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Restless legs syndrome (RLS) has a high prevalence in the elderly, which significantly impacts sleep, quality of life, and increases the risk of falls while walking at night. There is sufficient research to support the concept of altered brain iron homeostasis in RLS as part of the underlying pathology of RLS. A Task Force was established by the International Restless Legs Syndrome Study Group to develop evidence-based and consensus guidelines for the iron treatment of RLS in adults. Consensus recommendations based on clinical practice are presented, including when to use oral iron or intravenous iron, and recommendations on repeated iron treatments. New iron treatment algorithms, based on evidence and consensus opinion have been developed. Iron therapy is of great importance in various structures, including improvement of the pathophysiology and clinical symptoms of RLS. It is necessary to develop treatment methods such as more active brain delivery and accurate monitoring, and additional long-term clinical guidelines are expected through various studies.

Purpose An increasing number of people are suffering from hair loss disorders. Niacinamide has long been used as an active ingredient for anti-hair loss preparations but the exact mechanism has not been clearly elucidated yet. The effects of niacinamide were investigated in cultured human dermal papilla cells (hDPCs). Methods To investigate the anti-hair loss effect of niacinamide and its molecular mechanisms, Western blot analysis, ELISA, quantitative RT-PCR and immunocytochemistry were performed. To study the protective effects of niacinamide against H2O2-induced oxidative stress, ROS generation and cytotoxicity were evaluated by DCF-DA assay and LDH release assay, respectively. Minoxidil was used as a positive control. Results Niacinamide decreased the protein expression level of DKK-1 which promotes regression of hair follicles by inducing catagen. The protein expression levels of cell senescence markers, p21 (CDKN1A) and p16 (CDKN2A) which are related to cell cycle arrest, were decreased. The expression of versican was increased by niacinamide treatment in cultured hDPCs. We have found that niacinamide decreased the H2O2-induced intracellular ROS production in cultured hDPCs. Moreover, niacinamide decreased the protein expression levels of H2O2-induced p21 and p16 and diminished the secretion of H2O2-induced DKK-1. Conclusion Our data demonstrate that niacinamide could enhance hair growth by preventing oxidative stress-induced cell senescence and premature catagen entry of hair follicles.

Studies regarding multiple chronic lacunes (MCLs) and clinical outcome according to stroke etiology are scarce. We sought to evaluate the association between MCL and short-term/long-term clinical outcomes according to stroke etiology.We analyzed a prospectively collected stroke registry of acute ischemic stroke patients over 4 years. The enrolled patients were classified as having large artery atherosclerosis (LAA), small vessel occlusion (SVO), cardioembolic (CE) stroke, and other etiology. The early neurological deterioration (END) and favorable outcome at 3 months were assessed.A total of 1070 patients were enrolled. Patients with MCL had significantly more END compared to those without MCL both in total population (adjusted odds ratio (OR), 1.7; 95% confidence interval [CI], 1.1-2.5; p = 0.013*) and in the LAA group (adjusted OR, 2.3; 95% CI, 1.3-4.2, p 0.006). Patients with MCL had a significantly lower OR for favorable outcome at 3 months compared to those without MCL both in total population (adjusted OR, 0.7; 95% CI, 0.5-1.0, p = 0.035) and in the LAA group (adjusted OR, 0.6; 95% CI, 0.3-1.0, p = 0.043). However, MCL was not associated with END or long-term functional outcome in patients with SVO, CE, or other etiology.The presence of MCL was an independent predictive factor for END as well as long-term poor functional outcome in acute ischemic stroke patients. These associations were only observed in patients with LAA, not in those with SVO, CE, or other etiology.

