compared the immunogenicity of an influenza vaccine administered concurrently with chemotherapy (day 1) and within the cytopenic period (day 11) during 3-week cytotoxic chemotherapy cycles.Methods: Adult patients with solid cancer undergoing scheduled 3-week cytotoxic chemotherapy were randomly assigned to receive the 2014-2015 seasonal influenza vaccine on day 1 or 11 during the chemotherapy cycle. Patients were stratified by their age (<60 and ≥60 years) and previous influenza vaccination status. Antibody responses to influenza vaccine strains H1N1, H3N2, and B were measured before and 21 to 28 days after vaccination with a hemagglutination inhibition antibody assay.Results: Ninety-seven patients were randomized into a day 1 group (n = 43) or a day 11 group (n = 54). Eighty-three patients were included in the final analysis. The mean age was 54 (± 11) years. Cancer types included breast (61%) and lung cancer (30%). Baseline characteristics were not significantly different between the groups. Seroprotection rates after vaccination were also not significantly different for the day 1 and 11 groups (strain H1N1, 67% vs 75% [P = .403]; strain H3N2, 77% vs 80% [P = .772]; strain B, 21% vs 27% [P = .472]). Seroconversion rates and postvaccination geometric mean titers were also similar for the groups. Vaccine-related adverse events were more common in the day 11 group (13% vs. 32%; P = .040).Conclusions: The antibody responses to influenza vaccination on days 1 and 11 during a 3-week cytotoxic chemotherapy cycle were comparable. Influenza vaccination can be performed concurrently with cytotoxic chemotherapy or during the cytopenic period. Cancer 2017;123:841-48. © 2016 American Cancer Society. [ABSTRACT FROM AUTHOR]

The species status of O eneis urda ( Eversmann) and O . mongolica ( Oberthür) has been argued based on morphological characters. Reexamination of their major morphological characters has shown a slight differentiation in the two species. Sequences of three mitochondrial genes ( COI, ND6, and ND1) and one nuclear region (internal transcribed spacer 2, ITS2) from two O . urda populations ( Yangyang and Mt. Hanla) and one O . mongolica population ( Uljin) were performed for phylogenetic and population genetic inferences. Sharing of identical sequences in the ND6 gene and ITS2, minimal sequence divergence in the COI and ND1 genes, and phylogenetically undividable sequence types in all mitochondrial genes and ITS2 suggest genetic continuity between the two species. Nevertheless, significant FST estimates ( P < 0.05) were found for the COI gene in comparisons between Yangyang ( O . urda) and Uljin ( O . mongolica), between Yangyang ( O . urda) and Mt. Hanla ( O . urda), and between Uljin ( O . mongolica) and Mt. Hanla ( O . urda) populations. These FST estimates, along with other gene-based analyses collectively suggest isolation of the two species at some point in the past, but incomplete separation between the two species on the mainland ( Yangyang and Uljin) and biogeographically forced isolation of the O . urda population on Mt. Hanla collectively appear to complicate species status of these two species that were once further clearly separated. [ABSTRACT FROM AUTHOR]