In the present study, we investigated the molecular mechanisms of adenosine for its hair growth promoting effect. Adenosine stimulated the Wnt/β-catenin pathway by modulating the activity of Gsk3β in cultured human dermal papilla cells. It also activated adenosine receptor signaling, increasing intracellular cAMP level, and subsequently stimulating the cAMP mediated cellular energy metabolism. The phosphorylation of CREB, mTOR, and GSK3β was increased. Furthermore, the expression of β-catenin target genes such as Axin2, Lef1, and growth factors (bFGF, FGF7, IGF-1) was also enhanced. The inhibitor study data conducted in Wnt reporter cells and in cultured human dermal papilla cells demonstrated that adenosine stimulates Wnt/β-catenin signaling through the activation of the adenosine receptor and Gsk3β plays a critical role in transmitting the signals from the adenosine receptor to β-catenin, possibly via the Gαs/cAMP/PKA/mTOR signaling cascade.

We develop a quantized-feedback-based adaptive delay-independent control design for systems with unknown strict-feedback nonlinearities and time-varying delays. It is assumed that full state variables quantized by uniform quantizers are only available for the feedback control design. Compared with the previous adaptive control designs of lower-triangular nonlinear time-delay systems, the major contribution of this paper is to develop quantized-states-basedmemoryless adaptive control and stability analysis strategies to deal with unmatched and unknown time-delay nonlinearities. An adaptive neural network controller and its adaptive laws are designed via quantized state variables where neural networks are employed to compensate for unknown time-delay nonlinear effects. By deriving theoretical lemmas on the boundedness of quantization errors of the closed-loop signals, the stability of the resulting closed-loop system and the convergence of the tracking error are analyzed. Finally, simulation results are provided to validate the effectiveness of the theoretical result.

Background:Early consciousness recovery after cardiac arrest (CA) is one of the most explicit and self-evident prognostic factors for clinical outcomes. We aimed to evaluate the prognostic value of electroencephalography (EEG) phenotypes according to the American Clinical Neurophysiology Society’s Critical Care EEG classification for predicting early recovery after CA.Methods:Consecutive patients admitted to the ICU after CA were enrolled. We analyzed Glasgow Coma Scale (GCS) score within 10 days after CA and evaluated mortality within 28 days according to EEG pattern subtype.Results:Among the total of 71 patients, 9 had periodic discharges (PDs) EEG pattern, 4 had rhythmic delta activity (RDA), 8 had spike-and-wave (SW), 22 had low voltage, 5 had burst suppression, and 23 had other EEG patterns. Initial GCS scores, GCS scores 3 days after CA (or 3 days after targeted temperature management [TTM]), and 10 days after CA (or 10 days after TTM) were significantly different among EEG subtypes (p < 0.001, respectively) (Table 2). GCS scores were significantly higher in RDA and the other EEG group compared to the PDs, SW, low voltage, and burst suppression groups (p < 0.001). Significant group × time interactions were observed for the follow-up period between EEG phenotypes (p < 0.001) demonstrating the most increase in the other EEG pattern group.Conclusions:Consciousness states were significantly worse in the PDs, SW, burst suppression, and low-voltage groups compared to the RDA and the other EEG pattern within 10 days after CA. The degree of consciousness recovery differed significantly by EEG pattern subtype within 10 days.

This paper investigates an adaptive output-feedback stabilization problem for a class of uncertain nonlinear systems with an unknown sensor sensitivity. A high-gain observer based on an inexact system output is designed to estimate unmeasurable state variables and an adaptive output-feedback dynamic surface control strategy is established to accomplish the robust stabilization in the presence of the unknown sensor sensitivity. Compared with the existing control results dealing with the unknown sensor sensitivity, the primary contribution of this paper is that the proposed adaptive control strategy does not require the information of the sensor sensitivity and its bound where the effect of the unknown sensor sensitivity is compensated by designing an adaptation structure. From the Lyapunov stability analysis, the ultimate uniform boundedness of all closed-loop signals and the convergence of the stabilization error to an adjustable neighborhood of the origin are ensured. A simulation for a numerical example and an experiment for a flexible-joint robot are provided to validate the effectiveness of the proposed theoretical approach.

Background Antiepileptic drug (AED) induced dyskinesia is an unusual manifestation in the medical field. In the previous case reports describing first generation-AED related involuntary movements, the authors suggested that a plausible cause is pharmacokinetic interactions between two or more AEDs. To date, development of dyskinesia after levetiracetam (LEV) has not been reported. Case presentation A 28-year-old woman with a history of brain metastasis from spinal cord glioblastoma presented with several generalized tonic-clonic seizures without restored consciousness. LEV was administered intravenously. Thereafter no more clinical or electroencephalographic seizures were noted on video-EEG monitoring, while chorea movement was observed in her face and bilateral upper limbs. Discussion and conclusions To our knowledge, there is no case report of dyskinesia after administration of LEV. Considering the temporal relationship and absence of ictal video-EEG findings, we suggest that development of choreoathetosis was closely associated with the undesirable effects of LEV. We propose that dopaminergic system dysregulation and genetic susceptibility might underlie this unusual phenomenon after LEV treatment.

Acute ischemic stroke in the territory of anterior cerebral artery (ACA) is uncommon. Therefore, large population studies evaluating ACA infarction are scarce. We sought to evaluate epidemiological and etiological characteristics of ACA infarction compared to other territorial infarctions. We analyzed a prospectively collected stroke registry of all acute ischemic stroke patients for 19 years at two tertiary hospitals. We included patients with acute ischemic stroke caused by large vessel stenosis or occlusion including ACA, middle cerebral artery (MCA), posterior cerebral artery (PCA), and vertebrobasilar artery (VBA). A total of 4171 patients were enrolled. Patients with ACA infarction (N = 288) were significantly older with more females than those with MCA, PCA, or VBA infarction. There were more patients with history of prior ischemic stroke in the ACA infarction group than in other groups. The etiology of the ACA infarction was similar to those of the MCA, PCA and also the total population (66.7–71.8% of LAA and 17.9–20.9% of CE). When patients had prior ischemic stroke history, ACA infarction was more likely to be caused by LAA than MCA or PCA infarction (OR = 6.2, 95% CI 2.0–19.2, p = 0.002 and OR = 4.0, 95% CI 1.1–14.6, p = 0.038, respectively). Patients with ACA infarction had significantly more prior ischemic stroke than those with MCA, PCA, or VBA infarction. The etiology of ACA infarction in patients with prior ischemic stroke showed significantly more LAA than that of MCA or PCA infarction.

The androgen receptor is a hormone activated transcription factor that regulates the development and maintenance of male characteristics and represents one of the most well-established drug targets, being implicated not only in prostate cancer but also in many non-cancerous human diseases including androgenetic alopecia, acne vulgaris, and hirsutism. In this study, the antiandrogenic effects of FMN were investigated in 22Rv1 and LNCaP prostate cancer cells. FMN inhibited dihydrotestosterone (DHT)-induced protein expression of androgen receptor in 22Rv1cells. In another prostate cancer LNCaP cells, FMN decreased the protein level of DHT-induced prostate specific antigen (PSA). In addition, FMN downregulated DHT-induced mRNA expression of androgen regulated genes in both cell lines, showing less prominent inhibition in 22Rv1cells where androgen receptor had been significantly decreased by FMN. FMN was found to bind androgen receptor, demonstrating that it acted as a competitive androgen receptor antagonist. FMN increased the phosphorylation of Akt in 22Rv1 cells and this increment was abrogated by PI3K inhibitor wortmannin, resulting in a rescued androgen receptor protein level which was decreased by FMN. Additionally, FMN was found to increase the mRNA and protein level of E3 ligase mouse double minute 2. Our data suggest that the androgen receptor signaling is regulated through PI3K-Akt-MDM2 pathway in 22Rv1 cells. Together, our results indicate that FMN facilitated the degradation of androgen receptor in 22Rv1 cells and inhibited the expression of androgen regulated genes by competing the binding of DHT to androgen receptor in LNCaP cells, demonstrating its therapeutic potential as an antiandrogen.

Dexpanthenol (D-panthenol) is a precursor of vitamin B5 (pantothenic acid) and is widely used for dietary supplements and topical applications. D-panthenol has long been used in hair care products for the purpose of anti-hair loss, its effects and the underlying mechanisms, however, were barely reported. In this study, the effects of D-panthenol on human hair follicle cells, including dermal papilla cells (hDPCs) and outer root sheath cells (hORSCs), were investigated. D-panthenol enhanced the cell viability, increasing the cellular proliferation marker Ki67 in cultured hDPCs. The markers for apoptosis (Caspase3/9) and cell senescence (p21/p16), reported to be expressed in aged or resting phase follicles, were significantly reduced by D-panthenol. Anagen-inducing factors (ALP, β-catenin, versican), which trigger or elongate the anagen phase, were stimulated by D-panthenol. On the other hand, D-panthenol reduced TGF-β1 expressions in both mRNA and protein levels. The expression of VEGF, which is important for peripheral blood vessel activation, was up-regulated by D-panthenol treatment. In cultured hORSCs, cell proliferation and viability were enhanced, while the mRNA expression of cell senescence markers (p21/p16) was significantly down-regulated. The expressions of both VEGF and its receptor (VEGFR) were up-regulated by D-panthenol. In conclusion, our data suggest that the hair growth stimulating activity of D-panthenol was exerted by increasing the cell viability, suppressing the apoptotic markers, and elongating the anagen phase in hair follicles.

This paper presents a consistent analytic kinematic formulation of the 3-PRS parallel manipulator (PM) with a parasitic motion by embedding the velocity level structural constraint equation into the motion expression. Inverse rate kinematics (IRK) is solved with a simple constraint compatible velocity profile, which is obtained by projecting the instantaneous restriction space onto the motion space. Moreover, the systematic method to reveal the parasitic motion is introduced. Thus, the parasitic terms are automatically identified from the main motions. Unlike the usual approach, this study does not consider any explicit parasitic motion expression. Consequently, the derivation of constraint compatible input velocity, which comprises the parasitic term, is simplified. To incorporate the parasitic motion into the task velocity, constraint Jacobian of the manipulator is analytically obtained first. The manipulator Jacobian is extended to incorporate the passive joint’s information apart from the active joints and structural constraint. Hence, the dimension of the Jacobian matrix used to solve IRK is 9 × 6. The validity of the IRK is proved by the Bordered Gramian based forward rate kinematics (FRK). Then, an accurate numerical integration, RK4, is applied to the joint velocity of IRK to obtain the manipulator’s joint values. Consequently, the moving plate’s pose is obtained via forward position kinematics computed using integrated active and passive joint values for validation. The projection matrix used to get compatible constraint motion adjusts our input velocity and makes it compatible with the structural constraint policy, and the parasitic motion is embedded easily. Thus, an explicit formulation of the parasitic motion equation is not required, as the usual practice. Finally, the study presented numerical simulations to show the validity of the outlined resolutions. This paper’s result and analysis can be uniformly applied to other parallel manipulators with less than 6 DoFs.

Objective: Insomnia and depression are prevalent disorders that often co-occur. This study aimed to investigate the impact of clinically significant insomnia symptoms on the prevalence and clinical presentation of clinically significant depressive symptoms and vice versa.Methods: This study used data from the Korean Headache-Sleep Study (KHSS), a nationwide cross-sectional population-based survey regarding headache and sleep. Clinically significant insomnia symptoms were defined as Insomnia Severity Index (ISI) scores ≥ 10 and clinically significant depressive symptoms were defined as Patient Health Questionnaire-9 (PHQ-9) scores ≥ 10, respectively. We referred clinically significant insomnia symptoms and clinically significant depressive symptoms as insomnia symptoms and depressive symptoms, respectively.Results: Of 2,695 participants, 290 (10.8%) and 116 (4.3%) were classified as having insomnia and depressive symptoms, respectively. The prevalence of depressive symptoms was higher among participants with insomnia symptoms than in those without insomnia symptoms (25.9 vs. 1.7%, respectively, P < 0.001). Among participants with depressive symptoms, the PHQ-9 scores were not significantly different between participants with and without insomnia symptoms (P = 0.124). The prevalence of insomnia symptoms was significantly higher among participants with depressive symptoms than in those without depressive symptoms (64.7 vs. 8.3%, respectively, P < 0.001). The ISI scores were significantly higher among participants with insomnia and depressive symptoms than in participants with insomnia symptoms alone (P < 0.001).Conclusions: Participants with depressive symptoms had a higher risk of insomnia symptoms than did those without depressive symptoms. The severity of depressive symptoms did not significantly differ based on insomnia symptoms among participants with depressive symptoms; however, the severity of insomnia symptoms was significantly higher in participants with depressive symptoms than in those without depressive symptoms.

Adenosine is a cellular metabolite with diverse derivatives that possesses a wide range of physiological roles. We investigated the molecular mechanisms of adenosine and cordycepin for their promoting effects in wound-healing process. The mitochondrial energy metabolism and cell proliferation markers, cAMP responsive element binding protein 1 (CREB1) and Ki67, were enhanced by adenosine and cordycepin in cultured dermal fibroblasts. Adenosine and cordycepin stimulated adenosine receptor signaling via elevated cAMP. The phosphorylation of mitogen-activated protein kinase kinase (MEK) 1/2, mammalian target of rapamycin (mTOR) and glycogen synthase kinase 3 beta (Gsk3b) and Wnt target genes such as bone morphogenetic protein (BMP) 2/4 and lymphoid enhancer binding factor (Lef) 1 were activated. The enhanced gene expression by adenosine and cordycepin was abrogated by adenosine A2A and A2B receptor inhibitors, ZM241385 and PSH603, and protein kinase A (PKA) inhibitor H89, indicating the involvement of adenosine receptor A2A, A2B and PKA. As a result of Wnt/β-catenin pathway activation, the secretion of growth factors such as insulin-like growth factor (IGF)-1 and transforming growth factor beta (TGFβ) 3 was increased, previously reported to facilitate the wound healing process. In addition, in vitro fibroblast migration was also increased, demonstrating their possible roles in facilitating the wound healing process. In conclusion, our data strongly demonstrate that adenosine and cordycepin stimulate the Wnt/β-catenin signaling through the activation of adenosine receptor, possibly promoting the tissue remodeling process and suggest their therapeutic potential for treating skin wounds.

A single function approximation (SFA) approach for event-triggered output-feedback tracker design is presented for uncertain nonlinear time-delay systems in lower-triangular form. Contrary to the existing event-triggered output-feedback control methods dependent on multiple function approximators in the presence of lower-triangular nonlinearities, the proposed SFA approach provides the following advantages: (i) the simple observer structure independent of function approximators; (ii) one event-triggering condition based on only a tracking error; and (iii) the simple control scheme using one function approximator. Thus, the structural simplicity is allowed for implementing the observer and the event-triggering law in the sensor part and the adaptive tracker in the control part. Under the proposed SFA-based event-triggered control scheme, it is shown that the boundedness of closed-loop signals and the existence of a minimum inter-event time are guaranteed regardless of unknown time-delay nonlinearities and unmeasurable state variables.

This paper investigates a minimal-function-approximation (MFA)-based decentralized event-triggered tracking problem for uncertain interconnected systems with completely unknown nonaffine nonlinearities. It is assumed that events are triggered to transmit state variables in the sensor-to-controller channel. The existing approximation-based event-triggered control schemes for single lower-triangular nonlinear systems require multiple neural-network-based or fuzzy-based function approximators and multiple event-triggering conditions that are equal to the order of the system. Thus, all error surfaces using virtual control laws should be computed to verify the triggering conditions in the sensor part. To overcome the complexity in using these multiple function approximators and event-triggering conditions, we propose an event-triggered tracking strategy using one function approximator and one event-triggering condition for each subsystem in the decentralized control framework, regardless of the order of pure-feedback nonlinear subsystems. The proposed strategy is based on the MFA design technique and thus one event-triggering condition using a local tracking error is established for the local tracking law of each subsystem. Using the impulsive system approach and the Lyapunov stability theorem, the total closed-loop stability is analyzed rigorously and the minimum interevent times for each subsystem are derived to exclude the unexpected Zeno behavior.